Axially Chiral Compounds: Asymmetric Synthesis and Applications [1 ed.] 3527347127, 9783527347124

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Axially Chiral Compounds

Axially Chiral Compounds Asymmetric Synthesis and Applications

Edited by Bin Tan

Editor Prof. Bin Tan

Southern University of Science and Technology Chemistry Department NO. 1088, Xueyuan Road Nanshan District 518055 Shenzhen China

All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.:

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The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2021 WILEY-VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978‐3‐527‐34712‐4 ePDF ISBN: 978‐3‐527‐82516‐5 ePub ISBN: 978‐3‐527‐82518‐9 oBook ISBN: 978‐3‐527‐82517‐2 Typesetting  Straive, Chennai, India Printing and Binding

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v

Contents Preface  xiii Part I  Asymmetric Synthesis  1 1 1.1 1.2 2 2.1 2.2 2.2.1 2.2.1.1 2.2.1.2 2.2.1.3 2.2.2 2.2.3 2.2.3.1 2.2.3.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.4 2.4.1 2.4.2

Introduction and Characteristics  3 Yong-Bin Wang, Shao-Hua Xiang, and Bin Tan ­Introduction and Classification  3 ­Specification of Configuration  9 ­References  11 Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers  13 Tao Zhou and Bing-Feng Shi ­Introduction  13 ­Biaryl Coupling  13 Cross-coupling  13 Kumada–Tamao–Corriu Cross-coupling  14 Negishi Cross-coupling  15 Suzuki–Miyaura Cross-coupling  15 Other Types of Cross-coupling  24 Oxidative Coupling  24 Cu-Catalyzed Oxidative Coupling  25 Oxidative Coupling Reactions with Other Metals  27 ­Desymmetrization and (Dynamic) Kinetic Resolution via Functional Group Transformation  29 Desymmetrization of Prochiral Biaryls  29 Kinetic Resolution of Racemic Axially Chiral Biaryls  30 Dynamic Kinetic Resolution of Racemic Axially Chiral Biaryls  30 Ring-opening Reactions  32 ­Formation of Aromatic Ring via [2 + 2 + 2] Cycloaddition  35 Cobalt-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions  35 Rhodium-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions  36

vi

Contents

2.4.3 2.5 2.5.1 2.5.2 2.5.3 2.6

Iridium-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions  36 ­C─H Bond Functionalization  38 Chiral Catalyst-Controlled C─H Bond Functionalization  38 Chiral Auxiliary-Induced C─H Bond Functionalization  40 Atroposelective C─H Arylation  40 ­Summary and Conclusions  42 ­References  42

3

Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers  47 Shaoyu Li, Shao-Hua Xiang, and Bin Tan ­Introduction  47 ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strategy  47 Conventional Kinetic Resolution  47 Kinetic Resolution via Asymmetric Alkylation  48 Kinetic Resolution via Asymmetric Acylation  50 Kinetic Resolution via Asymmetric Transfer Hydrogenation and Michael Addition  53 Dynamic Kinetic Resolution Strategy  54 DKR via Asymmetric Electrophilic Bromination  54 DKR via Asymmetric Nucleophilic Addition  56 DKR Based on Asymmetric Ring-Opening/Expansion Transformation  57 ­Atroposelective Synthesis of Biaryls by Desymmetrization Strategy  59 ­Atroposelective Arene Formation to Access Axially Chiral Biaryls  61 Intramolecular Atroposelective Arene Formation  61 Atroposelective Arene Formation via Intermolecular Annulation  63 ­Atroposelective Synthesis of Biaryls via Direct C–H Arylation Strategy  67 Organocatalytic C–H Arylation by [3,3]-Sigmatropic Rearrangement  67 Atroposelective Arylation Based on Quinone Derivatives  68 Atroposelective Nucleophilic Aromatic Substitution  71 ­Conclusion  72 ­References  72

3.1 3.2 3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.2 3.2.2.1 3.2.2.2 3.2.2.3 3.3 3.4 3.4.1 3.4.2 3.5 3.5.1 3.5.2 3.5.3 3.6 4 4.1 4.2 4.2.1 4.2.2 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.4.2

Enantioselective Synthesis of Heterobiaryl Atropisomers  75 Damien Bonne and Jean Rodriguez ­Introduction  75 ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Rings  75 Functionalization of Heterobiaryls  75 Atroposelective Ring Formation  81 ­Atropisomeric Heterobiaryls Featuring a Five-Membered Ring  87 From Preformed Cyclic Systems  87 Formation of the Heterobiaryl Axis  93 Atroposelective Ring Formations  95 ­Atropisomeric Heterobiaryls Featuring Two Five-Membered Rings  103 Functionalization of Heterobiaryls  103 Aromatization of a Bis-heterocycle  104

Contents

4.4.3 4.5

Atroposelective Ring Formations  105 ­Conclusion and Outlook  106 ­References  106

5

Asymmetric Synthesis of Nonbiaryl Atropisomers  109 Mirza A. Saputra, Mariel Cardenas, and Jeffrey L. Gustafson ­Introduction  109 ­Styrenes  109 Axially Chiral Styrenes via Point-to-Axial Chirality Transfer  110 Axially Chiral Styrenes Controlled by Chiral Auxiliary  111 Metal-Catalyzed Enantioselective Synthesis of Axially Chiral Styrene  111 Organocatalytic Synthesis of Axially Chiral Styrenes  114 ­Amides  118 Stereochemical Stability of Atropisomeric Amides  118 Lithiation of Atropisomeric Amides to Access Various Alkylations  118 Syntheses of Atropisomerically Stable Amides via Chiral Auxiliaries  120 Catalytic Asymmetric Dihydroxylation via Sharpless KR Conditions  121 Atroposelective Aldol Reactions via DKR Approach  121 Atroposelective Halogenation of Aromatic Amides  122 Atroposelective [2 + 2 + 2] Cycloaddition Toward Atropisomerically Stable Benzamides  123 Enantioselective O-alkylation of Axially Chiral Amides  123 ­Diaryl Ethers  124 Resolution Studies of Diaryl Ethers  124 Enantioselective Synthesis of Diaryl Ether  125 Enzyme-Catalyzed Synthesis of Diaryl Ether  126 Synthesis of Scaffolds Related to Diaryl Ethers via Csp2-H Activation  127 ­Anilides  127 Stereochemical Stability of Axially Chiral Anilides  129 Kinetic Resolution or DKR to Access Axially Chiral Anilides  129 Synthesis of Axially Chiral Anilides via Planar to Axial Chirality Transfer  130 Metal-Catalyzed Synthesis of Chiral Anilides  131 Organocatalytic Synthesis of Chiral Anilides  131 ­Lactams and Related Scaffolds  133 Stereochemical Stability of Atropisomeric Lactams  134 Diastereoselective Cyclization Toward Atropisomeric Lactams  134 Enantioselective N-arylation Toward Lactam Atropisomers  134 Atroposelective [2 + 2 + 2] Cycloaddition with Isocyanates  135 Chiral Auxiliary Approach Toward Resolving Atropisomeric Lactams  136 Enantioselective Brønsted Base-Catalyzed Tandem Isomerization–Michael Reactions Toward Atropisomeric Lactams  136 ­Diaryl Amines  137 Stereochemical Stability of Diaryl Amines  137 Atroposelective Approaches Toward Diaryl Amines or Related Scaffolds  138 ­References  138

5.1 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.3.6 5.3.7 5.3.8 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.6 5.6.1 5.6.2 5.6.3 5.6.4 5.6.5 5.6.6 5.7 5.7.1 5.7.2

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viii

Contents

6 6.1 6.2 6.2.1 6.2.1.1 6.2.1.2 6.2.1.3 6.2.1.4 6.2.1.5 6.2.1.6 6.2.1.7 6.2.2 6.3 6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.1.4 6.3.1.5 6.3.2 6.3.2.1 6.3.2.2 6.3.2.3 6.4 7 7.1 7.2 7.2.1 7.2.1.1 7.2.1.2 7.2.2 7.2.2.1 7.2.2.2 7.3 7.3.1 7.3.2 7.4 7.4.1

Asymmetric Synthesis of Chiral Allenes  141 Jinbo Zhao and Yunhe Xu ­Introduction  141 ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reactions  142 Chirality Transfer  142 Chirality Transfer from Propargyl Alcohol and Its Derivatives: Rearrangements  142 Processes Involving Stereospecific Rearrangements of Propargyl Amine  143 SN2′ Reaction  145 Pd-Catalyzed Stereospecific Reaction  146 Isomerization of Propargyl Metals  148 Chirality Transfer from Functionalized Allylic Derivatives  149 Chirality Transfer via Wittig Olefination  150 Asymmetric Reaction with Stoichiometric Chiral Reagents  151 ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allenes  151 Catalytic Enantioselective Synthesis from Achiral Substances  152 Enantioselective Proton Migration (Isomerization) of Alkyne  152 Enantioselective Addition to 1,3-Enyne  154 Enantioselective Elimination Reactions  160 Catalytic Asymmetric Reactions Involving Diazo Compounds  161 Desymmetrization  162 Enantioselective Allene Synthesis from Chiral Substrates  163 Kinetic Resolution  163 Dynamic Kinetic Processes  164 Deracemization  167 ­Conclusion and Perspective  168 ­References  169 Asymmetric Synthesis of Axially Chiral Natural Products  173 He Yang and Wenjun Tang ­Introduction  173 ­Diastereoselective Coupling–Point to Axial Chirality Transfer  175 Intramolecular Diastereoselective Coupling  176 Diastereoselective Coupling Enabled by Intrinsic Chirality  176 Diastereoselective Coupling Facilitated by Chiral Auxiliaries  182 Intermolecular Diastereoselective Aryl Coupling  183 Diastereoselective Coupling Enabled by Intrinsic Chirality  183 Diastereoselective Coupling Facilitated by Chiral Auxiliary  189 ­Atroposelective Aryl Coupling with Chiral Catalyst  191 Catalytic Oxidative Aryl Coupling  191 Transition Metal-Catalyzed Atroposelective Aryl Coupling  194 ­Asymmetric Transformation of Biaryls  196 Dynamic Kinetic Resolution of Biaryl Structure – The Lactone Method  196

Contents

7.4.2 7.4.3 7.4.4 7.5 7.6 7.7

Desymmetrization of Prostereogenic Biaryls  197 Catalytic Atroposelective C–H Functionalization of Biaryls  199 Diastereoselective Synthesis from Racemic Biaryls  199 ­Atroposelective Aromatization  200 ­Diastereoselective Macrocyclization  202 ­Conclusions and Perspectives  204 ­References  204 Part II  Applications  209

8 8.1 8.1.1 8.1.2 8.2 8.2.1 8.2.1.1 8.2.1.2 8.2.1.3 8.2.1.4 8.2.1.5 8.2.2 8.2.3 8.2.3.1 8.2.3.2 8.2.3.3 8.2.4 8.2.4.1 8.2.4.2 8.2.4.3 8.3 8.3.1 8.3.1.1 8.3.1.2 8.3.1.3 8.3.1.4 8.3.1.5 8.3.2 8.3.2.1

Asymmetric Transformations  211 Gaoyuan Ma and Mukund P. Sibi ­Asymmetric Transformation of Axially Chiral Biaryls and Heterobiaryls  211 Asymmetric Transformations with Preservation of Axially Chiral Backbone  212 Asymmetric Transformations with Axial-to-central Chirality Transfer  213 ­Asymmetric Transformation of Axially Chiral Non-biaryl Compounds  214 Cycloadditions and Cyclizations  214 [4 + 2]-Cycloaddition  214 [3 + 2]-Cycloaddition  214 Radical Cyclization  215 Heck Cyclization  217 Carbanionic Cyclization  217 Reaction with Nucleophiles  218 Reaction with Electrophiles  220 Reactivity as Enolates  220 Lithiation  221 Rearrangements  222 Photoreactions  224 Photocycloaddition  224 Photocyclization  225 Hydrogen Atom Abstraction  226 ­Asymmetric Transformation of Chiral Allenes  226 Cyclization  226 Palladium-Catalyzed Cyclization  226 Rhodium-Catalyzed Cyclization  228 Gold-Catalyzed Cyclization  231 Silver-Catalyzed Cyclization  231 Organic Reagent-Mediated Cyclization of Chiral Allene  232 Cycloaddition  233 Intermolecular Cycloaddition  233

ix

x

Contents

8.3.2.2 8.3.3 8.3.3.1 8.3.3.2 8.3.4 8.4

Intramolecular Cycloaddition  234 Reaction with Nucleophiles  236 Reaction with Carbon Nucleophiles  236 Reaction with Heteroatom Nucleophiles  238 Chiral Allene as Nucleophiles  240 ­Conclusion  242 ­References  243

9

Application for Axially Chiral Ligands  245 Bing-Chao Da and Bin Tan ­Introduction  245 ­Monodentate Phosphines  246 Asymmetric Hydrogenations  246 Asymmetric Hydrosilylation of Olefins  248 Asymmetric Allylic Substitutions  249 Miscellaneous Catalytic Asymmetric Transformations  250 ­Diphosphine Ligands  252 Hydrogenation Reactions  252 C─C Bond Formation  255 C─X Bond Formation  257 ­Phosphoramidite and Phosphamide Ligands  259 Asymmetric Conjugate Addition with Organometallic Nucleophiles  259 Hydrogenation  260 Hydroboration/Hydrosilylation Reactions  261 Allylic Substitutions  262 Other Asymmetric Transformations  263 ­N–P Ligands  264 Applications of N, P-Ligands  265 ­C2-Symmetric Diols  267 Mukaiyama Aldol Condensation Reactions  267 Diels–Alder Reaction  268 Arrangement Reaction  269 Reductive Reactions  269 ­Other Axially Chiral Ligands in Asymmetric Transformations  270 ­Conclusions  271 ­References  271

9.1 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.3 9.3.1 9.3.2 9.3.3 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.5 9.5.1 9.6 9.6.1 9.6.2 9.6.3 9.6.4 9.7 9.8 10 10.1 10.2 10.2.1 10.2.2 10.3

Application for Axially Chiral Organocatalysts  275 Takahiko Akiyama ­Introduction  275 ­Chiral Brønsted Acid Catalysts  276 Chiral BINOL Derivatives  276 Chiral Phosphoric Acid  276 ­Chiral Counteranion Catalysts and Chiral Phase Transfer Catalysts  285

Contents

10.4 10.5

­ rønsted Base Catalyst  288 B ­Lewis Base Catalysts  289 ­References  294

11

Application in Drugs and Materials  297 Yong-Bin Wang, Shao-Hua Xiang, and Bin Tan ­Drugs  297 ­Chiral Recognition  302 ­Chiral Additives in Liquid Crystals  307 ­References  313

11.1 11.2 11.3

Index  317

xi

xiii

Preface Axial chirality refers to stereoisomerism that is derived from the nonplanar arrangement of four substituents in pairs about a stereogenic axis. Compared to the immense research efforts dedicated to central chirality at the outset of the study of molecular chirality, the popularization of axial chirality has undergone a slower start. For instance, atropisomerism, as the most representative subclass of axial chirality, was not discovered until 1922 by Christie and Kenner. This form of molecular asymmetry then went largely unnoticed for the following half‐century probably because of the unveiled application potential as well as complications to deal with the dynamic nature of this stereoisomerism. In 1980s, the huge success of optically active 2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl (BINAP) ligand (creatively developed by professor Ryoji Noyori) in transition metal‐catalyzed asymmetric transformations ignited the research passion about axial chirality. Over the next several decades, axial chirality holds increasing attention and has since constituted an important arena for novel discoveries that impact diverse domains of chemical science. Today, axially chiral motifs are common in functional compounds in which well‐defined three‐dimensional scaffolds are valuable, such as those pursued in asymmetric synthesis, medicinal, and materials science. In conjunction with these demands, an exploding list of  prominent strategies has been ingeniously devised to access the privileged axially ­chiral  scaffolds, which have substantially benefited from the continuous evolution of asymmetric catalysis. Among the divergent research domains concerning axial chirality, the exploitation of novel molecular frameworks, the development of stereoselective and efficient synthetic approaches (particularly in a catalytic fashion), as well as the extension of the application range are the central themes. Meanwhile, comprehensive and instructive handbook that could enable fellow students and researchers to glean insights into this field concisely has remained scarce. Cognizant of this gap, we write this book focusing on the asymmetric synthesis and applications of axially chiral compounds with a view to inform readers about the development history, research status, and applications of axial chirality. This monograph is developed to cover two main themes that are categorized into 11 chapters. It commences with an in‐depth introduction of axial chirality, which sets the backdrop for subsequent discussions. This encompasses the tactic to assign stereochemistry for different subclasses of axially chiral molecules in accordance with Cahn–Ingold–Prelog priority rules, coupled with descriptions on their defining structural features. The focus is then shifted to introduce

xiv

Preface

various asymmetric approaches to synthesize enantioenriched axially chiral molecules, comprising atropisomerically enriched biaryls, heterobiaryls, non‐biaryls, allenes, as well as natural products bearing axially chiral elements in a collective manner. In the second part, the importance of axially chiral molecules is detailed by showcasing the versatile transformations that are demonstrated on these scaffolds, followed by their applications in asymmetric catalysis as chiral ligands or organocatalysts. Beyond chemical synthesis, the important roles of axial chirality elements in recognition and interaction events in biochemistry and materials science are described. The two main themes compose the content of this book, through which the high relevance of axial chirality to different chemistry disciplines and their interrelation are highlighted. It is projected to serve as guidance to chemists in the field and to inspire incursions into unexplored areas of axial chirality in both academic and industrial settings. I would like to take this opportunity to thank the Wiley–VCH editorial staffs for their proposal and guidance to complete this monograph. It has been my honor to collaborate with Prof. Bing‐Feng Shi and colleague (Dr Tao Zhou), Prof. Jean Rodriguez, Prof. Damien Bonne, Prof. Jeffrey L. Gustafson and his team (Dr Mirza A. Saputra, Mariel Cardenas), Prof. Yun‐He Xu, Prof. Jinbo Zhao, Prof. Wen‐Jun Tang and his colleague (He Yang), Prof. Mukund P. Sibi and his coworker (Dr Gaoyuan Ma), as well as Prof. Takahiko Akiyama who generously devoted their precious time and shared their expertise in accomplishing this book. I would also like to acknowledge the contributions of my colleagues and ­students, Yong‐Bin Wang, Bin‐Chao Da, Shaoyu Li, Shao‐Hua Xiang, and Jun‐Kee Cheng in ­composition and revision of this book.

 

Part I Asymmetric Synthesis

1

3

1 Introduction and Characteristics Yong-Bin Wang, Shao-Hua Xiang, and Bin Tan Department of Chemistry, Southern University of Science and Technology, No. 1088, Xueyuan Rd., Nanshan District, Shenzhen, 518055, China

1.1  ­Introduction and Classification If a rigid object or the spatial arrangement of points including atoms is nonsuperposable on its mirror image, such an object possesses no symmetry elements of the second kind and the geometric property displayed is denoted as chirality (IUPAC). Chirality is widely represented in nature and plays crucial roles in life-sustaining processes. In living systems, chiral homogeneity of monomer units (such as α-amino acid and nucleoside) is found to induce more rapid polymerization and longer chain length of biopolymers (proteins, DNA, or RNA). Thus, the biomacromolecules assembled from the homochiral monomeric building blocks exhibit homochirality, which is considered the sine qua non for molecule-based life. As such, virtually all chiral biomolecules including small monomers and biopolymers in living organisms are enantiomerically pure to engender biological homochirality. This affects the differential interactions between biomacromolecules with a pair of enantiomers [1]. For this reason, pharmaceuticals development is progressively gravitating toward deriving single isomers instead of racemates [2, 3]. In the domain of material science, chiral homogeneity is critical for the properties of materials [4, 5]. Taken together, asymmetric synthesis toward molecular targets with high stereochemical purities has been a central research theme in many organic chemistry-oriented research laboratories. Early investigations of asymmetric chemistry have centered on central chirality, which refers to stereoisomerism that arises from asymmetric spatial arrangement of a set of ligands attached to an atom (Cabcd, Nabcd+, and P(X)abc). With the progression of chemical science, additional types of stereoisomerisms began to garner increasing attention. Stereoisomers that feature axial chirality, helical chirality, and planar chirality assume different topological structures, but unlike those projecting central chirality, they exist as enantiomers in the absence of stereogenic center. Axial chirality refers to stereoisomerism resulting from nonplanar arrangement of four groups in pairs about a chirality axis (IUPAC). In diverse conformational topologies, atropisomers [6], chiral allenes [7], spiranes [8], and spiro chiral molecules [9] fulfill the definition of axial chirality. Among these Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

4

1  Introduction and Characteristics

axially chiral structures, atropisomers are unique in that the chirality is derived from restricted rotation about a single bond (chiral axis) and racemization proceeds simply through the rotation of this axis rather than the breaking and forming of chemical bond [6, 10] (Figure 1.1). Central Chirality: Stereoisomerism resulting from the asymmetric spatial arrangement of a set of ligands attached to an atom (Cabcd, Nabcd+, and P(X)abc). Helical Chirality: Stereoisomerism resulting from the arrangement of atoms in molecules along screw rotation. Planar Chirality: Stereoisomerism resulting from the arrangement of out-of-plane groups with respect to a plane (chirality plane) Axial Chirality: Stereoisomerism resulting from the nonplanar arrangement of four groups in pairs about a chirality axis. Atropisomerism: Subclass of axial chirality; stereoisomerism resulting from the restricted rotation about a single bond. When Christie and Kenner made the seminal discovery of atropisomerism in 1922, the importance of axial chirality has been largely overlooked until 1980. Noyori and coworkers developed and illustrated the superiority of axially chiral 1,1-biphenyl-derived 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) as a chiral ligand for asymmetric ­metal-catalyzed reaction [11]. This work spurred the development of several excellent ligands derived from axially chiral 1,1-biphenyl and related spiro frameworks [9]. 1,1′-Bi-2-naphthol (BINOL), as one representative axially chiral reagent, finds utility as a ligand in metal catalysis and also asymmetric organocatalysis [12]. The formative works of Akiyama and Terada revealed the valuable potential of axially chiral BINOL-derived phosphoric acids as robust hydrogenbonding catalysts in asymmetric Mannich reactions [13, 14]. Their discovery spawned intense research into organocatalysis and chiral Brønsted acid catalysis, from where the application of axially chiral skeletons in asymmetric catalysis vastly expanded. It is especially noteworthy that existing axially chiral catalysts, by empowering new stereoselective reaction manifolds, could in turn expedite the discovery of novel and more efficient axially chiral ligands/organocatalysts. Given many factors often govern the activity and stereoselectivity of catalysts/ligands, axially chiral architectures present high structural adaptability to Helical chirality

Central chirality

Planar chirality R

H Cl

Me

Me

Br

Br

R-

R

H Cl S-

M-

R

P-

Rp-

Sp-

R

Axial chirality R1

R1

R2

R2

R2

R1

R1

R2 Allenes

R2 R1

R1

B

A

R2

A

B

R2 R1

R2

A

A

B

B

R1 Spiranes

R1 R1

Spiro chirality

Figure 1.1  Various forms of chiralities and axial chiralities.

X

R2 R2

R2 R2

Atropisomers

X

R1 R1

1.1  ­Introduction and Classificatio

meet requirements of different catalytic reactions through convenient adjustment of their dihedral angles and substituents. To date, diverse types of axially chiral ligands and organocatalysts with highly enabling performance have been developed and constitute the most extensively used class of ligands in asymmetric catalysis [10, 15, 16] (Figure 1.2). In addition to atropostable analogs, conformationally more labile tropos ligands, characterized by high interconversion rate between enantiomers that could preclude isolation of single enantiomers, can be evolved toward integration in asymmetric catalysis. Herein, chiral activator preferentially induces redistribution of the atropisomeric composition of these ligands to single atropisomer through coordination to transition metal, even with the use of catalytic amount per tropos ligands [17]. This section will be discussed in Chapter 11 (Figure 1.3).

Metal ligands

P,P-ligands

PAr2 PAr2

Ar

R1

PAr2 PAr2

R2 R2

Ar BINAP

O X P R X

PAr2 PAr2

X

PAr2 N

PAr2 N X

R

R OH OH R SPINOLs

Box ligands N

PAr2

R

R1

N

O SIPHOX

R

R

R

OH OH

OH NH2

NH2 NH2

R

R

Ar Ar P Ph O

OH N

Ar

O P Ar Ar

SCp

QUINOL

R

O

Ar

R BINAMs

NOBINs

R

O

R1

R

N N

R

N N

R2

F5

O

O

R2

PPh2

R

N

O

BINOLs

PPh2

N

R1

IPHOX

QUINAP

N

P R X

N,P-ligands R

X

P-ligands

Ph

Organocatalysts Brønsted acids R

R

R

O O P O OH

O O P O OH

O O

R

R

Phase transfer catalysts

R P

O O P O NHTf

O NHTf

R

R

Bifunctional catalysts

R O N

N

HN

CF3

CF3

CO2H CO2H

SO3H SO3H

R

R R

R

NH

SO2 NH SO2

P R

HN

Ar

R

Phosphines

Secondary amines

Ar

R

R

R

R

Figure 1.2  Representative organocatalysts and ligands containing axial chirality.

Rapid L interconvertion L

L L

L Transition-metal L Chiral activator

L L

L

X M

* X

L

X M

* X

Main/Single isomer

Figure 1.3  Tropos ligands.

5

6

1  Introduction and Characteristics

Chiral biaryl or heterobiaryl axis is innate in many naturally occurring compounds where axial chirality could and often present in conjunction with other stereogenic elements. Therefore, natural products possessing axial stereogenicity could exhibit high structural diversity, from structurally sophisticated heptapeptide vancomycin to simple biaryls. The iconic antibiotic, vancomycin, contains numerous stereocenters, two chiral planes, and a rotationally hindered biaryl axis. The configurationally locked axis rigidifies the threedimensional framework thus enhances its efficient binding with the bacterial target, resulting in remarkable bioactivities. Naturally occurring atropisomers are generally isolated in enantiopure or racemic form [18]. Although modern bioassays have revealed the huge biological activity differences elicited by two atropochiral antipodes, several marketed drugs bearing stable chiral axes are used in racemic form. Efforts dedicated in interrogating activity differences between enantiomeric atropisomers through structure–activity relationship (SAR) studies have resulted in highly active and selective axially chiral candidates [19, 20]. The promising biological activities of enantiopure atropisomers render research into biological enantioselectivity of axially chiral compounds high desirable (Figure 1.4). Determining absolute configuration and enantiomeric purity of chiral compounds is one important if not mandatory procedure in the preparations of chiral compounds as well as in the research of biological enantioselectivity. Axially chiral skeletons have served well in this capacity, where they have been successfully applied in several characterization techniques based on chiral recognition. For example, the BINOL-derived chiral stationary phases for high-performance liquid chromatography (HPLC) aptly resolve a wide range of racemates containing amino group in diverse mobile-phase modes [21]. The fluorescent probe equipped with atropisomeric biphenyl skeleton can determine the enantiomeric excess (ee) of chiral hydroxycarboxylic acids and N-protected amino acids through fluorescent enhancement. The exquisite chiral recognition ability also enables real-time ee detection of asymmetric catalytic reaction, an application that is highly serviceable in optimization studies and one that is hardly achieved with conventional chiral HPLC [22, 23]. On top of chiral recognition, atropisomers are employed as chiral dopants of cholesteric liquid crystals since 40 years ago, a utility fostered by their ultrawide helical twisting power (up to 757 μm−1) [24]. Amalgamation of this property with cholesteric liquid crystals provide valuable stimulus-responsive optical device [25] (Figure 1.5). In summary, axial chirality is ubiquitously encountered and increasingly exploited in organic synthesis, asymmetric catalysis, research of medicinal chemistry, and functional materials [10, 18, 26–28]. This supplies steady demand to stimulate development of novel axially chiral scaffolds as well as preparations of the privileged ones in higher efficiency. Chiral resolution of racemates represents one stalwart method to obtain enantiopure axially chiral compounds. Before Tan’s report on enantioselective catalysis method in 2016 [29], enantiomerically enriched SPINOL skeletons have been routinely procured via chiral resolution with l-menthol [30] or cinchona alkaloid derivative [31], implying the necessity to use excess chiral materials. The chiral auxiliary-assisted reaction [18, 32] and stereoselective oxidative homo-coupling [33] are two earliest successful attempts in straightforward construction of atropisomeric biaryls. Although stoichiometric or even superstoichiometric chiral reagents are still required, these reactions are forerunner to catalytic synthesis of enantiopure axially chiral skeletons. The catalytic construction of axially chiral skeletons [27] such as atropochiral biaryls and allenes [7] has been foremostly realized within the

Marinopyrrole Cl

Natural products HO H2N

HO O

Me

OH OH

O O

O

Cl

O

O

N H

HN

O

H N

N H O

O

HO2C HO

N

HO O OMe

OH

N

N

N H

OMe

N

MeO

MeO

OH

F

O

CO2Me

O

CH2OH

OH

F

N

DBB

F

N

N N PI3Kβ Selevtive inhibitor

O N

O I

OH

O I Iomeprol

OH

NH2

Me Me HO

N

Br

Cl Me O

O O

N

NHMe O

Lamellarin analogue

H

H N

O

HN

O

N

O

F

HO NH2

I

O

OH OMe

H N

O N

NH2

OH N

Me

PBO

Laquinimod

O

O

N O

N H O

TMC-95A

O

F

N H HN O O

HO

NH

O

Methaqualone

HN O

Eupolyphagin

O N

O

OH

OMe

Murrastifoline-F

O

N

O

N

Drugs and bioactive molecules Cl

CHO

HO Me

N

N H

Vancomycin

O

OH OH

HO

Me

NH2

OH OH

HO

OH

O

H N

N H

O

O

MeO

OH

CHO OH

HO

OH O

H N

OH

(–)-Gossypol

OH

HO O

NH

Cl

Cl

HO

Cl O

N

OH O Cl

O

O

Me

Knipholone

PH-797804, p38 Inhibitor

BTK inhibitors

Figure 1.4  Natural products and bioactive molecules containing axial chirality element.

N Me

F

Materials for chiral recognition and liquid crystals O

Si

O

O O

Si

C6H13O O O

O O

C5H11

(CH2)12O

C5H11

C6H13O

Chiral stationary phases for HPLC R

(CH2)12O

Chiral dopants for cholesterol liquid crystals with high helical twisting power

R

NH HN OH OH

HO HO

OH OH

Ar

N

O N N

NH HN R R Fluorescent probe for chiral recognition

Tropos ligand for chiral recognition

Photo-responsive chiral dopants

Figure 1.5  Axially chiral materials for chiral recognition and liquid crystals.

N

Ar

O O

O FeII

Voltage-responsive chiral dopants

1.2  ­Specification of Configuratio

realm of asymmetric metal catalysis. This strategy has since undergirded the development of abundant and more efficient methodologies. Organocatalysis stepped into the limelight at the turn of the millennium and has evolved to turn into indispensable tool in contemporary asymmetric synthesis with its wide-ranging catalytic modes comprising hydrogenbonding catalysis, Lewis base catalysis, and covalent catalysis. Atropisomer-selective synthesis has largely benefited from this advancement of organocatalysis; revelation of new atropisomeric scaffolds that could supplement the existing core members has been promoted [10]. This has opened up new chemical space for medicinal chemistry and materials.

1.2  ­Specification of Configuration The R/S stereodescriptors are usually assigned to chiral compounds with reference to Cahn–Ingold–Prelog priority rules [34–39]. For the specific context of axial chirality, guidelines delineated below could be followed, which can be employed for allenes, spiranes, and analogs [40, 41]: (1) Target chiral molecule is arbitrarily viewed from one side along the chiral axis; (2) Fischer projection of the molecule is formed by setting the two groups nearer to eyes as horizontal axis; (3) in accord with Cahn–Ingold–Prelog priority rules, the priority of this pair on the horizontal axis is evaluated and ranked as highest priority (1) and second highest priority (2); (4) the group with higher priority on the vertical axis is set as third in order (3); and (5) the R/S configuration of the molecule is determined according to the direction of the line connecting the three groups in order from 1 to 3. A clockwise path represents R configuration and an anticlockwise path represents S configuration (Figure 1.6). With a modification of second step, this assignment process is relevant for atropisomeric biaryls, heterobiaryls, as well as anilines. In this case, the Fischer projection of the target chiral molecule is instead formed using the two pairs of groups flanking the rotation axis and the pair nearer to the eyes is taken as the horizontal axis (Figure 1.7). In compounds exemplified above, each Fischer projection features only four bonds. The Fischer projections of some atropisomers, such as chiral alkenes, could however depict five bonds where there will be one set of two bonds along one of the four directions. When assigning the priority of the substituents according to Cahn–Ingold–Prelog priority rules,

Allenes H

Spiranes CH3

H3C

H

H H Fischer projection

H3C

1 CH3 3

H Me

H 3

H

H 2 H

CH3

Me

CH3 Anti clockwise (S)

1 H 3C

2 H 3

CH3 Clockwise (R)

1 Me

Me

H Me

H

Fischer projection Me

Me H

2

H Anti clockwise (S)

2 H

3 1 Me

H Clockwise (R)

Figure 1.6  Chirality determination of axially chiral allenes and spiranes.

9

10

1  Introduction and Characteristics

Atropisomerism Biaryls

Heterobiaryls

OH OH

Fischer projection C(CCC)

2

C(CCC)

1

C(CCO)

3

Me

OH OH

2

MeO2C

Me

N

I

Me

Fischer projection C(HHH)

1

C(CCO)

C(CCC)

CO2Me I

3

C(CCO)

C(CCO)

C(CCC)

Clockwise (R)

C(CCC)

2 C

C(CCC)

C(CCC)

Anti clockwise (S)

N

Me

1 C

3

C(ICC)

C(OOO) C(CCC)

C(CCC)

C(CCC)

1 C

C(OOO) C(CCC) C(CCC)

2 C(HHH) C C(CCC)

3

C(ICC)

C(CCC)

Clockwise (R)

Anti clockwise (S)

Figure 1.7  Chirality determination of atropisomeric (hetero)biaryls.

the substituents on the set of two bonds will be considered as one CC unit, which has a priority ranked between N and C (N > CC > C) (Figure 1.8). As axially chiral molecules, stereogenic axis in spiro chiral compounds, on the other hand, may not immediately obvious. According to Cahn–Ingold–Prelog priority rules [36], the following sequence of steps is formulated to determine the R/S configuration: (1) The axially chiral molecule is viewed from one spiro cycle to the other spiro cycle; (2) Fischer projection of the chiral molecule is formed using the pair of groups attached to spiro atom nearer to eyes as the horizontal axis; (3) based on Cahn–Ingold–Prelog priority rules, the group with higher priority on horizontal axis and vertical axis are respectively assigned as highest priority (1) and second highest priority (2); (4) the lower priority group on the horizontal axis is then assigned as third in order (3) (assignments in steps 3 and 4 in this scenario differ from that applied to chiral allenes and spiranes); and (5) the R/S configuration of the molecule is assigned according to the direction of the line connecting the Alkenes Ph Bn Me

Ph N

CO2Me I

Bn

OH

N

CO2Me I

Me

OH

tBu

Fischer projection 3 1

N

C(ICC) C C

2

C(CCC) Anti clockwise (S)

OH

tBu

Fischer projection C(CCC)

1

OH

N 3

C C

2

C(ICC)

Clockwise (R)

1

3 C(CCO) C C

C

2

C(CCC) Anti clockwise (S)

Figure 1.8  Chirality determination of axially chiral alkenes.

1 C C

C(CCC) 2 C 3

C(CCO)

Clockwise (R)

 ­Reference SPINOL

Spiro chirality O

O

NH

NH

HN O

O NH

HN O

OH OH

O NH

HN

HN

O

O Fischer projection

Fischer projection 2

C 3 C

1 N

OH OH

2N Anti clockwise (S)

1 N

2

N 3 C

C Clockwise (R)

3

C(CHH)

C(CCC)

1

C(CHH)

C(CCC) C(CHH)

Anti clockwise (S)

3

1

C(CHH)

C(CCC)

2

C(CCC)

Clockwise (R)

Figure 1.9  Chirality determination of Spiro skeletons.

three members in order from 1 to 3. A clockwise path represents R configuration and the anticlockwise path represents S configuration (Figure 1.9).

­References   1 Barron, L.D. (2008). Space Sci. Rev. 135: 187–201.   2 Eriksson, T., Bjöurkman, S., Roth, B. et al. (1995). Chirality 7: 44–52.   3 Shah, R.R., Midgley, J.M., and Branch, S.K. (1998). Adverse Drug React. Toxicol. Rev. 17: 145–190.   4 Shen, J. and Okamoto, Y. (2016). Chem. Rev. 116: 1094–1138.   5 Dyer, D.J., Schröder, U.P., Chan, K.P., and Twieg, R.J. (1997). Chem. Mater. 9: 1665–1669.   6 Kumarasamy, E., Raghunathan, R., Sibi, M.P., and Sivaguru, J. (2015). Chem. Rev. 115: 11239–11300.   7 Huang, X. and Ma, S. (2019). Acc. Chem. Res. 52: 1301–1312.   8 Krow, G. and Hill, R.K. (1968). Chem. Commun.: 430–431.   9 Xie, J.-H. and Zhou, Q.-L. (2008). Acc. Chem. Res. 41: 581–593. 10 Wang, Y.-B. and Tan, B. (2018). Acc. Chem. Res. 51: 534–547. 11 Miyashita, A., Yasuda, A., Takaya, H. et al. (1980). J. Am. Chem. Soc. 102: 7932–7934. 12 Brunel, J.M. (2007). Chem. Rev. 107: PR1–PR45. 13 Akiyama, T., Itoh, J., Yokota, K., and Fuchibe, K. (2004). Angew. Chem. Int. Ed. 43: 1566–1568. 14 Uraguchi, D. and Terada, M. (2004). J. Am. Chem. Soc. 126: 5356–5357. 15 Carroll, M.P. and Guiry, P.J. (2014). Chem. Soc. Rev. 43: 819–833. 16 Kočovský, P., Vyskočil, Š., and Smrčina, M. (2003). Chem. Rev. 103: 3213–3246. 17 Mikami, K., Aikawa, K., Yusa, Y. et al. (2002). Synlett: 1561. 18 Bringmann, G., Gulder, T., Gulder, T.A.M., and Breuning, M. (2011). Chem. Rev. 111: 563–639. 19 LaPlante, S.R., Fader, L.D., Fandrick, K.R. et al. (2011). J. Med. Chem. 54: 7005–7022. 20 Lanman, B.A., Allen, J.R., Allen, J.G. et al. (2020). J. Med. Chem. 63: 52–65.

11

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1  Introduction and Characteristics

1 Okamoto, Y. and Ikai, T. (2008). Chem. Soc. Rev. 37: 2593–2608. 2 22 Zhang, X., Yin, J., and Yoon, J. (2014). Chem. Rev. 114: 4918–4959. 23 Pu, L. (2017). Acc. Chem. Res. 50: 1032–1040. 24 Akagi, K. (2009). Chem. Rev. 109: 5354–5401. 25 Bisoyi, H.K. and Li, Q. (2014). Acc. Chem. Res. 47: 3184–3195. 26 Rivera-Fuentes, P. and Diederich, F. (2012). Angew. Chem. Int. Ed. 51: 2818–2828. 27 Wencel-Delord, J., Panossian, A., Leroux, F.R., and Colobert, F. (2015). Chem. Soc. Rev. 44: 3418–3430. 28 Bringmann, G. and Menche, D. (2001). Acc. Chem. Res. 34: 615–624. 29 Li, S., Zhang, J.-W., Li, X.-L. et al. (2016). J. Am. Chem. Soc. 138: 16561–16566. 30 Birman, V.B., Rheingold, A.L., and Lam, K.-C. (1999). Tetrahedron: Asymmetry 10: 125–131. 31 Zhang, J.-H., Liao, J., Cui, X. et al. (2002). Tetrahedron: Asymmetry 13: 1363–1366. 32 Bringmann, G., Price Mortimer, A.J., Keller, P.A. et al. (2005). Angew. Chem. Int. Ed. 44: 5384–5427. 33 Brussee, J. and Jansen, A.C.A. (1983). Tetrahedron Lett. 24: 3261–3262. 34 Prelog, V. and Helmchen, G. (1982). Angew. Chem. Int. Ed. 21: 567–583. 35 Prelog, V. and Helmchen, G. (1972). Helv. Chim. Acta 55: 2581–2598. 36 Cahn, R.S., Ingold, C., and Prelog, V. (1966). Angew. Chem. Int. Ed. 5: 385–415. 37 Cahn, R.S., Ingold, C.K., and Prelog, V. (1956). Experientia 12: 81–94. 38 Cahn, R.S. and Ingold, C.K. (1951). J. Chem. Soc.: 612–622. 39 Cahn, R.S. (1964). J. Chem. Educ. 41: 116. 40 Wang, C. and Wu, W. (2011). J. Chem. Educ. 88: 299–301. 41 Bhushan, R. and Bhattacharjee, G. (1983). J. Chem. Educ. 60: 191.

13

2 Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers Tao Zhou and Bing-Feng Shi Zhejiang University, Department of Chemistry, 38 Zheda Rd., Hangzhou 310027, China

2.1 ­Introduction Metal-catalyzed asymmetric transformations provide efficient tools to access axially chiral biaryls [1]. In recent years, significant advances with different catalytic systems, chiral ligands, and auxiliaries have been established to acquire versatile atropisomeric molecules. These achievements offer practical avenues and enable distinct synthetic disconnection for enantioselective construction of axially chiral catalysts, ligands, and natural product atropisomers. The present chapter aims to describe the progress in the synthesis of axially chiral biaryls via metal-catalyzed asymmetric transformations. It will be categorized into four sections according to synthetic strategies, which include biaryl coupling, desymmetrization, and (dynamic) kinetic resolution (KR) via functional group transfer, [2 + 2 + 2] cycloaddition, and aryl C─H bond functionalization.

2.2 ­Biaryl Coupling 2.2.1 Cross-coupling Transition metal-catalyzed cross-coupling reactions are widely applied in organic synthesis, medicinal chemistry, and material science [2, 3]. Asymmetric cross-coupling reactions for direct formation of CAr─CAr bonds can be regarded as an elegant strategy to access chiral biaryls considering the diversity of ortho-substituted aryl electrophiles and nucleophiles that could be used as coupling partners (Scheme 2.1) [4, 5]. Extensive attainments have been made in constructing axially chiral biaryls via cross-coupling reactions with the development of new chiral ligands, where the Suzuki–Miyaura reaction constitutes a large proportion of these works.

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

14

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

Y

Ar1 X X = I, Br, Cl, OTf

Ar1

Cat. Metal

+ Ar2

Ar2

Y = Mg, Zn, Sn, Si, B, etc.

Scheme 2.1  Axially chiral biaryls synthesis via asymmetric cross-coupling reactions. Source: Yang et al. [4] and Baudoin [5].

2.2.1.1  Kumada–Tamao–Corriu Cross-coupling

In 1975, Tamao and Kumada reported the first asymmetric cross-coupling reaction to furnish biaryl atropisomers [6]. Binaphthyl molecules 3 could be obtained via nickel-catalyzed coupling of ortho-substituted aryl Grignard reagents 1 with aryl halides 2. Extremely low enantiomeric excess (ee) was obtained with enantiopure bidentatediphosphine (R,R)-(−)diop 4 as a chiral ligand. The employment of ferrocenyl bidentate ligand (S)-(pR)-PPFA 5 [6] or axially chiral diphosphine (S)-(−)-NAPHOS 6 [7] under similar conditions slightly improved enantiocontrol. The first efficient catalytic system was reported in 1988 by Hayashi and coworkers exemplifying the use of optically pure ferrocenyl ligand (S)-(pR)PPFOMe 7 [8]. The desired products 3 were isolated in moderate to excellent yields with up to 95% ee. The methyl group on the aromatic ring of Grignard reagent proved important to the high enantiocontrol (Scheme 2.2).

Br R1

R2

+

MgBr 1

[Ni]/Chiral ligand

R1 R2

–15 °C~r.t. 2

3

Chiral ligand NMe2 O O

PPh2 PPh2

4,(R, R)-(-)-diop 1.9% ee

Fe

PPh2

5, (R)-(pS)-PPFA 4.6% ee

PPh2 PPh2 6, (S)-NAPHOS 12.5% ee

PPh2 OMe Fe 7, (S)-(pR)-PPFOMe 95% ee

Scheme 2.2  Examples of Ni-catalyzed asymmetric Kumada–Tamao–Corriu reactions.

The palladium-catalyzed cross-coupling of aryl halides with aryl Grignard reagents using chiral bidentate ligands was developed by Frejd and coworkers (Scheme 2.3) [9]. Axially chiral diphosphine (6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine) (BIPHEMP) (9) gave better enantiocontrol (45% ee) than 2,2′-bis(di-phenylphosphino)-1,1′-binaphthyl (BINAP) (8, 13% ee). In 2013, Dorta and coworkers firstly applied chiral N-heterocyclic carbene (NHC) ligands in the palladium-catalyzed asymmetric Kumada–Tamao–Corriu reaction (Scheme  2.3) [10]. Binaphthyls 3 were obtained in good yields with moderate

2.2 ­Biaryl Couplin

Br R1

[Pd]/Chiral ligand

R2

+

R1 R2

r.t. ~80 °C

MgBr 1

2

3

Chiral ligand Ph

4-Hep Ph PPh2 PPh2

PPh2 PPh2

Me Me

N Cl

8, BINAP 13% ee

9, BIPHEMP 45% ee

N Pd

10, 48% ee

Hep-4

Ph

Scheme 2.3  Examples of Pd-catalyzed asymmetric Kumada–Tamao–Corriu reactions. Source: Modified from Frejd and Klingstedt [9].

enantiocontrol (up to 48% ee) from the coupling of 2-methoxy-1-naphthalenylmagnesium bromide with 1-bromonaphthalene at room temperature using palladium complex 10. 2.2.1.2  Negishi Cross-coupling

The synthesis of optically active binaphthyls 3 by Pd-catalyzed asymmetric Negishi cross-coupling reaction using organozinc species has rarely been explored with only two examples reported by Espinet and coworker (Scheme  2.4). Various 1-bromonaphthalenes and functionalized naphthylzinc reagents 11 were threaded together in the presence of a palladium source and planar chiral ligand 5 in moderate to good yields (55–95%) and enantioselectivities (49–85% ee) [11]. The use of microwave allowed a reduction of reaction time from several days to 45 minutes while maintaining the reaction efficiency [12]. Enantiocontrol was nonetheless slightly eroded because of the higher temperature. R1 2

Br Zn

11

R2

+

Pd2dba3•CHCl3 (5 mol%) 5 (10 mol%) THF, 50~60 °C 55–95%, 49–85% ee

2

R1 R2 3

Scheme 2.4  Pd-catalyzed asymmetric Negishi cross-coupling reaction.

2.2.1.3  Suzuki–Miyaura Cross-coupling

Because of ready availability, air and moisture stability, as well as functional group tolerance of organoboron reagents, the Suzuki–Miyaura cross-coupling of aryl halides or pseudohalides with aryl boronic acids or their derivatives is arguably the most powerful strategy in the asymmetric synthesis of axially chiral biaryls [13].

15

16

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

Suzuki–Miyaura Cross-coupling Using Phosphine Ligands  In 2000, the groups of Cammidge [14]

and Buchwald [15] independently described the first catalytic asymmetric variants of the Pd-catalyzed Suzuki–Miyaura reaction. BINAP, 2,2′-diamino-1,1′-binaphthalene (BINAM), as well as ferrocene-containing monophosphine ligands had been carefully screened by Cammidge and coworker (Scheme  2.5a) [14]. Experimental results showed that the combination of (S)-(pR)-PFNMe (15) harboring a diphenyl phosphine and a tertiary amine group with PdCl2 could yield binaphthalenes 14 with up to 85% ee. However, the R group of 12 was limited to H or Me. Buchwald’s methodology successfully avoided this restriction and achieved the biaryls 18 containing P(O)(OR)2, NO2, and OMe substituents (Scheme 2.5b) [15]. Using KenPhos 19 as a ligand, a variety of chiral phosphonate-functionalized biaryl compounds were obtained with up to 92% ee. The phosphonate products could be easily functionalized to novel chiral phosphine ligands without the loss of enantiopurity. (a) Cammidge and Crépy [14]

R1

+

I 12

13

(b) Yin and Buchwald [15] X

O P(OR1)2 +

16a: X = Cl 16b: X = Br

NMe2

PdCl2 (3 mol%) 15 (3 mol%)

B(OH)2 Me

R1 R2

CsF, DME, 50 °C up to 50%, 85% ee

14

Pd2(dba)3 (2 mol%) 19 (2.4 mol%) B(OH)2 K3PO4 (2.0 equiv) 2 R Toluene, 40~80 °C up to 98%, 92% ee 17

Fe

PPh2

15, (S)-(pR)-PPFA

R2

NMe2

P(OR1)2 O

PCy2

18 19, (S)-KenPhos

Scheme 2.5  The first catalytic asymmetric Suzuki–Miyaura coupling reactions. (a) Cammidge’s work, (b) Buchwald’s work. Source: (a) Based on Cammidge and Crépy [14] and (b) Modified from Yin and Buchwald [15].

Buchwald’s group also performed a series of control experiments and computational studies for mechanistic probations [16]. As shown in Scheme 2.6, an oxidative addition complex 20 was isolated when a stoichiometric amount of Pd(KenPhos) was reacted with (1-chloro2-naphthyl)diisopropylphosphine oxide 16a. Subsequently, the treatment of 20 with o-tolylboronic acid 17a in the presence of CsF afforded the atropisomeric biaryl phosphine oxide 18a with 90% ee. This atroposelective coupling protocol was operable for aryl bromides containing coordinating groups (such as esters, phosphine oxides, and amides) at orthoposition to generate axially chiral biaryls with excellent enantioselectivities (up to 94% ee). Cl

O P(iPr)2

(COD)Pd(CH2SiMe3)2 (1.0 equiv) (R)-KenPhos (19, 1.0 equiv)

Cl

19 Pd

16a

O

17a, CsF

P(iPr)2 50 °C, 15 h

THF, r.t., 15 h 20

Me P(iPr)2 O 18a, 80%, 90% ee

Scheme 2.6  Mechanistic studies of asymmetric Suzuki–Miyaura coupling reaction.

2.2 ­Biaryl Couplin

In the next 20 years, this reaction regime garnered immense research efforts, from which a series of structurally novel phosphine ligands (21–33), such as ferrocene- or biaryl-based monophosphine, bisphosphines, and hydrazone-phosphines, have been revealed to be effective (Scheme 2.7). At the same time, a broad range of arylation reagents, such as phenols, aryl ethers, esters, carbonates, carbamates, sulfamates, phosphates, phosphoramides, phosphonium salts, and fluorides, can now be coupled readily to boron reagents to afford functionalized axially chiral biaryl products with good to excellent yields and enantioselectivities. Ar Fe

OAr

PCy2

Fe

21, Ar =1-naphthyl Jenson and Johannsen [17]

26, Mikami et al. [22]

O O

Fe

N

N N +

CH2Mes

N

Fe

BF4 23, Labande and coworkers [19]

OMe

X PR2

27, Qiu and coworkers [23–25]

O H PSPEG

PCy2

22, Ar = 4-tBuPh Schaarschmidt and Land [18]

n

PCy2 PCy2

PPh2

Et PPh2

24, Gu and coworkers [20] (iPr)2N OMe

PCy2 28, Qiu and coworkers [24]

PPh2 PPh2 PPh2

25, Fujihara and coworkers [21] O

O P(iPr)2

tBu

R1

29, Sun and Dai [26]

30, Tang et al. [27, 28] P

PR2

R

P

P

P

P

P

PR2 =

N

P PCy2

O O

R2P N

P =

N

31, Uozumi et al. [29]

Me 32, Iwasawa and coworkers [30]

33, Suginone and coworkers [31]

Scheme 2.7  Representative chiral ligands in asymmetric Suzuki–Miyaura coupling.

In 2003, Johannsen and coworker synthesized a series of electron-rich chiral aryl-­ferrocenyl dicyclohexylphosphines for investigating Pd-catalyzed asymmetric Suzuki–Miyaura coupling [17]. The best result was obtained when monophosphines ligand 21 was used for coupling of 1-bromo-2-methylnaphthalene and 2-methyl-1-naphthylboronic acid (65%, 54% ee). In 2010, Schaarschmidt and Lang prepared an array of planar chiral ferrocenyl aryl ethers that were presented as hemilabile bidentate P,O-ligands [18]. This type of ligands proved particularly efficient for the reaction of chloroarenes as well as sterically hindered substrates under mild conditions with low catalyst loadings. However, the reaction proceeded with minimal enantioselectivity when 22 was employed in the coupling of 1-bromo-2-methylnaphthalene with 2-methoxyphenylboronic acid. Labande and coworkers diversely applied the planar chiral, bidentate NHC-phosphine ligand 23 in this asymmetric coupling reaction, achieving moderate enantioselectivities (up to 46% ee) [19].

17

18

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

In 2017, Gu and coworkers described a catalytic asymmetric method for synthesizing cyclohexenone-based atropisomers by using BoPhoz-type phosphineaminophosphine ligand 24 (Scheme  2.8) [20]. The target atropisomeric styrenes 36 were isolated in good yields and excellent enantioselectivities (up to 99% ee). These atropisomers were valuable platform molecules for the synthesis of biaryl atropisomers 37 and 38 bearing different ortho-substituents.

Gu and coworkers [20]

R1 [B]

1

R

OR

+ Me

O R2

I 34a, R1 = H 34b, R1 = Me

Me

I OMe

37, 75%, 99% ee

35

[Pd(acac)2] (5 mol%), 24 (7.5 mol%)

O OR

Me

KOH (2.5 equiv), DCE/H2O (1 : 1), 65 °C 55–99%, 79–95% ee R2

[B] = B(OH)2 or Bpin (1) N2H4•H2O, MeOH (2) I2, TEA, 0 °C ~ r.t. (3) DDQ, dioxane, 90 °C

36

Me

BPO (10 mol%) O Me OMe NBS, CCl , 80 °C 4

36a, 99% ee

OH OMe

38, 94%, 99% ee

Scheme 2.8  Asymmetric Suzuki–Miyaura coupling with BoPhoz-type ligand for the construction of atropisomeric styrene structures. Source: Based on Pan et al. [20].

In 2008, Fujihara and coworkers systemically investigated various bisphosphine ligands as stabilizers of Pd nanoparticles in asymmetric coupling of naphthylboronic acid with 1-bromo-2-methoxynaphthalene [21]. Both reactivity and enantioselectivity were significantly influenced by the nature of the protective ligand, regardless of the similar diameters (1.2–1.7 nm) of chiral Pd nanoparticles. Mikami and coworkers investigated the substituent effect on phosphine of BINAP analogs in great details [22]. The best results were afforded with cyclohexyl substituents (Cy-BINAP, 26), giving the corresponding product in 92% yield with 70% ee at 80 °C. The ee value could be improved to 84% when the reaction was conducted at room temperature but with significant compromise of product yield to 17%. In 2012, Qiu and coworkers developed a novel type of atropisomeric P,N-ligands via a highly efficient central-to-axial chirality transfer strategy [32]. When these P,N-ligands were tested in the asymmetric coupling reactions, 27a was found to be optimal, affording biarylphosphonates in moderate to good enantioselectivities (up to 82% ee). A collection of chiral-bridged P,O-ligands were also synthesized and then applied in the Pd-catalyzed asymmetric Suzuki–Miyaura coupling reaction by the same group [23]. Ligand 27b was found to be highly effective, giving the biaryl atropisomers 18 in excellent yields (up to 98%) and enantioselectivities (up to 97% ee). Later, they reported the construction of axially chiral 2-functionalized-2′-diarylphosphinyl-1,1′-biaryls in 34–99% yields with up to 94% ee when ligand 27c or Cy-MOP 28 was used (Scheme 2.9a) [24]. The use of Cy-MOP 28 enabled the

2.2 ­Biaryl Couplin (a) Qiu and coworkers [23, 24] Br

O P(OR1)2

B(OH)2 R2

+

16

R2

Pd2 (dba)3, 27–28

P(OR1)2 O 18

17 27b, R = H 27c, R = OMe

O

NMe2

O

OMe

O

PCy2

O

PAr2

OMe

tBu

Ar =

PCy2 R

27a, up to 82% ee

tBu

27b and 27c, up to 97% ee

28, Cy-MOP, up to 93% ee

(b) Qiu and coworkers [25] Br N

R2

O

B(OH)2

P(OR1)2

+

Pd2(dba)3, 42–44 O

45–90% 60–96% ee 39

40

O

R2

O PR2

O

42

N

41

O PR2

O

43

P(OR1)2

PR2

O

a, R = Ph b, R = p-tol c, R = Xyl d, R = 3,5-(tBu)2C6H3

44

Scheme 2.9  Synthesis of axially chiral biaryls using chiral-bridged atropisomeric monophosphine ligands. (a) Chiral-bridged P,O- or P,N-ligands, (b) removing the NMe2 and OMe moieties. Source: (a) Based on Zhou et al. [24] and (b) Modified from Xia et al. [25].

synthesis of multifunctionalized axially chiral biaryls bearing various functional groups, such as phosphonate, nitro, and formyl. Aside from the apparently improved coupling efficiency, products bore handles for versatile functionalizations. In 2017, Qiu and coworkers synthesized chiral-bridged atropisomeric monophosphine ligands 42–44 by removing the NMe2 and OMe moieties from hemilabile ligands 27 (Scheme 2.9b) [25]. With these ligands, the coupling reaction was successfully applied to electrophiles bearing heteroarenes, such as 8-bromo-7-quinolinylphosphonates 39, leading to quinolylbiaryl phosphonates 41 with excellent yields and enantioselectivities (60–96% ee). In 2011, Dai and and coworker prepared enantiomerically pure aromatic amide-derived phosphanes, namely, Aphos, by means of a chemical resolution process starting from a TBSO-substituted naphthamide [26]. The asymmetric coupling of 13 and 45 using Aphos 29 and Pd2(dba)3 led to chiral biaryl 46 in 95% yield and 84% ee, which could be upgraded to 99% ee after one recrystallization step (Scheme 2.10). The product could be transformed into (S)-2-methyl-1-(o-tolyl)naphthalene without loss of optical purity via a three-step sequence of deprotection, bromation, and hydrogenation.

19

20

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers Sun and Dai [26] B(OH)2 Me

Pd2(dba)3 (2 mol%) 29 (8 mol%)

+ I

13

OSi(iPr)3

CsF (3.0 equiv) Toluene, 40 °C

Me OSi(iPr)3

45 46, 95%, 84% ee

Scheme 2.10  Synthesis of axially chiral biaryl using aromatic amide-derived phosphine ligand. Source: Based on Sun and Dai [26].

In 2012, the Tang group developed a novel type of P-chiral phosphorus ligands for asymmetric Suzuki–Miyaura cross-coupling reactions [27]. Starting from enantiopure 47, the Suzuki–Miyaura cross-coupling with aryl boronic acids afforded intermediate 48. Following deprotonation, diastereoselective alkylation and reduction, ligands 30a–c with both C- and P-stereogenic centers were afforded. Applying ligand 30a in the asymmetric Suzuki– Miyaura coupling of aryl bromide 49a–d bearing different substitutions led to biaryls 50a–d with ee values varied from 20% to 96%. These results indicated that the R group on 49 played a decisive role in enantiocontrol. Density functional theory (DFT) calculations of the transition state at the reductive elimination stage revealed the presence of a π–π interaction between carbonyl benzooxazolidinone functionality and the naphthalene group of the other coupling partner (Scheme 2.11a). This protocol was also extended to substrates containing protected ortho-hydroxyl groups 51, which could establish a strong electrostatic effect and a secondary interaction with the π system of the other coupling partner. The rapid removal of the bis(2- oxo-3-oxazolidinyl)phosphiny (BOP) group and transformation to the triflate group allowed access to various chiral biaryl compounds through further derivatization (Scheme 2.11b) [28]. In 2009, Uozumi et  al. evaluated imidazoindole-phosphine ligands for asymmetric Suzuki–Miyaura couplings (Scheme  2.12) [29]. Good to excellent enantioselectivities (72–94% ee) were obtained when 1-iodo- or 1-chloro-2-methylnaphthalenes 53 were treated with 2-methyl-1-naphthaleneboronic acids 17. Additionally, this reaction could perform well in water with the immobilization of ligand 31 on a polystyrene-poly(ethyleneglycol) copolymer (PS-PEG) resin and the catalyst could be recycled up to four times without ­significant loss of catalytic activity and stereoselectivity. Iwasawa and coworkers, on the other hand, investigated the capability of sterically hindered phosphonite ligands possessing axially chiral substituents [30]. Remarkably, these new ligands realized a catalytic system with low catalyst and ligand loadings as well as shortened reaction duration, as compared to previous studies. Under these conditions, up to 91% yield and 78% ee were achieved for a selected set of coupling partners using ligand 32. The drawback lied in the isolation of coupled products, which required extraction of reaction media with supercritical CO2 before chromatographic purification. A highly enantioselective approach to access axially chiral biarylphosphonates 55 was established by Suginome and coworkers employing helical chiral polyquinoxaline-based chiral phosphine (PQXphos) ligands, demonstrating the potential of macromolecular

2.2 ­Biaryl Couplin (a) Tang et al. [27]

O

O

P O

[Pd]

P O

tBu B(OH)2

OTf tBu 47

48

Br

R1

+

30

COR

K3PO4 (3.0 equiv), THF, r.t.

O

R2

Pd(OAc)2 (5 mol%) 30 (6 mol%)

B(OH)2 R

P tBu

30a, R = Me 30b, R = Bn 30c, R = CH2(1-nap)

R1

R1

O

(1) LDA; 2) R2X (3) PMHS, Ti(OiPr)4

17 O

49a, R = H 49b, R = NMe2 49c, R =

O

O 49d, R =

N

N

O

50a, 90%, 20% ee 50b, 95%, 79% ee 50c, 96%, 87% ee 50d, 95%, 96% ee

(b) Tang and coworkers [28] B(OH)2 R2

+

OBOP Br 51

Pd(OAc)2 (1 mol%) 30a (1.2 mol%)

OBOP R2

K3PO4 (3.0 equiv) Toluene/H2O 5 : 1

17

BOP =

O N

P

O

O 52, 91–98%, 90–99% ee

N

O

O

Scheme 2.11  Synthesis of axially chiral biaryls using P-chiral phosphorus ligands. (a) Coupling with aryl bromides bearing carbonyl benzooxazolidinone functionality, (b) coupling with aryl bromides containing protected ortho-hydroxyl groups. Source: (a) Based on Tang et al. [27] and (b) Based on Xu et al. [28].

Uozumi et al. [29] B(OH)2

R1 R2

R3

+

X 53

17

O

O

HN n

nBu4F (10.0 equiv) H2O, 80 °C, 24 h O

O PS

Pd(OAc)2 (10 mol%) 31 (Pd:P = 1 : 1)

(CH2)3

31, PS-PEG-L*

N

H

R1 R2 R3

54, 53–96%, 88–99% ee

N PCy2

Scheme 2.12  Asymmetric Suzuki–Miyaura coupling reactions in water. Source: Modified from Uozumi et al. [29].

21

22

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

ligands for this chemistry [31]. They prepared 20 mer-based block copolymers by living block copolymerization of a chiral spacer monomer bearing (R)-2-butoxymethyl side chains and a phosphorus-containing monomer in the presence of a chiral initiator. In addition, 1000 mer-based high molecular weight block copolymers were also prepared by living random copolymerization of chiral and phosphorus-containing monomers in a 950/50 ratio using an achiral organonickel initiator. A screening of ligands showed that the 1000 mer-based PQXphos 33 bearing bulky P(2-nap)2 or P(3,5-Me2C6H3)2 group could successfully deliver the chiral biarylphosphinic esters with high ee values (Scheme 2.13). Suginome and coworkers [31] Br

O P(OR1)2

+

B(OH)2 Me R2

P

P

P

R2P

P

N

P =

P

Me P(OR1)2 O 55

K3PO4 (2.0 equiv) up to 93%, 98% ee

17

16

R2

[PdCl(allyl)]2 (1 mol%) 33a-b (P:Pd = 2 : 1)

33a: R = 3,5-Me2C6H3 33b: R = 2-nap

N Me

Scheme 2.13  Asymmetric Suzuki–Miyaura reactions with PQXphos ligands. Source: Modified from Yamamoto et al. [31].

Suzuki–Miyaura Cross-coupling Using Phosphine-Free Ligands  Undoubtedly, phosphorusbased chiral ligands represent a class of privileged ligands for asymmetric Suzuki–Miyaura cross-couplings; the employment of phosphorus-free ligands to prepare enantioenriched atropisomers through this process remains in its infancy. BINAM was first enlisted in the asymmetric variant of Suzuki–Miyaura coupling in 2000 by Cammidge and coworker despite the low enantioselectivity induced [14]. Subsequent studies exploiting N,N′-phebox ligands by Iwasa and coworkers afforded the desired biaryls with low to moderate enantioselectivities [33]. In 2008, Lassaletta and coworkers developed a series of glyoxal bis-hydrazones derived from C2-symmetric hydrazines for chirality induction in Suzuki–Miyaura cross-couplings (Scheme 2.14) [34]. A variety of substrates

Lassaletta and coworkers [34] Br R1 + 56

B(OH)2

R2

17

Ph Cat. (5 mol%) Cs2CO3, toluene up to 99%, >98% ee

1

R R2

Ph

N N Ph Cl

N N Pd 57

Cl Ph

Scheme 2.14  Asymmetric Suzuki–Miyaura reactions with bis-hydrazone ligand. Source: Based on Bermejo et al. [34].

2.2 ­Biaryl Couplin

were well engaged in this reaction and provided products with good to excellent enantioselectivities using 5 mol% of hydrazine 57 and PdCl2 complex as the catalyst. The introductory example of involving chiral NHCs in asymmetric Suzuki–Miyaura coupling was reported in 2010 by Labande and coworkers, which brought forth low to moderate enantioselectivities [35]. Kündig and coworkers implemented the synthesis and characterization of pyridine-enhanced precatalyst preparation, stabilization, and initiation (PEPPSI) complexes incorporating bulky monodentate NHC. The results with these air- and moisture-stable chiral PEPPSI complexes were highly dependent on the substrate used (Scheme 2.15a) [36]. The best enantioselectivity (80% ee) was observed for the coupling of 1-bromo-2-methylnaphthalene 56 with naphthylboronic acid 17, which also represented the best result that has been achieved with a palladium catalyst bearing a chiral NHC. Recently, Shi and coworkers reported a new chiral (NHC)-Pd complex 62 to catalyze Suzuki–Miyaura cross-coupling (Scheme 2.15b) [37]. The extremely bulky C2-symmetric chiral NHC ligand developed could enable the forging of atropisomeric biaryls that carried a remarkable scope of functional groups or heterocycles in high to excellent enantioselectivities (up to 99% ee). Moreover, the method was successfully applied to diastereo- and enantioselective synthesis of atropisomeric ternaphthalenes. (a) Kündig and coworkers [36] X

B(OH)2 R2

R1 +

17

56

tBu 58 (5 mol%)

1

R R2

KOH (3.0 equiv) dioxane/H2O (1/1) up to 85%, 80% ee

Het

R1

3 + R

X 59, X = Cl, Br, OTf

tBu

N

I Pd I N 58

Cl

(b) Shi and coworkers [37] B(OH)2 62 (0.2–2 mol%) R2 KOH (3.0 equiv) tBuOH, 50 °C 60 up to 99% ee

N

Ar 3

R2

R

R1 Het 61

Ar

Ar N

N Pd

Ar

Ph 62, Ar = 3, 5-tBu2C6H3

Scheme 2.15  Asymmetric Suzuki–Miyaura coupling using chiral NHCs. (a) Kündig’s work, (b) Shi’s work. Source: (a) Based on Benhamou et al. [36] and (b) Based on Shen et al. [37].

Palladium-chiral diene complex has also shown compatibility with Suzuki–Miyaura c­ oupling reactions; the π-interaction between double bond and metal center in the olefinpalladium complex is however weak, which tends to compromise the catalytic efficiency. In 2010, a number of functionalized biaryls with moderate to high optical purities were obtained using a combination of chiral diene and Pd–diene complex by Lin and coworkers (Scheme 2.16) [38]. The joint action of Pd–diene 63 and chiral diene 64 gave rise to the best ee value (up to 90%). It was found that the existence of an excess of free ligand in the reaction system was necessary to maintain catalyst turnover and efficient enantioselectivity induction. The detailed mechanism for this chemistry with the isolation and characterization of the key palladium intermediates was also disclosed [39].

23

24

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers Lin and coworkers [38] B(OH)2

Br R1

R2

+ 17

56

Ar 63

63 (5 mol%) 64 (15 mol%)

Ar 64

1

R R2

Cs2CO3, Toluene up to 99%, 90% ee

Pd Ar Cl Ar Ar = 3,5-Me2C6H3

Cl

Scheme 2.16  Asymmetric Suzuki–Miyaura coupling using chiral dienes. Source: Based on Zhang et al. [38].

2.2.2  Other Types of Cross-coupling Recently, Denmark and coworkers developed an asymmetric Hiyama–Denmark cross-coupling aryl bromides 2 and 65 employing bis-hydrazone ligand 57, providing binaphthyls 3 in good yields and enantioselectivities (Scheme  2.17, up to 90% yield and 90% ee) [40]. Same configuration and similar enantioselectivities were detected when the coupling partners were reversed, indicating that reductive elimination was the stereo-determining step. Computational modeling of diarylpalldium(II) complex revealed the origin of atroposelectivity in which the C─C bond formation occurs through conrotatory motion for the two aryl groups. Denmark et al. [40] Br R1 +

2

Me Me Si OK [Pd(allyl)Cl]2 (2.5 mol%) 57 (5 mol%) R2

65

Ar R1 R2

Toluene, 70 °C up to 90%, 90% ee

Ar

N N Ar

N N 57

Ar

3

Scheme 2.17  Asymmetric Hiyama–Denmark reaction using bis-hydrazone ligands. Source: Based on Denmark et al. [40].

Gu and coworkers reported a new strategy for the synthesis of axially chiral styrene structures employing carbene precursors 67 as the coupling partners instead of arylboronic acids. TADDOL-based chiral phosphoramidites ligand 69 proved superior to other ligands to give the desired product 68 with up to 97% ee (Scheme 2.18) [41]. Notably, this reaction was conducted under mild conditions and thus possessed a high substrate generality. The styrene atropisomers could be easily oxidized to biaryls or readily reduced to phosphine with the preservation of the stereochemical integrity.

2.2.3  Oxidative Coupling 1,1′-Bi-2-naphthol (BINOL) constitutes the core backbone of numerous chiral ligands and organocatalysts that are widely applied in asymmetric catalysis [42, 43]. For this reason, the construction of this privileged motif through the coupling of 2-naphthols largely dominates the field of enantioselective oxidative coupling reactions. A series of efficient catalytic systems based on Cu, V, and Ru chiral complexes have been developed.

2.2 ­Biaryl Couplin Gu and coworkers [41] Br

O P(Ar1)2 +

R1

R3 R3

NNHTs R2 R3 R3

66

Pd(OAc)2 (10 mol%) 69 (20 mol%)

R2

tBuOLi, 1,4-dioxane 50 °C, 24 h up to 97% ee

R1

O P(Ar1)2 68

67 Ar2 Ar2 DDQ, DCE, 50 °C O PPh2

O

O

PPh2

O

O P N O Ar2 Ar2

68a, 99% ee

70%, 97% ee

69, Ar2 = 4-FC6H4

Scheme 2.18  Asymmetric cross-coupling reaction using carbene precursors as coupling partners. Source: Modified from Feng et al. [41].

2.2.3.1  Cu-Catalyzed Oxidative Coupling

In 1978, Feringa and Wynberg reported the first biomimetic asymmetric oxidative coupling of 2-naphthols in the presence of stoichiometric amount of Cu(NO3)2·3 H2O and chiral amine [44]. However, this reaction could only bring about 16% ee as the best enantioselectivity outcome for the products with (S)-2-(methoxymethyl)pyrrolidine. Kočovský and Smrčina developed the first Cu-catalyzed oxidative coupling for the asymmetric synthesis of binaphthols using (−)-sparteine 72 as a chiral ligand in 1993 (Scheme 2.19) [45]. CuII catalyst is regenerated from CuI by using AgCl as the oxidant. Binaphthols were obtained in good yields but low enantioselectivities via the coupling of sodium salts of naphthol. Kočovský and coworkers [45] R + ONa 70

ONa 71

72 (–)-sparteine (20 mol%) CuCl2(10 mol%)

N

OH OH

AgCl (1.1 equiv) MeOH, r.t., 3 days

H

H 73

N

R 72

Scheme 2.19  First Cu-catalyzed asymmetric oxidative coupling of 2-naphthols. Source: Modified from Smrčina et al. [45].

The following investigations concerned the use of oxygen as an abundant, cheap, and green oxidant. Nakajima and coworkers developed the enantioselective oxidative homo-coupling of naphthols using 10 mol% of chiral amine 76 derived from proline, affording the corresponding 3,3′-substituted-BINOLs 75 in good enantioselectivities (Scheme 2.20a, up to 78% ee) [46]. It should be noted that the ester moiety at three-position of the substrate was found essential for good asymmetric induction (R = H, 17% ee). In 2015, the Breuning group systematically investigated the performance of 38 different prolinamines as chiral ligands for copper-catalyzed oxidative coupling of naphthols (Scheme 2.20b) [47]. The best enantioselectivity (87% ee) was obtained when the reaction was carried out at 0 °C using ligand 77.

25

26

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers R R

Copper source amine 76–79

OH

OH OH

O2

74 75 (a) Nakajima et al. [46]

N H

(b) Breuning and coworkers [47]

Ph NEtPh

76, up to 78% ee

N Me

(c) Kozlowski and coworkers [49]

H N NMe2

77, up to 87% ee

N

R (d) Ha and coworkers [50]

NHX NH2

H 78, up to 96% ee

79, up to 94% ee

Scheme 2.20  Asymmetric Cu-catalyzed oxidative coupling of 2-naphthols with different chiral amines. (a) Nakajima’s work, (b) Breuning’s work, (c) Kozlowski’s work, (d) Ha’s work. Source: (a) Modified from Nakajima et al. [46], (b) Based on Prause et al. [47], (c) Li et al. [48, 49] and (d) Based on Kim et al. [50].

A breakthrough was achieved when chiral 1,5-diaza-cis-decalin 78 was employed by Kozlowski’s group as the ligand in this aerobic coupling reaction (Scheme 2.20c) [48, 49]. High enantioselectivities were obtained for these substrates bearing a C-3 substituent including ester, ketone, phosphine oxide, phosphonate, as well as phosphoramide. The synthetic utility of this methodology was demonstrated in the total synthesis of several natural products such as (+)-Phleichrome and (S)-Bisoranjidiol [51–54]. Variedly, Ha and coworkers tested a series of BINAM-derived chiral ligands and BINOL-type products were obtained in up to 95% yield and 94% ee when the reaction was carried out using amine 79 (X = 3-pentyl) at 0 °C for 48 hours (Scheme 2.20d) [50]. The asymmetric oxidative coupling of 2-naphthols was also realized using dicopper complex as the chiral catalyst by Gao and coworkers (Scheme 2.21) [55]. Good yields and enantioselectivities were secured with both complex 80 and 81. Attempts to identify the active species that promote these reactions might provide insights to improve on enantioselectivity and robustness of this synthetic operation. The complex of copper and chiral amine could also enable the hetero-coupling of 2-naphthols following this asymmetric oxidative operation. Indeed, the major issue of this transform resides in the selectivity toward cross-coupling compounds over the two competitive homo-coupling products. In this context, Habaue and coworkers evaluated various chiral diamine ligands, for instance, 1-(2-pyrrolidinyl)pyrrolidine, sparteine as well as bisoxazolines (Scheme 2.22a) [56, 57]. A copper(I)-(S)-Phbox catalytic system was found to smoothly promote this reaction to produce the binaphthyl or quarter-naphthyl derivatives in good yields (up to 92%) with enantioselectivities up to 74% ee. Notably, the formation of homocoupling products was almost completely inhibited under this set of conditions. Recently, the enantiocontrol was significantly improved by Tu and coworkers by utilizing a novel type of chiral 1,5-N,N-bidentate ligands building upon a spirocyclic pyrrolidine oxazolone

2.2 ­Biaryl Couplin Gao et al. [55] Me

Me

OH H

O2 80–81

H

N

N O CU CU N N O

H

Ph Ph

H

H

H

N

O

N

CU CU N N O

H

H

Ph Ph

OH OH Me 80, 84%, 86% ee

Me 81, 85%, 88% ee

Scheme 2.21  Asymmetric dicopper complexes catalyzed oxidative coupling of 2-naphthol. Source: Based on Gao et al. [55].

R1 2

R

1

R

OH Cu /82 or 83 R2 I

+

R3 OH

OH OH R3

(a) Habaue and coworkers [56, 57] O

(b) Tu and coworkers [58]

O N

Ph

N H N

N Ph

82 (S)-Phbox up to 74% ee

Ph

O

83 SPDO up to 99% ee

Scheme 2.22  Cu-catalyzed asymmetric heterocouplings. (a) Habaue’s work, (b) Tu’s work. Source: (a) Temma et al. [57] and Based on Tian et al. [58].

(Scheme 2.22b) [58]. This reaction displayed broad substrate compatibility and provided structurally diversified 3,3′-disubstitued BINOLs with excellent enantioselectivity (up to 99% ee) and good chemoselectivity when diamine 83 was utilized as the chiral ligand (less than 10% of homo-coupling by-products were formed in most cases). 2.2.3.2  Oxidative Coupling Reactions with Other Metals

Despite the tremendous success of copper catalysts in the assembly of optically active BINOLs through atroposelectively oxidative coupling of 2-naphthols, chiral catalytic systems comprising other metals were also explored to augment selectivities. In 2000, ruthenium was, for the first time, used in the place of copper by the Katsuki group. Chiral salen complex 84 could facilitate the homo-coupling of 2-naphthols in high efficiency with up to 71% ee (Scheme 2.23a) [59]. Chiral salan iron dimers were also found to be effective by this group in 2009 (Scheme 2.23a) [60]. Good yields and enantioselectivities (up to 97% ee) were provided with 85 as the catalyst for 2-naphthol substrates with 3-substitution. On the other hand, oxovanadium(IV) complexes found broad utility in oxidation reactions with O2 or peroxide co-oxidants [67]. In 2001, Chen and coworkers attempted the application of chiral vanadium complexes 86 in catalytic asymmetric oxidative homo-coupling of

27

28

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers R3

R1 R1 2

R

R3

Catalyst 84–91

R2

OH

O2 or air

R2

*

R1 (a) Katsuki and coworkers [59, 60]

OH OH R3

(b) Chen and coworkers [61, 62]

(c) Uang and coworker [63]

Bn N V O O O OH

N O V O O O 86, up to 51% ee

N ON N Ru O Cl O Ph Ph

88, 52% ee Bn

tBu

84, up to 71% ee Ph H N

O

Ph H N

85, up to 97% ee

N V O O O OH

O

87, up to 88% ee

O

89, 8% ee

(d) Gong and coworkers [64, 65, 66]

Fe O O Ph Ph

O

N V O O O

O

R

2

N V O O O OO O V O N 90, 91, up to 98% ee R

R O

O

N V O OO OO O V O N 92, up to 97% ee

O

O

R

Scheme 2.23  Asymmetric homo-coupling of 2-naphthols with other metal complexes. (a) Chiral salen complex, (b) chiral oxovanadium(IV) complexes, (c) chiral vanadium catalysts possessing central and axial chirality, (d) chiral vanadium dimer complex. Source: (a) Irie et al. [59], Egami and Katsuki [60], (b) Hon et al. [61], Barhate and Chen [62], (c) Based on Chu and Uang [63] and (d) Sources: Luo et al. [64, 65], Guo et al. [66].

2-naphthols as depicted in Scheme 2.23b [61]. C2-symmetric BINOLs were synthesized in excellent yields; however, the enantiocontrol remained challenging. This system was also applicable for the construction of NOBINs. Further investigations from the same group revealed that excellent yields and very high enantioselectivities could be obtained by changing the ligand to O,N,O-ligand 87 derived from amino acid and ketopinic acid (Scheme 2.23b) [62]. Uang and coworker developed a new family of vanadium catalysts possessing central chirality (originated from amino acid fragment) and axial chirality. The relative configuration of two chirality elements strongly influenced the enantioselectivity outcome; 52% ee could be obtained with diastereoisomer 88 embodying a matched pair as a catalyst, while the mismatched pair in diastereoisomer 89 resulted in only 8% ee under same conditions (Scheme 2.23c) [63]. Gong and coworkers developed chiral vanadium dimer complex 90 (Scheme  2.23d) [64]. The ligands were prepared from 3,3′-diformyl-2,2′-dihydroxy-1,1′bi-2-naphthol and various chiral amino acids. Remarkable performance of this type of catalysts was reflected in the excellent efficiency (up to 99%) and enantioselectivity (up to

2.3  ­Desymmetrization and (Dynamic) Kinetic Resolution via Functional Group Transformatio

98% ee) delivered. Subsequently, catalysts 91, the second-generation catalysts, were developed by the same group through the replacement of binaphthyl with biphenyl framework. This alternation avoided the optically pure 1,1′-binaphthyl subunit, thereby could eliminate the matched/mismatched issue of two stereogenic elements [65, 66]. Notably, H8BINOL-derived catalyst 92 allowed the oxidative coupling of 2-naphthol using air as a safer and greener oxidant. The catalytic activity was maintained and the reaction duration could be shortened from 4–6 to 2 days. Recently, Pappo and coworkers exploited a new class of chiral catalysts containing iron center and axially chiral element from BINOL scaffold. When 93 was employed as the promoter, the homo-coupling reaction proceeded smoothly to generate the C2-symmetric BINOLs in high efficiency with up to 88% ee. Moreover, this catalyst could also be applied in the challenging hetero-coupling variant. However, low yields with moderate chemo- and enantioselectivities were observed for most cases (Scheme 2.24) [68].

Pappo and coworkers [68]

Ar O

R

+

OH

Catalyst 93

R

Low yield moderate selectivities OH

OH OH

O

O P

Fe O 3

Ar

93, Ar = 4-tBu-C6H4

Scheme 2.24  Asymmetric oxidative cross-coupling of 2-naphthols using iron catalyst. Source: Based on Narute et al. [68].

2.3 ­Desymmetrization and (Dynamic) Kinetic Resolution via Functional Group Transformation The previous section introduced the construction of axial chiral biaryls via metal-catalyzed asymmetric formation of the stereogenic axis. In this section, we will focus on an alternative approach to access the optically active biaryls via atroposelective transformations of existing prochiral or racemic biaryls bearing functional groups. Three strategies including desymmetrization of prochiral biaryls, (dynamic) KR of racemic biaryls, and ring opening of biaryl compounds are discussed.

2.3.1  Desymmetrization of Prochiral Biaryls In 1995, Hayashi and coworkers described the asymmetric cross-coupling of achiral biaryl ditriflates 94 with aryl Grignard reagents in the presence of chiral palladium complex PdCl2[(S)-Phephos] 95, affording axially chiral monophenylation products 96 with excellent enantioposition-selectivity (Scheme 2.25) [69]. The intact triflate group in the products could serve as a functionalization handle to allow transformation into a wide range of axially chiral biaryl molecules through conventional coupling reactions.

29

30

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers Hayashi et al. [69]

TfO

OTf

ArMgBr/LiX 95 (5 mol%)

Bn

Ar

Ar

OTf

Me N Pd P

up to 87%, 93% ee 94

Me

R Ph

96

Cl Cl

Ph

95 PdCl2[(S)-Phephos]

97

Scheme 2.25  Enantioselective desymmetrization of achiral biaryl bis-triflates through crosscoupling reactions. Source: Based on Hayashi et al. [69].

About 10 years later, the enantioposition-selective functionalization strategy to access axially chiral biaryls was revisited by Uozumi and Osako in a copper-catalyzed azide– alkyne asymmetric cycloaddition (CuAAC) (Scheme  2.26) [70]. Starting from achiral biaryls 98 bearing dialkyne substituents, the click reaction proceeded smoothly to afford the targeted axially chiral biaryls 100 harboring a 1,2,3-triazole with pretty good enantioselectivities (up to 99% ee) in the presence of l-serine-derived PyBOX ligand 101. Because of the competitive formation of bistriazoles, only moderate yields were obtained for most cases.

Osako and Uozumi [70] R1

R1 BnN3 99, (1.5 equiv) R2

R3 98

CuOTf•(C6H6)0.5 (10 mol%) 101 (20 mol%) up to 76%, 99% ee

Bn

N N

O

N R2 R2

O N

N

OTBS 100

TBSO 101

Scheme 2.26  Enantioselective desymmetrization of achiral biaryl dialkynes through CuAAC reaction. Source: Based on Osako and Uozumi [70].

2.3.2  Kinetic Resolution of Racemic Axially Chiral Biaryls In 2005, Tsuji and coworkers developed a Pd-catalyzed resolution protocol for asymmetric alcoholysis of racemic vinyl ethers 102 (Scheme 2.27) [71]. Various racemic biaryls reacted with excess methanol in the presence of diamine ligand 103 to afford BINOL derivatives 104 in 65–88% ee along with unreacted (R)-102 in 45–97% ee. The reaction appeared to resemble Pd-catalyzed transfer vinylation from vinyl ethers to alcohols, whereas a reverse reaction of alcohol 104 with ethyl vinyl ether as the vinylation reagent did not proceed in the same catalyst system.

2.3.3  Dynamic Kinetic Resolution of Racemic Axially Chiral Biaryls KR of racemic biaryls is innately limited by the maximum theoretical yield of enantiomer product at 50%, although the recovery of less active and enantioenriched starting material

2.3  ­Desymmetrization and (Dynamic) Kinetic Resolution via Functional Group Transformatio Tsuji and coworkers [71] R O OCOtBu

Pd(OAc)2 (5 mol%) 103 (10 mol%)

R

R

MeOH (10 equiv)

R

R rac-102 NH HN

Ar

Ar

O OCOtBu

OH + OCOtBu R 104, 65–88% ee

(R)-102, 45–97% ee

103, Ar = 2,3,4,5-PhC6H

Scheme 2.27  Pd-catalyzed resolution by alcoholysis of vinyl ethers. Source: Based on Aoyama et al. [71].

is viable. In this aspect, dynamic kinetic resolution (DKR) represents a more efficient strategy over KR in asymmetric catalysis domain for allowing access to enantioenriched product in 100% theoretical yield. In this scenario, the substrate is subjected to in situ racemization, ensuring the constant conversion of the less reactive enantiomer into the more reactive one. In 2018, Wang and coworkers reported a novel atropo-enantioselective redox-neutral amination of biaryl compounds triggered by a cascade of borrowing hydrogen and DKR under the cooperative catalysis of a chiral iridium complex 107 and an achiral Brønsted acid (Scheme  2.28) [72]. A variety of highly enantioenriched biaryls 108 (up to 98% ee) were obtained in good efficiency. The plausible reaction pathway was proposed as follows: the dehydrogenation of 105 by the iridium catalyst forms intermediate I. Next, condensation of aldehyde with aromatic amine 106 gives imine intermediates II and IV. The less active intermediate II could be converted into IV via a racemization event with lactol III as the key intermediate. The reduction of the more reactive IV affords the desired product with enantiocontrol. Zhang and Wang [72] R1

OH OH

+ ArNH2

Pentafluorobenzoic acid (5 mol%)

106

2

R

Ir catalyst 107 (5 mol%), 4 Å MS

105

R1

107

NHAr OH

R2

O O S

108

Ir N HN

Ir* Dehydrogenation

Ph

Hydrogenation

R=

F

F

Ir*–H2 R1

O

R1

NHAr

ArNH2

OH R2 I

F R1

NHAr

OH R2

F

R1

F

NAr OH

O R2

II

R

Ph

R2 III

Racemization

IV

Scheme 2.28  Atropo-enantioselective redox-neutral amination of biaryl compounds. Source: Based on Zhang and Wang [72].

31

32

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

2.3.4  Ring-opening Reactions In 1979, Wenkert and coworkers revealed that thiophenes were appropriate reactants for nickel-catalyzed cross-couplings [73]. Inspired by this observation, Hayashi and coworkers established an efficient approach to synthesize axially chiral binaphthyls 110 via nickel-catalyzed enantioselective ring-opening of the dinaphthothiophene 109 with aryl Grignard reagents (Scheme  2.29) [74]. Dinaphthothiophene 109 was considered to be achiral because of the rapid flipping even at room temperature. The ligand evaluations provided (S)-iPr-PhOX 111 as the optimal ligand for most cases to afford binaphthyls 110 in up to 97% yield with excellent enantiocontrol. The torsion angle of thiophene ring significantly affected the reactivity and the substrates with two bulky substituents at 1,9-positions will result in reduced energy barrier to cleave the C─S bond. However, the preparation of 1,9-substituted dibenzothiophenes usually required six steps, which may restrict their synthetic applications [75]. In addition, the same group put forward a pioneering attempt to adopt dinaphthaleneiodonium salt in palladium-catalyzed asymmetric carbonylation. The low enantioselectivity notwithstanding, it laid a foundation for the following ring-opening reactions [76].

Hayashi and coworkers [74]

S + RMgX

(1) Ni(cod)2/111 (3 mol%)

R

(2) H+, H2O

SH

Ph2P N

O

iPr 109

110, up to 95% ee

111 (S)-iPr-PhOX

Scheme 2.29  Asymmetric ring opening of dinaphthothiophene. Source: Based on Shimada et al. [74].

The successful application of the dinaphthaleneiodonium salts 112 in the construction of highly enantiopure biaryls was achieved in 2018 by Gu’s group with the use of Cu-bis(oxazolinyl)pyridine complex 114 or 115 (Scheme 2.30a) [77, 78]. Utilizing amines as ring-opening reagents, biaryl amination products 113 were generated in excellent yields and enantioselectivities (up to 99% yield and >99% ee) for most substrates. As expected, increasing the torsional strain of these cyclic compounds could significantly improve the activity of cyclic diaryliodoniums, which constituted another determining factor of successful reaction. Computational investigation attested the low rotational barrier between the two conformers of the cyclic diaryliodoniums. Furthermore, this ring-opening amination reaction featured high atom economy and the resulting aryl iodides were suitable precursors for diverse elaborations. Subsequently, they extended this strategy to O-alkylhydroxylamines to synthesize 2-hydroxyamino-2′-iodobiaryls 116 with copper catalyst and Box ligand 117 (Scheme 2.30b) [79]. Notably, the addition of 2.0 equiv of CaO was crucial to suppress the side reactions where water could act as the nucleophile, thus improved the yield.

2.3  ­Desymmetrization and (Dynamic) Kinetic Resolution via Functional Group Transformatio

Concurrently, the same group investigated the Cu-catalyzed asymmetric thiolative ringopening reaction of cyclic diaryliodoniums 112 as shown in Scheme 2.30c. Using potassium thioates as sulfur nucleophiles and commercially available bisoxazoline 82 as chiral ligand, atropisomeric 2′-iodo[1,1′-biphenyl]-2-yl thioates 118 were provided with high enantioselectivities (Scheme 2.30c) [80]. The products could be easily transformed to axially chiral P,S-ligands. Building on this work, Zhang and coworkers extended sulfur nucleophiles to heteroaryl thiols and bisoxazolines to give the corresponding products with excellent enantiocontrol in 2020 [82]. Moreover, carboxylic acids contributed another set of applicable ring-opening nucleophiles as independently examined by Gu’s [83] and Zhang’s [84] groups. Similarly, a wide spectrum of highly enantioenriched axially chiral biaryls bearing diversified functional groups could be assembled under mild and scalable conditions. In Gu’s work, seven-membered lactone-bridged biaryl atropisomers containing both axial and point chirality were yielded by a sequential palladium-catalyzed diastereoselective cyclization. This strategy was then advanced to include diarylphosphine oxides, producing phosphorylated biaryl products 119 by utilizing TEMPO as the oxidant (Scheme 2.30d) [81]. Control experiments with 18O-labeled substrates demonstrated that this reaction proceeded via oxidation, followed by C─O bond formation. Products with high enantiopurities would rearrange to

(a) Gu and coworkers [77, 78]

(c) Gu and coworkers [79]

O RNH2 R2

NHR

114 or 115 (5 mol%)

R1

I

Na2CO3 (3.0 equiv)

113

N

2

R R1

I

EWG OR

RO

H N

R 1

R

IX

R2

EWG

Cu(CH3CN)PF6 (5 mol%)

O P Ar H R

112

Cu(OTf)2 (5 mol%)

X = OTf, PF6

117 (7.5 mol%) CaO (3.0 equiv)

116

O

SK

82 (7.5 mol%)

R2 R1

R

S I 118

O P O Ar R I

2

R

1 Cu(OTf)2 (5 mol%) R 82 (6 mol%) Na2CO3 (3.0 equiv) TEMPO (50 mol%)

119

(d) Gu and coworkers [81]

(b) Gu and coworkers [80]

tBu O

Cu

N Cu

tBu

N

115

O

N

N

tBu

O

Ph

O

117 N

N O

O

N

N N

N

Bn Bn

114

N

O

N

N

N

O

O

N

Bn Bn

O

82

N O

Ph

O tBu

Scheme 2.30  Asymmetric ring opening reactions of cyclic diaryliodoniums with various nucleophiles. (a) Amine as nucleophiles [77, 78], (b) O-alkylhydroxylamine as nucleophiles [79], (c) potassium thiolates as nucleophiles [80], (d) carboxylic acids as nucleophiles [81]. Source: (a, c) Zhao et al. [77], Xu et al. [78] and (b, d) Modified from Li et al. [79].

33

34

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

atropisomeric 2′-hydroxyl biaryl phosphine oxides without loss of stereochemical integrity in the presence of tBuLi or tBuMgCl·LiCl. Computational studies elucidated that this phosphine oxide transfer follows a concerted C─P bond formation and P─O bond dissociation event. In addition to cyclic diaryliodoniums, 9-aryl-9H-fluoren-9-ols 120 were also exploited by the Gu group for asymmetric ring-opening reaction. Unlike previously used copper-­ centered chiral complex, this reaction with aryl halides was conducted under the catalysis of palladium salt and TADDOL-embedded phosphoramidite ligand 121 (Scheme 2.31) [85]. The activity of 9-aryl-9H-fluoren-9-ols 120 was elevated considerably by the torsional strain originated from the steric repulsion between two ortho-substituents on biaryl skeleton. These findings may set up a new platform for the design of novel synthetic methods via asymmetric C─C bond cleavage.

Gu and coworkers [85]

R2

OH

R2

R1

+ Ar Br

X

[Pd] (2.5 mol%) 121 (15 mol%)

R2

NaH (3.0 equiv)

R2

Ar R1 O

120

122

O

X O

O

O

N X

X

Me

121, X = 4-PhC6H4

Scheme 2.31  Asymmetric ring-opening of 9-aryl-9H-fluoren-9-ols. Source: Modified from Deng et al. [85].

In the 1990s, “lactone strategy” developed by Bringmann’s group attracted enormous attention for stereoselective synthesis of optically active biaryl atropisomers [86–88]. The rapid equilibrium of configurationally labile biaryl lactones opened the avenue for DKR. However, this strategy was initially restricted by the routine necessity of stoichiometric amounts of chiral nucleophiles. In 2008, Yamada and coworkers developed the catalytic atropo-enantioselective borohydride reduction to synthesize biaryl structures 124 through DKR of Bringmann’s lactones 123 with an optically pure cobalt(II) complex 125 (Scheme 2.32a) [89]. Chiral high-performance liquid chromatography (HPLC) analysis of the starting biaryl lactones was monitored at various temperatures to determine suitable conditions for DKR. In 2018, Zhang and coworkers developed a facile and column-free synthetic route toward a structurally unique oxa-spirocyclic diphenol O-1,1′-spirobiindane-7,7′-diol (SPINOL). By virtue of chiral tridentate O-SpiroPAP ligand 126, derived from enantiopure O-SPINOL, a highly efficient iridium-catalyzed asymmetric hydrogenation of bridged biaryl lactones under mild conditions was realized (Scheme 2.32b) [90]. The desired axially chiral molecules were gained in excellent yields and enantioselectivities (up to 99% yield and >99% ee). This method represents a rare example of constructing axially chiral molecules by direct reduction of esters with molecular hydrogen.

2.4  ­Formation of Aromatic Ring via [2  +  2  +  2] Cycloadditio (a) Yamada and coworkers [89] 125 (5 mol%), NaBH4 (3.0 equiv), EtOH (3.0 equiv) 1-(2-pyridinyl)ethanol (42 equiv)

R1

R1

O O

126 (1 mol%), H2 (50 atm) [Ir(COD)Cl]2 (1 mol%), K2CO3 (5 mol%)

R2 123

Ar

Ar

O

N

N O

OH R2 124

(b) Zhang and coworkers [90]

O

OH

Co 125

O

O

O

N N H P(DTB)2 126

Scheme 2.32  Asymmetric reduction with dynamic kinetic resolution of biaryl lactones. (a) Yamada’s work, (b) Zhang’s work. Source: (a) Modified from Ashizawa et al. [89] and (b) Modified from Chen et al. [90].

2.4 ­Formation of Aromatic Ring via [2 + 2 + 2] Cycloaddition Transition metal-catalyzed [2 + 2 + 2] cycloaddition has proven to be an efficient and straightforward method for the synthesis of axially chiral compounds [91–93]. Such a strategy allows the construction of an aromatic ring with concomitant generation of a stereogenic axis, which stands as a sound alternative to classical C–C coupling reactions. The racemic [2 + 2 + 2] cycloaddition reactions have been well studied; the asymmetric variants were independently reported in 2004 by three different research groups employing chiral cobalt, iridium, or rhodium complex as the catalyst. These pioneering contributions paved the way for further developments as well as establishment of other efficient approaches.

2.4.1  Cobalt-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions Cobalt was the first catalyst applied in enantioselective [2 + 2 + 2] cycloadditions. The tedious synthesis of ligand and the scarcity of available ligand significantly hindered its widespread applications. The utilization of cobalt complex was exemplified by Heller and coworkers in 2004, presenting the first asymmetric version of [2 + 2 + 2] cycloaddition to generate axially chiral heterobiaryls [94]. Three years later, the same group implemented this strategy in the synthesis of axially chiral biaryls bearing phosphorus functionality via asymmetric cross-cyclotrimerization of phosphine oxides 127 with 2 equiv of acetylene under photochemical conditions (Scheme 2.33) [95]. The desired products 128 were gained in moderate to good yields and enantioselectivities with chiral cobalt complex 129. Recrystallization improved the

35

36

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers Heller et al. [95] O

P

R R 129 (1–5 mol%)

+ O

THF, hv (λ = 420 nm)

O R P R O

Co(COD) 129

127

128

Scheme 2.33  Co-catalyzed enantioselective [2 + 2 + 2] cycloadditions. Source: Based on Heller et al. [95].

ee to >99% and the reduction of the recrystallized products could afford a series of enantiopure P,O-ligands.

2.4.2  Rhodium-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions Rhodium has been established as the privileged metal for asymmetric [2 + 2 + 2] cycloadditions because of the availability and tunability of chiral rhodium catalysts. Most examples made use of cationic rhodium(I) complexes associated with a chiral diphosphine ligand that embodied biaryl or binaphthyl backbone. In 2004, shortly after the first report on cobalt catalyst, Tanaka et  al. developed the synthesis of axially chiral phthalides 132 by cross alkyne cyclotrimerization of electron-deficient 1,6-diynes 130 and terminal monoynes 131 in the presence of [Rh(cod)2][BF4] and (S)-H8-BINAP (Scheme 2.34a) [96]. The regioselectivity control was difficult with at least 10% of by-product being formed. For symmetric 1,4-diacetoxy-2-butyne or 2-butyne-1,4-diol 134, moderate yields and excellent enantioselectivities were obtained. One year later, highly substituted biaryls 138 with remarkable enantiopurities were acquired in good efficiencies via intermolecular cyclotrimerization of asymmetric internal alkynes 137 with 2 equiv of dialkyl acetylenedicarboxylates 136 under the same catalytic system (Scheme 2.34b) [97]. Successively, the same group implemented this approach and catalytic system in the synthesis of structurally diversified biaryl molecules from 1,6-diynes, such as biaryl hydroxy phosphorus compounds [98], biaryl hydroxy carboxylic acid derivatives [99], and biaryl diphosphonates or dicarboxylates [100]. Furthermore, the construction of axially chiral biaryls via the formation of two aromatic rings was achieved by stepwise double intermolecular [2 + 2 + 2] cycloaddition of ether-linked tetraynes and electron-deficient monoynes [101]. Subsequently, the intramolecular variant of this type of reactions was established by the groups of Tanaka and coworkers [102] and Shibata [103] with hexayne compounds as the starting materials. Notably, highly enantioenriched 1,4-teraryls with two chiral axes have been accessed by Tanaka’s group in 2007, albeit in low diastereoselectivity [104].

2.4.3  Iridium-Catalyzed Enantioselective [2 + 2 + 2] Cycloadditions Aside from cobalt- and rhodium-centered catalytic system, iridium catalysts competently promoted the [2 + 2 + 2] cyclotrimerization as well. The pioneering work from the

2.4  ­Formation of Aromatic Ring via [2  +  2  +  2] Cycloadditio (a) Tanaka et al. [96]

OR H

131

up to 91% 132/133: up to 90/10

O O

(S)-H8-BINAP (5 mol%) [Rh(cod)2]BF4 (5 mol%)

X

up to 73% up to >99% ee

130

RO

OR

O

OR

O

X

OR

O +

O

X

133

132, up to 87% ee OR OR

O O

PPh2 PPh2

X

134

(S)-H8-BINAP

135 (b) Tanaka et al. [97]

E +

136

E

R

E 137

X

E

E

(R)-H8-BINAP (5 mol%) [Rh(cod)2]BF4 (5 mol%)

E R

E

up to 89%, 96% ee

Me

E

138

Scheme 2.34  Rh-catalyzed enantioselective [2 + 2 + 2] cycloadditions. (a) Cross alkyne cyclotrimerization of electron-deficient 1,6-diynes and terminal monoynes, (b) intermolecular cyclotrimerization of asymmetric internal alkynes with dialkyl acetylenedicarboxylates. Source: (a) Modified from Tanaka et al. [96] and (b) Modified from Tanaka et al. [97].

Takeuchi group validated the catalytic aptitude of iridium catalysts in this reaction [105]. In 2004, Shibata and coworkers reported the first iridium-catalyzed cycloaddition of 1,6-diynes 139 and monoalkynes 140 in enantio- and diastereoselective fashion (Scheme 2.35) [106]. Axially chiral teraryls 141 were obtained under excellent stereocontrol with MeDuPhos 142 as a ligand. One year later, a series of helically chiral quinquearyl and noviaryl compounds were synthesized in extraordinary enantioselectivities by the same group [107]. Similarly, enantioselective intramolecular stepwise double [2 + 2 + 2] cycloaddition of hexaynes proceeded smoothly in the presence of [IrCl(cod)]2 and BINAPderived axially chiral ligand [108].

Shibata et al. [106]

OR +

Z

OR 139

140

[IrCl(cod)]2 (5 mol%) 142 (10 mol%)

P Z

up to >99.5% ee dl/meso >95 : 5 141

OR OR

P 142 (S,S)-MeDuphos

Scheme 2.35  Ir-catalyzed stereoselective [2 + 2 + 2] cycloadditions. Source: Based on Shibata et al. [106].

37

38

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

2.5 ­C─H Bond Functionalization 2.5.1  Chiral Catalyst-Controlled C─H Bond Functionalization Enantioselective C–H activation represents an effective and straightforward synthetic tool for asymmetric structural elaboration, providing novel disconnection(s) in retro-synthetic analysis of complex target chiral molecule. The rapid advance in transition metal-catalyzed enantioselective C–H activation along with the continuous exploitation of new chiral ligands and catalytic systems collectively create opportunities to acquire atropochiral structures rapidly, especially those with a biaryl framework [109]. The seminal work was reported in 2000 by Murai’s group for the synthesis of axially ­chiral naphthyl-pyridine and naphthyl-isoquinoline structures [110]. Despite a moderate 49% ee as the best result, this work offered a facile avenue to construct atropisomers with effective handles to coordinate with metal center. Following this line, the Yang group achieved a collection of biaryls 144 bearing phosphine and olefin moieties with high enantiocontrol (up to 96% ee) through DKR of racemic biaryls 143 in 2017 (Scheme 2.36) [111]. This Pd-catalyzed enantioselective C–H olefination proceeded smoothly with diphenylphosphine oxide as a directing group and Boc-l-Val-OH 145 as a chiral ligand. Yang and coworkers [111]

R2 R1

O PPh2 143

+

R

Pd(OAc)2 (5 mol%) 145 (10 mol%) AgOAc (3.0 equiv) up to 99%, 96% ee

R2

O PPh2

O R

R1 144

O

O

OH

N H

145, Boc-L-Val-OH

Scheme 2.36  Enantioselective C–H olefination with diphenylphosphine oxide as the directing group. Source: Based on Li et al. [111].

In 2019, Shi and coworkers successfully introduced a Pd(II)/STRIP catalytic system for palladium-catalyzed enantioselective C–H olefination leveraging the nitrogenous quinoline ring of 146 as a directing moiety. This strategy enabled highly atroposelective synthesis of various aryl-quinoline atropisomers 147. The adoption of bulky chiral phosphoric acid (CPA) 148 with a SPINOL backbone was essential for enantiocontrol and the phosphate served as a counterion to stabilize the active palladium species (Scheme  2.37a) [112]. Following investigations validated that free amine could also function as a competent directing group for this type of reaction under similar catalytic conditions (Scheme 2.37b) [113]. Notably, the loading of ligand 151 could be reduced to 1 mol% without erosion of enantiocontrol in gram-scale synthesis. The intact amine group was an efficient handle for downstream functionalization to access other valuable biaryl atropisomers. Since Yu’s path-pointing disclosure, transient directing group-assisted C–H activation has emerged as an efficient strategy to functionalize C─H bond selectively without the need to install and remove directing group [114, 115]. In 2017, this strategy was successfully applied by the Shi group in the DKR of racemic biaryls 152 with an aldehyde at C2-position [116]. The C–H olefination products 153 were furnished in remarkable enantiopurities utilizing tert-leucine as transient chiral auxiliary (Scheme 2.38a). It should be

2.5 ­C─H Bond Functionalization (a) Shi and coworkers [112] Pd(OAc)2 (10 mol%) 148 (20 mol%)

R1 N

+

R

R2

R1 N R 148, Ar = 2,4,6-(iPr)3Ph

AgOAc (2.0 equiv) up to 99%, 98% ee

R2

146

Ar

147

O

R1 NH2

+

R

R2

P

O

(b) Shi and coworkers [113] Pd(OAc)2 (10 mol%) 151 (10 mol%)

O OH

Ar

R1

151, Ar = 3,5-(tBu)2Ph

NH2 R

Ag2CO3 (1.0 equiv) up to 91%, 97% ee

R2

149

150

Scheme 2.37  Pd-catalyzed enantioselective C–H olefination with nitrogen-containing directing group. (a) Quinoline as directing group, (b) free amine as directing group. Source: (a) Based on Luo et al. [112] and (b) Based on Zhan et al. [113].

noted that KR would instead be in operation for biaryl substrates with conformationally stable chiral axis. Imine formation by condensation of chiral amino acid and aldehyde was proposed to be an initiation step. Owing to steric factors, one of the imine diastereomers would preferentially undergo C–H palladation to afford an axially stereo-enriched biaryl palladacycle intermediate 154. The utility of this method was demonstrated by the asymmetric total synthesis of TAN-1085 [120]. Subsequent evaluation of this strategy has established halogenated alkynes as another applicable coupling reagent to give alkynylated biaryl products 155 with excellent enantiopurities (Scheme 2.38b) [117]. Compared to C–H olefination, this transformation may proceed through a PdII/PdIV catalytic cycle as proposed. The gram-scale formal syntheses of (+)-isoschizandrin and (+)-steganone further demonstrated the utility of this approach. Palladium-catalyzed atroposelective C–H R1

R1 CHO R2

H

[Pd ], L-tert-leucine

+

CHO

N Pd O 154

R2

152

(a) Shi and coworkers [116]

(b) Shi and coworkers [117] R1

R1 CHO

(c) Shi and coworkers [118]

(d) Shi and coworkers [119]

R1

R1

CHO SiR3

2-Nap R2

153

O

CHO

CHO

R R2

R

R2 155

156

R

R2 157

Scheme 2.38  Enantioselective C–H functionalization of racemic biaryl aldehydes with transient directing group. (a) C–H olefination, (b) C–H alkynylation, (c) C–H allylation, (d) C–H naphthylation. Source: (a) Modified from Yao et al. [116], (b) Based on Liao et al. [117], (c) Based on Liao et al. [118] and (d) Source: Modified from Liao et al. [119].

39

40

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

allylation (Scheme  2.38c) [118] and naphthylation (Scheme  2.38d) [119] reactions were developed by the same group successively. Because axially chiral aldehydes represent potential organocatalysts [121, 122], the chartered pathways to these structurally diversified biaryl atropisomers containing aldehyde will in turn be particularly advantageous for the development of asymmetric organocatalysis.

2.5.2  Chiral Auxiliary-Induced C─H Bond Functionalization Aside from chiral catalyst-controlled strategy, enantioenriched biaryls could also be accessed through diastereoselective C–H functionalization under the guidance of chiral auxiliary. In 2013, Colobert and coworkers reported the first palladium(II)-catalyzed oxidative Heck-type olefination of biaryls 158 with sulfoxide as both directing group and chiral auxiliary (Scheme  2.39a) [123]. Notably, the atropo-enantioenriched biaryls 158 would racemize at coupling temperature and the axial chirality of products 159 was controlled by stereochemistry of S-chiral sulfoxide. However, only poor to moderate diastereoselectivities were observed for most examples. One year later, Wencel-Delord and Colobert extended this strategy to atroposelective C–H acetoxylation and iodination with enhanced diastereoselectivities through DKR directed by the same auxiliary (Scheme 2.39b) [124]. In 2018, this group achieved the synthesis of chiral terphenyl scaffolds 162 containing two chiral axes via Pd-catalyzed atroposelective C–H arylation with aryl iodides (Scheme 2.39c) [125]. Both chiral axes were set with excellent stereoselectivity in a single transformation. Apart from S-chiral auxiliary, P-chiral auxiliary was also utilized to synthesize axially chiral biaryl phosphinate ligands by Yang and coworkers in 2015 [126]. R1

S R2

R2

159

[Pd], conditions

+

O S

pTol

R2 (b) Wencel-Delord/Colobert and coworkers [124] R1

O S

pTol

158

(a) Colobert and coworkers [123] R1

R1

O

O

R1

S pTol OAc

pTol CO2Me R2

160

(c) Colobert and coworkers [125] O

R1

S pTol X (Cl/Br) R2

161

R3 S*OpTol R2

162

Scheme 2.39  Atroposelective C–H functionalization using an enantiopure sulfoxide as the directing group and chiral auxiliary. (a) C–H olefination, (b) C–H acetoxylation and halogenation, (c) C–H arylation. Source: (a) Based on Wesch et al. [123], (b) Based on Hazra et al. [124] and (c) Based on Dherbassy et al. [125].

2.5.3  Atroposelective C─H Arylation In 2018, Cramer and coworkers reported the enantioselective assembly of axially chiral dibenzazepinones 164 featuring a biaryl framework from amide-tethered multiaromatic ring compounds 163. This Pd(0)-catalyzed atroposelective intramolecular C–H arylation

2.5 ­C─H Bond Functionalization Cramer and coworkers [127] R2

R2

Ph Ph O P N O O O

Pd(dba)2 (10 mol%), 165 (20 mol%)

Br

R R

N

Ph2MeCCO2H (30 mol%) K2CO3 (1.5 equiv) up to 96%, 96% ee

R1 163

N 164 R

1

R R

Ph Ph 165

O

Scheme 2.40  Intramolecular atroposelective C–H arylation. Source: Based on Newton et al. [127].

was enabled by the use of TADDOL-based phosphoramidite ligand 165 (Scheme  2.40) [127]. Catalytic amount of acid additive was essential for attaining excellent efficiency and enantioselectivity. Utilization of diazonaphthoquinones 166 as the arylation reagents were disclosed by Waldmann, Antonchick, and coworkers in 2017 (Scheme 2.41a) [128]. The arylation could proceed at mild conditions with benzamides 167 as coupling partners in the presence of chiral rhodium complex 169, affording a broad range of atropisomeric biaryls 168 in 37–93% yields and 79–91% ee values. In the following year, these arylation reagents were employed by the Cramer group for enantioselective coupling with aryl phosphine oxides (Scheme 2.41b) [129]. Differently, this reaction was catalyzed by an iridium(III) complex bearing an atropochiral cyclopentadienyl (Cpx) ligand 172 with phthaloyl tert-leucine 173 as a cocatalyst. This method allowed access to a series of axial and P-chiral compounds 171 (a) Waldmann/Antonchick and coworkers [128]

NH

O 1

R

H

4-Br-C6H4

N H

OMe

N2 +

O

R2 CO2Me

166

167

CO2Me

Rh 4-F-C6H4 169 (5 mol%) (BzO)2 (5 mol%) Dioxane, r.t., 48 h up to 93%, 91% ee

R1 CONHOMe OH R2 168

CO2Me

(b) Cramer and coworkers [129]

Ar N2

O R

O P

172 (3 mol%) AgSbF6 (12 mol%)

R1

Ar 170

167 MeO

OMe

173 (15 mol%) up to 98%, 98% ee, >20 : 1 dr

R

171

R O 172 (3 mol%) P Ar AgSbF6 (12 mol%) Ar MeO 173 (15 mol%) 174 up to 95%, 92% ee

OH O P Ar Ar R1

OMe

I OMe OH O P Ar Ar

tBu

Ir

I 2

172

CO2H

NPhth 173, Phthaloyl tert-leucine

OMe 175

Scheme 2.41  Atroposelective C–H arylation with diazonaphthoquinones. (a) Waldmann and Antonchick’s work, (b) Cramer’s work. Source: (a) Modified from Jia et al. [128] and (b) Modified from Jang et al. [129].

41

42

2  Metal-Catalyzed Asymmetric Synthesis of Biaryl Atropisomers

in high yields, diastereo- and enantioselectivities. When 3,5-dimethoxy-substituted substrates 174 were utilized, axial chiral MOP-type phosphine oxides 175 were furnished where the C(aryl)─H bond of 3,5-dimethoxyphenyl ring was exclusively activated.

2.6 ­Summary and Conclusions After several decades of research efforts, transition metal-catalyzed asymmetric reactions have now become methods of choice to access various chiral molecules in efficiency and brevity. This chapter has summarized the recent advances in the synthesis of biaryl atropisomers via several strategies with the aid of transition metal catalysts. We hope that this chapter will provide some insights into contemporaneous achievements in this thriving research area and inspires the design of novel synthetic approaches toward this class of highly important compounds with high optical purity and efficiency.

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3 Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Shaoyu Li, Shao-Hua Xiang, and Bin Tan Southern University of Science and Technology Shenzhen, Department of Chemistry, No.1088, Xueyuan Rd., Nanshan District, Shenzhen, 518055, China

3.1 ­Introduction Since its inception in the late 1990s [1, 2], organocatalysis has garnered widespread interest in the synthetic community because of the practical advantages including operational simplicity, catalyst stability, and high functional group tolerance. After nearly a decade of development, organocatalysis has become one of the most powerful tools for the asymmet­ ric construction of axially chiral biaryl frameworks [3]. In this chapter, significant advances in organocatalytic asymmetric synthesis of biaryl atropisomers will be elaborated. Descriptions will be categorized into four sections according to construction strategies, which include (dynamic) kinetic resolution (KR), desymmetrization, arene formation, and direct arylation.

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strategy 3.2.1  Conventional Kinetic Resolution The realization of KR hinges on unequal reaction rates of a pair of enantiomers in a ­particular asymmetric catalytic system. The efficiency of this process is measured by ­selectivity factor(s), which reflects the energy disparity between the diastereomeric transition states in the selectivity‐determining step. An inherent yield limit (50%) notwithstanding its value is particularly appreciated as it gives access to highly stereoenriched compounds, especially when direct catalytic asymmetric synthesis is difficult or elusive. Considerable achievements have thus been made in obtaining axially chiral biaryls via organocatalyzed KR process with the development of various catalytic systems (Scheme 3.1).

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

48

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers

G R2

R R1

Organocatalyst

G R2

R R1

+

R R1

R2

Scheme 3.1  Kinetic resolution of biaryl atropisomers.

3.2.1.1  Kinetic Resolution via Asymmetric Alkylation

Asymmetric alkylation is an effective synthetic operation to perform dynamic resolution of atropisomers that contain amino or hydroxyl groups. By virtue of the ion pair interaction that could be established between the catalyst and the amino group, the phase transfer catalytic system stands out in providing effective chiral recognition of axially chiral amino compounds. In 2013, Maruoka and coworkers reported the first phase‐transfer‐catalyzed N‐allylation reaction for the KR of axially chiral 2‐amino‐1,1′‐biaryls (Scheme 3.2) [4]. The biaryl substrates were resolved with good to high selectivities in the presence of only 2 mol% of chiral quaternary ammonium salt 3 and the selectivity factor could reach up to 43. As the most important example, 2‐amino‐2′‐hydroxy‐1,1′‐binaphthyls (NOBIN)‐derivative 2a was obtained in 53% yield and 81% ee, whereas 43% of the unreacted 1 was recovered with 93% ee. Additionally, without any loss of enantiomeric purity, the removal of protecting group on the recovered optically active 1 and allylation products 2a could be readily achieved, thereby delivering the privileged axially chiral NOBIN. Maruoka and coworkers [4] I

R

N SO2Ph 3 (2 mol%) H Y KOH, toluene, 0 °C s up to 43

R

R N SO2Ph Y

2 (up to 86% ee)

(rac)-1 N SO2Ph H OMe 1a, 43%, 93% ee 2a, 53%, 81% ee s = 32

MeO

N SO2Ph H OMe

1b, 45%, 94% ee 2b, 53%, 85% ee s = 43

N SO2Ph H Y

+

1 (up to 97% ee) Ar

– Br

+ N

Ar 3, Ar = 3,5-[3,5-(CF3)2C6H3]2C6H3

Scheme 3.2  Kinetic resolution of 2-amino-1,10-biaryls via PTC-induced N-allylation. Source: Based on Shirakawa et al. [4].

Considering the great utility of NOBIN in asymmetric catalysis, a highly practical and scalable organocatalytic N‐alkylative KR to access enantiopure NOBIN analogs has been accomplished by Zhao and coworkers recently [5]. The implemented catalytic system for N‐alkylation comprised a commercially available (dihydroquinidine [DHDQ])2 anth­ raquinone (AQN) catalyst and an Morita–Baylis–Hillman (MBH) carbonate reagent.

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strateg

Substrates bearing differently substituted aromatic rings were transformed smoothly to afford the alkylation products with good to high enantioselectivity, while unreacted mate­ rials were recovered in excellent enantiopurity (95–99% ee). The gram‐scale resolution of (rac)‐4d was carried out using a reduced catalyst loading (10 mol%) and gave rise to enan­ tiopure 4d in 35% yield with 99% ee. Investigation on the recovery and reuse of the catalyst revealed that by using 20 mol% of the recovered catalyst, the transformation could proceed with preserved efficiency and enantioselectivity, further highlighting the practicality of this catalytic system (Scheme 3.3). Zhao and coworkers [5] O R1

BocO

NHR OH

OtBu (0.8 equiv)

N R OH

NHR + OH

(DHQD)2AQN (20 mol%)

CH2Cl2:MeCN (1 : 1), air, 24 °C, 24 h s up to 30

R: Ms, Ts (rac)-4

4 up to 99% ee

5 up to 83% ee Me

MeO

MeO

NHTs OH

NHTs OH

NHTs OH MeO2C

4a: 38%, 98% ee 5a: 52%, 71% ee

4b: 38%, 99% ee 5b: 53%, 68% ee

Me BocO Me

NHMs OH Br

NHMs OH

Br 4d: 40%, 99% ee 5d: 54%, 73% ee

4c: 39%, 97% ee 5c: 52%, 73% ee

Me

MeO

MeO

Me

NHMs Me + OH

CO2tBu

OtBu (0.8 equiv)

(DHQD)2AQN (10 mol%)

CH2Cl2:MeCN (1 : 1), air, 24 °C, 96 h

(rac)-4d 1.2 g

(rac)-4d

Me

Me

O

MeO

CO2tBu

R1

R1

Recovered (DHQD)2AQN (20 mol%) 58% conv., s = 29

Br 5d 60%, 60% ee

Br 4d 35%, 99% ee 4d 38%, 99% ee

NMs OH

+

5d 52%, 70% ee

Scheme 3.3  Chiral amine-catalyzed KR in N-allylation of biaryl amino alcohol. Source: Based on Lu et al. [5].

The reductive amination of imines formed from the condensation of amines and a­ ldehydes offers a strategic alternative to N‐alkylation chemistry, which could exhibit bet­ ter chemical selectivity, especially for the alkylation of primary amines. Based on this indi­ rect alkylation strategy, in 2014, Tan, Liu, and coworkers have described a highly enantioselective KR of 2,2′‐diamino‐1,1′‐binaphthalenes (BINAMs) through a cascade of chiral Brønsted acid‐catalyzed imine formation and asymmetric transfer hydrogenation process using Hantzsch ester as the hydride source (Scheme  3.4) [6]. This KR showed ­excellent compatibility with different types of N‐protecting groups (sulfonyl, aroyl, ­2‐naphthylmethyl, Fmoc, and amido) and functional groups (Br, Cl, and TMS) at the

49

50

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Tan and coworkers [6] Ar2CHO (0.6 equiv) NHSO2Ar1 8 (10 mol%), 9 (0.7 equiv) NH2 EtOAc, r.t., 48–60 h s up to 340 Ar2= 2-naphthyl

(rac)-6 Ar1= 2-naphthyl

Ar O O

O P

O OH

Ar 8, Ar = 2-naphthyl

O

RO

OR

NHSO2Ar1 + NHCH2Ar2 (S)-7 43%, 97% ee

NHSO2Ar1 NH2 (R)-6 44%, 98% ee

(1) Ti(OiPr)4, TMSCl, Mg (2) Pd/C, H2

NH2 NH2

N H 9, R = allyl

(S)-BINAM 50%, 97% ee

Scheme 3.4  KR of BINAM derivatives through asymmetric reductive amination. Source: Based on Cheng et al. [6].

6‐ and/or 6′‐positions of (rac)‐6. A variety of rac‐BINAM derivatives were transformed into their enantioenriched derivatives (S)‐7 possessing modest to excellent enantiomeric excess (ee), while unmodified substrates could also be recovered in excellent optical purities (s  =  7 ~ 340). Notably, reaction of 2‐naphthaldehyde provided the best stereochemical ­outcomes considering the level of stereoenrichment observed in both functionalized ­product 7 and recovered starting material 6, which could point to the occurrence of ­aromatic ­stacking interaction during transfer hydrogenation step. The ­control experiments indicated that the formation of imine is not stereodetermining, but the cooperation of Hantzsch ester and phosphoric acid for transfer hydrogenation should play a vital role ­during the KR ­process. Furthermore, the bulky protecting groups of the resulting optically pure transfer hydrogenation product (S)‐7 and recovered starting material (R)‐6 could be facilely removed to reveal (S)‐BINAM and (R)‐BINAM without erosion of ee, thus corrobo­ rating the significance and utility of the methodology. Atroposelective alkylation of hydroxyl functionality was exemplified in Smith’s work in which mono‐protected C2‐ and non‐C2‐symmetric 1,1′‐biaryl‐2,2′‐diols (BINOLs) were resolved via chiral ammonium counterion‐mediated benzylation reaction (Scheme 3.5) [7]. The diastereoisomeric BINOLate ammonium salts (A, B) will be benzylated at different rates and the consumed species could be supplied through rapid reversible protonation/ deprotonation of the enantiomer. In the stereodetermining transition state, H‐bond inter­ actions connecting the BINOLate anion with α‐C–H of ammonium salt and secondary alcohol, as well as between benzylic C–H of electrophile and methyl ether, have been established. 3.2.1.2  Kinetic Resolution via Asymmetric Acylation

The prototypical alcohol acylation reaction could be leveraged in resolution of hydroxyl group(s)‐bearing atropisomeric biaryl compounds. In 2014, the group of Sibi designed fluxionally chiral 4‐dimethylaminopyridne (DMAP) catalyst 14, which was used as an effective chiral inductor to promote KR of racemic BINOL scaffolds 10 with isobutyric anhydride as the acylation reagent (Scheme  3.6) [8]. The envisioned resolution was

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strateg Smith et al. (2019)

OTs

Ar2 Ph

R1

R4N , BnOTs

OR3

fast

O R2

+

–

+

N 1

Ar

H

O Et H

H

H ‒O

OMe

Hydrolysis

H

A +

R4N

base

6

R1

6

2

7

OH OR3 2'

2

R

6'

BnOTs 12 (10 mol%) K2CO3 (aq.)

R1

+

OBn

+

OR3

Benzene : Et2O r.t., 20–48 h s up to 46

2

OR3 2

R

R

11

10

(rac)-10 R4N

R1 OH

Et

base

OH

Br N

R1 O

+

N

R4N , BnOTs, slow

–

H

OR3 +

2

R

12: R4N Br

B

–

+

–

F

F F Ph

Ph Ph

OH OMe

OH

OH

OH

OMe

OMe

OMe

Ph 10a, 40%, 98% ee 11a, 50%, 74% ee

10b, 47%, 90% ee 11b, 45%, 86% ee

Ph 10c, 37%, 90% ee 11c, 49%, 62% ee

Ph 10d, 33%, 98% ee 11d, 60%, 62% ee

Scheme 3.5  KR of BINOLs through asymmetric O-benzylation. Source: Based on Jones et al. [7].

Sibi and coworkers [8] O OR OH

(rac)-10

O O

OR

2,6-tert-Butylpyridine (0.6 equiv) 14 (15 mol%), CH2Cl2, –50 °C s up to 51 O tBu NMe2 N N

14

OH

OR

+

iPr

O O

10

13

N

Scheme 3.6  Chiral DMAP-catalyzed KR of BINOL derivatives. Source: Based on Ma et al. [8].

51

52

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers

achieved with moderate to high selectivity factor ranging from 10 to 51. Analysis of experimental results and single crystal structure of the catalyst have shown that the ­stereoselectivity of the resolution process was strongly influenced by the steric bulk of the β‐OR‐substituent. In Smith’s report, atroposelective acylation/KR of unprotected BINOL derivatives 15 was performed at gram scale to achieve a selectivity factor up to 190 using only 1 mol% of iso­ thiourea organocatalyst (R)‐BTM and unsymmetrical 2,2‐diphenylacetic pivalic anhydride 16 to prevent di‐acylation (Scheme 3.7) [9]. This chemistry was applicable on symmetrical binaphthyl diols, biphenyl diols, and biaryl amino alcohol, suggesting that the presence of two hydrogen bond donors was necessitated. As C3‐substitution was not tolerated, this feature was ingeniously used to achieve regioselective acylation of unsymmetric BINOLs. This set of conditions also enabled the resolution of N‐Boc protected NOBIN (rac)‐15b. Reasoning of experimental observations has been enclosed: the two hydrogen bond donors on substrates could aid stabilization of TS‐1, but the presence of 3‐ and 3′‐substituents could impose steric clash with the acyl group of the catalyst. Smith and coworkers [9] tBu

R1 OH + X

O O O Ph

R2

Ph

(R)-BTM (1 mol%) iPr2NEt (0.6 equiv) CHCl3, r.t., 18 h s up to 190

R1 OH + X R2

OH OH

15a, 46%, 90% ee 17a, 49%, 88% ee

X

15

OH NHBoc

15b, 48%, 72% ee 17b, 31%, 78% ee

Ph

Ph

17

HO

N N

Ph

O R2

16 (0.55 equiv)

(rac)-15

O

R1

S

(R)-BTM

R

O HO N O H Ph N + S TS-1 R O

Scheme 3.7  Isothiourea-catalyzed KR in acylation of BINOLs. Source: Modified from Qu et al. [9].

The polarity reversal strategy of aldehydes induced by N‐heterocyclic carbene (NHC) provides a new avenue toward acylation transformations. Zhao and coworkers applied the strategy for the first time for atroposelective acylative KR of BINOLs and protected NOBIN in 2014 (Scheme 3.8) [10]. The substituent of the aldehyde played key role in determining the selectivity of this resolution process as it is directly incorporated into the chiral acyl azolium intermediate that has controlling influence on the enantioselec­ tivity outcome. Screening of aldehydes identified α‐benzyloxy aldehyde 18 to give the best result, and in contrary, various binaphthyl and biphenyl diols with different ­substitution patterns were well accommodated: all substrates were recovered in >99% ee. A selectivity factor of 34 was obtained for the KR of Boc‐protected NOBIN (15b). Further study found that an intramolecular H‐bond interaction between the two ­phenols (or with aniline) of the substrate presumably increases the nucleophilicity of

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strateg Zhao and coworkers [10] R1 OH X

20 (10 mol%) iPr2NEt (1.0 equiv)

O +

iPr

R2

H

4 Å MS, CH2Cl2, r.t. s up to 190

OBz

OH X

iPr

O

+

X R2

R2

18

(rac)-15

O

R1

R1

15

19

Br

Br

OH

OH

OH

OH

OH

NHBoc

OH

OH

N+ N R

O N ‒

BF4

Br 15a, 99% ee 19a, 82% ee

15b, 99% ee 19b, 74% ee

15c, 99% ee 19c, 81% ee

Br 15d, 99% ee 19d, 77% ee

20, R = mesityl

Scheme 3.8  NHC-catalyzed kinetic resolution of axially chiral biaryls. Source: Based on Lu et al. [10].

the substrate and/or helps to organize the substrate conformation, leading to a better enantioselectivity outcome. 3.2.1.3  Kinetic Resolution via Asymmetric Transfer Hydrogenation and Michael Addition

A highly efficient KR of axially chiral quinoline derivatives was accomplished by Zhou et  al. through asymmetric transfer hydrogenation of heteroaromatic moiety with Hantzsch ester as the hydrogen source (Scheme 3.9) [11]. The strategy suited the KR of racemic 5‐ or 8‐substituted quinolines, affording two kinds of axially chiral biaryls with a selectivity ­factor of up to 209. Notably, the selectivity factor for 5‐substituted quinolone products was inferior as the nitrogen became more distal to the stereogenic non‐C2 symmetry axis. Zhao and coworkers [11] nPr R1 R2

N

(rac)-21

H N

nPr

CO2Me R1 N HEH (1.2 equiv) R2 CPA 23 (5 mol%) CH2Cl2, 30 °C 21 s up to 209 up to 99% ee

MeO2C

Ph R1 2 + R

N H

22 up to 97% ee

O O

P

O OH

Ph CPA 23

Scheme 3.9  KR of quinolines via asymmetric transfer hydrogenation. Source: Based on Wang et al. [11].

Zhou et  al. demonstrated an efficient KR of axially chiral 2‐nitrovinyl biaryls 24 through an asymmetric Michael addition of acetone onto the nitroolefin moiety (Scheme  3.10) [12]. Diastereomeric Michael adducts 25 and the resolved nitroolefin ­substrate 24 were afforded in excellent optical purities under the catalysis of a chiral thiophosphinamide 26.

53

54

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Zhou and coworkers [12] R1 NO2

R2

Acetone 26 (10 mol%) PhCO2H (10 mol%)

Ph (rac)-24

NH2

NO2 +

R2

toluene, r.t. Ph S N P Ph H Ph 26

R1

R1

R1

NO2

NO2 2

R

+

Ac

(aR)- or (aS)-24 (aS,S)- or (aR,S)-25 up to 24%, >99% ee up to 50%, >99% ee

2

Ac

R

(aR,S)- or (aS,S)-25 up to 34%, >99% ee

Scheme 3.10  KR of 2-nitrovinyl biaryl via asymmetric Michael addition. Source: Based on Cui et al. [12].

3.2.2  Dynamic Kinetic Resolution Strategy Relative to the KR strategy, a distinctive characteristic of dynamic kinetic resolution (DKR) that renders this approach synthetically more rewarding is that both atropisomers of the substrate could be converted into a single chemically modified enantiomer as racemization of the starting material is allowed during the reaction process (Scheme 3.11).

R1 R2

G R3

R1 R2

Organocatalyst

R3

Scheme 3.11  Dynamic kinetic resolution of biaryl atropisomers.

3.2.2.1  DKR via Asymmetric Electrophilic Bromination

In 2010, Miller et  al. reported an innovative and successful access to axially chiral biaryls 28 through tripeptide‐catalyzed asymmetric bromination involving a DKR (Scheme  3.12) [13]. On introduction of ortho‐bromine substituents, the rotation of the axis would be impeded, enabling the isolation of single brominated enantiomers.

Miller and coworkers [13] N R CO2H

OH

27 Rotational barrier ≈ 7 kcal/mol

BocHN

iPr

O N H O

NMe2 O

NMe2 29 (10 mol%)

NBP (3.0 equiv) CHCl3/Acetone, 25 °C 65‒85%, 70‒94% ee

R CO2H Br

Br

Me2N iPr + Br H O H O N O N

OH Br 28

H BocHN

O

O

H +

H

O

N

Me Me Proposed docking model

Scheme 3.12  DKR in peptide-catalyzed electrophilic aromatic bromination. Source: Based on Gustafson et al. [13].

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strateg

A docking model was proposed on the basis of control experiments and the crystal structure of the major enantioenriched atropisomer. The stereochemical outcome and the configuration of atropochiral products could be rationalized from folding ­properties of the peptide, conformation of N‐acyl piperidines, and hydrogen bonds between the phenolic proton and the amide diacetate. On a similar note, in 2017, Matsubara and coworkers incorporated a simple quinidine‐ derived bifunctional catalyst 32 imbedded with amino and urea functionalities in atropose­ lective aromatic electrophilic halogenation reactions to access axially chiral 8‐arylquinolines (Scheme  3.13) [14]. This reaction was however distinguishable in that the stereogenic ­­­­aryl‐aryl axis would only be configurationally stable following halogenation at both ortho carbon centers (31a–c). The molecular conformation of mono‐halogenated intermediate could be preserved via hydrogen bond interactions with 32. This unique characteristic was exploited to form aryl‐quinoline atropisomers bearing two different halogen groups (31d and 31e) from ortho‐halogen‐substituted substrates. Matsubara and coworkers [14]

N

Ar

32 (10 mol%) NBA (3 equiv)

N

THF, 0 °C, 6 h

H

H

*

N N

H N

NR2 O H X

O

Br

32, Ar = 3,5-(CF3)2C6H3

31, 99%, 90% ee

4.1 kcal/mol Calculated rotational barriers

From mono-ortho-substituted substrates

N

N Br

Br

12.2 kcal/mol

I

Br

31c 37.7 kcal/mol

N Cl

Br

OH

OH

31d, 51%, 88% ee

Br 31e, 73%, 88% ee

OH

OH 31b

N

N Br

OH 11.0 kcal/mol

Ar

N

N

30

31a

H

OH

OH

Br

O HN

O

Br

Br

NH

I

Scheme 3.13  Atroposelective halogenation of 8-arylquinolines. Source: Based on Miyagi et al. [14].

The DKR of the more stable cyanonaphthalenes 33 via enantioselective bromination toward the atropisomerically enriched tribrominated cyanoarenes 34 was subsequently accomplished (Scheme  3.14) [15]. Authors have modulated reaction temperature and delivery mode of N‐bromoacetamide (NBA) to facilitate substantial racemization while impeding the first enantiodetermining bromination event. Probably, because of more efficient racemization, aliphatic substituents (34c and 34d) gave rise to better enantiose­ lectivity. Inclusion of only 1.5 equiv of NBA provided analogs 34a and 34a‐1 in high ee, lending credence to an enantio‐determining mono‐bromination process. Substantial amounts of mono‐brominated derivatives formed concurrently suggested that the enan­ tioselectivity could have also been compromised by the poor regioselectivity of the first bromination reaction.

55

56

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Matsubara and coworkers [15] OMe 35 (5 mol%), NBA

CN

CH2Cl2, ‒30 °C, 24 h R

R

OH

33

CN Br

Br

OH 34a

Br

OH

R

34a-1

Br 51.7 kcal/mol

NH N

Ar O 35, Ar = 3,5-(CF3)2-Ph

OH 34 Br

CN

CN Br

N

CN Br

Br

Br OH

34b, R: CF3, 84%, 15% ee 34c, R: Me, 83%, 73% ee 34d, R: iPr, 93%, 60% ee 34e, R: OMe, 99%, 19% ee

Br

38.9 kcal/mol

(a) 3 equiv NBA in 5 portions: 34a, 99%, 51% ee (b) 1.5 equiv NBA in 5 portions: 34a, 22%, 65% ee; 34a-1, 75% ee

Scheme 3.14  Atroposelective bromination of cyanoarenes. Source: Based on Wada et al. [15].

3.2.2.2  DKR via Asymmetric Nucleophilic Addition

Gustafson’s group described enlistment of a cinchona alkaloid 39 to catalyze addition of thiophenol 37 onto rapidly interconverting aryl‐naphthoquinones 36, resulting in stable biaryl atropisomers 38 upon reductive methylation (Scheme  3.15) [16]. Experiments revealed that the stereochemical stability and reactivity of atropisomers could be ­modulated by appropriate control of the redox properties of the quinone moiety. Sequential SNAr‐like reaction of the obtained biaryl sulfide was performed to arrive at 38c in 71% overall yield on gram scale with near‐complete enantioretention, albeit the involvement of low‐barrier quinone oxidation state.

Gustafson and coworkers [16]

R OMe

SH 37

O

Ar HN

(1) 39 (5 mol%), toluene, 4 °C, 44 h R1

(2) Na2S2O4 (aq), toluene, THF, MeOH TBAB, 0 °C, then KOH, Me2SO4 up to 99%, 97% ee

O 36

OMe

S

CF3 Me

(1) m-CPBA (2) CAN

O 38b

N

MeO

N R 39, Ar = 2,4,6-Me C H 3 6 2 OMe

O

OMe

OMe 38a 92%ee

S 38

R1

O H

(1) DBU, nPrSH CF3 SO2 (2) reductive methylation Me

CF3 SnPr

OMe 38c, gram scale 71%, 90% ee

Scheme 3.15  Asymmetric addition of thiophenols onto aryl-naphthoquinones. Source: Based on Maddox et al. [16].

3.2  ­Atroposelective Synthesis of Biaryls by Kinetic Resolution Strateg

3.2.2.3  DKR Based on Asymmetric Ring-Opening/Expansion Transformation

One characteristic manifestation of DKR strategy in preparing biaryl atropisomers is the atroposelective ring‐opening or ring expansion reactions of preformed five‐ or six‐­ membered‐ring fused biaryls. The original contribution of this strategy could be the ­“lactone concept” put forward by Bringmann featuring intramolecular coupling of ester‐ embedded scaffolds to give biaryl lactones and stereoselective ring cleavage to yield a single atropisomerically enriched ring‐opened product [17]. In early reports, the use of ­stoichiometric chiral nucleophiles was common to form single atropisomers of biaryl diols. Yamada and coworkers disclosed the chiral metal catalytic variants with NaBH4 as the reductant [18]. Wang and coworkers has conducted atroposelective transesterification of Bringmann’s lactone 40 by using a chiral bifunctional amine thiourea catalyst 43 (Scheme 3.16) [19]. Aside from benzyl and aliphatic alcohols, weakly nucleophilic phenols were amenable nucleophiles even though milder conditions were applied to prevent racemization of ­phenolic ester products (42d and 42e) via reversible lactonization (i.e. a lower temperature of −10 °C and shorter reaction time of one hour). The high efficiency and enantioselectiv­ ity of nucleophilic addition were set on the cooperative action of thiourea and amine ­entities to respectively activate the strained lactone ring and alcohol nucleophile, whereas excluding 2′‐OMe group (R3) (42f and 42g) negatively affected the reaction, introducing nucleophilic 1,3‐dibenzyloxyl‐2‐propanol with embedded oxygen that could provide ­binding site for enhanced enantio‐discrimination has remedied this issue (42h). Wang and coworkers [19] R1

1

R

O

+

O

R2

H Fast

PhCF3, r.t.

chiral linker O

O

O OH

2

Fast

R

Et Br

N 43, Ar = 3,5-(CF3)2C6H3

N H

N H O

O

OMe

chiral linker O

O

N

H

fast

(S)-Product

R OMe

OMe

mismatch

Et Br

Fast

Ar

S

S Ar

N

H

H N

MeO

R

O

H N

H

42, up to >99%, 99% ee

H O

N

OR

43 (5 mol%)

41

40 Abbreviated reaction concept S Ar N N

(R)-Product

ROH

match

EtBr

Representative products O Br

R'

O OH

OMe 42a, R′ = 4-NO2, 99%, 96% ee 42b, R′ = 2-NO2, 98%, 96% ee 42c, R′ = 4-MeO, >99%, 93% ee

O Br

Ar

O OH

OMe Reaction temperature: –10 °C 42d, Ar = Ph, 75%, 96% ee 42e, Ar = 4-MeS-Ph, 60%, 94% ee

O

Et

R

O OH

Br

2

R 2

42f, R = 4-NO2Bn, R = OMe, 97%, 97% ee 2 42g, R = 4-NO2Bn, R = H, 79%, 62% ee 42h, R = (BnOCH2)2CH, R2 = H, 84%, 96% ee

Scheme 3.16  Organocatalytic transesterification of Bringmann’s lactones. Source: Modified from Yu et al. [19].

57

58

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers

Besides lactones, Akiyama and coworkers envisioned that racemic biaryl lactols 44 could undergo atropodivergent reductive amination when treated with aromatic amines and Hantzsch ester under chiral phosphoric acid (CPA) catalysis (Scheme  3.17) [3c]. Using two regioisomers of hydroxyl anilines, biaryl adducts (51 and 52) with opposite configurations were produced in excellent yields and enantiomeric excesses. In addition to tri‐substituted biphenyl (51a/52a and 51d/52d) and phenyl‐naphthyl (51b/52b and 51c/52c) scaffolds, tetra‐substituted analogs could be gained, although slow addition of Hantzsch ester was required to accommodate sluggish racemization of imine intermedi­ ate. This chemistry showcased an efficient KR process in transfer hydrogenation of imine enantiomer. On top of that, equilibrium of enantiomeric imines takes place with a rate that is appropriately different from that of transfer hydrogenation. Akiyama and coworkers [3c]

OH

OH

H2N N

45 Ar1 NH2

Ar1

46

CF3

OH

OH

H2N

Ar2 NH2

CF3

N

Ar2

OH

O 44

CPA 47 Hantzsch ester 49

H N

5 Å MS, toluene r.t., 24 h

H N

Ar1

OH

OH

51

52

CPA 48 Hantzsch ester 50 Ar2

Representative products

Me

H N

*

H N

Ar

*

OH

51a, Ar1, 98%, 90% ee 52a, Ar2, >99%, 93% ee Ar N O

H

H N

Ar

*

OH

51b, Ar1, >99%, 94% ee 52b, Ar2, >99%, 94% ee

O

P

O

O*

plausible activation mode

O O

Cl

OH

51c, Ar1, 93%, 87% ee 52c, Ar2, 84%, 90% ee

Ar H O

Ar

O

O

OH

O

Ar 47, Ar = Si(3-F-C6H4)3

RO2C P

O OH

Ar 48, Ar = 9-anthryl

*

Ar

OH

51d, Ar1, 84%, 77% ee 52d, Ar2, 79%, 86% ee

Ar P

H N

CO2R

Me

N Me H Hantzsch ester 49 R = Et Hantzsch ester 50 R = iPr

Scheme 3.17  Stereodivergent synthesis through dynamic kinetic asymmetric transfer hydrogenation. Source: Modified from Mori et al. [3c].

Because of higher bond dissociation energy, atroposelective ring‐opening reaction through cleavage of carbon–carbon bond poses more challenge. In Yeung’s successful ­pursuit, racemic 4,5‐dimethylfluorene 53 could be transformed into atropochiral phenan­ threnes 54 containing point and axial chirality through semipinacol rearrangement (Scheme 3.18) [20]. As with previous cases, installing two ortho substituents next to the

3.3  ­Atroposelective Synthesis of Biaryls by Desymmetrization Strateg Yeung and coworkers [20] HO

(DHQD)2PHAL (20 mol%) (±)‒CSA (24 mol%) NBP (1.2 equiv)

R

R

O

Br

O NaN3, MsOH

Br

60 °C, 10 h

(CH2Cl)2/EtOH (50 : 1 v/v) ‒30 °C, 48 h rac-53

54

R = Ph, 4-Cl-Ph, 4-F-Ph

R

HN

55

up to 85% 72‒83%, 90 : 10‒94 : 6 er, >20 : 1 dr 95 : 5 er, >20 : 1 dr

Scheme 3.18  DKR-semipinacol rearrangement of dimethylfluorenes. Source: Modified from Liu et al. [20].

stereogenic axis enhances substrate’s reactivity and product’s stability: two methyl groups were indispensable to uphold product’s selectivity. To expand synthetic utility, Schmidt reaction was implemented to yield building blocks of γ‐secretase inhibitors, the dibenzol­ actams 55 were furnished with inverted configuration and retained optical purities.

3.3  ­Atroposelective Synthesis of Biaryls by Desymmetrization Strategy The asymmetric desymmetrization of meso‐ or prochiral precursors is a remarkably valu­ able transformation in organic synthesis, especially for the construction of axially chiral molecules, because it breaks the symmetry of the molecule without incorporating new stereogenic centers (Scheme 3.19).

G

G

R1

R2

Organocatalyst

G R1

R2

or

G

G

R1

R2

Scheme 3.19  Atroposelective desymmetrization of biaryl atropisomers.

In 2013, Akiyama and coworkers developed an enantioselective synthesis of multisubsti­ tuted biaryl derivatives by CPA‐catalyzed atroposelective bromination reaction (Scheme  3.20) [21]. The merger of two consecutive asymmetric transformations has improved the stereochemical outcome: CPA catalyzes the desymmetric bromination of a symmetric biphenol moiety and ensuing KR/secondary bromination reaction further rein­ forces the enantioselectivity. A range of substrates 56 could be employed; biphenyl deriva­ tives with electron‐donating and electron‐withdrawing groups as well as some arylnaphthalenes afforded the mono‐brominated biaryls 57 with excellent enantioselectivi­ ties. According to experimental and computational studies, the realization of high

59

60

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Akiyama and coworkers [21]

9-anthryl

Br HO

CPA 58 (10 mol %) NBP (1.1‒1.2 equiv)

OH 2

R

OR1

R

O HO

CH2Cl2/toluene, ‒20 °C

R2

76‒91%, 91‒99% ee

R

56

OH OR1

9-anthryl

58 57

Br HO

Br

OH

MeO

HO

OMe

O Br

OH

HO

57b, 82%, 92% ee

H

N

O

Br O O H O P O O O *

OH

OMe

57a, 88%, 97% ee

O P OH

O

OMe

O H

O

57c, 82%, 95% ee

Crucial H-bond

Scheme 3.20  Desymmetrization via CPA-catalyzed asymmetric bromination. Source: Modified from Mori et al. [21].

stereochemical control in the transformation was attributed to a highly organized ­hydrogen bond network established among the substrate, CPA, and the brominating reagent. Also through a cascade of desymmetrization and kinetic resolution steps, Wang’s group realized NHC‐catalyzed atropoenantioselective acylation of prochiral amino biphenols 59 to procure enantiopure biaryl amino‐alcohols 61 (Scheme 3.21a) [22]. The successive KR/second acylation improves the enantiopurity of major atropisomer 61 further, but primary enantioinduction occurs during the desymmetrization event. An analogous acylation transformation of phenols with NHC 64 catalyst was accomplished to access a wide range of NOBIN derivatives 63 in uniformly excellent enantioselectivity by Zhao’s group (Scheme  3.21b) [23]. Instead of aliphatic aldehydes, this protocol entailed the use of aldehyde 18, with which a broad scope of biaryl amino alcohol part­ ners was established. (a) Wang and coworkers [22]

HO

OH NHR2

O

+ R

R1

NHC 62 (10 mol%) K2CO3 (1.2 equiv) DQ (1.2 equiv) CH2Cl2, r.t., Ar, 12‒24 h

3

H

O

(1.5 equiv)

59

O

tBu

R3

DQ

tBu

O O

OH

N+ N Ar N

NHCbz

tBu

tBu

60

O

BF4

NHC 62

R1 61 up to 94%, >99% ee

‒

NO2 Ar = 2,4,6-(iPr)3-Ph

(b) Zhao and coworkers [23]

HO

OH NHR2

R

1

NHC 64 (20 mol%) DIPEA (2 equiv)

O +

iPr

H OBz 18

59

(2.5 equiv)

THF, 0 °C, 24 h up to 86%, >99% ee

O HO

O NHBoc

iBu

O

N+ N Mes N

‒

BF4

1

R

NHC 64 63

Br

Scheme 3.21  Desymmetrization in NHC-catalyzed O-acylation of biaryl amino alcohols. Source: (a) Modified from Yang et al. [22]. (b) Based on Lu et al. [23].

3.4  ­Atroposelective Arene Formation to Access Axially Chiral Biaryl

3.4  ­Atroposelective Arene Formation to Access Axially Chiral Biaryls This section discusses the organocatalytic assembly of biaryl atropisomers through a more divergent reaction design. In contrast to other strategies commencing from substrates with a preinstalled arene ring (with or without the biaryl linkage), these methods involve ­concomitant generation of chiral axis and de novo formation of one (or more) aromatic ring (Scheme 3.22). FG2 FG3 +

FG2 FG1

Organocatalyst

R1

Organocatalyst

R2

R1

R2

FG1 FG4 R1

R2

Scheme 3.22  Atroposelective arene formation.

3.4.1  Intramolecular Atroposelective Arene Formation The systematic studies of atroposelective arene‐forming aldol reaction have been con­ ducted by Sparr’s research group as inspired by biosynthesis of aromatic polyketide. Proline‐derived chiral amine catalyst 67 would react with the aldehyde moiety in unsatu­ rated ketoaldehydes 65 to generate dienamine; this thus promotes a stereoselective intra­ molecular aldol addition to the ketone functionality (Scheme 3.23) [24]. To arrive at chiral 1,1′‐binaphthalene‐2‐carbaldehyde 66, the final dehydration‐aromatization step takes place with very efficient central‐to‐axial chirality transfer. Link and Sparr [24]

CHO N

N H

R1

O

N 67 (5 mol%) R1 HN N

CHO

CHCl3, r.t. up to 89%, 98% ee

R2

R2

66

65

N

Hydrolysis Abbreviated reaction pathway

O

Dienamine

Enantioselective aldol addition

H

*

*

OH

N +

Central chirality intermediate

Dehydration/ aromatization

N

*

+

Axial chirality intermediate

Scheme 3.23  Atroposelective aldol condensation. Source: Modified from Link and Sparr [24].

61

62

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers

They examined this strategy in deriving well‐defined 1,2‐naphthylene oligomers. Through the use of l‐isoleucine, 1,2‐ternaphthalene carbaldehyde (aS)‐68 that displayed two chiral axes was forged enantioselectively in 71% yield and 95 : 5 er from ketoaldehyde 67 (Scheme  3.24) [25]. After installation of another organometallic building block, ­substrate‐controlled diastereoselective aldol condensation could be triggered toward ­atropodiastereoisomeric quaternaphthalenes (69, 70). Sparr and coworkers [25] Me O Et

OH

NH2 L-isoleucine (40 mol%)

O

21 : 79

H2O, DMF, r.t. CHO

67

*

*

OHC

* OHC (aS)-68 (1,2′aS:1′,2′′aS)-69 71% yield, 95 : 5 er

CHO

* (1,2′aR:1′,2′′aS)-70

Scheme 3.24  Stereoselective aldol condensation toward oligo-1,2-naphthylenes. Source: Based on Lotter et al. [25].

Another illustrative utility of this chemistry was in the preparation of enantioen­ riched tetra‐ortho‐substituted binaphthalenes 72. The aminoethanol‐derived proline‐ based catalyst 73 was deployed to initiate a cascade of two arene ring formation reactions of noncanonical hexacarbonyl substrates 71 (Scheme  3.25) [26]. A particularly note­ worthy product was a highly congested tetra‐ortho‐diperi‐atropisomer (72d) that was also formed in excellent er. This has been made viable with relieved acute nonbonding interaction in the C─C bond formation process; two sequential aldol additions happen before double‐dehydration steps. Sparr and coworkers [26] O

R1 CHO

O

OH

N H CHO

O

R2

O

O HN

73 (80 mol%) CDCl3, r.t.

CHO CHO R2

71

72

OH

F

OH

CHO CHO

F F

CHO CHO

OH

F

OH

72a, 82%, 95 : 5 er

OH

R1

72b, 82%, 95 : 5 er

OH CHO CHO OH Ph 72c, 60%, 91 : 9 er

OH F OH F F

CHO CHO OH

F 72d, 24%, 98 : 2 er

Scheme 3.25  Twofold arene-forming aldol condensation. Source: Based on Witzig et al. [26].

3.4  ­Atroposelective Arene Formation to Access Axially Chiral Biaryl

From an enantioselective intramolecular hydroarylation reaction, Irie and coworkers realized highly atroposelective synthesis of novel benzo[a]carbazoles 75 from alkyne– indole substrates (Scheme 3.26) [27]. Cinchonidine or cinchonine promotes stereoselective 1,5‐proton shift on alkyne to generate the Sa‐ or Ra‐vinylidene ortho‐quinone methides (VQM) intermediates that bear axial chirality to control the successive stereospecific intra­ molecular electrophilic aromatic substitution at the C3‐position of indole. The facile prepa­ ration of these axially chiral π‐conjugated molecular frameworks that possess attractive physical attributes would stimulate advancement of organic functional materials. Irie and coworkers [27]

(R)-75 could be obtained with cinchonine as catalyst

Cinchonidine (10 mol%) R N

CH2Cl2, r.t., 24 h 94–97%, 90–96% ee

HO R1

74

R N HO R1

(S)-75

Scheme 3.26  Hydroarylation to form axially chiral benzo[a]carbazoles. Source: Based on Arae et al. [27].

The synthetic versatility of VQMs species is further illustrated in Yan’s protocol, which facilitated the highly diastereo‐ and enantioselective synthesis of carbo[6]helicenes 77 containing helix and two remote chiral axes with the aid of squaramide catalyst 78 (Scheme 3.27) [28]. The transformation would commence with a tautomerization toward VQM intermediate A, whereupon phenol nucleophile attacks to give tetrahelicene‐like intermediate B. The chiral axis I in B was stable with a half‐life of 433 hours (at 110 °C in toluene). However, axis III could rotate and helix could invert because of the low barriers. Thus, intermediate B could undertake catalyst‐controlled cyclization through a VQM tau­ tomer to yield helical compound with second stable chiral axis being installed diastereose­ lectively. While 2‐ethynylnaphthols 76 that were symmetrical and nonsymmetrical underwent double‐cyclization reaction under exquisite control, two methoxy substituents were required to ensure transformation efficiency (77a–77c). Smith’s group devised O‐alkylation of olefin substituent directed by chiral quinidine‐ derived ammonium salt 82 to obtain chiral enol ethers 80 as well as C2‐symmetric and nonsymmetric BINOL derivatives 81 after dichlorodicyanobenzene (DDQ)‐mediated ­oxidation (Scheme  3.28) [29]. The enantiomeric potassium enolates of racemic 1‐aryl‐2‐ tetralone 77 equilibrates through rapid protonation and deprotonation. Counterion metath­ esis generates two soluble diastereoisomeric ion pairs, which undergo alkylation at different rates, resulting in atropo‐enantioenrichment.

3.4.2  Atroposelective Arene Formation via Intermolecular Annulation Innovatively in intermolecular setting, Tong and coworkers showcased phosphine‐ catalyzed atroposelective [4 + 2] annulation between δ‐acetoxy allenoates 83 and

63

64

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Yan and coworkers [28] R

R3

R3

N

OMe

2

H

R4

HN

N R1

R1

First tautomerization

* QN N H O

R1

OH

R3

R3

HO

R1

77, up to 96%, 99% ee, >20 : 1 dr Second cyclization

Abbreviated reaction pathway

O

R4

R2

H

ClCH2CH2Cl, 40 °C, 36 h

76

O

OMe NH N

O O 78 (10 mol%)

OH

OH

N

Second tautomerization

* N NQ H H

II

First cyclization

HO R OH RR R Intermediate B I, stable chiral axis

OH

R R R R VQM intermediate A

II, ΔG≠ helix inversion = 74 kJ/mol ≠ III, ΔG ring rotation = 59 kJ/mol Unsymmetrical substrates

Symmetrical substrates

HO R

R OH

RR

(P, 5aR, 12aR)-77a, R = OMe 95%, 99% ee, dr > 20 : 1

III

I

R OH

HO R

(P, 5aR, 12aR)-77b, R = OMe 45%, 99% ee, dr = 10 : 1

Ar

HO R R OH RR (P, 5aR, 12aR)-77c, R = OMe, Ar = 4-ClPh 81%, 99% ee, dr = 15 : 1

Scheme 3.27  Stereoselective assembly of carbo[6]helicenes via VQM intermediates. Source: Based on Jia et al. [28]. Smith and coworkers [29] R1 O OR3

82 (10 mol%) R1 BnI (3 equiv) K3PO4 (10 equiv) C6H6/CH2Cl2 0 °C, 48 h

R2

R1 OBn DDQ (3 equiv) OR3 CH Cl , r.t., 2 h 2 2

R2

79

80

OBn OR3

R2

81 up to 99%, 96% ee OMe

R1

+

‒ O NR*4

R1

O NR*4 OR3 ‒

OR3 2

R

R

2

HO

+

N

+

H Br‒

N 82

unfavor

favor

F

F F

Scheme 3.28  Atroposelective construction of BINOL derivatives via cascade O-benzylation/ oxidative aromatization. Source: Based on Jolliffe et al. [29].

2‐hydroxyquinones 84, from which aryl‐naphthaquinones 85 were generated in good atro­ poselectivities (Scheme 3.29) [30]. To induce pseudo‐intramolecular setting for the inter­ molecular cycloaddition, bifunctional catalyst 86 plays pivotal role by orientating

3.4  ­Atroposelective Arene Formation to Access Axially Chiral Biaryl Tong and coworkers [30]

H Me2N

R2 R1

O

H

AcO

OH + R3

R3

O

83

R1

O

Fe

86 (20 mol%)

Benzene, r.t., 72 h up to 87%, 99% ee

H

EtO2C

R2

Ph2P

O 85

84

CO2Et H2O

Abbreviated reaction pathway HOAc Br O

ΔG≠ rot = 35.1 kcal/mol

O OH

OH

2.29A

Br

Br H H 2.47 A

O O

+

PR3

H

O

CO2Et

A

86

H CO2Et O B-1 (minor)

H CO2Et O B-2 (major) OMe

H

Br H O O

N +

O

Br

O

CO2Et

O

Br

O

CO2Et

O

OMe

P

Ph Fe Ph CO2Et

O Bifunctional catalytic mode

85a, 63%, 90% ee

85b, 60%, 99% ee

O

CO2Et

85c, 67%, 94% ee

Scheme 3.29  [4 + 2] Annulation of δ-acetoxy allenoates and 2-hydroxyquinones. Source: Based on Chen et al. [30].

2‐hydroxyquinone through hydrogen bonds while the phosphine functionality reacts with allenoate reactant to form phosphonium diene. A with defined stereocenter gives rise to rotamers B‐1 and B‐2, which have rotationally hindered 2‐bromonaphthyl ring because of the neighboring carbonyl group. B‐2 could draw the higher stability on intramolecular hydrogen bonds and a minimal congestion between bromonaphthyl and hydroxy groups. Hence, the major atropisomer observed is yielded from B‐2 after AcOH‐mediated dehydration. Diversely with NHC catalysts, Zhu accomplished formal [4 + 2] cycloaddition of conju­ gated dienals 87 and α‐aryl ketones 88 (Scheme  3.30) [31]. This annulation chemistry evolves through sequential 1,6‐addition, aldol reaction, and lactone formation to reach enantioenriched bicyclic adduct III. To arrive at enantioenriched multisubstituted arenes 89, decarboxylation, and oxidation coupled with central‐to‐axial chirality transfer have ensued. This reaction system reliably enabled production of a pair of biaryl atropisomers (89f, ent‐89f) that bear ortho‐phenyl rings with minimal steric difference, simply through exchange of the aryl substituents on the two reacting partners. Other features that are wor­ thy of note include the implementation of electrochemical oxidation that could reduce the loadings of organic oxidant to 1 equiv as well as the elaboration capability of products. They were readily functionalized into urea/thiourea/carbonyl organocatalyst as well as oxalyl amide/phosphine ligand.

65

66

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Zhu and coworkers [31] R2

R5 +

OHC

R3

R1

O

87 R5

R3

NHC*

R1

DABCO (50 mol%) NMP/tBuOH, 60 °C

[O]

up to 95%, 98% ee

88

O N

4

R2

R4 R2

R3

1

R

CO2

89

Abbreviated reaction pathway

O

O

R4

R5

NHC 90 (20 mol%) DQ (3.5 equiv)

R

NHC* 1,6-Addition

R3

O

R

O HO R3

Aldol reaction

R1

tBu

DQ

5

HO

re face

O

tBu

NHC 90

O

tBu

tBu N N Mes + O ‒ Cl

3 O R

R5

R2

III

R4

R5 Lactonization

*NHC 1

R

I

R2 R4

R1

II

R2

4

R

NO2

Representative products Cl O 2N

N

O2N

NO2 Ph

Ph

Ph

Ph 89a, 65%, 98% ee

Ph 89b, 63%, 98% ee Cl

O2 N Ph

ent-89f

76%, 95% ee

+ Ph

NO2

R3 O

CF3 Ph

Ph 89d, 61%, 92% ee

R2

Standard conditions 2 R = 4-ClPh OHC R3 = Ph

Ph

Ph 89c, 95%, 95% ee

CN Ph

Standard conditions

Ph 89e, 78%, 93% ee

Cl

NO2 Ph

R2 = Ph R3 = 4-ClPh 70%, ‒95% ee

89f

Ph

Scheme 3.30  NHC-catalyzed formal [4 + 2] cycloaddition. Source: Modified from Xu et al. [31].

To construct atropochiral vinyl–aryl amino sulfides 93, Zhao and coworkers applied tosyl‐protected bifunctional sulfide catalyst 95 to promote electrophilic carbothiolation of mesyl‐protected ortho‐alkynylaryl amines 91 with electrophilic arylthiolating reagent 92. A DDQ‐mediated oxidative aromatization of 93 afforded the axially chiral biaryl 94 in 82% yield and 91% ee (Scheme 3.31) [32]. Proper choices of amine‐protecting groups on sub­ strates as well as catalysts to facilitate a hydrogen bonding network were crucial for Zhao and coworkers [32] NHMs

91 +

95 (10 mol%) TMSOTf (3.0 equiv) CH2Cl2/CHCl3, –78 °C O

(p-Tol)S N 92

S(p-Tol) NHMs

Me S

O

S(p-Tol) DDQ, CH2Cl2, r.t. NHMs

OiPr

93, 95%, 93% ee

94, 82%, 91% ee

NHTs

Scheme 3.31  Chiral sulfide catalyst promoted electrophilic carbothiolation of alkynes. Source: Based on Liang et al. [32].

3.5  ­Atroposelective Synthesis of Biaryls via Direct C–H Arylation Strateg

stereocontrol: catalyst 95 would first activate 92 to react with substrate 91, generating a thiirenium ion that converts into the aza‐VQM intermediate. Intramolecular hydroaryla­ tion then affords target atropisomer.

3.5  ­Atroposelective Synthesis of Biaryls via Direct C–H Arylation Strategy Strategy that permits direct construction of chiral axis is relatively more attractive as tech­ nologies converting a prochiral or achiral axis into a chiral axis own inherent limitations, particularly with respect to product diversity. Transition‐metal‐free C–H arylation reaction for atroposelective construction of chiral axis in biaryls constitutes a rapidly growing realm of research for the past several years (Scheme 3.32).

X Organocatalyst

+ H

Arenes or aromatic precursors

Scheme 3.32  Atroposelective arylation strategy.

3.5.1  Organocatalytic C–H Arylation by [3,3]-Sigmatropic Rearrangement In 2013, List and Kürti independently presented organocatalytic [3,3]‐rearrangement protocol to construct axially chiral biaryls, which mounted a drive for research in this area (Scheme 3.33) [33, 34]. Both groups disclosed the ability of achiral N,N′‐binaphthyl hydrazines 96 to undergo a facile [3,3]‐sigmatropic rearrangement in the presence of Kürti and coworkers [33]; List coworkers [34] R1

R1 96

R2 NH

Kürti′s Method A: up to 86% ee 98 (20 mol%), 4 Å MS, toluene, –20 °C

NH R2

List′s Method: up to 94% ee 98 (5 mol%), CG-50, CHCl3, –50 °C

R2 NH2 NH2 R2

R1

R1

Ar O

O P OH O

(R)-97

Ar 98 Ar = 3,5-(CF3)2C6H3

Scheme 3.33  Asymmetric [3,3]-rearrangement for the construction of BINAMs. Source: Li et al. [33] and De et al. [34].

67

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers

CPA 98 to afford enantiomerically enriched BINAM 97 in good to excellent atroposelec­ tivity. Density functional calculations from Kürti’s group revealed that the phosphoric acid proton of catalyst is completely transferred to one of the N‐atoms of substrate in the transition state for C─C bond formation, and the resulting phosphate acts as a chiral counterion to induce the stereochemistry of this transformation. A significant negative nonlinear effect was observed by List, indicating that the rearrangement step to deter­ mine enantioselectivity has involved two catalyst anions.

3.5.2  Atroposelective Arylation Based on Quinone Derivatives The reactivity principle of an organocatalytic arylation involves the electrophilic addition of aromatic nucleophiles (usually alcohols or amines) where the electrophiles could be quinones, azonaphthalenes, among others. As a highly active aromatic electrophilic pre­ cursor, quinone‐based asymmetric arylation reactions have been extensively developed to construct axially chiral biaryls. In general, these transformations will embody intermedi­ acy of stereochemically enriched species with point chirality, generated from stereoselec­ tive addition controlled by organocatalyst. Aromatization occurs with central‐to‐axial chirality conversion to forge the biaryl axis with defined configuration. In this vein, Tan and coworkers outlined the direct arylation of 2‐naphthols 100 with ester quinones 99 using (R)‐3,3′‐bis(2,4,6‐triisopropylphenyl)‐1,1′‐bi‐2‐naphthol cyclic monophosphate 102 to generate nonsymmetric biaryldiols 101 in good yields with excellent enantioselectivities under mild conditions (Scheme 3.34) [35]. CPA catalyst activates both reacting partners through hydrogen bonding simultaneously to direct the conjugative addition at C1 of naphthols stereoselectively. Central‐to‐axial chirality transfer in aromatization step thus transmits the stereochemical information for the chiral axis in phenyl‐naphthyl diol products 101. Although majority of quinone ­substrates examined have contained C2‐ester substituent to enhance conformational stability and stereocontrol, chloro or bromo was found to be equally compatible. Complementarily, Salvio and Bella employed organo‐quinine catalyst 103 to affect arylation of 2‐naphthols with ortho‐halogen‐substituted quinones 99 as electrophiles

Tan and coworkers [35] O

O +

R2

(R)-102 (5 mol%) CH2Cl2, –78 °C, 24 h

100

Abbreviated reaction pathway R1 =

CO2Et

O O

P

O

TRIP

HO O O H O

O OEt

R1 R2

OH

O

OH

O

101 up to 90%, 99% ee

TRIP O H

Ar

HO OH

R1 99

(R)-BINOL

68

EtO2C

P

O OH

Ar (R)-102 Ar = 2,4,6-iPr3C6H2 HO

*

O central-to-axial EtO2C OH chirality transfer

OH OH

101a, 88%, 99% ee

Scheme 3.34  Arylation of 2-naphthols with quinones under CPA catalysis. Source: Based on Chen et al. [35].

3.5  ­Atroposelective Synthesis of Biaryls via Direct C–H Arylation Strateg

instead. Because of the lower activity of this catalytic system, arylation took place at ­temperature ranged from 4 °C to room temperature and aryl‐quinones were generated because of in situ oxidation by quinone substrates. For complete reductive conversion to biaryldiols 101, sodium borohydride was included (Scheme  3.35) [36]. Benzoquinone ­substrates bearing one or two halogen substituent were arylated in similar yields and ­selectivities, but the mono‐halogenated analogs necessitated longer reaction time (101b and 101c, 101d and 101e). Bella and coworkers [36]

HO

R1 OH

O + R2

O X

100

99

(1) 103 (15 mol%), THF

Quinine 103 OMe H O N

R1 OH

X

OH

(2) NaBH4,10 min, TFA R2 up to 99%, 93 : 7 er

H O

101 Cl

HO

Br

HO

Br

OH

Br

OH 101b, 82% 80 : 20 er (3 d, 4 °C)

HO OH

Cl

OH

Cl

O Stereocontrol model Cl O OH

OH

OH

101d, 99% 88 : 12 er (2 d, rt)

101e, 99% 89 : 11 er (3 d, rt)

OH 101c, 93% 92.5 : 7.5 er (4 d, rt)

HO

N OMe

X

Cl O

O OH Aryl-quinone

Scheme 3.35  Quinine-catalyzed arylation of naphthols with quinones. Source: Based on Moliterno et al. [36].

The Miller’s group diversely utilized a tetrameric peptide 104 embedded with β‐dimethylaminoalanine (Dmaa) as the Lewis basic catalytic residue (P1) to realize arylation of naphthols 100 with ortho‐ester quinones 99. A structurally different set of non‐C2‐symmetric biaryldiols 101 was provided with good yields and enantioselectivi­ ties (Scheme 3.36) [37]. This protocol has also been utilized to arylate an analog of non­ steroidal anti‐inflammatory drug (NSAID), naproxen in 7 : 1 dr (96% yield). This result was superior as the use of trimethylamine only led to a 1 : 1 ratio of diastereomers in 14% yield.

Miller and coworkers [37] R1 O + R2

O RO2C

(1) 104 (5 mol%) OH CH2Cl2, –78 °C, 18 h

99

100

(2) NaBH4 (5 equiv) up to 99%, 93 : 7 er

HO

R1 OH

RO2C

OH

R2 101

N Me2N O

NH

H N O O O HN 2-NaI O

OtBu 104 OMe

Scheme 3.36  Peptide-catalyzed naphthol-quinone coupling. Source: Based on Coombs et al. [37].

Differently, Xu and Kürti have demonstrated the use of N‐sulfonyl iminoquinones in arylation with aromatic alcohols in regio‐ and atroposelective manner toward non‐C2‐ symmetric biaryldiols 106 using (S)‐102 catalyst (Scheme  3.37) [38]. In this

69

70

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Xu and coworkers [38]

R2

NR R1

R2

R3

RHN + R5

R3

OH

(S)-102 (5 mol%)

R4

DCE or PhCl, r.t. or 50 °C up to 99%, 99% ee

100

O 105 R = Ms, Ts, Ac

R1

OH R5 106

O

Abbreviated reaction pathway

OH

R4

R3 (S)-102

R1

R2 NHR

O

aminal formation R5

[3,3]rearrangement aromatization

R4

Scheme 3.37  CPA-catalyzed arylation of hydroxyarenes with N-sulfonyl iminoquinones. Source: Based on Wang et al. [38].

methodology, the alcohol nucleophiles could also comprise phenols and 2,3‐dihy­ droxynaphthalenes. Another distinguished feature lies in the reaction pathway. In con­ trast to the direct 1,4‐addition mechanism proposed by Tan, this transformation proceeds through an initial hydroxy addition onto iminoquinone, which is enantio‐ determining. The enantioenriched aminal intermediate then follows a sequence of [3,3]‐rearrangement and aromatization steps. When symmetric or pseudosymmetric intermediate undergoes successive chirality transfer steps, the catalyst could miss the chance to  transmit chiral information, resulting in the formation of biaryls in low enantiopurities. With the combination of ortho‐substituted N‐sulfonyl iminoquinone and 10 mol% of (R)‐102, Tan and coworkers disclosed that chemoselective reaction at the C1 site of ­2‐naphthylamines 107 could be achieved to give biaryl amino alcohols 108 (Scheme 3.38) [39]. Enantioselectivity was preserved regardless of variations on naphthylamine (­aromatic substitutions and N‐aryl protecting group) and iminoquinone partners Tan and coworkers [39]

R2

NHR4

+ R3

O 105

(R)-102 (10 mol%) CH2Cl2, r.t., 12 h up to 85%, 99% ee

107

R1

Cl

Cl OH NH2

TsHN Cl

OH NHR4

R3

R = ArSO2, PhCO TsHN

R2

RHN

NR R1

108 Cl OH NH2

TsHN Br

Br OH NH2

BzHN Cl

Cl OH NH2

TsHN Me

Me OH NHPh

Ph 108a, 80%, 91% ee 108b, 80%, 91% ee 108c, 80%, 88% ee 108d, 85%, 88% ee 108e, 68%, 90% ee

Scheme 3.38  Arylation of 2-naphthylamines with iminoquinones. Source: Based on Chen et al. [39].

3.5  ­Atroposelective Synthesis of Biaryls via Direct C–H Arylation Strateg

(nature of sulfonyl group and substituents). Although a CPA‐guided 1,4‐addition–­ rearomatization ­mechanism was proposed, the cascade pathway devised by Kürti was not discounted. Xu’s group delivered biaryldiols 110 in excellent yields as well as regio‐ and atropose­ lectivities by arylation of 5‐hydroxyindoles 109 with iminoquinones 105 under the catalysis of chiral cyclohexanediamine‐derived thiourea 111 (Scheme  3.39) [40]. A large‐scale synthesis was smoothly carried out, and the catalytic efficiency of the thio­ urea catalyst was not significantly reduced after five recycles, further corroborating the practicability of this approach. Almost at the same time, the groups of Tan and Li reported a similar work for accessing atropisomeric BINOL analogs using CPA 112 as a catalyst, which was a good complement to Xu’s method concerning the substrate scope [41]. Xu and coworkers [40] NHR1

Cl

NR1 HO

Cl

R2

+

N H

Cl O

Xu: Condition A Li: Condition B

HO HO

Cl *

109

105

110

R2

Ar

Condtion A 111 (20 mol%), toluene, –40 °C up to 86%, >99% ee

S

O

S

O

NH HN Condtion B 112 (15 mol%), EA, –30 °C up to 95%, 95% ee

N H

Ar

NH

HN

111, Ar = 3,5-(CF3)2C6H3

P

O OH

Ar Ar 112, Ar = anthryl

Scheme 3.39  Asymmetric arylation of 5-hydroxyindoles with iminoquinones. Source: Based on Liu et al. [40].

3.5.3  Atroposelective Nucleophilic Aromatic Substitution In 2018, Tan’s group discovered for the first time that the azo group can not only effec­ tively activate an aromatic ring for nucleophlic attack but also efficiently direct a formal nucleophilic aromatic substitution, thus successfully establishing an unprecedented organocatalytic enantioselective arylation of indoles to access axially chiral aryl‐indoles [42]. Building on this work, an efficient organocatalytic arene functionalization strategy with 2‐nitrosonaphthalene 113 as the electrophile was developed, as guided by density functional theory (DFT) calculations. The nitroso group could serve as an electron‐with­ drawing directing moiety and as an oxidant for rapid conversion of the unstabilized σH‐adduct. Notably, novel CPA (R)‐115 with cyclohexane‐fused spirobiindane backbone was identified as the best catalyst and the inclusion of diisopropyl azodicarboxylate (DIAD) as an oxidant could significantly boost the yield. An array of valuable NOBINs 114 was auspiciously fashioned with remarkable enantiocontrol through the one‐pot, two‐step synthesis, namely, the asymmetric C–C cross‐coupling and reductive N─O bond cleavage (Scheme 3.40) [43].

71

72

3  Organocatalytic Asymmetric Synthesis of Biaryl Atropisomers Tan and coworkers [43] NO

R1

(1) (R)-115 (10 mol%) OH DIAD, CH2Cl2, –30 °C

+ R2

113

R1 NH2

(2) Raney Ni, H2 (1 atm) R2 MeOH/CH2Cl2, r.t. up to 80%, 93% ee

100

OH 114

Ar O O O P OH Ar

NH2 Me

NH2 OH

Me

114a, 44%, 89% ee

OH

114b, 72%, 89% ee

Me

NH2 Me I OH

114c, 79%, 93% ee

NH2 OH

(R)-115 Ar = 2,4,6-(Cy)3C6H2

114d, 45%, 92% ee

Scheme 3.40  Atroposelective arene functionalization of nitrosonaphthalene to access NOBINs. Source: Based on Ding et al. [43].

3.6  ­Conclusion Organocatalysis now owns a distinguished status in asymmetric catalysis, which could compare well to that of transition metal catalysis and biocatalysis. As the utility potential of atropisomers receives increasing recognitions in various chemistry contexts, it is natu­ ral that the organocatalytic assembly of atropisomers has garnered research interest and with that notable advancement has ensued. This chapter outlines the employment of organocatalysts in constructing biaryl atropisomers, an exemplary class of axially chiral compounds. The discussion has been classified according to the synthetic strategies. Despite the impressive pace, it can be discerned that the reaction types and hence product scopes remain confined. Encouragingly, the development of organocatalysts could often tie to progression in atroposelective synthesis, especially that of biaryl analogs, which is unsurprising considering the ubiquity of atropochiral biaryl backbone in organocatalyst scaffolds. Thus, it is expected that advances in organocatalyst‐controlled synthesis of biaryl atropisomers will continue to fascinate in the coming decades.

­References   1 List, B., Lerner, R.A., and Barbas, C.F. III. (2000). J. Am. Chem. Soc. 122: 2395.   2 Ahrendt, K.A., Borths, C.J., and MacMillan, D.W.C. (2000). J. Am. Chem. Soc. 122: 4243.   3 (a) Ma, G. and Sibi, M.P. (2015). Chem. Eur. J. 21: 11644. (b) Wencel‐Delord, J., Panossian, A., Leroux, F.R., and Colobert, F. (2015). Chem. Soc. Rev. 44: 3418. (c) Mori, K., Itakura, T., and Akiyama, T. (2016). Angew. Chem. Int. Ed. 55: 11642. (d) Zilate, B., Castrogiovanni, A., and Sparr, C. (2018). ACS Catal. 8: 2981. (e) Link, A. and Sparr, C. (2018). Chem. Soc. Rev. 47: 3804. (f) Wang, Y.‐B. and Tan, B. (2018). Acc. Chem. Res. 51: 534.   4 Shirakawa, S., Wu, X., and Maruoka, K. (2013). Angew. Chem. Int. Ed. 52: 14200.   5 Lu, S., Ng, S.V.H., Lovato, K. et al. (2019). Nat. Commun. 10: 3061.   6 Cheng, D.‐J., Yan, L., Tian, S.‐K. et al. (2014). Angew. Chem. Int. Ed. 53: 3684.   7 Jones, B.A., Balan, T., Jolliffe, J.D. et al. (2019). Angew. Chem. Int. Ed. 58: 4596.   8 Ma, G., Deng, J., and Sibi, M.P. (2014). Angew. Chem. Int. Ed. 53: 11818.   9 Qu, S., Greenhalgh, M.D., and Smith, A.D. (2019). Chem. Eur. J. 25: 2816.

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4 Enantioselective Synthesis of Heterobiaryl Atropisomers Damien Bonne and Jean Rodriguez Aix Marseille University, CNRS, Centrale Marseille, iSm2, Centre de St Jérôme, Avenue Escadrille Normandie Niemen, 13013, Marseille, France

4.1 ­Introduction Atropisomers are a subclass of restricted rotational conformers, resulting in a stereogenic sigma bond, which can be isolated as separate enantiomers and can be accessible by various enantioselective approaches. Among axially chiral molecules, biaryl atropisomers are the most common ones and many synthetic approaches are available. In sharp contrast, the enantioselective construction of atropisomeric heterobiaryl structures is less common and generally much more challenging. The presence of a heteroatom not only can bring new synthetic and biological perspectives but also can be used for the control of the reactivity based on the possible establishment of hydrogen-bonding networks, rendering this class of axially chiral molecules particularly attractive. However, besides these positive effects, introducing heteroatoms induces structural modifications, significantly affecting their configurational stability and rendering their enantioselective synthesis much more challenging. This chapter focuses on enantioselective synthesis of heterobiaryl atropisomers and has been divided in three parts, each one dealing with a particular ring size, namely, atropisomeric heterobiaryls featuring either (i) two six-membered rings, (ii) one five-membered ring, or (iii) two five-membered rings. In each of these parts, two main strategies arise for the assembly of these molecular architectures: the atropisomers are either synthesized (i) by functionalization of preformed heterobiaryls or (ii) directly constructed via an atroposelective ring formation.

4.2 ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Rings 4.2.1  Functionalization of Heterobiaryls The most direct way to form enantioenriched biaryl derivatives is the enantioselective metal-catalyzed C(sp2)–C(sp2) cross-coupling of two different aryl precursors, which has Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

76

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

been widely developed in the all carbon series [1]. However, for heterobiaryl analogs, this approach remains as a challenging, yet unsolved, problem. This is mainly due to the coordination ability of the heterocyclic substrates, their usually lower reactivity and/or stability, and the lower configurational stability of the resulting heterobiaryl products. Therefore, only two examples involving palladium-catalyzed reactions have been reported to date with only moderate success (Scheme 4.1). They concern either the coupling of a naphthyl boronic acid with a bromo pyridine [2] or a trinaphthyl organoindium reagent with halopyridines [3], leading to one biaryl pyridine 1 or three naphthylisoquinolines (2, 3a, and 3b), with only moderate and poor enantioselectivities of 70% ee and 20–32% ee, respectively.

Biaryl pyridine

Naphthylisoquinolines

Me Me O Me N Ph H

N

R

Me N N

1, 85%, 70% ee

2, 78%, 20% ee

3a, R = Me: 73%, 31% ee 3b, R = OMe: 45%, 32% ee

Scheme 4.1  Pd-catalyzed enantioselective C(sp2)–C(sp2) cross-couplings.

A synthetic alternative to this drawback concerns the direct functionalization of racemic configurationally stable and easily accessible heterobiaryl precursors involving either metal-catalyzed atroposelective C–H functionalizations or catalytic dynamic kinetic ­resolutions (DKRs) presented hereafter (Scheme 4.2). The atroposelective C–H activation/alkylation sequence of racemic heterobiaryl derivatives [4] constitutes an appealing approach pioneered by Murai and coworkers at the very beginning of this century [5]. Naphthylpyridines and isoquinolines were ethylated by ethylene using a rhodium(I) catalyst ligated by a chiral ferrocenyl phosphine ligand with 37% yield and 49% ee as the best result. More recently, the group of You reported the first efficient and scalable enantioselective dehydrogenative Heck coupling

R1

Z

Atroposelective C–H functionalization R3 = H

Y X R3

R2 Racemic configurationally stable

cat*

R1

Z

Y X FG

R3 ≠ H Dynamic Kinetic Resolution (DKR)

R2 Enantioenriched

Scheme 4.2  Synthetic alternatives to enantioenriched heterobiaryl atropisomers.

4.2  ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Ring

of isoquinoline derivatives 4 with various functionalized alkenes 5 catalyzed by the Cramer binaphthyl Cp*Rh(III) complex 7 (Scheme  4.3) [6]. The transformation tolerated various styrenyl or acrylic derivatives and even ethylene itself with moderate to excellent yields and acceptable enantioselectivities. The obtained atropisomeric isoquinolines 6 were tested as N/olefin ligands for the enantioselective rhodium-catalyzed conjugate addition of phenylboronic acid to cyclohexanone and showed good chemical efficiency but only moderate enantioselectivity not exceeding 78% ee. More recently, the same group proposed a series of novel chiral ­spirocyclopentadienyl ligands as superior catalysts resulting in improved enantioselectivity up to 96% ee [7]. You and coworkers [6] R1

R3 5 7 (5 mol%) (BzO)2 (5 mol%) Cu(OAc)2 (20 mol%)

R1 N

R3

Ag2CO3 (1 equiv) MeOH, 80 °C up to 99%, 88% ee 4

OMe

N Rh 7

R2

R2

OMe

6

Scheme 4.3  Rhodium-catalyzed enantioselective dehydrogenative Heck couplings. Source: Based on Zheng and You [6].

Alternatively, the peptide-catalyzed atroposelective C─H bond halogenation, introduced by Miller’s group in 2010 [8], has been exploited more recently by Asano and Matsubara in the isoquinoline N-oxide series [9]. The peptide has been replaced by a chiral bifunctional urea organocatalyst 10, which in the presence of an excess of N-bromoacetamide (NBA) triggered an efficient enantioselective tribromation, leading to axially chiral isoquinoline N-oxides 9 in excellent yield and enantioselectivity (Scheme 4.4). Key to the success is the presence of both the N-oxide moiety and a phenol nucleus, which can interact with the hydrogen bond donor and the hydrogen bond acceptor sites of the bifunctional organocatalyst, respectively. Finally, it has been evidenced that the first bromination at an ortho ­position of the axis is the enantio-determining step, preventing the enantiomerization by hampering bond rotation during the course of ­further brominations. Matsubara and coworkers [9] R1

N – + O

10 (10 mol%) NBA (3 equiv) THF, 0 °C, 6 h up to 99%, 99% ee

R2 8

OH

R1

N – + O Br

Br R2

OH 9

Br

Ar

H N

H N O

H N

OMe

N 10, Ar = 3,5-(CF3)2C6H3

Scheme 4.4  Atroposelective polybromation of isoquinoline N-oxides. Source: Based on Miyaji et al. [9].

77

78

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

Related racemic axially chiral isoquinoline N-oxides have also been involved in a Pd(II)catalyzed intermolecular C–H iodation, resulting in an efficient kinetic resolution [10]. Among various mono N-protected amino acid (MPAA) ligands, phenyl alanine derivative ligand 13 proved to be the most effective with the highest selectivity factor s = 27 using 10 mol% of Pd(OAc)2 in the presence of excess N-iodosuccinimide (Scheme  4.5). The ­atropisomeric iodide derivatives 12 were involved in a Suzuki–Miyaura coupling to build a new catalyst for the enantioselective allylation of benzaldehyde by allyltrichlorosilane with moderate success. You and coworkers [10] R1

N – + O

Pd(OAc)2 (10 mol%) R1 13 (20 mol%) NIS (1.5 equiv) CH3CN, 70 °C s up to 27

R2 rac-11

Me

Me N – + O

R

1

N – + O I

+ R2

R2 (R)-11 up to 73%, 94% ee

(S)-12 up to 60%, 83% ee

L* = HN

O

O OH 13

Scheme 4.5  Kinetic resolution of chiral isoquinoline N-oxides. Source: Based on Gao et al. [10].

A step forward is the elegant biocatalytic DKR by reduction of related biaryl pyridine and isoquinoline N-oxides carbaldehyde 14 with commercially available ketoreductase enzymes (KREDs) in the presence of a glucose/glucose dehydrogenase recycling system (GDH/NADP) (Scheme 4.6) [11]. The markedly greater configurational stability of about 50 kJ/mol for the resulting alcohols over the starting aldehydes accounts for an efficient DKR at ambient temperatures. Both enantiomerically enriched biaryl pyridine and isoquinoline N-oxides alcohols (15 and 16) have been evaluated as Lewis base organocatalysts for the enantioselective allylation of benzaldehydes by allyltrichlorosilane, resulting in moderate conversion (15–66%) and low to good enantioselectivity (17–80% ee). Clayden and coworkers [11]

N – + O O rac-14

N – + O

KRED, 30 °C, 16 h NADPH

Gluconic acid

NADP GDH

Glucose

N – + O OH

15, 73%, 96% ee on 500 mg scale (with KRED 130)

or

OH 16, 83%, >99% ee on 500 mg scale (with KRED 130)

Scheme 4.6  Biocatalytic DKR of pyridine and isoquinoline N-oxides. Based on Staniland et al. [11].

More recently, a complementary DKR approach involving Zn-catalyzed hydrosilylation of configurationally labile heterobiaryl ketones 17 was proposed by Lassaletta, effecting a new diastereo- and highly enantioselective preparation of heterobiaryl ­carbinols 18 ­containing both central and axial stereogenic elements (Scheme 4.7) [12].

4.2  ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Ring Lassaletta and coworkers [12] R3

R2

Y N

R4 R5

O

6

R

7

tBu R3

(EtO)2MeSiH (2 equiv) Zn(OAc)2 (5 mol%) R4 19 (6 mol%) R5 1 THF, reflux, 36 h R then HCl (1 M) R6 up to 20 : 1 dr

R rac-17 Y = N, CH

R2

Y N

R3

OH 1

R

R 7

R (RaR)-18, major up to 78%, 97% ee

N

R4 + R5

tBu

R2

Y

OH

NH 1

R

HN

6 7

R (SaR)-18, minor up to 32%, 95% ee

19 tBu

tBu

Scheme 4.7  Zn-catalyzed dynamic kinetic resolution of heterobiaryl ketones. Source: Based on Hornillos et al. [12].

The best chiral ligand was (S,S)-dibenzyl-1,2-diphenylethylenediamine (S,S)-L* 19, and the reaction was scalable to the 1 mmol level. Good to excellent enantioselectivity and acceptable diastereoselectivity were acquired in most cases, including substrates from either the 2-aryl-pyridine, -isoquinoline, or -1,3-diazine series. The newly prepared ­heterobiaryl alcohols featuring both central and axial chirality constituted interesting synthetic platforms and were involved in various post-functionalizations, allowing access to new potentially useful chiral bidentate ligands or bifunctional urea-based organocatalysts. Axially chiral isoquinoline derivatives were earlier identified as privileged structures for the first DKR involving a palladium-catalyzed C–P cross-coupling reaction, thus established an enantioselective synthesis of the original QUINAP ligand [13]. Although utilization of bromide and tosylate precursors resulted in only a kinetic resolution, the corresponding triflates 20 allowed a novel DKR involving isomerization of an arylpalladium intermediate when commercially available JOSIPHOS-type bidentate ligand (R,Sfc)-L* 21 was used (Scheme 4.8). The authors postulated that the isomerization ­proceeds through a chelated transition state where a stabilizing agostic interaction develops as the quinoline ring passes the cationic palladium atom. This pioneer study has opened the way to other interesting developments for DKR involving related palladium-catalyzed cross-coupling reactions especially from Lassaletta and

Virgil and coworkers [13] Pd[P(o-tol)3]2 (5 mol%) (R,Sfc)-L* 21 (10 mol%)

N OTf

rac-20

DMAP (4.0 equiv) Ph2PH (slow addition) dioxane, 80 °C

(R,Sfc)-L* 21 Me PCy2 Fe PCy2

N PPh2

+ +

N (S)-QUINAP 86%, 90% ee

– H OTf +

Pd P P *

Scheme 4.8  Pd-catalyzed DKR of isoquinoline triflate to QUINAP. Source: Based on Bhat et al. [13].

79

80

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

Lassaletta and coworkers [14] Z R1

Z

Pd2(dba)3 (5 mol%) 24 (10 mol%) Me3SiPR2 (2.0 equiv)

Y N X

R1

CsF (2.0 equiv) THF, 50 °C, 20 h

Y N PR2

Ph2P Fe 24

PtBu2

23 up to 91% ee

rac-22 X = OTf, ONf

Scheme 4.9  Pd-catalyzed DKR of heterobiaryls to P,N-bidentate. Source: Based on Ramírez-López et al. [14].

coworkers. Notably, several families of enantiomerically enriched heterobiaryl P,Nbidentate ligands including QUINAP, PINAP, and QUINAZOLINAP derivatives 23 have been granted easy accessibility starting from racemic triflates or nonaflates heterobiaryl precursors 22 by a modified P–N cross-coupling reaction (Scheme 4.9) [14]. In complement, the same group has also been very active in the development of DKR by enantioselective palladium-catalyzed C─C and C─N bond-forming reactions from racemic heterobiaryls (Scheme  4.10). This includes Suzuki–Miyaura coupling [15], alkynylation [16], Heck reaction [17], and Buchwald–Hartwig amination [18]. Lassaletta and coworkers [15–17] R

Y

R Y

X N

Z [Pd]-cat Z = OR, N(Me)Ac Z 25

R1 R

Ar Y

X N Ar

R1

up to 90%, 94% ee

27

B O

O

B O

Ar

B [Pd]-cat Ar up to 98%, 93% ee

[Pd]-cat R

Y

Z Z = O, NBoc up to 99%,>99% ee 20 : 1 dr

X N

Z 26

R1

R2

R Y R1 rac-22 R2 = OSO2R, Cl, Br

X N

[Pd]-cat, ArNH2

X N NHAr

up to 99%, 97% ee R1

28

Scheme 4.10  DKR by Pd-catalyzed C─C and C─N bond-forming reactions. Source: Ros et al. [15], Hornillos et al. [16], and Carmona et al. [17].

Finally, a unique organocatalytic desymmetrization of prochiral biaryl dihalopyrimidine electrophiles 29 was proposed by Smith’s group in 2014 [19]. This elegant approach was based on a cation-directed nucleophilic aromatic substitution under phase-transfer catalysis (PTC) using N-benzylquininium chloride 31 (Scheme 4.11). The reaction, in the ­presence of a slight excess of thiophenol, led to improved enantioselectivity by a kinetic resolution transforming the minor enantiomer to the achiral di-substituted derivative with a selectivity factor up to 32.

4.2  ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Ring

Smith Armstrong and Smith [19] R

R RL

PhSH (1.1 equiv) 31 (10 mol%)

RS X

X

K2CO3, CCl4/H2O, r.t. s up to 32 up to 97%, 94% ee

N N 29, X = Cl, Br

H

RL

RS SPh

X N

N

OMe H

+

–

Cl OHPh N

30

N

31

Scheme 4.11  Enantioselective PTC desymmetrization of prochiral biaryl pyrimidines. Source: Based on Armstrong and Smith [19].

4.2.2  Atroposelective Ring Formation The atroposelective ring formation is one of the most direct strategy to build axially chiral biaryl derivatives and metal-catalyzed (2 + 2 + 2) cycloadditions are largely in the lead. After the seminal work by Mori’s group in 1999 in the racemic series [20], the first enantioselective approach was proposed five years later by Gutnov, Heller, and coworkers [21]. They devised an elegant direct synthesis of axially chiral 2-arylpyridines 36 by a cobalt-catalyzed enantioselective (2 + 2 + 2) cocyclization of alkynes and nitriles. The intermolecular condensation of 1-cyano-2-methoxynaphthalenes 32 with simple alkynes 34 or diynes 33 proved to be moderately efficient (Scheme 4.12a) and the best optimized results were obtained in the combinations of di-alkynyl 2-methoxynaphthalene 37 and simple commercially available nitriles 38 catalyzed by a chiral cyclopentadienyl cobalt catalyst 35, leading to good yields and enantioselectivities up to 93% ee (Scheme 4.12b) [22]. (a) Gutnov et al. [21] R2

33

R2

N

R2

R2

R2 CN

35 (1 mol%) OR1

36 up to 81%, 39% ee

OR1

R2

34, R2 R2 35 (1 mol%)

R2 N

R2

OR1

THF THF 32 hν (λ = 420 nm) hν (λ = 420 nm) 1 R2 = propyl, pentyl R = Me, benzyl R2 = ethyl, pentyl

36 up to 34%,59% ee

(b) Hapke et al. [22]

OR1 37

N

THF, hν (λ = 420 nm) up to 88%, 93% ee

R2 = alkyl, N-Cy, (hetero)aryl

iPr

R2

38, R2-CN 35 (1 mol%)

Co OR1

Me 35

36

Scheme 4.12  Enantioselective (2 + 2 + 2) cocyclization of alkynes with nitriles. Source: (a) Based on Gutnov et al. [21]. (b) Based on Hapke et al. [22].

81

82

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

After these pioneer studies, the group of Tanaka has been particularly active in this field [23]. He has identified chiral rhodium(I) salts as the more efficient catalytic ­systems for atroposelective synthesis of functional axially chiral 2-pyridone [24] or ­isoquinoline [25] atropisomers through (2 + 2 + 2) cycloaddition of diynes and either isocyanates 40 or 1-alkynyl isoquinolines 44, respectively (Scheme 4.13a,b). Among various combinations, biaryl phosphines revealed to be the best chiral ligands and allowed to reach good yields and high levels of enantioselectivity when DTBM-SEGPHOS 42 or H8-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (H8-BINAP) was employed. Interestingly, two biarylisoquinolines were successfully derivatized to the corresponding axially chiral P,N ligand 46 and Lewis base catalyst 47 that were active in the enantioselective ­hydroboration of styrenes and allylation of benzaldehydes, respectively, albeit with moderate enantioselectivities (Scheme 4.13c). (a) Tanaka et al. [24a]

O

R1 + Z

N

[Rh(cod)2]BF4 (R)-L* 42 (5 mol%)

R2

CH2Cl2, ‒20 °C up to 89%, 92% ee

O 39

O

R1 N

Z

Z = CH2, O, C(CO2Me)2

40

(b) Tanaka and coworkers [25]

Me Z R 43, Z = O, NTs

R2 44

PAr2 PAr2

O (R)-DTBM-SEGPHOS 42 Ar = 4-MeO-3,5-(tBu)2C6H2

Z N

+

R2 O

41

O

[Rh(cod)2]BF4 (R)-H8-BINAP (5 mol%) CH2Cl2, 80 °C

R1

Me Me R2

R1

up to 90%, 99% ee

N

45

PPh2 PPh2 (R)-H8-BINAP

(c) Axially chiral P,N ligands and Lewis base catalyst TsN

TsN

Me

Me Me Me

PPh2 N

Me Me

P(O)Ph2 +

N 46

‒

O

47

Scheme 4.13  Atroposelective (2 + 2 + 2) synthesis of 2-pyridones and isoquinolines. Source: (a) Based on Tanaka et al. [24a]. (b) and (c) Based on Sakiyama et al. [25].

In the biarylpyridine series, the same group proposed an efficient regio- and enantioselective (2 + 2 + 2) cycloaddition of (o-halophenyl) diynes 39 with simple nitriles 38 under the same experimental conditions [26] (Scheme  4.14). Interestingly, the nature of the o-substituent (R2) on the phenyl group of the diyne had a decisive role on the selectivity. In the cases of halogens (R2 = Cl, and Br), axially chiral 3-arylpyridines 48 were formed regioselectively with high enantioselectivities, while the enantiocontrol was lowered significantly with methoxy and methoxycarbonyl substituents (R2 = OMe and CO2Me). In sharp contrast, with alkyl groups (R2  =  Me, CH2OMe, and CF3), regioselectivity was switched

4.2  ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Ring Tanaka and coworkers [26] R2

[Rh(cod)2]BF4 (R)-H8-BINAP (10 mol%)

R3 +

Z

CH2Cl2, r.t., 16 h

N 38

R1 39

R2 Z R1

48

Z = [C(CO2R)]2, NTs; R1 = H, Me R3

N +

= CO2Et, COMe, CH2CN, P(O)(OEt)2 + R2

Z

R2 = R3 Cl, Br, OMe, CO2Me up to 97%, 99% ee

+

R2

R2

Ph Ph R3 P Rh N P R1 Ph Ph

or

Z

Rh N R1

N

Z

R3

R3

R1

49

R2 = Me, CF3, CH2OMe up to 98% yield

Scheme 4.14  Rh(I)-catalyzed atroposelective (2 + 2 + 2) synthesis of biarylpyridines. Source: Based on Kashima et al. [26].

rendering achiral 6-arylpyridines 49 in high yields. This effect of the ortho substituent (R2) on both regio- and enantioselectivity was attributed to its coordinating ability to the cationic Rh(I) center in a bidentate fashion. This would guide the formation of a chiral rhodacycle intermediate from the two alkyne moieties, which is the precursor of the corresponding enantioenriched 3-arylpyridines. On the other hand, when the ortho substituent (R2) possessed a lower coordinating ability, the sterically less ­demanding alkyne coordinates with the nitrile to form an aza-rhodacyle intermediate, leading to the corresponding achiral 6-arylpyridines. Besides the direct metal-catalyzed atroposelective construction of axially pyridine ­derivatives, the central-to-axial chirality conversion, first hypothesized in 1955 by Berson’s group [27], and demonstrated by Meyers and coworker 30 years later in a diastereoselective approach [28], has been recently exploited to devise an atroposelective Hantzsch-type synthesis of axially chiral 4-arylpyridines [29]. The strategy combines the enantioselective organocatalyzed synthesis of 1,4-dihydropyridines (1,4-DHPs) 53 with central-to-axial chirality conversion upon oxidative aromatization (Scheme  4.15). The intermediates 1,4-DHPs 53 were obtained with acceptable yields and good to excellent Rodriguez and coworkers [29] R4 O

O

50

R2 R1 + R1 51 O

R3

(1) 54 (10 mol%) CH2Cl2, rt (2) NH4OAc, EtOH, 37 °C (3) MnO2 (20 equiv), C6H12, 20 °C

R5

S

up to 94%, 96% ee, 100% cp CF3

F3C

54

N H

N H

NMe2

R1 R1

R4 R2 O

52

R4 R2 O

R3

N

R5

R1 1 R

R3

N H

R5

53 up to 84%, 96% ee

Scheme 4.15  Atroposelective Hantzsch-type synthesis of 4-arylpyridines. Source: Based on Quinonero et al. [29].

83

84

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

enantioselectivities, while the delivery of axial chirality was accomplished with good to excellent conversion percentages (cp = 61–100%). This efficient central-to-axial chirality conversion has been exploited concomitantly by two different groups in the case of the Friedländer quinoline synthesis. They have devised chiral phosphoric acid (CPA)-catalyzed heteroannulation of ortho-substituted 2-aminobenzophenones 55 (R4   H) with 1,3-dicarbonyls 56 involving either 1,1′-spirobiindane-7,7′diol (SPINOL)-9-phenanthryl [30] or 1,1′-bi-2-naphthol (BINOL)-2,4,6-trisisopropylphenyl [31] derivatives. When SPINOL catalyst (R)-58 was used, addition of a catalytic amount of achiral primary amine, such as glycine tert-butyl ester, proved beneficial to allow the ­performance of reaction at only 70 °C in chloroform while enabled scope extension to 1,3-ketoesters (R2  =  alkyl, aryl, R3  =  alkyl, O-alkyl) (Scheme  4.16a). Alternatively, the ­reaction with acetylacetone (R2  =  R3  =  Me) proceeded at up to 120 °C with the BINOL ­catalyst (R)-59 in benzonitrile and in the presence of 5 Ǻ molecular sieves as an additive (Scheme 4.16b). (a) Cheng and coworkers [30]

2

3

R = alkyl, aryl, R = alkyl, O-alkyl

Ar

(R)-58, amine, 5 Å MS, CHCl3, 70 °C

O O P O OH

up to 94%, 97% ee O

R

4

Ar +

R1

O

O

R2

R4

R3

NH2 55

O R3

R1

56

(R)-58 Ar = 9-phenanthryl

R2

N

O O P O OH

57 2

Ar

3

R = R = Me (R)-59 (10 mol%), 5 Å MS, PhCN, r.t.~120 °C

Ar (R)-59 Ar = 2,4,6-(iPr)3-C6H2

up to 94%, 95% ee (b) Jiang and coworkers [31]

Scheme 4.16  Atroposelective Friedländer synthesis of axially chiral quinolines. Source: Shao et al. [30] and Wan et al. [31].

Although less represented, quinolinone atropisomers also constitute an interesting class of axially chiral heterocyclic derivatives, but their enantioselective synthesis is still underdeveloped. In this field, atroposelective construction of 2-aryl-4-quinolinones 62 has been proposed by Kitagawa and coworkers with only limited success (Scheme 4.17) [32]. Kitagawa and coworkers [32] O

O

NH2 tBu

+ Br 60

Ar

R 61

Pd2(dba)3 (5 mol%) (R)-MOP (10 mol%) K2CO3 (2 equiv) dioxane, reflux, 12 h up to 63%, 72% ee

N

Ar

OMe PPh2

tBu (R)-MOP 62

Scheme 4.17  Atroposelective synthesis of axially chiral 2-aryl-4-quinolinones. Source: Based on Takahashi et al. [32].

4.2  ­Atropisomeric Heterobiaryls Featuring Two Six-Membered Ring

They devised an interesting palladium-catalyzed domino aza-Michael/Buchwald–Hartwig ­amination of anilines 61 and arylethynyl ketones 60 but with only moderate yields and enantiocontrol. Alternatively, an elegant and more efficient strategy was proposed by Tanaka’s group based on a palladium-catalyzed enantioselective intramolecular hydroarylation of alkynes 63 (Scheme 4.18) [33]. Among various chiral ligands, BINAP derivatives were found the most efficient ones rendering the corresponding 4-aryl 2-quinolinones 64 in good yields and moderate to good enantioselectivities. Tanaka and coworkers [33] R1

R1

OMe [Pd(CH3CN)4](BF4)2 (10 mol%) (S)-xyl-H8-BINAP (12 mol%)

R2 N 63

CH2Cl2, r.t., 40 h up to 94%, 98% ee

O

PAr2 PAr2

OMe R2 O

N 64

Bn

(S)-xyl-H8-BINAP (Ar = 3,5-Me2C6H3)

Bn

Scheme 4.18  Atroposelective synthesis of axially chiral 4-aryl 2-quinolinones. Source: Based on Shibuya et al. [33].

More recently, isoquinolone analogs have been targeted by two different groups involving complementary strategies for the direct access either to axially chiral 3-aryl- or 4-aryl-isoquinolones (Scheme 4.19). In the case of 3-aryl-isoquinolones, the group of Tan and Liu reported the first nickel-catalyzed enantioselective denitrogenative transannulation of 1,2,3-benzotriazinones 65 with internal alkynes 66 bearing sterically encumbered substituents (Scheme  4.19a) [34]. This highly regioselective transformation proceeded (a) Tan and coworkers [34]

R1 Ni(cod)2 (10 mol%) (S,S)-L* (11 mol%)

O

R1

N 65

N N

Ar

+

1,4-Dioxane, r.t., 48 h R2

66

N

R2

Ar

iPr

Ni N R2

O

N

N

N

N iPr

Ar

O

O

O

O

O

67 up to 95%, 98% ee

L* = (b) Antonchick and coworkers [35] O

R1

N

O

( )3

H H

CsOAc (1 equiv), 0 °C

R2 68

cat* (10 mol%) (PhCO2)2 (10 mol%) ClCH2CH2OH/CH2Cl2 (1 : 1)

( )nX

X = CH, O; n = 0, 1 up to 95%, 98% ee

R1

O NH ( )3OH

R2 ( )nX 69

cat* = Rh

R1 CO2Me N R2 Me R1 = 4-F-C6H4 R2 = 4-Br-C6H4

Scheme 4.19  Atroposelective synthesis of axially chiral 3-aryl- and 4-aryl-isoquinolones. Source: (a) Based on Fang et al. [34]. (b) Based on Shan et al. [35].

85

86

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

efficiently with a cyclopropyl-linked chiral bis-oxazoline ligand in high yields and very good enantioselectivities. Based on DFT calculations, the origin of the axial chirality observed has been rationalized from a privileged aza-nickel-seven-membered ring intermediate. Alternatively, for the 4-arylisoquinolone series, Antonchick and Waldmann (Scheme  4.19b) proposed the first and still unique enantioselective rhodium-catalyzed annulation by C─H bond activation proceeding with good to excellent yields and enantioselectivities [35]. The method relied on the utilization of a chiral cyclopentadienyl ligand fused with a piperidine ring. The key points in this transformation were the chirality ­control during the alkyne insertion after the C–H activation, followed by the Rh-insertion into the N─O bond of the starting alkynyl hydroxamic esters 68. Interestingly, different cellular assays of a series of 4-aryl-isoquinolinones led to the discovery of novel nonsmoothened binding Hedgehog pathway inhibitors. Besides N-heterocyclic atropisomers, the first example of an enantioselective synthesis of O-heterocyclic six-membered ring analogs was reported by the group of Irie in 2013 (Scheme 4.20) [36]. They disclosed the first organocatalytic example of a new cinchona alkaloid-catalyzed atroposelective [4 + 2] cycloaddition of a symmetric cinchona bis-alkynylnaphthol 70, leading to an original axially chiral pyran 71 via a chiral vinylidene–quinone methide (VQM) [37]. Irie and coworkers [36]

HO

OH

Cinchona alkaloid (10 mol%) CHCl3, r.t., 24 h 90%, 60% ee

70

O HO 71

Scheme 4.20  First atroposelective synthesis of an axially chiral pyran. Source: Based on Furusawa et al. [36].

Although this unique transformation displayed moderate levels of enantioselectivity, it has been optimized and deeply developed five years later by the group of Yan involving a more efficient organocatalytic activation by bifunctional quinine-derived thiourea catalyst 74 [38]. Under optimized conditions, the transformation proceeds with high chemo- and enantioselectivity with various more challenging nonsymmetric but easily accessible bisalkynylnaphthols 72 (Scheme 4.21). DFT calculations have established that the chiral VQM intermediate arises from an enantioselective 1,5-proton shift and the transfer of chirality operates during the key intramolecular [4 + 2] hetero-Diels–Alder cycloaddition, leading to axially chiral pyrans 73 [39]. Another family of O-heterocyclic six-membered ring has been proposed in 2018 by the group of Wang [40] with the N-heterocyclic carbene (NHC)-organocatalyzed atroposelective synthesis of axially chiral fused bicyclic α-pyrones 77 (Scheme 4.22). The authors devised an original design involving a (3 + 3) annulation of simple 1,3-cyclohexadiones 75 and functionalized ynals 76 using chiral azolium ions 78 as precatalysts. Based on experimental

4.3  ­Atropisomeric Heterobiaryls Featuring a Five-Membered Rin Yan and coworkers [38]

R4

R4 3

R

R

5

74 (5 mol%), toluene, 25 °C

6

R2

XH HO

R

up to 99%, 99% ee

R5

R3

R5

R2

XH

R2

XH

O

H

R

H

1

R

N R1

NH

R1 72 (X = O, NBoc)

R6

O

H

R6

OMe 7

R4

R

3

N

R

S NHR 74, R = 3,5-(CF3)2C6H3

7

R1

73

7

R

Chiral VQM

Scheme 4.21  Development of atroposelective synthesis of axially chiral pyrans. Source: Based on Liu et al. [38].

Wang and coworkers [40]

R1

R2

OMe

toluene, r.t., 24 h up to 76%, 94% ee

O 75

O

H

76 H O H

–

N

N N

BF4

+

R R

+

R1

78 (15 mol%), 79 (1.5 equiv) nBu4NOAc (200 mol%) Mg(OTf)2 (20 mol%)

O

tBu

R R tBu

O

OMe

O 77

O

O

Ar

tBu 78, Ar = 2,4,6-Br3–C6H2

R2 O

tBu 79

Scheme 4.22  NHC-catalyzed (3 + 3) atroposelective synthesis of axially chiral α-pyrones. Source: Based on Zhao et al. [40].

observations and preliminary computational studies, the key intermediate seems to be an alkynyl acyl azolium salt generated in situ from the corresponding Breslow intermediate under oxidative conditions and in the presence of Mg(OTf)2 as an additive. The observed enantioselectivity was more likely determined during the C─C bond-forming event triggered in a Mg-chelated chiral allenoate intermediate; an intramolecular O-acylation delivers the expected α-pyrones with the release of the catalytic species.

4.3 ­Atropisomeric Heterobiaryls Featuring a Five-Membered Ring 4.3.1  From Preformed Cyclic Systems One of the most direct accesses to optically active atropisomeric biaryls is the enantioselective cross-coupling reactions. If this is a leading strategy for all-carbon biaryl motifs, the situation is much more complex for heterobiaryl systems, for which only few isolated

87

88

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

examples have been reported. This is mainly due to the necessary harsh reaction conditions to couple both hindered partners, resulting in high level of enantiomerization. The heteroatom itself can also be detrimental to the reactivity as it can unfavorably interact with the catalyst metal center. To date, limited reports describe the successful enantioselective metal-catalyzed cross-coupling reaction (Scheme  4.23). In 2012, Itami and Yamaguchi developed the first enantioselective C–H/C–B coupling of arylboronic acids 80 and 2,3-Me2–thiophene through a newly established Pd(OAc)2/iPrBox/TEMPO system. When the reactions were carried out in n-PrOH at 70 °C, axially chiral biaryl 81a could be obtained in 63% yield with 41% ee. The ee value could be enhanced to 72% by replacing the methyl substituent to isopropyl group (81b) but at the expense of the yield [41]. To avoid the use of stoichiometric co-oxidant TEMPO, an aerobic oxidative C–H/ C–B coupling catalyzed by Pd(II)–sulfoxide–oxazoline and iron–phthalocyanine (FePc) was established in their next studies. Under this set of conditions, the yield of 81b was improved to 61%, but only 61% ee was observed [42]. Soon after, the Kündig group showed that the combination of PEPPSI complexes with a chiral NHC ligand could promote enantioselective Suzuki–Miyaura cross-coupling reactions [43]. Unfortunately, the enantiocontrol remained challenging. Itami and coworkers [41, 42] Pd(OAc)2/iPrBox/TEMPO 81a, R = Me, 63%, 41% ee nPrOH, 70 °C, 24 h 81b, R = iPr, 27%, 72% ee B(OH)2 R

iPr

O

O

N

N

O –

iPr O S

iPr-Box

Me

80 +

p-Tol

S

N Sox

iPr

R Me

H

N N

Me

+

II

Fe

N N

Me

S

81

FePc

Pd-Sox, FePc, air, DMAc, 70 °C, 24 h 81b, R = iPr, 61%, 61% ee

Scheme 4.23  Enantioselective metal-catalyzed cross-couplings to heterobiaryls. Source: Yamaguchi et al. [41, 42].

Very recently, Baudoin and Cramer reported an atroposelective intermolecular Pdcatalyzed C–H arylation of 1,2,3-triazoles and pyrazoles (Scheme 4.24) [44]. They used a Pd(0) complex with a chiral monodentate phosphine ligand 85 for the arylation of a broad range of heterocycles in high enantioselectivity. The authors showed that the enantioselectivity of the reaction was correlated with the dihedral angle of the ligand, where higher enantiopurities being obtained with a large angle. Investigations of deuterium kinetic isotope effect revealed that the C–H activation is the rate-determining step but not the enantio-determining one. Interestingly, a bidirectional C–H arylation of

4.3  ­Atropisomeric Heterobiaryls Featuring a Five-Membered Rin Baudoin and coworkers [44]

R1

N N + X

Br

R3

82

83

R2

Pd(dba)2 (10 mol%) 85 (20 mol%) Pivalic acid

R1

Cs2CO3, MeCN, 80 °C R up to 98%, 95% ee

2

N N X 84

POPh2 PPh2

R3

85

Scheme 4.24  Atroposelective Pd-catalyzed C–H arylation. Source: Based on Nguyen et al. [44].

1,5-dibromo-2,6-dimethoxynaphthalene allowed the synthesis of a double-axis heteroatropisomer in a good yield (76%) under excellent enantiocontrol (>99% ee) without formation of the meso stereoisomer. Other approaches have emerged over the years to circumvent difficulties associated with the direct enantioselective cross-coupling reactions. Hence, from preformed cyclic systems, two main strategies have been developed (Scheme 4.25). Firstly, the incipient stereogenic biaryl axis is already present in the substrate, which can be either achiral (with low enantiomerization barrier) or prochiral (in symmetric starting materials). The stereogenicity is then revealed by DKR or desymmetrization reactions. The substrate may also be chiral, but racemic, and a kinetic resolution allows to obtain the enantioenriched product. A second strategy uses achiral activated substrates, and the stereogenic axis is created during the reaction. This approach typically applies to hindered indole heterocycles, which are functionalized at the C3 position using enantioselective organocatalysis.

R3 R2

R4

X

Z Y R5

Kinetic resolution or Dynamic kinetic resolution or desymmetrization

R1 Achiral, prochiral or racemic

R3 R2

R3 N

R4

X

Z Y

R1 Enantioenriched

C3 functionalization R2 of indole precursors

+ R

1

X

Achiral activated

Scheme 4.25  Enantioselective heterobiaryls from preformed cyclic systems.

Heterobiaryl atropisomers with small ortho-substituents possess low enantiomerization barriers. The chemical transformations of an existing small substituent into a larger one in such system allows to create stable atropisomers, and this strategy became very popular over recent years. Hence, a palladium-catalyzed enantioselective synthesis of indole atropisomers 87 has been developed by Gu and coworkers via an intramolecular dynamic kinetic resolution via C–H functionalization (Scheme  4.26) [45]. A TADDOL-phosphoramidite ligand 88 allowed to reach high yields and good enantioselectivies for the products. The transformation into the corresponding lactam was achieved (R = H, Ar = Ph), and its enantiomerization barrier was determined experimentally to be 130 kJ/mol at 90 °C. At this stage only, the MOM protecting group could be removed efficiently (HCl, MeOH, 50 °C).

89

90

4  Enantioselective Synthesis of Heterobiaryl Atropisomers Gu and coworkers [45] R

PdCl2 (5 mol%) OMOM 88 (6.5 mol%), pivalic acid

Ar

86

OMOM

Cs2CO3, DCE, 65 °C up to 99%, 91% ee

I N

R

N

Ar

Ar Ar O P N N Ph O O Ar Ar 88, Ar = 4-Ph-C6H4

O

87

Scheme 4.26  Pd-catalyzed DKR via intramolecular C–H functionalization. Source: Based on He et al. [45].

Shi and Zhang recently reported the possible intermolecular functionalization of the C2 position of the indole with various bulky electrophiles under organocatalytic activation with CPAs (Scheme  4.27) [46]. Hence, the use of azodicarboxylate 90 and 3-aryl indoles 89 allowed the enantioselective access to the corresponding axially chiral naphthylindoles 91 in good yields and high enantioselectivies (Scheme 4.27a). Interestingly, with bulky hydroxybenzyl alcohols 93 as electrophiles, the CPA organocatalyst activates the in situ generated o-quinone methide (o-QM) intermediate to simultaneously control the ­configurations of both the stereogenic axis and the carbon atom (Scheme 4.27b). The utility of the products was demonstrated by their easy transformation into a chiral ­phosphine ­organocatalyst, which showed good properties in the ­enantioselective (4 + 1) cycloaddition of o-QM with Morita–Baylis–Hillman adducts. Theoretical calculations confirmed an important increase of enantiomerization barriers between the C2-unsubstituted ­naphthylindoles ­precursors (ΔG‡rot  =  100 kJ/mol) and the final ­products (125 kJ/mol 20 : 1 dr

160 up to 95%, 99% ee > 20 : 1 dr

Scheme 4.47  Conversion of two stereocenters to one or two stereogenic axes. Source: Modified from Hu et al. [74].

In the next example, another sequential access to heterobiaryl atropisomers was ­realized, but here, the intermediate was an axially chiral styrene 162 that cyclized under strongly basic conditions in the subsequent step to afford the 2-arylpyrrole atropisomers 163 in good yields and with excellent transfers of chirality (95–100%) (Scheme 4.48) [75]. The enantioenriched atropisomeric alkenes were generated in good efficiency by an organocatalytic enantioselective N-alkylation of achiral secondary enamine p ­ recursors 161. Tan and coworkers [75] 2

R1HN

4

R 164 R4 Br 1 R N 2 CO2R 165 (10 mol%) R3 Cs2CO3 toluene, 0 °C, 6 d up to 99%, 94% ee

CO2R

161

4

R LDA (2.5–6 equiv) 2 THF, ‒78 °C, 1‒2 h R1 N CO2R up to 96%, 94% ee R 100% es

CO2R2

162

163

OH

N

+

CO2R

2

–

Br

F

O N

3

R

tBu

F Ar F 165, Ar = 3,5-(CF3)2C6H3 tBu

Scheme 4.48  Chirality transfer from axially chiral styrenes to heterobiaryls. Source: Modified from Wang et al. [75].

Inspired by the work of Bugaud, Bressy, and Rodriguez on the oxidative central-toaxial chirality conversion for the enantioselective access to 4-arylpyridines [29], Bertuzzi and Corti developed a central-to-axial chirality conversion approach to construct enantiomerically enriched indole-quinoline atropisomers 169 (Scheme 4.49) [76]. The use of a CPA as an organocatalyst directly furnished the highly hindered tetrahydroquinoline 168 in good yield and enantioselectivity via an enantioselective Povarov cycloaddition of 3-alkenylindole 167 and N-arylimine 166. An ensuing oxidative aromatization with DDQ then afforded the indole-quinoline atropisomers 169 in good yields and conversion percentages (cp = 66–100%). Interestingly, the introduction of a bulky R2 group (2-methoxynaphthyl or 2-methylindolyl) allowed the enantioselective synthesis of challenging quinoline atropisomers bearing two stereogenic axes but with moderate diastereoselectivity. In the case of the 2-methylindolyl substituent, the low enantiomerization barrier of this second stereogenic axis necessitated the additional oxidation with m-CPBA to obtain a configurationally stable double-axis atropisomer with efficiency (60% yield, 9.4 : 1 dr, 90% ee).

4.4  ­Atropisomeric Heterobiaryls Featuring Two Five-Membered Ring Bertuzzi and coworkers [76] R2

N

1

R

+ R3

166

HN

HN (R)-59 (5 mol%) toluene, r.t., 18 h

3

R1

R R4

Ar

R4

N H

O O P O OH N H 167

R3 R4

1 DDQ, MeCN R

0 °C, 64 h N

R2

2

R

169, up to 97%, 99% ee 100% conversion

168, up to 97%, 99% ee

Ar (R)-59 Ar = 2,4,6-(iPr)3-C6H2

Scheme 4.49  Enantioselective construction of indole–quinoline atropisomers. Source: Based on Bisag et al. [76].

4.4 ­Atropisomeric Heterobiaryls Featuring Two Five-Membered Rings The enantioselective access to heterobiaryls featuring two five-membered rings is even more difficult because of generally very low enantiomerization barriers. Only few examples have been reported to date and three main strategies exist: (i) the enantioselective functionalization of heterobiaryls, (ii) the aromatization of bis-heterocycles with a centralto-axial chirality conversion, and (iii) the atroposelective ring formation of one of the two five-membered heterocycles.

4.4.1  Functionalization of Heterobiaryls The group of Shi reported an efficient access to axially chiral biindole skeletons from prefunctionalized biindoles in which free rotation around the axis was possible (Scheme 4.50) [77]. The smart choice of an isatin-derived 3-indolylmethanol as the bulky electrophile under CPA-activation not only blocked the rotation and created the axial chirality but also forged a stereogenic quaternary carbon atom. The highly congested tri-indolic molecules were formed in high yields under excellent diastereo- and enantiocontrol. The use of a quinone imine ketal as an alternative electrophilic partner was possible even if lower enantioselectivities were observed in this case. The enantiomerization barrier of one final Shi and coworkers [77]

170

R2

H N

R2 R3

R2 R1

+

O

173 (5 mol%) Toluene, 30 °C, 5 Å MS, 3 h R5 N

N H

Ar R6 OH

R4

N H

171

O O P O OH Ar 173, Ar = 2-naphthyl

H N

R2

O

R3 R5 N

R1 N H

R6

HN R4 172, up to 95%, 99% ee > 95 : 5 dr

Scheme 4.50  Biindole heterocycles displaying axial and central chiralities. Source: Based on Ma et al. [77].

103

104

4  Enantioselective Synthesis of Heterobiaryl Atropisomers

compound (R1 = R3 = R4 = R6 = H; R2 = Ph; R5 = Bn) was estimated to 203 kJ/mol by theoretical calculation, representing a particularly high value for this class of atropisomers. Very recently, the same group extended this protocol to the use of isatin-derived imines as bulky and reactive electrophiles for the enantioselective synthesis of a related class of 3,3′-biindoles atropisomers [78]. The palladium-catalyzed atroposelective C–H alkynylation presented before (Scheme 4.28) was also used to access bis-thiophene and furan-thiophene heterocycles 175 as highly challenging substrates (Scheme  4.51) [47]. In the case of bis-thiophene [79], the reaction worked well and the alkynylated molecule was obtained in great efficiency. In contrast, replacing one sulfur atom by an oxygen atom dramatically decreased the enantiomerization barrier (from 132 to 103 kJ/mol), which explained the low enantioselectivity (5% ee) obtained in this case. The synthetic usefulness of the method was demonstrated by the conversion of the aldehyde moiety to the corresponding carboxylic acid using the Lindgren– Pinnick oxidation. Shi and coworkers [47] S TIPS

CHO +

Br

X 174

S

Pd(OAc)2 (10 mol%) (30 mol%)

X = S, 98%, 93% ee

CHO

+

L-tert-leucine

ΔG+rot = 132 kJ/mol = O, 98%, 5% eeDG

AgTFA, AcOH/toluene 55 °C, 72 h, N2

TIPS X

97

+

ΔG+rot = 103 kJ/mol

175

Scheme 4.51  Enantioselective Pd-catalyzed C–H alkynylation. Source: Based on Zhang et al. [47].

4.4.2  Aromatization of a Bis-heterocycle The second strategy to the challenging atropisomers featuring two five-membered rings consists of an aromatization of a centrally chiral bicyclic molecule with a chirality conversion. Two complementary methods have been reported in 2019 and exploited the Barton– Zard pyrrole synthesis. As seen before (Scheme 4.42), the work of Du and Chen was also applied to the synthesis of enantioenriched 5-5 heterobiaryls 177 with great success [68] (Scheme  4.52). Several enantiomerization barriers were determined by kinetics of racemization studies and confirmed to be reasonably high for atropisomers featuring two five-membered rings (ΔG rot = 111 kJ/mol for R1 = H; R2 = Ph; X = NH). Chen and coworkers [83]

R2 X R1

NO2 176, X = NR, O, S

CN CO2R1 141 Ag2O (2.5 mol%) 144 (5 mol%) K2CO3, PhCF3

O2N

NH

N

CO2tBu

DBU, PhCF3 R1

X

R2

R2 R1

X

Central-to-axial chirality conversion 177, 99%, 96% ee

Scheme 4.52  Barton–Zard reaction to indolopyrroles atropisomers. Source: Based on He et al. [68].

4.4  ­Atropisomeric Heterobiaryls Featuring Two Five-Membered Ring

The methodology of Zhu as discussed (Scheme 4.40) was also applied for the preparation of atropisomers made up of two five-membered rings even if the efficiency was slightly reduced (Scheme 4.53) [69]. Zhu and coworkers [68] N tBuO2C

NO2 Et

74 (10 mol%) Toluene, 5 Å MS, 30 °C

N

Ph

s = 19

N Me rac-178

EtO2C

Et

+

37% conversion

Ph

HN

NO2 Et

EtO2C

NMe 178, 50% ee

Ph MeN 179, 84% ee

Scheme 4.53  Kinetic resolution of racemic Barton–Zard indolodihydropyrroles. Source: Based on Zheng et al. [69].

4.4.3  Atroposelective Ring Formations The third approach to these valuable heterobiaryls involves the enantioselective construction of one of the heterocycles. This has been described by Li and coworkers who reported the Rh(III)-catalyzed atroposelective oxidative coupling of indoles 180 and o-alkynylanilines 181 for the synthesis of highly enantioenriched bi-indolyl 182 systems (Scheme 4.54) [80]. This methodology includes notably a C–H functionalization and a nucleophilic cyclization. The isolation of an enantiomerically pure rhodacycle from stoichiometric reaction provided information for mechanistic studies and allowed to identify a rationale for the atroposelectivity. Racemization studies were performed on several bi-indolyl atropisomers and the enantiomerization barriers were found to be relatively low for most of the products (ΔG rot  =  105–110 kJ/mol) unless a bulky group was present at R2 position (R1  =  Et; R2 = Cy, ΔG rot > 130 kJ/mol). Li and coworkers [69] R1

180

N Pym

+ 2

R

NHTs

183 (5 mol%) AgOAc (20 mol%)

181

PivOH (2 equiv) MeOH, air, 30 °C up to 93%, 97% ee

Pym N

R1 R2 NTs 182

OMe OMe Rh I I 2

183

Scheme 4.54  Rh(III)-catalyzed enantioselective synthesis of axially chiral bis-indolyls. Source: Based on Tian et al. [80].

When a five-membered ring heterocycle was included in an atropisomer, the ones with sulfur atom (thiophene or benzothiophene) gave rise to higher configurational stabilities, as compared with furans or pyrroles [81, 82]. This behavior followed the van der Waals radius order and revealed that bigger heteroatoms would tend to bring ortho substituents closer around the stereogenic axis. In this field, Kato’s group reported the enantioselective construction of axially chiral bis-benzothiophenes 185 via a domino cyclization-dimerization of o-alkynylphenyl sulfides 184 catalyzed by a Pd(II)–bisoxazoline catalyst

105

106

4  Enantioselective Synthesis of Heterobiaryl Atropisomers Kato and coworkers [80] [Pd(TFA)2(L*)] (14 mol%) R1 p-benzoquinone MeOH, –20 °C R2 up to 95%, 98% ee S O 184

R2

S

O

R1 R1 S 185

O N

R2

N

Ar Ar L* = Ar = 4-MeOC6H4

Scheme 4.55  Pd-catalyzed synthesis of axially chiral bis-benzothiophenes. Source: Based on Peng et al. [83].

(Scheme 4.55) [83]. Coordination of the Pd complex to the alkyne triggers the intramolecular nucleophilic addition of the sulfur atom on the alkyne, giving rise to a benzothienyl Pd(II) intermediate. DFT calculations indicated that the bisoxazoline ligand enhances the alkynophilicity of this intermediate and thus favors the coordination of a second o-alkynylphenyl sulfide, leading to the dimerization after a reductive elimination step.

4.5  ­Conclusion and Outlook The enantioselective synthesis of atropisomeric heterobiaryls is less developed compared to the more classical six-membered biarylic axially chiral molecules. However, in the last few years, synthetic chemists took up this challenge, opening important new synthetic opportunities, notably thanks to the huge progresses of organocatalytic activation methods that provide contemporaneous and smart solutions. Alternatively, well-established metalcatalyzed direct cross-coupling reactions are still poorly efficient when axially chiral ­heterobiaryls are considered and only a very recent breakthrough has been proposed in the cases of azole derivatives. With this chapter, we hope that the readers will be convinced that the design of ingenious methodologies is still possible and should open the way to other original strategies. Moreover, this will produce hitherto unseen chiral molecular ­species with potential applications for a wide cross section of chemistry including chiral ligands, organocatalysts, materials, and new biologically relevant molecules.

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109

5 Asymmetric Synthesis of Nonbiaryl Atropisomers Mirza A. Saputra, Mariel Cardenas, and Jeffrey L. Gustafson San Diego State University, Department of Chemistry and Biochemistry, San Diego, CA, 92182-1030, USA

5.1 ­Introduction While the majority of studies on atropisomerism have focused on biaryl and heterobiaryl systems, there are a multitude of common scaffolds that can exhibit stable atropisomerism (Figure 5.1) [1–4]. Although the majority of these systems exhibit lower energetic barriers to racemization than biaryls, with the right substitution pattern, many of these scaffolds can exhibit barriers to racemization approaching or exceeding 30 kcal/mol, the unofficial threshold for sufficient stability for drug development put forth by LaPlante and coworkers [5, 6]. As many of these scaffolds are ubiquitous throughout modern drug discovery, there is a growing literature on the enantioselective synthesis of these nonbiaryl atropisomers. In this chapter, we will discuss the state‐of‐the‐art enantioselective syntheses of the most studied nonbiaryl atropisomeric scaffolds. It should be noted that in 2015, Sivaguru and Sibi thoroughly reviewed this topic [3]; thus, we will focus on the seminal examples before as well as newer works that have been published after the Sivaguru review.

5.2 ­Styrenes The potential for axially chiral styrenes (Figure  5.2) was first studied by Adams and coworker in the 1940s [7]. The topic was then largely overlooked until Kawabata first ­proposed this type of atropisomer in 1991 to demonstrate a new concept of memory of chirality [8]. Despite this early work, only limited reports were found regarding studies of the catalytic asymmetric synthesis until recently. This is presumably due to the fact that atropisomeric styrenes possess lower stereochemical stabilities, making it difficult to achieve enantioselectivity. In the past few years, there have been several breakthroughs that have allowed chemists to overcome these difficulties, leading to many exciting ­strategies toward the enantioselective synthesis of axially chiral styrenes.

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

110

5  Asymmetric Synthesis of Nonbiaryl Atropisomers R4

R4 R4

O

R3

R1

R2

N

R3

Styrenes

O R1

R2

R1

O

Amides

R3

R3

R4 R2

N

R1

R2

Diaryl ethers

R4

O R2 R1

Anilides

N

N R4

R3

Ureas

N

O R1

Lactams

H N R1

R3 R2

Diaryl amines

Figure 5.1  Commonly studied classes of stereochemically stable nonbiaryl atropisomers (the axis is in bold). Source: Brandes et al. [1], Takahashi et al. [2], and Kumarasamy et al. [3, 4].

B C

A D

A C

B D

Bulky substituents A, B, C, and D E alkene geometry

Figure 5.2  Axially chiral styrene motif.

5.2.1  Axially Chiral Styrenes via Point-to-Axial Chirality Transfer Point‐to‐axial chirality transfer has been a long utilized strategy to achieve atropisomer‐selective synthesis [9, 10]. In 2001, the Miyano group demonstrated central‐to‐ axial chirality transfer via addition of naphthyl‐based Grignard reagent 1 to α‐chiral tetralone 2 using Lewis acid Yb(OTf)3 to afford a single diastereomer of carbinol 3 (Scheme  5.1a) [11]. Dehydration of this alcohol afforded dihydrobinaphthalene 4 in 93% ee. More recently, the Smith group exploited cation‐directed O‐alkylation of an enolate derived from racemic 1‐aryl‐2‐tetralones 5 to achieve the enantioselective (a) Miyano and coworkers [11] MgBr OMe

O Me

+

OMe (CF3CO)2O OH Me CH2Cl2, r.t., 2 h

Yb(OTf)3 THF, r.t., 2 h

1

2

OMe Me 4, 96%, 93% ee

3, 92% (b) Smith and coworkers [12]

R1

2

O OR3

R

5 Point chiral and racemic

6 (10 mol%), BnI (3 equiv) K3PO4 (10 equiv) C6H6/CH2Cl2, 0 °C, 48 h R1

R2

R4N+ OH OR3 7

Axially chiral enolate

R1

R2

OBn OR3

OMe

+

N

H

Br

OH

8 ∆Grac = 32 kcal/mol t1/2 (139 °C) = 64 min

N

F 6

F F

Scheme 5.1  Point-to-axial chirality approach to form axially chiral styrenes. Source: (a) Based on Hattori et al. [11]. (b) Based on Jolliffe et al. [12].

5.2 ­Styrene

synthesis of atropisomeric styrenes 8 (Scheme 5.1b) [12]. Their counter anion approach was directed by phase‐transfer catalyst 6 to furnish the enolate intermediate 7. Further aromatization of this scaffold with dichlorodicyanobenzene (DDQ) afforded axially chiral biaryl.

5.2.2  Axially Chiral Styrenes Controlled by Chiral Auxiliary One of the early methods to construct axially chiral styrenes is via chiral auxiliary. In 2009, Mori et al. reported their preparation of axially chiral styrene bearing a chiral sulfoxide as a precursor toward their asymmetric synthesis of antibiotic tan‐1085 [13]. Selective deprotection of the ortho‐phenol of sulfoxide 9 (Scheme  5.2) resulted in an intramolecular ­hydrogen bond that was present in diastereomer 11, but not 10, allowing for a diastereomeric equilibration upon heating to a 11 : 89 mixture, with 11 as a major isomer. Mori et al. [13] OMOM

MOMO O + S p-Tol

OMOM OTBDPS

SnBr2, toluene 63 °C, 4 h 70 %

OTBS

9, inseparable

OMOM OTBDPS +

HO p-Tol + S O– 10 ∆, toluene

OTBS

H

O

O + S

p-Tol

OTBDPS OTBS

Separable diasteromers 11 25 : 75 er (initial ratio) 11 : 89 er (after heating), 99% ee

Scheme 5.2  Mori’s sulfoxide axially chiral styrene. Source: Based on Mori et al. [13].

Simultaneously in the same year, Mori et al. also reported a study applying this strategy to synthesize enantiomerically pure C2‐symmetric paracyclophanes, which contain axial and planar chiralities [14]. Using the first‐generation Grubbs catalyst, they achieved diastereoselective ring‐closing metathesis in good diastereoselectivity (dr) and yields that varied based on the length of the chain and the geometry of the olefin (Figure 5.3).

5.2.3  Metal-Catalyzed Enantioselective Synthesis of Axially Chiral Styrene In pioneering work, Gu et al. developed an enantioselective construction of axially chiral styrenes from aryl bromides 16 and hydrazone 17 by using palladium catalyst with a chiral pyrrolidine‐based phosphoramidite ligand 18 (Scheme  5.3) [15]. Reduction of the phosphine oxide product 19 led to a new class of chiral (P. olefin)‐ligands that could be used for asymmetric allylation reactions [17]. The same approach was reported a year later by Wu et al. but by utilizing ligand 20 instead [16]. Following their previous report, the Gu group disclosed that this phosphine oxide scaffold 21 could be functionalized through photoredox C–H functionalization to form aryl cyclohexene 22 (Scheme 5.4a) [18]. Meanwhile, in 2018, the Xu group reported a different C–H functionalization pathway to synthesize axially chiral styrenes 24 by utilizing

111

112

5  Asymmetric Synthesis of Nonbiaryl Atropisomers Mori et al. [14] 10 OH

12 O + S O p-Tol O– H

+ H S O p-Tol

+ S

+ S HO p-Tol O–

12 89%, E/Z = 11 : 1

O p-Tol

13 41%, >99% ee, (Z) only 10

12 OH

OH

+ S p-Tol O HO

+ S

+ O p-Tol p-Tol S HO O– 14 77% (E), >99% ee, 9% (Z)

+ S

15 Not observed

O p-Tol

Figure 5.3  Some examples of Mori’s C2-symmetric paracyclophanes. Source: Modified from Mori et al. [14].

Gu and coworkers [15], Wu et al. [16]

Br

O

NNHTs

P(Ar)2 + R

Pd(OAc)2, 18 or 20

*

tBuOLi, 1,4-dioxane 17

16 (R = H, CO2iPr) F

Me Me O

O F

R

F

O

P N

OMe

O F

O

O

P

P tBu tBu

O P(Ar)2

19

OMe

18

20

(Gu and coworkers [15]) 40–99%, 85–97% ee

(Wu et al. [16]) 62–80%, 76–87% ee

Scheme 5.3  Pd-catalyzed synthesis of axially chiral styrenes bearing phosphine oxide. Source: Based on Feng et al. [15] and Wu et al. [16].

ketoxime ether 23 as a directing group in the presence of Pd(OAc)2 as a catalyst, mono‐protected amino acid as a ligand, and AgOAc as an oxidant (Scheme 5.4b) [19]. More recently, the Shi group detailed their findings on asymmetric synthesis of axially chiral styrenes via Pd catalysis [20, 21]. Their C–H functionalization strategy began with the reaction of styrenes bearing pyridyl 25 with alkene in the presence of Pd(OAc)2, ligand 26, and Ag3PO4 (Scheme  5.5a) to give axially chiral alkenyl styrenes 27 with barriers to racemization up to 30 kcal/mol for larger ortho‐substituents. By slightly changing the conditions and the coupling partner to a triisopropylsilyl ether (TIPS)‐protected alkynyl, the

5.2 ­Styrene

reaction provided adduct 28 in similar results. These transformations were proposed to occur via intermediate 29. They then expanded the olefination strategy by subjecting racemizing 30 to the reaction condition using transient chiral auxiliary 31 to form intermediate 32, which led to product 33 (Scheme 5.5b). (a) Gu and coworkers [18]

R H

+ Ar12IOTf

P(O)Ar2

R

Pd(OAc)2, PPh3 NaHCO3

Ar1 P(O)Ar2

36 W lightbulb DCE, 70 °C, 6 h 63–99%, 86–99% ee 22

21 (R = H, OMe, F) (b) Xu and coworkers [19]

R1

N H R3

R2

R4, Pd(OAc)2 MPAA (Ac-L-Ala-OH)

OMe

R1

OMe

N

R4

R2

AgOAc, MeOH, 40 °C, 48 h 96–99% ee

R3

23

24

Scheme 5.4  Gu’s and Xu’s enantioselective C–H functionalization strategies. Source: (a) Based on Feng et al. [18]. (b) Based on Sun et al. [19].

(a) Shi and coworkers [20] R3

R2

3

N H

R R1

Pd(OAc)2, Ag3PO4 L-pGlu-OH

R4

+

Pd(OAc)2, Ag2CO3 L-pGlu-OH MeOH/DMSO = 1/1 60 °C, 24 h, air Br

R2 TIPS

(b) Shi and coworkers [21] R

R2

H

3

R

30

4

R 26

O

27

O

R3 R1

N Pd

3

R R1

N

R3

R2

O

R3

CO2H N H (L-pGlu-OH)

N O H

Transition state 29

tBu

tBu

NtBu2 O

+

R

28

H2N

CHO

1

4

TIPS

28–86%, 97–99% ee

R3 R1

N

MeCN/tBuOH, 50 °C 36 h, air 20–99%, 4–96% ee

26

25

R3

R2

31

Pd(OAC)2, BQ Co(OAc)2•H2O (BnO)2PO2H, AcOH DMSO, O2, 40 °C, 48 h 10–95%, 73–99% ee

CHO

1

R

R4

R2

R3

33

R

1

R2

N

NtBu2

Pd

O OAc

R3 Transition state 32

Scheme 5.5  Shi’s Pd-catalyzed C–H olefination to synthesize axially chiral styrenes. Source: (a) Based on Jin et al. [20]. (b) Based on Song et al. [21].

113

114

5  Asymmetric Synthesis of Nonbiaryl Atropisomers

5.2.4  Organocatalytic Synthesis of Axially Chiral Styrenes Seminal work of organocatalytic atroposelective synthesis of axially chiral styrenes via a direct enantioselective nucleophilic addition to alkynal was proposed by Tan and coworkers in 2017 (Scheme 5.6) [22]. Activation of alkynal 34 with amine catalyst and substituted diones 35 as a nucleophile proceeded via in situ generation of allenamine intermediate 36 and iminium ion 37 that controlled the E/Z selectivity. When R was iodine, rotational barrier of compound 38 in chloroform was 28 kcal/mol with t1/2 ~ 4.8 days at 50 °C, which was stable for asymmetric synthesis and other transformations. Tan and coworkers [22]

R R OTIPS

N H

O H

Ac

+

Ar Ac 35

34

N H

R = 3,5-Me2-C6H3 CH2Cl2, 0 °C, 24 h 54–95% ee

N Nu

Ar

Ac

Ac CHO

38

Nu H

36 Allenamine

N H 37 (E/Z)-selective

Scheme 5.6  Tan’s Michael addition via allenamine intermediate. Source: Based on Zheng et al. [22].

As part of the effort to explore vinylidene o‐quinone methides (VQM) as an active intermediate in asymmetric synthesis, the Yan group has actively studied the application of VQM to construct axially chiral styrenes through a formal nucleophilic addition with sulfones [23–27]. The active VQM intermediate can be generated through a prototropic rearrangement (tautomerization) of 2‐(phenylethynyl)phenol 39 under basic condition in the presence of quinine‐derived thiourea catalyst 40 to set the allene’s configuration (Scheme 5.7) [23]. They proposed that proline would react with the sulfinate salt to generate a quaternary ammonium salt, which would increase the solubility and reactivity of the sulfinate salt, while the activated sulfonate anion would attack the highly reactive VQM intermediate to furnish a library of axially chiral sulfone‐containing styrenes 41 in good yields and excellent enantioselectivities. Simultaneously, the Yan group also reported a one‐pot formation of axially chiral sulfone‐containing styrenes 43 and β‐amino diesters 44 from α‐amido sulfones 42 via waste‐ reuse strategy (Scheme 5.8) [24]. This tandem enantioselective reaction proceeded using the same thiourea catalyst 40 to catalyze the Mannich reaction before the following nucleophilic addition occurred in similar condition as Scheme  5.8. The enantioselectivities of both axial chirality in products 43 and point chirality in amines 44 were shown to be excellent with up to 99% ee.

5.2 ­Styrene Yan and coworkers [23] R-SO2Na, 40 H3BO3 CHCl3, 25 °C, 48 h

Ar

H

L-proline,

OH

SO2R

Ar

39

OMe

CF3

S N H HN

N

41

Ar

N

H

OH

63–99% ee

40

CF3

H O VQM intermediate

Scheme 5.7  Yan’s initial VQM study for axially chiral styrene synthesis. Source: Based on Jia et al. [23]. Yan and coworkers [24] Ar

O

O

BnO

(1) 40, Na2CO3, CH2Cl2, 0 °C, 24 h

OBn

OH +

NH2

R1 39

2

SO2R

H SO2R2

Ar

OH

(2) L-proline, H3BO3, 40, CHCl3, 25 °C, 48 h

42

43, 87–99% ee

+

NH2 1

R * CH(CO2Bn)2 44, 85–96% ee

Scheme 5.8  Yan’s second VQM approach to synthesize axially chiral styrenes. Source: Based on Li et al. [24].

Yan and coworkers then extended their sulfone chemistry involving VQM intermediate by transforming 1,4‐bis(phenylethynyl)naphthalene 2,3‐diol 45 to a 1,4‐distyrene compound bearing two contiguous chiral axes 47 (Scheme 5.9) [25]. This occurred through a stepwise reaction of double atroposelective nucleophilic addition of α‐amido sulfone that was activated by biscinchona squaramide catalyst 46. The obtained chiral products 47 was found to be stable without showing racemization and could potentially be used as chiral ligands for asymmetric synthesis. Yan and coworkers [25] OMe H

Ar

N

N NH HN

N

OH OH 45

Ar

NHBoc

+

SO2R

Ph

42

46

O

O

H N

OMe

CHCl3, 30 °C, 24 h >99% ee, >20 : 1 dr, >99 : 1 E/Z

SO2R

Ar

OH OH Ar

RO2S 47

Scheme 5.9  Yan’s extended VQM exploration in asymmetric synthesis. Source: Based on Li et al. [25].

115

116

5  Asymmetric Synthesis of Nonbiaryl Atropisomers

The Yan group also discovered that VQM could be employed to access contiguous stereocenters in vicinal diaxial styrenes and multiaxes system by using alkynyl naphthalene 48 (Scheme 5.10) [26]. They found that on using N‐iodosuccinimide (NIS) as an electrophile during the prototropic rearrangement, a new type of tetra‐substituted VQM species was produced instead of the previously known tri‐substituted VQM intermediate. Replacing the nucleophile with sulfonic acid 49 instead of the sulfonate salt simplified the nucleophilic addition by exploiting hydroxy cinchona‐squaramide catalyst 50. This overall diastereo‐ and atroposelective reaction afforded a broad range of axially chiral styrenes 51 containing two to three stereogenic axes in good yields with excellent enantioselectivities. Yan and coworkers [26] N

R1

OH S O

+ OH

3

R

2

R

HO O

O

48 (X = C, N)

R1

R3

O

S O

I

N

50, Ar = 3,5-(CF3)2C6H3 NIS, CH2Cl2, 25 °C, 6 h 87–97% ee >20 : 1 dr, >99 : 1 E/Z

49

X

HN Ar

H N

H

OH

R2 X

51

Scheme 5.10  Yan’s tetra-substituted VQM strategy. Source: Modified from Tan et al. [26].

Sequentially, Yan and coworkers described different approach in exploiting VQM to construct axially chiral styrenes that also bear point chirality [27]. In situ formation of VQM from alkynyl naphthol 39 with bis‐cinchona squaramide catalyst 46 followed by nucleophilic addition of racemic 5H‐oxazol‐4‐ones 52 afforded 53 in high enantioselectivities (Scheme 5.11). This transformation showcased the one‐step generation of single isomers containing three types of stereogenic elements (E/Z configurations, central chirality, and axial chirality). Organocatalytic reaction involving VQM intermediacy was also reported by Tan et al. for the synthesis of axially chiral disubstituted 1,1′‐(ethene‐1,1‐diyl)binaphthol (EBINOL) scaffold (Scheme 5.12) [28]. The generation of chiral VQM intermediate was

Yan and coworkers [27] Ar2

O

R + OH

O

N Ar1

39

52

46, CHCl3, 25 °C, 48 h 88–96% ee >20 : 1 dr, >99 : 1 E/Z

Ar1

O

N

R Ar2

O HO

53

Scheme 5.11  Yan’s synthesis of axially chiral styrenes containing point chirality. Source: Based on Huang et al. [27].

5.2 ­Styrene Yan and coworkers [28]

9-anthryl

R1 OH

XH + R3

R2

R3

O O P NHTf O

R1

9-anthryl

PhCF3, 0 °C, 36 h 90–99% ee

55

OH XH

R2

54, X = O or N–Ar

56

Scheme 5.12  Tan’s EBINOL synthesis via VQM intermediacy. Source: Based on Wang et al. [28].

catalyzed by 1,1′‐spirobiindane‐7,7′‐diol (SPINOL)‐derived chiral Brønsted acid via a concerted 1,5‐H transfer. Direct hydroarylation with 2‐naphthol 55 afforded EBINOLs 56 with excellent enantiocontrol and complete E/Z‐selectivity control. This newly formed chiral scaffold demonstrated its potential as a chiral catalyst in asymmetric reactions as a complement to the existing versatile BINOL and SPINOL backbones. Also in 2019, Tan and coworkers disclosed the application of axially chiral styrene to prepare axially chiral 2‐arylpyrroles via direct cyclization and axial chirality transfer strategy [29]. The transformation began with a straightforward N‐alkylation reaction of substituted enamine 57 with allyl bromide in the presence of quaternary salt cinchonine‐derived organocatalyst 58. This step established the axial chirality in 59, which was retained during the following cyclization step using lithium diisopropylamide (LDA) to give axially chiral 2‐arylpyrroles (Scheme 5.13). Yan and coworkers [29] CO2R1

H N

Ar

CO2R

Br 1

58, Cs2CO3 Toluene, 0 °C, 6 d 84–94% ee

R2 57

= Br, I, CF3, Ph

CO2R1 Ar

N

Ar1

+

O

CO2R1

Br

F

N F

H F

R2

N

59

58

Ar2

Ar1 = 3,5-(CF3)2C6H3 Ar2 = 3,5-(tBu)2C6H3

Scheme 5.13  Tan’s axially chiral 2-arylpyrroles via axially chiral styrene cyclization. Source: Based on Wang et al. [29].

Unlike the previously reported methods utilizing nucleophiles to attack the formed VQM intermediate, the Zhao group in 2020 described their synthesis of axially chiral styrene via electrophilic carbothiolation (Scheme 5.14) [30]. o‐Alkynylaryl amine 60 was first reacted with the activated electrophilic sulfur reagent by Ts‐protected sulfide catalyst 62 in the presence of Lewis acid to form the thiirenium ion intermediate. The following conversion of this ion to a chiral aza‐VQM intermediate and subsequent intramolecular hydroarylation afforded the chiral amino sulfide 63. This scaffold has potential as (S,N)‐ligands and catalysts, as well as to undertake further functionalization toward axially chiral biaryl amino sulfide or other derivatives.

117

118

5  Asymmetric Synthesis of Nonbiaryl Atropisomers Zhao and coworkers [30] Me

NHMs + O 60

SR N O

S NHTs

Ph

OiPr 62

TMSOTf, CH2Cl2/CHCl3 61 –78 °C, 18 h R = aryl, CF3 56–96%, 89–98% ee

SR NHMs 63

+ R S NHMs

Thiirenium ion

Scheme 5.14  Zhao’s electrophilic carbothiolation of alkynes. Source: Based on Liang et al. [30].

5.3 ­Amides Atropisomeric benzamides are common moieties across many pharmaceuticals and have also been utilized as axially chiral ligands in asymmetric catalysis. While benzamides typically possess lower energetic barriers to racemization than biaryls, there have been numerous examples of compounds that possess barriers to racemization that are >28 kcal/mol. Because of the ubiquity of benzamides in synthesis, there have been numerous studies on their enantioselective synthesis that employ diverse reactivities. In 2015, Sivaguru and coworkers thoroughly reviewed the state‐of‐the‐art syntheses of axially chiral benzamides [3]. For this subchapter, we will highlight some of the seminal strategies and focus on the more recent examples of the asymmetric synthesis of atropisomeric amides.

5.3.1  Stereochemical Stability of Atropisomeric Amides The potential for stereochemically stable atropisomeric benzamides was thoroughly studied in seminal work from Clayden and coworkers [31–33]. For example, tertiary benzamides with one ortho‐substituent exist as rapidly interconverting class 1 atropisomers according to the LaPlante’s scale (Figure  5.4a). Similarly, sterically smaller substituents adjacent to the atropisomeric axis of di‐ortho‐substituted benzamides exhibit class 2 atropisomerism (Figure 5.4b). Finally, benzamides can exhibit substantial stereochemical stability when there are sterically bulky substitutions on the amide amine and two larger substituents ortho to the aryl‐carbonyl axis (Figure 5.4c).

5.3.2  Lithiation of Atropisomeric Amides to Access Various Alkylations Clayden and coworkers studied the racemic syntheses of stereochemically stable ortho‐ substituted tertiary 1‐napthamide atropisomers via lithiation with sec‐BuLi and subsequent quenching with various electrophiles [34, 35]. In 1996, Beak and coworkers extended this work to asymmetric synthesis by using a (−)‐sparteine/sec‐BuLi system (Scheme  5.15a) [36]. Clayden and coworkers later used similar conditions to affect an enantioselective silylation. The resulting point chiral center then allowed for the equilibration of the amide atropisomeric axis to a single atropisomer, which could be conformationally locked via the incorporation of a phosphine moiety using standard conditions

5.3 ­Amide (a) Et N

O

Et R1

64 R1 = iPr Grac = 15.5 kcal/mol 65 R1 = Et Grac = 14.2 kcal/mol

iPr

NCy2

O

O

N

Si

OH

66 Grac = 23.9 kcal/mol

(b)

iPr

67 Grac = 25.2 kcal/mol

(c)

iPr iPr N O Et

iPr iPr N O O O

68 Grac ~ 28.6 kcal/mol t1/2 ~ 1 year

iPr iPr N O OH Et

H

Grac ~ 31.1 kcal/mol t1/2 ~ 100 years

69

70

Figure 5.4  Evaluation of the atropisomeric stability of various ortho-substituted benzamides. (a) Racemic amides (Class 1 atropisomer), (b) Class 2 atropisomer, and (c) Stable atropisomers.

(a) Beak and coworkers [36]

R1

R1 N

O

72, sec-BuLi, R2-X

R1

R1 N

72, (–)-sparteine

O R2

Et2O or pentane, –78 °C 5–62%, up to 63% ee

H N

71

N H

(Sa)-73

(b) Clayden et al. [37] O

N(iPr)2 (1) 72, sec-BuLi, tBuOMe pentane, –78 °C

O

N(iPr)2 SiMe2 (1) sec-BuLi (2) Ph2PCl

(2) TMSCl

74

90%, 69% ee

(Sa)-75

O

N(iPr)2 SiMe2

Ph2P

(Sa)-76, >97% ee

Scheme 5.15  Examples of atroposelective lithiation-alkylations. Source: (a) Based on Thayumanavan et al. [36]. (b) Based on Clayden et al. [37].

(Scheme 5.15b) [37]. Since these works, there have been similar reports using other conditions and chiral ligands to accomplish similar transformations [38]. In 1998, Uemura and coworkers found that enantiopure benzamides (S)‐78a could be synthesized from enantiopure planar chiral (arene)chromium complexes 77a (Scheme 5.16a), observing near‐quantitative transfer of planar chirality to axial chirality upon removal of the chromium [39]. In 2002, Uemura and coworkers reported the asymmetric lithiation of prochiral (arene)chromium complexes 77b using chiral amide bases, the most optimal being 79, to differentiate between enantiotopic ortho‐methyl groups (Scheme 5.16b) [40].

119

120

5  Asymmetric Synthesis of Nonbiaryl Atropisomers (a) Koide and Uemura [39] O

Et N

Et

Cr(CO)3

Et N

O

(1) tBuLi, TMEDA, THF, –78 °C

Et

(2) EtI (3) hv, O2, Et2O, 0 °C 32%, 94% ee

(S)-78a

77a, enantiopure (b) Uemura and coworkers [40] Et N

O

(1) (R,R)-79, nBuLi, –76 to –30 °C (2) R1X

Et

O

Et N

(3) hv, O2, Et2O, 0 °C

R1

R1

Cr(CO)3 77b

Et

= Me, 85%, 86% ee (R)-78a, (R)-78b, R1= Bn, 41%, 83% ee (R)-78c, R1 = Allyl, 52%, 83% ee

NH

(R,R)-79

(R)-78

Scheme 5.16  Atropisomeric benzamides via desymmetrization of planar chirality. Source (a) Based on Koide and Uemura [39]. (b) Based on Koide et al. [40].

5.3.3  Syntheses of Atropisomerically Stable Amides via Chiral Auxiliaries Clayden et  al. have also observed that ortho‐lithiated benzamides could be quenched with chiral sulfinate 81 to afford a mixture of diastereomeric sulfoxide atropisomers (Scheme 5.17). At ambient temperatures, this mixture equilibrated to a major conformer in dr up to 99 : 1. A subsequent sulfur–lithium exchange, followed by an electrophilic quench, led to stereochemically stable atropisomeric amides 84 with no degradation in er [33]. Clayden and coworkers also demonstrated that atropisomeric amides that possess an aldehyde adjacent to the axis such as 85 could be equilibrated via the addition of proline‐derived Clayden et al. [41]

R1 O

N

R2

R1

(1) sec-BuLi, THF, –78 °C (2) 81, –78 to 0 °C (3) NH4Cl, 20–25°C

R1 O N 1 R (S) 2 S R O R3

82

(1) tBuLi, TMRDA, THF, –78 °C, 5 min @ 20–25 °C (2) R4X

R1

3

R

80

O

O S

81

O 2

R

3

(R)

50–97%, up to 99% ee

N R1

83

S O

R1 O

N

R2

R1 R4

R3 (R)-84

R

Preferred conformation after r.t. quenching

Scheme 5.17  Atropisomeric amides via diastereomeric equilibration using (−)-methyl sulfinate as chiral auxiliary. Source: Modified from Clayden et al. [41].

5.3 ­Amide

diamine 86 to give 87 in high dr (Scheme 5.18) [41]. In this process, amide 85 racemized under the reaction conditions, allowing for amine 86 to react with a favored enantiomer, thus permitting dynamic kinetic resolution (DKR). Importantly, deprotection followed with a reduction yielded stable atropisomer products 88 in high ee values. Clayden et al. [41]

R

R N

O

N H

O

NHPh

R N R

O

86

N

H Toluene, reflux N

N Ph

N

85 R = Et, iPr

H (1) 1 M HCl, THF, 0 °C

R N

O

(2) NaBH4, NaOMe 0 °C, 30 min

R OH

N

87 88–89%, >90 : 10 dr

88 84–88%, 90–96% ee

Scheme 5.18  Proline-derived diamine as a chiral auxiliary to synthesize atropisomeric amides. Source: Modified from Clayden et al. [41].

5.3.4  Catalytic Asymmetric Dihydroxylation via Sharpless KR Conditions In 2002, Walsh and coworkers [42] disclosed the asymmetric dihydroxylation of ortho‐alkene containing benzamides 89 by employing Sharpless’s “AD‐mix” conditions (Scheme 5.19) [43]. Notably, either AD‐mix‐α or β yielded excellent selectivity factors for the kinetic resolution, allowing for isolation of the recovered starting materials in up to 98% ee. It should be noted that the atropisomeric amides in this work exhibited class 2 atropisomerism. Walsh and coworkers [42] R1 O

N

R

3

2

R

R

O

AD-mix-α or AD-mix-β

1

Sharpless KR

R1 N

R1 R

1 3

R

2

R

+

1N

R

R

O

OH

2

OH

89

rac-89

∆Grac ~ 23.88 kcal/mol (99.9 kJ/mol)

iPr O

N

iPr O

MeO

R3

90 Byproduct

AD-mix-α, s < 32 57% conv, 98% ee OEt AD-mix-β, s < 27

89a

Scheme 5.19  Walsh’s catalytic asymmetric dihydroxylation via Sharpless conditions. Source: Modified from Rios et al. [42].

5.3.5  Atroposelective Aldol Reactions via DKR Approach In 2004, Walsh and coworkers disclosed conditions for an atroposelective aldol reaction on ortho‐aldehyde‐substituted benzamides 91 (Scheme 5.20) [44]. In the presence of L‐proline, they were able to perform the asymmetric aldol reaction to give 92, in which they

121

122

5  Asymmetric Synthesis of Nonbiaryl Atropisomers Walsh and coworkers [44]

iPr

O

iPr N

O

N H

O

OH

O

iPr iPr N OH O

DMSO/acetone = 4 : 1 r.t., 48 h

H 91

iPr iPr N OH O

O +

92 (Major) 71–82%, 8 : 1 dr, 95% ee

93 (Minor)

Scheme 5.20  An enantioselective aldol condensation toward atropisomeric amides. Source: Based on Chan et al. [44].

installed a stereogenic center that increased the stereochemical stability of the atropisomeric axis. It should be noted that the products have increased barrier to rotation; thus, this induction of axial chirality proceeded with significant DKR character.

5.3.6  Atroposelective Halogenation of Aromatic Amides The Miller group observed that catalytic amounts of a low molecular weight peptide bearing a Brønsted basic tertiary amine were able to affect the asymmetric bromination of 3‐hydroxyl 1‐benzamides (94) via electrophilic aromatic substitution [45]. Depending on the starting materials, stereochemically stable di‐ and tri‐brominated products (96) could be obtained in good yields and enantioselectivities (Scheme  5.21a). Similarly, Renzi showed that urea‐based quinine derivatives could affect atroposelective

Barrett and Miller [45] Br R1 O

N

R2

R1

N Br O

95, CHCl3, –40°C 60–90%, 94 : 6 er

94

R3O

O N

N

O

O

R2 Br

Br

N

Boc

R3O Br

NH

HN

O

O

95

96

HN O

N

OMe

Ph

Murelli and coworkers [46] MeO

MeO

O OH

N

H O

97

NBS 98, CHCl3, 0 °C

O

O

N

OH

50%, 75 : 25 er N

Br

O 99 ∆Grot = 30.1 kcal/mol

HN O

N Boc

NH

HN O

98

OMe

Scheme 5.21  Miller’s peptide-catalyzed bromination of atropisomeric benzamides. Source: (a) Based on Barrett and Miller [45]. (b) Based on Hirsch et al. [46].

O

5.3 ­Amide

bromination in a similar fashion [47]. Later on, Miller applied this chemistry to amides with different substitutions (R1   R2) on the amide nitrogen, which presented a two‐axis problem (axial chirality and amide rotamers). They observed that the amide rotamers yielded different enantioselectivities; however, eventually, the rotamer ratio would equilibrate to the favored “diastereomer” [48]. Finally, Murelli and Miller employed this approach toward the resolution of atropisomeric tropone‐based amides such as 97. Notably, atroposelective bromination of seven‐membered ring of tropones led to ortho‐ substituted 99 possessing bond angles oriented more toward the axis that could result in significantly higher barrier to rotations than ­benzamides, allowing for more diverse substitutions of the amide nitrogen while still maintained the stereochemical stability (Scheme 5.21b) [46].

5.3.7  Atroposelective [2 + 2 + 2] Cycloaddition Toward Atropisomerically Stable Benzamides In 2008, Tanaka and coworkers disclosed the first enantioselective construction of the atropisomerically enantioenriched benzamides via a rhodium‐catalyzed [2 + 2 + 2] cycloaddition. Venerable chiral phosphine ligands such as 4,4′‐bi‐1,3‐benzodioxole‐5,5′‐ diylbis(diphenylphosphane) (SEGPHOS) or 2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl (BINAP) were able to affect the [2 + 2 + 2] cycloaddition between diynes 100 and alkynamides 101 to yield benzamides 102 in excellent yields and enantioselectivities (Scheme 5.22) [49].

Tanaka and coworkers [49] O + R1 100

R2

R3 N

R1 3

R

Rh(cod)2BF4 (S)-BINAP or SEGPHOS CH2Cl2, r.t., 1–5h 81–99%, 99% ee, >50 : 1 dr 1

101 R = C(CO2Bn)2, NTs, O

R

2

R3 * N R3 O 102

O PPh2 PPh2

O O

PPh2 PPh2

O (S)-BINAP

(S)-SEGPHOS

Scheme 5.22  Atroposelective [2 + 2 + 2] cycloaddition conditions. Source: Based on Suda et al. [49].

5.3.8  Enantioselective O-alkylation of Axially Chiral Amides Smith and coworkers synthesized chiral benzamides via their enantioselective O‐alkylation strategy (Scheme 5.23) [50]. They achieved DKR by exploiting benzamides 103 that possessed a phenol adjacent to the axis that could form an intramolecular hydrogen bond with the amide, leading to a stabilization of the planar conformation, and thus a significantly lowered energetic barrier to racemization. Using quaternary ammonium salts derived from quinine 104, they demonstrated that the enantioselective alkylation of the phenol could be affected, leading to stereochemically stable amides 105 with er up to 99 : 1.

123

124

5  Asymmetric Synthesis of Nonbiaryl Atropisomers Smith and coworkers [50] R3 R1

O

R2

N

R3

BnI, 104, Cs2CO3 (aq)

O H

OBn R1

C6H6, r.t., 48 h

R2

103 Intramolecular H-bonding allows for lowered barrier to racemization

O

N R2

H

R2

N

+

Br–

R4

OH

105 53–99%, 99 : 1 er ∆Grac < 32.5 kcal/mol

N

R4 104, R = 3,5-(tBu)2C6H3 4

Scheme 5.23  Smith’s cation-directed atroposelective O-alkylation. Source: Based on Fugard et al. [50].

5.4 ­Diaryl Ethers Diaryl ethers and related scaffolds are prevalent structural motifs in natural products (i.e. vancomycin and bastidins) and pharmaceuticals. These scaffolds can exhibit atropisomerism about their C–O axes when there are four adjacent substitutions (Figure 5.5). The potential for axial chirality in diaryl ethers was first discussed by McRae and coworkers in 1954 [51], followed by Dahlgard and Brewster in 1958 who stated the possibility of diaryl ethers to exist as separable atropisomers [52]. Several groups then studied this phenomenon via spectroscopic and chromatographic analyses, revealing that they possessed lower energetic barriers to racemization than biaryls [53–57]. Clayden elucidated that this was due to the two‐axis nature of diaryl ethers, allowing for a concerted gearing mechanism of racemization wherein simultaneous rotation of both axes enabled a lower‐ energy pathway of racemization [58]. Despite this, it is possible for diaryl ethers to exist as class 2 or even class 3 atropisomers. Nonetheless, the asymmetric syntheses of these scaffolds have remained elusive.

5.4.1  Resolution Studies of Diaryl Ethers In 1998, Fuji and coworkers were the first to resolve diaryl ether in a nonmacrocyclic system (Scheme 5.24) [59]. Ullman coupling of aryl halide and naphthol provided binaphthyl 106. They then transformed the methyl substituent via benzylic bromination and a (a)

(b) D O

A

C C B

D A

NH

O B

O

H2N NH

Cl

NH O

O At least three unsymmetrical ortho-substituents Two out of three substituents should be bulky Two possible chiral axes

Lenvatinib

MeO NH2 OMe

N

O

OMe CF3

Tefanoquine

Figure 5.5  Axially chiral diaryl ether scaffold. (a) Diaryl ethers scaffold and (b) Examples of drug containing diaryl ether.

5.4 ­Diaryl Ether Fuji et al. [59] (1) NBS, Benzoyl peroxide, CCl4

Me Me

O

(2) 2-nitropropane Na salt, EtOH-DMSO 106

(1) PhLi (2) Jones oxidation (3) PhLi

OHC CHO O

HO HO Ph

107

Ph Ph O Ph 108

Scheme 5.24  Fuji’s synthesis of diaryl ether bearing two cogs on each wheel. Source: Based on Fuji et al. [59].

subsequent oxidation to give aldehyde 107. Finally, this aldehyde was subjected to a three‐ step sequence to furnish a sterically bulky substituted atropisomer 108. Nearly a decade later, Clayden et  al. carried out an extensive study on simple acyclic ­diaryl ethers and deduced practical rules for what is needed for diaryl ethers to be atropisomerically stable [58]. A variety of ortho‐substituted diaryl ethers were synthesized for the study of C–O atropisomerism (Figure 5.6). Research data show that the atropisomerism phenomenon in diaryl ethers depends less on the total number of substituents than the substitution pattern. Additionally, if one of the aryl rings possesses symmetrical substituents, this diaryl ether will not display atropisomerism because their stereoisomers could interconvert through concerted bond rotation. Lastly, unsymmetrically substituted diaryl ethers will exhibit stable atropisomerism when one of the substituents is as large as tert‐ butyl group.

5.4.2  Enantioselective Synthesis of Diaryl Ether The first enantioselective synthesis of atropisomeric diaryl ethers was reported by Clayden et al. in 2008 wherein they utilized chiral sulfoxide auxiliaries (Scheme 5.25) [60]. They transformed ether 111 to sulfoxide 114 with a dr of 98 : 2 after equilibration. The sulfoxide was then oxidized to give bulky sulfone 115 where the stereochemistry at the C–O axis was conserved. They referred this strategy as dynamic resolution under thermodynamic ­control, which was also used later for the synthesis of diaryl sulfones [61]. In 2011, Clayden and coworkers disclosed a carbamate‐directed benzylic lithiation to achieve the enantioselective synthesis of atropisomeric diaryl ether (Scheme  5.26) [62]. This was achieved via a desymmetrization of carbamoyloxymethyl 116 using a sec‐BuLi‐ sparteine system. The chiral organolithium was then quenched with tin chloride reagents HO

R1 OH R4

R3

O

R1

R2 OH 109

= I, Me, iPr, tBu, CMe2OH R2 = H, Me, iPr R3 = H, Me, Ph, CH2OMe R4 = H, Me

OH

O

R2 R1 110

Figure 5.6  Clayden’s atropisomerism in ortho-substituted diaryl ethers.

R1 = H, Me R2 = H, Me

125

126

5  Asymmetric Synthesis of Nonbiaryl Atropisomers Clayden et al. [60] O (1) nBuLi, –78 °C

O

Br (2) iPrS-S(O)iPr

R

112 or 113 –78 °C to –20 °C

111

(1) alkylation

O R

(2) oxidation

S O

R

O OO S Me

114

O H O

O

H O

115

O S

OH

112 = (Ss)[iPr] 113 = (Ss)[Cy]

Scheme 5.25  Clayden’s sulfoxide auxiliary for enantioselective synthesis of diaryl ethers. Source: Based on Clayden et al. [60]. Clayden et al. [62] Atroposelective stannylation

tBu O

Me OCb

CbO

(1) sec-BuLi, Et2O (–)-sparteine 72 –78 °C, 30 min (2) Bu3SnCl, 16 h

116

Stereospecific Sn-Li exchange/quench reactions

tBu Bu3Sn

O

(1) nBuLi, 2 h (2) Me3SiCl

Me

CbO

OCb

tBu

Me3Si

O

Me

CbO

117 >95 : 5 dr, 80 : 20 er

OCb

118 >95 : 5 dr, 80 : 20 er

Scheme 5.26  Clayden’s benzylic lithiation strategy. Source: Based on Clayden [62].

to give stannane 117 in moderate to good selectivities. This product could further be converted to product 118 via a stereospecific tin‐lithium exchange and electrophilic quenching with trimethylsilyl chloride (TMSCl).

5.4.3  Enzyme-Catalyzed Synthesis of Diaryl Ether Thus far, the only direct example in enzymatic synthesis of diaryl ether atropisomers is a novel biocatalytic approach reported by Clayden and coworkers in 2010 (Scheme 5.27) [63]. Symmetrical diol 119 was mono‐oxidized predominantly to (P)‐120 by galactose Clayden and coworkers [63]

tBu O

GOase kfast

tBu O HO

OH

O

P-selective KREDs

tBu

(+)-(P)-120

Me OH

119

GOase; kslow

Me

O O

tBu GOase kslow

O

Me

HO

O

GOase; kfast

Me O

121

M-selective KREDs

(+)-(M)-120

Scheme 5.27  Clayden’s biocatalytic redox synthesis of diaryl ethers. Source: Based on Yuan et al. [63].

5.5 ­Anilide

oxidase (GOase) through a combination of enantioselective desymmetrization and secondary kinetic resolution, where the minor isomer (M)‐120 was further oxidized to dialdehyde 121. Conversely, this dialdehyde could also be asymmetrically reduced to monoaldehyde (P)‐120 or (M)‐120 by using selective ketoreductase (KRED). These results showed the prospects of biocatalytic redox reactions for atroposelective synthesis via desymmetrization.

5.4.4  Synthesis of Scaffolds Related to Diaryl Ethers via Csp2-H Activation In 2018, Gustafson et  al. disclosed an atroposelective Csp2‐H activation to access O‐aryl quinoid motifs that are analogous to diaryl ether (Scheme 5.28) [64]. They observed that by subjecting O‐aryl quinoids 122 to nitromethane in the presence of quinine‐derived quaternary ammonium salt, catalyst 123 promoted yielding of methylated product 124 in moderate to good enantioselectivities. In some cases, several substrates resulted in competing “nitroethylated” adduct 125 in similar selectivities. Both of these alkylation products could be isolated in >95 : 5 er via trituration. These scaffolds exhibited high class 2 atropisomerism, with energetic barriers to racemization ranging from 25 to 28 kcal/mol. The stereochemical stability of this scaffold was studied via a dihedral angle contour diagram to demonstrate the potential for a concerted gearing mechanism (Figure 5.7), consistent with previously reported studies on diaryl ethers [58, 59].

Gustafson and coworkers [64]

R2

R2 tBu O

R1 O

123, MeNO2 K3PO4, 3 Å MS Toluene, –78 °C

R2

tBu

tBu O

Me

R O

1

+

OMe

O O2N

R O

O 122

O

123

124

125

10–80%, 42–60% ee 94% ee via trituration

30–65%, 20–50% ee 98% ee via trituration

Br CF3

NH N

O

+

N

H

1

O

NH

CF3

Scheme 5.28  Gustafson’s Csp2-H activation of O-aryl quinoid. Source: Based on Dinh et al. [64].

5.5 ­Anilides Atropisomeric anilides that possess a chiral Ar–N axis (Figure 5.8) have received a lot of recent attention as they can serve as building blocks in organic syntheses [65–67] or peptoid chemistry [68]. Axially chiral anilides can also be found in biologically active compounds such as metolachlor or other pharmaceuticals. While anilides possessing two large ortho substituents will exhibit high atropisomeric stability, they have proven difficult to access using current asymmetric methodologies. Anilides that possess one large and one small ortho substituent can still possess significant stereochemical stability, typically existing with energetic barriers to racemization around 28 kcal/mol [69]. This subchapter will

127

Me

180

O

140

Aryl dihedral (φ)

60

(Ra)-exo

O Ra

ce

Slow ∆G = 26.6 kcal/mol

–60

(Sa)-exo

–100

O

(Ra)-endo

–140 –180 –180

–140

tBu

R2

(Ra)-endo 0.001 (kcal/mol)

20 0 –20

–100

–60

–20 0 20

60

Quinone dihedral (θ)

Figure 5.7  The gearing mechanism contour diagram.

140

180

O

Slow ∆G = 26.6 kcal/mol

m

iza

n

Me

O tBu

O

q f

100

R2 (Ra)-endo 3.39 (kcal/mol)

tio

R1 (Sa)-exo 3.39 (kcal/mol)

R1

O

q f

1

R O

(Sa)-endo

100

O

FAST "Gearing"

O tBu

q f

R2

FAST "Gearing"

O

R1

q f

tBu O

R2

(Ra)-endo 0.000 (kcal/mol)

5.5 ­Anilide O R4

N

R3

O R2

or

R1

R2

N

O R1

• Ar–N twisted angle based on ortho substituents • R1 = H, R2 = tert-alkyl or I, large Ar–N twist angle (~90 °C)

Figure 5.8  Atropisomerism in axially chiral anilides or imides.

mainly focus on the newer chemistry of the acyclic anilides because there have already been several published reviews discussing axially chiral anilides [2, 3].

5.5.1  Stereochemical Stability of Axially Chiral Anilides The early examples of axially chiral anilide synthesis emerged in 1994 when Curran et al. first demonstrated that anilides can exhibit significant stereochemical stability [69]. Simpkins and coworkers then utilized axially chiral anilides as a “chiral auxillary” to allow for diastereoselective enolate alkylation [70]. A decade later in 2004, Curran reported a study on the energy needed for anilide racemization (Figure  5.9) [71]. As shown in the figure, ortho‐iodo anilides 126a–d with phenyl ring on the benzamide group possessed relatively high energetic barriers to racemization of 30–33 kcal/mol.

5.5.2  Kinetic Resolution or DKR to Access Axially Chiral Anilides Early examples of atroposelective anilide synthesis via kinetic resolution were reported by Simpkins where the atropisomers of ortho‐t‐Butyl anilide 127 were resolved via enantioselective deprotonation using chiral lithium amides, followed by quenching with haloalkane, returning unreacted 127 in 88% ee (Scheme  5.29a) [70]. Sequentially, the Taguchi group also accessed atropisomeric anilides by applying chiral pool approach (Scheme 5.29b) [72, 73]. Anilide 130 was achieved in 3 : 1 ratio of separable diastereomers from achiral aniline 129, which was further converged into atropisomeric anilide 131 in 96% ee. This scaffold was then used as a precursor in iodine‐mediated asymmetric Diels–Alder reaction. Around the same time, Simpkins and coworker also reported their Curran et al. [71]

O

O R1 Me

N

R2

(M)-126

I

O ∆Grot

R1 I

N

R2

4-Br-Ph Me

O Ph

N I

n

Me

N I

Me

(P)-126

Me (M)-126a 30.7 kcal/mol

Me (M)-126b, n = 0, 29.7 kcal/mol (M)-126c, n = 1, 32.6 kcal/mol (M)-126d, n = 2, 32.7 kcal/mol

Figure 5.9  Stability of atropisomeric anilides. Source: Based on Curran et al. [71].

129

130

5  Asymmetric Synthesis of Nonbiaryl Atropisomers (a) Simpkins and coworkers [70] O

(1) Ph N

N

O

Ph

N

Li

tBu

O

(2) MeI

N

128

rac-127

tBu

tBu

Me

127, 88% ee

(b) Taguchi and coworkers [72, 73] O OH

HN

EDC•HCl CH2Cl2 56%, 3 : 1 dr

(1) NaOH (2) MsCl, Et3N

N

OAc

tBu

129

O tBu

OAc

130

O N tBu

(3) PhSeNa (4) H2O2 80%, 96% ee

131

(c) Simpkins and coworkers [74, 75] O

O NH OAc

132

N

NaH, THF tBu

MEMCl 65%, 1 : 1.6 dr

O MEM tBu

OAc

SmI2, LiCl THF, r.t., 24 h 73%, 93% ee

N

tBu

H

133

MEM

134

Scheme 5.29  Early findings on kinetic resolution of axially chiral anilides. (a) Simpkins’ seminal kinetic resolution, (b) Taguchi’s chiral pool approach, and (c) Simpkin’s SmI2-mediated resolution of anilides. Source: (a) Based on Hughes et al. [70]. (b) Kitagawa et al. [72], and Kitagawa et al. [73]. (c) Hughes et al. [74] and Hughes and Simpkins [75].

resolution method using superstoichiometric amounts of SmI2 to get 2‐methoxyethoxymethyl ether (MEM)‐protected anilide 134 in 93% ee (Scheme 5.29c) [74, 75].

5.5.3  Synthesis of Axially Chiral Anilides via Planar to Axial Chirality Transfer Uemura and coworkers reported the first asymmetric synthesis of axially chiral anilides via lithiation of pro planar chiral anilide–chromium complex 135 in 2000 (Scheme 5.30) [76]. By using amide base 136, which was sobtained from reacting nBuLi with respective chiral amine, they stereoselectively deprotonated one of the ortho‐ methyl groups via electrophilic quenching to yield planar chiral anilide–chromium complex 137 with ee up to 97%. Exposure of ethereal solution of this complex to direct sunlight and air afforded chiral anilides (R)‐138 with retention of optical purity from the planar chiral precursor. They further studied this desymmetrization strategy of planar symmetry to generate axial chirality for the synthesis of axially chiral benzamides and anilides [40, 77].

5.5 ­Anilide Uemura and coworkers [76]

tBu

Ph

N

O N

Me

(1)

Me

Me

135

Cr(CO)3

MeN

Li

N

tBu

136

THF, –78 °C ~ –30 °C (2) E+, –78 °C

O Me

tBu N

Me CH2E Cr(CO)3 137, 92–97% ee

tBu hv, O2

O Me

N

Me CH2E

(R)-138

Scheme 5.30  Uemura’s desymmetrization strategy toward axial chirality. Source: Based on Hata et al. [76].

5.5.4  Metal-Catalyzed Synthesis of Chiral Anilides Independently, Taguchi and Curran disclosed the first catalytic asymmetric synthesis of atropisomeric anilides via N‐allylation strategy (Scheme  5.31a) [78, 79]. The method involved the allylation of N‐nonsubstituted anilide 139 with a chiral π‐allyl palladium complex to form axially chiral anilides 141 in excellent yields. Taguchi et al. then extended their Pd‐catalyzed chiral anilide synthesis to include N‐arylation by utilizing palladium/ SEGPHOS complex, facilitating the formation of N‐aryl anilides 144 with good ee values (Scheme 5.31b) [80, 81]. More recently in 2015, Du and coworkers described an asymmetric Pd‐catalyzed N‐allylation method toward achiral anilides 145 by employing a combination of Pd‐phosphorus amidite‐olefin ligand 147 to afford adducts 148 (Scheme 5.31c) [82]. Meanwhile, a rhodium‐catalyzed enantioselective intermolecular [2 + 2 + 2] cycloaddition was reported by Tanaka et al. in 2006 (Scheme 5.31d) [83]. The transformation began with 1,6‐diynes 149 and trimethylsilylynamides 150 in the presence of BINAP ligand to afford cycloaddition adducts 151, alongside major homo [2 + 2 + 2] cycloaddition of 1,6‐diynes byproduct. Following this report, Hsung and coworkers also reported a similar transformation of ynamides to cyclic adducts, in which configurations of both C–C and C–N chiral axes were established in one step [84].

5.5.5  Organocatalytic Synthesis of Chiral Anilides An asymmetric Friedel–Crafts amination reaction of 2‐naphthol was disclosed by Jørgensen and coworkers in 2006 (Scheme 5.32) [85]. Naphthol 152 was treated with azadicarboxylate in the presence of quinine‐based tertiary amine 153 to form intermediate 154, which eventually led to adduct 155 in 88% ee. Interestingly, the same transformation was able to modify catalyst 153 to a new type of cinchona alkaloid catalyst 156 that could increase the selectivities of reactions using naphthol. A binaphthyl‐modified chiral ammonium bromide‐catalyzed asymmetric synthesis of axially chiral o‐iodoanilides was reported by Maruoka and coworkers in 2012 (Scheme 5.33) [86]. Achiral o‐iodoanilide 157 was treated with alkyl or allyl bromide in the presence of catalyst 158 to afford adducts 160 or 161 via transition state 159. Sequentially, Maruoka group also reported a similar phase transfer catalysis approach to synthesize not only axially chiral o‐iodoanilides but also o‐tert‐butyl anilides [87].

131

132

5  Asymmetric Synthesis of Nonbiaryl Atropisomers (a) Taguchi and coworkers [78], Curran and coworkers [79]

O R2

NH tBu

+

O

(allylPdCl)2, 140 THF, r.t., 15 h

O O

O

R2

tBu

90–96%, 32–44% ee

R1

p-Tol P p-Tol P p-tolyl p-tolyl

N

R1 139

140, (S)-tol-BINAP

141

(b) Taguchi and coworkers [80, 81] O R2

NH

tBu +

Ar

Pd(OAc)2, 143, tBuOK toluene, 80 °C, 2–6 h

I

R2

Ar

O

N

PAr2 PAr2

O

tBu

40–84%, 89–95% ee

143

O

142

R1

O

O

1

R

139

(R)-DTBM-SEGPHOS Ar = 3,5-(tBu)2-4-MeO-C6H2

144

(c) Du and coworkers [82] O R3

O 4

NH

OCO2Et 146

R R1

R2 145

[PdCl(C3H5)]2, 147 KOEt, toluene, r.t. 51–92%, 33–84% ee

(d) Tanaka and coworkers [83] O R3 1 2 R R X R1 149

150

R3

R4

N

O

R1

Ph P N

R2

Bn

O 147

148 O

[Rh(cod)2]BF4/(S)-xyl-BINAP CH2Cl2, r.t., 15–42 h

2

R R1

12–79%, 50–98% ee

SiMe3

N

R3

PAr2 PAr2

SiMe3 R1

X

(S)-xyl-BINAP Ar = 3,5-Me2C6H3

151

Scheme 5.31  Examples of metal-catalyzed syntheses of axially chiral anilides. (a) Taguchi and Curran’s N-allylation method, (b) Taguchi’s N-arylation strategy, (c) Du’s Pd-P/Olefin catalysis toward N-allylation, and (d) Tanaka’s cycloaddition. Source: (a) Kitagawa et al. [78] and Terauchi and Curran [79]. (b) Kitagawa et al. [80] and Kitagawa et al. [81]. (c) Based on Liu et al. [82]. (d) Based on Tanaka et al. [83].

Jorgensen and coworkers [85] NH2

OH

Boc

N

O Boc

N

153 or 156, DCE, –20 °C

tBuO

H O N OtBu NH2 N OH

OH H

OH 153

N

152

Boc N N Boc NH2

N

155 H

Et O

+

NR3

O 154

tBuO with 153, 90%, 88% ee with 156, 91%, –96% ee

N

H HO NBoc

HO N

N H 156

Scheme 5.32  Jørgensen’s Friedel–Crafts amination of naphthol. Source: Based on Brandes et al. [85].

5.6  ­Lactams and Related Scaffold Maruoka and coworkers [86] O

O 3

R

4

NH

R

R5 Br or

Br R5

I

R2

alkyl

O R

N

R2

allyl

3

I

N

Ar I

R2

or

158, KOH, iPr2O, –20 °C R1 160 34–99%, 80–96% ee

R1 157 Ar +

N Ar

+N

R Br R

O + N R2

158

Ar = 3,5-[3,5-(tBu)2C6H3]2C6H3 R = nHex

R1

*

nHex

R1 161 53–97%, 88–93% ee

nHex R-Br I 159

Scheme 5.33  Maruoka’s phase transfer catalysis. Source: Based on Shirakawa et al. [86].

In 2018, Li and coworkers developed an asymmetric allylic alkylation reaction using achiral Morita–Baylis–Hillman carbonates and bis‐cinchona alkaloid catalyst (DHQ)2PYR (Scheme 5.34) [88]. The axially chiral N‐allylic products 164 were obtained from a broader scope of substrates with excellent cis : trans ratios as well as enantiomeric ratios. The barriers to rotation of several substrates were found to fall within the range of 27–29 kcal/mol, from which they concluded that not only sterics but electronics and structural properties also affected the stereochemical stability. Moreover, the linear free energy relationship analysis suggested the importance of ortho‐substituent on the aniline aryl ring in inducing the stereoselectivity. Li et al. [88] O HN

R1 162

R2 tBu

BocO

CO2R3 163

(DHQ)2PYR CH3CN:DMSO = 9 : 1, –10 °C cis:trans >99 : 1, 81–98% ee

R3O2C

Me

O N

Me N

R2 tBu

N O

MeO

R1 164

O N

N

N

OMe N

(DHQ)2PYR

Scheme 5.34  Li’s asymmetric allylic alkylation with Morita–Baylis–Hillman carbonates. Source: Based on Li et al. [88].

5.6 ­Lactams and Related Scaffolds Atropisomeric lactams are similar in stereochemical stability to anilides and thus typically exhibit class 2 or class 3 atropisomerism according to LaPlante’s scale. As such, there are many examples of racemic and asymmetric syntheses toward atropisomerically stable lactams. Notably, in many examples, the chiral axis is used as a “chiral auxiliary” to allow for diastereoselective modification of the lactam. Once again, Sivaguru thoroughly reviewed this concept in 2015, and for this writing, we will focus on the seminal reports as well as newer examples.

133

134

5  Asymmetric Synthesis of Nonbiaryl Atropisomers

5.6.1  Stereochemical Stability of Atropisomeric Lactams While atropisomeric lactams are analogous to anilides, the factors that contribute to stereochemical stability are somewhat complicated by the ring size of lactam, as the external bond angles of substituents on smaller rings orientate the substitutions further away from the axis compared to larger rings. For example, in 2000, Taguchi and coworkers reported some of the first syntheses of atropisomeric lactams of different ring sizes; finding that six‐membered lactams 165 led to higher stereochemical stability by 4–5 kcal/mol relative to the five‐membered lactams 166 (Scheme 5.35) [89].

(a)

N MeO

O tBu

trans-165

∆Grac = 28.3 kcal/mol t1/2 (27 °C) = 602 d

N MeO

T = 80 °C 30 h for cis, 15 h for trans complete racemization

O tBu

cis-165

(b)

MeO

O

N

tBu

trans-166

∆Grac ~ 23–24 kcal/mol r.t., 14 h cis equilibrates to the trans product

MeO

O

N

tBu

cis-166

Scheme 5.35  Atropisomeric stability of lactams based on ring size. (a) Six-membered lactam and (b) Five-membered lactam. Source: (a) and (b) Based on Kitagawa et al. [89].

5.6.2  Diastereoselective Cyclization Toward Atropisomeric Lactams Taguchi group disclosed a diastereoselective amino cyclization of (S)‐mesylate anilide 167a toward highly enantioenriched, atropisomerically stable lactams 166 (Scheme 5.36) [89]. Atropisomeric five‐membered lactams were initially formed in the cis‐conformation. However, because of the smaller bond angle that led to an equilibration of the atropisomeric axis, this resulted in the more stable trans‐product (Scheme  5.36a). In contrast, six‐membered lactam atropisomers with considerably higher barriers to racemization remained cis as in 165 (Scheme 5.36b).

5.6.3  Enantioselective N-arylation Toward Lactam Atropisomers In 2010, Kitagawa and coworkers described conditions for a chiral palladium complex‐ catalyzed intramolecular N‐arylation that gave atropisomeric lactams 169 with high ­enantioselectivities (Scheme 5.37) [90].

5.6  ­Lactams and Related Scaffold Taguchi and coworkers [89] O (a) MeO

(S)

tBuOK, toluene

NH tBu

OMs 167a

r.t., 3 h 87%, 98% ee

OMe

N

isomerizes via low ∆Grac

O tBu

OMe

cis-166 not preferred

O tBu

N

trans-166 preferred

O (b) MeO

(S)

tBuOK, toluene, rt, 3 h

NH tBu

OMs

84%, cis:trans = 3 : 1

N

O tBu

OMe

N

+

O tBu

OMe

167b cis-165

trans-165

Scheme 5.36  Taguchi’s atropisomeric lactam formation. Source: Based on Kitagawa et al. [89].

Taguchi and coworkers [90]

O

O

NH I

tBu

Pd(OAc)2, (R)-SEGPHOS, Cs2CO3, toluene, 80 °C, 24 h

O tBu

N

98%, 98% ee

R1

R1

R2

168

R2

169

O O

PPh2 PPh2

O (R)-SEGPHOS

Scheme 5.37  Asymmetric N-arylation toward lactam atropisomers. Source: Based on Takahashi et al. [90].

5.6.4  Atroposelective [2 + 2 + 2] Cycloaddition with Isocyanates Tanaka has applied atroposelective [2 + 2 + 2] cycloaddition strategy developed by his group toward synthesizing atropisomeric lactams. In 2008, Tanaka et  al. disclosed their conditions for the asymmetric Rh‐catalyzed syntheses toward atropisomeric lactams using enantiopure phosphine ligands such as BINAP (Scheme  5.38) [91]. The 1,6‐dynes 100 reacted with ortho‐substituted phenyl isocyanates 170 to readily give atropisomeric ­lactams 171 with good enantioselectivity. Following this report, Takeuchi and coworkers have ­disclosed a variant of this chemistry using Ir and H8‐BINAP [92]. Tanaka et al. [91] O

R1 +

100

R2

C

R1 N

[Rh(cod)2]BF4, (R)-BINAP CH2Cl2, r.t., 1–18h 27–92%, up to 87% ee R1 = C(CO2Me)2, NTs, O

170

N

O R2 171

PPh2 PPh2

(R)-BINAP

Scheme 5.38  Tanaka’s atroposelective [2 + 2 + 2] cycloaddition. Source: Based on Tanaka et al. [91].

135

136

5  Asymmetric Synthesis of Nonbiaryl Atropisomers

5.6.5  Chiral Auxiliary Approach Toward Resolving Atropisomeric Lactams In 2000, Simpkins et al. described a chiral auxiliary approach to access atropisomerically stable lactams that, upon separation of the diastereomers 173 and 174, would be further functionalized via various lithiation–electrophile quenching chemistries (Scheme  5.39) [93]. In contrast, for six‐membered lactams, the intermediate with the l‐menthol chiral auxiliary was not observed, but instead, an enamide was formed via an elimination of the hydroxy group under their reaction conditions [94].

Simpkins and coworkers [93]

HO

O

N

tBu

L-menthol, PTSA-Py CuSO4, CH2Cl2, r.t., 18 h

R2

O

N

tBu

R1 172

+

R2

R2 =

O

N

tBu

R1

R1

173 (Major) 41–56%

174 (Minor) 23–25%

O iPr

Scheme 5.39  Chiral auxiliary approach to synthesize atropisomerically stable lactams. Source: Based on Godfrey et al. [93].

5.6.6  Enantioselective Brønsted Base-Catalyzed Tandem Isomerization– Michael Reactions Toward Atropisomeric Lactams Tan and coworkers demonstrated an asymmetric tandem isomerization–Michael reaction of an alkynylamide 175 toward atropisomeric lactams 177 in the presence of chiral guanidine 176 (Scheme  5.40). An isomerization of the alknylamide to a chiral conjugated ­allenoate intermediate 178 was then followed by an aza‐Michael addition toward the final product in high enantioselectivity [95].

Tan and coworkers [95] tBu

H N

O O

N

tBu

OtBu

tBu N

N H

176

O

tBu

OtBu

N tBu

THF, r.t., 3 d 67%, 89% ee

175

O

177

O Intermediate 178 HN CO2tBu H

H

Scheme 5.40  Tan’s allene isomerization toward atropisomeric lactams. Source: Based on Liu et al. [95].

5.7 ­Diaryl Amine

5.7 ­Diaryl Amines Diaryl amines and related scaffolds are perhaps the most ubiquitous class of nonbiaryl atropisomers in drug discovery (Figure  5.10). In the following sections, we will discuss seminal examples on the potential for axially chiral diaryl amines and related scaffolds as well as some recent examples of atroposelective synthesis of related scaffolds.

5.7.1  Stereochemical Stability of Diaryl Amines Diaryl amines typically possess stereochemical stabilities that are lower than traditional biaryl atropisomers. Much like diaryl ethers, diaryl amines have two atropisomeric axes, which could enable a lowered energy, concerted “gearing” mechanism toward spontaneous racemization. Works by Kawabata and coworkers provided insights into diaryl amine atropisomers, wherein they found that the stereochemical stability of these compounds could be increased by an intramolecular N─H─N hydrogen bond (Figure 5.11) [96, 97]. Essentially, the hydrogen bond locks one of the atropisomeric axes into a planar conformation, preventing a concerted “gearing” mechanism of racemization. It should be noted that Kawabata observed that the stereochemical stability of diaryl amine was dependent on the strength of the intramolecular hydrogen bond, with weaker interactions leading to stereochemical instability.

O NH

MeO

O

Br H N

N

H N

N

F

Afatinib

Cl

N N

N F

O

O

Me2N Cl

MeO

O

N

NMe

NC

Cl

Vandetanib

N H N

OMe

Bosutinib

Figure 5.10  Examples of diaryl amine-containing FDA-approved drugs that exist as stereochemically unstable atropisomers.

O2N

N N H NO2

iPr

Intramolecular H-bonding stabilizes one of the atropisomeric axis into a planar conformation ∆Grac = 28.2 kcal/mol, (80 °C)

Figure 5.11  Kawabata’s intramolecular H-bonding hypothesis.

137

138

5  Asymmetric Synthesis of Nonbiaryl Atropisomers

Since Kawabata’s work, there have only been a few examples disclosed of the racemic syntheses of atropisomeric diaryl amines, and there is little precedence of the asymmetric syntheses of diaryl amines or related compounds.

5.7.2  Atroposelective Approaches Toward Diaryl Amines or Related Scaffolds At the time of this writing, there have been no reports of direct atroposelective syntheses toward diaryl amines. However, in 2020, Gustafson group disclosed the atroposelective synthesis of N‐aryl quinoids, close analogs to diaryl amines [98]. They found that chiral phosphoric acid 181 could affect the atroposelective halogenation of stereochemically unstable N‐aryl quinoids to give stereochemically stable products in up to 98 : 2 er. In analogy with Kawabata’s studies about diaryl amines, Gustafson et al. proposed that the N‐aryl quinoids engage in an intramolecular hydrogen bond that locks one of the axes in a planar conformation, preventing lower energy “gearing” racemization pathway (Scheme 5.41). Gustafson and coworkers [98] Intramolecular H-bond O

H N

R2 1

O

N X (Cl, Br, I)

R3

H R 179

O

O 180, PhCH3/n-hexane 4 Å MS, r.t., 12 h

Ar

R3

O

R

NH X

R1

O 181, 95%, 97 : 3 er

2

O O P O OH Ar 180, Ar = 1-naphthyl

Scheme 5.41  Atroposelective halogenation of N-aryl quinoids. Source: Modified from Vaidya et al. [98].

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141

6 Asymmetric Synthesis of Chiral Allenes Jinbo Zhao1 and Yunhe Xu2 1 Changchun University of Technology, Department of Chemistry and Biology, 2055 Yan’an Street, Changchun, 130012, PR China 2 University of Science and Technology of China, Department of Chemistry and Hefei National Laboratory for Physical Sciences at Microscale, 96 Jinzhai Road, Hefei, 230026, PR China

6.1 ­Introduction Allene holds a unique position in an axially chiral compound family. Its sp-hybridized central carbon connects two perpendicular πC─C bonds, a rendering that, when the substituents of both terminal carbons are mutually different (i.e. R1   R2 and R3   R4), can lead to two non-superimposable enantiomers (Figure 6.1). The allene moiety is found in over 150 naturally occurring bioactive compounds and serves as a useful chiral backbone of catalysts and ligands. These properties arise from the relatively high configurational stability around the C═C═C axis. On the other hand, the high functionality density in its cumulene structure confers allenes with an extraordinary reactivity profile, including the exceptional axial-to-central chirality transfer capability. These features make allene an intensively pursued ­synthetic target; especially, the asymmetric synthesis of the axially chiral allenes has become a highly attractive endeavor. In 2004, a monograph compiled by professors Krause and Hashmi on allene chemistry [1] summarized key early developments on enantioselective synthesis of allene. The subject has been further partially covered by a few recent topical reviews from different perspectives [2–5]. Nonetheless, the field is expanding at such a rate that key advances are emerging annually, making not only new summarization necessary but also an overview urgent. In this chapter, we summarize the strategies for the synthesis of enantioenriched allenes bearing an axial-chiral allene moiety, with an emphasis on the key developments since 2004. To provide an overall perspective, for each reaction type, representative early examples are also described or referenced. For simplicity and consistency, we classified the reactions by mechanistic stereotypes in asymmetric synthesis whenever appropriate, although a few closely related examples of different types are discussed together.

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

142

6  Asymmetric Synthesis of Chiral Allenes Natural products 1

3

R1

R3

R

R

R2

R4

R4

R2

Reactivity Applications

R1 ≠ R2 & R3 ≠ R4

Figure 6.1  The structure and properties of axially chiral allene.

6.2 ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reactions 6.2.1  Chirality Transfer As of 2004, reports on chirality transfer reactions of enantioenriched starting materials had laid the foundation for many protocols in chiral allene synthesis. A majority of reactions involve propargyl alcohol or its derivatives and proceed under many modes known today, including SN2′ displacements/reduction, rearrangements, and catalytic stereospecific transformations. 6.2.1.1  Chirality Transfer from Propargyl Alcohol and Its Derivatives: Rearrangements

Stereospecific rearrangement is a highly efficient strategy to build chiral allene from enantioenriched propargyl derivatives in the early years. A reliable protocol is Claisen rearrangement of orthoester as shown in Scheme  6.1 [6, 7], which showed broad synthetic utility [8, 9].

Kobayashi et al. (1991) TMS

CHO 1

TMSO + EtS

2

O

Sn(OTf)2/L*

O

OTMS

(1) Deprotection

EtS Me

Me 3, 92% ee

TMS

(2) EtC(OEt)3 EtCO2H

•

EtS Me

CO2Et

TMS 4, 92% ee

Scheme 6.1  Synthesis of chiral allenes via stereospecific orthoester Claisen rearrangement.

In 2004, Toste and coworker reported a gold(I)-catalyzed Claisen rearrangement of propargyl alkenyl ether for the synthesis of allenes [10]. Chiral substrates 5 afforded homoallenic alcohols 6 after rearrangement and reduction with NaBH4 with perfect fidelity of chirality transfer (Scheme 6.2). Analogous pseudo-Claisen rearrangement of the propargyl alcohol phosphonate delivers enantioenriched allenyl phosphonates [11]. Besides [3,3]-rearrangement, [2,3]-Wittig rearrangement was also documented to give high level of chirality transfer [12].

6.2  ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reaction Toste et al. (2004) O

H

[(Ph3PAu)3O]BF4 (1 mol%)

R1

1

R

•

CH2Cl2, r.t. NaBH4, MeOH, r.t. up to 98%, 92% ee

R2 5

OH 2

R 6

Scheme 6.2  Au(I)-catalyzed stereospecific Claisen rearrangement.

Use of readily available optically active propargyl alcohols provides a more straightforward route. An inspiring early example (vide infra) is Myers’ report that enantioenriched propargylic alcohol 7 can be converted to axially chiral allene 8 with net configurational inversion and complete retention of enantiopurity with o-nitrobenzenesulfonylhydrazine (Scheme 6.3) [13]. The reaction may proceed via elimination of the Mitsunobu product, propargylic hydrazine 9, followed by an intramolecular [1,5]-H transfer rearrangement of the resulting propargylic diazene 10. Myers et al. (1996) OH

Ph

ArSO2NHNH2 (Ar = o-NO2C6H4)

Cy

PPh3, DEAD, –15 to 30 °C

Ph 7, 78% ee

H •

H

Cy

8, 77% ee H HN

N

SO2Ar ArSO2H

N

N Cy

Cy

Ph

9

Ph

H

10

Scheme 6.3  Synthesis of chiral allene via Mitsunobu reaction–elimination–rearrangement sequence.

6.2.1.2  Processes Involving Stereospecific Rearrangements of Propargyl Amine

Che and coworkers reported that enantioenriched propargylic amines 11, prepared from AuIII-catalyzed three-component coupling of terminal alkynes, aldehydes, and chiral prolinol [14], can undergo AuIII-catalyzed [15] and AgI-mediated [16] rearrangement to afford axially chiral allenes 12 (Scheme 6.4). Isotope labeling studies suggest an intramolecular [1,5]-H migration mechanism from the endocyclic methylene directly attached to the nitrogen atom. Che et al. (2008, 2010) N R2

R1

OH

H 11 (99% de)

[Au] or [Ag]

R1 • H 12

H

AgNO3 (50 mol%), microwave, 70 °C 49–100% conversion, 91–99% ee

R2

KAuCl4 (10 mol%), CH3CN, 40 °C 46–95% conversion, 50–97% ee

Scheme 6.4  Stereospecific isomerization of optically active propargylic amines for the synthesis of chiral allenes.

143

144

6  Asymmetric Synthesis of Chiral Allenes

The above rearrangement was invoked in a Cu-catalyzed one-step synthesis of allene from terminal alkyne, iPr2NH, and paraformaldehyde in a seminal report by Crabbé et al. in 1979 [17], which only worked for paraformaldehyde to afford mono-substituted allene in low yields. Ma and coworkers developed modified protocols to allow for efficient synthesis of 1,3-disubstituted and 1,1,3-trisubstituted allenes from terminal alkynes 13 with aldehydes [18] or ketones [19] (14) catalyzed by ZnI2 or CdI2, respectively. These reactions, as suggested, may proceed via metal-assisted formation of propargylamine 16, its [1,5]-H migration, and elimination of the resulted iminium 17 (Scheme 6.5). Ma et al. (2010, 2013) R4 +

R1

+

R2COR3

13

14 R5 R4

R2 R3

[M] R1

16

R4

R2

Cu+, Zn2+, or Cd2+

R2 R3 [M]

R4 + N

1,5-H

R5 N Elimination

H

R2

Migration

R1

R3

R1

R1 R4

R5

H

N

H •

R3

R5 H

N

R5

HN 15 H

[M] 17

Scheme 6.5  The Crabbé reaction and proposed mechanism.

Ma and coworkers further examined the chirality transfer strategy under the modified Crabbé conditions, i.e. the “enantioselective allenation of terminal alkynes (EATA).” In the “chiral amine” approach, inexpensive, readily available diphenylprolinol (S)-18 was employed to form chiral propargyl amines. Initially, only bulky terminal alkyne gave good results (Scheme 6.6a) [20]. After optimization, a Cu+/Zn2+ bimetallic system was found to display both high reactivity and selectivity for a spectrum of alkynes 13 and aldehydes 14, except for heteroaromatic and α,β-unsaturated aldehydes (Scheme  6.6b) [21]. Control experiments showed that both zinc and copper salts were crucial for the rearrangement of ­propargyl amine intermediate. In the meantime, Periasamy et al. reported similar results [22, 23] and extended the protocol to the synthesis of optically active β-allenoates [24]. Ma et al. (2012, 2013) R2CHO

R1 13

+

14

Ph N Ph H OH (S)-18

R1 = p-NO2C6H4CH2OCH2, R2 = nBu: 46%, 98% ee R1 = nC10H21, R2 = Ph: 26%, 82% ee R1 = CH2OH, R2 = Cy: trace ZnI2 (0.8 equiv) Toluene, 120 °C, 12 h (a)

R2

H •

R1

H (R)-12

ZnBr2 (50 mol%), CuBr (10–20 mol%)

(b) up to 73%, 99% ee

Toluene, 110 °C or dioxane, 120 °C

Scheme 6.6  Modified Crabbé reaction for the synthesis of optically active 1,3-disubstituted allenes by the “chiral amine” approach.

6.2  ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reaction

Under similar conditions, propargyl alcohol TBS (tert-butyltrimethylsilyl) ethers 19 reacted with aliphatic aldehydes 14 to deliver α-allenols 20 in good yields and high enantioselection (Scheme  6.7) [25]. All the four diastereomers of the allenol product could be obtained by arbitrarily changing the configuration of the chiral amine and/or propargyl alcohol silyl ether. Ma et al. (2012) OTBS

+ R2CHO +

R1 19

14

Ph ZnBr2 (0.75 equiv) N Ph Toluene, 130 °C H OH 45–74% 96–99% ee or de (S)-18

R2

H

•

R1

H HO (R)-20

Scheme 6.7  “Chiral amine” strategy for the enantioselective synthesis of allenols.

Ma et al. also developed a highly efficient and enantioselective approach for the synthesis of α-allenols from secondary and tertiary propargyl alcohols 21 by combining the powerful A3 reaction with zinc salt-mediated rearrangement (Scheme 6.8) [20]. Ma et al. (2013) R1 R2 21 OH + R3CHO 14

N H 22

Me

(1) CuBr (5 mol%), L1 (5.5 mol%) 4 Å MS, toluene, 25 °C R3 (2) Removal of Cu(I) with filtration (3) ZnI2 (0.45 equiv), NaI (0.5 equiv) H toluene, 110 °C up to 97%, 99% ee

HN

Ph

H R1 HO R2 (R)-23

PPh2

L1

Scheme 6.8  Sequential asymmetric A3 reaction/stereospecific propargyl amine rearrangement for the synthesis of chiral allenols.

6.2.1.3 SN2′ Reaction

Crabbé’s report on the SN2′ reaction of organocuprate with propargyl acetate to prepare allenes with partial chirality transfer in 1968 [26] incited extensive efforts to improve its efficiency. By 2000s, the reaction had become highly reliable [27], allowing for the use of a variety of propargyl derivatives, and had seen applications in in natural product synthesis. However, the functional group tolerance remained relatively limited because of the use of organocuprates, and in situ racemization of allene products is sometimes observed. As an endeavor to address these issues, Kondo and coworkers found that use of organozinc reagents provided high enantiospecificity in the reaction of propargyl mesylate 24 (Scheme 6.9) [28]. The use of dimethyl sulfoxide (DMSO) as a solvent was key for the high reactivity. From 2011 to 2012, Sawamura and coworkers reported the Cu-catalyzed reaction of alkyl, alkenyl, and arylboron reagents with enantioenriched propargylic phosphates 28 to deliver tri-substituted chiral allenes 30 (Scheme 6.10a) [29] and 33 (Scheme 6.10b) [30]. Almost simultaneously, the Lalic group independently reported that an N-heterocyclic carbene (NHC)-ligated copper catalyzed a similar reaction with alkyl- and arylboron reagents 32 in moderate to high yields and high enantiospecificity [31].

145

146

6  Asymmetric Synthesis of Chiral Allenes Kondo et al. (2008) ZnCl2 + NaOMe + nBuMgCl OMs

Zn(nBu)2 (2.0 equiv) Me

Me

DMSO, r.t., 24 h 87%

CO2Me

nBu

•

H (R)-25

(R)-24, >99% ee

O

O nBu

IBr (1.5 equiv)

O

CO2Me CH2Cl2, –78 °C nBu 81%

Me

O

Me I

26

Pd(PPh3)4 (5 mol%) Bu3SnH, THF, r.t., 30 min 100%

H

(R)-(–)-27, 98% ee

Scheme 6.9  Stereospecific SN2′ reaction of propargyl mesylate with organozinc reagent. (a) Sawamura et al. (2011) OPO(OEt)2

R2 +

Me R1 (R)-28, 97–99% ee

B 29

CuOAc (15 mol%) KOtBu (1.5 equiv)

CH2R2

Me •

THF, 70 °C, 6 h

R1

H

up to 86%, 96% ee

30

(b) Sawamura et al. (2012) OPO(OPh)2 Me

O + R B O OMOM

(S)-31, 99% ee

32

CuCl2 (5 mol%) KOtBu (3.0 equiv) H2O (3 equiv) CH3CN, 25 °C up to 83%, 99% ee

H

R • CH2OMOM

Me 33

Scheme 6.10  Cu-catalyzed stereospecific SN2′ reaction of propargyl phosphonate with organoboron reagent.

Enantioselective synthesis of tetra-substituted allenes is more challenging and lack efficient methods. Ma et al. reported in 2015 a [Cp*RhCl2]2-catalyzed C–H activation-based aryl addition/elimination protocol to synthesize tetra-substituted allenes 36 from enantioenriched propargyl carbonates 35 (Scheme 6.11) [32]. The reaction proceeded under very mild conditions and the high fidelity of chirality transfer arose from exclusive syn-β-oxygen elimination step of the alkenyl intermediate 38. A Rh(I)-catalyzed highly enantiospecific synthesis of optically active tri-substituted allenes 41 was reported by Carreira and coworker in 2016 (Scheme 6.12) [33]. The reaction was also proposed to take place via alkyne arylrhodation followed by syn-elimination. 6.2.1.4  Pd-Catalyzed Stereospecific Reaction

The cross-coupling reaction based on chirality transfer from an enantioenriched propargyl derivative was first reported in 1997 with organozinc reagent (Scheme  6.13a) [34]. Later, couplings with organoindium [35] and boron reagents [36] were documented (Scheme 6.13b,c). However, erosion of optical activity is often observed, especially in the coupling with the organoboron reagent, which proceeds at a higher temperature. The observation was attributed to the isomerization between η1-propargyl and η1allenylpalladium intermediates.

6.2  ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reaction Ma et al. (2015) MeO2CO

O N

R

OMe

Et

O Me

+

[Cp*RhCl2]2 (4 mol%) NaOAc (30 mol%) MeOH/H2O, 0 °C

H 34

36 Me

O *Cp

O OMe O

N

OMe

Rh 37

O

*Cp Rh

OMe O

O

Ph

Et

OMe N

R

OMe

•

up to 77%, 98% ee

Ph 35, 98% ee

R

N H Ph

R

Ph

Me Et

Et 38

Scheme 6.11  Synthesis of tetra-substituted chiral allenes via Rh(III)-catalyzed C─H activation.

Carreira et al. (2016) OBz + Ar-B(OH)2

R1 39

R2

40

[Rh(cod)Cl]2 (3 mol%) L2 (13 mol%) K3PO4 (2 equiv) DCE, 50 °C, 24 h

Ar

•

N

R2

R1 41

L2

up to 97%, >99% es

Scheme 6.12  Synthesis of chiral tri-substituted allenes via Rh(I)-catalyzed stereospecific SN2′ reaction of chiral propargyl benzoate with aryl boronic ester.

(a) Roberts et al. (1997)

nBu

•

THF

OCO2Et H Me 42a, 93% ee

H

nBu

cat. Pd(PPh3)4, PhZnBr

Ph Me 43a, 84%, 83% ee H

nBu cat. Pd(PPh3)4, CuI, ZnCl2 Ph

iPr2NH, THF

• Me 44 Ph 63%, 85% ee

(b) Sestelo, Sarandeses et al. (2006) H R PhOCO 42b–c, >95% ee

+

Ph3In

cat. Pd(DPEphos)Cl2 THF, r.t., 8 h up to 80%, >95% ee

H

Ph •

R

43b–c

H

(c) Yoshida et al. (2007) OCO2Bn R 42d–f, 96–99% ee

+

ArB(OH)2

cat. Pd(PPh3)4, K3PO4

R

dioxane/H2O, 100 °C

H

up to 99%, 94% ee

H • Ar 43d–f

Scheme 6.13  Synthesis of chiral allenes via Pd-catalyzed stereospecific cross-coupling of chiral propargyl alcohol derivatives with various metallic reagents.

147

148

6  Asymmetric Synthesis of Chiral Allenes

Marshall et al. reported in 1997 that the Pd-catalyzed carbonylation of enantioenriched propargyl mesylates 45 en route to chiral 2,3-allenoates 46 proceeded with high degree of fidelity of chiral transfer in the case of terminal alkyne substrates, while for internal alkynes, an obvious drop of enantiopurity was observed (Scheme 6.14a) [37]. Ma and coworkers resolved this issue with the aid of bidentate ligands (S)-SegPhos L3 or DPEphos L4 (Scheme 6.14b) [38, 39]. (a) Marshall et al. (1997) OMs R1

cat. Pd(PPh3)4

R2

CO (200 psi), ROH, THF

H

C5H11 n H

(S)-46a

(S)-45a, 95% ee (R1 = nC5H11, R2 = H) (S)-45b, 95% ee (R1 = Me, R2 = nC7H15)

or

•

H3 C

•

H

CO2R

(S)-46b

R = TMSE, 80%, 95% ee R = Bn, 80%, 93% ee TMSE = Me3SiCH2CH2

nC7H15 CO2R

R = Bn, 84%, 80% ee R = TMSE, 80%, 84% ee R = Me, 86%, 84% ee

(b) Ma et al. (2003, 2004) Pd(dba)2 (3 mol%), L3/L4 (3 mol%) (NH4)2HPO4 (1.1 equiv)

OMs R1 R2 (S)-45c, 99% ee

BnOH, MTBE, CO (100–200 psi) R1 = akyl, R2 = alkyl

H R1

CO2Bn •

R2

(S)-46c

(S)-SegPhos (L3) up to 90%, 97% ee DPEphos (L4) up to 86%, 99% ee

Scheme 6.14  Enantioselective synthesis of allenoates via Pd-catalyzed carbonylation of optically active propargyl mesylates.

6.2.1.5  Isomerization of Propargyl Metals

In 2012, Aggarwal and coworkers disclosed the synthesis of chiral tertiary boronic esters 48 from lithiation/borylation of chiral secondary alcohol carbamates 47 (Scheme 6.15) [40]. Compound 48 can undergo protodeboration and Pd-catalyzed Suzuki–Miyaura coupling to afford tri- and tetra-substituted allenes 49 and 50 with high enantiospecificity. Notably, the use of sterically non-hindered glycol boronic ester to trap the propargyl lithium was found to be key for the stereochemical outcome, as a consequence of the configurational liability of propargyl lithium intermediate.

Aggarwal et al. (2012) OCb (1) n-BuLi, TMEDA (1.1 equiv) Bpin Et2O, –78 °C R O –78 °C to r.t. tBu tBu (2) R1 B 47 48 O Cb = CON(iPr) 2 (3) pinacol, Et2O TBAF•3H2O Toluene, 50 °C

R1 R

Pd2(dba)3 (2.5 mol%) ArI, PPh3 (10 mol%) AgF (1.5 equiv), DME MS, 100 °C, 16 h

O O B R1 H F O R H tBu

R1 tBu

R

•

Ar 50, 98–100% es R1 tBu

•

R

H 49, 100% es

Scheme 6.15  Stereospecific synthesis of propargyl boronic ester and its isomerization to chiral allenes.

6.2  ­Substrate- and Reagent-Controlled Chiral Allenes Synthesis: Stoichiometric Asymmetric Reaction

6.2.1.6  Chirality Transfer from Functionalized Allylic Derivatives

Stereoselective or stereospecific 1,2-elimination from suitably functionalized enantioenriched allylic derivatives to synthesize chiral allenes is a much explored strategy as shown in Scheme 6.16. By 2014, documented methods including 1,2-R3Si/OAc [41], 1,2-R3Sn/OAc [42], 1,2-ArS(O)/OAc [43, 44], and 1,2-Ph2P(O)/OH [45] eliminations under various conditions in a syn- or anti-selective manner had achieved varied success. A chiral-at-Se 1,2-RSe(O)/H elimination [46–48] was also realized with high enantioselectivity.

XY

X

•

1,2-elimination

Y

McGarvey (1998): X = OTf, Y = [Si]*, 18% ee (anti) Araki (1992): X = OAc, Y = [Sn], 94% ee (anti) Satoh (1999–2002): X = OAc, Y = tolS(O), up to 68% ee (anti) Warren (2001): X = OH, Y = Ph2P(O), up to 23% ee (syn) Uemura (1993–1995): X = H, Y = R*Se(O), up to 89% ee (syn)

Scheme 6.16  Various 1,2-elimination approaches to chiral allenes.

Recently, the Aggarwal group developed an enantiodivergent synthesis of various di-, tri-, and tetra-substituted allenes by homologation of α-seleno alkenyl boronic esters 51 with lithiated carbamates, followed by controlled selective elimination (Scheme 6.17) [49]. The use of a seleno group of weak leaving ability ensured that it is not eliminated in the borate rearrangement step (51 to 53). Treating 53 with m-CPBA (meta-chloro peroxobenzoic acid) oxidized the seleno group and triggered clean syn-elimination to afford 54. Antielimination could be realized by alkylating 53 with MeOTf, followed by addition of a weak base to activate the boronic ester. Aggarwal et al. (2018)

SePh R1 R2 51

Bpin

Li•(+)sp R4 CbO R3

m-CPBA syn-elimination

52

SePh R1

Bpin R2

53

R3 R4

(1) MeOTf (2) NaHCO3 anti-elimination

R1

R4 •

R2 R3 54 up to 89%, 98% ee R2 R1

•

R4

R3 55 up to 88%, 96% ee

Scheme 6.17  Enantiodivergent synthesis of chiral allenes through controlled elimination of 1,2-selenoboronic ester.

Ready and coworker found that hydrozirconation of internal propargyl alcohols 56 with Schwartz reagent provided a highly stereospecific access to chiral 1,3-disubstituted allenes 58 (Scheme 6.18) [50]. When R2 = H, the zirconium intermediate can be trapped by an electrophile. The shift of reactivity toward allene when R2   H was believed to arise from an A1,3 strain between R1 and R2, which facilitates syn-elimination of Cp2Zr═O to allene 58.

149

150

6  Asymmetric Synthesis of Chiral Allenes Ready et al. (2008) OH R1

Cp2Zr(H)Cl, base

H

cis-addition

R1

R2 56, 95–98% ee

Cp2Zr=O

O [Zr]

H

syn-elimination

R2 H 57

H •

R1

58

R2

R2 ≠ H up to 90%, 98% ee

Scheme 6.18  Synthesis of chiral allene via elimination of propargyl alcohol with Schwartz reagent.

6.2.1.7  Chirality Transfer via Wittig Olefination

The Wittig reaction of ketenes with ylides was also shown to furnish multi-substituted allenes. Optically active allenes can be envisioned to form by using enantioenriched ylides. Pioneering contributions by Bestmann and coworker [51] and Musierowicz and coworker [52] proved the feasibility of this approach, although the ee of the products remained low. Tanaka and coworkers reported that BINOL-derived phosphonate 60 could react with the in situ-generated ketene to obtain 4,4-disubstituted 2,3-allenoates 61 in moderate to good yield and enantioselection (Scheme  6.19a) [53]. Tang and ­coworkers subsequently reported the use of pseudo-C2-symmetric mono-ylides for the synthesis of optically active 2,3-allenoates 64 (Scheme  6.19b) [54]. Although an expanded scope of ketene was included, the enantioselectivities of most substrates were generally moderate, and high enantioselectivities (90% and above ee) were observed only for R1 = linear alkyl and R2 = aryl. Zhou and coworkers also reported that the iron–porphyrin complex could catalyze olefination of ketenes 63 with chiral ylide generated from a chiral BIPHEP analog 65 and diazoacetate, providing several 4,4-disubstituted 2,3-allenoates 66 in good yields and excellent enantioselectivities, although the scope was essentially the same with that of Scheme 6.19b (Scheme 6.20) [55]. The chiral phosphine oxide by-product could be recovered by treatment with silane post-isolation. Mono-ylide was found to be the true intermediate in the catalytic reaction.

(a) Tanaka et al. (2001) R1 2

R

CO2Ph

Me

(1) LDA, ZnCl2, THF, –78 °C (2) 60, LDA, THF, –78 °C to r.t.

59

up to 71%, 89% ee

R1

H

O O P O CH2CO2Me

• R2

CO2Me

61

Me 60

(b) Tang et al (2006) Ph Ph O P Br Ph 62

(1) NaHMDS, THF, r.t. OR (2)

R1 R2

• O –78 °C 63

R1 R2

H •

CO2R 64 up to 80%, 92% ee

Scheme 6.19  Asymmetric Wittig reaction with BINOL-derived phosphonate and C2-symmetric chiral phosphacyclopentane.

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene Tang, Zhou et al. (2007) CO2Et MeO MeO

PAr2 + N2CHCO2Et PAr2

Fe(TCP)Cl (0.5 mol%) Toluene, r.t.

MeO MeO

PAr2 PAr2

R1

• O 63 R2 THF, –65 °C

65, Ar = 3-MeOC6H4 R1

H

• 66 CO2Et up to 90%, 98% ee R2

Phosphine oxide

Scheme 6.20  Fe-catalyzed asymmetric ketene Wittig reaction with chiral C2-symmetric ylide.

6.2.2  Asymmetric Reaction with Stoichiometric Chiral Reagents Examples of asymmetric reaction with stoichiometric reagents are relatively rare and lack recent updates. Naruse et  al. reported the first example of deracemization of allenes 67 [56]. A stoichiometric amount of the nuclear magnetic resonance (NMR) shift reagent Eu(hfc)3 was found to be competent for this purpose, but the substrate was limited to only dicarboxylate, and the chiral allene could not be isolated from the reaction mixture without loss of optical purity (Scheme 6.21) [57]. Naruse et al. (1997) RO2C

(+)-Eu(hfc)3

• CO2R (rac)-67

CDCl3

RO2C H

•

H CO2R

(S)-67 R = Et, 94% ee R = iPr, 95% ee

Scheme 6.21  Eu(hfc)3-mediated allenoate deracemization.

Racemic propargyl alcohol phosphate 68 could be used to synthesize optically enriched 1,3-disubstituted allenoate 69 under Pd catalysis with a stoichiometric amount of SmI2 and chiral proton source 70/71 (Scheme 6.22) [58]. SmI2 reduces the Pd(II) species generated from oxidative addition, itself being oxidized to the propargyl/1,2-allenyl Sm(III) 72/73, whose configurational liability allows for dynamic establishment of the axial chirality in the product with the chiral proton source.

6.3 ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allenes The first example of enantioenriched allene synthesis reported in 1935 is chiral acid-catalyzed dehydration of racemic allylic alcohol, although the enantiomeric excess was only

151

152

6  Asymmetric Synthesis of Chiral Allenes Yoshida et al. (1997) Chiral proton source

OPO(OEt)2 R 68

CO2Me

Pd(PPh3)4, SmI2

H

Chiral proton source

R

• 69

up to 86%, >95% ee

CO2Me

Ph

H

HO

Ph

70

SmIIILn H

CO2Me

OH

71

OH

SmIIILn

• 72

O

O

73

CO2Me

Scheme 6.22  Pd-catalyzed synthesis of optically active allenoates with a stoichiometric proton source.

nominal [59]. It was not until the in new millennium, however, that catalytic asymmetric protocols began to dominate in chiral allene synthesis.

6.3.1  Catalytic Enantioselective Synthesis from Achiral Substances 6.3.1.1  Enantioselective Proton Migration (Isomerization) of Alkyne

Alkynes bearing a relatively more acidic propargylic methylene are suitable substrates for enantioselective isomerization. In 2000, Arai and Shiori et  al. reported the asymmetric isomerization of 1,3-diaryl alkyne to axially chiral allene under phase transfer catalysis (PTC) conditions, but only a single example was shown with low enantioselectivity [60]. In 2009, Huang and Tan et al. showed that a highly enantioselective route to chiral disubstituted 2,3-allenoates 76 could be realized with a chiral guanidine catalyst 75 from isomerization of 3-alkynoates, which bears more acidic propargylic protons (Scheme 6.23a) [61]. However, the incomplete conversion and inseparability of the starting materials with the products undermined its synthetic utility. Takemoto and coworkers reported in 2011 a benzothiadiazine-1,1-dioxide-type catalyst 78 promoted highly enantioselective isomerization of propargyl esters, ketones, and amides 77 to the corresponding allenes 79 (Scheme  6.23b) [62]. To overcome the issue of inseparability with an unreacted starting material, the allenes were in situ converted to Diels–Alder and [3 + 2] dipolar cycloaddition products.

(a) Huang, Tan et al. (2009) 75 (1–10 mol%)

R 74

H

R

CO2tBu Hexane or THF, –20 °C H up to 94%, 95% ee

78 (2 mol%), THF, r.t.

76

77

R2

O

up to 100%, 98% ee R2 = alkyl, OR, NR2

R1

O

H R2 79 O

tBu N

75

O S

• H

N H

CO2tBu

(b) Takemoto et al. (2011) R1

N

tBu

•

N H

N

78

N H

NMe2

Scheme 6.23  Chiral organocatalyst-promoted asymmetric isomerization of propargylic ester, ketone, and amides.

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene

A route to tri-substituted chiral allenes can be envisioned from the isomerization of 2-substituted 3-alkynoates. In a report on chiral thiourea-catalyzed Michael addition/isomerization of nitroalkanes with electron-deficient functionalized enynes 80 (Scheme  6.24) [63], Sun et al. found that the by-product alkyne would be facilely converted to the corresponding allene irrespective of its optical activity. A separately prepared racemic alkynoate 85 was also efficiently converted to allenoate 86 in high yield and enantioselectivity.

Sun et al. (2013) R2 R1O2C 80

Me

R4

CH2Cl2, 0 °C, 36 h

81

83/84 = 3 : 1 to >25 : 1 up to 95%, 98% ee

CO2tBu

CH2Cl2, 40 °C, 23 h

Ph H

98%, 98% ee

•

R3 NO2

Me CO2tBu

86

H

+

R2

R3 R4 O 2N

83

Et3Si

•

R1O2C

R2

R1O2C R4

82 (20 mol%)

NO2

82 (20 mol%)

Ph 85

+

R3

N

H N

84

H N

CF3

S

MeO N

CF3

82

Scheme 6.24  Chiral thiourea-catalyzed Michael addition/isomerization of nitroalkane with electron-deficient functionalized 1,3-enynes.

Most recently Kanai et al. showed that the catalytic enantioselective isomerization of simple non-activated 1,4-enynes 87 to hydrocarbon alkenyl allenes 88 could be realized with a chiral copper catalyst under mild conditions (Scheme 6.25) [64]. The Cu(I) catalyst plays an important role in acidifying the propargylic hydrogen. A structural feature of the JosiPhos ligand L5, namely, the o-MeO substituent in the benzylic P-aryls, was found to be beneficial for the reactivity and crucial for the regio- and enantiocontrol. Density functional theory (DFT) studies identified a key intramolecular hydrogen bonding between the o-MeO substituent on the phosphorus and the benzylic methine proton on the ferrocene, which afforded space for the substrate to access the catalytically active copper center.

Kanai et al. (2019)

R3

MesCu/L5 (1–10 mol%) R3 R2

R1 87

methoxymethanol (20 mol%) up to 99%, 94% ee

R1

• R2 88

H

Ar2P

Fe

PAr′2

L5 Ar = 4-MeO-3,5-Me2C6H2 Ar′ = 2-MeOC6H4

Me Ar′ H O

Fe P

PAr 2

Cu OR

Catalyst

Scheme 6.25  Cu(I)-catalyzed asymmetric isomerization of non-activated 1,4-enyne to alkenyl allene.

The well-known carbophilicity of gold catalysts is mainly deployed to effect alkyne activation for nucleophilic attack. Zhang et al. reported the Au-catalyzed synthesis of 1,3-dienes from aryl alkynes [65]. More recently, the same group developed a chiral catalyst to enable enantioselective isomerization of propargyl alcohols 89 to chiral 2,5-dihydrofurans 91

153

154

6  Asymmetric Synthesis of Chiral Allenes Zhang et al. (2019) [(R)-L6]AuCl (5 mol%) H H stereospecific NaBAr4F (20 mol%) R2 R1 cyclization • enantioselective R3 R1 R3 R2 O OH 91 (aR)-90

OH R1 R2 89

Ad

aR P

Ad

R3

Au

R2 R1 HO

N Cy

H

92

H R3

Scheme 6.26  Bifunctional ligand-enabled, Au(I)-catalyzed alkyne isomerization.

(Scheme 6.26) [66]. In both cases, an allene is involved as a rapidly consumed intermediate that resulted from deprotonation of non-activated propargyl proton. The bifunctional catalysts enable soft activation of propargyl protons with a very weak aniline base. The rigid backbone, bulky P-substituents, as well as right position and basicity of the aniline moiety turned out to be crucial for the reactivity. The chiral ligand L6 bearing a C1-chiral tetrahydroisoquinoline with an axially fluxional biphenyl-2-ylphosphine was found to be highly enantioselective. Mechanistic study revealed that the center chirality can induce rapid fluxional behavior of the axial moiety, forming the more thermodynamically favored (aR, R)-configuration, which happens to be the requisite asymmetric catalyst. In the pathway leading to (aR)-allene, R3 projects away from the Cy group and is thus favored (92). 6.3.1.2  Enantioselective Addition to 1,3-Enyne

Entry to allenes by way of 1,4-addition to 1,3-enynes is another intensively studied topic. In 1993, Hayashi and coworkers reported the asymmetric 1,4-hydroboration of 1,3-enynes 93 to allenyl boranes 94 in moderate enantioselectivity (Scheme 6.27a) [67]. Related hydrosilylation was reported with improved stereoinduction, but the reactions suffer from a limited scope and insufficient enantiocontrol (Scheme 6.27b) [68]. (a) Hayashi et al. (1993) R + HB

H

Me

H

93

O

Pd/(S)-L7

O

Moderate ee

R Me

• 94

B O

OMe

O

PPh2

R

+ 95

HSiCl3

Ar

[Pd(π-allyl)]2/L8 or L9 0 ~ 20 °C L8: up to 90% ee L9: up to 92% ee

R Cl3Si

• (S)-96

H Me

Me Me

Ar

P Fe

Me

Me L9

P Fe

Ph OMe

(S)-L7

(b) Hayashi et al. (2001)

Fe

MeO

Me L8 Ar = MeO

Me

Scheme 6.27  Synthesis of heteroatom-substituted allenes via Pd-catalyzed asymmetric hydroboration and hydrosilylation.

Hayashi et al. also reported the Rh-catalyzed asymmetric 1,6-addition of aryl titanates to conjugated enynones 97 (Scheme  6.28a) [69]. The reaction was proposed to proceed via alkyne arylrhodation, followed by isomerization to rhodium enolate and trapping by

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene (a) Hayashi et al. (2004) O R + ArTi(OiPr) 4Li

Me3SiO [RhCl(C2H4)2]2 (5 mol%) (R)-SegPhos (ent-L3) (11 mol%)

97

ClSiMe3, THF, 20 °C, 0.5 h

O N 99

R2

R3

F F

ArB(OH)2 [RhCl(S,S)-L10]2 (2.5 mol%) K3PO4 (20 mol%) dioxane/H2O, 50 °C

•

Fe

F

Ar

CH2CONR2R3 (S)-100

up to 89%, 99% ee

F

H

R1

R

98

up to 91%, 93% ee

(b) Hayashi et al. (2010)

R1

Ar •

Fe

L10

Scheme 6.28  Rh-catalyzed asymmetric addition to conjugated enynone and enynamides.

trimethylsilyl chloride (TMSCl) to afford the product. Without TMSCl, 1,2-addition takes place to deliver the allylic alcohol. However, high enantiocontrol was only realized for n-butyl-substituted enynone substrate, while for other substituents, less than 80% ee were obtained, suggesting that arylrhodation might be the enantiodetermining step. Hayashi and coworkers further showed that Rh/chiral diene-catalyzed addition of aryl boronic acid to silyl-substituted enynamide 99 proceeded with high yields and excellent enantiocontrol (Scheme 6.28b) [70]. The bulky ferrocene moiety on the ligand and the silyl groups on the substrate were both critical for realizing high regio- and stereoselectivity. Loh, Xu, and coworkers reported in 2015 that the Cu-catalyzed asymmetric 1,4-protosilylation of (Z)-2-alken-4-ynoates 101 with silylboronate afforded enantioenriched allenyl silanes 102 (Scheme 6.29) [71]. Enantiocontrol significantly dropped when the R1 = alkyl or when R2 on the alkene was not hydrogen. Loh, Xu et al. (2015) R2

R1 101

PhMe2Si-Bpin CuTc (5 mol%) L11 (6 mol%)

R1

CO2R3 tAmOH, 0 °C PhMe2Si up to 90%, 94% ee

CO2R3

• 102

O

O N

N

R2 L11

Scheme 6.29  Cu-catalyzed asymmetric 1,4-protosilylation of (Z)-2-alken-4-ynoates with silylboronate.

Xu and coworkers further showed that CF3-substituted enynes 103 could be converted to chiral allenes 104 and 105 in Cu-catalyzed protosilylation with silylboronate and protoboration with B2Pin2, both of which have been realized with high enantiocontrol by applying a suitable bisoxazoline (BOX) ligand (Scheme 6.30) [72]. In the meantime, Liao et al. reported a synergistic Cu/Pd-catalyzed reaction of 1,3-enynes 106 with (hetero)aryl iodides to deliver an array of highly enantioenriched tri- and tetrasubstituted α-allenyl alcohols 107 after oxidation (Scheme  6.31) [73]. A sulfoxide phosphine L14 for asymmetric induction along with a relatively high loading of the palladium

155

156

6  Asymmetric Synthesis of Chiral Allenes Xu et al. (2020) CF3 + PhMe Si-BPin 2 R

103

R

B2(pin)2

H

H

CF3

• 104

SiMe2Ph

CF3

• 105

Bpin

R1

O

O N

R

R

hexane/MeOH, –10 °C up to 96%, 95% ee

103 R1

4 Å MS, EtOH, –10 °C up to 95%, 97% ee CuBr (5 mol%) L13 (6 mol%)

CF3 +

Cu(eacac)2 (5 mol%) L12 (6 mol%)

N

O

NTs

N N

L12 R2 R2 R1 = 4-tBuC6H4 R2 = sBu

NTs

O

L13

Scheme 6.30  Synthesis of CF3-containing chiral allenes via Cu-catalyzed asymmetric protosilylation and hydroboration.

Liao et al. (2020)

R2 + R1

106

R3 I

CuBr/L14 (5 mol%) PdCl2(dppf) (15 mol%) TFP (10 mol%) B2(pin)2, NaOEt THF/Me-THF up to 92%, 94% ee

L14 R1 R3

R2

S

• 107

OH

MeO

O

PiPr 2 OMe

Scheme 6.31  Synergistic Cu/Pd-catalyzed asymmetric synthesis of tetra-substituted allenols.

to promote efficient stereospecific Cu-to-Pd transmetalation of the allenyl group ensured the high enantiocontrol. CuH is a versatile intermediate that attracted intensive interest in recent years. In 2018, Hoveyda and coworkers [74], Engle and coworkers [75], and Ge and coworkers [76] groups independently reported the asymmetric 1,4-hydroboration of 1,3-enynes 108 for the synthesis of enantioenriched tri-substituted allenyl boroates 109 (Scheme 6.32). Hoveyda et al. proposed a mechanism that involves generation of CuH species by CuL* with HB(pin), hydrocupration with 1,3-enyne to form the allenyl copper intermediate 110/110′, and metathesis of the allenyl copper with HB(pin) to release the product while regenerates CuH. Catalytic generation of CuH species from silane in lieu of borane is also established by the Buchwald group in 2019 [77]. Ge et al. also developed conditions to trap the allenyl copper intermediates with quinonline N-oxides to generate chiral quinoline-substituted allenes (Scheme 6.33) [78]. DFT calculations suggested a pathway involving a five-membered addition transition structure 114 to be the most energetically feasible. Non-functionalized 1,3-enyne was shown to undergo facile hydropalladation with Pd–H species in the presence of a few C- or N-nucleophiles under neutral conditions [79]. In 2019, Tsukamoto et  al. reported the Pd-catalyzed asymmetric hydroalkylation of 1,3-enynes 95

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene Hoveyda et al. (2018)

Ph

Cu(OAc)2, L15 (5 mol%)

R1 108

H

(pin)B •

R1

R2 HBpin (2 equiv), THF, 22 °C

109 H

up to 80%, 98% ee

Energies in kcal/mol 109

L*Cu-H

R1

HBpin

•

0.0

108

rac H

H

R1

R2

P

Ph L15 (R,R)-Ph-BPE ‡

R2 111, 17.0 R1

H •

R2 H

Ph

Ph

CuL*

HBpin

L*Cu L*CuOR

P

*LCu 110/110′

0.9

R2 H

Scheme 6.32  Asymmetric synthesis of allenyl boronate via Cu–H intermediate.

Ge et al. (2019)

R1 R2 108

R

+

CuOAc (4 mol%) ent-L15 (6 mol%)

R N O 112

(EtO)2MeSiH (2 equiv) PhH, 5 °C, 24 h up to 95%, 99% ee

N

H •

R1

113

R2 H Ph

O N H Cu • Ph

114

P

Ph

Ph

P

H

Ph

Me

(S,S)-Ph-BPE ent-L15

Scheme 6.33  Cu-catalyzed enantioselective synthesis of quinoline-substituted allenes via Cu–H intermediate.

(Scheme 6.34a) [80]. The enantiocontrol for malonate nucleophiles could reach >90% ee, but only moderate enantiomeric ratios were observed for 1,3-diketone (78 : 22 er for acetoacetone) or 1,3-dinitrile (75 : 25 er for malononitrile). Catalytic LiI was found to play a significant role in enantiocontrol; it recovers and improves the intrinsic selectivity by promoting the dynamic process of the involved alkylidene π-allylic palladium intermediates. In the same year, Malcolmson and coworkers reported the Pd-catalyzed addition of amines 116 with 1,3-enynes 95 for the highly enantioselective synthesis of α-allenyl amines 117 (Scheme 6.34b) [81]. Early studies on this system afforded diamination products [82]. By including 2 equiv of Et3N as an additive, the second amination step could be largely suppressed. A ferrocene-based electron-deficient Phox ligand L17 was developed to ensure high enantiocontrol for the reaction of aryl and pyridyl enynes with secondary aliphatic amines, as control experiments revealed the facile racemization of the allenyl amine product in the presence of electron-rich ligands. For alkyl-substituted enynes, low enantiocontrol was observed, possibly owing to more facile ionization of the C─N bond of product.

157

158

6  Asymmetric Synthesis of Chiral Allenes (a) Tsukamoto et al. (2019)

R′

+

R

(allyl)CpPd (5 mol%) L16 (7.5 mol%)

EWG 95

EWG LiI (5 mol%), MeOH up to 100%, 96% ee

O

H

•

R

H

R′

115

EWG

O

PAr2

EWG

O

PAr2

O Ar = 3,5-tBu-4-MeOC6H2 (R)-DTBM-SegPhos (L16)

R = Ph, Cy, t-Bu EWG = CO2Me, MeCO, CN, PhSO2

(b) Malcolmson et al. (2019)

+

R1

R2

N H 116

95

R3

[Pd(allyl)Cl]2 (1 or 2.5 mol%) L17 (2 or 5 mol%) NaBAr4F (2.5 or 6 mol%)

O

H R1

Et3N (2 equiv), Et2O or CH2Cl2

•

N

117

up to 69%, 91% ee

R1 = aryl

H

R2

Fe

R3

tBu

N P(C6F5)2

L17

Scheme 6.34  Pd-catalyzed enantioselective 1,4-hydrocarbofunctionalization of 1,3-enyne.

A notable recent breakthrough concerns the asymmetric synthesis of allenes via 1,2-allenyl radical generated by radical addition to non-activated 1,3-enyne. Shortly after the racemic version of Cu-catalyzed 1,4-difunctionalization of 1,3-enynes with was disclosed [83–84], Bao and coworkers showed that high enantiocontrol can be realized with chiral BOX ligand L18 for substrates bearing aryl substituents at the alkene moiety (Scheme 6.35) [85]. DFT calculations suggest that this reaction proceeds via enantioselective group transfer process between the generated allenyl radical 121 with isocyanide Cu(II) species, rather than inner sphere reductive elimination from Cu(III). At the same time, Liu et al. independently reported a very similar reaction with several types of electrophiles, such as α-halo carbonyl and phosphonate, CCl4, Togni reagent, etc., as radical precursor, terminal alkyne as the nucleophilic coupling partner, and a N,N,P-ligand for reaction initiation and high enantiocontrol [85]. Bao et al. (2020)

N Ph

Ar R = alkyl 119

R

+

BPO or CnF2n+1I TMSCN

O

O

Ph

Ph

N

L18 CuX/L18

tAmOH/CHCl 3

(2/1 v/v) 0 °C

L *

Ph

L

G

CuII N C

R CN

Ar 120

up to 95 : 5 er

G R Ar

121

Scheme 6.35  Cu-catalyzed asymmetric radical 1,4-functionalization of 1,3-enyne.

1,3-Enynes bearing a suitably posited electron-withdrawing group turn out as good substrates for organocatalytic or Lewis acid-catalyzed Michael addition-type reactions. Liu, Feng, and coworkers reported a N,N′-dioxide/scandium(III) complex-catalyzed highly enantioselective conjugate addition of malonic esters to enynones 122 for the synthesis of tri-substituted allenyl ketones 127 (Scheme 6.36a) [87]. Similar substrates have been recently reported by Jørgensen and coworkers to undergo prolinol silyl ether-catalyzed Michael addition and vinylogous Michael addition with aldehydes 125 and α,β-unsaturated aldehydes 126, respectively, to afford highly functionalized tri-substituted allenes (Scheme 6.36b) [88]. The reaction features one-step construction of

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene (a) Feng et al. (2016)

CO2R4 R4O2C [Sc]/119 H R2 CO2R4 • up to 98%, 3 O 99% ee, 95 : 5 dr R 124 R1

R3

O 1

4

+

R

122

R O2C

R2

(b) Jørgensen et al. (2018)

O R4

R2

R1

N H

+

O

R 122

125 O

R X

Ph 122

O

–

O H

N

Ar

H

H

•

O

Conditions Ph3P R4 as above

Ph

H

OH –

123, Ar = 2,6-Et2-4-MeC6H2

R3

H R1 R2 127

CO2Me

O +

126

Ar

O

PhCO2H (20 mol%) toluene, r.t. up to 95%, >99% ee, >20 : 1 dr

3

N

R4

Ph Ph (20 mol%) OTMS

+ N

+ N

O

CO2Me

H

CH2Cl2, r.t. R up to 99%, >99% ee, >20 : 1 dr

Ph

O •

X 128

H

Ph

Scheme 6.36  Catalyzed asymmetric Michael and vinylogous Michael addition to electrondeficient enynone.

two additional stereocenters besides the axial chirality of allene in high diastereoselectivity (typically >20 : 1). Nucleophilic addition to non-activated enynes can also be realized when triggered by an electrophile. Tang and coworkers reported in 2010 a highly enantioselective syn1,4-bromolactonization (Scheme  6.37) [89]. The bifunctional chiral urea catalyst 131 simultaneously activates the brominating reagent and the nucleophile, orchestrating the syn-addition. In 2020, Morken and coworkers reported the conjunctive cross-coupling reaction of cis-borylenynes 134 with aryl and alkenyl bromides or triflates to afford α-allenyl boronic esters 135 with high enantio- and diastereoselectivities, which upon oxidative treatment yielded α-allenols with both axial and point chirality (Scheme 6.38) [90]. When the migrating group was alkyl, a planar, secondary diol-derived ligand, “hac*”, was necessary as the

Tang et al. (2010) X O

R1

R2 129, X = O, NTs, CH2

O OH

R3 130

N

N

O

O

Br

•

O

R2 132 up to 88%, 99% ee, 20 : 1 dr

OMe

NH

R1 R2

O

131

OH

R1

X

131 (20 mol%), NBS (1.2 equiv)

NHTs

H

R1 R2

O

•

131 (20 mol%), NBS (1.2 equiv) R3

Br

O O 133

Scheme 6.37  Chiral urea-catalyzed enantioselective intramolecular syn-1,4-bromolactonization.

159

160

6  Asymmetric Synthesis of Chiral Allenes Morken et al. (2020) Aryl – B(pin)

R + C(sp2)-Br

134a

+

Pd(OAc)2 (3 mol%) (S,S)-L19 (3.6 mol%)

H

up to 73%, 96% ee, >20 : 1 dr

MgX

Alkyl – B(hac*)

+

R

C(sp2)-OTf

134b

C(sp2)

•

KOTf, THF, 55 °C, 15 h Aryl then NaOH, H2O2

Ph

R

OH

Pd(OAc)2 (3 mol%) (S,S)-L19 (3.6 mol%)

NMe2

Ph

PAr2

NMe2

135a

Ar = 4-methoxy-3,5-xylyl MandyPhos L19 hac* =

R

OH •

CsF (2 equiv) Alkyl NaOTf or KOTf THF/DMSO, 55 °C,15 h then NaOH, H2O2 up to 66%, 96% ee, >20 : 1 dr

Fe

Ar2P

C(sp2) H

H

H 135b

O

B

O

Scheme 6.38  Asymmetric conjunctive cross-coupling of borylenyne for the synthesis of chiral α-allenols.

boronate ligated to impose high enantio- and distereocontrol. The reaction also needed DMSO to stabilize the boronate complex, CsF to improve the reactivity, as well as a triflate salt to sequester the halide, which may inhibit the coupling. Some miscellaneous reactions with achiral substrates, such as alkynylogous aldol reaction [91–92] and catalytic “traceless Petasis reaction” [93], are also notable advances. 6.3.1.3  Enantioselective Elimination Reactions

In 2013, Frantz and coworkers demonstrated that from stereo-defined alkenyl triflates 136, the palladium-catalyzed enantioselective β-H elimination could result in 1,3-disubstituted allenoates and allenamides 137 (Scheme 6.39) [94]. The high enantiocontrol was realized by chiral BINOL-based phosphite ligands L20 and its enantiomer ent-L20 bearing bulky 3,3′-substiutents, after observing that racemization of allene products was slower with phosphite ligands than with phosphines. For fully substituted triflates where R3   H, only very poor enantioselectivity could be obtained. Frantz et al. (2013)

R1

O

R3 136 (X = O, NH)

H R1

Me

iPr L20

O C XR2

R3 (with L20)

up to 87%, 96% ee

O P O O

•

H

Pd2dba3 (5 mol%) L19 or ent-L19 (10 mol%) Hunig’s base (4 equiv), iPrOAc, r.t.

XR2

TfO

R1

Me O P O O

H R1 L2Pd

•

O C XR2

R3 (with ent-L20) 137

OTf

H O XR2 R3

138

tBu ent-L20

Scheme 6.39  Synthesis of chiral allene via Pd-catalyzed enantioselective β-H elimination from alkenyl triflates.

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene

Pd-catalyzed Heck reaction between aryl triflates and alkynes to afford allenes was first discovered in 1989 as a side reaction [95]. In this reaction, an alkenyl palladium species generated from alkyne carbopalladation (rather than direct oxidative addition with alkenyl halides such as the reaction in Scheme 6.39) undergoes the key β-H elimination to afford allenes. In 2019, Ma, Zhang and coworkers developed its asymmetric version (Scheme  6.40) [96], wherein key to the high enantiocontrol was the use of Xu-Phos ligand L21, a type of sulfinamidephosphine ligands developed by the Zhang group. N-Substituent was found to be critical to the reactivity and beneficial to the enantiocontrol, probably because of the promotion of β-H elimination. The reaction could not work in cases where R2 = aryl. Ma et al. (2019)

OTf

[Pd] (4 mol%) L21 (12 mol%)

2 +R

1

R

139

R3 140

Na3PO4 (2.1 equiv) THF/H2O, 65 °C

Carbopalladation

Ar

PdL*

R2

H

N Pd

H

•

R2

N Pd

Cl Cl

[Pd]

R3

141

up to 91%, 92% ee

O.A. Ar Pd+L*

R1

N β-H elimination

O tBu S

PCy2

H R3 142

L21

Scheme 6.40  Enantioselective synthesis of allenes via Pd-catalzyed aryl triflates with alkyne enabled by a customized monophosphine ligand.

6.3.1.4  Catalytic Asymmetric Reactions Involving Diazo Compounds

Direct coupling of readily available terminal alkyne with diazo compounds or its surrogates is a straightforward approach for the synthesis of chiral allenes. In 2015, Liu and coworkers reported the first asymmetric C–H insertion of α-diazoesters 143 into 1-alkynes using chiral cationic guanidinium salt 145 and copper(I) complexes, which provided tri-substituted allenoates in high yields and enantioselectivities (Scheme 6.41a) [97]. The enantiocontrol was typically excellent for aliphatic alkynes (R1  =  alkyl) but only moderate for aromatic ones (R1 = aryl). Mechanistic studies excluded the possibility (a) Liu et al. (2015) R1

H +

R2

145 (5 mol%) CuBr (50 mol%)

CO2R3 or CuBr•Me S (15 mol%) 2 CH2Cl2, 30 °C up to 99%, 94% ee

N2 R1 = alkyl,aryl 143 (b) Wang et al. (2016) N2

R1 146

R2

+ H

R3

H

R1

Cu(MeCN)4PF6 (10 or 20 mol%) L22 or L23 (11 or 22 mol%)

• 144

CONHCHPh2

R2

N

CO2R3

145 Cy Bn O

R1

Et3N (1–2 equiv), CH2Cl2, r.t. R2 up to 96%, 98% ee

• 147

H R3

N

NHCy NH Br

Bn

O

N

Ar

Ar L22, Ar = Ph L23, Ar = 2-naphthyl

Scheme 6.41  Cu-catalyzed asymmetric synthesis of allenes from terminal alkyne and diazo compounds.

161

162

6  Asymmetric Synthesis of Chiral Allenes

of enantioselective formation of a propargyl ester via C–H insertion with the alkyne, followed by stereospecific isomerization. The same group subsequently extended this method in 2018 to an asymmetric three-component synthesis of tetra-substituted allenoates by reacting with isatins [98]. In 2016, Wang and coworkers reported a Cu(I)-catalyzed coupling between non-stabilized aryldiazoalkanes 146 and terminal alkynes, which furnished tri-substituted allenes 147 in good to excellent enantiocontrol (Scheme 6.41b) [99]. The reaction scope complements that of the previous reaction, providing good enantiocontrol for donor/ donor-type aryl/alkyl diazo compounds, but a limitation is that only aryl alkynes were applicable. 6.3.1.5  Desymmetrization

Examples on enantioselective synthesis of allenes via desymmetrization strategy are rare, possibly owing to the limited suitable substrate structures. Deska and coworkers reported an enzymatic desymmetrization of tri-substituted prochiral allenic diols 148 with porcine pancreatic lipase (PPL) to produce the corresponding acylated products 149 in moderate to high yields with high enantioselectivity (Scheme 6.42a) [100]. PPL was also found to be highly competent in the desymmetrizing hydrolysis of the ­corresponding diester 150 (Scheme  6.42b). The lipase from Pseudomonas fluorescens (PFL) was found superior for tetra-substituted substrates, with respect to rate and ­selectivity [101].

(a) Deska et al. (2011) R1 R2

OH

• 148

OH

cat. PPL or PFL vinyl butyrate, dioxane, 40 °C up to 96%, 99% ee

R2 R1

•

OCOnPr OH

(R)-149

(b) Deska et al. (2012) • Ph 150

OCOnPr

cat. PPL

•

OCOnPr Heptane/nbutanol, 40 °C Ph (R)-151a 90%, 97% ee

OCOnPr OH

Scheme 6.42  Enzymatic kinetic resolution.

Alexakis and coworkers reported in 2012 the Cu/simplePhos-catalyzed desymmetrization of readily available propargyl dichlorides 152 with Grignard reagents (Scheme 6.43a) [102]. Exclusive formation of allene products 153 was observed in high enantioselectivities (62–96% ee). Cu-catalyzed cross-coupling of these enantioenriched allenyl chloride products with Grignard reagent afforded the corresponding allene (R = aryl) 154 or terminal alkyne (R = alkyl) 155 with perfect chirality transfer. However, Suzuki and Sonogashira coupling applications were unsuccessful. In 2019, Xu and coworkers reported Cu-catalyzed silylative desymmetrization of propargyl dichlorides to afford functionalized allenyl silanes in high enantiocontrol (Scheme 6.43b) [103].

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene (a) Alexakis et al. (2012)

R R = Ar

CuBr (5 mol%) L24 (5.5 mol%)

Cl Cl R1

152

R2

H

R2MgBr (1.2 equiv) toluene, –78 °C, 2 h

R2

Cl

•

R1 154

CuCN (15 mol%) RMgBr (2 equiv)

R1 153

H

•

R

R = Ak

R2

up to 92%, 96% ee

R1 155

N P

Simplephos L24

(b) Xu et al. (2019) Cl R 156

Cl

+ PhMe2Si-BPin

CuF2 (10 mol%) ent-L18 (20 mol%) PhMe2Si MeOH –30 °C, Ar

R = aryl, 1°, 2° - alkyl

R

Cl H

157 62–96% ee

O

Ph

O N

Ph

N

ent-L18

Ph

Ph

Scheme 6.43  Synthesis of allenes via Cu-catalyzed desymmetrization of readily available propargyl dichloride with Grignard reagents.

6.3.2  Enantioselective Allene Synthesis from Chiral Substrates 6.3.2.1  Kinetic Resolution

When racemic allenes are readily available and inexpensive enzymes can be applied, enzymatic kinetic resolution provides a practical approach for the synthesis of chiral allenes. In 1986, Jones and coworkers reported that pig liver esterase (PLE) can catalyze the hydrolysis of allenoic ester for the preparation of allenoic acid [104]. However, >90% ee were observed in only two examples. In 2010, Gong and coworkers reported resolution of 2,3-allenoates 158 by a bisphosphoric acid-catalyzed dipolar cycloaddition reaction with in situ generated azomethine imine (Scheme 6.44) [105].

Gong et al. (2010) ArCHO EtO2C

+ NH2

EtO2C

Up to 48% >99% ee

R1

159 (7.5 mol%)

rac-158

CO2R3

Toluene, r.t., 3 d

up to 57% 94% ee

R2 •

H

R2 •

H

R1

(R)-158 Ar HN

CO2R3 CO2R3 R2 R1

EtO2C CO Et 160 2 O O

O P

HO

O

159

HO

O O P O

Scheme 6.44  Bisphosphoric acid-catalyzed kinetic resolution of allenoate via dipolar cycloaddition.

163

164

6  Asymmetric Synthesis of Chiral Allenes

In 2019, Ma and coworkers reported a synthesis of optically active tetra-substituted allenes 162 via Pd-catalyzed kinetic resolution of propargyl alcohols 161 (Scheme  6.45) [106]. Reaction was catalyzed by a binary Pd/Brønsted acid system and enabled facile access to tetra-substituted allenoic acid in high enantioselectivity with decent yields because of the observed significant selectivity factors. Notably, without the electron-rich chiral ligand, the conversion was very low, suggesting that the process is initiated by the oxidative addition of protonated alcohol with the electron-rich chiral PdL*.

Ma et al. (2019) R2

R3 OH

R1

+

CO

+

H2O

161

PdCl2 (2 mol%) (R)-DTBM-SegPhos (L16) PPh3 (20 mol%) (PhO)2PO2H (20 mol%) toluene, –5 °C, 18 h up to 46%, > 99% ee

R2

R1 •

R3

162

CO2H

Scheme 6.45  Pd-catalyzed kinetic resolution of propargyl alcohol for the synthesis of enantioenriched allenoic acids.

In addition, oxidative kinetic resolutions of chiral racemic allenes were also described under Sharpless epoxidation [107] and Katsuki epoxidation [108] conditions. 6.3.2.2  Dynamic Kinetic Processes

In contrast to kinetic resolution, dynamic kinetic processes (including dynamic kinetic resolution, DKR and dynamic kinetic asymmetric transformation, DyKAT, and differentiation between those that are not made herein) transform readily available racemic starting materials in a stereoconvergent fashion to optically enriched products in ideally 100% ­conversion and yield. Bäckvall and coworkers reported such a one-pot chemoenzymatic dynamic kinetic resolution of chiral racemic allenes by a combination of porcine pancreatic lipase with an optimized NHC-based palladium catalyst [109]. In one class of reactions, Pd-catalyzed nucleophilic substitution of α-allenyl alcohol derivatives with amine or malonate derivative for the asymmetric synthesis of 1,3-disubstituted allenes has been extensively studied since 2002, delivering a variety of functionalized allenes in good enantiocontrol. Representative highly enantioselective examples are summarized in Scheme 6.46 [110–114]. Ma and coworker also reported a highly enantioselective decarboxylative version in 2013 [115]. A limitation of this asymmetric “allene-to-allene” approach is the requirement of bulky R1 groups for the high enantiocontrol. In 2019, Ma and coworkers reported conditions that converted substrates with small substituents (R1) with high enantiocontrol in the reaction with malonates (Scheme  6.47) [116], thus significantly improved the synthetic utility of this protocol. With this reaction as a key step, the first enantioselective total synthesis of natural product (R)-traumatic lactone was accomplished. A mechanistically closely related process is the reaction of achiral 2-halo-1,3-butadiene as a substrate to afford chiral allenes in moderate to good enantiocontrol [117].

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene Murahashi, Naota et al. (2002); Naota et al. (2005, 2008); Trost et al. (2005); Hamada et al. (2009)

R1 H

•

H

Pd(0)/L* LG

163

•

H

1

•

•

H CO2Me CO2Me 2 R

H

•

tBu

(R)-164c up to 99% ee (L27)

H

H

H

•

Nu

164

Bn

L26

L25

O

Ph PhHN

•

(R,R)-164d 95% ee (L16)

O NH HN PPh2 Ph2P

H

N

O

PPh2 PPh2

MeO MeO

(R)-164b up to 91% ee (L26)

H

R

CO2Me CO2Me Me

R

(R)-164a 69%, 90% ee (L25)

PdL*

H

H

CO2Me CO2Me NHAc

R1

Nu

R1 PdL*

H

tBu

R1

N

tBu H

H

N

O

P OTMS

PAr2 PAr2

O

Bn

O

L27

L16

Scheme 6.46  Pd-catalyzed synthesis of chiral allenes via dynamic kinetic asymmetric transformation of chiral racemic allenol esters.

Ma et al. (2019) OCO2Me

• R1

165

R1 = 1°, 2°, or 3°-alkyl

CO2Me R2

H CO2Me

•

[Pd (π-cinnamyl)Cl]2 (2.5 mol%) R1 L16 (6–7 mol%), K2CO3 (2.0 equiv) up to 91%, 96% ee

166

H

CO2Me CO2Me R2

O O

OH (R)-traumatic lactone

O

Scheme 6.47  Pd-catalyzed decarboxylative dynamic kinetic asymmetric transformation of allenic alcohol carbonate with malonates.

The acidic hydrogen in chiral allenoates enables a subset of dynamic kinetic transformations. In 2013, Maruoka and coworkers reported an approach for the enantioselective generation of tetra-substituted allenes under phase transfer catalysis (Scheme  6.48a) [118]. Under basic conditions, the allenoates 167 are deprotonated to form an achiral cumulenolate anion, which combines with the PTC catalyst to form a chiral ion pair 171. Alkylation via a Mannich-type reaction with tosyl imines provides chiral tetra-substituted allenes 170 with high diastereoselectivities and enantioselectivities. Moreover, alkyl halides were verified to be competent electrophiles for this reaction. A peptide-catalyzed Mannich reaction of a similar functionalized allene with imine to afford tetra-substituted allene in good to high stereocontrol was reported by Miller and coworker in 2014 [119]. Allenoates bearing less acidic protons such as 172 was also found to participate in a related Aldol reaction under chiral bis-N-oxide 174 ligated AuIII Lewis acid catalysis (Scheme 6.48b) [120]. A chiral gold-bound alk-3-yn-2-enolate intermediate 175 was proposed as the key intermediate

165

166

6  Asymmetric Synthesis of Chiral Allenes Maruoka et al. (2013) H •

CO2tBu +

R1

tBuO2C

N

SO2Ar

K2CO3 (5 equiv), CPME, –20 °C tBuO2C up to 98%, 96% ee, 97 : 3 dr

R2

167

R2

169 (2 mol%)

168 Ar

NHSO2Ar CO2tBu • R1

170

Chiral quaternary ammonium salt

– Br

OBn

+ O

+N

–

Q*

OBn

169

•

tBuO

CO2tBu

•

R1

171

Ar Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3 Ammonium cumulenolate ion pair

Feng et al. (2016) R2 • 3

1

R

R O2C

R3

O

H

+ R4

AuCl3/174 (1 : 2, 1 mol%)

O

172

173

3 Å MS, EtOAc, 35 °C R4

N H

O N H

R3

CO2R1

•

HO

R2

176

OR1 O

[Au]

O

2

R

175

Ar

N

H

N

N

O

O

O H

174, Ar = 2,6-iPr2C6H3

N

Ar

Scheme 6.48  Catalyzed dynamic kinetic processes of allenic esters.

to attack isatin to give the final product, tri- and tetra-substituted allenoate 176 in moderate to good diastereo- and enantiocontrol. While it was well documented that the elementary steps in Pd-catalyzed cross-coupling with propargyl derivatives were all stereospecific to ensure efficient chirality transfer (see Schemes 6.13 and 6.14), evidence of the configurational liability of allenyl palladium species also exists [121]. This offers an opportunity to develop dynamic kinetic asymmetric transformations from racemic chiral propargyl alcohol derivatives to enantioenriched allenes. Ma and coworkers reported a highly enantioselective synthesis of allenoates 178 from carbonylation of racemic secondary propargyl alcohol carbonates 177 (Scheme 6.49) [122]. The process hinges on the evolvement of a BIPHEP

Ma et al. (2013) RO2CO R1

R2 177

[(π-allyl)PdCl]2(1 mol%) (R)-ECNU-Phos L28 (4 mol%)

H

LiF, CO balloon, toluene, r.t. R1 up to 89%, 97% ee

• 178

CO2R

MeO MeO

PAr2 PAr2

R2 (R)-ECNU-Phos L28 Ar = 3,5-(MeO)2C6H3

Scheme 6.49  Pd-catalyzed dynamic kinetic asymmetric carbonylation of propargyl alcohol carbonate for the efficient synthesis of chiral allenoates.

6.3  ­Catalytic Asymmetric Strategies for the Syntheses of Chiral Allene

analog, (R)-ECNU-Phos L28. Most recently, Ma, Zhang, and coworkers further extended the strategy to direct coupling of propargylic alcohol ester with organoboronic acids [123]. Propargyl alcohols bearing cation-stabilizing α-substituents can be dehydrated in the presence of an acid to form achiral carbocation intermediates, which can react with an exogeneous nucleophile to form products in an enantioselective manner if a chiral catalyst is involved in the bond formation event. A breakthrough was made by Sun and coworkers in 2017, in a strong Brønsted acid N-triflylphosphoramide-catalyzed enantioselective synthesis of tetra-substituted allenes from racemic bisaryl propargylic alcohols 179 with 1,3-dicarbonyl compounds and thioacid (Scheme 6.50a) [124]. Notably, a highly electron-donating group at one aryl substituent was identified to be important for the reactivity. For the addition of thioacid (Scheme 6.50b), a para-OH at the aryl substituent was necessary as the para-MeO analog only exhibited low conversion. Mechanistic studies suggest that the reaction may invoke a cationic intermediate or a quinone methide (QM) intermediate depending on the para-substituent. In 2019, Li and coworkers reported an analogous reaction with thiazolones and azlactones as nucleophiles [125]. Sun et al. (2017) R2

R3

OH

O R1

O

+

CCl4, 0 °C or –20 °C up to 96% 97% ee, 13 : 1 dr

R

R1

HO

+

R

O C

HO

•

up to 93%, 94% ee

R2

Ar

O Ar

(R)-182a

R4

CCl4, –5 °C, 3 Å… MS

rac-179

O

180

R3

(S)-182b (5 mol%) SH

COR

• R1

(b)

OH

R4

R2

(R)-182a (5 mol%)

rac-179 R2

O

(a)

181

R1 SCOR

Ar P

O

O

NHTf

O

Ar = 2,4,6-iPr3C6H3

P

O NHTf

Ar

(S)-182b

Scheme 6.50  Synthesis of chiral tetra-substituted allenes via Brønsted acid-catalyzed nucleophilic substitution of propargyl alcohols.

6.3.2.3  Deracemization

Deracemization is a mechanistically distinct class of asymmetric reactions that enables direct synthesis of one enantiomer from a racemic mixture. Under photoirradiation, chiral allenes could be transformed to an achiral diradical triplet state, resulting in configurational liability. An early report showed that a discernible ca. 3.4% ee can be induced when penta-2,3-diene was irradiated by UV in the presence of a stoichiometric

167

168

6  Asymmetric Synthesis of Chiral Allenes Bach et al. (2018, 2020)

H

H R

n

184 (2.5 mol%) hv (λ = 420 nm)

MeCN (10 mM), 4 or 8 h N O H 25 °C or –40 °C rac-183 n = 0, 1, 2 R = 1°, 2°, 3°-alkyl

R

N H ON O

n

N H

O

O S 184

183

H N H O O H N N O

H O d = 363 pm

hv

achiral triplet complex

S ent-183–184

hv

N H O O H N N O

O d = 510 pm

S 183–184

Scheme 6.51  Photochemical asymmetric deracemization of allenylidene lactam with a chiral photosensitizer catalyst.

chiral sensitizer [126]. Bach et al. reported in 2018 that in the presence of a chiral thioxanthone catalyst 184, racemic allenylidene lactam rac-183 can be rapidly deracemized to one enantiomer 183 in high ees under visible light irradiation (Scheme 6.51) [127]. In the DFT-calculated catalyst–substrate complexes, the distances between the distal allene double bond and the chromophores are markedly different. The shorter distance in the ent-183·184 complex could be responsible for more efficient energy transfer, driving this enantiomer to its enantiomer, the observed product, via the achiral triplet state. In 2020, they extended the chemistry to five- and seven-membered lactam homologs [128].

6.4 ­Conclusion and Perspective Enantioselective construction of the axial chirality in allene has attracted the creative input of many imaginative scientists for almost a century. While early successes were mainly on chirality transfer and resolution, by the 2000s, a preponderance of important reaction types had been disclosed, and catalytic asymmetric versions gradually became more prevalent. While chirality transfer as a reliable concept has continued to evolve since, the past two decades have witnessed further blossoming of catalytic asymmetric versions. Some racemic reactions have been rendered enantioselective; some catalytic asymmetric processes were upgraded to be more generally applicable; and most importantly, conceptually novel approaches were also put forward. Nonetheless, it is also not difficult to find that many apparently dissimilar reactions are in fact interrelated, and the seemingly diverse collection of reactions are actually underpinned by just a few fundamental reaction modes, by way of a few common intermediates. In the context of the ever-increasing emphasis on atom economy and sustainability, more elegant and green protocols will be expected. It is our hope that this compilation, although not necessarily comprehensive, can offer a glimpse of the breadth of the topic and help further developments in this fascinating field.

 ­Reference

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173

7 Asymmetric Synthesis of Axially Chiral Natural Products He Yang1,2 and Wenjun Tang1,3 1

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China Shenzhen Grubbs Institute, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen, 518055, China 3 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China 2

7.1 ­Introduction Axially chiral natural products are a class of important naturally occurring compounds with a diversity of biological activities [1, 2]. Because of the presence of axial chirality that arises from the restricted rotation along a chemical bond, these entities exist as single atropisomers at ambient conditions, although some of them were isolated as a mixture of atropisomers. Different structure features and architectures have been found in these natural products (Figure  7.1), ranging from axially chiral biaryls with axial chirality as the sole asymmetric element, such as kotanin and gossypol, to natural products containing both axial and central chirality, as exemplified by rugulotrosin A and michellamine B. Many natural products have complex or rigid structures, for example, the heptapeptide antibiotic vancomycin possessing an axially chiral biphenol moiety embedded in a macrocycle and isoplagiochin D, which contains a chiral di‐ortho‐substituted biaryl unit to form a highly strained cyclophane ring system. Besides biphenyl or binaphthyl‐type structures, natural products containing chiral C–N and N–N axis have been disclosed, including murrastifoline‐F, dixiamycin B, and many others. The naturally occurring non‐biaryl‐type atropisomers are another subclass of axially chiral natural products, such as bismurrayaquinone A, which is characterized by a bicarbazolequinone framework. To obtain enantioenriched or enantiopure natural products, the resolution method by either separating enantiomers via analytic methods or forming separable atropdiastereoisomers has been employed in the early age for small‐scale preparation. However, these approaches are not scalable or economic. Attracted by the diverse biological activities and unique structural features of axially chiral natural products, significant synthetic efforts have been made during the past decades (Figure 7.2) [3]. The efficient generation of axial chirality, as well as central stereogenic centers and complex skeletons, poses significant

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

174

7  Asymmetric Synthesis of Axially Chiral Natural Products Me

OMe HO

MeO

M

MeO

O

O

O

O

Me

OH

M HO

O

M

H N

H O

Cl O H N H

NH HO2C OH

O

H O

O

N H H2NOC

HO

O MeO2C OH

P

H N

OH

H O

NR

OMe OH HO

Me

Me

N N P

Me OH

Me

O H N

Me O M O Me

HO

Me

M

OH Michellamine B HOOC H

Me

OMe

H

Vancomycin aglycon

OMe Me

OH

NH

Me

OMe Murrastifoline-F

Me OH Me

OH OH

OH

OH

HN

Cl

P

Isoplagiochin D

N H

OH Me

O

Rugulotrosin A OH

OG

HO

N

O

Gossypol

OH

M

OH

OH

OMe

Kotanin

HO

Me OH M

OH

CHO OH Me Me

HO CO Me 2 O

CHO

N H

O

H COOH Dixiamycin B

Bismurrayaquinone A

Figure 7.1  The diversity of axially chiral natural products.

challenges in their asymmetric total synthesis. Because of the large structural variety, the synthetic methods are varied toward these axially chiral natural products. From the perspective of generating axial chirality, the contents of this chapter will emphasize the synthetic strategy for axial chirality formation and the key steps involved. The detailed total synthesis of the corresponding natural products will not be introduced. Among axially chiral natural products, the biaryl‐type members are the most common ones. The asymmetric aryl–aryl coupling is a straightforward and ideal approach to axially chiral biaryl natural products, as the axially chiral biaryl moieties are generated directly during the coupling process [4]. The atroposelective point to axial aryl–aryl coupling method, assisted by the intrinsic stereogenic centers or chiral auxiliaries, represents a robust and concise method through efficient transfer of chiral information from central chirality to axial chirality (Figure 7.2a). Alternatively, the recent development of enantioselective catalytic aryl–aryl coupling enables the efficient synthesis of chiral natural products using chiral catalysts (Figure  7.2b). Besides aryl–aryl coupling, the asymmetric C–N or N–N coupling represents a convenient route to natural products with C–N or N–N stereogenic axes (Figure 7.2e). The asymmetric transformation of racemic or prochiral biaryl structures to enantioenriched biaryls represents another route to axially chiral natural products (Figure 7.2c). A

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe Ar1 1

Ar1 3

R

R X Y

R2

* R4

Chiral substrate

Ar1 R2

R4 2

Ar

R1

N H

Chiral catalyst 1

Ar

R3

(b) Catalytic asymmetric R aryl-aryl coupling

(a) Diastereoselective aryl-aryl coupling

2

R1

1

c) Asymmetric transformation of biaryls

R3 + R2

Y X

R

R

R2

R4

Axially chiral biaryl natural products

Ar2

R4

Ar1 R1 (d) Diastereoselective 2 R macrocyclization

1 (e) Atroposelective C‒N or N‒N coupling R

R4

R2

3

R3 X Y

R2

N X

Ar2

R3 R4

Figure 7.2  Strategies for the asymmetric synthesis of axially chiral natural products. Source: Modified from Bringmann et al. [3].

representative approach is Bringmann’s lactone strategy, which have significant applications in the asymmetric synthesis of a wide range of biaryl natural products [5]. With the advent of new methods for asymmetric functionalizations of biaryls, such as enantioselective C–H functionalization of biphenyls and desymmetrization of biaryl units, this synthetic strategy toward axially chiral natural products has been further expanded [6]. The enantio‐ or diastereoselective macrocyclization is mostly used for the synthesis of axially chiral natural products with rigid structures (Figure 7.2d) [7]. The asymmetric cyclization can be facilitated by chiral catalysts, auxiliaries, or intrinsic chirality of the substrates. The axial chirality is generated concurrently during this process.

7.2 ­Diastereoselective Coupling—Point to Axial Chirality Transfer The establishment of axial chirality assisted by the central chirality of substrates during the aryl coupling process, commonly named as point‐to‐axial chirality transfer, has tremendous applications in the asymmetric total synthesis of axially chiral natural products (Figure  7.3). This synthetic strategy bases on the perquisite that the stereogenic carbon centers are formed before the formation of axial chirality. With respect to the origin of central chirality, the stereogenic centers in the coupling substrate can be the intrinsic central chirality that possessed by target molecules. On the other hand, central chirality is derived from a chiral auxiliary that is installed into the substrate molecules and cleaved at a late stage of the synthesis after the aryl coupling step. By using chiral substrates, an atropdiastereoselective intra‐/intermolecular aryl coupling will afford axially chiral biaryl motif favoring a major atropstereoisomer.

175

176

7  Asymmetric Synthesis of Axially Chiral Natural Products

R1

Ar1

R3

*

X Y 2

Oxidative aryl coupling

4

R

R Ar2

Intermolecular

* metal-catalyzed coupling SNAr

Ar1 1

3

R

R

R2

R4 Ar

2

Intramolecular

R1

Oxidative aryl coupling metal-catalyzed coupling 2 R photo-induced coupling

Facilitated by intrinsic central chirality or artificial chiral auxiliary

Ar1

R3

X Y

* R

4

Ar2

Figure 7.3  Diastereoselective coupling approach to axially chiral natural products.

7.2.1  Intramolecular Diastereoselective Coupling The intramolecular diastereoselective aryl–aryl coupling is an ideal approach for the synthesis of bridged axially chiral natural products such as lignans, biarylic lactones, and cyclopeptides. The chiral bridge containing stereogenic centers in substrates facilitates the generation of axial chirality during the aryl coupling process. To date, the frequently employed aryl coupling protocols include direct oxidative aryl coupling, transition metal‐ catalyzed or mediated coupling, and photo‐induced aryl coupling. By exploiting an artificial chiral linkage to tether the two aromatic rings together, unbridged axially chiral natural products can also be synthesized through intramolecular diastereoselective aryl coupling approach. A transient chiral ether or ester linkage is commonly employed for this purpose and this strategy is suitable for the synthesis of lignans, biflavonoids, and bicumarins. 7.2.1.1  Diastereoselective Coupling Enabled by Intrinsic Chirality

The oxidative phenolic coupling constitutes an important transformation in the biosynthesis of phenolic or phenyl ether biaryl natural products. The chemical synthesis of biaryl structures via oxidative coupling of electron‐rich arenes represents a biomimetic synthetic approach toward these natural products. For bridged axially chiral biaryls, when the two aryl moieties are tethered together by chiral backbones, such as the aliphatic chain possessing at least two stereogenic centers in lignans, the ester linkage attached to a chiral glucose core in ellagitannin‐type natural products and the stereogenic center‐containing peptide bridge in biarylic cyclopeptides, an intramolecular oxidative aryl coupling is suitable to construct the biaryl moiety. This process proceeds in a diastereoselective fashion to afford a major atropdiastereoisomer because of the diastereocontrol imposed by the chiral linkage. Lignan Natural Products  The lignan natural products have attracted considerable synthetic interests over the past two decades owing to their diverse biological activities. Most axially chiral lignans feature a dibenzocyclooctadiene framework, which contains a highly substituted axially chiral biphenyl unit and a chiral aliphatic bridge. As a representative example of oxidative coupling in lignan synthesis, a VOF3‐mediated coupling reaction was employed by Koga and coworkers to convert lactone 1 to (+)‐isostegane in 61% yield as a single atropodiastereomer (Scheme 7.1) [8]. The presence of two stereogenic centers in 1 led to substantial internal asymmetric induction during the aryl coupling process. The full conversion of axially chiral (+)‐isostegane to thermodynamically stable isomer (−)‐stegane was realized at high temperature. (−)‐Steganacin was synthesized from (−)‐stegane within three steps.

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe Tomioka et al. [8] OMe

OMe MeO H

O

O O

O

OMe

MeO

OMe

OMe

MeO

MeO

O VOF3 MeO

O

O 200 °C 100%

P

61%

MeO

O

H 1

M

61%

O

O (+)-isostegane Single atropdiastereomer

O

(1) NBS MeO M O (2) H2O (3) AcCl

O OAc

O

O (‒)-stegane

O (‒)-steganacin

Scheme 7.1  Diastereoselective intramolecular oxidative coupling. Source: Modified from Tomioka et al. [8].

By using oxidants including V(V)‐, Fe(III)‐, and Tl(III)‐based agents and dichlorodicyanobenzene (DDQ), this asymmetric coupling strategy was applicable to the synthesis of other enantioenriched lignan natural products or their enantiomers, such as 5‐detigloyloxy‐steganolide C, isoschizandrin, schizandrin, and gomisins (Figure 7.4) [9, 10]. Alternatively, the chiral biaryl linkage could be generated through atroposelective aryl coupling via a higher‐order cuprate intermediate. As delineated in Scheme  7.2, bis‐aryl bromide 2 was converted to a diarylcuprate intermediate 3 after Li–Br exchange and treatment with a Cu(I) reagent (CuCN or CuBr·SMe2) [12]. Exposure of this diaryl cuprate to an oxidant, such as 1,3‐dinitrobenzene and molecular oxygen, enabled the formation of a higher‐order diarylcuprate, which underwent reductive elimination to provide coupling product 4 in a stereospecific fashion. Alcohol 4 was derivatized to angeloylgomisin and interiotherin A after Mitsunobu reaction with angelic acid and benzoic acid, respectively. Direct oxidative coupling

Oxidative coupling via organocuprates

OMe

OMe

MeO

OMe

MeO H

H

MeO

OH O

M

O

MeO OMe 5-Detigloyloxy-steganolide C

OMe

MeO

MeO M MeO

OH MeO M MeO

MeO

MeO MeO

O OMe Schizandrin

OMe OH

P

MeO

O O Gomisin A

OH

MeO MeO

P

O O Gomisin E

O Gomisin O

Figure 7.4  Diastereoselective intramolecular coupling to lignans. Source: Pelter et al. [9] and Tanaka et al. [10]. Coleman et al. [11] O O O O OTBS tBuLi MeO MeO CuCN Br Li2(CN)Cu Br MeO MeO O

2 O

O

NO2 O OTBS

OH P

MeO PPh3 MeO DIAD ROH

O OR P

O

O O O4 Angeloylgomisin, R = , 51% Single atropdiastereomer Interiotherin A, R = Bz, 62% O

3 O

NO2 MeO then TBAF MeO 61%

O

O

Scheme 7.2  Diastereoselective oxidative coupling of organocuprate intermediate. Source: Based on Coleman et al. [11].

177

178

7  Asymmetric Synthesis of Axially Chiral Natural Products

Natural products such as gomisin E and O were synthesized by this oxidative aryl coupling method (Figure 7.4) [11]. Macropeptide Natural Products  The vancomycin‐related glycopeptides are a class of

important macrocyclic antibiotics that have attracted significant attention from synthetic chemistry, biological science, and clinical studies [13]. The atroposelective oxidative aryl coupling is one of the most frequently used tactics for the construction of the axially chiral biaryl moieties in these glycopeptides. Evans and coworkers established a V(V)‐ mediated oxidative aryl coupling protocol to generate the biaryl linkage in vancomycin (Scheme  7.3) [14]. Upon treatment with VOF3, peptide 5 was converted to biaryl intermediate 6 in 65% yield and with high diastereoselectivity (dr > 95 : 5). Although the undesired configuration with respect to the biaryl motif was obtained, the natural occurring configuration in vancomycin could be realized through thermodynamic interconversion between intermediates 7 and 8. The vancomycin aglycon was synthesized after several steps from 8. The intramolecular oxidative aryl coupling approach was also Evans et al. [14]

NO2

Cl

OPiv

F

F

O OH

OH O CF3 VOF3, AgBF4 Cl O2N O BF3 OEt2 O O NH NaBH(OAc)3 O N O H N BnO 65% MeHN H dr > 95 : 5 MeHN MeO

OMe

OMe 5

O

H N

H O

NHCOCF3 OH

OMe OMe 6

O

Cl H N H

O

H N H O H NOC 2

H N H O

OH O H N H

OH OH

HO

NH

NHMe

OPiv

Me

OMs

Cl O H N

H N

H

O

7

55% °C dr > 95 : 5

HO

NH O F3C

HO OH

HO

OMs

Cl O H N

N H

O

NHCOCF3

O

O

NH

Me

HO2C

O O

Cl

O

NH

O

N H

MeHN

MeO

OH HO

NH

HO

MeHN OH OH

O

Vancomycin aglycon

HO

8

Scheme 7.3  Diastereoselective intramolecular oxidative coupling in vancomycin synthesis. Source: Based on Evans et al. [14]. OH

OH O HO H O NH HO2C HO

O N H

H N H

O

O O H N H O H NOC 2

H N H O

HO

OH O

H N H

NHMe

O

Me Me

OH OH Orienticin aglycon

H

H N

O

Cl H N H

NH HO2C HO

OH OH

Cl O

O

H N H

O

H N H O O

HO

Teicoplanin aglycon

Figure 7.5  Axially chiral glycopeptides from oxidative aryl coupling.

O HO

H NH NH2

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe

exploited in the asymmetric synthesis of the aglycons of orienticin [15], teicoplanin [16], and their derivatives (Figure 7.5). Besides oxidative aryl coupling, transition metal‐catalyzed intramolecular coupling was employed in Snapper and Hoveyda’s synthesis of chloropeptin I (Scheme 7.4) [17]. Peptide 11, prepared from the coupling between 9 and arylstanne 10, underwent a diastereoselective Stille coupling to provide 12 with desired M configuration. Further manipulation of 12 delivered the final product. Deng et al. [17] Me3Sn OMe I HN

OMe O

HO2C

H H N O

O N Me

H N H

Cl

I

O Cl

OH

O

H N H

O (1) HCl (2) HATU NHBoc Me3Sn H

Cl

HO2C

O

N Me

H N H

Cl OH

O Cl

OH

N Me

H N H

O Cl

OH

NHBoc

NH H

Cl

OH Chloropeptin I

Cl

N H

Cl

H N

M

O

O HO2C

NHBoc O

OH

OH

Cl Cl

H N H

Pd(PtBu3)2 40% (3 steps) collidine, CsF

O

O O

O

H N H

11

OH

H N

M H N H

O

Cl 10

NaO2C

OH

O

O

OH

O

H H N

HN

Cl

OH 9

H H N

HO2C

H H N

Cl

O

OH

O N Me

H N H

Cl OH

O Cl

OH

H N H

NH H

Cl 12

NHBoc

O O

Cl OH

Scheme 7.4  Transition metal-catalyzed diastereoselective intramolecular coupling. Source: Based on Deng et al. [17].

Diazonamide A is a macrocyclic indole natural product displaying potent antimitotic activity and has attracted significant synthetic interests. Because of the presence of two rigid macrocycles, rotation along the biaryl axes between the two oxazoles, oxazole/indole, and indole/indoline is restricted. Accordingly, axially chirality exists within these biaryl linkages. In most reported asymmetric synthesis of diazonamide A, the aryl–aryl coupling between the indole and indoline units constitutes to be the key step of axial chirality formation (Scheme 7.5). Representatively, a photo‐induced aryl coupling protocol was employed to form the oxindole‐indole linkage [18, 20]. The presence of the quaternary stereogenic center in the oxindole of 13 exerted significant control on the orientation of this moiety, which reacted with the oxazole‐indole side chain to form the corresponding macrocycle 14 with limited flexibility. An intramolecular Suzuki–Miyaura coupling was also possible for the atroposelective macrocyclization in diazonamide A synthesis. MacMillan and coworkers effected a domino Miyaura borylation–Suzuki coupling with substrate 15 and axially chiral 16 was obtained in 50% yield as a single diastereoisomer [19]. This entity was converted to diazonamide A after several transformations.

179

180

7  Asymmetric Synthesis of Axially Chiral Natural Products Me Me

H O

N

H

O

30%

OBoc O

N H

O

N

hν (200 nm) LiOAc N

NHCbz

H N

Me O

N

Br

Me

NHCbz

H N

O Nicolaou et al. [18] O

P O

OBoc O

N H

M

M

Me

H N

Me

H O

N

HN N 14 H Single diastereoisomer

13

O

O Me Me

H N

O

Me

HN

H N

OTIPS

Br

OTf

H N

Pd(PPh3)4 (Bpin)2, KF

O TfN

Me

O

N N H H

Microwave 50%

O

N

H

Me

Me OH

O

N H H

O

Cl N H

O

O

M

M

Me

H

Me

P O

Cl

OTIPS

Diazonamide A

P

Knowles et al. [19]

O M

M N Tf

15

HN

H N

N

HN

N H H

O

16

Scheme 7.5  Diastereoselective intramolecular aryl coupling in the synthesis of diazonamide A. Source: Nicolaou et al. [18] and Knowles et al. [19].

Macrolactone Natural Products  The ellagitannins are a class of polyphenols that are

characterized by a glucose core and biarylic macrocyclic lactones. Limited flexibility of the macrocyclic lactone structure renders these molecules exist as single atropisomers. From the perspective of asymmetric synthesis, the axially chiral biphenol moiety could be constructed via a diastereoselective intramolecular oxidative coupling approach [21]. As demonstrated in Scheme  7.6 for the asymmetric synthesis of tellimagrandin II [22], polyphenol 17 participated into a Cu(II)‐mediated oxidative phenolic coupling reaction to provide axially chiral biaryl 18 as a single diastereoisomer. The diester linkage connecting

Takeuchi et al. [22] MOMO HO HO O

O

MOMO

O RO O

HO

MOMO

OH

72% O

RO

17 OMOM

OMOM

R=

HO HO P

CuCl2, nBuNH2

OR

MOMO HO

HO

OH

O O RO O 18

HCl

O

82% O

RO

OR

O O O OG HO OG Tellimagrandin II OH O

HO

O

OG

OH

G=

OMOM O

OH

HO HO P

OH O

Scheme 7.6  Diastereoselective intramolecular oxidative coupling in tellimagrandin II synthesis. Source: Based on Takeuchi et al. [22].

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe

to the chiral glucose backbone in 17 dictated the favorable conformation of the two phenol rings and affected the absolute asymmetric induction during the coupling process. A global deprotection of 18 delivered tellimagrandin II in 82% yield. The intramolecular oxidative aryl coupling was successfully applied to the asymmetric synthesis of coriariin A, a dimeric ellagitannin natural product with promising tumor‐ remissive properties (Scheme  7.7) [23]. Under the Wessely oxidation conditions using Pb(OAc)4, precursor 19 underwent a double oxidative cyclization to generate the two axially chiral biaryls possessed by coriariin A. It was noted that several regioisomers were observed during the coupling process. A final global deprotection of this complex mixture under catalytic hydrogenolysis conditions and judicious purification provided the target natural product.

Feldman and Lawlor [23] Ph

Ph

O

O

R1O

O Ph

O O

HO

1

HO HO HO HO HO

BnO

O O O O R2O R2O

O

O O

O R1O

OH

BnO BnO OBn

O O BnO

Ph

R1 =

OH

OBn O O

O

O

O

O

OBn

O

RO

O

Ph

Ph

HO

O

O

O

OR1 19

OBn

OH

O

O

Ph Ph

(1) Pb(OAc)4, 74% (mixture) (2) H2/Pd, 80% OH

HO

OH O O

O O HO

O R2O

HO OH

O

O OR2 O

Coriariin A

O

OH

O

O

OH

O

OH

R2 =

HO HO OH

OH OH

Scheme 7.7  Diastereoselective intramolecular oxidative coupling in coriariin synthesis. Source: Based on Feldman and Lawlor [23].

The intramolecular oxidative aryl coupling is a direct approach to ellagitannin natural products without the prefunctionalization of coupling substrates. However, regioselectivity and productivity can be issues in certain cases. To solve these synthetic challenges, the oxidative coupling of diarylcuprates represents a mild coupling method and has been applied in ellagitannin synthesis (Scheme 7.8). In Spring and coworkers’ synthesis of sanguiin H‐5 [24], by installing two aryl bromide fragments on the glucose core, the intramolecular oxidative aryl coupling of bis‐aryl bromide 20 via a diarylcuprate intermediate afforded 22 as a single atropisomer, which served as the precursor of sanguiin H‐5.

181

182

7  Asymmetric Synthesis of Axially Chiral Natural Products Su et al. [24] BnO

Ph OO

BnO

O O

(1) Reike zinc (2) CuBr·SMe2

O

O

Br O Br BnO BnO BnO

O

(3) O

RO

NMe

O

BnO

O Ph O O OO O

RO OR

OR RO

OBn

OBn 20

O2N

O

RO

N

OBn

O O

NO2 21 70% (3 steps)

Pd/C, H2 99%

OR OR

OR R = Bn (22) R = H, sanguiin H-5

Scheme 7.8  Oxidative coupling via organocuprate in the asymmetric synthesis of sanguiin H-5. Source: Based on Su et al. [24].

7.2.1.2  Diastereoselective Coupling Facilitated by Chiral Auxiliaries

In ellagitannin syntheses, the late‐stage atroposelective biaryl coupling enabled by intrinsic chirality represents a linear synthetic approach. Alternatively, the axially chiral biaryl motif could be constructed initially as a building block and installed into the glucose core to generate the macrolactone structure, as a convergent synthetic route to ellagitannin natural products. The asymmetric synthesis of cuspinin is depicted in Scheme 7.9 that the two aromatic rings were tethered together by a chiral diester linkage to provide 23 [25]. Intramolecular oxidative phenol coupling afforded axially chiral 24 as a single diastereoisomer. Cleavage of the chiral bridge auxiliary delivered 25, which underwent a double esterification with the corresponding glucose core to give 26. The other axially chiral biaryl linkage in cuspinin was prepared from 26 and chiral biaryl 27 that was prepared via Yamaguchi et al. [25] OH

OBn

O

MeO MeO

H

OBn

O OH OH

H

O

(1) CuCl2, nBuNH2 100% de

MeO

(2) BnBr, K2CO3 73% (2 steps)

MeO

O

H O

M

O H

O

23

O HO

O

O O O

HO2C

88%

HO2C

25 (Single enantiomer)

BnO O

O

BnO OBn

BnO

O

OBn

P

OBn

BnO

HO HO O

O HO

M OH HO Cuspinin

OBn

(1) EDCI, DMAP, 75% O Ph O O OR HO OH (2) HCl (aq), 83% O

O

OBn

M

OBn

24

OH

HO

LiOH

OBn

OBn

OH

HO

OBn

OBn

OH

HO OH P

OBn

OBn

OBn O

OBn OBn

OR

O

O HO OH

OH

O O

OH OH

O

O

O 27

BnO BnO BnO 26

OBn OBn

Scheme 7.9  Diastereoselective intramolecular aryl coupling facilitated by artificial chiral linkages. Source: Modified from Yamaguchi et al. [25].

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe

a similar atropdiastereoselective intramolecular aryl coupling facilitated by an artificial chiral bridge. The intramolecular diastereoselective aryl–aryl coupling by using a chiral linkage has enabled convenient synthesis of many unbridged axially chiral natural products. Scheme 7.10 demonstrated the key aryl coupling step in the synthesis of bicumarin natural product kotanin [26], whose biosynthesis was reported to involve an intermolecular regio‐ and stereoselective oxidative phenol coupling. Enantioenriched axially chiral biaryl structure 29 was synthesized from the intramolecular oxidative coupling of the corresponding organocuprate intermediate generated from bis‐aryl bromide 28. After recrystallization, enantiopure 30 was obtained and transformed to kotanin. The axial chirality in related natural products such as desertorin C and biflavone derivative was established in a similar manner [27, 28]. Lin and Zhong [26] Me

MeO Br Br MeO

Me

Me O H OBn nBuLi, CuCN, O2 MeO 60% O H OBn

Me 28 Lin and Zhong [28]

O H OBn P

MeO

82% ee (>99% ee after Me recrystallization) 30

Me

O MeO MeO

M

O O

OMe OMe

OMe

MeO Me MeO

M

OMe O O

MeO MeO

OH O 5,5″-dihydroxy-4′,4′′′,7,7′′tetramethoxy-8,8′′-biflavone

OH OH

P

O H OBn

Me 29 Kyasnoor and Sargent [27] O

OH O

MeO MeO

Me OMe desertorin C

P

Me

O O

O O

OMe

(+)-kotanin

Scheme 7.10  Synthesis of unbridged axially chiral natural products facilitated by chiral linkages. Source: Lin and Zhong [28] and Kyasnoor and Sargent [27].

7.2.2  Intermolecular Diastereoselective Aryl Coupling 7.2.2.1  Diastereoselective Coupling Enabled by Intrinsic Chirality

The intermolecular oxidative aryl coupling is a convenient route to unbridged biaryl natural products, in particular, the dimeric and symmetrical ones. When the natural products bear both axial and central chirality, an atropdiastereoselective coupling is possible via point‐to‐axial chirality transfer. Although organisms are able to produce a single atropisomer, chemical synthesis tends to generate a mixture of atropisomers, whose ratio is mainly dependent on substrate structure.

183

184

7  Asymmetric Synthesis of Axially Chiral Natural Products

Dimeric Quinones, Chromanones, Xanthones, and  Limonoids  The perylenequinones are

biquinone‐type natural products with one biaryl C─C single bond and a double bond between the two quinoid moieties. Two chiral side chains are attached to this axially chiral and twist motif. The diastereoselective homocoupling of functionalized naphthylene was developed as a common route to these axially chiral natural products. As shown in Scheme 7.11, aryl bromide 31 bearing a stereogenic center was used as an advanced synthetic precursor of phleichrome [29]. The oxidative coupling of the arylcuprate generated from 31 afforded axially chiral biaryl 32 in 70% yield with good diastereoselective control (78% de). Phleichrome was synthesized from 32 after deprotection and intramolecular oxidative phenolic coupling. The atroposelective intermolecular oxidative aryl coupling was applicable to the asymmetric synthesis of other perylenequinone natural products. Coleman and Grant [29]

OMe OBn

OH O

OMe Me

OMe Me

OMe OBn OMe Me

nBuLi, CuCN, O2

70%, 78% de OBOM

MeO

MeO MeO

OBOM OBOM

P

MeO MeO

Me OMe

Br

Me OMe OH O (‒)-phleichrome

OMe OBn 32

31

OH OH

P

Scheme 7.11  Diastereoselective coupling in phleichrome synthesis enabled by intrinsic chirality. Source: Based on Coleman and Grant [29].

Gonytolide A is a dimeric chromanone lactone natural product with potent innate immune promoting activity. This C2‐symmetric natural product has one chiral biaryl axis and four chiral centers. In Porco’s synthesis, a V(V)‐mediated intermolecular phenolic coupling was exploited to forge the biaryl moiety (Scheme 7.12) [30]. Enantioenriched chromanone 36, which was obtained from the kinetic resolution of 33 via Cu‐catalyzed enone reduction and subsequent chlorination, was synthesized as an advanced substrate for Wu et al. [30] OH O H

Cu(OAc)2 (8 mol%) Josiphos SL-J001-2 (9 mol%) O (EtO) SiH (5 equiv) Me

O CO2Me (±)-33 OH O

Me

O

3

H O 34 OH O

H

O

O

Me CO2Me O

O CO2Me Me O

H O OH (‒)-atrop-gonytolide A, 27%

OH O

OH O

O CO2Me

H O + O

O

Me CO2Me O H

+ O Me

O O CO2Me (+)-35 49% yield, 78% ee (94% ee after recrystallization)

O O CO2Me Me (1) VOF3

O

NCS 44%

O

OH O Cl

(2) Pd/C, H2 Me

O OH (+)-gonytolide A, 23%

H

H O CO2Me 36

O

Scheme 7.12  Diastereoselective oxidative dimerization approach to (+)-gonytolide A. ­Source: Based on Wu et al. [30].

O

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe

oxidative dimerization reaction. Gonytolide A was obtained in 23% yield, along with its unnatural atropstereomer (27% yield). This constitutes to be the first synthesis of (+)‐gonytolide A, albeit low atropdiastereoselectivity was observed at the oxidative dimerization step. Tetrahydroxanthones are secondary fungal metabolites and have emerged as an important class of natural products. Among these, rugulotrosin A is a representative dimeric tetrahydroxanthone with antibacterial activity. Because of its 2,2′‐linked pattern of the tetra‐ortho‐substituted biaryl structure, this natural product possesses both central and axial chirality. By employing a point‐to‐axial chirality transfer strategy, Porco and coworkers achieved the atroposelective synthesis of this chiral natural product (Scheme 7.13) [31]. The key step involved a Pd‐catalyzed, one‐pot Miyaura borylation/Suzuki‐coupling of monomer 37. The chiral tricyclic skeleton exerted significant asymmetric control on the atroposelective dimerization. By using Pd/Sphos, the coupling reaction delivered biaryl 38 in 45% yield and a diastereomeric ratio of 88 : 12, favoring the M configuration of rugulotrosin A. Qin et al. [31] OH O

OMe

I Me

O MeO2C

MeO CO Me 2 O

Pd catalyst (BPin)2 K3PO4, 70 °C

OH

37 Condition 1: Pd(OAc)2 (0.2 equiv) SPhos (0.42 equiv) 45%, dr 88 : 12 Condition 2: Cy2 P Pd N OMe H 2 OMs 39 (0.2 equiv) 44% dr 95.5 : 4.5

OH O

Me OH O

OH Me 38

O MeO2C

OH

HO CO Me 2 O 3 M HCl 60 °C 89%

MeO

HO

OH O Me (‒)-rugulotrosin A MeO2 C OH

MeO

OH Me O

Me OH O

Me O

O MeO

OH CO2Me

OH

OH O

OMe

MeO O Cy HO Cy Pd Pd OMe Me

Me OH O

CO2Me OH

40

OH O OMe Me Me OH Ascherxanthone A

Scheme 7.13  Atropdiastereoselective Suzuki coupling in the synthesis of xanthone natural products. Source: Based on Qin et al. [31].

Conformational analysis of the coupling reaction revealed the possible geometry of the diaryl Pd complex at pre‐elimination stage. Transition‐state 40 was anticipated to have a minimal steric clash between the two substrate moieties, as well as the two substrates and the ligand. This lowest energy structure led to the observed atroposelectivity of the Suzuki reaction. The employment of a proper chiral catalyst could potentially improve the atroposelectivity of the coupling reaction, as the use of catalyst 39 resulted in a dr of 95.5 : 4.5. Nevertheless, the point‐to‐axial chirality transfer is believed to be the predominant factor of stereochemical control. An acidic hydrolysis of 38 led to rugulotrosin A. Dimeric ­tetrahydroxanthone ascherxanthone A was synthesized in a similar fashion [32]. The limonoid dimer krishnadimer A is a C2‐symmetric nonbiaryl axially chiral natural product with a P‐configured stereogenic axis. Biological investigations indicated that the unnatural M‐diastereomer of krishnadimer A exhibited potent and selective antitumor activities while P‐krishnadimer A was inactive [33]. This indicated the important influence

185

186

7  Asymmetric Synthesis of Axially Chiral Natural Products Li et al. [33]

MeO

O Me

Me

O Me H

MeO

Me H

O DDQ

O O

O Me O

O

Me

Me

OH

O Me O

H O

Me H

H O

OR O

O HO HO P OH OH O

Me Me

41% P:M = 3 : 1

O

HMe

O

RO

H

H Me

Me O O Me O

Me H

O

41

Me

R = isobutyryl (43)

LiOH 44%

krishnadimer A (R = H)

OMe

42

Scheme 7.14  Atropdiastereoselective oxidative coupling in the semisynthesis of krishnadimer A. Source: Based on Li et al. [33].

of axial chirality on bioactivity. An atroposelective DDQ‐mediated oxidative coupling of dienol 41 was exploited in Bringmann and coworkers’ semisynthesis of this natural product (Scheme  7.14) [33]. The coupling reaction provided dimer 42, favoring P‐configured axial chirality, which was possessed by naturally occurring krishnadimer A. Axially Chiral Alkaloids  P‐(+)‐Dispegatrine is a dimeric indole alkaloid featuring a

cycloocta[b]indole framework. This natural product showed antihypertensive activity and is more potent than its monomer. The presence of electron‐rich phenolic indole ring enables the application of oxidative aryl coupling as the key step for the biaryl formation. Cook and coworkers employed a Tl(III)‐mediated arene dimerization to convert enantioenriched indole monomer 44 to atropdiastereomer 45, with efficient internal asymmetric induction by chiral sarpagine skeleton (Scheme 7.15) [34, 35]. The final natural product was obtained after the demethylation of two phenol methyl ether moieties in 45 and the formation of two quaternary amine salts. Axially chiral natural products with N–N chiral axes represent an unexplored type of naturally occurring substances. To date, scarce studies have been reported to solve their chemical synthesis. Dixiamycin B is a dimeric indole terpene alkaloid containing a stereogenic N(sp3)–N(sp3) axis. The high rotational energy barrier (201 kJ mol−1) indicates that the interconversion between the two atropisomers is not possible at ambient conditions. By using an unprecedented electrochemical oxidative N–N coupling, Baran and coworkers achieved the asymmetric synthesis of dixiamycin B (Scheme 7.16) [36]. Enantiopure carbazole 46 underwent oxidative dimerization to provide the natural product as a single Edwankar et al. [34] H

H

OMe H N H

H

N H

N

Tl(OAc)3 CH2OH BF ·Et O HO 3 2 60% b.r.s.m

H

H N

H OMe

H 44

45 Single N atropdiastereomer H

H (1) BBr3, 80% ‒ (2) MeI, AgCl Cl 70% HO H MeO H CH2OH

H

H OH

H N

P

HO H

H

H

N (+)-dispegatrine H

CH2OH ‒

+

N H

H +

N

N H

Cl H

Scheme 7.15  Diastereoselective oxidative dimerization approach to (+)-dispegatrine. Source: Based on Edwankar et al. [34].

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe Rosen et al. [36] HOOC H NH Me

Carbon anode (+1150 mV) Et4NBr

HO

H COOH

Me

Me

Me

Me

+

Br HO

HO Me

46

OH NH

N N

13% SM recovered

Me

H COOH

Me Dixiamycin B (28%)

H COOH 47 (17%)

Scheme 7.16  Atropdiastereoselective oxidative N–N coupling approach to dixiamycin B. Source: Based on Rosen et al. [36].

atropstereoisomer, accompanied by brominated substance 47 and several regioisomers from C–N or C–C coupling. The naphthylisoquinoline alkaloids are an emerging class of secondary metabolites with diverse biological activities, some of which have potential medicinal value. These natural products contain a naphthyl unit and a tetra‐ or dihydroisoquinoline that are linked via either a chiral C–C or C–N axis. As most of these natural products possessing at least one stereogenic carbon center, it is feasible to generate the axial chirality through an atropdiastereoselective C–C or C–N coupling reactions using substrates with preformed chiral centers. A representative example was demonstrated by Lipshutz and coworkers’ total synthesis of (+)‐korupensamine B (Scheme 7.17) [38]. The Pd/SPhos‐catalyzed Huang et al. [38] OBn OMe

B(OH)2 I

OBn OMe

OTIPS

PdI2 (4 mol%) SPhos (8 mol%)

48

K3PO4, nBuOH

+

BnO

NH

OBn Me

NTs

OH Korupensamine B

50 72%, dr 11 : 1

49 Slack et al. [37]

Bringmann et al. [39] MeO

OBn OMe

+

OMe OMe OMe Me

BnO Pd L O O

OBn N

MeO

M

Me Me N

Ts p-stacking

Me OH

OMe

N P

OTIPS L

M

HO

O

OMe

NTs

O

OBn Me

OTIPS O

M

O

BnO

OH

O,N-dimethylhamatine (Negishi coupling)

(C‒N coupling)

Me

Me

OMe Me

Me

‒

TFA Ancistrocladinium B

N

MeO

+

M

Me

‒

TFA

OMe OMe

OMe Ancistrocladinium A

Me (C‒N coupling)

Scheme 7.17  Catalytic atropdiastereoselective coupling approach to naphthylisoquinoline alkaloids. Source: Slack et al. [37] and Huang et al. [38].

187

188

7  Asymmetric Synthesis of Axially Chiral Natural Products

Suzuki–Miyaura coupling between aryl iodide 49 and naphthyl boronic acid 48 afforded biaryl 50 with high diastereoselectivity. The stereogenic centers in 49, in combination with the potential π stacking between isoquinoline ring and the naphthyl group of 49, were proposed to be the source of asymmetric induction for the formation of M‐configured product 50. The desired atropstereoisomer of 50 was separated from its P‐configured isomer and converted to korupensamine B after several transformations. The transition metal‐catalyzed atroposelective coupling reactions, such as the Negishi coupling and Buchwald–Hartwig amination, were successfully applied to the asymmetric synthesis of other naphthylisoquinoline alkaloids, such as dimethylhamatine and ancistrocladiniums [37, 39]. Vancomycin-Related Glycopeptides  Complementary to the intramolecular oxidative coupling

for biaryl formation in the synthesis of vancomycin‐type antibiotics, an intermolecular aryl–aryl coupling approach was developed by Boger and Nicolaou independently to forge the chiral biaryl moiety [40, 41]. An example is shown in Scheme 7.18, which belongs to the Boger’s synthesis of the ABCD ring system of vancomycin [40]. A Suzuki coupling between aryl bromide 51 and boronic acid 52 installed the A ring to the B–C–D skeleton, affording biaryl 53 as a mixture of atropstereomers. Although the coupling reaction favored the undesired M configuration, a thermal equilibration realized the interconversion between two atropstereoisomers, resulting in a P/M ratio of 3 : 1. A subsequent macrolactamization generated the ABCD ring system. Boger et al. [40]

OMe O

TBSO MeO2C

O N H

Pd2(dba)3, P(o-tolyl)3 88% OMEM NHBoc

Cl H N O

Br OMe 51

OMe

O

OH

(HO)2B

TBSO

NHCbz P

A

OMe 52

MeO

H N H

N H

MEMO

OH D

Cl

O

MeO2C

OMe

CbzHN

C

B

NHBoc

Vancomycin aglycon

O

OMe 120 °C OMe

P-(53):M-(53) = 1 : 1.3 P-(53):M-(53) = 3 : 1

Scheme 7.18  Atropdiastereoselective Suzuki coupling in vancomycin synthesis. Source: Based on Boger et al. [40].

Biphenyl Sesquiterpenes  The emergence of new catalytic aryl–aryl coupling methods has expanded the toolbox for the synthesis of biaryl natural products. A Pd‐catalyzed dimerization of aryl halides was developed by Feringa and coworkers for the construction of symmetrical biaryl compounds. This method was applied to the asymmetric synthesis of mastigophorene A, a biphenyl‐type sesquiterpene with nerve growth stimulating activities (Scheme  7.19) [42]. Specifically, the homocoupling of bromide 54 was catalyzed by Pd‐ PEPPSI‐IPent in the presence of tBuLi to give (P)‐55 as the major atropstereoisomer (dr 9 : 1). A final demethylation converted 55 to mastigophorene A. Mechanistically, the aryl coupling reaction proceeded via the coupling between aryl bromide 54 and an aryl lithium reagent generated from Li–I exchange of another aryl bromide. The chiral cyclopentyl unit induced significant asymmetric control.

7.2  ­Diastereoselective Coupling—Point to Axial Chirality Transfe Buter et al. [42] OMe OMe Br 54

RO

Pd-PEPPSI-IPent (5 mol%) tBuLi (1.2 equiv)

RO OR

R

OR

R N

R Pd R Cl Cl N R = iPent

P

dr 9 : 1

Me

R = Me (55) R = H, mastigophorene A

BBr3 27% (2 steps)

N

Cl

Scheme 7.19  Pd-catalyzed atropodiastereoselective dimerization in mastigophorene A synthesis. Source: Based on Buter et al. [42].

7.2.2.2  Diastereoselective Coupling Facilitated by Chiral Auxiliary

In lignan synthesis, the intramolecular aryl coupling provides excellent atropdiastereoselectivity owing to the presence of a chiral linkage. As a different synthetic strategy, the intermolecular aryl coupling approach to bridged lignans features an early stage formation of the axially chiral biaryls. An aryl substrate possessing a chiral auxiliary is usually employed to induce efficient stereochemical control in the coupling reaction. These chiral auxiliaries include sulfoxide derivatives, arene–chromium complexes, and oxazolines (Scheme 7.20). In Colobert and coworkers’ formal synthesis of (−)‐steganone, a chiral sulfoxide moiety was installed to one of the aryl section 56 [43]. The intermolecular Suzuki coupling between 56 and boronic ester 57 provided biaryl product 58 in 68% yield and high diastereoselectivity (dr 98 : 2) by using XPhos palladacycle as a catalyst. Alternatively, an atropdiastereoselective Suzuki coupling was conducted by Uemura and coworkers using Chiral sulfoxide

Yalcouye et al. [43]

O O

O

Bpin

O

Me

MeO

OMe

+ S I

MeO

OAc O 56

MeO

CH2OH

+ OMe 60

O

Pd(PPh3)4 Na2CO3

(CO)3Cr Ph

62

M

O

CHO

O

MeO

CH2OH

O OMe

MeO

61

Singe atropisomer after chromatography

O N

OMe

O O

OMe (–)-steganone O

O

OMe O

MeO

58

Chiral oxazoline

Meyers et al. [45]

MeO

OAc O OMe

OMe

MeO 67% Single atropisomer MeO

MeO (CO)3Cr

S

M

O

Br

B(OH)2 59

MeO MeO

Chiral chromium complex

O

CHO

68%, dr 98 : 2

OMe 57

Kamikawa et al. [44] O

XPhos palladacycle

OMe

O O

+ MgBr 63

O O

65% MeO

M

O

O N 64

MeO

Ph

OMe

OMe

Scheme 7.20  Intermolecular atropdiastereoselective coupling approach to (−)-steganone. Source: (a) Based on Yalcouye et al. [43]. (b) Based on Kamikawa et al. [44]. (c) Based on Meyers et al. [45].

189

190

7  Asymmetric Synthesis of Axially Chiral Natural Products

aryl boronic acid 59 and enantiopure bromoarene‐chromium tricarbonyl complexes 60, providing axially chiral biaryl 61 as a single atropstereoisomer [44]. Both axially chiral biaryls 58 and 61 were converted to (−)‐steganone after removal of the corresponding chiral auxiliaries. Chiral oxazolines are another class of useful auxiliaries for use in chiral biaryl synthesis. The nucleophilic aromatic substitution of 62 containing an oxazoline moiety with Grignard reagent 63 gave axially chiral biaryl 64 in 88% de [45]. Pure M‐64 was obtained after chromatography and converted to (−)‐steganone. The auxiliary strategy was also applicable to the asymmetric synthesis of other lignans [46, 47], as well as binaphthoquinones and naphthylisoquinoline natural products (Figure 7.6) [48, 49]. The oxazoline auxiliary strategy possesses a wide application in chiral biaryl synthesis. Besides the above SNAr reaction for unsymmetrical axially chiral biaryl structures, the Ullmann homocoupling of aryl halide enables the generation of symmetrical chiral biaryls. The key coupling step in Meyers and coworkers’ synthesis of gossypol is shown in Scheme  7.21 [50, 51]. Aryl bromide 65 containing an oxazoline moiety underwent a Chiral Cr complex

Oxazoline-based nucleophilic substitution O OMe O MeO OH MeO MeO

MeO MeO

P

P

H

MeO

O

O HO

OR

O

OH

OH OMe

Me

P

P

HO

Me

NH

O

O OMe Interiotherin A (R = Bz) angeloylgomisin R (‒)-isoschizandrin (R = angeloyl)

OH O (+)-isodiospyrin

Korupensamine A

Figure 7.6  Auxiliary-facilitated intermolecular atropdiastereoselective coupling in natural product synthesis. Source: Baker et al. [48, 49]. tBu

Meyers and Willemsen [50] MeO

N

OMe

MeO Br

MeO

N

MeO iPr

O

Cu, DMF

O

reflux tBu 80% 17 : 1 dr

P

MeO MeO

MeO

65

tBu

OMe

OMe OMe

HO

O

OMe Me

O

(+)-gossypol

HO OH

OH

P

O

O

HO HO

Isokotanin

Mastigophorene A

OH

HO HO P

P

OMe Me MeO

OH

OMe N 66

HO HO

OMe

OH CHO OH

Oxazoline-based Ullmann coupling O

OH CHO

HO

O

O

O GO O

O

OG

GO Tellimagrandin II

Scheme 7.21  Auxiliary-facilitated intermolecular Ullmann coupling in natural product synthesis. Source: Based on Meyers and Willemsen [50].

7.3  ­Atroposelective Aryl Coupling with Chiral Catalys

Cu‐mediated coupling reaction, providing 66 in high diastereoselectivity. This advanced intermediate was subsequently converted to (+)‐gossypol, a polyphenolic biaryl natural product with a wide range of pharmacological activities. This atropdiastereoselective Ullmann coupling strategy facilitated by chiral oxazoline auxiliaries were utilized widely in the asymmetric syntheses of axially chiral natural products, such as isokotanin [52], mastigophorenes [53], and tellimagrandins [54].

7.3 ­Atroposelective Aryl Coupling with Chiral Catalyst The atroposelective aryl–aryl coupling facilitated by chiral catalysts has been emerged as one of the most attractive methods for chiral biaryl synthesis. The transformation can be realized via an oxidative C–H/C–H coupling of electron‐rich arenes in the presence of a chiral catalyst and an oxidant. Alternatively, a transition metal‐catalyzed cross‐coupling by using a chiral ligand would deliver axially chiral biaryl structures. As the chiral catalyst is the origin of asymmetric induction, the configuration of the biaryl products can be controlled by selecting catalyst with an appropriate configuration. This demonstrates the significant advantage of chiral catalyst‐mediated coupling over atropdiastereoselective coupling approach, where chiral substrates might not be able to provide predictable or adjustable control on the axial chirality of biaryl products. In addition, the catalytic aryl coupling with a chiral catalyst eliminates the installation and removal steps of chiral ­auxiliary, significantly simplifying the synthetic sequence.

7.3.1  Catalytic Oxidative Aryl Coupling Nature’s synthesis of axially chiral biaryl natural products through enzyme‐mediated oxidative coupling of arene precursors provides inspiration and considerable confidence that the asymmetric chemical construction of chiral biaryls is feasible via aryl–aryl coupling in the presence of chiral catalysts. Over the past decades, a series of chiral high‐valent metal‐ based catalysts have been developed for the asymmetric oxidative dimerization of electron‐ rich arenes to afford axially chiral biaryl structures. In the synthesis of perylenequinone natural products, a Cu(II) catalyst supported by a chiral diaza‐cis‐decalin ligand was employed for the oxidative dimerization of naphthol 67 (Scheme 7.22) [55]. The reaction was performed in a substoichiometric amount of chiral Cu catalyst, with oxygen as the terminal oxidant to regenerate the active catalyst. The axially chiral binaphthyl 68 was afforded in 80% yield and 81% ee. Enantiopure 68 was obtained after trituration and was converted to binaphthylquinone 69 after further oxidation. The formation of unsymmetrical seven‐membered carbocyclic ring afforded four perylenequinones, favoring hypocrellin A and its atropisomer as a thermodynamic mixture (4 : 1). This dimerization method was successfully applied to the synthesis of other perylenequinone [56], binaphthopyrone [57], and bisanthraquinone natural products (Figure 7.7) [58]. The chiral V(V)‐catalyzed oxidative coupling was suitable for the synthesis of binaphthopyranone natural products, such as viriditoxin (Scheme  7.23) [59, 60]. The oxidative coupling of 70 with 20 mol% achiral catalyst VO(acac)2 provided dimer 71 with a diastereomeric ratio of 76  :  24. The atroposelectivity was attributed to the chiral lactone in 70,

191

192

7  Asymmetric Synthesis of Axially Chiral Natural Products O'Brien et al. [55] OAc MeO2C HO 67 OH O

MeO MeO

OAc H MeO2C N N Cu I OMe H HO OH HO 80%, 81% ee I >99% ee MeO2C after trituration

CH3

P

OH

MeO MeO

O OMe

OH O Hypocrellin A

4:1 52% yield

OMe O

I I

HO HO

OAc

68

CH3 MeO + OH MeO

M

O OMe

OMe CH3

M

MeO MeO

OH O OMe

OH O Shiraiachrome A

OH O atrop-Hypocrellin A

(2) MgI2 P:M = 4 : 12

OH O

OH O

OMe

(1) LiN(SiMe2Ph)2 74%, dr 10 : 1

O OMe OMe O 69

OMe

OH O

OMe

OMe O

OMe

OMe CH3

P

OH O OMe

OH O >10 : 1 5% yield atrop-Shiraiachrome A

Scheme 7.22  Enantioselective oxidative coupling in natural product synthesis. Source: Based on O’Brien et al. [55].

Morgan et al. [56], DiVirgilio et al. [57], and Podlesny and Kozlowski [58] OH

OH

O

O

MeO MeO

O

M

OH

O

O

OH OMe

(+)-calphostin D

OMe OH

O

M

O O

OMe OH

O

O

OH Me

OMe OH

OMe OH

MeO

M

OH

MeO

O

OH OMe

Cercosporin

Me

HO P

Me

O O

HO

(‒)-nigerone

Me O OH Bisoranjidiol

Figure 7.7  Chiral catalyst-facilitated intermolecular oxidative coupling in natural product synthesis. Source: Morgan et al. [56], DiVirgilio et al. [57], and Podlesny and Kozlowski [58].

which induced different degrees of steric interaction in the two possible transition states A and B. The favorable transition state B led to the major atropstereoisomer. It is noted that the use of a chiral vanadyl catalyst 72 enhanced the dr to 89 : 11, demonstrating the pronounced effect of chiral catalyst on atroposelectivity. Mechanistic studies have shown that the two vanadium (V) species in 72 both involved, with each coordinating to a substrate (A′). The coupling reaction proceeded following an intramolecular radical–radical coupling mechanism (B′). Both the axially chiral binaphthyl backbone and the chiral amino acid units in catalyst 72 controlled the conformation of substrates. The radical coupling led to intermediate C′ which isomerized to axially chiral binaphthol product. The catalytic asymmetric oxidative phenol coupling permits the synthesis of axially chiral biphenyl structures, which could be manipulated into a diverse category of axially ­chiral natural products. The chaetoglobins are axially chiral azaphilone dimers possessing two identical oxygenated bicyclic cores. These natural products have been reported to exhibit inhibitory activity against several human cancer cell lines. An atroposelective oxidative phenol coupling was employed in Kozlowski’s asymmetric synthesis of chaetoglobin A to generate the axial chirality of the molecule (Scheme 7.24) [61]. The coupling reaction of phenol monomer 75 was facilitated by a chiral vanadyl catalyst containing a substituted

7.3  ­Atroposelective Aryl Coupling with Chiral Catalys Park et al. [59] iPrO

iPrO

O

N V

O O O O O O O V N

O

MeO

R

72 87%, dr 89 : 11

Ar

Ar

O O V O O N iPr

iPr

O

O

H

Ar

N O O V O O

Ar

O O V O O N

O O V L n

OiPr OMe A

O

iPrO

iPr O N O O V O O H O O V O N O

O Ar

Radical coupling

O

O B′ iPr (Substituents of the substrate are not shown) With 72

A′

R

O

MeO

H B O With VO(acac)2 Favorable transition state

Steric clash O

Electron transfer

Ln

H H R

COOMe

OH OH O Viriditoxin iPrO Ln MeO V O H O O H H O V O R Ln

O V H

iPr

iPr

OiPr

O O

71

OMe O

iPrO

iPr

M

O

O

70

COOMe

MeO MeO

OTIPS OTIPS

O 72 (20 mol%), air HO HO OTIPS

N O O V O O

O

O

OMe O

HO

OH OH O

OMe O

iPr

H

C′

Scheme 7.23  Chiral catalyst-facilitated intermolecular oxidative coupling in viriditoxin synthesis. Source: Park et al. [59] and Grove et al. [60].

Kang et al. [61] Me HO

73 +

tBu

O2N

OH

I

O V O O OEt

OH

PdCl2(PPh3)2 CuI, Et2NH

Me

98%

HO

OAc

N

OAc

tBu 76 (20 mol%)

HOAc, O2 67% brsm, dr = 94 : 6

75

74

Me HO HO Me OH Me –

Cl Me AcO

O NH

OH

O O

OAc

O O

O O Me AcO

Me AcO

NH O Chaetoglobin A

OH

Me AcO

O O 79

OAc

AcO

OH O

(1) AgOTf (2) IBX, Bu4NI (3) Ac2O 22% (3 steps)

Me

+

N

77

Cl

AcO

86% brsm

Me OH

AcO CHO

HO HO Me

CHO OH 78

AcO

Scheme 7.24  Chiral catalyst-facilitated oxidative coupling in chaetoglobin A synthesis. Source: Based on Kang et al. [61].

amino acid ligand and provided axially chiral biphenol 77 in high diastereoselectivity. The introduction of two formyl groups to 77, followed by Ag‐catalyzed cycloisomerization and oxidation, provided bicyclic dimer 79, which was converted to chaetoglobin A after several transformations.

193

194

7  Asymmetric Synthesis of Axially Chiral Natural Products

7.3.2  Transition Metal-Catalyzed Atroposelective Aryl Coupling The transition metal‐catalyzed asymmetric aryl–aryl coupling with chiral catalysts has become an attractive approach to axially chiral biaryl structures. The past decades have seen the advent of tremendous transition metal‐catalyzed coupling methods targeting ­axially chiral biaryl natural products [62]. The coupling between an aryl halide and an arylmetallic reagent has no regioselectivity issue, which is different from the oxidative C–H/C–H ­coupling that a mixture of regioisomers could be obtained in certain cases. Among the transition metal‐catalyzed cross‐coupling reactions, the Suzuki–Miyaura coupling is the most convenient and reliable one because of the ease of operation, nontoxic nature, the ready availability, and high stability of starting materials. As shown in Scheme 7.25, the cross‐coupling between boronic acid 80 and aryl iodide 81 in the presence of Pd(PPh3)4 afforded atropisomers ancistroealaine A and ancistrotanzanine B in 50% combined yield [64]. The atropisomeric ratio (M : P = 45 : 55) indicated the weak internal asymmetric induction from chiral substrate. By employing chiral catalyst Pd/ (S)‐BINAP (2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl), the dr value was improved to 75 : 25, in favor of the M atropisomer ancistrotanzanine B. This result demonstrated the reliability of catalyst‐controlled atroposelective aryl coupling. Bringmann et al. [63] I

OMe OMe +

N

Me B(OH)2 80 Pd(PPh3)4(10 mol%) 50%, M : P = 45 : 55

OMe OMe

OMe OMe Me

MeO

Pd catalyst NaHCO3

OMe Me 81 Pd2(dba)3 (10 mol%) (S)-BINAP (30 mol%) 50%, M : P = 75 : 25

MeO

Me Me

P

N OMe Me Ancistroealaine A

+ MeO

M

Me N

OMe Me Ancistrotanzanine B

Scheme 7.25  Atropdiastereoselective Suzuki coupling using a chiral catalyst. Source: Based on Bringmann et al. [63].

The development of many prominent chiral catalysts and ligands in the past decade facilitated the asymmetric synthesis of axially chiral natural products. This is exemplified by Tang and coworkers’ application of P‐chiral monophosphorus ligand (R,R)‐87 to the synthesis of korupensamines [63, 65]. The axial chirality in the natural products was established by an enantioselective Suzuki–Miyaura cross‐coupling between aryl bromide 82 and arylboronic acid 83 in the presence of Pd/(R,R)‐87 (Scheme 7.26). Chiral biaryl 84 was afforded in 96% yield and 93% ee. The high enantioselectivity was attributed to the rigid structure of Pd(II) complex at the reductive elimination step. The asymmetric induction originated from the chiral ligand and the polar‐π interaction between the highly polarized bis(2‐oxo‐3‐oxazolidinyl)phosphinyl (BOP) group and the extended π system of the boronic acid partner. After converting 84 to enamide 85, a Rh‐catalyzed asymmetric hydrogenation with chiral bisphosphoindole ligand 88 afforded amide 86 in high diastereoselectivity. Further installation of the tetrahydroquinoline moiety provided korupensamine A.

7.3  ­Atroposelective Aryl Coupling with Chiral Catalys Xu et al. [65] Br BOPO

OBn OMe

OBn OMe CHO

+

96%, 93% ee OTBS 82

OBn OMe

Pd-(R, R)-87 K3PO4 P

BOPO

B(OH)2 83

84 O O

iPr

O

N O P O N O O

P

P Pd

Ar

tBu OMe

MeO

O O

85 OBn H 99% Rh-88, 2 dr: 92 : 8

OTBS

O

OH

NHAc

BnO

CHO

OMe

OBn OMe

O (R, R)-87 H

H

P H P tBu OMe tBu 88

Polar-p interaction

HO

P

NHAc

BnO NH

OMe

OH Korupensamine A

OBn 86

Scheme 7.26  Enantioselective Suzuki coupling in korupensamine A. Source: Based on Xu et al. [65].

The asymmetric Suzuki–Miyaura coupling enabled the synthesis of axially chiral biaryls 89 and 90 by using chiral ligands with opposite configuration (Scheme 7.27). The coupling reaction between these two axially chiral intermediates led to 91, which was easily transformed to michellamine B after global debenzylation. The synthesis of tetra‐ortho‐substituted biaryls via transition metal‐catalyzed coupling has been a challenging task because of the steric congestion of the four substituents at the ortho positions of the coupling sites. Low yields of the coupling products, or even no reactivity, were usually observed. In addition to the reactivity issue, the difficulty in enantioselectivity control further renders it an elusive method for the synthesis of Xu et al. [65] OBn OMe Br OBn BnO

Bn

P N

N

HN P

Bn

OBn 89

OH

OBn

P

OBn OMe Pd(PPh3)4 K3PO4 84%

OBn OMe

MeO

93%

OBn M

M

N

Bn

OMe

OBn 91

OMe OH HO

N BnO

OH Pd/C, H2

BnO

(HO)2B

OH

M

NH

Bn OH Michellamine B

OBn 90

Scheme 7.27  Asymmetric synthesis of michellamine B facilitated by enantioselective Suzuki coupling. Source: Based on Xu et al. [65].

195

196

7  Asymmetric Synthesis of Axially Chiral Natural Products Yang et al. [66]

OTMB

OMe Br

OMe

OHC

OMe 92

OTMB

Pd2(dba)3 (2.5 mol%) (R,R)-94 (5.0 mol%)

MeO

B2pin2, K3PO4, DCE 62%, 83% ee >99% ee after recrystallization

MeO

CHO OMe OMe OMe OHC (–)-93

OMe OTMB

O

TMB =

OH tBu OMe P

MeO MeO

OMe

HO

OH CHO OH

OMe

CHO OH

HO

94

OH

(–)-gossypol

Scheme 7.28  Enantioselective synthesis of (−)-gossypol by enantioselective Suzuki coupling. Source: Based on Yang et al. [66].

tetra‐ortho‐substituted biaryl natural products. By rational design of chiral ligands, an enantioselective Suzuki–Miyaura coupling was developed for the synthesis of fourfold ortho‐substituted biaryl natural product gossypol (Scheme 7.28) [66]. The key reaction involved a Pd‐catalyzed homocoupling of 92 in the presence of chiral ligand 94 and B2pin2, proceeding via a domino Miyaura borylation–Suzuki coupling sequence. The reaction provided chiral binaphthylene (−)‐93 in 62% yield and 83% ee. After recrystallization, enantiopure (−)‐93 was obtained and further converted to (−)‐gossypol. This represents the first catalytic enantioselective synthesis of gossypol.

7.4 ­Asymmetric Transformation of Biaryls The asymmetric manipulation of racemic or prochiral biaryls to enantioenriched atropisomers has broad application in natural product synthesis. As the axial chirality is generated after the formation of biaryl C─C bond, this method is conceptually distinctive in comparison with asymmetric aryl–aryl coupling approach. The asymmetric transformation of biaryls includes the (dynamic) kinetic resolution of racemic materials and asymmetric functionalization of prochiral biaryls.

7.4.1  Dynamic Kinetic Resolution of Biaryl Structure – The Lactone Method There are several approaches available for the generation of axial chirality via the dynamic kinetic resolutions of biaryls with labile configuration. However, only a few have been applied to natural product synthesis. One of the most widely used strategies is the lactone method, which was firstly developed by Bringmann and coworkers [67]. As exemplified in Scheme 7.29 for mbandakamine A synthesis, the key step involved a biarylic lactone 96, which was synthesized from the linkage of a substituted benzoic acid and a phenol unit,

7.4  ­Asymmetric Transformation of Biaryl Schies et al. [68]

N

Pd(OAc)2 O P(o-tolyl)3

O O

Br

O Me

O

Me NaOAc 81%

B

OMe

Ph

O BH3

Me 78%, dr 94 : 6

HO

NBn

OMe Me

96a

P

97

96b

OH OMe

Me OH OMe OH P

HN Me

OMe

Mbandakamine A

CH2OH Me

OMe Me

OMe OH Me

P

NBn

OMe Me OMe OH

95

Me e

O

NBn

NBn OMe Me

H Ph

OMe

OMe

OMe

HO

Me Me

P

NH OMe Me

HO Pb(OAc)4 BF3⋅OEt2 8%

P

Me Me NH

OMe Me 99

HO

P

Me Me NH

OMe Me 98

Scheme 7.29  The lactone method in mbandakamine A synthesis. Source: Based on Schies et al. [68].

followed by an intramolecular aryl–aryl coupling [68]. Because of the short length of the ester bridge, this lactone intermediate exists as a mixture of two rapidly interconverting atropisomers (96a and 96b). A chiral nucleophile, which could react with the ester group, would attack preferentially one atropisomer. Axially chiral biaryls would then be obtained through a dynamic kinetic resolution process. In specific, treatment of 96 with a stoichiometric amount of borane activated by chiral oxazaborolidine led to alcohol 97 with high diastereoselectivity. It has been shown that good results were achieved by using a catalytic quantity of chiral reducing agent in related reactions. Axially chiral biaryl 97 was ­transformed independently to 98 and 99, the oxidative coupling of which afforded mbandakamine A containing three stereogenic axes. The lactone method suits the asymmetric synthesis of axially chiral natural products possessing a C1 (usually a methyl group) and an oxygen group in the opposite ortho‐positions of the biaryl axis. The reduction of lactone would cleave the ester bridge to generate the corresponding C and O functionalities. In addition, this method also allows the formation of two atrop‐diastereoisomers by simply changing the configuration of the oxazaborolidine reagents. To date, a wide range of axially chiral natural products, such as naphthylisoquinolines [3, 69], biacarbazole alkaloids [70], biphenyl sesquiterpenes [71], bicoumarins [72], and anthraquinones, have been successfully synthesized using the lactone method (Figure 7.8) [73, 74].

7.4.2  Desymmetrization of Prostereogenic Biaryls The desymmetrization of prochiral biaryls provides a valuable and innovative method for building axial chirality. An asymmetric lithium–halogen exchange was employed to synthesize the axially chiral building blocks of isokotanin A and kotanin (Scheme 7.30) [75]. With prochiral tetrabromo biphenyl 100 as a substrate, double Li–Br exchange afforded the corresponding axially chiral bis–aryl lithium species in the presence of

197

198

7  Asymmetric Synthesis of Axially Chiral Natural Products OMe OMe

Me O

H N

OMe OH

O

O Me

Me

N H

OMe OMe

Me Me HO

Me Me

NH

O Bismurrayaquinone A MeO OMe OH

NH

OH Me Dioncophylline C Me

HO

N

OMe Me Ancistrocladine

HO OH

Me Ancistrocladisine

OH

N

OH O

OMe Me Me Ancistrocladidine MeO OMe OH

OH

Mastigophorene A Me

N

Me OMe

MeO

O

OMe Me

O

Me O HO

OMe

OH

Me

OMe Me Me Ancistrotectorine

OMe Me O MeO (R)-isokotanin

OMe O

O

Knipholone

Figure 7.8  Axially chiral natural products synthesized by lactone method. Source: Bringmann et al. [73] and Bringmann and Menche [74]. Graff et al. [75] OMe

MeO

OMe

OMe

O Br Br

Br Br (1) nBuLi

Me Me

Br Br

101

(2) MeI OMe 102 84%, 68% ee (>99.9% ee after recrystallization)

OMe 100

tBu

tBu

Me

N Br Br

Br Br (1) nBuLi

Me 103

OMe Me

O

OMe Me MeO

OMe

O

O

(+)-Isokotanin A

Me

Me

OMe

N

104

(2) BF(OMe)2 (3) NaOH, H2O2 (4) NaH, MeI

Br Br

OMe OMe

105 Me 51%, 64% ee (81% ee after recrystallization)

MeO MeO

O O

O O

Me OMe (–)-Kotanin

Scheme 7.30  The synthesis of isokotanin A and kotanin via desymmetrization. Source: Based on Graff et al. [75].

chiral diether ligand 101. Upon quenching with an electrophile, chiral biaryl 102 was delivered in 84% yield and 68% ee. A recrystallization increased the optical purity of this advanced intermediate, which was transformed to isokotanin after several steps. In a

7.4  ­Asymmetric Transformation of Biaryl

similar manner, tetrabromo biphenyl 103 was converted to axially chiral 105 by using chiral diamine 104 as a chiral ligand. Enantioenriched 105 served as the synthetic precursor of kotanin.

7.4.3  Catalytic Atroposelective C–H Functionalization of Biaryls The transition metal‐catalyzed asymmetric functionalization of aromatic compounds has attracted significant attention. A series of valuable catalytic atroposelective transformations have been developed for the synthesis of axially chiral biaryl structures. This is demonstrated by palladium‐catalyzed atroposelective C–H alkynylation of biphenyls, which serves as the key step in Shi and coworkers’ synthesis of dibenzocyclooctadiene lignan natural products (Scheme  7.31) [76]. The C–H alkynylation of biphenyl 106 proceeded in the presence of a catalytic amount of l‐tert‐leucine, which reacted with the aldehyde functionality in 106 to generate a chiral imine as an efficient transient chiral auxiliary. C–H alkynylation at the ortho‐position of the biaryl axis delivered biaryl 107 in 85% yield and 98% ee. (+)‐Isoschizandrin was synthesized after several steps from chiral building block 107. Enantioenriched tri‐ortho‐substituted biaryl 109 was synthesized from 108 following a similar protocol and was elaborated to (+)‐steganone.

7.4.4  Diastereoselective Synthesis from Racemic Biaryls The diastereoselective synthesis of axially chiral natural products from racemic biaryl building blocks is a convenient route when highly functionalized biaryl is possessed by the target molecules. By reacting racemic biaryl with a chiral component, a mixture of Liao et al. [76] OMe MeO MeO MeO

Br

TIPS (3 equiv) 85%, 98% ee

MeO OMe 106

MeO OH

MeO

MeO MeO

MeO

MeO

CHO TIPS

OMe

OMe 107

(+)-Isoschizandrin OMe

OMe

OMe MeO MeO

OMe

OMe Pd(OAc)2(10 mol%) MeO L-tert-leucine (30 mol%) KH2PO4, AgTFA CHO MeO

CHO

Pd(OAc)2(10 mol%) L-tert-leucine (30 mol%)

MeO

KH2PO4, AgTFA

MeO

O CHO TIPS

MeO

O

Br O

O 108

TIPS (3 equiv) 68%, 98% ee

MeO

O O

O O 109

O

(+)-Steganone

Scheme 7.31  The synthesis of lignans via catalytic atroposelective C–H functionalization. Source: Based on Liao et al. [76].

199

200

7  Asymmetric Synthesis of Axially Chiral Natural Products Liau et al. [77] OTBS OBn nPr O O O Me OBn OH O OMe SiMe3 Me OMe SPh

OMe O

MeO OBn

O NC

SPh OMe

OBn O OMe OBn

O

LiHMDS KHMDS

O

50–59%

BnO

110

MeO SiMe3 O OH OBn O M

nPr H OTBS

OH OBn 112 M : P = 1.3 : 1

+ OTBS OBn nPr O Me O O

OMe

H 2

×

O

SiMe3 Me 111

H

HO nPr HO HO

O H

O OH

MeO OH O P OH OH O OMe

H

OH nPr

OH

OH OH

OH

OH O Hibarimicinone

Scheme 7.32  Diastereoselective synthesis of hibarimicinone from racemic biaryl building blocks. Source: Based on Liau et al. [77].

atropstereoisomers is usually obtained. The desired product can be easily isolated from its atropisomer because of significant conformational difference. Scheme 7.32 exemplifies one of the key steps in the total synthesis of hibarimicinone, a pseudo‐dimeric axially chiral natural product with potent inhibitory activity against v‐Src tyrosine kinase [77]. By reacting racemic biaryl 110 with two equiv of 111, a two‐directional double annulation was forged to give 112 with an M : P ratio of 1.3 : 1, in favor of the desired atropdiastereoisomer. Although a low level of kinetic resolution of 110 was achieved during this sequence, it represents an efficient way to construct the polycyclic skeleton of hibarimicinone.

7.5 ­Atroposelective Aromatization The conversion of central chirality to axial chirality can be realized through a stereospecific aromatization of nonaromatic precursors. In the asymmetric synthesis of bismurrayaquinone A, Thomson and coworkers synthesized a chiral diketone intermediate 114 from an enantiospecific oxidative dimerization of enantioenriched enone 113 (Scheme 7.33) [78]. Upon treatment with BF3·OEt2, diketone 114 aromatized and was converted to biphenyl 115 without erosion of enantiomeric purity. Methylation and catalytic amination of 115 led to biaryl 116, which was elaborated to bismurrayaquinone A. While most axially chiral natural products bear at least three substituents at the ortho positions of the chiral axis, exceptions are found in some natural products containing an axially chiral di‐ortho‐substituted biaryl moiety that is embedded in a highly strained architecture. Because of the rigidity of the molecule, rotation along the biaryl axis is not possible. This structural feature is possessed by haouamine A, a biologically active alkaloid featuring a [7]‐azaparacyclophane macrocycle. Restricted rotation is observed for the biphenol moiety contained in the 11‐membered paracyclophane at ambient conditions. To construct such an unconventional biaryl linkage, the stereospecific aromatization of a

7.5 ­Atroposelective Aromatizatio Konkol et al. [78] O

O LDA, CuCl2

MeO

63%

Me OMe

MeO

113 (99% ee) O Me O

H N

O Me

O H

Br HO Me OMe OMe (1) BF3 ∘ OEt2 87% OMe H (2) Br2, 90% Me Me OMe Me OH Br MeO 114 115 (1) MeI, KOH 78% (2) 2-chloroaniline, NaOtBu Pd(OAc)2, [HPtBu3][BF4] NH MeO Me

N H

OMe Cl

Cl MeO

O (99% ee) Bismurrayaquinone A

Me OMe HN 116

Scheme 7.33  Point-to-axial chirality transfer in the asymmetric synthesis of bismurrayaquinone A. Source: Based on Konkol et al. [78].

more accessible nonaromatic precursor is a reliable solution [79]. As shown in Scheme 7.34, cycloenone 118 was synthesized initially from the macrocyclization of 117. Subsequent aromatization led to 119 containing a bent phenol ring. While the hybridization changes from an enone to a phenol group significantly increased the rigidity of the molecule, the aromaticity obtained was anticipated to compensate for the strain energy. The synthetic challenge of axially chiral haouamine A was also met from the transformation of cyclohexadiene 121, which was synthesized from 120 via an intramolecular pyrone– alkyne Diels–Alder reaction [80]. Intermediate 121 containing an embedded CO2‐leaving group underwent an aromatization process afforded the final target.

Burns et al. [79] and Baran and Burns [80] MeO

OMe

MeO

OMe

LHMDS

TFA, iPr2NEt O

N H Boc 117

M

79% M : P = 1.45 : 1

H

O

N

Ph H BBr3

OAc AcO

OAc µ wave H

OMe

OMe

S NtBu Cl 60% + 23% SM

118

I

AcO

63%

HO

OAc –CO2 K2CO3

OAc

N

O

OH

N 119

OH

OH

OAc O

120

MeO

OMe

OMe

M

N H 121

OAc O

O

H

N

OH

Haouamine A

Scheme 7.34  Asymmetric synthesis of haouamine A via atroposelective aromatization. Source: Burns et al. [79] and Baran and Burns [80].

201

202

7  Asymmetric Synthesis of Axially Chiral Natural Products

7.6 ­Diastereoselective Macrocyclization Several types of natural products have an axially chiral di‐ortho‐substituted biaryl linkage, which is embedded in a macrocycle with limited flexibility. Rhazinilam is a monoterpene indole alkaloid possessing a tetracyclic structure and an axially chiral phenylpyrrole ­moiety. This natural product exhibits potent in vitro tubulin‐binging properties and has triggered significant synthetic efforts. Most syntheses feature a late‐stage conformation‐ directed cyclization to form the macrocycle. As shown in Scheme 7.35, an intramolecular Banwell et al. [81] Et

R

Johnson et al. [82] CO2Me

R

(1) KOH (2) EDCI

N OHC

68%

R MeO2C

M

O

Et

O

N

NMOM

Pd(OAc)2 K2CO3

N H 123

89%

R N

38%

(1) Pd/C, dppb CO, HCO2H (2) NaOH 52%

BCl3 Et3N

M

R N

70%

N O MOM 126

I

125

124

(Ph3P)3RhCl

Shemet and Carreira [83] R

NH2

N

N OHC

H 2N 122

Et

M

N O H (–)-Rhazinilam

Scheme 7.35  Diastereoselective macrocyclization in rhazinilam synthesis. Source: Banwell et al. [81], Johnson et al. [82], and Shemet and Carreira [83]. Groh et al. [85] and Meidlinger et al. [86] OMe MeO

Pd(M-BINAP)2 (20 mol%) PMP, DMF

OTf

OMe MeO

M

HO

M

S

69% 2 steps OMe OMe 128

OMe p-Tol

M

BBr3

H2, Pd/C

22%, 37% ee OMe OMe 127

OH

OMe MeO

129

OH OH (M)-Isoplagiochin D

OMe OMe

OMe

OMe

O

OMe I

Pd2(dba)3 (40 mol%)

P O I Pd S p-Tol

M

I Pd S O p-Tol

p-Tol

S

O M

80% M : P = 99 : 1

OMe OMe 130

OMe OMe 131a

OMe OMe 131b

132

OMe OMe

Scheme 7.36  Diastereoselective Heck coupling in the synthesis of isoplagiochin D. Source: Groh et al. [85] and Meidlinger et al. [86].

7.6 ­Diastereoselective Macrocyclizatio

amide coupling of 122 [81, 84], or a palladium‐catalyzed hydrocarbonylation of 124, afforded rhazinilam skeleton [82], with concurrent generation of axial chirality. Besides the above methods, the metal‐catalyzed intramolecular aryl coupling is an alternative approach to the axially chiral lactam structure of rhazinilam [83]. As shown in Scheme  7.35, a Pd‐catalyzed intramolecular biaryl coupling with intermediate 125 was employed to deliver 126 as a single atropdiastereoisomer, which was converted to (−)‐rhazinilam. Cyclophanes are a class of strained macrocyclic natural products containing biphenol rings and aliphatic chains. Because of their rigid macrocyclic architecture, these molecules exist as configurationally stable atropisomers. Atroposelective macrocyclization is frequently employed in the synthesis of these natural products. Isoplagiochin D is a bis(bibenzyl)‐type cyclophane, which was synthesized by using a palladium‐catalyzed enantioselective Heck reaction as the key step (Scheme 7.36) [85]. Ring closure of linear substrate 127 led to 128 in 22% yield and 37% ee when (R)‐BINAP was employed. A subsequent hydrogenation and demethylation delivered isoplagiochin D. By employing an atropdiastereoselective Heck coupling, the synthesis of a highly enantioenriched isoplagiochin D was accomplished [86]. This asymmetric synthetic sequence featured an aryl iodide intermediate 130 containing a chiral sulfinyl auxiliary. In the presence of Pd2(dba)3, 130 underwent an intramolecular Heck coupling to provide 132 in 80% yield and diastereomeric ratio of 99 : 1. The reaction was anticipated to proceed via transition state 131b with minimal steric hindrance between the palladacycle coordinated with the double bond and the bulky p‐tolyl moiety. Intermediate 132 was transformed to the natural product after several steps. A regio‐ and enantioselective Diels–Alder reaction was applied in the asymmetric synthesis of cavicularin (Scheme 7.37) [87]. In the presence of cinchona alkaloid catalyst 134, Zhao and Beaudry [87] O PhO2S

O O

OH OMe

O

PhO2S

134

O

MeO

MeO

OH

O

O

–HOSOPh –CO2 HO

OMe MeO

OMe 133

OMe

MeO 136 (er 89 : 11)

135

Tf2O 45% (2 steps) OMe N

HO

MeO O

O

NH N

HN

(1) NH4CO2H, Pd/C, quant.

S OH

F3C

134

CF3

HO (+)-Cavicularin

TfO

(2) BBr3, 80%

OMe MeO 137

Scheme 7.37  Diastereoselective cycloaddition in the synthesis of (+)-cavicularin. Source: Based on Zhao and Beaudry [87].

203

204

7  Asymmetric Synthesis of Axially Chiral Natural Products

the intramolecular cycloaddition between the pyrone diene and vinyl sulfone group of 133 occurred smoothly and afforded 136 in 78% ee. The reaction presumably proceeded via intermediate 135, which could further undergo elimination of phenylsulfinic acid and CO2 under the same conditions. Subsequent deoxygenation and demethylation converted 136 to (+)‐cavicularin.

7.7 ­Conclusions and Perspectives The asymmetric synthesis of axially chiral natural products has become an important theme in the field of total synthesis. Significant achievements have been made in this area, triggered by both the valuable biological activities and unique structural features of these naturally occurring axially chiral molecules. This chapter summarized the available strategies in generating the axial chirality of these natural products, which constituted the key steps in overall synthetic sequences. The atroposelective coupling represents the most straightforward way for the generation of the chiral axis. Diastereoselective coupling making good use of the intrinsic central chirality contained in the natural products or exploiting artificial chiral auxiliaries have been frequently applied in total synthesis. The development of catalytic asymmetric aryl–aryl coupling method, such as oxidative ­coupling and transition metal‐catalyzed coupling, has enabled the concise and efficient synthesis of several axially chiral biaryl natural products, in particular, the unbridged ones. The asymmetric transformation of existing racemic or prochiral biaryls has provided an alternative approach to ­axially chiral biaryl natural products. This was featured by the lactone method, as well as catalytic enantioselective functionalization of biaryls. Besides the above, other strategies, including atroposelective aromatization and macrocyclization, have been developed to suit natural products with specific structural features. The past two decades have witnessed substantial progress in catalytic asymmetric synthesis of axially chiral structures. However, only a few methods have been successfully applied to natural product syntheses. It is certain that future attention will be drawn by transforming these state‐of‐the‐art methods into powerful tools for efficient synthesis of chiral natural products. Meanwhile, axially chiral natural products with more complex architectures will be isolated and identified with the assistance of modern analytical techniques. This will further pave the way for new methodology development to meet their synthetic challenges. It is also expected that the asymmetric synthesis of axially chiral natural products will facilitate their biological studies as well as the identification of potential therapeutic agents.

­References   1 Bringmann, G., Günther, C., Ochse, M. et al. (2001). Progress in the Chemistry of Organic Natural Products, vol. 82 (eds. W. Herz, H. Falk, G.W. Kirby, et al.), 1–249. Vienna: Springer.   2 Smyth, J.E., Butler, N.M., and Keller, P.A. (2015). Nat. Prod. Rep. 32: 1562.   3 Bringmann, G., Gulder, T., Gulder, T.A.M., and Breuning, M. (2011). Chem. Rev. 111: 563.

 ­Reference

  4   5   6   7   8   9 10 11 12 13 14 15 16 7 1 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 7 3 38 39 40 41 42 43

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Part II Applications

209

211

8 Asymmetric Transformations Gaoyuan Ma and Mukund P. Sibi North Dakota State University, Department of Chemistry and Biochemistry, 1340 Administration Ave, Fargo, ND, 58108, USA

Asymmetric transformations of axially chiral compounds comprise a crucial strand of organic chemistry research to establish preparations of valuable chiral building blocks, biologically active chiral scaffolds, and chiral intermediates in natural product synthesis [1]. This chapter focuses on asymmetric transformations of axially chiral biaryls and heterobiaryls, non-biaryls, and allenes.

8.1  ­Asymmetric Transformation of Axially Chiral Biaryls and Heterobiaryls The phenomenon of atropisomerism in biaryl and heterobiaryl compounds arises from the hindered rotation around the sigma bond connecting the two (hetero)aromatic rings. This unique stereochemical behavior renders them an attractive class of precursors toward functionalized and structurally diverse frameworks bearing predictable projection of functionalities that could be used for chiral recognition in different settings and/or for the relay of stereochemical information. The significance of latter is evident as ligands and organocatalysts embedded with axially chiral (hetero)biaryl backbones are well appreciated in contemporary asymmetric catalysis, for which a brief presentation has been provided in Chapter 1. These structures are mostly accessed through asymmetric transformations of fundamental building blocks such as BINOL, BINAM, and NOBIN. Naturally, synthetic elaborations of readily available enantioenriched biaryl or heterobiaryl atropisomers to supply scaffolds for stereocontrol have largely formed the basis of this research domain. As the representative utilizations of these organocatalysts and ligands in asymmetric catalysis will be detailed in Chapters 9 and 10, we focus herein on different chemical modifications, which occur with chirality transfer as well as those that retained the original axially chiral backbones. In these scenarios, they serve as platform molecules to synthesize useful structures for other roles.

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

212

8  Asymmetric Transformations

8.1.1  Asymmetric Transformations with Preservation of Axially Chiral Backbone Toward enantioselective total synthesis of an axially chiral bisanthraquinone (S)-bisoranjidiol ((S)-4), Kozlowski and coworkers developed regioselective tandem Diels–Alder/­ aromatization reactions to construct the core bisanthraquinone structure from an axially chiral precursor (S)-1 [2]. In the key reaction transforming into (S)-3, a bromo directing group on (S)-1 ensured good yield and retained the optical purity upon cycloaddition with diene 2 (Scheme 8.1). This cycloaddition of diene 2 with (S)-1 was complete to afford bisanthraquinone (S)-3 in 80% yield after an aromatization process over silica. A final demethylation yielded target (S)-4 in 80% yield with no erosion of the enantiomeric excess. Kozlowski et al. (2012) O Br

OH TMSO

OMe

OH

O

OMe Me

O O

OMe

2

O O

OMe Toluene, 55–60 °C, 2 d then silica, air 80%

Br

OMe

OH (S)-1

OH BBr3, CH2Cl2

O O

0 °C, to r.t. 80%

OH Me

Me

O

O

Me

Me

OH

O (S)-3

O

(S)-4, >99% ee

Scheme 8.1  Synthesis of bisanthraquinone via tandem Diels–Alder/aromatization. Source: Based on Podlesny and Kozlowski [2].

Bridged biaryl atropisomers are structural units common in bioactive molecules. A synthesis of lactone-bridged biaryl atropisomers was realized by palladium-catalyzed diastereoselective cyclization of axially chiral biaryl precursors (Scheme 8.2). The formation of seven-membered rings via palladium-catalyzed cyclization is often regarded as a formidable task, particularly for highly strained compounds. The cyclization reaction to build strained seven-membered lactone was far from trivial, and the yields were often unreliable. Tackling this synthetic defiance, Gu and coworker have described conditions to perform Heck cyclization reaction of 5 to construct atropisomeric seven-membered lactone 6 [3]. Axially chiral phosphines present synthetic value as exceptional ligands in asymmetric catalysis. Gu has demonstrated that by treating 7 with t-BuLi or t-BuMgCl·LiCl at 0 °C to room temperature smoothly furnished the 2-hydroxyl biaryl phosphine oxides 8 in moderate to good yields (Scheme 8.3) [4]. This metal-mediated phosphine oxide transfer reaction proceeded with high stereoretention without any detectable racemization event. para-Substituents, including methyl, phenyl, t-butyl, methoxy, fluoro, trifluoromethyl, and methylthio, were found compatible. With an adjacent methyl group to C─I bond, product 8b could not be obtained, possibly because of the tremendous steric hindrance. On the other hand, the n-butylaryl phosphonate 7c (dr 1.8 : 1) smoothly rearranged to afford a pair of diastereomers (aS,S)-8c and (aS,R)-8c.

8.1  ­Asymmetric Transformation of Axially Chiral Biaryls and Heterobiaryl Gu et al. (2019)

R1

I O

R1

R2

Pd(acac)2, PPh3 Cu(OTf)2, Ag2CO3,

R2 R3

R1

O

Me Me

Ph

Me

Me

Me Me

O O

6a 21%, 99% ee

O 6

5 Me

O

R1

DMF or CH3CN, 150 °C or 100 °C, 12 h up to 79%, 99% ee

R4

Me

O

O

O

O

6b 73%, 99% ee

6c 57%, 99% ee

Scheme 8.2  Synthesis of atropisomeric seven-membered lactone by Heck cyclization reaction. Source: Based on Xue and Gu [3].

Gu et al. (2019) R1

R1 I O

R1

R2 P Ar O

R2 P Ar O OH

tBuLi, tBuMgCl•LiCl THF or Et2O up to 80%, >99% ee

R1 8

7 OMe Me Me Me

O

P OH

8a 78%, >99% ee

Me Me

O

P OH

8b, 0%

OMe

Me Me

nBu ∗ P O OH

8c (aS,S) 38%, 99% ee (aS,R) 14%, 99% ee

Scheme 8.3  Synthesis of 2-hydroxyl biaryl phosphine oxides by phosphine oxide transfer reaction. Source: Based on Duan et al. [4].

8.1.2  Asymmetric Transformations with Axial-to-central Chirality Transfer He and coworkers reported a highly efficient Pd-catalyzed axial-to-central chirality transfer of (S)-BINOL to synthesize chiral spiro compounds in up to 99% yield and 99% ee (Scheme 8.4) [5]. The stereogenic quaternary carbon center in product 11 was installed by way of dearomatization of BINOLs on treatment with a range of propargyl carbonates in the presence of palladium catalyst and phosphine ligand 10. This reaction boasted a large substrate scope that included both arylpropargyl and alkylpropargyl carbonates, irrespective of the size and electronic effect of substituents.

213

214

8  Asymmetric Transformations He et al. (2019)

OH OH

+

O

Pd2(dba)3 (5 mol%) 10 (10 mol%)

R OCO2Me R = Ar or Alkyl 9 (S)-BINOL

R

O

DCE, 50 °C P(tBu)2 Ph 10

11 43–99%, >99% ee Z/E up to >20 : 1

Scheme 8.4  Pd-catalyzed axial-to-central chirality transfer. Source: Based on Min et al. [5].

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compounds As a divergence to the general applications of biaryl and heterobiaryl atropisomers as chiral ligands, catalysts, or building blocks, non-biaryl atropisomers can undertake the role as stoichiometric chiral auxiliaries in asymmetric transformations. In most cases, the stability of non-biaryl atropisomers is tied to the existence of bulky ortho substitutions, which implies that the rotational barrier of substrates would be high enough to restrict bond rotations during the course of atropselective transformations. Although without ostensibly more rigid bi(hetero)aryl backbone, appropriately substituted non-biaryls including amides, imides, and related heterocycles display axial chirality originated from rotationally impeded C(sp2)─C(sp2) or C(sp2)─N bonds because of the high inversion barriers. Hence, this class of atropsimers could also affect asymmetric induction or permit the transfer of chirality from chiral axis to a new stereocenter [6].

8.2.1  Cycloadditions and Cyclizations 8.2.1.1  [4 + 2]-Cycloaddition

Taguchi and coworkers reported that enantioenriched axially chiral anilides 12 underwent asymmetric Diels–Alder reaction with diene in the presence of I2 [7]. In the case of cyclopentadiene, the Diels–Alder product endo-15 was obtained with good yield and high diastereoselectivity through the formation of a cationic iodocyclization intermediate 13 promoted by iodine (Scheme 8.5). The diastereofacial selectivity was likely to be imposed by the ortho-t-butyl group as observed from NMR experiments. The cyclopentadiene plausibly attacks from the opposite face of the t-butyl group in preference. 8.2.1.2  [3 + 2]-Cycloaddition

Curran and coworkers conducted asymmetric [3 + 2]-cycloaddition of acrylate derivatives 16 with nitrile oxides [8]. At room temperature, when R1 = t-Bu and R2 = H, the cycloaddition proceeded with high diastereoselectivity in a ratio of 90 : 10. In contrast, cycloaddition of TMS derivative 16b and 16c revealed lower yields but similar stereoselectivity. Overnight heating of the mixture of 17 and 18 at 100 °C decreased the equilibrium ratio to about 2 : 1 for the t-butyl derivative (Scheme 8.6).

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compound Taguchi et al. (1998) O I2, diene

N tBu

O

AcOEt, nBu4NI –78 °C to r.t. 92%

12

N

tBu

endo-15 endo/exo = 30 : 1

I2

nBu4NI I

O

I

O N I

N I tBu

13

tBu

14

Scheme 8.5  Synthesis of chiral anilides via asymmetric Diels–Alder reaction. Source: Based on Kitagawa et al. [7]. Curran et al. [1997] O

O N

R1

tBuCNO, 25 °C

O N

tBu N O

R2

R2

16

R1 +

N

tBu N O

R1

R2 17

16a, R1 = tBu, R2 = H

Ratio = 90 : 10, 93% yield

16b, R1 = C(OTMS)Me2, R2 = H

Ratio = 85 : 14, 51% yield

16c, R1 = C(OTMS)iPr2, R2 = H

Ratio = 89 : 11, 42% yield

18

Scheme 8.6  Synthesis of chiral anilides via asymmetric cycloaddition [8]. Source: Based on Curran et al. [8].

8.2.1.3  Radical Cyclization

Conducting radical reaction in stereoselective manner has been a challenge but transfer of chirality provides a promising avenue by virtue of the rapid kinetics of radical reactivity. Curran and coworkers have exploited axial chirality of non-biaryl systems in developing several radical cyclization strategies that portrayed efficient chirality transfer. In one paper published in 1999 [9], they investigated the cyclization of acrylanilide 19, which adopts a nearly orthogonal orientation between the aryl ring and the amide plane. Rotation barriers of isomeric (M)-19 and (P)-19 were calculated, followed by investigation of radical cyclization (Scheme 8.7). In their hypothesis, if C─N bond rotation of 19 is more rapid than the radical cyclization, racemic products will be generated from chiral starting materials.

215

216

8  Asymmetric Transformations Curran et al. [1999] O

O N

Me I

Me

Bu3SnH

Me

N

O NMe Me

Me

Et3B/O2 25 °C, C6H6 Me

Me

Me M-20

(M)-19 (97% ee)

(R)-21, 87% ee

100 °C O

O N I

Me Me

Bu3SnH

N

Me

O NMe

Me

Me

Et3B/O2 25 °C, C6H6 Me (P)-19 (95% ee)

Me P-20

Me (S)-21, 86% ee

Scheme 8.7  Synthesis of chiral anilides via radical cyclization [9]. Source: Based on Curran et al. [9].

Contrariwise, stereospecific transformation becomes operable. The rotation barrier between (M)-19 and (P)-19 was high enough for them to exist as stable enantiomeric atropisomers at room temperature. Iodine at ortho position acted as a radical precursor while radical chain reagent Bu3SnH and combination of Et3B/O2 promoted the radical generation and initiation process, respectively. Radical cyclization of 19 afforded oxindole 21 through five-exo cyclization with axial-to-central chirality transfer and high enantioselectivity. The absolute configuration of starting material was preserved in the product, suggesting that radical cyclization had occurred faster than racemization. As an extension of this chemical process, if the methyl group at ortho position is replaced by a second radical element with concomitant installation of a second handle to accept radical, intramolecular double cyclization could be brought forth [6b]. The Curran group explored to use chiral auxiliaries in their radical cyclizations [10]. They prepared 22 bearing a chiral N-substituent and an ortho-iodo group as a radical precursor while the other ortho carbon was nonsubstituted. When (M,S)-22 and (P,S)-22 in 68/32 ratio were subjected to radical cyclization at 110 °C, 50/50 ratio of (R,S)-25 and (S,S)25 were provided. This product ratio increased with decreasing reaction temperature. In another case, cyclization of (M,S)-22/(P,S)-22 with a ratio of 91/9 at −78 °C afforded diastereomeric (R,S)-25/(S,S)-25 in 95/5 ratio, whereas at the same temperature, cyclization of (M,S)-22/(P,S)-22 (in a ratio of 2/98) afforded (R,S)-25/(S,S)-25 in a ratio of 16/84 (Scheme 8.8). The cyclization of (M,S)-22 was more favored over (P,S)-22. It was reasoned that when temperature started to drop, the cyclization would begin to compete with racemization and when the reaction was cooled below a certain temperature, interconversion between radicals of (M,S)-23 and (P,S)-23 would no longer be operative, permitting

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compound Curran et al. (2005) H

O N I

Ph Me

H

O Bu3SnH

N

Ph High Me selectivity

H

O

Ph Me

N

H

O N

Ph Me

Et3B/O2, –78 °C

(R,S)-24

(M,S)-23

(M,S)-22 (91 : 9 dr)

(R,S)-25 95 : 5 dr

Minor

H

O N I

Ph Me

H

O Bu3SnH

N

Ph Me

H

O Major

N

Ph Me

H

O N

Ph Me

Et3B/O2, –78 °C

(P,S)-22 (2 : 98 dr)

(P,S)-23

(S,S)-24

(S,S)-25 16 : 84 dr

Scheme 8.8  Employing chiral auxiliaries in radical cyclizations. Source: Based on Petit et al. [10].

cyclization toward respective favored diastereomer 24. Radical (M,S)-23 underwent intramolecular cyclization to (R,S)-24 exclusively, but (P,S)-23 would cyclize to (S,S)-24 as a major product with minute amounts of (R,S)-24. 8.2.1.4  Heck Cyclization

The Curran group also conducted intramolecular Heck reaction of axially chiral o-iodoacylanilide catalyzed by an achiral palladium catalyst with transfer of chirality from the stereogenic axis in acylanilide substrate to a new stereocenter in product [11]. To avoid atropisomerization during the reaction, room temperature was applied. (M)-26 and (P)-26 were cyclized in the presence of 10 mol% Pd2(dba)3 and 40 mol% of (t-Bu)3P formed in situ. It was proposed that the oxidative addition of Pd to carbon–iodide bond to form 27 is the stereocontrolling step. Alkene 27 will twist to 28 to facilitate Pd insertion at Re face, ­followed by chiral C─C bond formation and β-elimination to provide 31 (Scheme 8.9). 8.2.1.5  Carbanionic Cyclization

Pyrrole structures are of significance in drug discovery and serve as crucial building blocks in a series of organic transformations. In a more recent pursuit, Tan et al. have demonstrated their strategy to construct axially chiral two-arylpyrrole frameworks through a direct ­chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes (Scheme 8.10) [12]. The strong base lithium diisopropylamide (LDA) proved to be a superior facilitator for cyclization of 32, affording the axially chiral, fully substituted pyrroles 33 with acceptable yields and perfect chirality transfer in THF (tetrahydrofuran) under mild reaction conditions. Under the catalysis of rhodium on carbon, the axially chiral 2-arylpyrrole 34, obtained from methylation of 33 (90% yield), was hydrogenated by molecular hydrogen (40 bar) to afford (1R,2S)-35 (74% ee) displaying two contiguous chiral centers, with 80% chirality transfer rate. Reduction of 33 with DIBAL-H gave rise to aldehyde 36, which could be further cyclized toward 2-arylazepine (aS,R)-37 through successive imine formation and intramolecular ene reaction upon treatment with n-propylamine and TfOH.

217

218

8  Asymmetric Transformations Curran et al. (2007) O N

Me

I

O

Pd2(dba)3 (10 mol%) (tBu)3PH•BF4 (40 mol%)

NMe

Et3N, PhMe, r.t., 24 h 69–95%, 86–91% ee

R (R)-31

R (M)-26 O

O N

Me

PdLn

PdLn

Rotation

R 27

Me

Me

O

O N Pd

Me

R 28

Complexation

N

R 29

Me

N

Me

PdLn

Insertion chirality transfer

R 30

Scheme 8.9  Synthesis of chiral anilides via intramolecular Heck reaction. Source: Based on Lapierre et al. [11].

Tan et al. (2019) R2 R

CO2R1 N

CO2R1

TMS LDA (2.5–6.0 equiv), THF –78 °C, 1–2 h

3

R

up to 96% yield up to 94% ee

R

2

OH

R N

OMe

CO2R1 R3

32

MeI, –78 °C to rt N R = Bn, R1 = Et R2 = TMSCC R3 = CF3

33

CF3

34, 90%, 93% ee

R = Bn, R1 = Et, R2 = Allyl, R3 = I

Rh/C, H2 EtOH, 31 °C

DIBAL-H, Et2O, –78 °C

TMS

N

CO2Et I

OMe

NHnPr

CHO Bn

CO2Et

nPrNH 2

TfOH, Et2O, 0 °C

36, 69%, 92% ee

Bn

N

CO2Et I

37, 84%, 78 : 22 dr, 90% ee

N

CO2Et CF3

35, 68%, 74% ee

Scheme 8.10  Synthesis of axially chiral 2-arylpyrrole from atropisomeric alkenes. Source: Based on Wang et al. [12].

8.2.2  Reaction with Nucleophiles The incorporation of nucleophilic hydride source was presented by Clayden and coworkers in diastereoselective nucleophilic addition of 2-acyl-1-naphthamide 38 with NaBH4 or LiBHEt3 [13]. They proposed that in structure 38, the amide group and the naphthalene ring are nearly perpendicular and could interconvert slowly, engendering the axial chirality

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compound

in naphthamide 38. They investigated the stereoselective reduction of 38 by tuning the size of R1 and R2 as well as the use of NaBH4 or LiBHEt3. It was found that the non-biaryl axial chiral element in 38 could control the chirality, giving rise to anti-product 39 and syn-product 40 with diastereoselectivities up to 99.3/0.7 in the presence of bulkier reducing reagent, LiBHEt3 (Scheme 8.11). Simpkins and coworkers developed an atropselective nucleophilic addition of a cyclic iminium intermediate with complete stereocontrol [14]. The installation of l-menthol provides enantiopure cyclic lactam 41, which, on treatment with a Lewis acid, produces N-acyliminium 42 following departure of the menthyl group. Nucleophilic addition of propargyl silane or allyl silane to 42 would generate alkylation product 43 or 44 in enantiomerically pure form as determined by HPLC (Scheme 8.12). Clayden et al. [1996] R1 N R1 O

O

O

NaBH4 or LiBHEt3

R1 1 N R OH

NaBH4 : 39/40 = 79 : 21 to 95 : 5 LiBHEt3 : 39/40 = 83 : 17 to 99.3 : 0.7

R2

O

R2 anti-39

38

+

R1 1 N R OH R2

syn-40

Scheme 8.11  Synthesis of chiral anilides via atropselective amine addition [13]. Source: Based on Clayden et al. [13].

Simpkins et al. (2000) or O H

N

O tBu

SiMe3 SiMe3

H

Me3SiOTf (3 equiv) CH2Cl2, –40 °C

41

N

O tBu

43 74%, 99% ee Le

wis

ac

id

N

O tBu

or

H

N

O tBu

44 88%, 99% ee

hile

op

le uc

N

42

Scheme 8.12  Synthesis of chiral anilides via atropselective nucleophilic addition. Source: Based on Godfreyet al. [14b].

Enantioselective conjugate addition of thiol to N-phenyl substituted itaconimides was investigated by Tan and coworkers, utilizing a bicyclic guanidine as the catalyst [15]. Guanidine 46 stereoselectively catalyzed the addition of thiol to atropisomeric 45 and yielded 1  :  1 mixture of anti diastereomer 47 and syn diastereomer 48 (Scheme  8.13). Notably, 47 was obtained with high enantioselectivity of up to 89% ee when using t-Bu or t-octyl thiol as the Michael donor.

219

220

8  Asymmetric Transformations Tan et al. (2009)

O

O

N

tBu

RS

RS

R SH 46 (10 mol%)

O

N

Toluene N

tBu N H

45

O tBu

+

O tBu

O

N

tBu N

47, 66–89% ee

46

48, 53–72% ee

63–92%, dr = 1 : 1

Scheme 8.13  Synthesis of chiral anilides via enantioselective conjugate addition. Source: Modified from Lin et al. [15].

8.2.3  Reaction with Electrophiles 8.2.3.1  Reactivity as Enolates

An important reactivity of non-biaryl atropisomers is manifested in their ability to form transient atropochiral enolates because of the prevalence of carbonyl functionality in these systems. There are also examples where atropisomerism is displayed by the enolate intermediate but not the starting material. With efficient chirality transfer from the anionic intermediates, intercepting of electrophiles would forge products with new chiral element(s). Stoodley and coworkers reported an atropselective cyclization of thiazolidine 49 to enantiopure 51 under basic condition (Scheme 8.14) [16]. The observed stereoselectivity could be attributed to the formation of an ester enolate intermediate 50 as promoted by the basic reagent, which exhibits transient axial chirality and adopts a trans-conformation. When sequential intramolecular trapping of enolate by the nearby electrophilic diazo group proceeds faster than racemization, enantiopure product 51 is obtained. Stoodley et al. (1993) MeO

S O O

N

CO2Me

N2

49

Et3N, MeOH Refux

S O N

S

N 50

O

N CO2Me

O O

CO2Me NH

N N

51, 65% Enantiopure

Scheme 8.14  Electrophilic interception of axially chiral ester enolate intermediate. Source: Based on Beagley et al. [16].

The Clayden’s group developed atropselective alkylation reaction of rotationally restricted tertiary naphthamide with alkylating reagent through remote 1,5-asymmetric induction [17]. Ketone 52 reacted with potassium bis(trimethylsilyl)amide to form the potassium enolate, followed by stereocontrolled benzylation with benzyl bromide to afford 94 : 6 ratio of diastereomer syn-53 under kinetic control (Scheme 8.15). Extension of reaction time to two days at 20 °C led to a reversed ratio of 17 : 83 with anti-product as the major compound.

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compound Clayden et al. [1997] nBu N nBu O

O

KN(SiMe3)2, –78 °C

nBu N nBu O

O

BnBr, 0 °C 83% yield, 94 : 6 dr Ph

52

syn-53

Scheme 8.15  Atropselective alkylation reaction of restricted rotational tertiary naphthamide. Source: Based on Clayden et al. [17].

Kawabata and coworkers developed highly enantioselective cyclization of alkyl aryl ether bearing a rotationally restricted C─O bond (Scheme 8.16) [18]. They designed chiral alkyl aryl ether 54, which, on treatment with a base such as NaHMDS, could generate the short-lived axially chiral enolate 55 to undergo fast intramolecular cyclization, affording cyclic ether 56 in up to 99% ee. They found that the bulkiness of the substituent R at sixposition could affect the asymmetric induction in product, likely through a key role in increasing the rotational barrier around the chiral C–O axis. Kawabata et al. [2013] Br

Br NaHMDS

CO2Et O R

Me

Me

THF, –78 °C

54

O R

55

CO2Et OEt ONa

O R

Me

56

20–82%, 84–99% ee

Scheme 8.16  Short-lived axially chiral enolate. Source: Based on Yoshimura et al. [18].

8.2.3.2  Lithiation

Clayden and coworkers studied the asymmetric electrophilic addition of ortho-lithiated naphthamides 57 with aldehydes and two atropisomeric diastereoisomers could be formed as syn- and anti-products [19]. The stereoselectivity was explained by transition states 58 and 59. After coordination with lithium, aldehyde would preferably approach the naphthyl C2-position with R2 orientated far away from R1, leading to syn-isomer as the major product (Scheme 8.17). It stands to reason that bulkier R1 group on the dialkylamide unit would lead to higher diastereoselectivity. Clayden and coworkers revealed that by installing an (−)-ephedrine-derived oxazolidine at the ortho position of atropisomeric ketoamide, the oxazolidine could exert stereochemical influence on the conformation of ortho-lithiation/electrophilic substitution [20]. Lithiation of 62 with s-BuLi followed by trapping with dimethylformamide produces a substituted benzaldehyde. Further treatment with Grignard reagent gives rise to alcohol 63 with 95  :  5 dr (Scheme  8.18). The stereochemistry of the alcohol is relayed from chiral ephedrine backbone to the new stereogenic center through oxazolidine unit and the rotationally restricted amide axis.

221

222

8  Asymmetric Transformations Clayden et al. (1995)

R1 O

N

THF

R1 O

N

R1 (1) sBuLi, THF, –78 °C

O

R1 O H

Li

R1 N R1 OH R2

R2

58 ( Favored)

syn-60 67–92% 60/61 = 51 : 49 to 90 : 10

(2) R2CHO, –78 °C

R1

R1

57

O Li THF

N

O

R1 O R2

N R1 OH

R2

H

59 (Disfavored)

anti-61

Scheme 8.17  Asymmetric electrophilic addition of ortho-lithiated naphthamides. Source: Based on Bowles et al. [19].

Clayden et al. [2001] O

iPr N iPr H O N

(1) sBuLi, THF, –78 °C (2) Me2NCHO

O OH

iPr N iPr H O N

Ph (3) PhMgBr Me 89%, >95 : 5 dr

62

Ph Me

63

Scheme 8.18  Using amide conformation to influence stereochemistry. Source: Based on Clayden et al. [20].

8.2.3.3 Rearrangements

Clayden and coworkers performed a stereospecific [3,3]-sigmatropic Claisen rearrangement of atropisomeric N,N-dialkylnaphthamide-derived allylic alcohol 64 (Scheme 8.19) [21]. On reaction with dimethylacetamide dimethoxy acetal, the generated intermediate 65 would undergo a stereospecific Claisen rearrangement to give 66 (1  :  1 mixture of epimers). The reaction between 64 and triethyl orthoacetate gives acetal 67, whereas the ensuing rearrangement affords a single diastereomer 68. Following this rearrangement sequence, the stereochemistry of axially chiral dialkylnaphthamide in 64 has transferred to the newly formed allylic stereogenic center in rearrangement products 66 and 68. Metzner and coworkers also performed an asymmetric thio-Claisen rearrangement of axially chiral thioamides with stereochemical control [22]. This method afforded a series of substituted allyl thioacetals in good yields and diastereoselectivities.

Clayden et al. [2000]

iPr MeC(OMe)2NMe2 cat. EtCO2H xylene, reflux

iPr MeO

O

MeO

N iPr O

O

N iPr OH

iPr

NMe2 Xylene R

MeO

O

N

iPr

130 °C

CONMe2 R

66

65

89% (1 : 1 mixture of epimers)

R iPr

64 MeC(OEt)3 cat. EtCO2H toluene, reflux

MeO

O

iPr

OEt N iPr O

110 °C

MeO

O

N

iPr

R 67

CO2Et R

68 84%, (Single diastereomer)

Scheme 8.19  [3,3]-Sigmatropic Claisen rearrangement of atropisomeric allylic alcohol. Source: Based on Clayden et al. [21].

224

8  Asymmetric Transformations

8.2.4  Photoreactions 8.2.4.1  Photocycloaddition

Atropisomers could be amenable toward alternative activation modes that trigger their chemical conversions. As early as 1999, Bach et al. reported a Paterno–Buchi reaction of atropisomeric enamide 69 with benzaldehyde from which four diastereomers were obtained [23]. Two cis-isomers 70 and 71 were isolated with diastereomeric excess up to 62% de (Scheme  8.20). This investigation indicated the possibility of face shielding for short-lived radical. However, the concern for difficult stereocontrol of reactions with reactive short-lived excited-state species likely forestalled research activity for this chemistry. Bach et al. [1999] Ph

O N

Me tBu

Ph O

O

PhCHO, hv, 30 °C

N

63%, 62% de

Me tBu

N

+

Me tBu

71

70

69

O

O

Scheme 8.20  Paterno–Buchi reaction of atropisomeric enamide. Source: Based on Bach et al. [23].

It was not until 2013 for Sivaguru and coworker devised the stereospecific [2 + 2]-photocycloaddition of atropisomeric 3,4-dihydro-2-pyridones under triplet sensitized irradiation and produced photoproducts with good yields and excellent diastereoselectivities [24]. The photocycloaddition of 72 with R1  =  H proceeded through an excited triplet state under sensitization. In details, on sensitization, 72 would cyclize to form the triplet biradical 73 that undergoes a rapid intersystem crossing toward a singlet biradical. Cyclization of this biradical forms product 74 (Scheme 8.21). Overall, the complete chirality transfer of axial chirality from 72 is achieved. When R1 was methyl group, the pyramidal inversion of 73 could occur thus led to lower diastereocontrol. In a separate report, Sivaguru and coworkers performed the [2 + 2]-photocycloaddition of atropisomeric N-alkyl maleimides in the presence of UV/visible light [25]. They found that the substituents at the maleimide double bond greatly affected the stereocontrol and this [2 + 2]-cycloaddition was achieved with up to 99 : 1 dr and more than 98% ee. Sivaguru et al. (2013) R1 R1 H

R2 H N O

R1 hv

H

R1

3 R2 H N O

72

73

R1 H

R1

R2 H N O

74 >98 : 2 dr, >98% ee

Scheme 8.21  Stereospecific [2 + 2]-photocycloaddition. Source: Based on Kumarasamy and Sivaguru [24].

8.2  ­Asymmetric Transformation of Axially Chiral Non-biaryl Compound

8.2.4.2  Photocyclization

Sivaguru and coworkers also investigated an enantioselective 6π-photocyclization of atropisomeric acylanilides 75 that possess fairly high rotation barriers. They found that the conrotatory 6π-photocyclization of 75 bearing N-methyl group occurred exclusively on the aromatic carbon that was linked to the t-butyl substituent [26]. Elimination of two-methylpropene and hydrogen migration of 77 generated cis-78 with up to 99% ee as well as trans79 with up to 99% ee. In this case, the axial chirality of 75 was transferred to the central chirality of diastereomeric cyclic products (Scheme 8.22). Sivaguru et al. (2009) O R2

O

N

hv

tBu

R1

R3

N

+

R2 R1

R3

cis-78, 87–99% ee

75

O

R3

N

R2 R1 trans-79, 88–99% ee

78/79 = 70 : 30 to 22 : 78 O

O R2

R2

N tBu

R1 R3

6π-cyclization

R1 H

76

Hydrogen migration N

hv

77

R3

Scheme 8.22  Enantioselective 6π-photocyclization of atropisomeric acylanilides. Source: Based on Ayitou et al. [26a].

Subsequently, a report delineating light-induced 4π-photocyclization of optically pure 2-pyridone 80 to obtain bicyclic-β-lactam 81 in 21–95% ee with different solvents, temperatures, and irradiation time was presented [27]. The axial chirality in 80 is transferred to the stereocenters in 81 during the ring closure process. The bulky group at ortho position of phenyl ring blocks one face, enabling the formation of enantioenriched product 81 (Scheme  8.23). In this process, the ability to establish H-bonding plays decisive role on stereocontrol in the presence of different R and X substituents. Sivaguru et al. (2011)

R R X

R R X

N hv

N O 80

Favored

4π-cyclization

H H

O R R X

Disfavored

H

N O

H H

81, 21–95% ee

N O

R R X

H

Scheme 8.23  Light-induced enantiospecific 4π-photocyclization. Source: Based on Kumarasamy et al. [27].

225

226

8  Asymmetric Transformations

8.2.4.3  Hydrogen Atom Abstraction

Sivaguru group synthesized optically pure α-oxoamide 82 with ortho-t-butyl substitution and investigated its γ-hydrogen abstraction under photoirradiation [28]. The product β-lactam 83 was obtained in >95% yield and up to 80% ee. The photoirradiation of 82 excites the carbonyl entity to initiate γ-hydrogen abstraction from the N-methyl substituent, leading to a 1,4-diradical. Subsequent new C─C bond formation results in enantioenriched β-lactam 83 (Scheme  8.24). In this process, they found that low temperature has led to higher product enantioselectivity. In a separate report, they showcased the synthesis of chiral oxazolidinones from benzoylformamide through light-induced proton abstraction. Replacing the chloroform with a MeOH/HCl mixture as a reaction medium gave rise to optically active oxazolidinone products [29]. Sivaguru et al. (2009) Ph

O

O

N

Ph

H hv, CHCl3, –40 °C to 40 °C

tBu

O

R1 82

N

CH2

O

N

tBu

Hydrogen Abstraction >95%, 48–80% ee

R1

Ph OH

OH

tBu R1 83

Scheme 8.24  γ-Hydrogen abstraction under photoirradiation of α-oxoamide. Source: Modified from Ayitou et al. [28].

8.3  ­Asymmetric Transformation of Chiral Allenes Allene molecule embodies a linear three-carbon skeleton comprising two orthogonal πbonds, which are connected through a sp-hybridized carbon [30]. Allenes are unique scaffolds for organic synthesis as they potentially carry axial chirality that can be transferred to the products of subsequent chemical manipulations. This attractive synthetic potential of chiral allenes for asymmetric transformations will be discussed in this section.

8.3.1  Cyclization The good reactivity of allenes toward transition metals has been well represented. Moreover, they are ready substrates to undergo various cyclization pathways toward myriad carbo- or heterocycles. It follows that axially chiral allenes have also been studied to yield stereochemically enriched cyclic compounds with an efficient transfer of chirality. This section covers such reactivity patterns, which are classified according to metal types. 8.3.1.1  Palladium-Catalyzed Cyclization

The asymmetric endo cyclization of axially chiral 2,3-allenoic acids 84 to synthesize β-allylpolysubstituted butenolides 85 was developed by Ma and coworker [31]. Optimization of reaction temperature has unveiled a more effective chirality transfer from 84 to 85 at 25 °C. On further reduction of temperature to 0 °C, the product was obtained with high

8.3  ­Asymmetric Transformation of Chiral Allene Ma et al. [2003] R2

R3 R1

PdCl2 (5 mol%)

Br

+

R2

DMA, 25 °C 80–91%, 90–99% ee

CO2H

84 (>97% ee)

R1 R3

O

O 85

Br R2

L2ClPd R1 R3 O

PdClL2 R2

Allyl bromide

O

R1 R3

O

O

Scheme 8.25  The asymmetric endo cyclization. Source: Based on Ma and Yu [31].

enantioselectivity but in low yield. They proposed that this transformation might arise through a three-step pathway catalyzed by Pd(II) rather than Pd(0): cyclic oxypalladation of the allene moiety, insertion of the double bond of allylic bromide, and β-dehalopalladation (Scheme 8.25). Ma and coworkers also developed Pd-catalyzed oxidative dimeric cyclization of chiral 2,3-allenoic acids 86. A couple of bibutenolide derivatives 87 were obtained with excellent yields, diastereoselectivities, and enantioselectivities (Scheme  8.26) [32]. They proposed that the reaction may proceed via Pd(II)-mediated oxypalladation instead of a π-allyl–Pd cation transition state. The double oxypalladation was accounted for the highly efficient chirality transfer and the production of intermediate. Ma et al. [2005]

R1

86 (97–99% ee)

R2 O

R3

R2

O

O R2 R1

BQ

Pd(II)

R1 R3 O

O

DMF, 80 °C, 2 h 86–100% yield, 98–99% ee 20 : 1–99 : 1 dr

CO2H

PdII

R1

PdCl2 (5 mol%) Benzoquinone (0.6 equiv)

R2

R3

O R3

87

Pd(0) 1 R3 R

86

O O

R2 (II) Pd

R2

O O

R1

R3

Scheme 8.26  Pd-catalyzed oxidative dimeric cyclization. Source: Based on Ma et al. [32].

Later, they reported the PdCl2-catalyzed cross-coupling cyclization of chiral allenoic acid with 2,3-allenol, corresponding furanone derivatives were formed with complete chirality transfer via the addition of TFA, which could inhibit partial racemization as the reaction progressed [33].

227

228

8  Asymmetric Transformations

In 2013, Ma and coworkers reported exo-cyclization of chiral 2,3-allenyl amine 88 with propargylic carbonate 89 in the presence of Pd2(dba)3 and monophosphine ligand GorlosPhos-HBF4. The oxazolidinone derivative 90 was produced following an axial-to-central chirality transfer (Scheme 8.27). The reaction temperature was found to largely affect the outcome of this chirality transfer process; an optimal temperature range of 45–70 °C provided products in good yields and high enantioselectivities [34]. An efficient protocol for the synthesis of enantiopure fused bicycles 96 from allene propargylic carbonates 91 and geminal bis(nucleophiles) 92 was also envisioned [35]. In the presence of palladium(0) catalyst, 91 undergoes oxidative addition to form allenylpalladium intermediate 93. This is followed by the coplanar cis insertion of n-Bu-attached double bond and nucleophilic substitution of deprotonated 92 to invert the stereochemistry of the carbon stereocenter. Subsequent cyclization of the vinyl allene 95 affords the bicyclic compound 96 with high enantioselectivity (Scheme 8.28). 8.3.1.2  Rhodium-Catalyzed Cyclization

Blakey and coworkers discovered that an electrophilic metallonitrene could activate an allene species to produce 2-aminoallylcation intermediate as 1,3-dipole synthetic equivalent that is

Ma et al. (2013) H

R1 H

88

R3

CH2NHBn

R1 = c-C6H11, 98% ee R1 = nPr, 97% ee

Pd2(dba)3•CHCl3 (2.5 mol%) Gorlos-Phos•HBF4 (10 mol%) K2CO3 (2 equiv), DMSO, 45–70 °C

3

R

OCO2Me

+ iPrO

R2

R3

R2

H

PHCy2 OiPr

R1 N Bn

O

BF4

89

R3

90

O 66–84%, 94–96% ee

Gorlos-Phos•HBF4

Scheme 8.27  Exo-cyclization of chiral allenyl amine with propargylic carbonate. Source: Based on Ye et al. [34].

Ma et al. (2013) nBu H

Z

+ RO2C

OCO2Me 91 (Z = O or NTs) Pd(0) nBu PdOMe

Z

CO2R

(2) K2CO3 (3 equiv), 50–90 °C 67–78%, 88–95 ee

92

CO2R CO2R

Z 96

RO2C

CO2R H nBu

H

nBu H CO2R

PdOMe Z

93

nBu

(1) Pd(PPh3)4 (5 mol%) DMSO, 25 °C, 3–4 h

Coplanar insertion

Z 94

CO2R

Configuration inversion 95

Scheme 8.28  Synthesis of enantiopure fused bicycles. Source: Based on Ye and Ma [35].

8.3  ­Asymmetric Transformation of Chiral Allene Blakey et al. (2010) OSO2NH2

O

(1) Rh 2(esp)2 (5 mol%) PhI(O2CC(CH3)2Ph)2

H3C

HN MeO

(2) p-MeOPhMgBr•LiCl

H

H

R

97, 96% ee

R Rh

N

N 1 R Rh 2-Aminoallylcation

R1

O S O

H3C 98, 53%, 82% ee

Scheme 8.29  Synthesis of multisubstituted aminocyclopropane. Source: Based on Stoll and Blakey [36].

well suited for many synthetic transformations [36]. In the presence of catalytic Rh2(esp)2 and a hypervalent iodine oxidant, chiral 1,3-disubstituted allenyl sulfamate ester 97 rearranged to iminocyclopropane intermediate before reacting with para-methoxyphenylmagnesium bromide to provide multisubstituted aminocyclopropane 98 as a single diastereomer in 82% ee (Scheme 8.29). During this transformation, a compromise in stereochemistry (racemization) was however observed. Schomaker and coworkers developed Rh-catalyzed intramolecular cyclization of enantiopure allene sulfamate ester 99 to a strained nitrogen-containing stereotriad 103 with 99% ee [37]. Intramolecular cyclization of 99 with Rh2(TPA)4 catalyst and PhIO first yields E bicyclic methylene aziridine 100. PhSH then promotes the ring opening of aziridine in situ to form enesulfamate 101. Bromine incorporation using NBS followed by reduction using NaBH3CN gives rise to the final enantioenriched 103 containing three adjacent stereogenic centers (Scheme 8.30).

Schomaker et al. (2012) H

H

(1) Rh 2(TPA)4 (1 mol%), PhIO (2) PhSH (3 equiv)

C5H11

(3) NBS (1.2 equiv) (4) NaBH3CN, HOAc

OSO2NH2 99, 99% ee

H C5H11

H 100

HN

C5H11

O S O

Br SPh 103, 99% ee

Rh 2(TPA)4 PhIO O O S N O

O

NaBH3CN O

PhSH

HN

O S O

H C5H11

SPh 101

O NBS

C5H11

HN Br

O S O

SPh

102

Scheme 8.30  Rh-catalyzed intramolecular cyclization of allene sulfamate ester. Source: Based on Burke and Schomaker [37].

229

230

8  Asymmetric Transformations

They also investigated Rh-catalyzed axial-to-central chirality transfer of optically active silyl-substituted allene sulfamate 104 to produce enantioenriched endocyclic methyleneaziridine 106 [38]. The TBS group on 104 could direct the Rh-catalyzed aziridination of nitrene, which has been generated in situ from sulfamate and Rh complex to the distal C═C bond of allene. Rearrangement promoted by m-CPBA furnished the azetidin-3-one 105 and PhSH mediated the ring-opening of sulfamate, leading to TBS–azetidinone 106 with high stereocontrol (Scheme 8.31). Diversely, Brummond and coworker developed Rh-catalyzed cyclocarbonylation of allene to yield 5,7-bicylic rings [39]. In Scheme 8.32a, a series of chiral silyl-substituted allene-yne derivatives 107 containing internal alkyne were transformed to the corresponding cyclocarbonylation products 108 with enantioselectivity greater than 96%, indicating a complete chirality transfer from the allene-yne substrates. A range of trisubstituted allene–ynes 109 containing a phenyl group at one end of the allene were subjected to the Schomaker et al. (2015) TBS

H

(1) Rh2(OAc)4, PhIO CH2Cl2, r.t. (89%)

Me

(2) m-CPBA, CH2Cl2 60 h (61%)

OSO2NH2 104, 98% ee

Me O

O O S PhSH, K2CO3 N O TBS 105

MeCN 10%, 96% ee

Me

NH SPh

O

TBS 106

Scheme 8.31  Rh-catalyzed axial-to-central chirality transfer. Source: Based on Burke and Schomaker [38].

Brummond et al. (2013) DPS

Me H

TsN

(a)

R 107, >93% ee nBu

H Ph

R 109, >79% ee

R 111, >99% ee

O

[Rh(CO)2Cl]2 (10 mol%)

N Ts nBu

R 108 Ph O R

X 110

Me

(c)

CO (1 atm), PhMe, 90 °C 66–95%, 96–99% ee

Me

H

X

Me

[Rh(CO)2Cl]2 (10 mol%)

CO (1 atm), PhMe, 90 °C 46–91%, 74–80% ee

X (b)

DPS

[Rh(CO)2Cl]2 (10 mol%) CO (1 atm), PhMe, 90 °C X = NTs, 81–88% ee X = O, 22–52% ee X = C(CO2Et)2, 50–72% ee

O R X 112, 24–96%

Scheme 8.32  Rh-catalyzed cyclocarbonylation of allene. Source: Based on Grillet and Brummond [39].

8.3  ­Asymmetric Transformation of Chiral Allene

cyclocarbonylation conditions where enantiopurity of all substrates have been analyzed to be higher than 79% ee (Scheme 8.32b). It turned out that all bicyclic products 110 were obtained with ee greater than 74% (the enantioselectivity of substrate 109), suggesting that a complete axial-to-central chirality transfer was effected. They also examined disubstituted allene-ynes: treatment of 111 (>99% ee) with Rh catalyst and CO furnished cyclocarbonylation product 112 with diminished enantioselectivities (Scheme  8.32c). The efficiency of this chirality transfer under the same conditions was lower than that of ­tri-substituted analogs. In this case, the tether and alkyne substitution could influence the chirality transfer: the tosylamide tether gave the highest ee, whereas the oxygen tether led to the lowest ee. They postulated that partial racemization could be related to relative nucleophilicities of the heteroatoms in the tether moiety, leading to an isomerization in equilibration process of η1-Rh and η3-Rh intermediates. 8.3.1.3  Gold-Catalyzed Cyclization

Lalic and coworkers reported gold-catalyzed asymmetric exo-selective cyclization of enantioenriched trisubstituted allenols 113 to synthesize cyclic ethers 114 containing a chiral α-tetrasubstituted carbon center (Scheme 8.33) [40]. The stereochemical integrity of chiral axis in 113 was successfully transferred to the central chirality in the cyclic ether product. Exclusive production of E isomer was achieved with effective chirality transfer via the use of gold tosylate as catalyst and t-Bu3P as ligand. A variety of cyclic ethers were obtained in enantiomerically enriched form, which also accommodated diverse functional groups. The authors additionally achieved the asymmetric synthesis of chroman derivatives containing a tetrasubstituted chiral center in excellent yields and high enantioselectivities by applying this methodology. Lalic et al. (2013) tBu3PAuCl (1 mol%) AgOTs (1 mol%)

R1 n

OH

R2

113 Enantioenriched

toluene, 25 °C, 2 h 75–99%, 85 : 15 to 99 : 1 er

R2 O n

R1

114

Scheme 8.33  Gold-catalyzed asymmetric exo-selective cyclization. Source: Based on Cox et al. [40].

Ma and coworkers disclosed conditions for a gold-catalyzed six-endo cyclization of benzylic allenes to prepare 1,4-dihydroarenes bearing a chiral center [41]. The hydroarylation of enantioenriched allenes 115 toward 116 has exhibited highly efficient chirality transfer with the use of dinuclear gold catalyst [(dppm)Au2Cl2, dppm = methylene bis(diphenylphosphine)] and AgOTf. The bulkier ligand, for example, dppm was found to be more effective in improving the enantioselectivity for this chemistry (Scheme 8.34). 8.3.1.4  Silver-Catalyzed Cyclization

The employment of silver catalyst was documented by Woerpel and coworkers in one-pot reaction of chiral allene involving silylene transfer to generate oxasilacyclopentane with

231

232

8  Asymmetric Transformations Ma et al. (2015) [(dppm)Au2Cl2] (2.5 mol%) AgOTf (5 mol%)

R1

toluene, r.t. 81–95%, 92–99% ee

R2

H

R1 R2

116

(R)-115 Enantioenriched

Scheme 8.34  Gold-catalyzed six-endo cyclization of benzylic allenes. Source: Based on Qiu et al. [41]. Woerpel et al. (2009) H

H Me

+

Si

c-C6H11 117, >98% ee

118

tBu

tBu tBu Si O

Ag3PO4 (5 mol%) CF3CO2 Ag (1 mol%)

tBu CuI, iPrCHO, –18 °C to 22 °C 65%, 95% ee tBu

c-C6H11 120

tBu Si

CF3CO2Ag

Me

iPr

CuI, iPrCHO

Me c-C6H11 119

Scheme 8.35  Silver-catalyzed one-pot reaction. Source: Based on Buchner et al. [42].

efficient chirality transfer [42]. Silver catalyst mediates transfer of silylene to chiral allene, leading to alkylidenesilacyclopropane intermediate 119, which undergoes carbonyl insertion with butyraldehyde to afford enantioenriched oxasilacyclopentane 120 (Scheme 8.35). Protodesilylation of 120 could generate homoallylic alcohol with high stereocontrol. 8.3.1.5  Organic Reagent-Mediated Cyclization of Chiral Allene

Tan and coworkers reported on using N-iodosuccinimide to mediate the lactonization of chiral allene 121 toward β-iodobutenolide 122 [43]. During the iodo-lactonization process, partial racemization happened as a loss of enantiopurity to 75% ee in 122 was observed (Scheme 8.36). Tan et al. (2009) OMe

OMe

NIS, CHCl3, 0 °C to r.t., 1 h H

H

CO2tBu

121, 93% ee

O

49%, 75% ee

O I 122

Scheme 8.36  N-Iodosuccinimide mediated lactonization of chiral allene. Source: Modified from Liu et al. [43].

8.3  ­Asymmetric Transformation of Chiral Allene

8.3.2  Cycloaddition 8.3.2.1  Intermolecular Cycloaddition

Diels–Alder reaction of chiral allenoate 123 with cyclopentadiene was demonstrated by Tan and coworkers [43]. On heating at 80 °C for 12 hours, the cycloaddition proceeded to yield endo product as the major diastereomer and the chirality transfer efficiency was high, in upward of 85% ee (Scheme 8.37). Tan et al. (2009) H

R H H

PhMe, 80 °C, 12 h

CO2tBu

123

R

CO2tBu +

CO2tBu H

endo-124 R

123a, R = OH, 86% ee 123b, R = NHCbz, 91% ee 123c, R = PhthN, 94% ee

85%, 4 : 1 dr 98%, 3 : 1 dr 99%, 2 : 1 dr

endo-124a, 85% ee endo-124b, 87% ee endo-124c, 93% ee

exo-124

exo-124a, 89% ee exo-124b, 85% ee exo-124c, 93% ee

Scheme 8.37  Diels–Alder cycloaddition reaction of chiral allenoates. Source: Based on Liu et al. [43].

Sawamura and coworkers developed conditions of an asymmetric coupling reaction to synthesize aryl- and alkenyl-conjugated allenes with excellent enantioselectivity [44]. They demonstrated the synthetic utility of enantioenriched alkenyl-conjugated allene 125 by performing an intermolecular cycloaddition with electron-deficient dienophile N-phenylmaleimide under thermal conditions. The fused bicyclic products were obtained with high diastereoselectivity and with complete transfer of chirality from the allene (Scheme 8.38).

Sawamura et al. (2012)

Me H

Ph O

N

Me

O

MOMO

NPh

Toluene, 110 °C

nBu

OMOM

125, 98% ee

nBu

Me H O

H O + MOMO

H O

126, 78%, 98% ee

NPh nBu

126/127 = 92 : 8

H

O

127

Scheme 8.38  Intermolecular cycloaddition reaction. Source: Based on Yang et al. [44].

Frantz and coworkers reported the application of enantioenriched allene in natural product synthesis [45]. AlCl3-catalyzed Diels–Alder reaction of disubstituted chiral allene 128 and N-Boc pyrrole at −78 °C, delivering endo-cycloadduct 129 in 57% yield and ~89% ee. The axial chirality from allene 128 was almost completely transferred to the corresponding product. After several steps of synthetic manipulations, target ketone 130 was obtained in 89% ee (Scheme 8.39).

233

234

8  Asymmetric Transformations Frantz et al. (2013) O

H

H

Et

NBoc

Et

OCy

Et

Boc N

AlCl3 (1.5 equiv) CH2Cl2, –78 °C

128, 96% ee

O

Et O

Boc N

OCy

130, 89% ee

129, 57%, 89% ee

Scheme 8.39  Application of enantioenriched allene in natural product synthesis. Source: Based on Crouch et al. [45].

Wang and coworkers investigated the intermolecular Diels–Alder reaction of enantioenriched allene 131 with furan [46]. Good diastereoselectivity was achieved for the endoproduct 132, where it was also obtained as the major isomer with 92% ee (Scheme 8.40). The authors further conducted the cycloaddition with an azomethine dipole from which a single diastereomer of pyrrolidine was forged with complete chirality transfer.

Wang et al. (2014) Ph H

CONH2 H

O

O

O Ph

+

CONH2

80 °C, 60 h CONH2 132, 77%, 92% ee

131, 95% ee

Ph 133, 15%, 93% ee

Scheme 8.40  Intermolecular Diels–Alder reaction of enantioenriched allene. Source: Based on Ao et al. [46].

8.3.2.2  Intramolecular Cycloaddition

The first example of Rh-catalyzed intramolecular [5 + 2]-cycloaddition of chiral allene containing vinylcyclopropane moiety was put forward by Wender and coworkers [47]. In the presence of 1 mol% RhCl(PPh3)3, the vinylcyclopropane–allene 134 was effectively transformed to fused-5,7-bicycle 135 as a single diastereomer with 92% ee, indicating that the stereochemical information in 134 was completely conserved in the cycloaddition product (Scheme 8.41). In this process, the internal alkene of allene reacted preferentially with the vinylcyclopropane subunit under Rh catalysis. They also found that the level of exo–endo selectivity of the product could be controlled and amplified by tuning of catalyst.

Wender et al. [1999]

E

H tBu

RhCl(PPh3)3 (1 mol%) Toluene, 100 °C

E 134, 91% ee

tBu H E

H E E

E

H Rh

H tBu

H 135, 92% ee

Scheme 8.41  First example of Rh-catalyzed intramolecular [5 + 2]-cycloaddition. Source: Based on Wender et al. [47].

8.3  ­Asymmetric Transformation of Chiral Allene

Trost et al. synthesized chiral allene-diene compounds 136 with high level of enantioselectivity and evaluated the efficiency of chirality transfer [48]. Upon treatment of 136a or 136b with 2–3 mol% of [(C10H8)Rh(COD)]SbF6 for 30 minutes, the enantioenriched cis-fused-5,6-bicycle 137a and 137b with E-diene moiety were obtained as single diastereomer, respectively, with the retention of optical purity from allene substrates (Scheme 8.42). Trost et al. [2005] MeO2C

H R

[(C10H8)Rh(COD)]SbF6 (2–3 mol%) CH2Cl2, r.t., 30 min

MeO2C

R H MeO2C

Me

MeO2C

H 137 137a, R = nC4H9, 93%, 87% ee 137b, R = C(CH3)2OBn, 89%, 91% ee

136 136a, R = nC4H9, 87% ee 136b, R = C(CH3)2OBn, 90% ee

Scheme 8.42  Rh-catalyzed intramolecular cycloaddition. Source: Based on Trost et al. [48].

When it comes to a N-Ts linker instead of the malonate linker shown above, Ma and coworkers reported a Rh-catalyzed intramolecular [4 + 2]-cycloaddition of the chiral disubstituted allene-diene 138 with N-Ts tether, in which the internal olefin bond acted as dienophile and afforded efficiently cis-5,6-fused bicyclic products 139 (Scheme 8.43) [49]. In their catalyst system, AgSbF6 was added to promote the formation of cationic Rh catalyst and the solvent’s (ethanol) coordination ability with Rh seemed beneficial. A range of 138 derivatives with different R1 and R substituents were examined, which provided cycloaddition products bearing three stereocenters in high enantioselectivity, implying the excellent chirality transfer. They also proposed a reaction mechanism that involves concerted cyclometalation, allylic rearrangement, and reductive elimination steps, contributing to the high stereocontrol observed. Ma et al. (2019) R1

X

EtOH, r.t. 138

R1 H

RhCl(PPh3)3 (3 mol%) AgSbF6 (5 mol%) R H

X = NTs, 93–98% ee X = C(CO2Me)2, 94% ee

R

X H 139 59–79%, 93–99% ee 80–82%, 94% ee

Scheme 8.43  Rh-catalyzed intramolecular [4 + 2]-cycloaddition. Source: Based on Han et al. [49].

Brummond and coworkers reported an intramolecular [2 + 2]-cycloaddition of enantiopure allene-yne 140 under microwave irradiation at 225 °C, forging the chiral spirooxindole 142 in upward of 95% ee (Scheme 8.44) [50]. They proposed that the reaction has proceeded

235

236

8  Asymmetric Transformations Brummond et al. [2011]

tBu Microwave 225 °C, 5 min

N

tBu

Ph o-Dichlorobenzene

O

N

O O

O 140, enantiopure

141

Ph N

Ph O

O 142, 44%, >95% ee

Scheme 8.44  Synthesis of chiral spirooxindoles via [2 + 2]-cycloaddition. Source: Based on Brummond and Osbourn [50].

through a biradical intermediate 141 containing the bulky t-butyl substituent that could limit the rotation of C─C bond, leading to 142 with complete chirality transfer. Himbert’s protocol delineating intramolecular arene/allene Diels–Alder cycloaddition could permit access to polycyclic compounds. Vanderwal and coworkers revisited this unique cyclization protocol and performed computational study to understand the mechanism [51]. In their experimental study (Scheme 8.45), treatment of enantioenriched allene 143 with microwave at 170 °C generated cycloaddition product 144 with 80 : 20 er after four hours, but extended reaction time led to decreased enantiomeric ratio. When heated at 140 °C for 10 hours, the enantiomeric ratio was improved but with lower yield. They hypothesized that the competition between racemization and stereospecific cycloaddition would determine the final er. A mechanistic study indicated that this transformation might proceed through a concerted process. Vanderwal et al. (2013) Me

Me

Microwave, heat Me

N

Toluene

Me N

O 143, 99 : 1 er

H

(170 °C, 4 h) (170 °C, 10 h) (140 °C, 10 h) (140 °C, 24 h)

69%, 80 : 20 er 77%, 70 : 30 er 20%, 90 : 10 er 39%, 85 : 15 er

O 144

Scheme 8.45  Mechanistic study of intramolecular arene/allene Diels Alder cycloaddition. Source: Based on Schmidt et al. [51].

8.3.3  Reaction with Nucleophiles 8.3.3.1  Reaction with Carbon Nucleophiles

Hiroi and coworkers developed Pd-catalyzed asymmetric carbopalladation of enantiopure allene 145 when combined with iodobenzene and Pd2(dba)3 to form the π-allylpalladium complex. Subsequent nucleophilic substitution with malonate anion would furnish enantiopure 1,2-addition olefinic product 146 [52]. The stereochemical outcome exemplified a completely stereospecific transformation (Scheme 8.46). Alexakis and coworkers performed a reaction between chiral chloroallene and Grignard reagent under copper catalysis [53]. When 147a or 147b was reacted with aryl Grignard

8.3  ­Asymmetric Transformation of Chiral Allene Hiroi et al. (2004) Ph H

Me H

+ PhI + Na

Ph

CO2Me

Pd(dba)2

CO2Me

dppe, THF, 66 °C

CO2Me

Ph H Me

145, 100% ee

H

CO2Me

146, 100% ee

Scheme 8.46  Pd-catalyzed three-component asymmetric transformation. Source: Based on Kato and Hiroi [52].

reagent in THF, the corresponding aryl-substituted allene 148a or 148b could be obtained with complete chirality transfer. Furthermore, following treatment of 147a or 147b with bulky alkyl Grignard reagents in CH2Cl2, instead of THF, terminal alkyne containing a quaternary chiral center 149a or 149b was exclusively produced with a complete retention of enantioselectivity (Scheme 8.47). Alexakis et al. (2012) ArMgBr (2 equiv), CuCN (15 mol%) THF, –20 °C to r.t. 84–85%, 90% ee

Me Cy

Cl

147a, 90% ee

79–97%, 90% ee Alkyl MgBr (2 equiv), CuCN(15 mol%)

Me Cy

nBu TMS

Cl 147b, 85% ee

THF, –20 °C to r.t. 75%, 83% ee 87%, 83% ee Alkyl MgBr (2 equiv), CuCN (15 mol%) CH2Cl2, –20 °C to r.t.

Ar

Alkyl Me

CH2Cl2, –20 °C to r.t. ArMgBr (2 equiv), CuCN (15 mol%)

148a

Cy 149a nBu TMS

148b

Ar

Alkyl nBu 149b TMS

Scheme 8.47  Cu-catalyzed asymmetric arylation/alkylation of chloroallenes. Source: Based on Li et al. [53].

Rh-catalyzed ortho-allylation of N-methoxybenzamide with enantiopure allene 150 was developed by Ma and coworkers [54]. N-Methoxybenzamide undergoes ortho C–H activation in the presence of Rh(III) catalyst ensued by hydroarylation with chiral allene 150 to yield intermediate 151. Lactonization upon the addition of TsOH produces enantiopure bicyclic lactone 152 (Scheme 8.48). In this process, highly efficient axial-to-central chirality transfer was too realized. Arai and coworkers reported that a transfer of axial chirality from enantioenriched allene 153 through Ni-catalyzed asymmetric hydrocyanation could afford chiral carbonitriles 154 in up to 97% ee (Scheme 8.49) [55]. The key intermediate was the π-allylnickel complex,

237

238

8  Asymmetric Transformations Ma et al. (2012)

O

R Me

OH

NHOMe OH R

[Cp*RhCl2]2 (2 mol%) CsOAc (30 mol%)

150

O

O NHOMe

151

O

TsOH•H2O

R 152

Me

R = Cy, 99% ee R = BnCH2, 99.7% ee

Me

R = Cy, 70%, 99% ee R = BnCH2, 56%, 99.7% ee

Scheme 8.48  Rh-catalyzed ortho-allylation of N-methoxybenzamide. Source: Based on Zeng et al. [54].

Arai et al. (2017) H

Ar

R

H

153

R = tBu, R = Cy, R = nHep,

+

OH Me CN Me (5.0 equiv)

88–98% ee 85–98% ee 96–97% ee

Ni[P(OPh)3]4 (10 mol%) PMePh2 (40 mol%) Toluene, 60 or 80 °C R = tBu, R = Cy, R = nHep,

H R

Ar CN 154

84–97%, 84–95% ee 78–93%, 65–82% ee 68–74%, 47–63% ee

Scheme 8.49  Ni-catalyzed asymmetric hydrocyanation. Source: Based on Amako et al. [55].

which yields hydrocyanation product after reductive elimination. Ligand screening showed that PMePh2 was optimal for the chirality transfer. Substrate scope study was performed, and when R1 was t-butyl group, the axial chirality could be transferred smoothly; with a secondary alkyl substituent (such as cyclohexyl) or a primary alkyl substituent (such as n-heptyl), the ee of corresponding products deteriorated. It turned out that the starting allene with a Csp3 H at the allylic site tended to be partially racemized in the β-H elimination step. 8.3.3.2  Reaction with Heteroatom Nucleophiles

Au-catalyzed intermolecular hydroamination of chiral allenes with arylamines was attained by Yamamoto and coworker [56]. The axial chirality in allene 155a was transferred to point chirality in 157a with retention of enantioselectivity. Enantioenriched 155b was similarly transformed to 157b with complete chirality transfer. It was proposed that the coordination of gold with amine should occur before the formation of intermediate 156 (Scheme 8.50). Toste and coworkers conducted a mechanistic study for Au-catalyzed hydroamination of allene with a hydrazide [57]. In the reaction of enantioenriched allene 158 with methyl carbazate and Ph3PAuNTf2 at 45 °C, the highest enantioselectivity was found when more than 4 equiv of methyl carbazate was added (Scheme 8.51). They explained that the concentration dependence was due to the competition between the racemization of chiral π-allyl–gold complex and fast trapping of the nucleophile. In the absence of nucleophile, only racemization occurred and enantioenriched 158 would convert into a racemic mixture.

8.3  ­Asymmetric Transformation of Chiral Allene Yamamoto et al. (2006) H

PhNH2 (2 equiv) AuBr3 (10 mol%)

H

Me Ph 155a, 94% ee H

THF, 30 °C

NHPh

NHPh

H

Ph

Me 157a 68%, 88% ee

Me

Ph 156

H

npentyl

Au H

NHPh

PhNH2 (2 equiv) AuBr3 (10 mol%), THF, 30°C

npentyl

npentyl

npentyl

157b, 80%, 99% ee

155b, enantioenriched

Scheme 8.50  Au-catalyzed intermolecular hydroamination. Source: Based on Nishina and Yamamoto [56].

Toste et al. (2010) Ph

Ph

NH2NHCO2Me (X equiv) Ph3PAu NTf2 (6 mol%)

Ph

MeNO2, 45 °C

158, 87% ee

Ph 159

X = 1.0, 81%, 28% ee X = 2.0 , 75%, 48% ee Ph

Ph

Ph3PAu NTf2 (6 mol%)

158, 87% ee

MeNO2, 45 °C

HN

NHCO2Me

X = 4.0 , 81%, 56% ee X = 8.0, 79%, 56% ee

Ph

Ph rac-158

Scheme 8.51  Mechanistic study of Au-catalyzed hydroamination. Source: Based on Wang et al. [57].

Au-catalyzed intermolecular hydroalkoxylation of enantioenriched allene 160 with benzyl alcohol was reported by Widenhoefer and coworker (Scheme 8.52) [58]. Compound 160 reacted with 0.44 M of benzyl alcohol and gave allylic alcohol with decreased enantiomeric ratio. Raising the concentration to 1.76 M provided 161 with improved enantioselectivity. Similar to Toste’s report described above, the loss of chirality was due to the formation of π-allyl gold complex intermediate.

Widenhoefer et al. (2008) H Me

+ OBz 160, 97% ee

BnOH

AuCl (5 mol%) AgOTf (5 mol%) Toluene, r.t.

Me OBz

BnO

BnOH = 0.44 M, 30 min, 83%, 64% ee BnOH = 1.76 M, 20 min, 83%, 79% ee

161

Scheme 8.52  Au-catalyzed intermolecular hydroalkoxylation. Source: Based on Zhang and Widenhoefer [58].

239

240

8  Asymmetric Transformations

8.3.4  Chiral Allene as Nucleophiles Chiral allenes could also exhibit a reversal of reactivity profile by acting as the nucleophilic reaction partner. Jamison and coworkers reported a three-component Ni-catalyzed intermolecular addition of aldehyde to the sp-hybridized carbon of enantioenriched allenes with high regioselectivities and enantioselectivities (Scheme 8.53) [59]. Treatment of chiral allenes 162 with aromatic aldehydes 163 and silanes 164 as a reducing agent in the presence of Ni(cod)2 and imidazolinyl carbene ligand (NHC–IPr) enabled formation of allylic products 165 with Z/E > 95 : 5. They proposed that the bulky Ni–L complex is more likely to attack from the less-hindered allene face as shown in conformation A. This is ensued by oxidative addition of benzaldehyde to form B, which will react with silane selectively to furnish D. Final reductive elimination operates with retained chirality to afford Z-alkene 165a, realizing the highly efficient chirality transfer. Jamison et al. (2005) H

H

R1

R2

+

162 (R1 > R2) 95–98% ee

Ar

Cy

D Ni Me

iPr N

iPr iPr NHC–IPr

Ph L Ni Et3Si-D O H H

H B

Ph

Cy

R1

H

Me H Ph H Ni L D OSi D

Cy

H

L Cy

H H

H OSi C, unfavored

H Ph

Ar R2 165

40–80%, 95–98% ee >95 Z/E

Me O

OSiR3

THF, –78 °C to r.t.

164 (3 equiv)

Ni L

iPr N

Ni (cod)2 (20 mol%) NHC-IPr (40 mmol%)

R3SiH

Me

HH A

+ H

163 (3 equiv)

H Cy

O

D

Me H Ph OSi

165a 98% ee, >95 : 5 dr

Scheme 8.53  Three-component Ni-catalyzed intermolecular addition. Source: Based on Ng and Jamison [59].

Enantioenriched allenylsilanes could also engage in three-component reaction with aldehydes and sulfonamides with the promotion of TMSOTf, as disclosed by Panek and coworkers (Scheme 8.54) [60]. A range of syn-propargylic sulfonamides were obtained with high diastereoselectivities. The chirality transfer from axial chiral allene to the propargylation product was highly efficient (>97% ee). The selective formation of syn-isomer could be explained by synclinal transition state. The R′ group of iminium ion and ester group reside on opposite sides to minimize steric interaction. Conducting this transformation in dichloromethane with aromatic imines would instead give rise to lactones in moderate to high yields.

8.3  ­Asymmetric Transformation of Chiral Allene Panek et al. (2009) H

SiMe2Ph

HN

TMSOTf, EtCN, –78 °C

CO2Me

Me

tBuCHO + TsNH3

PhMe2Si

N

MeO2C

Me

H H R' Synclinal transition state

HN

SiMe2Ph

167, 98% ee

SiMe3

RO2S

CO2Me

Me

CO2Me

tBu

(R)-166, 98% ee

H

Ts

Ts CO2Me

tBu

TMSOTf, EtCN, –78 °C

169, >99% ee

(S)-168, >99% ee

Scheme 8.54  Three-component reaction promoted by TMSOTf. Source: Based on Brawn and Panek [60].

Ogasawara, Takahashi, and coworkers developed Pd-catalyzed asymmetric synthesis of chiral allenylsilanes and applied these allenes to desilylative SE2′ reaction to synthesize a variety of tertiary and quaternary propargylic products with good chirality transfer (Scheme 8.55) [61]. Enantioenriched allenes (R)-170 reacted with propanal dimethyl acetal and TiCl4 to afford diastereomeric propargylic methyl ethers containing a tertiary center with 4 : 1 diastereomeric ratio and complete chirality transfer. Selectfluor-mediated desilylation of (R)-170 also gave fluorinated (S)-173 with a well-defined tertiary center. Treatment of (R)-174a or (R)-174b with acetic acid-derived reagent gave propargyl products (R)-175a or (R)-175b, respectively, with retained enantioselectivity.

Takahashi et al. (2010)

H

EtCH(OMe)2, TiCl4 CH2Cl2, –78 °C 73%, 171/172 = 4 : 1

H R = CPh(CO2Et)2 (R)-170, 94% ee

Me3Si

H

R F (S)-173, 77%, 94% ee

R1

R = CMe(CO2Me)2 (R)-174 R1

H

(S,R)-172, 94% ee

R

H

R OMe

Et

Selectfluor (2 equiv), CH3CN, 23 °C

Me3Si

(R)-174a,

Et

H OMe

+

(S,S)-171, 94% ee

R

H

H R

= Me, 76% ee

(R)-174b, R1 = Et, 60% ee

R1

CH3CO2H•BF3 (1.5 equiv)

R

CH2Cl2, –78 °C to 23 °C 175 (R)-175a,

R1

H

= Me, 61%, 74% ee

(R)-175b, R1 = Et, 60%, 59% ee

Scheme 8.55  Asymmetric formation of propargylic stereocenters via chiral allenylsilanes. Source: Based on Ogasawara et al. [61].

241

242

8  Asymmetric Transformations

They also investigated the SE2′ chirality transfer of chiral allenylmethyl silanes to produce asymmetric 5-silylpenta-1,3-dienes [62]. TiCl4 promoted the reaction of a range of enantioenriched (R)-176 with acetals 177 to form diene products with E configuration selectively as well as with good chirality transfer (Scheme 8.56). In this process, electrophilic acetals would attack the middle carbon of allenes from opposite side of R1 to avoid steric interaction, giving rise to the E configuration. Chirality transfer in the presence of pivalaldehyde dimethyl acetal as electrophile was more favorable than when phenylacetaldehyde dimethyl acetal was used. Additionally in reaction with pivalaldehyde dimethyl acetal, bulkier silyl substituents attached on 176 could enhance the transfer efficiency.

Takahashi et al. (2012) [Si]

R1

H (R)-176

+ RCH(OMe)2

H

177

TiCl4 (1 equiv)

MeO

CH2Cl2, –78 °C, 1 h

H R 178

[Si]

ee% (176)

R

yield %

ee% (178)

SiMe3

79

tBu

87

70

SiEt3

80

tBu

71

71

SiiPr3

87

tBu

71

80

SiMe3

79

PhCH2

89

21

SiiPr3

87

PhCH2

36

15

R1

Scheme 8.56  Investigation of the SE2′ chirality transfer reactions. Source: Based on Ogasawara et al. [62].

8.4  ­Conclusion This chapter has discussed classic examples and recent advances on asymmetric ­transformations of atropisomeric systems (namely, the (hetero)biaryl and non-biaryl ­systems) as well as axially chiral allenes. Although not in a comprehensive manner, it illustrates how different classes of axially chiral molecules can be transformed via ­different ­reactivity modes. Although the chemical derivatizations of (hetero)biaryl atropisomers are broadly performed toward atropochiral ligands/catalysts (which is excluded in this section), transformations undergone by other classes of axial chiral compounds have involved translation of existing stereochemical information (axial chirality) to newly introduced chiral element(s). It is apparent from the examples quoted that the transfer of axial chirality to point chirality is the most common mode. The unique structural characteristics have allowed unusual synthetic accesses toward biologically active ­natural products, chiral ligands, and other molecules of interest. This is particularly valued when alternate preparation methods could be challenging or even elusive.

  ­Reference

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9 Grillet, F. and Brummond, K.M. (2013). J. Org. Chem. 78: 3737. 3 40 Cox, N., Uehling, M.R., Haelsig, K.T., and Lalic, G. (2013). Angew. Chem. Int. Ed. 52: 4878. 41 Qiu, Y., Zhou, J., Li, J. et al. (2015). Chem. Eur. J. 21: 15939. 42 Buchner, K.M., Clark, T.B., Loy, J.M.N. et al. (2009). Org. Lett. 11: 2173. 43 Liu, H., Leow, D., Huang, K.-W., and Tan, C.-H. (2009). J. Am. Chem. Soc. 131: 7212. 44 Yang, M., Yokokawa, N., Ohmiya, H., and Sawamura, M. (2012). Org. Lett. 14: 816. 45 Crouch, I.T., Neff, R.K., and Frantz, D.E. (2013). J. Am. Chem. Soc. 135: 4970. 46 Ao, Y.-F., Wang, D.-X., Zhao, L., and Wang, M.-X. (2014). J. Org. Chem. 79: 3103. 47 Wender, P.A., Glorius, F., Husfeld, C.O. et al. (1999). J. Am. Chem. Soc. 121: 5348. 48 Trost, B.M., Fandrick, D.R., and Dinh, D.C. (2005). J. Am. Chem. Soc. 127: 14186. 49 Han, Y., Qin, A., and Ma, S. (2019). Chin. J. Chem. 37: 486. 50 Brummond, K.M. and Osbourn, J.M. (2011). Beilstein J. Org. Chem. 7: 601. 51 Schmidt, Y., Lam, J.K., Pham, H.V. et al. (2013). J. Am. Chem. Soc. 135: 7339. 52 Kato, F. and Hiroi, K. (2004). Chem. Pharm. Bull. 52: 95. 53 Li, H., Müller, D., Guénée, L., and Alexakis, A. (2012). Org. Lett. 14: 5880. 54 Zeng, R., Fu, C., and Ma, S. (2012). J. Am. Chem. Soc. 134: 9597. 55 Amako, Y., Arai, S., and Nishida, A. (2017). Org. Biomol. Chem. 15: 1612. 56 Nishina, N. and Yamamoto, Y. (2006). Angew. Chem. Int. Ed. 45: 3314. 57 Wang, Z.J., Benitez, D., Tkatchouk, E. et al. (2010). J. Am. Chem. Soc. 132: 13064. 58 Zhang, Z. and Widenhoefer, R.A. (2008). Org. Lett. 10: 2079. 59 Ng, S.-S. and Jamison, T.F. (2005). J. Am. Chem. Soc. 127: 7320. 60 Brawn, R.A. and Panek, J.S. (2009). Org. Lett. 11: 4362. 61 Ogasawara, M., Okada, A., Subbarayan, V. et al. (2010). Org. Lett. 12: 5736. 62 Ogasawara, M., Ge, Y., Okada, A., and Takahashi, T. (2012). Eur. J. Org. Chem. 2012: 1656.

245

9 Application for Axially Chiral Ligands Bing-Chao Da and Bin Tan Department of Chemistry, Southern University of Science and Technology, No.1088, Xueyuan Rd., Nanshan District, Shenzhen, 518055, China

9.1 ­Introduction Axial chirality made the first literature appearance in 1920s and has since become one constant theme of various literature reports. Unlike point chirality molecules, these molecules are configurationally stabilized because of sterically hindered rotation of a chiral axis rather than a stereogenic center with four different substituents. As such, they are also not superimposable on respective mirror image. Chiral element of this class is epitomized by biaryl system (e.g. biphenyl) with rotation constraints, such as 1,1′-conjugated (2-naphthol). As shown in Table 1, thermodynamic and kinetic data for thermal racemization experiments of chiral 1,1′-bi-2-naphthol (BINOL), 2,2′-diamino-1,1′-binaphthalene (BINAM), and 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) indicate that these axially chiral biaryl molecules are sufficiently stable under normal reaction conditions [1]. To date, widespread utility of axially chiral compounds could be found in biologically active molecules [2, 3], organocatalysts [4, 5], and one of their most venerable uses is as chiral ligands for metal-catalyzed asymmetric transformations [6–10]. The extensive use of axially chiral compounds as chiral catalysts and ligands garners immense research efforts with regard to their chemical synthesis and application over the past decades. Axially chiral ligands with diverse skeletons could now be industrially ­produced and applied [11], and they represent privileged class of chiral inductors for different stereoselective reactions catalyzed either by metal/ligand complexes or organocatalysts. Among them, monodentate phosphines, diphosphines, phosphoramidites, N,P ligands, Box ligands, C2-symmetric diols, and N,O ligands constitute the most highly cited ligands in asymmetric catalysis. In this chapter, instead of comprehensive overview, we will ­highlight the recent development of asymmetric reactions catalyzed by these axially chiral metal–ligand complexes, which effectively generated chiral products with excellent enantioselectivities and yields.

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

246

9  Application for Axially Chiral Ligands

9.2 ­Monodentate Phosphines Chiral monodentate phosphines appear as first type of ligands to be successfully applied in the field of asymmetric hydrogenation as contributed by the pioneering works of Knowles and coworker [12], Horner et al. [13], Kagan and coworker [14], and others in the late 1960s. Several useful stereoretentive transformations from enantiopure feedstocks emerged to prepare monodentate phosphines. The optically active substrate 1 is deprotonated by nBuLi to form carbanion, which is primed for substitution reaction with trivalent phosphorus reagents to yield monodentate phosphine ligands 3 [15]. Several types of common axially chiral monodentate phosphine ligands (L1–L8) embodying classic frameworks were listed in Figure 9.1. One most symbolic member is built on binaphthol backbone; the low cost, commercial availability, and high structural tunability of starting materials are appealing features for asymmetric catalysis. Phosphoramidite ligands, which represent one prominent subclass, will be discussed in detail in the following sections. Herein, several manifest examples will be selected to highlight the broad applications of monodentate phosphine ligands in transition metal-catalyzed asymmetric transformations, especially hydrogenation reactions.

9.2.1  Asymmetric Hydrogenations Catalytic asymmetric hydrogenation reactions establish one of the most concise and economical entries to derive enantioenriched compounds from prochiral substrates. Through appropriate selection of transition metals and chiral ligands, coupled with carefully optimized reaction conditions, the asymmetric reduction of unsaturated ­systems including

Me Me

nBuLi, TMEDA 1

(1) HCl

P NR1R2

2

Cl2P‒NR R

1

P R

(2) RMgBr or RLi

3, Phosphines

2, Aminophosphines nBuLi, TMEDA, Cl2P-R

R PAr2

MeO

R PPh2•BH3

P R PPh2

L1

L2

L3

TMS

L4 Ar

Ph P

OMe

O P O O

P(cC7H13)2 L5

O P O

Ph

Ar L6

L7

L8

Figure 9.1  Representative axially chiral monodentate phosphines and general synthetic routes.

9.2 ­Monodentate Phosphine

carbonyl compounds, olefins, and imines can be efficiently achieved with high stereoselectivities [16–20]. From numerous reports in past decades, the essential role of axially chiral monodentate phosphine ligands in enantioselective hydrogenation reactions has been attested, especially those catalyzed by palladium, rhodium, ruthenium, or iridium. Beller and coworkers explored axially chiral binepine-based monophosphine ligands for enantioselective hydrogenation of unsaturated dehydroamino acid esters 4 or 1,3-dicarbonyl compounds, which fruitfully yielded products 5 in moderate to excellent ee values (Scheme 9.1a) [21, 22]. This type of axially chiral ligands could be facilely synthesized in three to five steps from commercially available chiral BINOL on gram scale. Although bidentate phosphine ligands are known to possess robust asymmetric induction capability for hydrogenation reactions, the comparable product’s stereoselectivity to that offered by bisphosphine ligand in this case has evinced the complementary competency of the monodentate analogs. This protocol unveiled a new potential class of chiral scaffolds that could be generalized in transition metal catalyzed asymmetric transformations. In 2006, Gladiali showcased the robustness of Ph–binepine ligand (L3) to impart asymmetry in hydrogen transfer reduction of C═C bonds (Scheme 9.1b) [23]. This ligand intriguingly imparted slightly better enantioselectivity in the reduced products than the most optimal bidentate chelating diphosphines previously used. This implied that monodentate phosphines could exhibit superiority in reduction of specific substrates. Table 9.1  Thermodynamic and kinetic data for biaryl thermal racemization reaction.

NH2 NH2

OH OH

(R)-BINOL

(R)-BINAM

NH2 OH

(R)-NOBIN

Analyte

ΔG# (kJ · mol−1)

Temp (°C)

t1/2 (h)

BINOL

165.4 ± 0.3

190

180

210

29

230

5.4

250

1.15

210

740

230

85

250

23

270

4.9

200

295

220

48.5

240

9.2

260

2.0

BINAM

NOBIN

178.4 ± 0.4

171.0 ± 0.3

247

248

9  Application for Axially Chiral Ligands (a) Beller and coworkers [21, 22] CO2Me

R

[Rh(cod)2]BF4 (1 mol%) (S)-L3, (2 mol%)

* CO2Me

R

H2 (1 bar), 25 °C

NHAc

R = H, 94% ee R = Ph, 95% ee

NHAc

5

4

P Ph

(b) Gladiali and coworkers [23] CO2R2 CO2R1 6

L3

CO2R2

[Rh(nbd)(L3)2]BF4 (1.5 mol%)

*

HCO2H/NEt3, DMSO, 22 °C

R1 = R2 = H, 97% ee CO2R1 1 R = R2 = Me, 13% ee 7

Scheme 9.1  Enantioselective hydrogenation using axially chiral binepine-based phosphine ligands. Source: (a) Junge et al. [21, 22]. (b) Based on Alberico et al. [23].

9.2.2  Asymmetric Hydrosilylation of Olefins As petrochemical feedstock, asymmetric functionalization of olefins is an important task in organic synthesis. Among myriad functionalization techniques, catalytic asymmetric hydrosilylation reaction is one important chemical operation to build molecular diversity with stereogenic centers from simple olefins, constructing crucial chiral C─Si bonds and Si-containing compounds that possess extraordinary utilities in materials science [24, 25]. The C─Si bonds forged with defined stereochemistry can be derivatization handles to obtain chiral alcohols through Fleming–Tamao oxidation process with retention of chirality [26, 27]. In 1995, the Hayashi group applied this palladium-catalyzed hydrosilylation methodology to styrene 8 employing MeO–MOP ligands with varying substituents at C2′-position [28]. The degree and sense of enantioselectivity induced by these ­modified [1,1′-binaphthalen]-2-yldiphenylphosphane (MOP) ligands as exemplified in alcohol 10 were summarized in Scheme 9.2. These results indicated that the electronic property of substituents was not the determining factor of stereochemical bias because MOPs

Hayashi and coworkers [28] [Pd(η3-C3H5)Cl]2 (0.01 mol%) L1 (0.02 mol%)

Ph

HSiCl3 (1.2 equiv), –10~0 °C 8

R PPh2

L1

SiCl3 Ph

OH

[O]

*

9

Ph

*

10

R = OMe: (R)-L1, 14% ee (R) R = Et: (S)-L1, 18% ee (R) R = CN: (R)-L1, 26% ee (R) R = CO2Me: (R)-L1, 30% ee (S) R = OH: (R)-L1, 34% ee (S) R = H: (S)-L1, 93% ee (R)

Scheme 9.2  Pd-catalyzed asymmetric hydrosilylation of styrene. Source: Based on Kitayama et al. [28].

9.2 ­Monodentate Phosphine

substituted with methoxy, hydroxyl, ester, cyano, and ethyl invariably provided low enantioinduction in this catalytic process. In other words, their electron-withdrawing or electron-donating characteristics were irrelevant. However, (S)-H-MOP devoid of methoxy substituent was found to be particularly effective for this hydrosilylation process of styrene, which gave (R)-10 in 93% ee after oxidative transformation.

9.2.3  Asymmetric Allylic Substitutions Palladium-catalyzed asymmetric allylic substitution is a classic organic transformation that has storied history of more than 50 years. Since Tsuji et al. [29] and Trost and coworker [30] independently reported stoichiometric and catalytic variants of allylation reaction, application range of Tsuji–Trost reaction greatly expanded; various nucleophiles and ligands have been successfully introduced into this reaction regime with control of regio- and enantioselectivity. The general mechanism of palladium-catalyzed allylation reactions involve the ­following steps: (i) palladium catalyst coordinates with olefin substrate to form π-complex; (ii) oxidative addition takes place to produce η3-allyl palladium species; (iii) soft and stable nucleophiles adds to the allyl moiety anti to the metal center, whereas hard nucleophiles such as organometallic reagents (organozinc or Grignard reagents) undergo transmetalation to form C-bond preferentially. In 1994, Hayashi and coworkers reported palladium-catalyzed asymmetric reduction of allylic esters 11 with formic acid to prepare optically active olefins 12 (Scheme 9.3a) [31]. Based on previous studies of Pd/MOP catalytic process, they designed and synthesized biphenanthrylmonophosphine ligand L2 for this reduction protocol, which brought forth better enantioselectivity compared to the binaphthyl analog. The successful incorporation of deuterated formic acid (DCO2D) signified the realization of deuterium incorporation at stereocenter and demonstrated the compatibility of this reduction chemistry with deuterium atom. No deuterium scrambling was observed in the reduction products. In 1996, the same group accomplished the asymmetric reduction of racemic allylic esters 13 with formic acid in the presence of palladium catalyst (1 mol%) coordinated with L2 to give optically active terminal alkenes 14 with up to 93% ee (Scheme 9.3b) [32]. Better enantioselectivity was resulted from η3-allyl palladium species with a bulky group at the (a) Hayashi et al. [31] R

OCO2Me

Pd2(dba)3•CHCl3 (1 mol%) (R)-L2 (2 mol%) Proton sponge (1.4 equiv) HCO2H (2.3 equiv), dioxane, 20 °C up to >99%, 85% ee

Me 11

R Me H 12

MeO

(b) Hayashi et al. [32]

n 13

PPh2

Pd2(dba)3•CHCl3 (1 mol%) (R)-L2 (2 mol%)

X

Proton sponge (1.2 equiv) HCO2H (2.2 equiv), dioxane-THF, 20 °C n =1 or 2, X = OCO2Me or OCOtBu up to 93% ee

L2

H n 14

Scheme 9.3  Pd-catalyzed asymmetric reduction of allylic esters with formic acid. Source: (a) Based on Hayashi et al. [31]. (b) Based on Hayashi et al. [32].

249

250

9  Application for Axially Chiral Ligands

syn-position. On the other hand, the general challenge of catalytic asymmetric allyl alkylation lies in the control of regioselectivity in reaction process, which would determine the site of substitution in allyl substrates. Therefore, linear and branched products could be formed in different ratios.

9.2.4  Miscellaneous Catalytic Asymmetric Transformations In 1993, Hayashi’s group disclosed the use of a chiral monodentate phosphine ligand, (S)MeO-MOP (L1) in palladium-catalyzed asymmetric hydroboration of 1,3-enynes 15 to afford axially chiral allenylboranes 16 [33]. Despite moderate enantioselectivity, this reaction was the first example of catalytic asymmetric synthesis of axially chiral allenylboranes and has been adopted to study the mechanism of SE′ reaction with an aldehyde (Scheme 9.4). In 1998, Miyaura and coworkers described rhodium-catalyzed addition reaction of aryland 1-alkenylboronic acid 19 to aldehyde 18 in aqueous medium, wherein the axially chiral monodentate phosphine MOP ligand controlled the enantioinduction in chiral alcohol product 20 (Scheme  9.5a) [34]. Two years later, Hayashi reported highly asymmetric Hayashi and coworkers [33] R +

HB

Pd2(dba)3•CHCl3 (1 mol%) L1 (Ar = Ph, R = OMe, 2 mol%)

O

15 Me

Me

Ph

+ OH 17a

Ph

OH syn:anti = 3 : 1 17b

H

• Me

CHCl3 R = nC5H11, 40% ee R = H, 61% ee

O

R

B 16b (R = H)

PhCHO CHCl3, ‒78 °C

Scheme 9.4  Pd-catalyzed hydroboration of but-1-en-3-ynes. Source: Based on Matsumoto et al. [33].

(a) Miyaura and coworkers [34] CHO +

B(OH)2

18

Ar1

SO2Ar3

+

Ar2SnMe3

H 21

HO

22

Ph

DME/H2O, 60 °C, 36 h 78%, 41% ee

19

(b) Hayashi and Ishigedani [35]

N

[Rh(acac)(CH2=CH2)2] (3 mol%) (S)-MeO-MOP L1 (6 mol%)

20 [Rh(acac)(CH2=CH2)2] (3 mol%) (R)-MOP L1 (6 mol%) (Ar = Ph or 3,5-Me2-4-OMeC6H2) LiF (10 equiv), dioxane, 110 °C up to 90%, 96% ee

HN Ar1

SO2Ar3 Ar2

23

Scheme 9.5  Rh-catalyzed asymmetric 1,2-addition reactions. Source: (a) Based on Sakai et al. [34]. (b) Based on Hayashi and Ishigedani [35].

9.2 ­Monodentate Phosphine

arylation of imines 21 with organostannanes 22. The reactants were treated with 3 mol% of chiral rhodium catalyst (generated from Rh(acac)(CH2=CH2)2 and MOP) and lithium fluoride in dioxane at 110 °C for 12 h (Scheme 9.5b) [35]. In 2011, Iuliano’s group applied a novel axially chiral monodentate phosphine ligand L9 for palladium-catalyzed asymmetric Suzuki–Miyaura cross-coupling of bromonaphthalenes 24 and aryl boronic acids 25 to afford axially chiral biaryls 26 with moderate enantioselectivity (Scheme 9.6a) [36]. Almost concurrently, Iwasawa and coworkers performed palladium-catalyzed asymmetric Suzuki–Miyaura cross-coupling of aryl chlorides and arylboronic acids, where low catalyst loading (0.5 mol%) and shortened reaction time compared to previously described methods were achieved (Scheme 9.6b) [37]. (a) Iuliano and coworker [36]

R1 24

Br

+

2

R

K2CO3 (2.5 equiv), CH2Cl2, r.t. up to 96%, 55% ee R2 26

R3 B(OH)2

25

O Me P O Me O Me

R1 R3

Pd(dba)2/L9 (1 : 1) (1 mol%)

CO2Me L9

AcO

(b) Iwasawa and coworkers [37] R 1

R

Cl

OMe 27

+ B(OH)2

Pd2(dba)3 (0.5 mol%) L10 (1.2 mol%) KF/CsF, THF/toluene up to 94%, 78% ee

R R2 MeO

O R P Ar O

R1

R

L10 Ar, R = 4-MeC6H4

29

R2 28

R

Scheme 9.6  Pd-catalyzed asymmetric Suzuki–Miyaura cross-coupling. Source: (a) Based on Jumde and Iuliano [36]. (b) Based on Kamei et al. [37].

In 2004, Genêt’s group disclosed an atom-economical platinum-catalyzed asymmetric alkoxycyclization of 1,6-enynes 30. A combination of silver salt and chiral binepine ligand L3 allowed stereoselective assembly of functionalized five-membered carbo- and heterocycles 31 in good to excellent yields (Scheme 9.7) [38].

Genêt and coworkers [38] R1

X 30

R2

PtCl2 (5 mol%), L3 (15 mol%) AgSbF6 (25 mol%) Dioxane, R3OH, 60–80 °C X = C(CO2Me)2, NTs up to 100%, 85% ee

X

H R2 OR3 R1 31

P Ph L3

Scheme 9.7  Pt-catalyzed asymmetric cycloaddition. Source: Based on Charruault et al. [38].

251

252

9  Application for Axially Chiral Ligands

9.3 ­Diphosphine Ligands The iconic 2,2′-bis(di-phenylphosphino)-1,1′-binaphthyl (BINAP) developed by Ryoji and Noyori in 1980s belongs to one emblematic member of axially chiral diphosphine ligands broadly applied in transition metal-catalyzed asymmetric transformations [39]. Attributed to C2-symmetric chelation of transition metal and axially chiral information that arises from restricted rotation around the C─C single bond connecting two aryl rings, BINAP presents a parent framework to derive more congeners. It follows that BINAP-type ligands are the pioneering ligands that inspired development of other structurally novel and divergent axially chiral diphosphine ligands. These efforts have been of great success; they are found vital for numerous enantioselective transformations, which include but not limited to hydrogenation reaction, cyclization, and C─C and C─X bond formation. The representative axially chiral diphosphine ligands were shown in Figure  9.2. To fine-tune the scaffold of BINAP-type ligands, steric and electronic properties of the aryl groups tethered to phosphorus atom can be modulated. More extensive modification involves varying the aromatic substitution of two arenes flanking the chiral axis. Collectively, the electron cloud density at the coordination point between ligand and metal as well as the surrounding coordination environment could be effectively modified, which is significant to improve reactivity and enantioselectivity in the reaction process. Herein, we present a few remarkable enantioselective transformations mediated by axially chiral diphosphine ligands according to reaction types.

9.3.1  Hydrogenation Reactions Since BINAP was discovered by Noyori and coworkers in 1980 [40], an abundance of asymmetric catalytic reactions have been made viable with the use of this chiral diphosphine

PAr2 PAr2

BINAP Tol-BINAP Xyl-BINAP DTBM-BINAP

Ar = Ph Ar = 4-MeC6H4 Ar = 3,5-Me2C6H3 Ar = 4-MeO-3,5-Me2C6H2

PPh2

R

PPh2

PPh2

R

PPh2

L12, H8-BINAP

L11

L13, BIPHEMP

O

R

O

R

O

PPh2

R

O

PPh2

R

O

R=H SEGPHOS DIFLUORPHOS R = F R = Me SUNPHOS

L14

O n

O

PPh2

O

PPh2

O

PPh2

PPh2

O

PPh2

O

PPh2

L15, Cn-TUNAPHOS

O L16, SYNPHOS

L17, BICMAP OMe

OMe

Me N

S

N

O

PPh2

PPh2

MeO

PPh2

MeO

PPh2

MeO

PPh2

O

PPh2

PPh2

MeO

PPh2

MeO

PPh2

MeO

PPh2

N Me L18, SOLPHOS

N

S

OMe

OMe L19, BITIANP

L20, MeO-BIPHEMP

L21, GARPHOS

L22, P-PHOS

Figure 9.2  Representative examples of axially chiral diphosphine ligands.

9.3  ­Diphosphine Ligand

ligand, most notably in asymmetric synthesis of bulk chemicals on industrial scale. At present, according to data retrieved by Scifinder, more than 12 000 papers have described or reviewed the application of BINAP ligand itself, which underscores the central position of this ligand. The introduction of cationic BINAP‑rhodium complex into asymmetric hydrogenation was reported by Noyori and coworkers in the synthesis of unnatural amino acids 33. This formative work was accomplished with excellent efficiency and enantioselectivity (up to 99% yield and 100% ee) (Scheme 9.8) [40]. Noyori and coworkers [40] CO2H R1

NHCOR2 32

H2 (4 atm) (R)-BINAP-Rh (1 mol%) EtOH, 48 h, r.t. up to 99%, 100% ee

CO2H

R1

NHCOR2 33

ClO‒4 PPh2H +Rh OCH3 OCH3 PPh2H (R)-BINAP-Rh

Scheme 9.8  Rh/BINAP-catalyzed asymmetric hydrogenation of unnatural amino acids. Source: Modified from Miyashita et al. [40].

Subsequently, in 1987, the first highly enantioselective hydrogenation reaction of unsaturated carboxylic acids 34 was established by employing ruthenium(II) catalyst complexes bearing selected chiral phosphine ligands (Scheme 9.9) [41]. Since then, the substrate scope has evolved greatly [42]. The utility of ruthenium catalysts based on axially chiral diphosphine ligands BINAP has since stepped into the limelight and has been a subject of intensive research for the past decades. Noyori and coworkers [41] R2

CO2H

R1

R3 34

H2 (4~112 atm) (R)-BINAP-Ru(II) (0.2~1 mol%) MeOH, 12~72 h, 15~30 °C up to 95% ee

PPh2

R2 1

R

CO2H

* * R3 35

OAc Ru OAc PPh2 (R)-BINAP-Ru(II)

Scheme 9.9  Ru/BINAP-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids. Source: Based on Ohta et al. [41].

In contrary to the hydrogenation reaction of N-acyl enamines, successful applications of catalytic enantioselective hydrogenation to unfunctionalized enamines are rarer. Indeed, from enantioselectivity-centric viewpoint, N,N-dialkyl enamines present the most challenging substrates in this reaction type. In 1994, Buchwald and coworkers disclosed the asymmetric hydrogenation of 1,1-disubstituted enamines using chiral ansa–titanocene complex as the catalyst [43]. Over the past two decades, rhodium and iridium complex containing chiral phosphorus ligands have been implemented to enable asymmetric hydrogenation of N,Ndialkyl enamines and enamines without protecting groups. In 2009, Zhou and coworkers applied [Ir(COD)Cl]2/MeO-BIPHEP/I2 catalytic system for the hydrogenation of unprotected exocyclic enamines 36 with high efficiency and enantiocontrol (Scheme 9.10) [44].

253

254

9  Application for Axially Chiral Ligands Zhou and coworkers [44] R1

1 H2 (600 Psi), [Ir(COD)Cl]2 (1 mol%) R (S)-L13, BIPHEP (R = OMe, 2.2 mol%)

N H 36

R2

O

N H

C6H6, I2 (10 mol%), r.t., 16 h up to 99%, 96% ee

37

R2

O

Scheme 9.10  Ir/BIPHEP-catalyzed asymmetric hydrogenation of exocyclic enamines. Source: Based on Wang et al. [44].

Beyond activated olefins, ketones, imines, and heteroaromatic compounds are also amenable substrates for asymmetric hydrogenation catalyzed by BINAP–transition metal complexes. For instance, in 2005, Noyori and coworkers attained highly asymmetric hydrogenation of tert-alkyl ketones 38 using BINAP/PICA–Ru complex (Scheme 9.11) [45]. This method successfully facilitated asymmetric hydrogenation of aromatic, aliphatic, heteroaromatic, olefinic ketones, and specific cyclic ketones. Noyori and coworkers [45] H2 (5‒20 atm) BINAP-Ru (< 0.05 mol%)

O R

tBuOK, EtOH, 25~27 °C up to 100%, 98% ee

38

Ar2 P X N Ru P X N H2 Ar2

OH * 39

R

Ar = p-MeC6H4, X = Cl

Scheme 9.11  Ru/BINAP-catalyzed asymmetric hydrogenation of ketones. Source: Based on Ohkuma et al. [45].

In 2006, asymmetric hydrogenation of quinolines 40 and isoquinolines 41 activated by chloroformates was disclosed by Zhou’s group using chiral (S)-SEGPHOS/Ir system (Scheme  9.12) [46]. This methodology provided a new avenue toward enantioselective Zhou and coworkers [46] R1

R1 up to 87%, 83% ee

N

R1 40

H2, [IrCl(cod)]2/SEGPHOS ClCO2R, Li2CO3, THF

R3 42

N

N

R1

R2

R4

CO2R

41

R2

43

N R4 CO2R

R3

up to 91%, 90% ee

Scheme 9.12  Ir/SEGPHOS-catalyzed asymmetric hydrogenation of quinolines and isoquinolines. Source: Modified from Lu et al. [46].

9.3  ­Diphosphine Ligand

hydrogenation of heteroaromatic compounds with high efficiency and its successful application in the synthesis of several biologically active compounds including alkaloids further validated the reaction generality.

9.3.2  C─C Bond Formation The asymmetric cross-coupling reaction catalyzed by transition metals is one most indispensable chemical tool to construct stereodefined carbon–carbon bonds. In 1992, Shibasaki’s group reported on a highly enantioselective Pd/BINAP-catalyzed asymmetric Heck reaction, which served well to prepare functionalized decalin derivatives 45 (Scheme  9.13a) [47]. On the other hand, Lu and coworkers established palladium-catalyzed asymmetric tandem reaction of ortho‑boronate-substituted cinnamic ketones and internal alkynes, thus streamlined the synthesis of optically active and multiply substituted indene derivatives (Scheme 9.13b) [48]. (a) Shibasaki and coworkers [47] OPiv

Pd(OAc)2 (5 mol%) (R)-BINAP (10 mol%)

TfO OPiv

K2CO3 (2 equiv), toluene, 60 °C 60%, 91% ee

H 45

44 (b) Lu and coworkers [48] R2

COR5

R1

Bpin

46

+ R4 47

R3

Pd(OTf)2•2H2O (4 mol%) (S)-SUNPHOS (Ar = 4-MeC6H4, 4.4 mol%) THF/H2O (10/1), reflux, 20 h up to 99%, 93% ee

R3

R1

R4

*

R2

R5OC

48

Scheme 9.13  Pd-catalyzed asymmetric cyclization and cycloaddition. Source: (a) Based on Sato et al. [47]. (b) Based on Zhou et al. [48].

In 2003, the Ito group realized high-yielding asymmetric allylation of 1,3-diketones 49 using palladium/BINAP complex (Scheme 9.14) [49], which charted a convenient pathway to achieve highly enantioenriched 2,2-dialkyl-1,3-diketones 51 (64–89% ee).

Ito and coworkers [49] O

O R3 + R

R1 R2

49

OAc 50

[Pd(η3-C3H5)Cl]2, (R)-BINAP tBuOK, toluene, ‒60 °C, 24 h up to 99%, 89% ee

O

R3

O

R R2 R1 51

Scheme 9.14  Pd/BINAP-catalyzed asymmetric allylation of 1,3-diketones. Source: Based on Kuwano et al. [49].

255

256

9  Application for Axially Chiral Ligands

More recently, Yin and coworkers disclosed a copper-catalyzed enantioselective decarboxylative Mannich reaction using (6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl) bis(diphenylphosphane) (BIPHEP) ligand (Scheme  9.15) [50]. Mechanistically, basic 2H-azirines are activated by a cyanoacetic acid through protonation to form more electrophilic iminium, and after formation of copper(I) cyanoacetate and extrusion of CO2, resultant nucleophilic copper(I) ketenimide 57 is poised for asymmetric electrophilic addition to afford chiral aziridines 54 in excellent yields and enantioselectivities. Yin and coworkers [50] Ar

Me

NC

CO2H

+

53

Ar

R

Ar

Me

NC

CO2[Cu]

+

NC Me

THF, –60 °C, 36 h up to 99%, 98% ee

N

52

55

CuOAc (3 mol%) (R)-DIPA-MeO-BIPHEP (3 mol%)

R

Me

56

NH

Ar 54

MeO MeO

R •

+

NH

R

N

[Cu]

+

57

PAr2 PAr2

BIPHEP ligand

+

NH

56

Scheme 9.15  Cu/BIPHEP-catalyzed asymmetric decarboxylative Mannich reaction. Source: Based on Zhang et al. [50].

Also, integration of chiral BINAP-type 5,5′-bis(diphenylphosphaneyl)-4,4′-bibenzo[d] [1,3]dioxole (SEGPHOS) ligands and transition metals into enantioselective transfer hydrogenation of aromatic, α,β-unsaturated as well as aliphatic aldehydes was exemplified by Krische and coworkers. In 2009, asymmetric C─C bond-forming transfer hydrogenation of disubstituted allene 60 was documented for the first time, affording an effective methodology to obtain chiral homoallyl alcohols 61 through carbonyl reverse prenylation (Scheme 9.16) [51]. In 2016, they elaborated on this protocol to forge secondary homopropargyl alcohols using chiral Ru/BINAP complex [52]. The Pauson–Khand reaction is commonly used to assemble substituted cyclopentenones through formal [2 + 2 + 1]-cycloaddition of an alkene, alkyne, and CO. The synthetic importance of this annulation method led to development of nonracemic variants [53]. In

Krische and coworkers [52] R

O

iPrOH (2 equiv), up to 96%, 93% ee

58

Me •

Me (S)-Ir-SEGPHOS (5 mol%) PhMe, 30~60 °C R

OH

60

OH EtCHO (5 mol%), up to 94%, 91% ee 59

Me

R Me 61

Ph2P Ir O

PPh2

O NO2 (S)-Ir-SEGPHOS

Scheme 9.16  Ir/SEGPHOS-catalyzed asymmetric transfer hydrogenation. Source: Based on Han et al. [51].

9.3  ­Diphosphine Ligand

Jeong and coworkers [54]

[Rh(CO)2Cl]2 (5 mol%) (S)-DTBM-MeO-BIPHEP (10 mol%) AgOTf (15 mol%), THF Ar : CO = 10 : 1 (1 atm)

R X

R

62 X = O, NTs, C(CO2Et)2

H 63

Ar = MeO MeO

tBu

PAr2 PAr2

O

X

up to 99%, 99% ee

OMe tBu (S)-DTBM-MeO-BIPHEP

Scheme 9.17  Rh/BIPHEP -catalyzed asymmetric Pauson–Khand-type reaction. Source: Based on Kim et al. [54].

2010, Jeong’s group described a rhodium(I)-catalyzed asymmetric intramolecular Pauson– Khand-type reaction using a chiral biphosphine ligand (Scheme 9.17) [54]. Under reduced pressure of CO, a broad range of substrates 62 undertook this chemistry with excellent yields and stereoselectivities.

9.3.3  C─X Bond Formation Hydroamination reaction refers to the addition of a N─H bond across an unsaturated bond, which is an effective synthetic route to construct enantiopure N-containing molecules especially chiral amines. However, simultaneous control of regio- and stereoselectivity in this catalytic manifold could be tedious. In 2003, dicationic BINAP/Pd(II) complex was introduced for hydroamination of alkenoyl-N-oxazolidinones 64 by Hii and coworker wherein various primary and secondary aromatic amines as well as alkenoyl oxazolidinones participated in this reaction with moderate to good enantioselectivity (Scheme 9.18) [55]. Hii and coworker [55] O R1

O N

64

O

ArNHR2 (R)-BINAP/Pd(II) (10 mol%) toluene, r.t., 18 h up to 96%, 93% ee

2+ Ar R

N 1

R2

O

O

*

N

O

PPh2 OH2 Pd PPh NCMe 2

65

Scheme 9.18  Pd/BINAP-catalyzed enantioselective hydroamination reaction. Source: Based on Li and Hii [55].

On the other hand, construction of stereogenic silicon centers has been a long-sought synthetic goal but stays underdeveloped compared to stereogenic carbon centers. A significant challenge in controlling the chirality of silicon resides in its tendency to form pentacovalent intermediates. In 2013, a rare example of the formation of a quaternary silicon center was reported by the Takai group who applied Rh/BINAP complex to achieve asymmetric synthesis of spirosilabifluorene derivatives 67 (Scheme 9.19) [56].

257

258

9  Application for Axially Chiral Ligands Takai and coworkers [56] Ar1 SiH2 Ar2

[RhCl(cod)2] (0.5 mol%) (R)-BINAP (1.2 mol%) 1,4-Dioxane, 135 °C, 3 h up to 95%, 81% ee

66

Ar1 Si Ar2 67

Scheme 9.19  Rh/BINAP-catalyzed asymmetric C─Si bond formation. Source: Based on Kuninobu et al. [56].

For stereogenic C─B bond formation, direct catalytic hydroboration of alkenes has been promoted widely by Rh or Cu catalysts. In the process, a base is required to activate the formation of nucleophilic metal–Bpin intermediate from HBpin or (Bpin)2. In this regard, Gevorgyan and coworkers conceived the use of rhodium–(R)-BINAP complex to realize hydroboration of cyclopropenes 75 with pinacol borane, permitting practical procurement of cyclopropylboronates 76 that contained quaternary stereocenter with high yields and enantioselectivities (Scheme  9.20) [57]. Ito and coworkers alternately applied copper–(R)-SEGPHOS complex to achieve asymmetric hydroboration of allylic carbonates with diboron reagent, providing cyclopropylboronates in high yields, diastereo- and enantioselectivities [58]. Gevorgyan and coworkers [57] [Rh(COD)Cl]2 (3 mol%) (R)-BINAP (6 mol%)

R1 CO2R2 68

HBpin (1.0 equiv), THF, r.t., 20 min up to 99%, 97% ee, cis:trans >99 : 1

R1 R2O2C

Bpin

cis-69

Scheme 9.20  Rh/BINAP-catalyzed asymmetric C─B bond formation. Source: Based on Rubina et al. [57].

In 2003, Yamamoto’s group developed a sliver-catalyzed O-selective addition of tin enolates 70 to nitrosobenzene 71 that took place with excellent efficiency and enantioselectivity. The obtained products 72 could be successfully transformed into highly stereoenriched α-hydroxy ketones (Scheme 9.21) [59]. Yamamoto and coworker [59] OSnR3 R3 + R1 R2 70

Ph

N 71

O

[Ag]/L* (10 mol%),THF, –78 °C L* = (R)-BINAP or TolBINAP [Ag] = AgClO4 or AgOTf up to 97%, 97% ee

O R1

* R2

O R3

N H

Ph

72

Scheme 9.21  Ag/BINAP-catalyzed asymmetric C─O bond formation. Source: Based on Momiyama and Yamamoto [59].

9.4  ­Phosphoramidite and Phosphamide Ligand

9.4 ­Phosphoramidite and Phosphamide Ligands Transition metal-catalyzed enantioselective synthesis largely forms the basis of contemporaneous stereoselective transformations and has great influence on modern organic synthetic chemistry, material science, and pharmaceutical science. Because of convenient preparation methods and easily modifiable structures, chiral phosphoramides, combined with numerous transition metals, could exhibit high catalytic reactivity and excellent stereoselectivity, rendering them one of the most widely used chiral ligands [60, 61]. Incorporation of atropochiral phosphoramidite ligands in a vast array of enantioselective reactions ensued thereupon, with more congeners displaying varied substitutions being designed. In this section, we will discuss the application of the privileged phosphoramidite ligands in several classes of asymmetric reactions, including addition reactions, hydrogenation reactions, hydroboration/hydrosilylation reactions, arylation, and allylic substitution reactions. Representative constructions of axially chiral phosphoramidite and phosphamide ligands are listed in Figure 9.3.

9.4.1  Asymmetric Conjugate Addition with Organometallic Nucleophiles In 1996, the seminal application of chiral phosphoramide ligands in copper-catalyzed stereoselective conjugate addition of dialkylzinc reagents to unsaturated ketones (73 and 75) as Michael acceptors emerged [62, 63]. With low loadings of metal and ligand, excellent yields and enantioselectivities were obtained of chalcone 74 and cyclohexenone 76 (Scheme 9.22). Ligand screening results upon these two model substrates suggested that incorporation of chiral amine moiety into axially chiral phosphoramidite ligands could positively impact the stereoselectivity of this addition process. This breakthrough brought out the untapped potential of phosphoramidite ligands. They were subsequently found to exert exquisite stereocontrol in wide-ranging reaction classes, which have been reviewed elsewhere in great details [64, 65]. R1

R1

R4

R1

O R2 P N R3 O

O R2 P N R3 O

R5 R5

O R2 P N R3 O

R1

R4

R1 L23

L24 R1

R1

R2

O P O

O P N O Ph2P R1 R1

= H,

R2

= tBu, L26, Quinaphos

R1 L25 Me

Ph2P

NH

Fe

R1 R1

= H, L27, PPFAPhos

Figure 9.3  Representative examples of axially chiral phosphoramidite ligands.

259

260

9  Application for Axially Chiral Ligands

Feringa and coworkers [62,63] O Ph 73

Et

Cat. Cu(OTf)2, L23-1 Ph Et2Zn (1.1 equiv), toluene, –50 °C Ph 84%, 90% ee

O Ph 74

O P N O L23-1

O 75

Cat. Cu(OTf)2, L23-2

O

Et2Zn (1.5 equiv), toluene, –30 °C Et 94%, 98% ee

76

Ph O P N O Ph L23-2

Scheme 9.22  Cu-catalyzed conjugate addition of dialkylzinc reagent to unsaturated ketones. Source: de Vries et al. [62] and Feringa et al. [63].

With oxygen functionality in place, achieving transition metal-catalyzed ring-opening reaction of epoxy compounds with regio- and enantioselectivity would lead to meaningful chiral alcohol compounds. In 2000, Feringa and coworkers assessed this reaction platform to devise kinetic resolution and desymmetrization of methylidene cycloalkene oxides (­77 and 79) using Cu(OTf)2/phosphoramidite as a highly effective catalyst system (Scheme 9.23) [66]. This was a novel catalytic methodology toward chiral allylic alcohols via selective nucleophilic displacement of vinyloxiranes. Two years later, the same group applied this catalytic system to promote enantioselective ring-opening reaction of oxabicyclic alkene derivatives with dialkylzinc reagents with high efficiencies [67]. Feringa and coworkers [66] O

Kinetic resolution, 88% ee

Et OH

77

78

ZnEt2, Cu(OTf)2 (1.5 mol%) L23-3 (3 mol%) Et O

OH

Desymmetrization, 90%, 97% ee 79

Ph O P N O Ph L23-3

80

Scheme 9.23  Cu-catalyzed kinetic resolution and desymmetrization with organozinc reagent. Source: Based on Bertozzi et al. [66].

9.4.2  Hydrogenation Axially chiral phosphoramidites contributes as another potent class of ligands on union with transition metals to facilitate asymmetric hydrogenation [68, 69]. In 2009, de Vries and coworkers conceived chiral iridium complex based on BINOL-derived phosphoramidite to catalyze asymmetric hydrogenation of N-aryl imines (Scheme 9.24) [70]. Imines 81

9.4  ­Phosphoramidite and Phosphamide Ligand de Vries and coworkers [70] N R1

Ar

[Ir(cod)2]BArF (1 mol%) (S)-L23-4 (2 mol%)

R2

H2, CH2Cl2, r.t.

81

up to 99%, 99% ee

HN R1

Ar

O P N O

R2

L23-4

82

Scheme 9.24  Ir-catalyzed asymmetric hydrogenation of N-aryl imines. Source: Based on Mršić et al. [70].

carrying assorted aromatic amines were reduced with high conversion rates, yields, and enantioselectivities. With suitable aromatic substituent present on the obtained secondary amines 82, oxidative deprotection could be implemented to generate enantioenriched primary amines, revealing the good application prospects of this strategy. An array of amino acids, diacids and esters, hydrocinnamic acids, amines, and various heterocyclic compounds could be obtained in optically active forms from hydrogenation reaction catalyzed by metal/phosphoramidite complex.

9.4.3  Hydroboration/Hydrosilylation Reactions Complexes of chiral phosphoramidites and transition metals possess attested efficacy in catalyzing hydroboration and hydrosilylation reactions, which become one of the most direct and effective ways to construct chiral carbon–boron or carbon–silicon bonds. In 2008, Takacs’s group described a rhodium-catalyzed asymmetric hydroboration of α,βunsaturated amides 83 using BINOL-derived phosphoramidite as the chiral ligand (Scheme 9.25) [71]. This reaction constituted an effective tool to attain alkene hydroboration in high level of regio- and enantioselectivity with amide as the directing moiety, where isopropyl-, isobutyl-, and phenethyl-substituted amides were well suited. Highly enantioenriched hydroboration products 84 could be facilely converted into chiral alcohols 85 following an oxidative process using hydrogen peroxide in alkaline condition. Meanwhile, palladium-catalyzed hydrosilylation of styrene was demonstrated by Seebach’s group in 1993 using TADDOL–phosphoramidite [72], although the oxidative Takacs and coworkers [71] O Ph

N H

R 83

Rh(nbd)2BF4 (0.5 mol%) L23-5 (1.1 mol%) HBpin (2 equiv), THF, 40 °C

Ph O P N O L23-5

Bpin

O Ph

R

N H

84 O

H2O2 NaOH (aq.) OH

Ph

R N H 85 up to 80%, 99% ee

Scheme 9.25  Rh-catalyzed asymmetric hydroboration reaction. Source: Based on Smith et al. [71].

261

262

9  Application for Axially Chiral Ligands

(a) Johannsen coworkers [73]

R

Ar

[Pd(η3-C3H5)Cl]2 (0.5 mol%) L23-2 (2 mol%)

SiCl3

[O]

OH

R

HSiCl3 (1.2 equiv), r.t., 40 h

R

Ar * Ar * 87 up to 95%, 99% ee 88

86 (b) Han and coworkers [74] [Pd(η3-C3H5)Cl]2 (1 mol%) L23-6 (2 mol%)

SiCl3

OH PhCHO, DMF

Ph

HSiCl3 (1.2 equiv), –10 °C 89

90

97%, 87% ee

Ph O P N O Ph L23-2

Ph O P N O Ph

91

Ph Ph

L23-6

Scheme 9.26  Pd-catalyzed asymmetric hydrosilylation of alkenes. Source: (a) Based on Jensen et al. [73]. (b) Based on Park et al. [74].

product-alcohol was obtained in only 34% ee. Nearly a decade later, Johannsen et  al. improved on this methodology using BINOL-based phosphoramidite and secured excellent enantioselectivity (up to 99% ee) and high yield (Scheme  9.26a) [73]. Direct enantioselective hydrosilylation of nonactivated styrene analogs 86 proceeded smoothly in moderate conditions and C─Si bond could be easily replaced with C─O bond through Fleming–Tamao oxidative process with enantioretention. In 2013, Han and coworkers leveraged this chemistry to fulfill palladium-catalyzed desymmetrization of cyclohexa-1,3-diene 89 with 87% ee using chiral BINOL-based phosphoramidite ligand (Scheme 9.26b) [74].

9.4.4  Allylic Substitutions With the assistance of metal-π-allylic species, allylic substitution reactions could take place with regio- and enantioselectivity. In this context, various transition metals have demonstrated promising reactivity and selectivity attributes. Among them, Ir, Rh, and Ru Hartwig and coworker [75]

R1

R2 OCO2Me + HN R3 92

[Ir(cod)Cl]2 (1 mol%) ent-L23-3 (2 mol%) THF, r.t. up to 95, 97% ee

R

NR2R3 1 * 93

Ph O P N O Ph ent-L23-3

Scheme 9.27  Ir-catalyzed asymmetric allylic substitution reaction. Source: Based on Ohmura and Hartwig [75].

9.4  ­Phosphoramidite and Phosphamide Ligand

catalysts usually impose more intense steric crowding, thus hinders the nucleophiles to approach from allylic position during substitution step. Conversely, allylic substitution reactions catalyzed by palladium catalysts tend to occur on the terminal position where the leaving group resides. Therefore, the selective formation of SN2- or SN2′-substituted products is a crucial consideration in the design of this chemistry. In 2002, Hartwig and coworker disclosed that iridium/phosphoramidite complex could promote allylic amination of achiral allylic esters 92 with high regio- and enantioselectivity (Scheme 9.27) [75]. Both aromatic and aliphatic amines including heterocycle-substituted amines reacted with excellent compatibilities with this catalytic system to form branched allylic amination products 93. In 2007 and 2012, Carreira and coworkers reported racemic [76] and asymmetric (Scheme 9.28a) [77] amination of chain allylic alcohols, respectively, with iridium/phosphoramidite catalyst complexes. Aminosulfonic acid served as the nucleophilic amine source and single isomers of allyl-substituted amination products 95 were obtained. In the introduction of chiral phosphoramidite ligand, highly stereodefined products were rendered in good yields. In 2014, Beller and coworkers utilized this strategy to cyclohex-2en-1-ol ­analogs 96 [78]. With the cooperative catalysis of palladium/phosphoramidite complex and chiral phosphoric acid, near-quantitative yields and excellent enantioselectivities were achieved in this methodology (Scheme 9.28b). (a) Carreira coworkers [77] 1) [Ir(coe)2Cl]2 (2.5 mol%) L23-7 (5-10 mol%), H3NSO3 (1.2 equiv) DMF/2-Me-THF, r.t., 24 h

OH

2) Et3N (4 equiv), BzCl (2 equiv), r.t., 4 h

R

R

up to 87%, 99% ee (R = aryl, alkyl)

94

O P N O

NHBz

95

L23-7

(b) Beller and coworkers [78] OH

Pd(dba)2 (5 mol%), L23-8 (10 mol%) (S)-BINOL-CPA (5 mol%) 1

OMe 1

*

2

NR R

O P N O

2

R R NH, THF, 25 °C, 48‒72 h 96

up to 96%, 92% ee

97 L23-8

Me Me OMe

Scheme 9.28  Metal-catalyzed asymmetric amination of racemic allyl alcohols. Source: (a) Based on Lafrance et al. [77] and (b) Based on Banerjee et al. [78].

9.4.5  Other Asymmetric Transformations In 2006, Kündig and coworkers presented the asymmetric hydrogenolysis of [Cr(CO)3(5,8-dibromonaphthalene)] 98 with lithium borohydride promoted by palladium/phosphoramidite system (Scheme  9.29a) [79]. Later in 2011, they stretched the scope of this strategy through palladium-catalyzed Suzuki cross-coupling with boronic acids (Scheme 9.29b) [80]. This enantioselective cross-coupling protocol was general to accommodate aryl-, vinyl-, and even alkylboronic acids to afford products 100 with moderate yields and excellent ee values.

263

264

9  Application for Axially Chiral Ligands Kündig and coworkers [79, 80] (a)

LiBH4 (2 equiv) Pd(dba)2 (5 mol%) L23-9 (20 mol%)

Br H Cr(CO)3 99

DME, –10 °C 78%, 97% ee

RB(OH)2 (5 equiv) Pd(dba)2 (5 mol%) L23-9 (6 mol%)

Br

Br KF, toluene, 10 °C up to 72%, 98% ee Cr(CO)3 98

Br

(b)

R Cr(CO)3 100

Ph

Ph O P N O Ph

Ph O P N O Ph Ph L23-9

Scheme 9.29  Pd-catalyzed asymmetric desymmetrization reactions. Source: Kündig et al. [79] and Urbaneja et al. [80].

In 2006, Minnaard and coworkers reported enantioselective arylation of protected aldimines under the catalysis of chiral rhodium/phosphoramidite complex (Scheme 9.30) [81]. N,N-dimethylsulfamoyl was used as an inexpensive protecting/activating group on substrates 101. The aryl addition products 102 were formed in high yields and enantioselectivities and this trend persisted throughout phenylboronic acids with different substituents as well as heterocyclic boronic acids (such as furanyl derivative). The protected sulfamides could be hydrolyzed in a brief microwave-assisted reaction with retention of configuration. Minnaard and coworkers [81] N Ar1

SO2NMe2 H 101

Rh(acac)(eth)2 (3 mol%) L23-10 (7.5 mol%) Ar2B(OH)2 (1.3 equiv) Acetone, 40 °C, 4 h up to 98%, 95% ee

HN Ar1

SO2NMe2 Ar2 102

O P NHR O L23-10 (R = 4-MeOC6H4)

Scheme 9.30  Rh-catalyzed asymmetric arylation of aldimines. Source: Based on Jagt et al. [81].

9.5 ­ N–P Ligands In 1980s, Hayashi and Kumada reported the application of ferrocene-based N–P ligands in diverse fields of asymmetric transformations, with particular focus on C─C and C─X bond formation. This new skeleton provided inspiration toward the design of new N,P ligand analog of axially chiral BINAP, 1-(2-(diphenylphosphaneyl)naphthalen-1-yl)isoquinoline (QUINAP). Thereupon, a variety of QUINAP analogs emerged for the application in enantioselective organic synthesis. Illustrative atropochiral N,P ligands were represented in Figure 9.4. In this section, several examples that could manifest the distinctive features of asymmetric reactions catalyzed by complexes of transition metals/N,P ligands will be included, such as hydroboration reactions, cycloaddition reactions, and conjugate addition reactions.

9.5  N–P Ligands R1

N

N

N

N

N

PPh2

PPh2

PPh2 PPh2

L28, (R)-QUINAP

L29, (R)-Quinazolinap

L30 N

NMe2

NMe2

PPh2

PPh2

NMe L31 Ph

O

N

N

N

PPh2

Ph N

R

PPh2 F5

L32

L33

L34, Quinazox

L35, StackPhos

Figure 9.4  Representative examples of axially chiral N,P ligands.

9.5.1  Applications of N, P-Ligands QUINAP and its analogs have manifested utility in many significant asymmetric syntheses, owing to the preeminent scaffold of axially chiral N,P-ligands as well as the high catalytic activity on combination with transition metals to incur precise stereochemical control in the reaction process [10, 82]. From 2002 to 2006, Knochel and coworkers [83–85] documented a suite of protocols to access propargylamines 105 in an enantiocontrolled manner through copper/QUINAP complex-catalyzed asymmetric 1,2-addition of alkynes 103. Moderate to good enantioselectivities were observed when enamines 104 were selected as the reactants (Scheme 9.31a). Later, a three-component reaction featuring high flexibility was developed through in situ generation of the imine intermediates under the same catalytic system (Scheme 9.31b). In the mechanistic investigation, a strong positive nonlinear effect was present: with optical purity of only 5% ee, the QUINAP ligand could induce enantioenrichment of propargylamines 105 in up to 50% ee. Copper/StackPhos catalytic system was later applied in a highly enantioselective alkynylation of quinoline by Aponick and coworkers (Scheme 9.32) [86]. StackPhos as a newly

(a) Knochel and coworkers [83] R1

+

103

R4

R3 N 104

R2

(b) Knochel and coworkers [85] R1 + R2 103

O +

HNR3R4

CuBr (5 mol%) (R)-QUINAP (5.5 mol%) toluene, r.t. up to 99%, 90% ee

R1 R4 R2

CuBr (5 mol%) (R)-QUINAP (5.5 mol%) toluene, r.t. up to 99%, 96% ee

N

R3 105

NR3R4 R2 R1

105

Scheme 9.31  Cu/QUINAP-catalyzed asymmetric addition of alkynes to enamines and imines. Source: (a) Based on Koradin et al. [83]. (b) Based on Gommermann et al. [85].

265

266

9  Application for Axially Chiral Ligands Aponick and coworkers [86] +

N

R

106

O OMe

N CO2Et 107

ClCO2Et, DIPEA (1.4 equiv) CH2Cl2, ‒20 °C up to 86%, 98% ee

103 O

CuBr (5.5 mol%) L35, (S)-StackPhos (5.5 mol%)

(+)-Galipinine (69%)

R

(1) H2, Pd/C, EtOH/EtOAc R

N Me

(+)-Cuspareine (71%)

OMe

(2) LAH (10 equiv), THF, 55 °C

(‒)-Angustureine (74%)

Scheme 9.32  Cu-catalyzed asymmetric alkynylation of quinolines. Source: Based on Pappoppula et al. [86].

developed imidazole-based chiral biaryl N,P ligand, cooperated with CuBr to catalyze a three-component reaction between quinoline 106, ethyl chloroformate, and a terminal alkyne 103. Broad range of substrates from alkyne and quinoline components undertook the chemistry with excellent yields and enantioselectivities. Additionally, this protocol granted an effective entry to tetrahydroquinoline alkaloids such as (+)-galipinine, (−)-angustureine, and (+)-cuspareine. Utilization of StackPhos ligand in various transition metal-catalyzed stereocontrolled transformations has gained much popularity after this work [87–91]. In 2004, Carreira and coworkers designed an unprecedented class of N,P-ligands and showcased their synthetic values in three disparate asymmetric reactions: Rh-catalyzed Carreira and coworkers [92]

R

X

OH

(2) H2O2, NaOH, H2O up to 94%, 92% ee

108

Me

PINAP

(1) [Rh(L36-1)(cod)]BF4 (1 mol%) Catecholborane

Ph N N

R 109

PPh2 N

R

AgOAc (3 mol%) Hünig base, THF, –40 °C

110

R1 103

O +

tBuO2C

CO2tBu 111 L36-1 (3 mol%)

CO2Et

R

H

+

HNBn2

N H H R

112

CO2Et

L36-1, X = O L36-2, X = NH

R = CN, 94%, 95% ee R = OMe, 88%, 92% ee

CuBr (5 mol%), L36-2 (5.5 mol%) toluene, r.t. 1

R = iPr, R = SiMe3, 84%, 98% ee R = iPr, R1 = Ph, 88%, 90% ee

NBn2 R * 105

R1

R = iBu, R1 = nBu, 74%, 91% ee

Scheme 9.33  Metal/PINAP-catalyzed asymmetric transformations. Source: Based on Knöpfel et al. [92].

9.6  C2-Symmetric Diols

hydroboration of alkenes, Ag-catalyzed [3 + 2] cycloaddition reaction, and Cu-catalyzed addition of alkynes to imines (Scheme 9.33) [92]. 1-(2-(diphenylphosphaneyl)naphthalen1-yl)-4-((R)-1-phenylethoxy)phthalazine (PINAP) analogs, on coordination with transition metals, often engender exquisite reactivity and stereoselectivity. This provided strong incentive to expand the application range of axially chiral PINAP ligands in different reaction regimes. In 2006, the development of QUINAP ligands inspired the invention of tridentate N,N,Pligands containing two stereogenic elements through conjoining an axially chiral Quinazolinap skeleton and centrally chiral 2-oxazoline subunit (Scheme 9.34) [93]. This report of Guiry and coworkers presented a five-step synthetic route of axially chiral Quinazox and its aptitude to mediate asymmetric allylic alkylation with excellent yield and good enantioselectivity. To embrace a broader reaction scope in asymmetric catalysis, efforts to improve selectivity via modification of electronic and steric environment of Quinazox could be undertaken [94].

Guiry and coworkers [93] OAc Ph

Ph rac-113

+

CO2Me

[(η3-C3H5)PdCl]2 (2.5 mol%) L34, Quinazox (R = iPr, 6 mol%)

CO2Me

LiOAc (1 equiv), CH2Cl2, r.t., 24 h

114

>95%, 81% ee

MeO2C Ph

CO2Me Ph

115

Scheme 9.34  Cu/Quinazox-catalyzed asymmetric allylic alkylation. Source: Based on Fekner et al. [93].

9.6 ­ C2-Symmetric Diols Although BINOL was first synthesized in 1920s, it was not until 1979 that Noyori recognized its potential utility as a chiral ligand in metal-mediated catalysis and documented an insightful work concerning reduction of aromatic ketones and aldehydes [95]. Accordingly, studies on diverse applications of C2-symmetric BINOL analogs emerged. However, satisfactory results were often not afforded by BINOL itself; rather, modulation of both steric and electronic properties of BINOL skeleton was required. To meet this demand, a wide range of coupling reactions have been contrived to prepare enantiomerically pure or racemic BINOL and analogs. Representative examples are shown in Figure 9.5, and these dioltype ligands have promoted multiple asymmetric syntheses including ene reactions, allylation reactions, alkynylation reactions, Diels–Alder reactions, cycloaddition, etc.

9.6.1  Mukaiyama Aldol Condensation Reactions Although Lewis acid catalyzed aldol-type reactions between nucleophilic alkenes with carbonyl compounds have been described over the past century, the introduction of silyloxyalkenes by Mukaiyama in 1973 marked an important breakthrough [96, 97]. Tetravalent titanium, salts such as TiCl4 or Ti(OiPr)4, serves as highly active Lewis acids and upon forming a chiral species with a chiral ligand, which can efficiently activate silyl enol ether

267

268

9  Application for Axially Chiral Ligands

R

R

OH

OH

OH

OH

R

L38, (R)-H8-BINOL

3

R

OH

Ph

OH

Ph

OH

Ph

OH

R

L37, (R)-BINOL 2

Ph

L39, (R)-VANOL

2

R

R

Ar

L40, (S)-VAPOL O

Ar

OH

R1

OH

OH HO

R

OH

1

R

OH

OH HO

R2

R3

R2

R1 1

L41

Ar

Ar

L42

L43

Figure 9.5  Representative axially chiral C2-symmetric diols and analogs.

Wulff and coworkers [103] R2 R1

R3 +

Ph

R4

N

OMe

Toluene, 25 °C up to >99%, >99% ee

OH 116

R2

Zr-(S)-VAPOL (L40, 20 mol%) OTMS NMI (24 mol%)

117

Me MeO2C

Me

R1 Ph

R3

N H

R4 OH

118

Scheme 9.35  Zr/VAPOL-catalyzed asymmetric imino aldol reaction. Source: Based on Xue et al. [103].

and promote various types of aldol condensation reaction of unsaturated system with transmission of chiral information. To date, amalgamation of Lewis acids and chiral ligands has become a C─C bond formation strategy with prime importance in enantioselective synthesis. Specifically, asymmetric aldol reactions between enolates and imines have accumulated considerable amount of reports in the synthesis of chiral amines [98–102]. The investigation of chiral catalysts for this useful transformation is thus a vital task. In 2001, Wulff and coworkers conducted imino aldol reaction with Zr/(S)-VAPOL catalyst combination (Scheme 9.35) [103]. This high yielding and enantioselective Mukaiyama-type condensation of ketene acetals with imines constitutes a practical protocol to construct C─C bond.

9.6.2  Diels–Alder Reaction In 2002, Ding and coworkers deployed chiral BINOL–zinc complex to foster high asymmetric induction in hetero-Diels–Alder reaction of Danishefsky’s diene 119 and aldehydes [104]. 2-Substituted 2,3-dihydro-4H-pyran-4-ones 120 were constructed using this methodology in moderate to excellent yields (Scheme 9.36a). Later, in 2007, the employment of

9.6  C2-Symmetric Diols (a) Ding and coworkers [104]

Br

OMe +

RCHO

then CF3CO2H

TMSO

O Zn O

O 120

up to 99%, 98% ee

119

R

O

Zn/L37-1 (R = Br, 10 mol%) toluene, –25 °C

Zn/L37-1

Br

(b) Whiting and coworkers [105] OMe

OMe + TMSO

N

then H+ up to 78%, 93% ee

R

119

OMe

Zn-(S)-BINOL (>10 mol%) toluene or CH2Cl2, 0 or 25 °C

121

N O

R 122

Scheme 9.36  Zn/BINOL-catalyzed asymmetric [4 + 2] cycloaddition. Source: (a) Based on Du et al. [104]. (b) Based on Bari et al. [105].

zinc–BINOL as a Lewis acid catalyst was extended by Whiting and coworkers to formal aza-Diels–Alder reaction of diene 119 and N-aryl imines 121 (Scheme 9.36b) wherein the cycloadducts 122 were provided in moderate to excellent enantioselectivities [105].

9.6.3  Arrangement Reaction In 2014, Wulff’s group identified zirconium/(R)-VANOL catalyst combination to outcompete aluminate complexes in promoting catalytic asymmetric rearrangement of α-iminol 123 to α-amino ketones 124 through a 1,2-carbon shift, which afforded 97 to >99% ee for most cases (Scheme  9.37) [106]. The catalyst was prepared by mixing Zr(OiPr)4(HOiPr) with (R)-VANOL and N-methylimidazole in a solution of toluene at room temperature for half an hour. X-ray diffraction study of the catalyst indicated that the zirconium coordinates with three VANOL ligands and two protonated N-methyl imidazoles. Wulff and coworkers [106] Ph

Ph

N

H R 123

R OH

Zr-(R)-VANOL (L39, 2.5 mol%) toluene, 60 °C, 1 h up to >99%, >99% ee

NH O

R R 124

Scheme 9.37  Zr/VANOL-catalyzed asymmetric α-iminol rearrangement. Source: Based on Zhang et al. [106].

9.6.4  Reductive Reactions In 2006, Nguyen and coworkers reported the use of chiral BINOL–Al(III) complex to catalyze asymmetric Meerwein–Schmidt–Ponndorf–Verley reduction of N-phosphinoyl ketimines 125 with 2-propanol as the reductive H-transfer reagent [107]. Moderate yields

269

270

9  Application for Axially Chiral Ligands Nguyen and coworkers [107]

N

P(O)Ph2 +

R1

R

OH

AlMe3 (1.2 equiv) (S)-BINOL (1.2 equiv) Toluene, 60 °C

O O

R * R1

up to 85%, 98% ee

125

O Al O

P(O)Ph2

HN

N

R Me Proposed transition state

126

Ph P Ph

R1 H Me

Scheme 9.38  Al/BINOL-catalyzed asymmetric reduction of ketimines. Source: Based on Graves et al. [107].

and excellent enantioselectivities were observed with various substituted ketimines (Scheme 9.38). The highly selective reduction to amide is accomplished through hydride transfer from AlOiPr/BINOL in a six-membered transition state.

9.7 ­Other Axially Chiral Ligands in Asymmetric Transformations In 1997, Hayashi and coworkers described a catalytic enantioselective Wacker-type cyclization using Pd(II) coordinated with chiral bis(oxazoline) ligand that bore BINOL backbone (Scheme 9.39) [108]. From examination of a series of ligands modulated via different substituents, isopropyl group-bearing ligand L44 promoted this transformation in up to 86% yield, and 97% ee under mild conditions. In 1998, Chan and coworkers synthesized axially chiral bisaminophosphine ligands, which were evaluated in asymmetric hydrogenation of enamides 129; corresponding amides 130 were obtained in excellent optical purities under mild conditions. Notably, L45 with H8–BINAM backbone displayed better performance in the enantiocontrol than that with BINAM backbone (Scheme 9.40) [109]. In 2003, Hu and coworkers disclosed a copper-catalyzed asymmetric conjugate addition of diethylzinc to α,β-unsaturated ketone in which NOBIN derivative was enlisted as the chiral ligand (Scheme  9.41a) [110]. The same ligand enabled asymmetric tandem dual Michael addition reactions that could introduce three contiguous stereogenic centers in acyclic products (Scheme 9.41b) [111]. Both reactions provided excellent yields and enantioselectivities while the chemistry was tolerated by various unsaturated ketones.

Hayashi and coworkers [108] Me R

Me Me OH 127

Pd(TFA)2 (10 mol%) L44 (10 mol%) Benzoquinone 60 °C, MeOH up to 86%, 97% ee

O

Me R

Me O 128

iPr

N

N

iPr

O L44, (S,S)-ip-boxax

Scheme 9.39  Pd-catalyzed asymmetric Wacker-type cyclization of o-allylphenols. Source: Based on Uozumi et al. [108].

 ­Reference Chan and coworkers [109] Me

[Rh-L45(cod)]BF4 (0.5 mol%) Ar

NHPPh2 NHPPh2

NHCOCH3 H2 (1 atm), THF, 5 °C, 30 min Ar * NHCOCH3 129 130 up to 99% ee

L45

Scheme 9.40  Rh/BINAM derivative-catalyzed asymmetric hydrogenation. Source: Modified from Zhang et al. [109]. (a) Hu et al. [110] O R1

H N

[Cu(CH3CN)4]BF4 (1 mol%) Et2Zn, L46 (2.5 mol%) Toluene, –10 °C up to 86%, 97% ee

R2 131

Et

O

R1

O

R2 132

N

Me

O O P O

L46 (b) Huang and coworkers [111] O 1

2

Ar

Ar 133

NO2

+ R 134

Et2Zn CuCl (1 mol%), L46 (1.2 mol%) Et2O, –20 °C up to 90%, 99:1 dr, 97% ee

Et

H

1

Ar2

Ar

135

O

R

NO2 H

Scheme 9.41  Rh/BINAM derivative-catalyzed asymmetric conjugate additions. Source: (a) Based on Hu et al. [110] and (b) Based on Guo et al. [111].

9.8 ­Conclusions This chapter reviewed the development and evolution of axially chiral ligands based on various skeletons. The facile preparation methods and high structural modularity have rendered them one privileged class of chiral ligand to be used in combination with transition metals for a multitude of asymmetric transformations. The utility of each ligand type was illustrated through disparate reaction classes, which they were deployed for. It is projected that the extensive application of these ligands in organic synthesis will in turn accelerate the discovery of new ligand scaffolds as well as facilitate exploration of novel enantioselective catalytic systems to derive optically active molecules with higher efficiency and selectivity.

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87 Pappoppula, M. and Aponick, A. (2015). Angew. Chem. Int. Ed. 54: 15827. 88 Paioti, P.H.S., Abboud, K.A., and Aponick, A. (2016). J. Am. Chem. Soc. 138: 2150. 89 Mishra, S., Liu, J., and Aponick, A. (2017). J. Am. Chem. Soc. 139: 3352. 90 DeRatt, L.G., Pappoppula, M., and Aponick, A. (2019). Angew. Chem. Int. Ed. 58: 8416. 91 Mishra, S. and Aponick, A. (2019). Angew. Chem. Int. Ed. 58: 9485. 92 Knöpfel, T.F., Aschwanden, P., Ichikawa, T. et al. (2004). Angew. Chem. Int. Ed. 43: 5971. 93 Fekner, T., Müller-Bunz, H., and Guiry, P.J. (2006). Org. Lett. 8: 5109. 94 Hargaden, G.C. and Guiry, P.J. (2009). Chem. Rev. 109: 2505. 95 Noyori, R., Tomino, I., and Tanimoto, Y. (1979). J. Am. Chem. Soc. 101: 3129. 96 Mukaiyama, T., Narasaka, K., and Banno, K. (1973). Chem. Lett.: 1011. 97 Mukaiyama, T., Banno, K., and Narasaka, K. (1974). J. Am. Chem. Soc. 96: 7503. 98 Beutner, G.L. and Denmark, S.E. (2013). Angew. Chem. Int. Ed. 52: 9086. 99 Kitanosono, T. and Kobayashi, S. (2013). Adv. Synth. Catal. 355: 3095. 100 Matsuo, J.-i. and Murakami, M. (2013). Angew. Chem. Int. Ed. 52: 9109. 101 Kalesse, M., Cordes, M., Symkenberg, G., and Lu, H.-H. (2014). Nat. Prod. Rep. 31: 563. 102 Frías, M., Cieślik, W., Fraile, A. et al. (2018). Chem. Eur. J. 24: 10906. 103 Xue, S., Yu, S., Deng, Y., and Wulff, W.D. (2001). Angew. Chem. Int. Ed. 40: 2271. 104 Du, H., Long, J., Hu, J. et al. (2002). Org. Lett. 4: 4349. 105 Bari, L.D., Guillarme, S., Hanan, J. et al. (2007). Eur. J. Org. Chem. 2007: 5771. 106 Zhang, X., Staples, R.J., Rheingold, A.L., and Wulff, W.D. (2014). J. Am. Chem. Soc. 136: 13971. 107 Graves, C.R., Scheidt, K.A., and Nguyen, S.T. (2006). Org. Lett. 8: 1229. 108 Uozumi, Y., Kato, K., and Hayashi, T. (1997). J. Am. Chem. Soc. 119: 5063. 109 Zhang, F.-Y., Pai, C.-C., and Chan, A.S.C. (1998). J. Am. Chem. Soc. 120: 5808. 110 Hu, Y., Liang, X., Wang, J. et al. (2003). J. Org. Chem. 68: 4542. 111 Guo, S., Xie, Y., Hu, X., and Huang, H. (2011). Org. Lett. 13: 5596.

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10 Application for Axially Chiral Organocatalysts Takahiko Akiyama Gakushuin University, Department of Chemistry, Mejiro, Toshima-ku, Tokyo, 171-8588, Japan

10.1 ­Introduction Both metal catalysts and biocatalysts play significant roles in the preparation of chiral organic compounds from achiral starting materials, and industrial applications of these catalysts have been successfully achieved. Recently, small organic molecules have emerged and been recognized to function as chiral catalysts, which are termed the “organocatalysts.” A range of enantioselective reactions mediated by this class of catalysts have been successfully developed [1–4]. The salient features of these catalysts are listed as follows: (1) Product contamination with metal is obviated because organocatalysts do not contain metals. (2) Organocatalysts are, in general, stable toward moisture and oxygen as well as easy to handle. (3)  Organocatalysts are, in general, cheaper than transition metal catalysts. A number of organocatalysts have been developed mainly after 2000; enamine catalysts such as (S)-proline and the Hayashi–Jørgensen catalyst, chiral Brønsted acid catalysts such as chiral phosphoric acid, hydrogen bond catalysts such as thiourea, and phase transfer catalysts are important catalyst families. Axial chirality element is present in these numerous kinds of organocatalysts. In this chapter, discussions will be centered on organocatalysts bearing axial chirality according to the following classification. These include the well-studied subclasses stated below, as contributed by pioneering works on organocatalysis:

(1) Chiral Brønsted acid catalysts (2) Chiral counteranion catalysts and chiral phase transfer catalysts (3) Brønsted base catalysts (4) Lewis base catalysts

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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10  Application for Axially Chiral Organocatalysts

10.2 ­Chiral Brønsted Acid Catalysts Chiral Brønsted acids are one of the most important subgroup organocatalysts, within which a range of acid catalysts have been developed in the past two decades [5–8].

10.2.1  Chiral BINOL Derivatives 1,1′-Bi-2-naphthol (BINOL) is a commercially available source of chiral scaffold bearing axially chirality; both R and S isomers are sold at almost the same price. This allows synthetic access to both enantiomers of BINOL derivatives by proper choice of the catalyst. 3,3′- Di-substituted chiral BINOLs are commonly used as chiral Brønsted acids. Examples of BINOL-derived Brønsted acids are shown in Figure 10.1. In 2003, Schaus and coworkers reported an enantioselective Baylis–Hillman reaction between aldehyde 4 and α,β-unsaturated ketone 5 mediated by (R)-BINOL-derived Brønsted acid catalyst 1 with 3,5-(CH3)2C6H3 at 3,3′-position and triethylphosphine (Scheme 10.1). This reaction gave the desired product 6 in 88% yield with 90% ee [9, 10]. In 2005, Dixon and coworker reported an enantioselective addition reaction of methyleneaminopyrrolidine 8 to imines 7 with Brønsted acid 2 as the catalyst to give α-aminohydrazolones 9 with moderate enantioselectivity (Scheme 10.2) [11]. Yamamoto and Ishihara successfully applied BINOL-derived Brønsted acid catalyst 3 in the Mannich-type reaction of aldimines 10 with ketene silyl acetals 11 to provide a series of β-amino esters 12 with moderate enantioselectivities for most cases (Scheme 10.3) [12].

10.2.2  Chiral Phosphoric Acid Chiral phosphoric acid 13, elaborated from BINOL scaffold, has been extensively employed as a resolving reagent for amines [13]. Variously, metal/BINOL phosphate-catalyzed enantioselective reactions have been exemplified by Alper [14] and Inanaga [15–17]. Application of chiral phosphoric acid to enantioselective reaction was revealed by Akiyama and Terada in 2004 (Figure 10.2).

Me

Me

Ph

Me

OH OH

Ph OH

OH OH

1

Me

2

OH Ph Ph

Tf Tf OH

3

Figure 10.1  Typical examples of BINOL-derived Brønsted acids.

10.2 ­Chiral Brønsted Acid Catalyst

McDougal and Schaus [9] O Ph

+

O

H

4

5

OH

1 (2 mol%) Et3P, THF, –10 °C, 48 h

O

Ph 6

88%, 90% ee

Scheme 10.1  Baylis–Hillman reaction catalyzed by BINOL-derived Brønsted acid. Source: Based on McDougal and Schaus [9]. Dixon and Tillman [11] N Ar

Boc

N

+

2 (20 mol%), CDCl3, r.t.

N

7

NH N

Ar

up to 87%, 75% ee

H

Boc

8

N

9

Scheme 10.2  Addition reaction of methyleneaminopyrrolidine to imines. Source: Based on Dixon and Tillman [11]. Yamamoto and coworkers [12] N

R1

OSiR3 +

3 (10 mol%) 2,6-xylenol or tBuOH (1 equiv)

OMe

Ar

nPrCl, –78 °C up to 99%, 87% ee

11

10

R1

NH

O

Ar

OMe 12

Scheme 10.3  Mannich-type reaction catalyzed BINOL derivative. Source: Based on Hasegawa et al. [12].

O O

P

CF3

O NO2

OH 14a

13 R O O

14

R

iPr

iPr P

O

iPr

OH iPr

14c CF3

14b

14d

SiPh3 14e

iPr

14f

14g

Figure 10.2  Typical examples of chiral phosphoric acid. Source: Modified from Yang et al. [18].

Akiyama reported a Mannich-type reaction of ketimines 15 with ketene silyl acetals 16 by means of chiral phosphoric acid 14a derived from (R)-BINOL bearing substituents at the 3,3′-positions (Scheme  10.4a). Terada and coworkers independently reported the direct Mannich reaction with acetyl acetone 18 as a nucleophile utilizing 14b as the catalyst

277

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10  Application for Axially Chiral Organocatalysts

(a) Akiyama et al. [19] HO

HO

OTMS H

+

N

OR2 1

Ar

R

15

16

14a (10 mol%) Toluene, –78 °C up to 100%, 96% ee 100 : 0 syn:anti

HN CO2R2

Ar R1

17

(b) Uraguchi and Terada [20] N R

7

Boc

Boc

O

+ H

14b (10 mol%)

O

CH2Cl2, r.t., 1 h

18

up to 99%, 98% ee

NH

R * 19 Ac

Ac

Scheme 10.4  Mannich reactions catalyzed by chiral phosphoric acid. Source: (a) Based on Akiyama et al. [19]. (b) Based on Uraguchi and Terada [20].

instead (Scheme 10.4b). The substituents on 3,3′-position were found critical for the high stereoinduction, while 4-nitrophenyl and 4-(2-naphthyl)-phenyl groups were the substituents of choice [19, 20]. These two reports have ushered in the development of diverse asymmetric reactions by virtue of chiral phosphoric acid catalysts [21–24]. Various chiral phosphoric acids with different substituents at the 3,3′-position were then synthesized to pursuit the satisfied stereoinduction as shown in Figure  10.2 [18]. Rueping et  al. [25], List and coworkers [26], and MacMillan and coworkers [27] reported transfer hydrogenation of ketimine 20 by employing Hantzsch ester 21 as a hydrogen donor and chiral phosphoric acid as the chiral Brønsted acid to furnish corresponding amines with good to excellent enantioselectivities. Interestingly, different 3,3′-substituents were incorporated: Rueping selected 14c bearing 3,5-(CF3)2C6H3 moiety and the reaction gave amine 22 in 70% ee. 2,4,6-(iPr)3C6H2 substituted chiral phosphoric acid 14d was employed by List, and the ee value was dramatically improved to 88%. When aromatic substituents were replaced by SiPh3 (14e), MacMillan synthesized the amine 22 with 94% enantiopurity (Scheme 10.5).

N

PMP Me

20

EtO2C

CO2Et

+

14c–e, Conditions

HN

PMP Me

N H 21

22

Rueping, 14c (20 mol%), benzene, 60 °C, 3 d

82%, 70% ee

List, 14d (10 mol%), toluene, 35 °C, 45 h

96%, 88% ee

MacMillan, 14e (10 mol%), MS 5 Å, benzene, 50 °C, 24 h

87%, 94% ee

Scheme 10.5  Asymmetric reduction catalyzed by chiral phosphoric acid.

10.2 ­Chiral Brønsted Acid Catalyst

Notably, 14d (TRIP), derived from 2,4,6-triisopropylphenyl-subsituted BINOL, is one of the most popular and important chiral phosphoric acids, and a wide spectrum of enantioselective reactions have been successfully achieved by using this catalyst. In 2008, the List group reported an asymmetric three-component Kabachnik–Fields reaction by virtue of a bulky phosphoric acid 14f bearing 4-(9-anthryl)-2,6-(iPr)2C6H2 group (Scheme 10.6) [28]. Optically active α-amino phosphonates 26 were assembled by the reaction of aldehydes 23, aromatic amine 24, and phosphite 25 in moderate to high efficiency with good stereoselectivities. Moreover, a bulky catalyst with similar steric hindrance from the branches on the BINOL backbone proved to be effective for enantiocontrolled protonation and hydrogenation by the groups of Yamamoto and Akiyama, respectively [29, 30].

List and coworkers [28] (S)-14f (10 mol%)

R

O

+

H2N

Ar

OMe 24

23

+

O O P H O 25

cyclohexane, 50 °C up to 89%, 28:1 dr 94% ee

PMPHN R

O P O Ar O 26

Scheme 10.6  Three-component Kabachnik–Fields reaction. Source: Based on Cheng et al. [28].

Nonetheless, the axially chiral framework of phosphoric acid is not limited to BINOL structure. Other types of phosphoric acids embedding different chiral motifs were also elegantly developed, and the representative examples are shown in Figure 10.3 (27–30). In addition, privileged BINOL scaffold derived novel chiral bisphosphoric acid 31 and 32, as well as non-C2-symmetric 33 also displayed potential in asymmetric catalysis.

Ar O

Ar

P

O

O OH

O

Me Me

O

Ar

Ar P

O OH

O

Ph Ph

O

28

O

O P

O

O

OH

O

31

HO

P O

P

O OH

Ar 29

30

Ar

Ar O OH P O O OH O P O O Ar

O

HO

O

Ar

27

O

P

O 32

O O

P

O OH

33

Figure 10.3  Representative examples of chiral phosphoric acids with other backbones. Source: Storer et al. [27], Cheng et al. [28], Cheon and Yamamoto [29], and Horiguchi et al. [30].

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10  Application for Axially Chiral Organocatalysts

In 2007, Gong and coworkers reported direct three-component Mannich reaction [31]. Adopting H8-BINOL-derived chiral phosphoric acid 27a as the promoter, the reaction of aromatic aldehyde 34, ketone 35, and aromatic amine 36 proceeded smoothly to afford highly enantioenriched α-amino carbonyl molecule 37 in up to >99% isolated yield (Scheme 10.7). The anti-isomers dominated the obtained products as expected. Gong and coworkers [31] O

O +

NO2 34

NH2 +

S 35

36

Ph (R)-27a, Ar = Ph (2 mol%) Toluene, 0 °C, 48 h up to >99% 98 : 2 dr, 95% ee

NH

O2N

O

S 37

Scheme 10.7  Direct Mannich reaction. Source: Based on Guo et al. [31].

Chiral phosphoric acid 28a with a biphenol unit has been employed as a chiral Brønsted acid for an internal redox reaction involving [1, 5] hydrogen transfer and subsequent cyclization to furnish tetrahydroquinoline derivatives 39 with high enantioselectivities by Akiyama and coworkers in 2011 (Scheme 10.8) [32, 33]. Akiyama and coworkers [33] MeO2C

CO2Me

R NBn2 38

(S)-28a, Ar = 2,4-(CF3)2C6H3 (10 mol%) Toluene, 70~120 °C up to >99%, 97% ee

R N Bn

CO2Me CO2Me Ph

39

Scheme 10.8  Enantioselective synthesis of tetrahydroquinoline by enantiotopic C(sp3)–H hydrogen activation. Source: Akiyama et al. [32] and Mori et al. [33].

A novel vaulted biaryl ligand 2,2′-diphenyl-[3,3′-biphenanthrene]-4,4′-diol (VAPOL) was developed by Wulff and Bao for stereoselective catalytic Diels–Alder reaction in 1993 [34]. Building upon this core structure, Antilla and coworkers synthesized phosphoric acid 29 and meanwhile applied this chiral catalyst to the enantioselective nucleophilic addition of sulfonamide 40 to imines 7. The chiral N,N-aminals 41 were produced in excellent reaction outcomes (Scheme 10.9) [35]. In 2010, List and Wang coincidentally developed chiral phosphoric acid 30, a derivative of 1,1′-spirobiindane-7,7′-diol (SPINOL) [36]. In List’s work, 30a bearing 2,4,6-(iPr)3C6H2 substitutions was prepared and then a highly enantioselective kinetic resolution of homoaldols 42 by transacetalization was realized employing this catalyst (Scheme 10.10a) [37]. Wang and coworkers introduced 1-naphthyl on the branch of SPINOL backbone and the corresponding chiral phosphoric acid (30b) was verified to be an effective facilitator for

10.2 ­Chiral Brønsted Acid Catalyst

Antilla and coworkers [35] N Ar

Boc +

TsNH2

7

40

29, derived from S-VAPOL (10 mol%)

HN

diethyl ether, r.t., 1~20 h up to 99%, 99% ee

Boc

Ar * NHTs 41

Scheme 10.9  Imine amidation. Source: Based on Rowland et al. [35].

(a) List and coworkers [37] OEt

R2 R1

EtO

(rac)-42 OH

30a, Ar = 2,4,6-(iPr)3C6H2 (1 mol%) 4 Å MS, CH2Cl2, 20 °C

EtO

up to 57%, 99% ee, 18 :1 dr

R2 R1

O 43

OEt +

EtO

(R)-42 OH up to 97% ee R2

(b) Lin and coworkers [38] R 1

R

N H

O

+

44

N

R2 R1

2

S

HN

Toluene, –60 °C

O

up to 97%, >99% ee

45

Ar

O

30b, Ar = 1-Naphthyl (10 mol%)

S O Ar

R1

46

N H

Scheme 10.10  SPINOL derived phosphoric acid-catalyzed kinetic resolution and Friedel–Crafts alkylation reaction. Source: (a) Based on Čorić et al. [37]. (b) Based on Xu et al. [38].

the Friedel–Crafts alkylation of indoles 44 with N-Ts imines 45 (Scheme  10.10b) [38]. Furthermore, various SPINOL-derived chiral phosphoric acids were explored and applied in diversified asymmetric transformations [39]. Gong and coworkers devised a bisphosphoric chiral acid 31 connected by an ether linker; its application in a three-component 1,3-dipolar cycloaddition reaction gave rise to highly enantioenriched pyrrolidine derivatives 49 in excellent efficiency for most examples (Scheme 10.11) [40]. Terada and coworkers designed bisphosphoric acid 32, harboring single S axial chirality at 3,3′-biaryl substituents on (R)-binaphthyl and intramolecular hydrogen bonding between the two phosphoric acid moieties. This new acid catalyst 32a was effective for Diels–Alder reaction of 1,3-butadienes 50 and α,β-unsaturated aldehydes 51 to furnish cyclohexenylamines 52 with high enantioselectivity (Scheme 10.12) [41]. Gong and coworkers [40] RCHO

R1

+

34

+ CO2R2

H2N 47

CO2R3 CO2R3 48

31 (2 mol%) 3Å MS, CH2Cl2, 0 °C up to 97%, 99% ee

R3O2C R

CO2R3 N H 49

R1 CO2R2

Scheme 10.11  Three-component 1,3-dipolar cycloaddition reaction. Source: Based on Chen et al. [40].

281

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10  Application for Axially Chiral Organocatalysts

Terada and coworkers [41] Cbz

NH

R1

+ R

CHO

32a, Ar = 2,4,6-(iPr)3C6H2 (2.5 mol%) 4 Å MS, toluene, –80 °C up to 92%, 99% ee

51

50

Cbz

NH

R1 CHO

R 52

Scheme 10.12  Bis-phosphoric acid-catalyzed Diels–Alder reaction. Source: Based on Momiyama et al. [41].

Ohshima and coworkers reported a non-C2-symmetric chiral phosphoric acid 33a with substitution at the C3 position and its ability to catalyze a Friedel–Crafts alkylation reaction of indoles 53 or pyrroles with trifluoromethylated N-unprotected α-imino ester 54 in a highly enantioselective manner (Scheme 10.13) [42]. Computational studies indicated that the C–H–π interaction between the C2 position of indole and anthranyl substituent of 33a was a crucial factor to stabilize the transition state.

Oshima and coworkers [42] R

NH

+

N H

F3C

CO2Et 54

53

33a, Ar = 9-anthranyl (5 mol%)

NH2

F3C

CHCl3, –60 °C, 1~24 h up to 99%, 96% ee

R

EtO2C 55

N H

Scheme 10.13  Fridel–Crafts alkylation reaction of indole with N–H ketimine catalyzed by C1-symmetric chiral phosphoric acid. Source: Based on Yonesaki et al. [42].

In addition to chiral phosphoric acid derivatives, a collection of strong Brønsted acids bearing binaphthyl backbone have emerged (Figure 10.4). F Ar

Ar

Ar

Ar F4

O O

P

O

O

NHTf

O

Ar

OO P

N H

O

O

O

O

Ar2 Ar1

O

SO2

P

N

P

O

N O NH O2S Ar1 Ar2 Ar1

O

59

NHTf

58 F NO2 Ar

Ar

CO2H CO2H

SO2 NH SO2

Ar 60

O

Ar

57 Ar1

P

F4 Ar

Ar

56

P

Ar NO2 61

Figure 10.4  Representative strong Brønsted acids with binaphthyl backbone.

10.2 ­Chiral Brønsted Acid Catalyst

Yamamoto and coworkers developed BINOL-derived N-triflyl phosphoramide 56a with which a highly enantioselective Diels–Alder reaction of ethyl vinyl ketone 62 with siloxydienes 63 was established. The resulting cyclohexene derivatives 64 were obtained in high yields and with excellent enantiocontrol (Scheme  10.14) [43]. The strong acidity of the catalyst was critical for the reaction to proceed efficiently. Yamamoto and coworker [43] O +

Et

R1

62

OSiR3 Me 63

Me

(S)-56, Ar = 2,4,6-(iPr)3C6H2 (5 mol%)

COEt

Toluene, –78 °C, 12 h up to >99%, 92% ee

R3SiO

R1 64

Scheme 10.14  Chiral N-triflyl phosphoramide catalyzed Diels–Alder reaction. Source: Based on Nakashima and Yamamoto [43].

List’s group developed a series of confined Brønsted acids 57 on the basis of a C2symmetric imidodiphosphoric acid motif. With 57a as an optimal catalyst, a highly stereoselective spirocyclization reaction was implemented in moderate to good yields (Scheme 10.15) [44]. Additionally, the enantioselective oxidation of sulfide with H2O2 to furnish chiral sulfoxide was accomplished by the same group [45]. List and coworker [44] O

n

57a, Ar = 2,4,6-Et3C6H2 (5 mol%)

OH

MTBE, –25 or –35 °C

65

n

up to 88%, 97% ee

O

O

n n

66

Scheme 10.15  Spiroacetalization catalyzed by confined Brønsted acid. Source: Based on Čorić and List [44].

More recently, the authors revealed confined and strong chiral Brønsted acid 59a, realizing the activation of simple alkenes 67 to synthesize various 2,2-disubstituted tetrahydrofurans 68 through intramolecular cyclization with up to 97% ee (Scheme 10.16) [46, 47]. Terada also developed a type of stronger Brønsted acid 58 from F10-BINOL. The pKa value of the catalyst with a phenyl at 3,3′-positions is estimated to be −4.95 by density functional theory (DFT) calculation, while the pKa value is 3.33 for BINOL-derived phosphoric acid. List and coworkers [46] R1 R1 R

n

67

59a (5 mol%) Ar1 = 4-tBuC6H4, Ar2 = 3,5-(CF3)2C6H3

OH

cyclohexane, 60 °C, 2 d up to 94%, 97% ee

Me R

O n

68

R1 R1

Scheme 10.16  Activation of alkene. Source: Tsuji et al. [46] and Schreyer et al. [47].

283

284

10  Application for Axially Chiral Organocatalysts Terada and coworker [48] O +

R

Ar

O N

n

69

70

O

R

58a, Ar = 1-pyrenyl (5 mol%)

O

CHCl3, –10 ~ –60 °C, 48 h

Ph

n

up to 92%, 93% ee 98: 2 syn:anti

Ar N 71

Ph

Scheme 10.17  Addition reaction to strenes by Strong chiral Brønsted acid. Source: Kikuchi and Terada [48] and Kikuchi et al. [49].

Simple alkenes 69 could be activated by 1-pyrenyl substituted N-triflyl phosphoramide 58a to undergo intermolecular addition with azlactones 70 as nucleophiles under moderate enantiocontrol for most cases (Scheme 10.17) [48, 49]. On the other hand, Maruoka and coworkers developed chiral dicarboxylic acid 60a, which was employed as a chiral Brønsted acid catalyst for aziridination reaction of α-diazoamides 72 with N-Boc protected imines 7 (Scheme 10.18) [50].

Maruoka and coworkers [50] N Ar1

O

Boc +

7

N H N2 72

Ar2

60a, Ar = 2,4,6-Me3C6H2 (5 mol%)

Boc

O

N

1

Ar

4 Å MS, toluene, 0 °C, 2 h

73

up to 70%, 99% ee trans:cis= >20 : 1

N H

Ar2

Scheme 10.18  Azirizination reaction catalyzed by dicaroboxylic acid. Source: Based on Hashimoto et al. [50].

C2-Symmetric dinitro-substituted disulfonimide as another type of chiral Brønsted acid was forged by List and coworkers for a Torgov cyclization reaction in 2014. The illustration of this protocol included a very concise synthesis of (+)-estrone (Scheme 10.19) [51]. An important utility of chiral Brønsted acids lies in their combination with photoredox catalysis. Knowles and coworkers reported a catalytic asymmetric reductive coupling of ketones and hydrazones with Hantzsch dihydropyridine 21 in the presence of 14e. This intramolecular aza-pinacol asymmetric cyclization of ketohydrazones 76 proceeds through neutral ketyl radical intermediates, which in turn are generated via a concerted

List and coworkers [51] O R2 n

R

O R1 74

R2 O

61a, Ar = 3,5-(SF5)2C6H3 (5 mol%) 4Å MS, toluene up to 98%, 97% ee

O

(+)-Estrone H

n

R R1

75

H HO

Scheme 10.19  Togrov cyclization. Source: Based on Prevost et al. [51].

H

10.3  ­Chiral Counteranion Catalysts and Chiral Phase Transfer Catalyst

Knowles and coworkers [52] Ar

N O

Ir(ppy)2(dtbpy)PF6 (2 mol%) NMe2 21 (1.5 equiv), 14e (10 mol%)

76

HO Ar

NHNMe2

dioxane, blue LED, r.t., 3 h

77

up to 96%, 95% ee SiPh3 EtO2C

CO2Et

O

N H 21

O

P

O OH

SiPh3

14e

Scheme 10.20  Photoredox catalysts enable by proton-coupled electron transfer reaction. Source: Rono et al. [52] and Yayla and Knowles [53].

proton-coupled electron transfer (PCET) jointly mediated by chiral phosphoric acid 14e and photoredox catalyst (Ir(ppy)2(dtbpy)PF6). The neutral ketyl radical remains H-bonded to the chiral conjugate base of the chiral Brønsted acid during the course of carbon–carbon bond formation step, thereby furnishing syn-1,2-amino alcohol derivatives 77 with excellent diastereo- and enantioselectivities (Scheme 10.20) [52, 53]. Another interesting feature of chiral phosphoric acids is displayed through their merger with metal catalysis, such as relay catalysis and cascade reaction. Gong and coworkers reported an efficient tandem reaction of 2-(2-propynyl)anilines 78 consisting of intramolecular hydroamination and asymmetric transfer hydrogenation under the relay catalysis of an achiral gold complex and chiral phosphoric acid 14 g to furnish 2-aryl tetrahydroquinolines 79 with remarkable enantiopurities (Scheme 10.21) [54]. In a cooperative catalysis system involving metal carbene intermediate documented by Hu, the combined use of chiral phosphoric acid and Rh catalyst was applied [55, 56]. Gong and coworkers [54] Ph3PAuCH3 (5 mol%) 21 (1.2 equiv), 14g (15 mol%)

R NH2 78

R1

Toluene, 25 °C, 16 h up to >99%, >99% ee

R N H 79

R1

Scheme 10.21  Intramolecular hydroamination. Source: Based on Han et al. [54].

10.3 ­Chiral Counteranion Catalysts and Chiral Phase Transfer Catalysts Beyond the extensive utility of chiral phosphoric acids in Brønsted acid catalyzed reactions, chiral phosphate anionic structure is effective for enantioselectivity control as well. In this regard, List and coworkers employed morpholine salt of (R)-TRIP, which consisted of an

285

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10  Application for Axially Chiral Organocatalysts

achiral ammonium ion and a chiral phosphate anion, as a catalyst for the transfer hydrogenation of α,β-unsaturated aldehydes 80 in the presence of Hantzsch ester 81 (Scheme 10.22) [57, 58]. This concept has expanded the scope of iminium catalysis and is separately classified as asymmetric counteranion-directed catalysis (ACDC). They subsequently reported an enantioselective direct α-allylation of aldehydes using a combined catalyst system of Pd(0) and chiral phosphoric acid. The phosphoric acid played the dual role of a Brønsted acid to release proton, whereas the resulting conjugate base functions as the counteranion/ligand for the cationic π-allyl–Pd-intermediate [59]. List and coworkers [57] CHO

CHO

14d-1 (20 mol%), 81(1.1 equiv) dioxane, 50 °C, 24 h

Ar

Ar

up to 90%, >99% ee

80

82 Ar

MeO2C

CO2Me N H 81

O O

iPr

P

O

O

+ N H2

O–

Ar 14d-1, Ar = 2,4,6-(iPr)3C6H2

Scheme 10.22  Counteranion-directed catalysis. Source: Mayer and List [57] and Mahlau and List [58].

By means of the anionic chiral phase transfer catalysis, Toste and coworkers realized an enantioselective fluorocyclization reaction of olefins 83 with cationic fluorinating agent (Selectfluor) in the presence of C6-modified (R)-TRIP 14d-2 as a precatalyst (Scheme 10.23) Toste and coworkers [60]

R

O O

+

N +

Cl N + BF – 4

F

83

Selectfluor

BF4

O

R

O N

up to 96%, 97% ee >20 :1 dr

84

Ar O O

C8H17

F

C6H5F, –20 °C, 24 h

–

NH

C8H17

14d-2 (5 mol%) Protone Sponge (1.1 equiv)

P

Ar

O OH

O *

O

P

O O

–

N+ F

Cl

N +

–

O O

P

O O

*

Chiral ion pair

14d-2, Ar = 2,4,6-(iPr)3C6H2

Scheme 10.23  Phase-transfer catalysis. Source: Rauniyar et al. [60] and Phipps et al. [61].

10.3  ­Chiral Counteranion Catalysts and Chiral Phase Transfer Catalyst

[60, 61]. Although Selectfluor was achiral, active chiral fluorinating cationic species could be generated in situ. This represented a novel type of phase transfer catalysis that is based on the charge-inverting strategy, wherein chiral phosphate anion efficiently controls the enantioselectivity through the chiral ion pair. Subsequently, Toste and coworkers found that BINOL-derived phosphoric acid 14 h was capable of establishing attractive hydrogen-bonding interactions with peptide-like substrates 85. The chiral phosphate anion generated by anion exchange of 14 h with cationic oxidant oxoammonium salt 86 affected an enantioselective C─N bond forming reaction and then produced 1,2,3,4-tetrahydroisoquinoline-derived cyclic aminals 87. The introduction of 3,3′-triazolyl on catalyst was central to the high enantioselectivity of this crossdehydrogenative coupling reaction (Scheme 10.24) [62, 63]. Toste and coworkers [62] 14h (5 mol%), 86 (2.2 equiv) Na3PO4 (2.4 equiv)

N R

H N

R1 O 85

– O BF4 N +

p-xylene, r.t., 48 h

R

up to 93%, 94% ee

C8H17

N

N

R1 O 87

N O O

NHAc 86

*

N P

N Ar O OH

C8H17

N Ar N N 14 h, Ar = 2,4,6-Cy3C6H2

Scheme 10.24  Asymmetric cross-dehydrogenative coupling reaction. Source: Neel et al. [62] and Milo et al. [63].

In the more recent endeavor, they studied the allenoate-Claisen rearrangement using doubly axially chiral phosphate sodium salt, generated in situ from the reaction of sodium carbonate and the corresponding chiral phosphoric acid 90. The desired β-amino acid derivatives 91 with vicinal stereocenters were produced with up to 95% enantiopurity (Scheme 10.25) [64]. The following section illustrates charge-inverting strategy of phase transfer catalysis. Maruoka and Ooi developed C2-symmetric chiral ammonium salt as a phase transfer catalyst 94 and reported its use in alkylation of t-butyl glycinate–benzophenone Schiff base 92 with various alkylation reagents. Corresponding α-alkylated amino esters 93 were yielded with excellent enantioselectivity. Removal of the N-protecting group led to efficient formation of α-alkylated glycine [65–68]. They subsequently found that mono-binaphthyl-based chiral ammonium salt 95 exhibited high catalytic activity and the alkylation reaction proceeded smoothly with as low as 0.01 mol% catalyst loading (Scheme 10.26) [69].

287

288

10  Application for Axially Chiral Organocatalysts

Toste and coworkers [64] O OR1

∙ R

+ R2

88

90 (10 mol%) Na2CO3 (1.5 equiv)

N

BF4– CO2R1

cyclohexane, 25 °C, 24~48 h then HBF4•Et2O 89

+ N

R2

R

up to 98%, 95% ee, >99 : 1 dr

91

O O

Ar P Ar HO O 90, Ar = 4-Ad-C6H4

Scheme 10.25  Allenoate–Claisen reaction. Source: Based on Miró et al. [64].

Maruoka and coworkers [65, 69] Ph +

N Ph

RX

CO2tBu

cat. (Y mol%) Toluene/50% aq KOH, 0 °C

Ph N Ph

up to 99%, 98% ee

92 RX = BnBr

Ar – Br

CO2tBu R H 93

94 (1 mol%), 0.5 h, 95%, 96% ee 95 (0.01 mol%), 9 h, 92%, 98% ee Ar

N+ Ar 94, Ar = 2-naphthyl

nBu

–

N + Br nBu Ar

95, Ar = 3,4,5-F3C6H2

Scheme 10.26  Chiral phase-transfer catalysis. Source: Ooi et al. [65] and Kitamura et al. [69].

10.4 ­Brønsted Base Catalyst Relative to phosphate anion, guanidine constitutes stronger Brønsted base [70]. Terada and coworkers have disclosed C2-symmetric chiral guanidium bases and their successful implementation in asymmetric transformations (Scheme 10.27a) [71–73]. The 1,4-addition reaction of malonates 100 to nitrostyrenes 99 was promoted by 96 and analog 97 triggered direct vinylogous aldol reactions between compounds 102 and 103. Axially chiral guanidine base 98 containing a seven-membered ring structure was effective for the α-hydrazination of β-keto ester 105 with azodicarboxylate 106 (Scheme 10.27b) [74].

10.5 ­Lewis Base Catalyst

Ar

(a)

Ar H N

Ar

H N

NMe

Ar

NH

NH

NH

N

N

Ar

NH2

Ar Ar Ar 96, Ar = 3,5-(tBu)2C6H3

97, Ar = 3,4,5-(OMe)3C6H2

(b) Terada and coworkers [71] O O NO2 + 1 2 R R R3 4 R 99 100 Terada and coworkers [72] O Br + ArCHO O Br 102

O

96 (2 mol%), Et2O, –40 °C

R4

O

R2

up to >99%, 98% ee

R1

R3 NO2 101

O 97 (5 mol%) acetone-THF, –40 °C up to 99% ee 94:6 syn/anti

103

Terada and coworkers [74] O N Boc + N Boc CO2Et 105

98, Ar = 3,5-(tBu)2C6H3

106

98 (2 mol%) THF, –60 °C, 5 min quant yield, 97% ee

O Br

Ph Br

104

OH

O HN Boc N

Boc CO2Et 107

Scheme 10.27  Chiral Brønsted base catalysts. Source: (a) Terada et al. [71], Ube et al. [72], and Terada and Ando [73]. (b) Terada et al. [74] and Ube et al. [72].

10.5 ­Lewis Base Catalysts Lewis bases promote reactions by activating nucleophile through coordination with them or by performing nucleophilic attack on one substrate [75]. Denmark developed a chiral Lewis base-catalyzed reaction in 1994. He reported that the asymmetric allylation and crotylation of aromatic aldehydes 103 with allylic trichlorosilanes 110 promoted by chiral phosphoramides could occur in high yields and under modest enantiocontrol [76]. Hashimoto and Nakajima developed axially chiral pyridine N-oxides, which were subjected to allylation of aldehydes with allyltrichlorosilanes. Although bisisoquinoline N-oxide 108 gave moderate results, chiral pyridine N-oxide 109 furnished homoallylic alcohols with excellent enantioselectivity (Scheme 10.28) [77]. In 2002, Hayashi and coworkers developed pyridine derived axially chiral N-oxide catalyst 112 for this type of reaction with good to excellent enantioselectivities [78].

289

290

10  Application for Axially Chiral Organocatalysts Nakajima et al. [77]

103

iPr2NEt, CH2Cl2 –78 °C, 6 h

110

Ph

108: 82%, 52% ee 109: 85%, 88% ee N +

+

N

OH

108 or 109 (10 mol%)

SiCl3

+

PhCHO

111

HO

OH

–

O – O +

108

N N+ –O O–

Ph

+

N N+ –O O–

Ph

112

109

Scheme 10.28  Chiral N-oxide catalyzed asymmetric 1,2-addition reaction. Source: Based on Nakajima et al. [77].

The Morita–Baylis–Hillman reaction occurs under the action of a Lewis base catalyst, and a number of chiral base catalysts bearing axially chirality have been reported. Shi and coworkers developed chiral phosphine 113 bearing a binaphthyl unit, which found utility in the enantioselective aza Morita–Baylis–Hillman reaction (Scheme 10.29) [79, 80]. Sasai and coworkers developed a collection of bifunctional organocatalysts originated from BINOL and evaluated their activity in the aza-Morita–Baylis–Hillman reaction. Both types of catalysts exhibited excellent catalytic activity. Interestingly, although 3-pyridylaminomethyl-substituted catalyst 114 [81] gave the (R)-adduct selectively, 2-phosphinophenyl-substituted catalyst 115 furnished the (S)-isomer preferentially [82]. In Wang’s protocol, hydrogen bond catalyst with amino moiety 119 was successfully applied to enable Morita–Baylis–Hillman reaction (Scheme 10.30) [83]. O

N

+ H

Ts

cat. (10 mol%), Conditions

O

Ts Ph

Ph 118

117

116

HN

Shi, 113, 4 Å MS, THF, –30 °C, 83%, 83% ee Sasai,114, toluene-CPME, –15 °C, 93%, 87% ee Sasai, 115, tBuOMe,–20 °C, 97%, 87% ee

OH PPh2

113

N iPr OH OH 114

N PPh2 OH OH 115

Scheme 10.29  Asymmetric aza Morita–Baylis–Hillman reaction. Source: Shi and Chen [79] and Shi et al. [80].

10.5 ­Lewis Base Catalyst Wang et al. [83] O

S O

+ H

OH

N NHAr H NMe2

R

CH3CN, 0 °C

R

up to 84%, 94% ee

121

120

O

119 (10 mol%)

122

119, Ar = 3,5-(CF3)2C6H3

Scheme 10.30  Morita-Baylis-Hilman reaction catalyzed chiral thiourea catalyst. Source: Based on Wang et al. [83].

Chiral phosphine derivatives comprise another class of Lewis base catalysts, which include axially chiral diphosphine and monophosphine [84–87]. Kerrigan and coworkers reported a formal [2 + 2] cycloaddition reaction of ketenes 124 with aldehydes 103 through the use of (R)-BINAPHANE (123) as the chiral phosphine catalyst (Scheme 10.31) [88]. Kerrigan and coworkers [88] O •

O

+

R3

R1 R2 124

103

123 (10 mol%) CH2Cl2, –78 °C up to 99%, 99% ee 99: 1 dr

O

O

R1 2

R 125

P

P

R3 123

Scheme 10.31  [2 + 2] Cycloaddition reaction catalyzed by chiral diphosphine. Source: Based on Mondal et al. [88].

Fu and coworkers designed and synthesized a type of novel phosphephine catalysts with mono-binaphthyl scaffold. Monophosphine 126 proved to be the optimal catalyst for [3 + 2] cycloaddition reaction of allenes 127 with electron-deficient alkenes 128 to generate cyclopentenes 129 bearing quaternary carbon center with high stereocontrol (Scheme 10.32) [89]. Fu and coworker [89] R

2

R +

• CO2R 127

1

128

EWG

R 126 (5 mol%), iPr2O, r.t. up to 98%, 99% ee 50 :1 dr

** R1O2C

129

Ph 2

R EWG

P Ph Ph 126

Scheme 10.32  [3 + 2] Cycloaddition reaction catalyzed by chiral phosphine. Source: Based on Fujiwara and Fu [89].

Besides, monophosphine 130 embedding a biphenyl framework was utilized by Fu and coworkers in a phosphephine-catalyzed [4 + 1] annulation reaction of allenoates 132 with α-cyano ketone 131 to afford cyclopentene derivatives 133 with excellent enantiopurities (Scheme 10.33) [90]. Sasai employed spirocyclic phosphine (R)-SITCP (134) [91] in a phosphine-catalyzed β,γumpolung domino reaction of allenic esters 135 with dienones 136 to access the

291

292

10  Application for Axially Chiral Organocatalysts Fu and coworkers [90]

Ar 130 (10 mol%) Cs2CO3(1.3 equiv)

AcO

O CN

R1

+

• CO2R 132

131

O

R1

CN

Toluene, –10 °C, 24 h

2

133 CO2R2

up to 96%, 94% ee

MeO MeO

P Ph

Ar 130, Ar = 3,5-Ph2C6H3

Scheme 10.33  [4 + 1] Cycloaddition reaction catalyzed by chiral phosphine. Source: Based on Ziegler et al. [90].

tetrahydrobenzofuranones 137 bearing a chiral tetra-substituted stereogenic carbon center (Scheme  10.34a) [92]. On the other hand, Fu and coworkers developed catalyst 138 by installing two point chiralities on the spirophosphine and validated its activity in enantioselective [4 + 1] annulation of γ-substituted allenoates 139 with sulfonamides 140 to give dihydropyrroles 141 with high enantioselectivities (Scheme 10.34b) [93].

(a) Sasai and coworkers [92] O

O CO2R1 •

134 (20 mol%)

+ R2 OH 136

135

P Ph

CH2Cl2–toluene, 0 °C up to 78%, 96% ee >1 : 20 E/Z

CO2R1

R2 O 137

134

(b) Fu and coworker [93] 1

AcO

R

•

+ ArSO2NH2 CO2R2 139

140

138 (10 mol%) NaOPh (1 equiv)

SO2Ar R

1

N

CPME-toluene, 40 °C up to 94%, 92% ee

2 141 CO2R

P Ph 138

Scheme 10.34  Reaction with allenoates by chiral phosphine bearing spiro backbone. Source: (a) Based on Takizawa et al. [92]. (b) Based on Kramer and Fu [93].

Axially chiral 4-dimethylaminopyridne (DMAP) analog 142 was disclosed by Suga and Mandai; enantioselective acyl transfer reaction of indole derivatives 143 mediated by this catalyst has been demonstrated concurrently. Oxindole derivatives 144 were obtained in high enantiopurities with as low as 0.5 mol% of catalyst loading (Scheme 10.35) [94]. (S)-Proline and its derivatives could serve multiple roles in enamine catalysis and iminium catalysis, thus induce a range of enantioselective reactions [95]. Maruoka and coworkers judiciously developed a novel secondary amine catalyst 145 bearing a highly acidic triflimide group to activate electrophiles as well as a less nucleophilic dibenzylic secondary amine moiety, with the expectation of suppressing side reactions. A direct Mannich reaction between acetaldehydes 146 and N-PMP-protected imines 147 was successfully attained with excellent enantioselectivities (Scheme  10.36a) [96]. It is noted that whereas

10.5 ­Lewis Base Catalyst Mandai et al. [94]

Ar

R

R 142 (0.5 mol%)

OCO2Ph N CO2Ph 143

THF, –20 °C, 5 h up to 98%, 98% ee

CO2Ph

Ar OH

N

O N CO2Ph 144

N

OH Ar

Ar 142, Ar = 4-tBuC6H4

Scheme 10.35  Acyl transfer catalysis by chiral dimethylaminopyridine derivative. Source: Based on Mandai et al. [94].

(a) Maruoka and coworkers [97] O

PMP +

H

CO2R2

R1 146

147

dioxane, r.t.

NHPMP

O

145 (0.2~5 mol%)

N

CO2R2

H

NHTf

R1 148

up to 99%, >99% ee >20 :1 anti/syn

NH

(b) Maruoka and coworkers [97] O

Boc +

H

R2

1

R 146

7

dioxane, r.t. up to 93%, >99% ee >20 :1 anti/syn

NHBoc

O

145 (1~10 mol%)

N

R2

H

145

1

R

149

Scheme 10.36  Mannich reaction catalyzed by chiral amino sulfonamide. Source: (a) Based on Kano et al. [96]. (b) Based on Kano et al. [97].

syn-selectivity was observed in the proline-catalyzed reactions, 145 exhibited excellent anti-selectivity. They subsequently reported anti-selective Mannich reaction with N-Boc imines 7 (Scheme 10.36b) [97]. By treatment with 10 mol% of axially chiral primary amine catalyst 150 harboring a  binaphthyl backbone and 3,5-dinitrobenzoic acid (10 mol%), Shibatomi and coworkers ­performed an highly enantioselective fluorination of aldehydes 151 with Nfluorobenzenesulfonimide (NFSI) 152 to yield 2-fluorophenylpropanals efficiently. The fluorinated aldehyde was reduced by NaBH4 to furnish fluoroalcohols 153 with excellent enantiopurity retention (Scheme 10.37a) [98]. Moreover, in 2017, the application of this novel primary amine catalyst was extended to decarboxylative chlorination of β-ketocarboxylic acids 154 under mild organocatalytic conditions in high yields and enantioselectivities (Scheme 10.37b) [99]. In summary, a range of axially chiral compounds possess attested potency to catalyze diverse enantioselective reactions. Most of the catalysts embrace binaphthyl backbone that contributes to their rigid structures. These works inspire the design and examination of novel axially chiral compounds to attain novel catalytic transformations with stereocontrol. It is my hope that this chapter will be helpful to chemists who are interested in organocatalysis and axially chiral compounds.

293

294

10  Application for Axially Chiral Organocatalysts (a) Shibatomi et al. [98] Ar

CHO R

+ (PhSO ) NF 2 2

151

152

150 (10 mol%) 3,5-(NO2)2C6H3CO2H (10 mol%) toluene, 0 °C

Ar

CHO

NaBH4

Ar

F

R

CH2OH R

F 153

up to 98%, 95% ee Ar

(b) Shibatomi et al. [99] O

Cl R2

R1 R3

CO2H

+ O

154

N

155

O

Toluene, 15 or 25 °C up to 97%, 98% ee

NH2

O

150 (10 mol%) R1

* R3 156

R2 Cl

CO2Et Ar 150, Ar = 3,5-tBu2C6H3

Scheme 10.37  Halogenation reactions catalyzed by chiral primary amine. Source: (a) Based on Shibatomi et al. [98]. (b) Based on Shibatomi et al. [99].

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295

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10  Application for Axially Chiral Organocatalysts

71 Terada, M., Ube, H., and Yaguchi, Y. (2006). J. Am. Chem. Soc. 128: 1454. 72 Ube, H., Shimada, N., and Terada, M. (2010). Angew. Chem. Int. Ed. 49: 1858. 73 Terada, M. and Ando, K. (2011). Org. Lett. 13: 2026. 74 Terada, M., Nakano, M., and Ube, H. (2006). J. Am. Chem. Soc. 128: 16044. 75 Denmark, S.E. and Beutner, G.L. (2008). Angew. Chem. Int. Ed. 47: 1560. 76 Denmark, S.E., Coe, D.M., Pratt, N.E., and Griedel, B.D. (1994). J. Org. Chem. 59: 6161. 77 Nakajima, M., Saito, M., Shiro, M., and Hashimoto, S.-i. (1998). J. Am. Chem. Soc. 120: 6419. 78 Shimada, T., Kina, A., Ikeda, S., and Hayashi, T. (2002). Org. Lett. 4: 2799. 79 Shi, M. and Chen, L.-H. (2003). Chem. Commun.: 1310. 80 Shi, M., Chen, L.-H., and Li, C.-Q. (2005). J. Am. Chem. Soc. 127: 3790. 81 Matsui, K., Takizawa, S., and Sasai, H. (2005). J. Am. Chem. Soc. 127: 3680. 82 Matsui, K., Takizawa, S., and Sasai, H. (2006). Synlett: 0761. 83 Wang, J., Li, H., Yu, X. et al. (2005). Org. Lett. 7: 4293. 84 Wang, Z., Xu, X., and Kwon, O. (2014). Chem. Soc. Rev. 43: 2927. 85 Wei, Y. and Shi, M. (2014). Asian J. Org. Chem. 9: 2720. 86 Guo, H., Fan, Y.C., Sun, Z. et al. (2018). Chem. Rev. 118: 10049. 87 Ni, H., Chan, W.-L., and Lu, Y. (2018). Chem. Rev. 118: 9344. 88 Mondal, M., Ibrahim, A.A., Wheeler, K.A., and Kerrigan, N.J. (2010). Org. Lett. 12: 1664. 89 Fujiwara, Y. and Fu, G.C. (2011). J. Am. Chem. Soc. 133: 12293. 90 Ziegler, D.T., Riesgo, L., Ikeda, T. et al. (2014). Angew. Chem. Int. Ed. 53: 13183. 91 Zhu, S.-F., Yang, Y., Wang, L.-X. et al. (2005). Org. Lett. 7: 2333. 92 Takizawa, S., Kishi, K., Yoshida, Y. et al. (2015). Angew. Chem. Int. Ed. 54: 15511. 93 Kramer, S. and Fu, G.C. (2015). J. Am. Chem. Soc. 137: 3803. 94 Mandai, H., Fujii, K., Yasuhara, H. et al. (2016). Nat. Commun. 7: 11297. 95 List, B. (2006). Chem. Commun.: 819. 96 Kano, T., Yamaguchi, Y., Tokuda, O., and Maruoka, K. (2005). J. Am. Chem. Soc. 127: 16408. 97 Kano, T., Yamaguchi, Y., and Maruoka, K. (2009). Angew. Chem. Int. Ed. 48: 1838. 98 Shibatomi, K., Kitahara, K., Okimi, T. et al. (2016). Chem. Sci. 7: 1388. 99 Shibatomi, K., Kitahara, K., Sasaki, N. et al. (2017). Nat. Commun. 8: 15600.

297

11 Application in Drugs and Materials Yong-Bin Wang, Shao-Hua Xiang, and Bin Tan Department of Chemistry, Southern University of Science and Technology, No.1088, Xueyuan Rd., Nanshan District, Shenzhen, 518055, China

11.1 ­Drugs Proteins constitute primary biological targets of chemical drugs to elicit therapeutic effects. The structure of protein is fundamentally governed by a sequence of amino acids that invariably display l‐configuration except for achiral glycine. The specific interactions between chiral amino acid residues control folding of proteins into a well‐defined conformation and establish unique active‐site microenvironments with translated asymmetry from the monomers [1]. Therefore, the absolute configuration of bioactive molecules, determined by atom connectivity and corresponding spatial arrangement, decisively impacts the ability and efficiency of this effector to interact with proteins. Enantiomers of axially chiral molecules thus bear different binding specificities and activities. Additionally, enzymes could exhibit differential metabolic activity toward a pair of enantiomers, also altering the effective dose and toxicity profile of each enantiomer [2–5]. To develop effective, safe, and stable medicinal substances that function with target specificity, the differing response of biological system toward enantiomers of chiral compounds adds additional level of complexity. Atropisomerism now stands with central chirality and are intensively studied stereochemical behaviors in modern day drug discovery [6–9]. The bond breaking and making process to scramble the stereochemistry in point chiral compounds render them stereochemically stable. On the contrary, atropisomerism represents potentially dynamic chirality phenomena as atropisomers racemize via rotation of axis with a specific barrier. Molecules’ half‐lives thus could range from minutes to years, depending on steric hindrance and/or external factors such as solvent and temperature [10, 11]. Consequently, classifying these chiral molecules according to axial stability is crucial for practitioners to decide how to develop them. Laplante and Edwards categorized the atropisomeric compounds into three groups based on rotational energy barriers in an article reviewing atropisomer axial chirality in drug discovery and development [7, 8].

Axially Chiral Compounds: Asymmetric Synthesis and Applications, First Edition. Edited by Bin Tan. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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11  Application in Drugs and Materials ●●

●●

●●

Class I, compounds with torsion rotation energy barrier (ΔErot)  ΔErot   20 kcal/mol, the racemization half‐lives are on the order of minutes to years. Class III, compounds with ΔErot   30 kcal/mol, the racemization half‐lives are on the order of years [7, 8].

Using this guideline, the atropisomeric bioactive molecules are classified and strategies implemented to bring about successful development in each scenario will be detailed. As rGlyT1 inhibitors, the R‐isomer of atropisomeric compound 1 was found to be nearly 300 times more active than its S‐isomer, which is not surprising given a vast biological activity difference is often observed for antipodes of chiral bioactive molecules (Scheme 11.1a) [12]. Incorporating atropisomerism in drug candidates could be laborious as synthesis, characterization, evaluation of bioactivity, and absorption, distribution, metabolism, excretion (ADME) properties for individual stereoisomers are mandated. Researchers nonetheless often opt to take on the challenge to stabilize Class I atropisomers by modulating steric hindrance surrounding the axis, as new chemical entities are appealing in competitive intellectual property landscape [16–21]. Marine polycyclic alkaloids Lamellarins are one attractive family of

N N N

Ph

MeO

MeO

Et

N

OH

CN

N

N

Et

IC50 = 20 μM

CN

(a) F

O

F

F

N

S-3 Selective inhibitor of GSK-3α/β; PIM1; DYRK1A

F

4 NHMe

O

N

p38 IC50 = 2.3 nM

O PH-797805, R-5 NHMe

O

O NH2

O

Desired atropisomer

NHMe

O

O Me

NH

R

NH2

N NH

p38 IC50 = 247 nM

O NH

R

N

N

Br

O O

(d)

F O

O PH-797804, S-5

p38 IC50 = 17 nM

O

R-3

Br

O

N H

O

O

Br

NH2

O N

Non-selective inhibitor of CDK1,2,5; GSK-3α/β; PIM1; DYRK1A; CLK3

F

O

(c)

N

Non-selective inhibitor of CDK1,5; GSK-3α/β; PIM1; DYRK1A (b)

S-1: rGlyT1

OH

HO

Lamellarin N, 2

N

MeO

MeO

O

O

N N Ph

OH

HO

HO

R-1: rGlyT1 IC50 = 0.064 μM

MeO

MeO

O

NH

Me

N N H

NH

O 6, R = H, FVIIa Ki = 510 nM Undesired atropisomer 7, R = Me, FVIIa Ki = 46 nM

N H

NH

O 8, Single atropisomer FVIIa Ki = 1.4 nM

Scheme 11.1  Atropisomers display significantly different bioactive potency. Source: (a) Modified from Sugane et al. [12]. (b) Based on Yoshida et al. [13]. (c) Based on Selness et al. [14]. (d) Based on Glunz et al. [15].

11.1 ­Drug

targets because of their interesting biological activities and potential for various therapeutic purposes. Lamellarin N 2 can potently inhibit several protein kinases (CDKs, GSK‐3, PIM1, and DYRK1A) implicated in cancer and neurodegenerative diseases. However, the nonselective inhibition of other kinases could give rise to cytotoxicity. The Iwao group introduced a methyl group on the 16‐position of Lamellarins, thus afforded a pair of separable and stable axially chiral Lamellarin analogs 3. Isomer aS‐3 selectively inhibited GSK‐3α/β, PIM1, and DYRK1A while aR‐3, as with the case of compound 1, exerted potent but nonselective inhibition of all protein kinases except CK1 (Scheme 11.1b) [13]. On top of enhanced selectivity, introduction of new chiral axis could augment the activity of a new analog to a great extent. From achiral compound 4, which inhibited p38 with IC50 of 17 nM, Selness and coworkers introduced a sterically demanding group onto the biaryl moiety, arriving at configurationally stable axially chiral compound 5. From enzyme and cell‐based assays, racemic 5 was identified as a more potent inhibitor of p38 than the achiral analog (IC50 : 2.5 nM). Individual stereoisomers nonetheless exhibited considerably different activities: the S‐isomer was two orders of magnitude more active than R‐5 in inhibiting p38 (Scheme 11.1c) [14]. Glunz group incorporated a methyl group in the phenylglycine core of a macrocyclic FVIIa inhibitor and fruitfully improved the potency by about 10‐fold. This synthetic operation also introduced unstable atropisomerism to the macrocyclic structure (7) and desired activity resided in isomer depicted in Scheme 11.1d. As guided by computational studies, appending benzylic methyl group in R‐configuration on the linker locked the atropisomers into desired conformation. The R‐benzylic methyl group and 2‐methyl group improved potency of 8 by 180‐fold against FVIIa compared to the unsubstituted macrocycle 6 (Scheme 11.1d) [15]. Subsequent examples showcased improvement of both inhibition activity and target selectivity on introduction of chiral axis, engendering new chemical entities with better druggability. Class I PI3K lipid kinase comprises α, β, δ, and γ isoforms and catalyzes the production of intracellular second messenger, phosphatidylinositol‐3,4,5‐trisphosphate (PIP3). Previous report has demonstrated that the down‐regulation of PI3Kβ in tensin homolog‐deficient cancer cells could result in inactivation of signaling pathway and subsequent inhibition of cell growth. Compound 9 developed by Gilead Sciences, Inc., is an adenosine triphosphate (ATP)‐competitive PI3Kβ inhibitor [22]. The quinoline ring and imidazole ring of compound 9 adopt orthogonal conformation, and the protruding portion of quinoline partially fills the pocket between Met773 and Trp781 on binding to the ATP site of the kinase domain of p110β (catalytic subunit of PI3Kβ). To gain binding free energy while 9 and PI3Kβ rearrange to preferred binding conformation, Chandrasekhar and coworkers attempted to minimize entropic cost by restricting the free rotation around the C─N bond linking quinoline ring and imidazole ring (Scheme  11.2). The resulting racemic compound 10 equipped with stable chiral axis showed better activity against PI3Kβ in biochemical assays. Enantiopure (P)‐10 inhibited PI3Kβ with an IC50 of 2 nM and displayed good selectivity over other three isoforms of PI3Ks. Contrariwise, the M‐isomer possessed considerably lower activity against all four isoforms. Using cryopreserved human hepatocytes, the potent atropisomer (P)‐10 showed very low intrinsic clearance (0.08 l/h/kg) while a much higher value was identified for (M)‐10 (1.97 l/h/kg). In the active site‐directed competition assay, the conformationally locked single atropisomer (P)‐10 showed higher binding affinity for PI3Kβ and maintained the low off‐kinase activity, in comparison to non‐atropochiral compound 9. This report of Chandrasekhar and

299

300

11  Application in Drugs and Materials F

F N

N N

F

N

N F

NH2

N

F

N HN

N N

NH2

HN

9

F

PI3K IC50 (nM)

F

N

N N (rac)-10

9

F

(rac)-10

N

N

M-10

N F

N

N F

NH2

N

F

N HN

N N

α

δ

γ

233

67

440

3

264

43

4156

1423 >10 000>10 000 >10 000 2

P-10

42

188

4269

NH2 F

N HN

M-10

β 11

N N

P-10

Scheme 11.2  Novel atropisomeric PI3Kβ inhibitors with different bioactive potency.

coworkers presented development of a potent, selective, and orally bioavailable PI3Kβ inhibitor through creation of a chiral axis [22]. There are many other instances where great disparity in biological activity is observed between unstable atropisomer and more stable analog derived from attachment of ­sterically congesting groups. Beyond active introduction of stable chiral axis, structure– activity relationship (SAR) study revealed that significant enhancement of bioactivity could also be achieved through introduction of suitable ortho‐substituents on biaryl entity. Substituents at these positions could hamper the rotation of biaryl axis, giving rise to Class III stable atropisomers. This allows separation of two isomers and evaluation of the difference in their biological activity  [23, 24]. This strategy has directed the successful Ph nPr

O

Ph CO2H

N H

nPr

O

Ph CO2H Cl

N H

N

O

Ph CO2H Cl

N H

N NH

(a)

nPr

O CO2H Cl

N H

N NH

11: 5.7 ± 2.8 nM

nPr

N NH

(rac)-12: 0.20 ± 0.15 nM

NH

(S)-12: 0.093 ± 0.054 nM

(R)-12: 22 ± 20 nM

hAPJEC50 N

N

N

N

N

Me

N

N

Me

N

N

Me

N

N O

O

N

N O

D1 EC50(cAMP): emax: D1 Binding Ki: (b)

Me

13 821 nM 61% 98.9 nM

O

Me

N O

14 123 nM 62% 8.5 nM

O N

O (rac)-15 64 nM 64% 6.8 nM

N

Me

Me

O N

O

(rac)-16 106 nM 86% 8.9 nM

O

(S)-16 33 nM 91% 11.9 nM

Scheme 11.3  Bioactive molecules bearing stable axial chirality derived from achiral ones. Source: (a) Based on Su et al. [25]. (b) Based on Davoren et al. [26].

11.1 ­Drug

development of APJ receptor agonists (S)‐12 (Scheme 11.3a) [25] and dopamine receptor 1 agonists (S)‐16 (Scheme 11.3b) [26]. For metastable axially chiral compounds (Class II), isolation of individual conformer for activity testing or for development into stable enantiopure drugs may not be easy. Watterson and coworkers disclosed that carbazole 17 yielded from the SAR study of Bruton’s Tyrosine Kinase (BTK) inhibitors could exist as four interconverting atropisomers. From a kinetic stability study in methanol, lability of these isomers toward interconversion was found to be very high. Although removal of methyl group would remarkably diminish the inhibitory activity, framework modulation via stabilization of two chiral axes forged stable isomers. Isolation of isomers and follow‐up biochemical assay confirmed that satisfactory BTK inhibitory activity resided in (R,S)‐19 (Scheme  11.4a) [27]. In the study of KRASG12C NH2

O

O

H N Me Me HO

Me Me HO

Me O N

t1/2 (37 °C) = 38 min

BTK IC50 N

t1/2 (37 °C) 30 kcal/mol), which in turn enhanced the biochemical and cellular activity (p‐ERK IC50 = 28 nM). Additionally, replacing the o‐cumenyl ring of 20 with symmetrical 2,6‐diisopropylpyrimidine gave achiral 22, wherein good activity was retained and issue of stereochemical integrity could be circumvented altogether (Scheme 11.4b) [28]. Although the author advanced the study with former method, removing chiral structure presents one viable strategy to develop atropisomeric candidates with stability issues [8]. The thalidomide incident [29] sounded the alarm on the importance of drug safety; subsequent research further sheds light on the potential adverse effects if chirality of drug molecules is overlooked. Some marketed drugs, leads in preclinical or clinical stage bear atropisomeric properties and are used as racemates. Omeprazole as the first marketed proton pump inhibitor to inhibit gastric acid secretion represents one such example. Having discovered the better inhibitory activity and fewer side effects of S‐isomer with respect to the racemates, this single isomer was taken forward and yielded new generation of proton pump inhibitor drug, esomeprazole [30]. This successful case uncovered the feasibility of this strategy, which could be generalized to other racemic marketed drugs featuring stable chiral axis (Scheme 11.5). Current toolbox for atroposelective synthesis and analytical techniques would aid and accelerate the establishment of this endeavor. OH O H2N

Cl

OH O

N

O N

N F Afloqualone, 23 ΔErot = 35.7 kcal/mol

N

O

Laquinimod, 24 ΔErot = 23.7 kcal/mol

O

O

N

O

MeO

OH

OMe MeO2C CH2OH

OH

DBB, 25 ΔErot = 34.0 kcal/mol

H N

I

O

I

O I

H N

O

OH OH

Lomeprol, 26 ΔErot = 38.9 kcal/mol

Scheme 11.5  Representative drugs displayed atropisomerism.

11.2 ­Chiral Recognition In an era with surging demand of chiral compounds for various societal needs, chiral recognition becomes one important domain of research because of its broad utility in the discrimination of chiral molecules and enantiomeric excess (ee) determination [31, 32]. In 1858, Louis Pasteur seminally found organism could enantioselective consume chiral molecules. However, until the end of the twentieth century, most synthetic chiral drugs were used as racemates because of the difficulty in obtaining and analyzing single enantiomers [33]. The increasing significance of enantiopure compounds in areas such as pharmaceutical science, food science, and material science has motivated the design of different entry toward enantiopure compounds. This encompasses direct isolation from nature products, resolution, and asymmetric synthesis from chiral building blocks as well as asymmetric

11.2 ­Chiral Recognitio

catalysis. Determining ee of chiral compounds is a crucial step in preparations of nonracemic compounds and in studies of biological enantioselectivity. The principle of chiral recognition sets the basis of several determination techniques, including nuclear magnetic resonance (NMR) spectroscopy, fluorescent sensor, circular dichroism (CD), gas chromatography (GC), and high‐performance liquid chromatography (HPLC) with chiral stationary phases (CSPs), etc. [34, 35]. Chiral recognition is, in turn, founded on the differential interactions elicited by the chiral host molecule with two enantiomers or on the different properties of diastereoisomeric host–guest complex [35, 36]. The synthesis and evaluation of chiral host molecules, which can form host–guest complex with the enantiomers, are thus the crucial pillars of chiral recognition research. Currently, chiral chromatography comprising HPLC, GC, and ultra‐performance supercritical fluid chromatography is the routine ee determination method. The CSPs used in chiral chromatography could be of brush‐type or polymer‐type. Axially chiral compounds are usually incorporated in brush‐type CSPs, which are prepared through immobilization of optically active small molecules on a silica gel or an organic polymer gel [33, 34]. CSP 27 containing axially chiral 1,1′‐bi‐2‐naphthol (BINOL) group was the first crown ether‐based CSP developed by Cram et al. Variability of crown ether‐based CSPs was modulated via the chiral units introduced into the crown ether frameworks [37], and among them, variant bearing optically active binaphthyl 28 represents one of the most successful CSPs [33]. The oxygen atoms of crown ether would interact with the amino group of guests under reversed phase conditions, and the atropisomeric BINOL skeleton constitutes the asymmetric environment for stereodiscrimination. Additionally, natural isolates such as macrocyclic glycopeptide (vancomycin, ristocetin A, teicoplanin, and teicoplanin aglycone) displaying axial chirality have been integrated in CSPs, which are compatible with diverse mobile‐phase modes and enable resolution of a wide range of racemates (Scheme 11.6) [38].

H3C H3C

H3C H3C

R

R

Si

Si O O

O

O

O

Me

Si

O

CH3 CH3

27

O O

O O 28

O

O

O O

HN HO2C HO

Cl

Cl

HO O

Si

OH

O

O

Me

OH

O

Si

Si

HO O

O

O R

HO H2N

CH3 CH3

N H

O H N O

N H O

OH O

H N O

N H

H N

NH2 OH OH Vancomycin 29

Scheme 11.6  Application of atropisomers in chiral stationary phases. Source: Modified from Armstrong et al. [38].

Although reliable, these chiral chromatography techniques are typically ­time‐consuming and involve expensive sophisticated instrumentations, limiting their use especially in real‐time analysis and high‐throughput screening (HTS) of asymmetric catalysis. To this end, chiral fluorescent and colorimetric sensors provide practical appeals with high sensitivity, reduced cost, diverse signal output modes, and adaptability to real‐time analysis

303

304

11  Application in Drugs and Materials

[39]. On interaction with chiral targets, the chemosensors convert the information from asymmetric recognition into optical outputs as radiomeric changes, fluorescence quenching/enhancement, or UV–vis spectral changes. Chemosensors are generally constructed from suitable fluorophores, liners, and binding units [31]. The properties of elected fluorophores and the linking approaches between the fluorophores and the binding units determine the sensing mechanism, which could involve photoinduced electron transfer (PET), aggregation‐induced emission enhancement (AIEE), and formation of excimer/ exciplex species, etc. The introduced chiral sources together with resultant interaction modes (hydrogen bond interaction, covalent interaction and charge–charge electrostatic interaction) play vital roles in dictating the efficacy of the produced sensor for enantioselective recognition of chiral organic molecules. In recent decades, a wide variety of fluorescent chemosensors have been developed. Axially chiral binaphthyls and analogs are the chiral fluorophores of choice because of their particularities in terms of rigid structure, relatively high emission efficiency, high configurational stability, and amenability for functionalization [31]. BINOL 30 and BINAM 31 are representative, commercially available atropisomeric molecules owning to extensive applications in asymmetric catalysis and material preparation. Both BINOL and 1,1′‐binaphthyl‐2,2′‐diamine (BINAM) could discriminate between enantiomers of α‐methylbenzylamine (MBA, 32). The hydrogen bond formed between fluorophores and chiral analytes was key in this chiral recognition, giving rise to small but detectable reduction of fluorescence intensity as a result of PET process [31]. On this basis, several BINOL derivatives have been developed to magnify the fluorescence signal and elevate the sensitivity of chiral recognition for binaphthyls [40, 41]. The Stern–Völmer constants KS and KR of BINOL and the axially chiral dendrimers containing BINOL core, which indicate the extent of chiral interaction, indicated that phenyleneethynylene dendrimers could pronouncedly enhance the fluorescence intensity of BINOL derivatives 33–35, allowing a very small loading of chiral materials to discriminate optically active amines as 36 (Scheme 11.7) [41–43].

R

R

R

OH

tBu

33, R = tBu

R1 tBu

OH R BINOL, 30

tBu

OH

37

OH 35, R =

32

38

NH2

NH2 HO R

*

tBu

36 R

R

33–35: 1.21–1.27 (4 × 10–8~10–6 M)

O O

BocHN

R

BINAM, 31

OH R1

NH2

KS/KR: 30: 1.02 (10–4 M)

OH

tBu

* NH2

O

34, R =

tBu

*

O–

R2

R1 = R2 = Ph KS = 3.9 ± 0.12 × 104 M–1 KR = 4.53 ± 0.30 × 103 M–1 KS/KR = 7.18

Scheme 11.7  BINOL derivatives for chiral recognition through fluorescence quenching. Source: Pu [41], Pugh et al. [42], Gong et al. [43], and Xu et al. [44, 45].

11.2 ­Chiral Recognitio

In addition to chiral amine, chiral recognition of N‐protected alanine is operable with BINOL derivatives. Wang and coworker found that axially chiral 37 bearing acetyl groups at 3,3′‐positions of BINOL skeleton performed excellently in enantioselective discrimination of the enantiomers of N‐protected alanine anion or N‐protected phenylalanine anion 38. Control experiment demonstrated that these sensors mainly interact with the chiral anionic analytes through multiple hydrogen bondings (Scheme  11.7) [44, 45]. Compared to fluorescence quenching, fluorescence enhancement is considered to be the more reliable and efficient mode in the domain of fluorescence recognition. Since 2002, Pu and coworkers have synthesized a series of axially chiral BINOLs with embedment of amino group, providing lone pair of electrons to quench fluorescence of molecule through intramolecular PET process [46]. When 39 was treated with chiral mandelic acid, protonation of amine nitrogen by acid would suppress the PET fluorescence quenching, resulting in huge fluorescence enhancement. This fluorescence enhancement was highly enantioselective [46]. Introduction of dendritic branch was also found to enhance fluorescent emission of the binaphthyl cores through intramolecular transfer [47]. Based on this atropisomeric skeleton, Pu and coworkers fashioned several macrocyclic sensors to enable highly enantioselective fluorescent recognition of mandelic acid. The enantiomeric fluorescence difference ratio (ef = ΔIS/ΔIR) of 42 was as high as 46 [48]. Under similar conditions, macrocyclic 42 functioned competently for hydroxycarboxylic acids and N‐protected amino acids as well [48, 49]. The use of 42 in optimization of the catalytic conditions for asymmetric transformation of achiral aldehyde to chiral hydroxycarboxylic acids evidenced the practical advantage of chiral fluorescent sensors. Axially chiral fluorescent sensors could bring additional advantages: a single molecular system 44 could be used to simultaneously determine the concentration and enantiomeric excess of chiral diamines [50], while 45 and 46 could operate in fluorous phase [51] and aqueous phase, respectively. These are a select few examples to showcase the efficacy of axially chiral fluorescent sensors based on BINOL skeleton (Scheme  11.8). Since this topic has been reviewed intensively elsewhere [31, 32, 52], we will not discuss further in this treatise. CD is another prevalent method to determine absolute configuration and enantiomeric excess of chiral small molecules. For effective detection of crude analytes, CD should be measured at near ultraviolet region where signal interferences from common chemicals are minimal. However, many analytes are also CD silent at this region [53]. Conformationally flexible atropisomers bearing unstable chiral axis could serve to amplify the chirality of analytes through chiral recognition. The central‐to‐axial chirality transfer from analytes to sensors results in favorable axial conformation, which can induce intense Cotton effect. In their independent works, Rosini and Toniolo have connected chiral small molecules to axially chiral unstable biphenyls to afford axially chiral amides 48 or simple linear dipeptides 49, respectively. Resultant biphenyl derivatives were efficient CD probes to assign absolute configurations for chiral carboxylic acids and amino acids (Scheme  11.9a) [54–56]. The racemic mixture of atropisomeric N,N‐chelate ligand 50 could discriminate the enantiomers of 51 through the formation of complex 52 and the ee could be determined using CD spectroscopy (Scheme 11.9b) [57]. The same strategy applied for determination of absolute configuration and ee of diverse amines with the use of CD silent diarylacetylene‐based 54 that contained three unstable chiral axes (Scheme 11.9c) [58].

305

306

11  Application in Drugs and Materials

H

O

R H

H

H

O O

NH

R

OH

O

O O

N H

R

OH

HO

OH

HO NH

R 39, R = H, ef = 2.49, 9.5 × 10–5 M 40, R = Ph, ef = 2.05, 1.0 × 10–5 M 41, R = 3,5-Ph2Ph, ef = 1.75, 1.0 × 10–5 M Ph NH

HN

HN

42, ef = 46, 5.0 × 10–4 M

Ph

O

HN

NH2 R

OH

HO

OH

HO

N

OH

NH OH

OH

OH

R NH Ph

HN

NH N

O 44, R = CF3 45, R = C7F15

Ph

43, ef = 12, 1.0 × 10–4 M

NH2

46

Scheme 11.8  BINOL derivatives for chiral recognition through fluorescence enhancement.

NH

O

O

Chiral acid

RM

(a)

COXaa*OMe

RM R S RL

R S RL P-48

47

NHBoc

N

N

M-48

49 O

O N N Br N

+

N

iPr

H

50

O Zn

N

O)2Zn

H

N

N

O

(b)

O

Br iPr H

Br iPr

N

51 52

OHC

N H2N

CHO

NH2

N 53

54

(c)

Scheme 11.9  Tropos molecules for chiral recognition through CD. Source: (a) Mazaleyrat et al. [54], Dutot et al. [55], and Superchi et al. [56]. (b) Modified from McCormick and Wang [57]. (c) Based on Iwaniuk and Wolf [58].

11.3  ­Chiral Additives in Liquid Crystal

11.3 ­Chiral Additives in Liquid Crystals Liquid crystals as special anisotropic materials that combine the fluidity of liquid and orderly arrangement of crystals find utility in displays, filters, and special optical devices [59, 60]. Immense efforts are continuously devoted to develop diverse liquid crystal materials and to explore their potential application in different fields. Cholesteric liquid crystals (CLCs) are self‐organized helical superstructures formed by enantiopure chiral liquid crystal materials (such as cholesterol) or nematic liquid crystals (NLCs, Scheme 11.10) mixed with chiral dopants [61]. CLCs are known to selectively reflect light of wavelength (λ) according to Bragg’s law (λ = np), where n is the average refractive index of the medium and p is the pitch length of the helical superstructures. External stimuli will change the pitch, which in turn changes the wavelength of circularly polarized light (CPL) selectively reflected by CLCs. Taking advantage of this property, researchers have identified widespread applications of CLCs in reflective LC displays, tunable lasers, and thermography, etc. [62, 63]. Additionally, CLCs could establish asymmetric reaction field for acetylene polymerization to afford novel helical materials [64].

p/2

Right-handed nematic liquid crystals

Left-handed nematic liquid crystals

Scheme 11.10  Nematic liquid crystals.

CLCs are usually prepared by mixing NLCs and chiral dopants, where several chiral substances could be deployed to achieve the desired effect through chirality transfer from dopants to nematic host. Helical twisting power (HTP) (β), which represents the ability of a chiral dopant to twist an achiral nematic LC phase, is an important indicator to evaluate chiral CLC dopants. The HTP is expressed by the equation βM = 1/(pc), where p is the pitch length of the helical superstructure and c is the molar concentration of the chiral dopant. It can thus be inferred from this formula that HTP and concentration change of dopants will directly affect the pitch of CLC [62, 65]. From another perspective, in order to obtain CLC with specific helical pitch, higher HTP signifies that lower dopant concentrations will be required. Chiral perturbation model revealed that the

307

308

11  Application in Drugs and Materials

handedness of dopant is transferred to racemic host via chiral conformational interaction. Upon receiving chiral information, the achiral host molecules will arrange into enantiomeric conformations and chiral perturbation could be propagated throughout the host via similar conformational interaction between host molecules. Hence, the magnitude of HTP often depends on structural complementarity between nematic host and chiral dopant [65–68]. Atropisomeric biaryl derivatives are the most utilized axially chiral dopants for CLCs. The correlation between the helicity of atropisomeric dopants and the helical sense of induced cholesteric phases was seminally disclosed by Gottarelli and coworkers [60, 69]. They found that the magnitude of HTP has positive correlation with structural similarity between nematic host and chiral dopants. Additionally, the sign of β (positive or negative) is determined by the dihedral angle between two aryl moieties of atropisomeric dopant, wherein the core with helical topography is more effective at chirality transfer in nematic phase than the core featuring nearly orthogonal alignment of two aryl groups. Locking the atropisomeric biaryls in cisoid conformation through introducing suitable ring structure on the biaryl skeleton or enforcing the biaryls into a transoid conformation by appending sterically congesting group are both effective methods to attain favorable dihedral angle of axially chiral dopants (Scheme 11.11) [68].

Left-handed helix

Right-handed helix X

X

X X

X

X

(S)-transoid

(S)-cisoid

θ

θ

θ X

X X

X

X

X

Scheme 11.11  Helical sense and the conformation of atropisomeric biaryls. Source: Modified from di Matteo et al. [68].

R N N

R UV

N N

Vis or ∆ R R trans-Azo

cis-Azo

Scheme 11.12  Bistable phenylazos bearing different HTPs between trans- and cis-conformations. Source: Modified from Wu et al. [70].

11.3  ­Chiral Additives in Liquid Crystal

It follows that adjusting the dihedral angle of atropisomeric core as well as the similarity between the dopant and nematic host through structural modification of atropisomeric biaryls will afford differing chiral dopants with distinctive HTP values (Scheme  11.12). In keeping with the common rod‐like structures of the molecules of NLC [65], Diederich and coworkers designed and synthesized a series of rod‐like molecules (56 and 59), which possessed β values of 130–315 μm−1 (Scheme 11.13) [70]. BINOL derivative 61 equipped with substituents that resembles nematic host PCH302/304 showed an extremely high HTP value of 757 μm−1. The high HTP and miscibility of 61 allowed preparation of highly twisted N*‐LC with helical pitch of 270 nm. The highly screwed chiral NLCs could depress the formation of the bundle of fibrils, leading to highly twisted bundle‐free helical polyacetylene composed of single fibrils. Compared to bundle of fibrils, the more closely packed morphology of single fibrils could benefit the invention of important functional materials [64, 71]. Photochromic molecules that change color upon irradiation offer numerous opportunities to be integrated in light‐driven molecular switches as well as reversible optical data

Nematic liquid crystal N H2n+1Cn

CN

C4H9O PhP

nCB E7, mixture of diverse nCBs

OC8H17

C3H7

O

OCnH2n+1

n = 2, PCH302; n = 4, PCH304

C7H15

O C10H21O

N

C9H19 F F NCB76

O

C4H9

PhB

OCH3

N MBBA

Chiral dopants O

S

55, R =

R O

O

N

R Me Me O In 5CB, β = 58 ± 6 µm–1

N

R

In E7 57, R = I, β = +130 µm–1 58, R = SiMe3, β = +160 µm–1

N 56, In E7, β = +220 µm–1

OC4H9

O S O N S O O

TBSOH2C CH2OTBS

O O S N O S O

In E7, 59, β = –315 µm–1

C6H13O O O 60 in 5CB, β = 80 µm–1 in MBBA, β = 56 µm–1

O O

(CH2)12O

C5H11

(CH2)12O

C5H11

C6H13O in PCH302/304, 61, β = 510–757 µm–1

Scheme 11.13  Atropisomeric exemplars bearing high HTPs.

309

310

11  Application in Drugs and Materials

storage and processing. Bistable molecules are a class of compounds that can interconvert between two stable conformations on irradiation [72]. Chiral NLCs doped with bistable molecules could thus exhibit photochromism because of conformation alternation of bistable dopants that induces a change in helical pitch and reflective light wavelength of the CLCs. In early studies, the photochromic and chiral components of chiral optical switches are separate entities. The photochromic entity could influence the chiral properties (magnitude of the helical pitch) but not the handedness of CLCs [73]. Gottarelli and coworkers pioneered the synthesis and evaluation of axially chiral switch 62, which acted as both a chiral dopant to induce CLCs and a photoresponsive dopant (Scheme 11.14). The applied azo group could undergo reversible light‐driven E–Z isomerization, which drastically changed the conformation of 62. This new axially chiral azo‐switch was shown to induce cholesteric phases in E7 and ZLI2359 hosts with strong HTP. Irradiation with 365 nm light visibly increased the pitch of CLCs and the system switched back when exposed to visible light of 546 nm. However, the irradiation time required to reach the photostationary states (PPSs) was rather long, presenting a limitation to be addressed [74]. In 2007, the Li’s group synthesized several analogs of 62 with high helical pitch and delineated their reversible photoresponsive properties. These azo‐containing atropisomeric compounds were revealed to be well‐suited dopants for CLCs. The authors constructed an optically addressed display from cholesteric mixture of 63 and nematic host 5CB. A high‐resolution grayscale image could be projected onto the display after a few

N

OCnH2n+1

N N

H2n+1CnO

RO RO

N

N

62, n = 9, β = +148 μm–1 In E7, 63, n = 8, 10, 12, 14, β = 153–172 μm–1

N

OR OR

64, β = 52 μm–1 (molar) R

C3H7

R= R N

OCnH2nO

N N

OH2 n C O n

O O

365 nm

65, β = 176.1 μm–1 (molar)

O O

N

β = 60.1 μm–1 (molar)

R=

in E7 (trans, trans) to (trans, cis) to (cis, cis)

N

OC6H12O C8H17O

N β = +27 μm–1

66

–1

β = +39 μm

β = +34 μm–1

N

N

OC8H17 OC6H12O

in 5CB

β = –50 μm–1

in E7

β = –33 μm–1

in ZLI-1132

β = –17 μm–1

Scheme 11.14  Atropisomeric azo compounds showed reversible photoresponsive properties.

11.3  ­Chiral Additives in Liquid Crystal

seconds of irradiation, and the image could be retained on the screen for 24 hours at room temperature before being thermally erased. This display founded on azobinaphthyl chiral switches was inherently of high‐resolution, cost‐effective, electronics‐free and could be rendered flexible [75]. On the basis of these structures, Li’s group synthesized two novel light‐driven chiral molecular switches 65 with axial and central chirality elements [76]. The reflection color of the CLC mixture of 65 in nematic host E31 could be phototuned over entire visible region by these novel switches. It is noteworthy that short irradiation time (