Contemporary Aspects of Boron: Chemistry and Biological Applications 9780444520210, 044452021X

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Studies in Inorganic Chemistry 22

Contemporary Aspects of Boron: Chemistry and Biological Applications

Studies in Inorganic Chemistry 22 Other titles in this series 1. Phosphine, Arsine and Stibine Complexes of the Transition Elements by C.A. McAuliffe and W. Levason 2. Phosphorus: An Outline of its Chemistry, Biochemistry and Technology (Second Edition) by D.E.C. Corbridge 3. Solid State Chemistry 1982 edited by R. Metselaar, H.J.M. Heijligers and J. Schoonman 4. Gas Hydrates by E. Berecz and M. Balla-Achs 5. Sulfur: lts Significance for Chemistry, for the Geo-, Bio-, and Cosmosphere and Technology edited by A. Müller and B. Krebs 6. Phosphorus: An Outline of its Chemistry, Biochemistry and Technology (Third Edition) by D.E.C. Corbridge 7. Inorganic High Pressure Chemistry: Kinetics and Mechanisms edited by R. van Eldik 8. Graphite Fluorides by N. Watanabe, T. Nakajima and H. Touhara 9. Selected Topics in High Temperature Chemistry: Defect Chemistry of Solids edited by Ø. Johannesen and A.G. Andersen 10. Phosphorus: An Outline of its Chemistry, Biochemistry and Technology (Fourth Edition) by D.E.C. Corbridge 11. Chemistry of the Platinum Group Metals edited by F.R. Hartley 12. Luminescence and the Solid State by R.C. Ropp 13. Transition Metal Nuclear Magnetic Resonance edited by P.S. Pregosin 14. Chemistry of Inorganic Ring Systems edited by R. Steudel 15. Inorganic Polymeric Glasses by R.C. Ropp 16. Electron Paramagnetic Resonance of d Transition Metal Compounds by F.E. Mabbs and D. Collison 17. The Chemistry of Artificial Lighting Devices. Lamps, Phosphors and Cathode Ray Tubes by R.C. Ropp 18. Structure and Chemistry of the Apatites and Other Calcium Orthophosphates by J.C. Elliott 19. Molybdenum: An Outline of its Chemistry and Uses edited by E.R. Braithwaite and J. Haber 20. Phosphorus 2000: Chemistry, Biochemistry & Technology by D.E.C. Corbridge 21. Luminescence and the Solid State, 2nd Edition by R.C. Ropp

Studies in Inorganic Chemistry 22

Contemporary Aspects of Boron: Chemistry and Biological Applications Hijazi Abu Ali Valery M. Dembitsky Morris Srebnik Department of Medicinal Chemistry & Natural Products School of Pharmacy Hebrew University of Jerusalem Israel

Edited by Hijazi Abu Ali

2005

JJl c %?Sf I »

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Vll

Preface The excitement and challenges in medicinal chemistry research have never been greater. The breathtaking speed at which scientific advancements are made and their diversity, coupled with the range and complexity of today's technologies, can easily leave the medicinal chemist confused and exhausted. While boron is not usually associated with medicinal chemistry, great strides in the last few years in the use of boron reagents in the synthesis of pharmacologically active molecules (Chapters 3, 4 and 6), and the discovery of novel natural products containing boron as essential to their activity (Chapter 9), as well as the introduction to the clinic of the first synthetic boron drug containing a B-C bond, Velcade*, (Chapter 8), has given impetus to the field of boron medicinal chemistry. The authors hope that the material presented in this book will make the concepts and methods of boron chemistry clear and interesting to aspiring and experienced medicinal chemists alike, as well as to medicinal chemistry students all over the world. Furthermore, this book is expected to give new insights to active researchers in the field. One of the most important objectives of this timely and comprehensive book is to highlight the biological activity and applications of boron containing compounds.The main aim of the medicinal chemist is to identify an active compound which may prove to be a potential drug precursor and to develop the properties required for its introduction in the clinic. The limited scope of this book does not permit a comprehensive review of all aspects of boron chemistry, but we initially survey some general features of the subject, with emphasis on unique synthetic aspects and on properties particularly characteristic of boron-containing compounds, followed by a review of the most relevant components that comprise the pharmaceutical, medicinal and environmental applications of boron-containing compounds. Chapter 1 focuses primarily on features of the chemistry of diboron compounds, of particular interest from the organometallic and biological point of view. Diborane reagents of the general formula B2(OR)4 are currently utilized as reagents for a series of transition metal-catalyzed reactions. Bis(pinacolato)diborane(4) is preferred over other (alkoxo)diborons, because it exhibits high stability towards hydrolysis. An overview of recent multi-stage synthesis shows the need for new strategies composed of a minimum number of chemical steps. Therefore, the combination of multiple reactions in a single operation represents a particularly efficient approach. Among these strategies, the synthesis and reactivity of bisdiboranes has yet to be reviewed, although its popularity as a step in the synthesis of complex architectural molecules has been steadily increasing during the last decade. Chapter 2 highlights the use of partly geminated boranes (B-C-B), and also bisdiborane reagents (B-C-C-B, B-C=C-B, B-C=C-B), and will provide the chemist with knowledge to utilize this important tool in future work. Chapter 3 focuses on the synthesis, characterization and application of Suzuki cross-coupling reaction, organometallic, inorganic and metal organic compounds. It also includes the total synthesis of different bioactive natural products such as antibiotics, antifungal agents, antiviral compounds and anticancer agents.

viii

Preface

These endeavors, which include the design of new synthetic methodology, enantioselective transformations, heterocyclic chemistry, parallel synthesis and combinatorial chemistry, are directly relevant to pharmaceutical innovation. The demand for natural drugs is likely to increase in the near future, but unfavorable pharmacological properties such as non-selectivity, poor oral availability, and rapid hydrolysis have limited the usage of unmodified natural-like compounds as drugs. The development of asymmetric synthesis during the past two decades aided organic chemists considerably in the synthesis of complex natural products. Organoborane chemistry continues to play an important role in asymmetric synthesis. One of the important reactions that have become very common in the arsenal of synthetic chemists is allylboration and related reactions. Synthesis of selected biologically active compounds via allylboration is reviewed in chapter 4. The need to develop new methods of treating cancer has arisen from the failures of existing therapies, especially in the treatment of glioblastomas and anaplastic astrocytomas by surgery, chemotherapy and conventional radiation therapy that has had only limited success. The major constraint in the treatment of cancer was and still remains the differentiation between normal and cancerous tissues. The need for more effective targeted treatment led to the development of boron neutron capture therapy (BNCT), which refers to the radiation generated from the capture reaction of thermal neutrons by l0Boron isotopes, Chapter 5. Enolates are in principle capable of reacting as either a carbon atom or oxygen atom nucleophiles. Boron enolates mainly are intermediates which react to give products similar to those from an aldol reaction. The reaction proceeds with high diastereoselectivity via a cyclic transition state and is analogous to the transition state of allylboranes. Its use in organic syntheses, and also in the synthesis of some natural products, is partly reviewed in Chapter 6. The interaction of boronic acids with saccharides is a subject of considerable research. Chapter 7 discusses the interaction of boronic acids with saccharides and the usefulness of this kind of interaction in chemosensing, transport, chromatography, diabetes, cancer, drug delivery and few other miscellaneous applications. Chapter 8 describes the importance of a-aminoboronic acids and amine carboxyboranes in the area of pharmaceutical chemistry. a-Aminoboronic acids are inhibitors for serine proteases, proteasomes, arginase, NOS and cysteine, while amine carboxyboranes possesses antitumor, anti-inflammatory, hypolipidemic, antiostoeoporotic, and anti-neoplastic activities. Boron is an important element in rocks, soils, water and plants. Chapter 9 includes description of boron chemistry, the presence of boron in soils and plants as well as in water desalination processes. Hijazi Abu Ali Valery M. Dembitsky Morris Srebnik July 2005

IX

Table of Contents Chapter 1: Chemistry of the diboron compounds H. Abu Ali, V.M. Dembitsky andM. Srebnik 1. Introduction 2. Preparation of Diboron Compounds and their Properties 3. Reactions of Diboron Compounds References Chapter 2: Recent developments in bisdiborane chemistry: B-C-B, B-C-C-B, B-C=C-B, and B-C=C-B compounds and their biological applications H. Abu Ali, V. M. Dembitsky and M. Srebnik 1. Introduction 2. Formation of B-C-B Compounds 3. Geminal Organoboron Compounds 4. Formation, Reactivity and Biological Activity of B-C-C-B, B-C=C-B, and B-C=C-B Compounds References

1

2 3 16 52

59

60 61 68 85 113

Chapter 3: Applied Suzuki cross-coupling reaction for syntheses of biologically active compounds 119 V.M. Dembitsky, H. Abu Ali and M. Srebnik 1. Introduction 2. Synthesis of Biologically Active Compounds via Cross Coupling Reaction Catalyzed by Palladium 3. Cross-coupling of Alkynylborane Derivatives with Haloarenes 4. Cross-coupling of Alkynylborane Derivatives 5. Cross-coupling of Alkylborane Derivatives 6. Synthesis of Macrocycles 7. Modification of Nucleosides using Suzuki-Miyaura Coupling 8. Synthesis of Substituted Porphyrins 9. Additional Application of the Suzuki Cross-coupling Reaction 10. Synthesis of Macrocyclic Compounds 11. Synthesis of Tetracyclic Systems 12. Synthesis of Polycyclic Ethers 13. Synthesis of Disubstituted Furans 14. Synthesis of GeranylGeranyl Diphosphate Derivatives 15. Synthesis of Spiroquinolizidine Derivatives 16. Synthesis of Carbohydrate-Substituted Phosphines 17. Synthesis of Novel Thyroid Hormone Analogues: 5'-Aryl Substituted GC-1 Derivatives References

120 120 133 155 166 184 222 236 241 243 250 261 267 270 271 273 280 282

X

Table of Contents

Chapter 4: Synthesis of selected biologically active compounds via allylboration V. M. Dembitsky, H. Abu AH andM. Srebnik

299

1. Introduction 2. Synthesis of Heterocyclic Compounds 3. Synthesis of N-Lactone Rings 4. Allylboration of Nitrogen Heterocycles References

300 301 319 326 331

Chapter 5: Boron neutron capture therapy. A. K. Azab, H. Abu AH andM. Srebnik

337

1. Introduction 2. The Concept of Boron Neutron Capture Therapy 3. BNCT in the Treatment of Cancer 4. Boron Targeting to Cancer Tissues 5. Summary References

338 338 341 344 360 361

Chapter 6: Boron enolates in the syntheses of natural products V. M Dembitsky, H. Abu AH andM. Srebnik

367

1. Introduction 2. Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide 3. Enantioselective Total Synthesis of (+)-Leucascandrolide- A Macrolactone 4. Synthesis of the C29-C51 Subunit of Altohyrtin C (Spongistatin 2) 5. Asymmetric Synthesis of the Polyene Macrolide Antibiotic RK-397 6. Asymmetric Total Synthesis of Spongistatins 1 and 2 7. Synthesis of the Microtubule-Stabilizing Agent (-)-Laulimalide 8. Synthesis of (2S,3S)-and (2R,3R)-/?-Hydroxyornithine 9. Synthesis of Concanamycin F 10. Synthesis of an Isomer of Membrenone C 11. Synthesis of Doliculide 12. Synthesis of Tri- and Tetrapeptide S: the Extended C-Terminus of Bleomycin A2 13. Synthesis of A (9S)-Macrolide Intermediate for Oleandomycin 14. Synthetic Studies on Antitumor Antibiotic Bleomycin 15. Synthesis of the Esterase Inhibitor (±)- Ebelactone A 16. Synthesis of the Oviposition-Deterring Pheromone in Rhagoletis cerasi 17. Synthesis of (±)-Hernandulcin 18. Synthesis of Beta-Lactam Antibiotics 19. Synthesis of (+)-Pseudomonic Acid C 20. Synthesis of Masamune Norephedrine Esters 21. Synthesis of L-Daunosamine and D-Ristosamine Derivatives 22. SEMI- Synthesis of Taxol 23. Synthesis of the Pyrrolizidine Ring System 24. Synthesis of (-)-Branched Unusual Amino Acids 25. Synthesis of cc-Amino Acids

369 369 370 371 372 372 373 374 374 375 376 376 377 377 378 378 379 379 380 381 381 382 382 383 383

Table of Contents

xi

26. Synthesis of 1 - Beta-Methylcarbapenem Antibiotics 27. Synthesis of Nakadomarin 28. Synthesis of ll-^,17-je-Diaryl-18A-Homo-19-Norsteroids 29. Synthesis of the Central C18-C30 Core of the Phorboxazole 30. Synthesis of A C17-C32 Subunit of Scytophycin C 31. Synthesis of the Archaebacterial C40 Diol 32. Synthesis of Anthracycline Glycosides References

384 385 385 386 386 387 387 388

Chapter 7: Boronated saccharides: potential applications R. Smoum and M. Srebnik

391

1. Introduction 2. Boronic Acids-Saccharide Interaction; the Basics 3. Chemosensing 4. Transport 5. Boron and Plants 6. Chromatography 7. Boron and Diabetes 8. Boron and Cancer 9. Drug Delivery 10. Miscellaneous Biological Applications of Boron Saccharide Interactions References

393 393 396 434 446 451 461 465 470 472 479

Chapter 8: a-Aminoboronic acids, amine cyanoboranes, amine carboxyboranes and their derivatives 495 K. Takrouri, V.M. Dembistky and M. Srebnik 1. Introduction 2. a-Aminoboronic Acids 3. Amine Cyanoboranes and Amine Carboxyboranes 4. Biological Activities of Amine Cyano- and Carboxyboranes and their Derivatives References

496 496 522

Chapter 9: Environmental aspects of boron A. Shibli andM. Srebnik

551

1. Introduction 2. Boron Chemistry 3. Boron in Soils 4. Boron in Plants 5. Water Desalination References

552 553 560 562 580 593

Index

599

537 544

This Page is Intentionally Left Blank

Chapter 1 Chemistry of the diboron compounds H. Abu Ali, V.M. Dembitsky and M. Srebnik Department of Medicinal Chemistry & Natural Products, School of Pharmacy, P.O. Box 12065, Hebrew University of Jerusalem, Jerusalem 91120, Israel

Contents 1. INTRODUCTION 2 2. PREPARATION OF DIBORON COMPOUNDS AND THEIR PROPERTIES 3 2.1. Formation of B—B bond 3 2.2. Synthesis, structure and properties of some halogenated diboranes 3 3. REACTIONS OF DIBORON COMPOUNDS 16 3.1 Miscellaneous reactions 16 3.2. Reactions with allenes 25 3.3. Synthesis of bisdiboron from diboron compounds 27 3.4. Reactions with diols and thiols 28 3.5. Synthesis of arylboronates 28 3.6. Synthesis and reactions of diborametal complexes 39 3.7. Reactions with dienes and alkenes 49 REFERENCES 52

H. Abu Ali et al. 1. INTRODUCTION Diborane reagents of the general formula B2(OR)4 have been utilized recently as reagents for a series of transition metal-catalyzed reactions. The first example of a reaction employing these reagents was reported in the early 1990's by Miyaura and co-workers, who described the diboration of alkynes catalyzed by Pt(PPli3)4 [I]. Metal-catalyzed diboration has since been extended to a useful methodology. Boron-containing compounds with a boron-boron single bond are important intermediates in structural complexity between simple monoboron derivatives and the polyhedral electron-deficient compounds of the element. The properties of diboron compounds, particularly the simple derivatives of the B2X4 type, have attracted the attention of many laboratories around the world since Stock's initial discovery of B2CI4 nearly 80 years ago [2]. These boron-containing compounds provide the simplest examples of catenation in boron chemistry and offer suitable systems to study properties of the covalent B—B bond and the characteristic chemistry of compounds containing this linkage. Studies on the organic and inorganic chemistry of the B-B compounds have been reviewed [3]. Boronic acids and esters are used in a wide variety of research applications [4]. They also continue to attract attention as versatile functional group tolerant crosscoupling substrates in organic synthesis [5]. Synthetic methodology allowing for the direct attachment of boron to aromatics to afford arylboronates is thus an important challenge [6]. Arylboronic esters are generally purified more easily than arylboronic acids, can be synthesized without organolithium or Grignard reagents and promote one-pot cross-couplings [7]. Aryl borylation reactions, which directly afford arylboronic esters, have been successfully performed using aryl halides and triflates [6]. Two aspects of the boron chemistry of this class of compounds are particularly relevant: First, synthesis and properties of organodiboron derivatives, and, indeed, even authentic synthetic failure in this area, are of interest in comparison with the rich organic chemistry of monoboron derivatives. Second, the chemistry of subvalent boron compounds and their interactions with organic and organometallic systems can lead to novel reactions that make organoboron derivatives accessible. This chapter will concentrate primarily on features of the chemistry of diboron compounds of particular interest from the organometallic and biological point of view. While our limited scope does not permit a comprehensive review of all aspects of diboron chemistry, we will initially survey some general features of the subject, with emphasis on unique synthetic aspects and on properties particularly characteristic of compounds containing a simple electron-pair bond between boron atoms. Previously we published several review articles provided some aspects on boron chemistry [8-16], and including natural boron-containing compounds [17-18].

Chapter 1 2. PREPARATION OF DIBORON COMPOUNDS AND THEIR PROPERTIES 2.1. Formation of B—B bond Synthesis of diboron compounds may involve either reductive coupling reactions of monoboron derivatives to form the boron-boron bond [19], or reactions of compounds possessing preformed B2 fragments [20]. The earliest synthesis of characterized diboron compounds was the preparation of B2CI4 by Stock [1], using an electric discharge between zinc electrodes immersed in liquid BCI3. Many discharge procedures have been reported for the synthesis of B2CI4 [21-26]. Structures of some halogenated diboranes, 1, 2, and 3 are shown in Fig. 1. Diborane(6) 3 (or diboron hexahydride) has been reviewed [27-31].

II

3

"

H

Fig. 1. Structures of some halogenated diboranes, 1, 2, and 3. Adapted by authors 2.2. Synthesis, structure and properties of some halogenated diboranes The first formation of B2Br4 and B2I4 from the trihalides by discharge methods has also been reported [32,33], but these boron halide sare rarely used in synthesis. Attempts to prepare B2F4 from BF3 in a discharge between mercury electrodes were unsuccessful [34]. Conventional chemical reduction of boron trihalides with active metals, metal borides, hydrogen plus metal, or other reducing agents is not a satisfactory route to the tetra(halo)diboranes [2,22]. Synthesis of B2CI4 has been reported by Timms, who condensed BCI3 at -196 °C with copper atoms produced by vaporization of the metal [35], or high-temperature approach to the formation of B-B bonds by the insertion of BF (formed at 2000 °C from boron and BF3) into the B-F bond [36]. Formation of tetra(methoxy)- and tetra(ethoxy)diborane(4) from the corresponding dialkoxychloroboranes and sodium was reported by Wiberg and Ruschmann [37], although later workers were unable to reproduce the synthesis of the ethoxy derivative [38]. Boron reacts vigorously with CI2 and F2 to form BCI3 and BF3 respectively, which when reacted with boron halides gave compounds 4 and 5 (Scheme I). Synthesis of other diboron derivatives 6-10 have also been reported (Scheme 1) [38,39-50].

H. Abu Ali et al.

2BCI3 + BCI3

2B + 3F,

2(R2N)2BCI

^ 2BF, + BF

+

2M

R = Me, Et M = Na or K 2(Me2N)2BRX + 2M R = Me, Et, Ph, Pr, n-Bu M = Na or K X = Cl, Br 2Et2NPBNEt2CI + 2M M = Na or K

2R1O(R2N)BCI + 2M

*-

Rcf^OR 9

M = Na/K PrO, 2(Rr2O)2BCI + 2K

*~

pPr B-Bs PrO °P r

10 Diborane compounds with common structure 11 (Scheme 2) have been synthesized [46,49]. The synthesis of a series of bis(catecholato)diborane(4) compounds 12-16, B2[1,2-O2C6H4]2 12, B 2 [l,2-O2C 6 H 3 Me-4] 2 13, B 2 [l,2O2C6H2Me2-3,5]2 14, B2[l,2-O2C6H3-?Bu-4]2 15, and B 2 [l,2-O 2 C 6 H 2 mu 2 -3,5] 2 16 (Scheme 2) have recently been reported [51]. The above compounds have been synthesized by reaction of 1% sodium/mercury amalgam with the corresponding halocatecholboranes, which are cleanly formed from the reaction of BCI3 or BBr3 and catechol. Combining these two steps in one pot, B2[l,2-O2C6H3fflu-4)]2 was prepared from BCI3 and 4-tert-buty I catechol, and B2[l,2-O2C6H2/Bu2-3,5]2 was prepared from 3,5-di-tert-butylcatechol and BBr3 on a multigram scale. Bis(pinacolato)diborane(4) was not formed from reaction of chloropinacolborane and Na/Hg, but it was formed by in situ addition of pinacol to either B2[1,2-O2C6H3?Bu-4)]2 or B2[l,2-O2C6H2fBu23,5]2.

Chapter 1

Scheme 2 ~B-CI

X = 0, S, N(Me, Et,/-Pr) Y = (CH2)n n = 2, 3

x'

Y 11

Reaction of sodium naphthalide with B2CI4 at room temperature was reported to give a liquid product with a suggested structure, 17. The compound 17 reacts with 4 equiv of (CH3)3N to form an adduct which decomposes above 100 °C to give the bis(trimethylamine) adduct of B2CI4 and an unstable product that is thought to be 18 (Scheme 3). It was reported that the trimethylamine complex of tetra(methyl)diborane(4) was obtained from the reduction of bromodimethylborane with sodium or silver in trimethylamine [52].

H.AbuAlietal. Scheme 3

Scheme 4

Me2N

Me2N B-CI 2 Me2N

B-CI

NMe2

4K -4KCI

80% 23 Me2N NMe2

B-B

S

Me2N

B-B

/ NNMe2

26

25

NMe2 B-B'

Me,N 24

H. Abu Ali et al.

Fig. 3. View of the molecular structure of 22 showing the atom numbering scheme. Ellipsoids represent thermal displacement parameters at the 50% probability level. The molecules are located in the crystal on twofold symmetry axes; primed atoms are related to non-primed atoms by symmetry transformation: 1 - x, y, l'/2 - z . Selected bond distances (A) and angles (°) include: B1-B2 1.739(4), B1-N3 1.424(2), B1-N4 1.427(2), mean C-N 1.472, mean C-C 1.523, N4-B1-N41 121.7(2), N3-B2-N3' 120.8(2), N4-B1-B2 119.1(1), N3-B2-B1 119.6(1), N4-B1-B2-N3 -103.6(1), N4-B1-B2-N31 76.4(1) However, tetra(amino)diboranes(4) of type R2N(Me2N)B-B(NMe2)NR2 are more readily accessible from LiNR.2 and B2(NMe2)2Cl2. Similarly, amination of B2(NMe2)2Cl2 with N,N'-dimethylethylenediamine gives B[bis(dimethylamino)boryl]-N,N'-dimethyl-l,3,2-diazaborolidine 29, while reactions with Li(Me)N-CH2CH2-N(Me)Li also give 2,3-bis(dimethylamino)-l,4-dimethyl-l, 2,3,4diazadiborinane 30 as the kinetically controlled product. Diborane(4) dihalides B2(NMe2)2X2 (X = Cl, Br) 20a reacts only in a 1:1 ratio with TMP-B=N-CMe 3 leading to 28 (molecular structure shown in Fig. 4 and 29 (Scheme 6) [54].

Chapter 1

Scheme 6 Me 2 N

M

—N

NMe 2

N— (CH 2 NLiMe 2 ) 2

28

Fig. 4. Molecular structure of heterocyclic compound 28. Adapted by authors Heterocyclic organodiboron compounds 31 and 32 have been obtained by transamination of dialkylbis(dialkylamino)diborane(4) derivatives with o-diamines (Scheme 7) [49], and reaction of B2[NMe2]2(«-C4H9)2 with o-aminophenol gave an unstable heterocycle 33. Organoboron heterocycles 34 and 35 containing the boronboron bond have been prepared by the reaction of yV-lithio derivatives of alkylbis(alkylamino)boranes with l,2-dichloro-l,2-bis (dimethyl-amino)diborane(4) [55].

10

H.AbuAlietal.

Scheme 7

R Me2N R

R

NMe2

= alkyl, aryl, C\

NMe

NMe, -B i

-B. NMe?

NMe2

R 34

35

The synthesis and characterization of a series of bis(catecholato)diborane(4) compounds, B2(1,2-O2C6H4)2 38, B2(l,2-O2-3-MeC6H3)2 40, B 2 (l,2-O 2 -4-MeC 6 H 3 ) 2 41, B 2 (l,2-O 2 -4-/Bu-C 6 H 3 ) 2 42, B 2 (l,2-O 2 -3,5-/Bu 2 C 6 H 2 ) 2 43, B 2 (l,2-O 2 -3MeOC6H3)2 44, bis(dithiocatecholato)diborane(4) compounds, B2(1,2-S2C6H4)2 47, B 2 (l,2-S 2 -4-MeC 6 H 3 ) 2 48, and tetra(alkoxy)diborane(4) compounds, B2(OCH2CMe2CH2O)2 45 and B 2 (0CMe 2 CMe 2 0) 2 46 from B2(NMe2)4 36 was described (Scheme 8). Compound 36 was synthesized by reductive coupling of BCl(NMe2)2, which in turn is prepared from reaction of BC13 with B(NMe2)3 in a 1:2

11

Chapter 1

stoichiometry. Also were characterized [B2CU-(NHMe2)2] 37 formed from addition of HCI to 36 prior to complete reaction with diols, and the salt, [NH2Me2]-[B(l,2C>2C6H4)2], which arises from addition of catechol to B(NMe2)3. Thus, any B(NMe2)3 impurity present after the preparation of 36 needs to be removed by distillation prior to reaction with alcohols [56]. Scheme 8 BCI3

2B(NMe2)3

Me2N

NMe2 N

3BCI(NMe2)2

B-B' V

Me2N

NMe2 36

HCI

Rn-

NMe,

XT*38: Rn = H 4 39: Rn = 3,5-f-Bu-4,6-H2 40: Rn = 3-Me-4,5,6-H3 41: Rn = 4-Me-3,5,6-H3 42: Rn =4-(-Bu-3,5,6-H3 43: Rn = 3,5-f-Bu-2,4,6-H3 44: Rn = 3-MeO-4,5,6-H3

P Rn-

-Rn

O

45

O

47: Rn = H 4 48: Rn = 4-Me-3,5,6-H3

The X-ray structures have been described for the bis(catecholato), bis(dithiocatecholato), and tetra(alkoxy)diborane(4) compounds B2(l,2-O2CeH4)2, B2(l,2-O2-4-/BuC6H3)2, B2(l,2-O2-3,5-tBu2C6H2)2, B2(l,2-S2C6H4)2, B 2 (l,2-S 2 -4MeC6H3)2, and B2(OCH2CMe2CH2O)2. In the solid state, all the compounds adopt planar structures for the B2O4 or B2S4 units, Fig. 5.

12

H. Abu Ali et al.

Fig. 5. Molecular structures of some diboron compounds. Structure of B20,2-02-3Me2C6H3)2 45, B-B bond length was determined as 1.315 A; and structure of B2(l,2-O2-3,5(Bu2C6H2)2(NHMe2)2, B-B bond length was found as 1.788 A; Structure of B2(l,2-S2-4MeC6H3)2 48, B-B length was determined as 1.737 A Adapted by the authors A series of mixed tetra(amino)diborane(4) compounds bearing pyrrolyl. indolyl, and carbazolyl substituents besides dimethylamino groups has been prepared and subjected to reduction with elemental lithium in the presence of diethyl ether [60]. Tetra(amino)diborates(2-) are formed, which feature a boron-boron double bond (Scheme 9). The new diborates are isoelectronic with tetra(amino)ethylenes and are expected to be electron-transfer reagents [57]. X-ray crystal structures for 49 and 50 were studied and are depicted in Fig. 6.

Chapter 1

13

Scheme 9

Cl

R2N

N— B-B

N—

B-B' NR, -N \

LiNR, Cl

49: NR2 = pyrrolyl 50: NR2 = indolyl

B

Fig. 6. Molecular structures of 49 (A) and 50 (B) with B-B bonds 1.723 (A) and 1.718 (B) A respectively. Adapted by the authors Tetra(dimethylamino)diborane(4) was treated with o-phenylene isothiocyanato-boronate, to give an interesting reaction which involve not only disproportionation but also cleavage of the B-B bond giving compounds 51 and 52. The products were isolated in good agreement with this stoichiometry: 2-(l,3,2benzodioxaborolo)-l,3,2-benzodioxaborole 12, by comparison of its properties with those previously reported elsewhere [58] was indicated as the third product (Scheme 10).

14

H. Abu Ali et al.

Scheme 10

r

|

^NCS

Me2N

NMe2

Me,N

NMe,

+

O NMe2 'NMe,

Me2NB(NCS)2 52

51

12

The first synthesis of bis(pinacolato)diboron(4) 46 was reported more than 20 years ago by Noth [59], and the practical procedure is described below. A 2L, three-necked flask fitted with a mechanical stirrer, dropping funnel, and a reflux condenser connected to a nitrogen source and a bubbler is flushed with nitrogen. To the flask are added 53.7 g (0.271 mol) of tetra(dimethylamino)diborane(4) and 510 mL of toluene, and then a solution of 64.4 g (0.545 mol) of pinacol in 340 mL of toluene is added. The flask is immersed in an ice-water bath and a 5.4 M ethereal solution of hydrogen chloride (203 mL, 1.10 mol) is added dropwise during 2 h. As soon as the addition is started, a white precipitate of dimethylamine hydrochloride appears. The slurry is stirred at room temperature for an additional 4 h. The precipitate is removed by suction filtration, and the filtrate is concentrated on a rotary evaporator to give a white solid. The solid is dissolved in ca. 700 mL of pentane and the remaining solid is again removed by filtration. The filtrate is washed three times with 500 mL of water and dried over anhydrous MgSCU. The drying agent is removed by filtration and the filtrate is concentrated to ca. 150 mL. The flask is heated to dissolve the resulting precipitate, allowed to cool to room temperature, and then thoroughly chilled in a freezer (-30 °C). The first crop is collected by filtration and washed twice with 30 mL of cold pentane. The mother liquor is again concentrated to give another crop of crystals. The procedure is repeated two additional times. The combined crystals are dried under reduced pressure (0.1 mm) for 16 h at room temperature to give 54.3 g (79%) of 46 as colorless plates, mp 138 °C [59] (Scheme 11).

Chapter 1

15

Scheme 11 pentane BBr-,

Me,NH

- 7 8 ° C "*"

NMe,

NMe2

BBro

Me 2 N' "NMe 2

. 7 8 =c

p e n tane

Me 2 N'

R

2Na toluene

2 pinacol, benzene 4 HCI/ether

2

-g_

Me2N

NMe2

Structural changes as a function of the torsional angle about the B-B bond angle have been studied for the diborane tetrahalides X2B-BX2 (X = F, Cl, Br) by abinitio calculations [59]. The perpendicular structure with Dod symmetry was predicted to be the most stable conformation when the double-zeta basis 6-31G* set was used in the calculations. A triple-zeta basis set augmented with diffuse functions and polarization functions of the type 6-311+G* showed that the planar D2h conformation is the most stable conformation for B2F4 which is in agreement with experimental results. Inclusion of correlation through the MP2 level of theory affects mostly the B-F bond length, and only to a small degree the barrier hight. For intermediate states with one X-B-B-X torsional angle constrained to lie between 0 and 90° a pyramidal arrangement around the boron atoms is predicted with an overall symmetry of C2, and with two unequal B-X bond distances and two unequal B-B-X bond angles. Vibrational frequencies have been calculated and compared with experimental assignments [59]. As shown by Dewar et al. [60] the N atom of azoniaboratanaphthalenes can be lithiated, when the B atom is protected by an alkyl group. The B-ferfbutyl derivative 53 was lithiated with LiMe in the presence of tetramethylethylenediamine (tmen). Subsequently, the AMithio derivative 54 was borylated with the diborane and the corresponding l,2-bis(azoniaborata-lCl-B(NMe2)-B(NMe2)-Cl naphthyl)diborane 55 was obtained (Scheme 12) [61].

16

H.AbuAlietal.

Scheme 12 Li(tmen) i

1)MeLi, hexane, -30 °C

^ p j B ^

k^kx 1

^X/NL^t-Bu

2) (tmen), hexane, -78 °C to rt, 3h __

^

*~

IQIQj 53 t-Bu

Li(tmen)

B2Cl2(NMe2)2 (etheral solution)

/t-Bu

o °C , then rt, 6h —

~

55 "2 (tmen) = tetramethylethylenediamine

54, 80%

3. REACTIONS OF DIBORON COMPOUNDS 3.1 Miscellaneous reactions The insertion of CO into the B-B bond of l,2-bis(diisopropylamino)-2,5dihydro-7H-l,2-diborole 60 and l,2-bis(diisopropylamino)-3-methylidene-l,2diborolane 56 leads to the dimeric spiro products 1,7,9,14-tetrakis(diisopropy 1amino)-6,13-dioxa-l,7,9,14-tetraboradispiro[4.2.4.2]tetradeca-2,10-diene 61 and 1,7,9,14-tetrakis(diisopropyl-amino)-bismethylidene-6,13-dioxa-1,7,9,14-tetraboradispiro[4.2.4.2]-tetradecane 57. The reaction of 60 with tert-butyl isocyanide and 2,6dimethylphenyl isocyanide in THF leads to the formation of the monomeric insertion products l,3-bis(diisopropylamino)-2-ferf-butylimino-l,3-diboracyclohex-4-ene 62 and l,3-bis-(diisopropylamino)-2-(29,69-dimethylphenylimino)-l,3-di-boracyclohex4-ene 63. Treatment of 56 with the isonitriles gives 2-/ert-butylimino-l,3bis(diisopropylamino)-4-methylidene-l,3-diboracyclohexane 58 and 1,3bis(diisopropylamino)-2-(29,69-dimethylphenylimino)-4-methylidene-),3-diboracyclohexane 59 (Scheme 13) [62]. Commercially available Pt(cod)Cl2 catalyzes the diboration of alkenes, alkynes, and aldimines using bis(catecholato)diborane(4) (cod = 1,5-cyclooctadiene). Catalyzed aldimine diboration provides the first direct route to r-aminoboronate esters. The diboration product from N-benzylidene-2,6-dimethylaniline was structurally characterized by physico-chemical methods (Scheme 14) [63].

17

Chapter 1 Scheme 13

2C0 (/-Pr)2N=B-B=N(/-Pr)2 56 (/-Pr)2N

N(/-Pr)2

57

II ^N(/-Pr)

(;-Pr)2N

2

(/-Pr)2N=B-B=N(/-Pr)2 60

The development of novel strategies for effectively linking organic compounds to solid supports has become essential as solid-phase chemistry and combinatorial technology have evolved into fundamental tools for drug discovery [64]. In principle, the ideal linker should provide effective loading onto the support, stability under a diverse variety of reaction conditions, and easy product removal without contamination from the linker [65].

18

H. Abu Ali et al.

Scheme 14

87%

A novel linking strategy has been developed for synthesizing configurationally stable w-amino aldehyde on polymeric supports. Alkylation of Lalanine methyl ester with 9-bromo-9-/>-bromophenylfiuorenene, followed by ester hydrolysis and coupling to isoxazolidine, provided JV-(9-/>-bromophenylfluoren-9-yl)alanine isoxazolidide(5) 64, which was transformed into its corresponding boronate 65 by a palladium-catalyzed cross-coupling reaction with bis(pinacolato)-diborane(4). Boronate 65 was anchored to four different polymeric aryl halides Ra-d in 60-99% yields. Polymer-bound alaninal was then synthesized on non-cross-linked polystyrene by hydride reduction of isoxazolidide 66. Treatment of alaninal with phenylmagnesium bromide, cleavage of the resulting amino alcohol in a 1:2:2 TFA/CI-bCb/anisole cocktail, and acylation with di-tert-butyl dicarbonate furnished 7V-(BOC)norephedrines 67 that were demonstrated to be enantiopure by conversion to diastereomeric thioureas 68a (99%) and 68b (1%) (Scheme 15) [66].

19

Chapter 1

Scheme 15

/)

PdCI2(dppf), KOAc, DMSO, 80 °C

PdCI2(dppf), DMF 2M Na 2 CO 3 , 80 °C

MeO

66a: 99%, 66b: 70% 66c: 78%, 66a: 60%

OH

AcO

q

AcO'

NH

AcO.

NH

AcO

AcO AcO

OAc

(1R.2S), 68a

OH NCS OAc

0 H

Et 2 N, CH 2 CI 2 NH BOC AcO.

Y

AcO' AcO

NH

NH OAc

(1S.2S), 68b

67

20

H. Abu Ali et al.

The solvent-free, microwave-assisted coupling of thienyl boronic acids and esters with thienyl bromides, using aluminum oxide as the solid support, served to rapidly check the reaction trends on changing times, temperature, catalyst, and base and easily optimize the experimental conditions to obtain the desired product in fair amounts. This procedure offers a novel, general, and very rapid route to the preparation of soluble thiophene oligomers. Quaterthiophene 69 was obtained in 6 min by reaction of 2-bromo-2,2'-bithiophene with bis(pinacolato)diborane(4) in 65% yield, whereas dithiophene 70 was obtained with 70% yield. The synthesis of new chiral 2,2'-bithiophenes also was reported. The detailed analysis of the byproducts of some reactions elucidates a few aspects of reaction mechanisms (Scheme 16) [67]. Scheme 16

AI 2 O 3 , PdCI 2 (dppf)/KF *~

Q 0 B-B 0 0

MW, 3min, 70 °C

69

AI2O3, PdCI2(dppf)/KF >MW, 3min, 70 °C

B-B JL;

o

cr\

Br

Synthesis of chiral 2,2'-bithiophenes 72 and 73 have been reported [67]. The new methodology for the synthesis of the two enantiomers of bithiophene bearing R(-) and S(+) chiral groups at the terminal positions (compounds 72 and 73) presented here and the synthetic pattern is shown in (Scheme 17). As shown in the scheme, the monobrominated monomers were obtained by condensation of commercial 5-bromo-2-thiophene aldehyde with R(-) and S(+)l-phenylethylamine. Afterwards, they were reacted with bis(pinacolato)diborane(4) using the same experimental conditions employed for the preparation of quaterthiophene 71. After a few minutes of microwave irradiation, bithiophenes 72 and 73 were recovered in high yield (isolated yield in both compounds >70%).

Chapter 1

21

Scheme 17

Q .0 B-B O O

Free-base porphyrins react with haloboranes to give diboryiporphyrins 74-76 in which the porphyrin ligands show marked rectangular distortions (Scheme 18) [68]. As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exists in nature. Recently a new palladium catalyzed, bis(pinacolato)diborane(4) mediated process has been developed to attain such a structural motif. The reaction consists of a domino process involving a Miyaura's arylboronic ester synthesis and an intramolecular Suzuki coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 77, a neurotensine receptor antagonist, with an endo aryl—aryl and an endo aryl—aryl ether bond was described (Scheme 19) [69].

22

H. Abu Ali et al.

Scheme 18

1)CI3B-NCMe Li 2) B2CI4 -2LiCI

23

Chapter 1 Scheme 19 H

Q O B-B O O

COOMe

o

PdCI2(dppf) KOAc DMSO

OMe

OMe

Me

l,2-Bis(dimethylamino)-l,2-dibora-[2]-ferrocenopane 216 was synthesized by the reaction of 1,1 '-dilithioferocene with 1,2-dichlorobis(dimethylamino)-diborane(4) [117]. Conformation of 216 (a-c) has been studied. The staggered conformation causes non-equivalence of 2- and 5-, and 3and 4-positions at low temperature was shown (Scheme 39).

Chapter 1

41

Scheme 39 CIN

B

NMe 2

Bs C l ' NMe 2 hexane THF

NMe 2 216

216b

216c

The l,2-diaminodichlorodiboranes(4) and E^CNCsHnxbCh served as starting materials for the syntheses of the iron diborane(4)yl complexes [Cl(R.2N)BB(NR2)Fe(C5H5)(CO)2] (217a, NR 2 =NC 4 H 8 , brown, and 217b, NR 2 =NC 5 Hi 0 , red colors, in 22% and 10% yields, respectively). Upon reaction with the anionic manganese hydride complex K.[(CsH4Me)lVlnH(CO)2], the bridged borylene complexes [{(C5H4Me)Mn(CO)2}2BNR2] (218a, NR 2 =NC 4 H 8 , ; 218b, NR 2 =NC 5 H 10 , both obtained as dark red crystalline solids in 48%, and 40% yields, respectively) were obtained with cleavage of the boron-boron bond, hydrogen migration from manganese to boron, and formation of the corresponding diboranes(6) (Scheme 40) [118].

42

H.AbuAlietal.

Scheme 40 Cl

OC

Fe s

CO

O R2N

=

217a N 217b

217

CI—B"

-

KCI

R2N

=

2 1 8 a

218b NR

Reaction of the diborane(4) B2(NMe2)2h with two equivalents of C5H5)M(CO)3] (M = Mo, W, Cr) yielded the dinuclear boryloxycarbyne complexes [{(^5-C5H5)(OC)2M=CO}2-B2(NMe2)2] (219, M = Mo; 220, M = W; 221, M=Cr), which were fully characterized in solution by multinuclear NMR techniques (Scheme 41) [119].

43

Chapter 1 Scheme 41

,

NMe 2

I'

NMe 2

Na

oc

ioco

- NaCI

o—c=

oc-'/ oc Me2N

NMe2 219: M = Mo 220: M = W 221: M = Cr

Direct borylation of hydrocarbons catalyzed by a transition metal complex has been extensively studied by several groups and has become an economical, efficient, elegant, and environmentally benign protocol for the synthesis of a variety of organoboron compounds. The Rh-, Ir-, Re-, and Pd-catalyzed C- H borylation of alkanes, arenes and benzylic positions of alkylarenes by bis(pinacolato)diborane(4) or pinacolborane provide alkyl-, aryl-, heteroaryl- and benzylboron compounds have recently been partly reviewed [120]. Rhodium-catalyzed l,4-addition reactions of bis(pinacolato)diborane(4) and bis(neopentyl glycolato)diboron to ec,/?-unsaturated ketones give the corresponding boron derivatives 222, 223 (Scheme 42a) and 224-230 (Scheme 42b) [121]. This is the first reported example in which a rhodium catalyst was used in addition reaction of diboron reagents to a,/?-unsaturated electron deficient alkenes. Scheme 42a

o 222, 78%

223, 75%

44

H. Abu Ali et al.

Scheme 42b o

6 ; * ,

225, 67%

Ph o.^o

o "B

6

226, 63%

p Bs

o

228, 62%

cx = ^o H 229, 72%

Alkanes regiospecifically reacted at the terminal carbon with pinB-Bpin at 150 °C. In the presence of Cp*Rh(r|4-C6Me6) (4.0-6.0 mol%), one equivalent of pinBBpin afforded almost two equivalents of 1-borylalkanes, thus indicating participation of pinBH in the catalytic cycle. Indeed, pinBH in n-octane gave pinacol noctylboronate in 65% yield (Scheme 43) [122]. Scheme 43

B-B

Cp*Rh(

4

-C 6 Me 6 ), 150°C

45

Chapter 1

The C-H coupling of aromatic heterocycles with bis(pinacolato)diborane(4) was carried out in octane at 80-100 °C in the presence of a 1/2 equiv [lrCI(COD)]2(4,4'-di-ferf-butyl-2,2'-bipyridine) catalyst (3 mol%). The reactions of five-membered substrates such as thiophene, furan, pyrrole, and their benzo-fused derivatives exclusively produced 2-borylated products (Scheme 44), whereas those of sixmembered heterocycles including pyridine and quinoline selectively occurred at the 3-position (Scheme 45). Regioselective synthesis of bis(boryl)-heteroaromatics was also achieved by using an almost equimolar amount of substrates and the diborane [123]. Scheme 44

// w

0

it \

0-

N'

0 231,83%

232,83%

H

J^/ Q-B

.6 234, 79%

233, 67%

lrCI(COD)2

Q

,0

dtbpy

0

0

octane, 80 °C

B-B

Q X = S, O, NH, NSi(/-Pr)3

Q

lrCI(COD)2

O

B-B O O

dtbpy octane, 80 °C

1.1 equiv

n 6

0

235,71%

0-

6. 236, 80%

0

N H 237, 80%

B'O

46

H. Abu Ali et al.

Scheme 45

,Si(/-Pr) 3 241,

83%

lrCI(COD)2 dtbpy

P

octane, 80 °C

B—B

o

X = S, O, NH, NSi(/-Pr)3

lrCI(COD)2 dtbpy 1.1 equiv

242, 28%

octane, 80 °C

243, 14%

244, 84%

A combination of a Cp*Ir complex and an electron-donating alkylphosphine such as P(Me)3 is effective for aromatic C-H borylation by pinBH gave good Irreagent (Scheme 46) [124]. Scheme 46

+

6

B-H

95 °C

Me3pA""Cy H

Ir - reagent

Chapter 1

47

Further studies resulted in significant improvement in catalyst efficiency. A maximum turnover number (4500 TON) was achieved at 150 °C when Ir(r|5C9H7XCOD) and a bidentate alkylphosphine such as dmpe (1,2bis(dimethylphosphino)ethane) were used at 150 °C in a sealed ampule (Scheme 47) [125]. The orientation was kinetically determined, thus giving statistical meta/para isomers (ca. 2/1) for monosubstituted arenes. Borylation selectively occurred at the common meta-carbon for 1,3-disubstituted arenes, such as 1,3-dichlorobenzene and methyl 3-chlorobenzoate, since the reaction was more sensitive to steric hindrance than electronic effects of the substituents. Scheme 47

245 MeO.

MeO.

246 F-.C.

247 S

( T I - C 9 H 7 ) C O D + dmpe

-"^

150 °C , 61 h 248 lrCI(COD) 2 + bpy

°

80 °C , 16 h

249 OMe OMe

250 OMe OMe

Br

H. Abu Ali et al.

48

Hartwig and co-workers [126] have shown that using photochemical activation of Cp*Re(CO)3 with irradiation from a 450-W medium-pressure mercury lamp, reaction of bis(pinacolato)diborane(4) in alkane in the presence of Cp*Re(CO)3 (2.4- 5.0 mol%) and CO (2 atm) produced the corresponding alkylboronates. Photochemical reaction of n-hexane with Cp*Re(CO)2(Bpin)2, prepared from Cp*Re(CO)3 and pin2E$2, led to the regiospecific formation of 1-borylpentane in quantitative yield (Scheme 48). Scheme 48

B-B

Cp*Re(CO)3 1

hv, 100%

6

The catalyzed borylation of octane using rhodium complex 252 with bis(pinacolato)diborane(4) selectively adds at the terminal carbon of octane to give the borylated product in 88% yield. The product 253 can be converted into octylboronic acid 254 by hydrolysis (Scheme 49) [122,127]. Scheme 49

Rh

CH3(CH2)6CH3

ft 150°C

253, 88%

hydrolysis

254

Chapter 1

49

3.7. Reactions with dienes and alkenes The cross-coupling reaction of bis(pinacolato)diborane(4) [(M B(C>2C2Me4)] with allyl acetates provided the pinacol esters of aiiylboronic acids with common structure 255 with regio- and ii-stereoselectively in high yields 256-265 as have been reported (Scheme 50). The reaction was efficiently catalyzed by Pd(dba)2 inDMSOat50°C[128]. Scheme 50

Pd(dpa)2 I

ts

DMSO, 50 °C

7-0

o255 4

Ph CF 3 CO 2 .

256, 86% Ph

MeOCO 257, 3%

Ph

Ph PhCO, 258, 55% Ph ArO

259, 89%

ArO

260, 16%

ArO-.

ArO

263, 26%

264, 24% Ph

265, 16% Ph

50

H. Abu Ali et al.

Commercially available Pt(cod)Cb catalyzes the diboration of terminal alkenes, vinylarenes, and alkynes using B2cat2 to give compounds 266-270 in excellent yields (Scheme 51) [63]. The first metal-catalyzed diboration of aldimines to form ^-amino boronate esters was also obtained when Pt(cod)Cb was used. Scheme 51 Beat

Beat

Beat Pt(cod)CI2, benzene

268, 93%

Beat

Beat 269, 92% Beat Bcat x

/ Bcat

270, 91% Bis(pinacolato)diborane(4) was selectively added to alka-l,3-dienes in the presence of a catalytic amount of platinum(O) complexes [129] (Scheme 52). Scheme 52 R

R

271

(RO) 2 B

B(OR) 2

Chapter 1

51

Initial studies involving phosphine-containing bis(boryl) platinum compounds indicated no activity for the diboration of alkenes [130]. Subsequently however, Smith and co-workers demonstrated an immediate reaction between [Pt(nbe)3] (nbe — norbornene) and E$2cat2 (Scheme 53), providing the norbornene diboration product 273 in 88% yield [83a]. In this case, oxidative addition of B2cat2, followed by insertion of norbornene into the Pt-B bond is a likely mechanism although there is no experimental data to support this. Theoretical studies of Pt-boron compound indicated that insertion of ethylene into the Pt-B bonds in [Pt(PH3){B(OH)2}2] was less favorable energetically compared to the reaction involving acetylene [131]. The substitution of a ^-bound ligand for a phosphine ligand should result in an overall reduction of the activation barrier to insertion of alkenes by destabilizing the bis(boryl) platinum complex prior to the insertion step. Scheme 53

nbe nbe-Pt

nbe

The palladium-catalyzed coupling reaction of bis(pinacolato)diborane(4) and vinyl halides or trifluoromethanesulfonates yields vinylboronates 274 (Scheme 54) [132]. Scheme 54 R-i

PdCI2(PPh3)2

R2

B-B R3

KOPh 1.5equivtoluene, 50°C

X

O, 274 274a: R1 274b: R., 274c: R-, 274d: R:

= H, R2 = CH3(CH2)7, R3 = H, X = Br, 92% = H, R2 = H, R3 = CH3(CH2)7, X = Br, 74% = R2 = (CH2)4, R3 = H, X = Br, 99% = R2 = (CH2)4, R3 = H, X =OTf, 88%

52

H.AbuAlietal.

REFERENCES [I]

[2] [3]

[4]

[5]

[6]

[7] [8] [9] [10] [II] [12]

[13]

T. Ishiyama, N. Matsuda, N. Miyaura and A. Suzuki, J. Am. Chem. Soc. 115(1993) 11018; T. Ishiyama, N. Matsuda, M. Murata, F. Ozawa, A. Suzuki and N. Miyaura, Organometallics 15 (1996) 713. A. Stock, A. Brandt and H. Fischer, Chem. Ber. 58 (1925) 643. (a) R.J. Brotherton, in "Progress in Boron Chemistry" (H. Steinberg and A.L. McClos-key, eds.), Vol. 1, Chap. 1, p. 1. Pergamon Press, Oxford, (1964); (b) A.K.. Holliday and A.G. Massey, Chem. Rev. 62 (1962) 303; (c) A.G. Massey, Adv. Inorg. Chem. Radiochem. 10 (1967) 1; (d) G. Urry (E.L. Muetterties, Ed.), The Chemistry of Boron and Its Compounds, Wiley, New York, (1967) Chapter 6, 325; (e) B.M. Mikhailov, Y.N. Bubnov, Organoboron Compounds in Organic Synthesis. Harwood Academic Publ. GMBH, Amsterdam, (1984). (a) Molecular recognition and sensing: T.D. James, K.R.A.S. Sandanayake and S. Shinkai, Angew. Chem., Int. Ed. Engl. 35 (1996) 1910; (b) Boron neutron capture therapy: A.H. Soloway, W. Tjarks, B.A. Barnum, F.-G. Rong, R.F. Barth, l.M. Wyzlic and J.G. Wilson, Chem. Rev. 98 (1998) 1515; (c) Enantioselective reactions: D.S. Matteson, Tetrahedron 45 (1989) 1859; (d) Novel organic transformations: N.A. Petasis and I.A. Zaivalov, J. Am. Chem. Soc. 120 (1998) 11798; (e) Free radical chemistry: J.C. Walton, A.J. McCarroll, Q. Chen, B. Carboni and R. Nziengui, J. Am. Chem. Soc. 122 (2000) 5455; (f) Protease and enzyme binding, see for example: E. Tsilikounas, C.A. Kettner and W.W. Bachovkin, Biochemistry 31 (1992) 12839; (g) Solid phase synthesis linkers: B. Carboni, C. Pourbaix, F. Carreaux, H. Deleuze and B. Maillard, Tetrahedron Lett. 40 (1999) 7979. (a) N. Miyaura and A. Suzuki, Chem. Rev. 95 (1995) 2457; (b) S.P. Stanforth, Tetrahedron 54 (1998) 263; (c) A. Suzuki, J. Organometal. Chem. 576 (1999) 147. (a) T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem. 60 (1995) 7508; (b) M. Murata, S. Watanabe, Y. Masuda, J. Org. Chem. 62 (1997) 6458; (c) M. Murata, T. Oyama, S. Watanabe and Y. Masuda, J. Org. Chem. 65 (2000) 164. A. Giroux, Y. Han and P. Prasit, Tetrahedron Lett. 38 (1997) 3841. V.M. Dembitsky, M. Srebnik, Tetrahedron 59 (2003) 579. V.M. Dembitsky, H. Abu Ali, M. Srebnik, Appl. Organometal. Chem. 17 (2003) 327. V.M. Dembitsky, G.A. Tolstikov and M. Srebnik, Eurasian ChemicoTechnological Journal 4 (2002) 87. V.M. Dembitsky, G.A. Tolstikov and M. Srebnik, Eurasian ChemicoTechnological Journal 4 (2002) 153. H. Abu Ali, V.M. Dembitsky and M. Srebnik, Organometallics: Boron Compounds. (D.S. Matteson, D. Kaufmann, Eds.), Science of Synthesis, Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, (2004) Vol. 6, Chapter 29. H. Abu Ali, V.M. Dembitsky and M. Srebnik, Organometallics: Boron Compounds. (D.S. Matteson, D. Kaufmann, Eds.), Science of Synthesis, Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag,

Chapter 1

[14]

[15]

[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]

53

Stuttgart, Germany, (2004) Vol. 6, Chapter 30. H. Abu Ali, V.M. Dembitsky and M. Srebnik, Organometallics: Boron Compounds. (D.S. Matteson, D. Kaufmann, Eds.), Science of Synthesis, Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, (2004) Vol. 6, Chapter 31. H. Abu Ali, V.M. Dembitsky and M. Srebnik, Organometallics: Boron Compounds. (D.S. Matteson, D. Kaufmann, Eds.), Science of Synthesis, Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, (2004) Vol. 6, Chapter 37. V.M. Dembitsky and M. Srebnik, 2003, Mini Rev. Med. Chem. 4 (2004) 1018. V.M. Dembitsky, R. Smoum, A.A. Al-Quntar, H. Abu Ali, 1. Pergament and M. Srebnik, Current Topics in Phytochemistry 5 (2002) 67. V.M. Dembitsky, R. Smoum, A.A. Al-Quntar, H. Abu Ali, I. Pergament and M. Srebnik, Plant Science 163 (2002) 931. G. Abeler, H. Noth and H. Schick, Chem. Ber. 101 (1968)3981. E.F. Apple and T. Wartik, J. Am. Chem. Soc. 80 (1958) 6158. T. Wartik, R.E. Moore and H.I. Schlesinger, J. Am. Chem. Soc. 71 (1949) 3265 G. Urry, T. Wartik, R.E. Moore and H.I. Schlesinger, J. Am. Chem. Soc. 76 (1954) 5293. J.W. Frazerand R.T. Holzmann, J. Am. Chem. Soc. 80 (1958) 2907. A.K. Holliday and A.G. Massey, J. Am. Chem. Soc. 80 (1958) 4744. A.G. Massey, D.S. Urch and A.K. Holliday, J. Inorg. Nucl. Chem. 28 (1966) 365. T. Wartik, R. Rosenberg, W.B. Fox, Inorg. Syn. 10 (1967) 118. F.A. Cotton, G. Wilkinson, C.A. Murillo and M. Bochmann, Advanced Inorganic Chemistry, John Wiley & Sons, (1999). A.F. Trotman-Dickenson, (Ed.) Comprehensive Inorganic Chemistry, Pergamon, Oxford, UK, (1973). R.W.G. Wyckoff, Crystal Structures, Volume 1, Interscience, John Wiley & Sons, (1963). D.R. Lide, (Ed.) Chemical Rubber Company Handbook of Chemistry and Physics, 77th, CRC Press, Boca Raton, Florida, USA, (1996). J.W. Mellor, A Comprehensive Treatise on Inorganic and Theoretical Chemistry, Vol. 1-16, Longmans, London, UK, (922-1937). W.C. Schumb, E.L. Gamble and M.D. Banus, J. Am. Chem. Soc. 71 (1949) 3225. W. Diener and A. Pflugmacher, Agnew. Chem. 69 (1957) 777 . A. Finch and H.I. Schlesinger, J. Am. Chem. Soc. 80 (1958) 3573. P.L. Timms, Chem. Commun. (1968) 1525a. P.L. Timms, J. Am. Chem. Soc. 89 (1967) 1629. E. Wiberg and W. Ruschmann, Chem. Ber. 70B (1937) 1393. H. Noth and P.Z. Fritz, Anorg. Allgem. Chem. 324 (1963) 129. E. Wiberg and W. Ruschmann, Chem. Ber. 70 (1937) 1583. H.I. Schlesinger and G. Urry, Annual Technical Reports to the Office of

54

[41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65]

[66] [67]

H.AbuAlietal. Naval Research, (1949-1956). R.W. Auten and C.A. Kraus, J. Am. Chem. Soc. 74 (1952) 3398. R.J. Brotherton, A.L. McCloskey, L.L. Petterson and H. Steinberg, J. Am, Chem. Soc. 82(1960)6242. H. Noth and P. Fritz, Angew. Chem. 73 (1961) 408. H. Noth and P. Fritz and W. Meister, Angew. Chem. 73 (1961) 762. H. Noth and W. Meister, Chem. Ber. 94 (1961) 509. M.P. Brown, A.E. Dann, D.W. Hunt and H.B. Silver, J. Chem. Soc. (1962) 4648. H. Noth and W. Schragle, Angew. Chem. 74 (1962) 587. R.J. Brotherton, H.M. Manasevit and A.L. McCloskey, Inorg. Chem. 1 (1962) 749. G.L. Brubaker and S.G. Shore, Inorg. Chem. 8 (1969) 2804. K.H. Hermannsdorfer, E. Matejcikova and H. Noth, Chem. Ber. 103 (1970) 516. N.R. Anastasi, K.M. Waltz, W.L. Weerakoon and J. F. Hartwig, Organometallics 22 (2003) 365. T.D. Coyle and J.J. Ritter, Adv. Organomet. Chem. 10 (1972) 237. H. Firxh, H. Pritzkow and W. Siebert, Angew. Chem. Int. Ed. Engl. 23 (1984) 608. D. Loderer, H. Noth, H. Pommerening, W. Rattay and H. Schick, Chemische Berichte 127(1994) 1605. H. Noth and G. Abeler, Chem. Ber. 101 (1968) 969. F.J. Lawlor, N.C. Norman, N.L. Pickett, E.G. Robins, P. Nguyen, G. Lesley, T.B. Marder, J.A. Ashmore and J.C. Green, Inorg. Chem. 37 (1998) 5282. H. Noth, J. Knizek, W. Ponikwar, Eur. J. Inorg. Chem. (1999) 1931. US Borax Research Corp., WADD Rept. 37 (1961) 60. S. Samdal, V.S. Mastryukov and J. E. Boggs, J. Molecul. Struct. 380 (1996) 43. M.J.S. Dewar in Progress in Boron Chemistry, Vol. 1 (H.Steinberg, A.L. McCloskey, Eds.), Pergamon, Oxford 1964. P. Paetzold, C. Stanescu, J.R. Stubenrauch, M. Bienmiiller and U. Englert, Z. Anorg. Allg. Chem. 630 (2004) 2632. J. Teichmann, H. Stock, H. Pritzkow and W. Siebert, Eur. J. Inorg. Chem. (1998)459. G. Mann, K.D. John and Baker, Org. Lett. 2 (2000) 2105. Recently reviewed: R.C.D. Brown, J. Chem. Soc, Perkin Trans. 1 (1998) 3293 and refs therein. Examples include the following. Germanium- and silicon-based traceless linkers: (a) M.J. Plunkett and J.A. Ellman, J. Org. Chem. 62 (1997) 2885. Safety-catch linkers: (b) B.J. Backes and and J.A. Ellman, J. Am. Chem. Soc. 116(1994) 11171. F. Gosselin, J. Van Betsbrugge, M. Hatam and W.D. Lubell, J. Org. Chem. 64 (7) (1999) 2486. M. Melucci, G. Barbarella and G. Sotgiu, J. Org. Chem. 67 (2002) 8877.

Chapter 1 [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80]

[81] [82] [83]

[84] [85] [86] [87] [88] [89] [90] [91] [92] [93]

[94] [95]

55

A. Weiss, H. Pritzkow, P.J. Brothers and W. Siebert, Angew. Chem. Int. Ed. 40(2001)4182. S. Boisnard, J. Zhu, Tetrahedron Lett. 43 (2002) 2577. Y.G. Lawson, M.J.G. Lesley, T.B. Marder, N.C. Norman and C.R. Rice, Chem. Commun. (1997) 2051. T. Ishiyama, S. Momotaand N.Miyaura, Synlett (1999) 1790. M. Suginome, H. Nakamura and Y. Ito, Angew. Chem. Int. Ed. Engl. 36 (1997)2516. T. Ishiyama, T. Kitano and N. Miyaura, Tetrahedron Lett. 39 (1998) 2357. F.Y. Yang, M.Y. Wu and C.H. Cheng, J. Am. Chem. Soc. 122 (2000) 7122. F.Y. Yang and C. H. Cheng, J. Am. Chem. Soc. 123 (2001) 751. G. Urry, G. Kerrigan, T.D. Parsons and H.I. Schlesinger, J. Am. Chem. Soc. 76(1954)5299. T. Onak, Organoboron Chemistry, Academic Press: New York, 1975, pp 3840. E.L. Muetterlies, The Chemistry of Boron and its Compounds; Wiley: New York, (1967)398. H. Abu Ali, I. Goldberg and M. Srebnik, Eur. J. Inorg. Chem. (2002) 73. (a) T. Ishiyama, M. Yamamoto and N. Miyaura, Chem. Commun. (1997) 689; (b) R.T. Baker, P. Nguyen, T.B. Marder and S.A. Westcott, Angew. Chem. Int. Ed. Engl. 34(1995) 1336 T.B. Marder, N.C. Norman and C.R. Rice, Tetrahedron Lett. 39 (1998) 155. C.N. Iverson and M.R. Smith, Organometallics 16 (1997) 2575. (a) T. Ishiyama, N. Matsuda, M. Murata, F. Ozawa, A. Suzuki and N. Miyaura, Organometallics 15 (1996) 713; (b) Q. Cui, D.G.M. Musaev and K. Morokuma, Organometallics 17 (1998) 742. Q. Cui, D.G.M. Musaev and K. Morokuma, Organometallics 17 (1998) 1383. W. Siebert, H. Pritzkow and A. Maderna, Angew. Chem. Int. Ed. Engl. 35 (1996)1501. W. Clegg, A.J. Scott, G. Lesley, T.B. Marder and N.C. Norman, Acta Cryst. C52(1996) 1989. H.Z. Noth Naturforsch. 39B (1984) 1463. F.J. Lawlor, N.C. Norman, N.L. Pickett and E.G. Robins, Inorg. Chem. 37 (1998)1777. E.J. Corey and Cheng, The Logic of Chemical Synthesis, Wiley-Interscience: New York. (1989). P.A. Wender (Ed). Frontiers in Organic Synthesis thematic issue. Chem. Rev. 96(1996)1. V.M. Dembitsky and M. Srebnik, Titanium and Zirconium in Organic Synthesis. Marek I. (Ed)., Wiley-VCH Verlag GMBH, Weinheim (2002) 230. I. Marek, Chem. Rev. 100 (2000) 2887. W. Clegg, T.R.F Johann, T.B. Marder, N.C. Norman, A.G. Orpen, T.M. Peakman, M.J. Quayle, C.R. Rice and A.J. Scot, J. Chem. Soc, Dalton Trans. (1998) 1431. H.C. Brown and S.P. Rhodes, J. Am. Chem. Soc. 91 (1969) 4306. T. Ishiyama, K. Ishida, J. Takagi and N. Miyaura, Chem. Lett. (2001) 1082.

56 [96] [97] [98]

[99]

[100]

[101]

[102] [103] [104] [105] [106] [ 107] [108] [109] [110] [Ill]

H.AbuAlietal. A.B. Margaret and Y.H. L. Michelle, Org . Biomol . Chem . 1 (2003) 4227. Y. Ma, C. Song, W. Jiang, G. Xue, J.F. Cannon, X. Wang and M.B. Andrus, Org. Lett. 5 (2003) No. 24. (a) S.B. Singh, D.L. Zink, J.M. Liesch, R.G. Ball, M.A. Goetz, E.A. Bolessa, R.A. Giacobbe, K..C. Silverman, G.F. Bills, F. Pelaez, C. Cascales, J.B. Gibbs and R. B. Lingham, J. Org. Chem. 59 (1994) 6296; (b) D. Vilella, M. Sanchez, G. Platas, O. Salazar, O. Genillound, I. Royo, C. Cascales, I. Martin, T. Diez, K.C. Silverman, R.B. Lingham, S.B. Singh, H. Jayasuriya and F. Pelaez, J. Ind. Microbio; (c) K. Krohn, U. Florke, M. John, N. Root, K. Steingrover, H.-J. Aust, S. Draeger, B. Schulz, S. Antus, M. Simonyi, F. Zsila, Tetrahedron 57 (2001) 4343. (a) L.A. McDonald, D.R.; Abbanat, L.R. Barbieri, V.S. Bernan, C M . Discafani, M. Greenstein, K. Janota, J.D. Korshalla, P. Lassota, M. Tischler and G.T. Carter, Tetrahedron Lett. 40 (1999) 2489; (b) T. Wang, O. Shirota, K. Nakanishi, N. Berova, L.A. McDonald, L.R. Barbieri and G.T. Carter, Can. J. Chem. 79(2001) 1786. (a) P. Wipf and J.-K. Jung, J. Org. Chem. 63 (1998) 3530; (b) A.G. Barrett, D. Hamprecht and T. Meyer, Chem. Commun. (1998) 809; (c) J.P. Ragot, M.-L. Alcaraz and R.J.K. Taylor, Tetrahedron Lett. 39 (1998) 4921; (d) S. Chi, C.H. Heathcock, Org. Lett. 1 (1999) 3; (e) J.P. Ragot, C. Steeneck, M.-L. Alcaraz, R.J.K. Taylor, J. Chem. Soc, Perkin Trans. 1 (1999) 1073; (f) P. Wipf, J.-K. Jung, J. Org. Chem. 64 (1999) 1092; (g) P. Wipf and J.-K. Jung, J. Org. Chem. 65 (2000) 6319; (h) A.G.M. Barrett, F. Blaney, A.D.Campbell, D. Hamprecht, T. Meyer, A.J.P. White, D. Witty and D.S. Williams, J. Org. Chem. 67 (2002) 2735; (i) M. Inoue, K. Nabatame and M. Hirama, Heterocycles 59 (2003) 87. For reviews and books, see: (a) B.A. Bunin, The Combinatorial Index; Academic Press: San Diego, 1988. D. Obrecht, J.M. Villagordo, SolidSupport Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Librararies; Pergamon: New York, 1998; (b) I.W. James, Tetrahedron 55 (1999) 4855. (a)S.A. Nair, M.H. Kim, S.D. Warren, S. Choi, Z. Songyang, L.C. Cantley and D.G Hangauer, J. Med. Chem. 38 (1995) 4276. J.H. Lai, T.H. Marsilje, S. Choi, S.A. Nair and D.G Hangauer, Int. J. Peptide Protein Res. 51 (1998)271. T. Ishiyama, Y. Itoh, T. Kitano and N. Miyaura, Tetrahedron Lett. 38 (1997) 3447. T. Ishiyama, T. Kitano and N. Miyaura, Tetrahedron 57 (2001) 9813. A.A. Fuller, H.R. Hester, E.V. Salo and E.P. Stevens, Tetrahedron Lett. 44 (2003) 2935. A. Izumi, R. Nomura and T. Masuda, Chem. Lett. (2000) 728. S.M. Korneev and D.E. Kaufmann, Synthesis Stuttgart 4 (2002) 491. K. Albrecht, V. Kaiser, R. Boese, J. Adams and D.E. Kaufmann, J. Chem. Soc. Perkin Trans 2 (2000) 2153. N.A. Tsarev and Bumagin, Tetrahedron Lett. 44 (1998) 8155. D.M. Willis and R.M. Strongin, Tetrahedron Lett. 41 (2000) 8683.

Chapter 1

57

[112] (a) P. Nguyen, G. Lesley, N.J. Taylor, T.B. Marder, N.L. Pickett, M.R.J. Elsegood and N. C. Norman, Inorg. Chem. 33 (1994) 4623; (b) T.B. Marder, N.C. Norman, C.R. Rice and E.G. Robins, Chem. Commun. (1997) 5; (c) W. Clegg, F.J. Lawlor, T.B. Marder, P. Nguyen, N.C. Norman, A.G. Orpen, M.J. Quayle, C.R. Rice, E.G. Robins, A.J. Scott, F.E.S. Souza, G. Stringer and G.R. Whittell, J. Chem. Soc, Dalton Trans. (1998) 301. [113] T. Ishiyama, N. Matsuda, N. Miyaura and A. Suzuki, J. Am. Chem. Soc. 115 (1993) 11018. [114] C.N. Iverson, M.R. Ill Smith, J. Am. Chem. Soc. 117 (1995) 4403. [115] (a) W. Clegg, F.J. Lawlor, G. Lesley, T.B. Marder, N.C. Norman A.G. Orpen, M.J. Quayle, C.R. Rice, A.J. Scott, F.E.S. Souza, J. Organomet. Chem. 550 (1998) 183 ; (b) G. Lesley, P. Nguyen, J. Taylor, T.B. Marder, A. J. Scott, W. Clegg and N. C.Norman, Organonetallics 15 (1996) 5137. [116] H. Noth, Ninth International Meeting on Boron Chemistry, July 14-18, 1996, Ruprecht-Karls-Universitat, Heidelberg, Germany. [117] M. Herberhold, U. Dorfler and B. Wrackmeyer, J. Organomet. Chem. 530 (1997) 117. [118] H. Braunschweig and M. Koster, J. Organomet. Chem. 588 (1999) 231. [119] H. Braunschweig, K.W. Klinkhammer, M. Koster and K. Radacki, Chem. Eur. J.(2003) 1303. [120] T. Ishiyama, N. Miyaura, J. Organomet. Chem. 3 (2003) 680. [121] G.W. Kabalka, B.C. Das and S. Das, Tetrahedron Lett. 43 (2002) 2323. [122] H. Chen, S. Schlecht, T.C. Semple and J.F. Hartwig, Science 287 (2000) 1995. [123] J. Takagi, K. Sato, J.F. Hartwig, T. Ishiyama and Miyaura, Tetrahedron Lett. 43 (2002) 5649. [124] C.N. Iverson, M.R. Ill Smith, J. Am. Chem. Soc. 121 (1999) 7696. [125] J.-Y. Cho, M.K. Tse, D. Holmes, Jr.R.E. Maleczka and M.R.III Smith, Science 295 (2002) 305. [126] H. Chen, J. F. Hartwig, Angew. Chem. Int. Ed. 38 (1999) 3391. [127] K.M. Walts, C.N. Muhoro and J.F. Hartwig, Organometallics 18 (1999) 3383. [128] T. Ishiyama, T. Ahiko and N. Miyaura, Tetrahedron Lett. 37 (1996) 6889. [129] T. Ishiyama, M. Yamamoto and N. Miyaura, Chem. Commun. (1996) 2073. [130] T. Ishiyama, N. Matsuda, N. Miyaura and A. Suzuki, J. Am. Chem. Soc. 115 (1993) 11018. [131] Q. Cui, D.G. Musaev and K. Morokuma, Organometallics 16(1997) 1355. [132] K. Takahashi, J. Takagi, T. Ishiyama and N. Miyaura, Chem. Lett. (2000) 126. A. Giroux, Tetrahedron Lett. 44 (2003) 233.

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Chapter 2 Recent developments in bisdiborane chemistry: B-C-B, B-C-C-B, B-C=C-B, and B-OC-B compounds and their biological applications H. Abu Ali, V. M. Dembitsky and M. Srebnik Department of Medicinal Chemistry & Natural Products, School of Pharmacy, P.O. Box 12065, Hebrew University of Jerusalem, Jerusalem 91120, Israel

Contents 1. INTRODUCTION 60 2. FORMATION OF B-C-B COMPOUNDS 61 3. GEMINAL ORGANOBORON COMPOUNDS 68 4. FORMATION, REACTIVITY AND BIOLOGICAL ACTIVITY OF B-C-C-B, BC=C-B, AND B-C=C-B COMPOUNDS 85 REFERENCES 113

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H.AbuAlietal.

1. INTRODUCTION Bis(pinacolato)diborane(4) is used preferentially over other (alkoxo)diborons, because both it and the borylated products derived from it can be handled in air and exhibit high stability towards hydrolysis, which facilitate reaction workup and purification. An overview of the development of new strategies in organic synthesis with a minimum of chemical steps is becoming increasingly necessary for the efficient assembly of complex molecular structures. Therefore, the combination of multiple reactions in a single operation represents a particularly efficient approach. Among these strategies, the synthesis and reactivity of bisdiboranes has never been reviewed although its popularity for the synthesis of complex architectural molecules has been steadily increasing during the last decade. This chapter is intended to highlight the use of partly geminated boranes (B-C-B), and also bisdiborane reagents (B-C-C-B, B-C=C-B, B-OC-B). Bisdiborane derivatives are an important class of compounds in boron chemistry. The addition of diborons (X2B-BX2) to unsaturated hydrocarbons, first discovered by Schlesinger in 1954 [1], is an attractive and straightforward method to introduce two boryl units into organic molecules [2-4]. Diborane itself, B2H4, is stable only when complexed by Lewis base ligands such as amines or phosphines. Although the tetrahalides, B2X4 (X = F, Cl, Br, 1), have a reasonably well-established chemistry, they suffer from low thermal stability (with the exception of B2F4) and preparative difficulties. Tetraorganodiborane compounds, B2R4, are stable only when substituted with sterically demanding R groups such as t-Bu, CH2-^-Bu, and mesityl. The most stable derivatives are those in which good 7r-donor groups are present such as amido (NR2) or alkoxy (OR) [5,6]. More recently, as part of the interest in the oxidative addition chemistry of the B-B bond and metal-catalyzed diborations of alkenes [710] and alkynes, [11-16] synthesis of stable, crystalline bis(pinacolato) and bis(catecholato) diborane(4) derivatives have been reported [17,18]. The development of new strategies in organic synthesis with a minimum of chemical steps is becoming more and more important for the efficient assembly of complex molecular structures [19,20]. The combination of multiple reactions in a single operation represents a particularly efficient approach. Among these strategies [21], geminated organobismetallic derivatives (1,1-bis anions) are becoming more and more useful [22]. During the past decades considerable efforts have been made to find new routes for the preparation of geminated sp2 organobismetallic derivatives and for their selective reactions with several electrophiles [22,23]. This chapter will concentrate primarily on features of the chemistry of diborane compounds with particular structures: B-C-B, B-C-C-B, B-C=C-B, and B-C=C-B. We will also survey some of the chemistry of organoboron compounds derived from diboron precursors.

Chapter 2

61

2. FORMATION OF B-C-B COMPOUNDS Bisdiborane, BCB, compounds are usually prepared by double hydroboration of terminal alkynes with dialkylboranes [24-26]. They are interesting precursors to gembimetallics such as BCLi [27-30] and BCMgX [31]. Recently, we reported that the parent compound (pinacolato)2BCH2B, 1, can be prepared in high yield by reaction of bis(pinacolato)diborane(4) with diazomethane (Scheme 1) [32]. This reaction gave good results and had not been described before. Scheme 1 Q

B-B: O O

CH 2 N 2

Pt(PPh3)4 Et2O, 0°C

Insertions into (R2N)2B—B(NR2)2, where R = Me, Et, w-Pr, were not successful. Two mechanisms for the insertion are possible: (a) addition/1,2-migration to and from boron as in the Hooz reaction [33-35] or (b) oxidative addition of B-B to a Pt(0) complex, insertion of CH2 into the Pt-B bond, migration, and reductive elimination [36]. Alternatively, formation of 1 from (pin)BCH2l by coupling with metals has been reported [32]. Reflux of 1 and 3 with 6M HC1 gave stable boronic acids: 4 and 5 respectively, (Scheme 2). Scheme 2

I-CH 2 -B;

M = Na, K, Mg

;B-CH 2 -CH 2

6M HCI reflux, 3h HQ ,OH B— CH 2 —CH 2 -B HO 5 OH

6M HCI reflux, 3h HQ

OH

B-CH2-B

HO

.

OH

Novel Cl-bridged bisboronate derivatives 8a-d has been recently reported by insertion of diazoalkanes into bis(pinacolato)diborane(4) by Abu Ali et al [37] (Scheme 3) and the proposed catalytic cycle is shown in Fig. 1. The molecular structures of 8a and 8b were determined by single-crystal X-ray diffraction. The low temperature diffraction experiments of the two derivatives (which contain seven crystailographicaiiy independent

62

H.AbuAlietal.

units of the boronic ester moiety) at similar conditions, allowed precise determination of the covalent parameters around the boron atom. The results of the diffraction analysis, crystal data and details of the structure determination are shown in Fig. 2a and Fig. 2b, respectively. pt(PPh3)

V Q ?1 d B-C-Pt-B

Fig. 1. The proposed catalytic cycle for formation of B-C-B compounds Scheme 3

Pt(PPh 3 ) 4

toluene 8O °C

B —Pt—B 5

o

I

R2


20°C

H. Abu Ali et al.

66

Fig. 2c. Molecular structure of compound 19. Adapted by authors The 1,1'-spirobistannoles 22a-d are an intermediate for synthesis of borolenes 23. and 24a,b with B-C-B structure were prepared from the reaction of tetra- 1-alkynyltin 21 with triethylborane (Scheme 6) [42]. Scheme 6

Et3B

-Sn21a: R = Et 21b:R = n-Pr 21c:R = /-Pr 21d:R = Bu

R 21

Et

Et 2 B v Et

HN

Et

,Sn, "R ,R

MeBBr2 CD2CI2, -40 °C

CD2CI2, -40 °C

pr Me 24a

Et

+4BX, -SnX4

Et X = CI, Br

R

B X 23

Me i;

Br Me 24b

22a-d

Et

.E

MeBBr,

Br

Chapter 2

67

Another B-C-B compound, 2,5-doborylated 3-borolene 26 could be obtained by reacting 25 and MeBBr2 in a 1:2 ratio (Scheme 7) [42]. Scheme 7 Me Me2Sn

BMe +

2MeBBr2

-Me 2 SnBr 2

Me Me

Me. Me

..R

B,,.

H

B Me 26

H

^Br

Synthesis of heterodiborolanes 27 and 28 with a B-C-B structure have been demonstrated in Walter Siebert's papers (Scheme 8) [43,44]. Scheme 8

X(SiMe3)2

R = CI, Dur R = S, NMe

H. Abu Ali et al.

3. GEMINAL ORGANOBORON COMPOUNDS Chemistry of geminated boron compounds has been reviewed recently [22,23]. The synthesis of (diethylcyclopropyl)borane or cyclopropyl-9-BBN was performed by dihydroboration of either propargyl chloride or bromide, followed by the addition of methyllithium to the resulting 1,1 -diborio compound 29 (Scheme 9) [24]. Also the gemdiboron 30 could be obtained if tosylate was chosen as the leaving group [11]. The best synthesis of (£)-alkenyl-9-BBN's is an indirect route involving oxidative elimination of one boron fragment from the easily formed diboryl intermediate 31 [45]. Scheme 9

ArCHO

The dihydroboration of 1-hexyne with diborane results in the formation of a highly branched, polymeric product. Since it was anticipated that the reaction product would contain the two boron atoms either on adjacent carbons or on the same carbon, oxidation with alkaline hydrogen peroxide should lead either to 1,2-hexanediol or cohexaldehyde, respectively. Unexpectedly, however, oxidation of the dihydroborated I hexyne gave, in addition, 1-hexanol as the major product. The formation of l-hexanol from the dihydroboration intermediate can be rationalized in terms of a rapid

Chapter 2

69

hydrolysis of one boron-carbon bond of either the 1,1-, 32, or the 1,2-diboron, 33, compounds prior to the oxidation step (Scheme 10) [25]. The only reasonable explanation for the high yield of primary alcohol is that the hydroboration product, whatever its structure, undergoes a rapid hydrolysis to lose one of the two boron-carbon bonds prior to oxidation. Since the alkaline hydrolysis involves an attack by a base on the electrophilic boron atom, these substituents which decrease the acidity of the boron atom should greatly reduce the hydrolytic stability of the 1,1-diborio derivative. So, the diborioalkane was hydrolyzed first and oxidized in a second step with alkaline hydrogen peroxide at pH 8, to give the aldehyde in 68% yield [26]. Scheme 10

C4HQ

—

B - OH

The double hydroboration of 3-hexyne was examined first with an excess of diborane, [46,47] but the oxidation of the product from dihydroboration of 3-hexyne gave 1,1-diborioalkane 34 as the major product [46] (Scheme 11). Scheme 11 H BH, + BF,

H

70

H. Abu Ali et al.

The hydroboration of 1-hexyne produced gem-1,l-bis(dichloroboryl)hexane 35, which could be converted to well-known l,l-bis[2-(l,3,2-dioxaborinyl)]hexane 36. (Scheme 12) [48]. Scheme 12

3-Butyn-l-ol tosylate can be converted by 9-BBN to 9-cyclobutyl-9-borabicyclo[3.3.1]nonane 38 via geminal compound 37, which is oxidized to cyclobutanol 39 (Scheme 13) [49]. Scheme 13

-OTs

HB

"OTs

[O] OH B

39 38

Tetracyclohexyldiborane adds to 1-hexenyldicyclohexylborane mainly with the formation of a geminal 1,1-diborane 40 compound, (Scheme 14) [50]. Cainelli et al. [51] found that the 1,1 -diborane compounds 41 formed by the dihydroboration of 1 -hexyne, 1 decyne, or phenylacetylene with tetracyclohexyldiborane which undergo transmetalation by the action of two equiv of butyllithium in heptane at -70 °C to form mixed 1-bora-llithium compounds.

Chapter 2

71

Scheme 14

C4H0

H

—\

/ \

/ C4H9

HO

B(C 6 H 1 1 ) 2

C 4 Hg

40 COOH

A"

/ 4

9

* (v

R

COOH

1/2

41 41a: R = n-C< 41a: R = n-CfjH-17

Binder and Koster [52] have found that hydroboration of 3-chloro-l-propenyldialkylborane gave gew-l,l-bis(dialkylboryl)-3-chloropropane 42. When 42 was heated with sodium tetraethyl borate, it was cyclized to cyclopropyldialkylborane 43 (Scheme 15). 43 in the presence of compounds with B-H bond, symmetrizes to tricyclepropylborane 44. Later 44 was formed directly from 42 by reaction with NaBRsH [49]. Scheme 15

Cl

RoB H

H

R2BH

Cl

R2B R2B

NaBR3H

42

H

NaBR4

43 Geminated compound 45a could be formed during the exchange reactions between alkoxyvinylboranes and an alkyl borate, apparently preceded via the formation of intermediate 45 (Scheme 16) [53].

72

H. Abu Ali et al.

Scheme 16

45a

(ROCH=CH) 2 B^BO(CH 3 ) 2 45 A novel and efficient method for geOT-dimetalation of carbenoids has been reported by Shimizu [54]. Treatment of alkylidene-type lithium carbenoids with interelement compounds such as silylborane or diborane to generate the corresponding borate complex, followed by warming to room temperature, induced migration of the silyl or boryl group from a negatively charged boron atom to the carbenoid carbon to afford 1-boryl-1-silyl-1-alkenes or 1,1-diboryl-l-alkenes in good yields. Carbon-carbon bond forming transformations of the gew-dimetalated compounds mediated by boron or silicon is also described. gem-Diborylation of alkylidene-type carbenoids with diboranes has been demonstrated. Thus, commercially available diboranes A-D were used in the reactions (Scheme 17). Bis(pinacolato)diborane(4) A and optically active bis((+)pinanediolato)-diborane B reacted with 46 to give gew-diborylated compounds 47a and 47b in high yields. In contrast, reaction with bis(neopentanediolato)diborane C resulted in low yield of 47c due probably to its low solubility under the reaction conditions, while any desired diborylated compound was not obtained when bis(catecolato)diborane(4) D was employed.

73

Chapter 2

Scheme 17

Br BuU-110°C THF/Et2O(2:1*

ex N

—'

B-B

or X

Br

46

—'

p B-0

47

°

47a

Q O B-B O O

930%

47b o

>99.0%

47c

15.0%

47d

By use of A (Scheme 17), various kinds of alkylidene-type carbenoids 49a-f were ge/w-diborylated as shown in Scheme 18. Unsubstituted and 2,2-disubstituted carbenoid 49a gave 1,1-diborylalkene 50a in high yields. Dichloroalkene 48b could also be used, which after chlorine-lithium exchange underwent gew-diborylation, giving rise to 50b in 40% yield, while optically active 1,1-diborylalkene 50c was obtained from the corresponding dibromide 48c in 65% yield. Double deprotonation of 48d generated 49d which reacts with A to afford 1,1-diborylbutadiene 50d in 89% yield. gew-Diborylation of lithium carbenoids 49e and 49f prepared from conjugated chloroalkenes 48e and 48f proceeded smoothly, producing conjugated compounds 50e and 50f bearing two boryl groups at the terminal positions [54].

74

H. Abu Ali et al.

Scheme 18

Li

Br

Ph

Ph

Cl

MEMO

%

40%

MEMO

MEMO 48c

91

Li

Ph49bCI

Ph48bCI

Br

50a

49a Br

48 Br

BuLi or LiTMP

65% 50c

49c

Br

Cl

48d

89% 50d

48e

82% 50e

Hex Hex Hex 49f

Cl 50f

48%

Some synthetic applications of gew-bismetallic compounds are shown in Scheme 19. When an equimolar amount of allyl bromide was used as the coupling partner, stepwise coupling was possible. Thus, when 47a was treated with an equimolar amount of allyl bromide allylated alkenylboronate 51 was obtained. Furthermore, the allylation followed by coupling with iodobenzene in one pot gave the corresponding bis-coupled product 52 in a good overall yield. Rh-catalyzed Michael-type addition reaction of 47a to methyl vinyl ketone proceeded smoothly to give diketone 53 in 74% yield [55]. Two C-B bonds in 47a were simultaneously converted into two C-C bonds as exemplified by Pdcatalyzed cross-coupling reaction, with iodobenzene giving rise to 54.

75

Chapter 2 Scheme 19

//

51,83%

B-0 o B

1.Pd(PPh3)4, 3mol% aqKOH 2. dioxane, 70 °C , 12 h

1. Pd(acac)(CO2)dppb, 6mol aqKOH 2.methanol/H2O, 50 °C , 24

r

^ ^

1.Pd(PPh3)4, 3mol%, aqKOH 2.1-Ph, 1eq, 70 °C , 12 h

1.Pd(PPh3)4, 3mol%, aqKOH 2. dioxane, 70 °C , 12 h

54, 80%

Castle and Matteson reported the successful preparation of 1,1,1 -triboryl compounds 55 (Scheme 20) [56]. Octamethyl methanetetraboronate 55 appears stable indefinitely in neutral methanol, and with NaOH degraded to 56 which under H2O2 conditions transformed to 58 and 59 via 57.

H.AbuAlietal.

76

Scheme 20

CCI4

B(OCH3)2

8 Li

+ 4CIB(OCH3)2

(CH3O)2B—^B(OCH3)2

THF

B(OCH3)2 55

(CH 3 O) 2B -

(CH 3 O) 2B B(OCH3)2

(CH 3 O) 2 B /

V—B(OCH3)2 (CHaO^B 7

56

\C6H5CH2Br

C6H5CH2C[B(OCH3)2]3 57 1. RMgBr 2. C6H5CH2Br .3. H2O2

\

//

According to Castle and Matteson [57] 55 reacts with carbanion [ ( M e O ^ B ^ C to form methanetetraboronic ester 60. The resulting adduct 60 might then lose methoxide, add another carbanion, and continue the process to form polymer 62 via 61 with a C-BC-B-C ... backbone (Scheme 21). Scheme 21 B(OCH3)2 (CH 3 O) 2 B -^B(OCH 3 ) 2 B(OCH3)2

[(CH3O)2B]3C~

(CH 3 O) 2 B x | " -*- ( C H 3 O ) 2 B ^ B " ( C H

^ B

55

/

J

/B(OCH 3 ) 2 ^E

BOCH3

60 -CHoO" B(OCH3)2 —BB(OCH3)2 BOCH3 62

(CH3O)2B

B(OCH3)2

(CH3O)2B

B(OCH3)2

11

Chapter 2

Synthesis of cyclic boronic esters 63 and 64 containing B-C-B bound (Scheme 22) and tetrametallomethanes containing group IV metals have been reported by Matteson and Wilcsek [58]. Scheme 22 B(OCH3)2 (CH 3 O) 2 B-^B(OCH 3 ) 2 B(OCH3)2 55

4 HOCHoCHoOH,

4 HOCH2CH2CH2OH

Reaction of 64 with butyllithium followed by Ph3SnCl gave good yields of 65, 66 and 67 (Scheme 23) [58]. Compounds 69-75 could be prepared via carbanion 68 with two different metal atoms M and M| if base-catalyzed disproportionation of 65-67 occurred. The ditin 69, dilead 70, tin-lead 71, tin-germanium 72, and lead-germanium 74 compounds were synthesized in good yields [58,59]. Scheme 23

-O°" B

oto —-c 64

BuLi > 68 65:M = Sn 66:M = Pb 67:M = Ge

69:M = M, =Sn 70:M = M,= Pb 71:M = Sn, M, = Pb 72:M = Sn, M, = Ge 73:M = Ge, M, = Sn 74:M = Pb, M, = Ge 75:M = Ge, M, = Pb

Ph^Ph

78

H.AbuAlietal.

Treatment of tetrakis(dimethoxyboryl)methane 62 with bases such as methyllithium or lithium methoxide, lead to the tris(dimethoxyboryl)methide ion 76 (Scheme 24) [60] which reacted with methyl iodine to give the monomethylation product 77. Loss of a dimethoxyboryl group from monomethylation product 77 gave l,l-bis(dimethoxyboryl)ethide ion 78, which reacted with methyliodide to form 2,2-bis(dimethoxyboryl)propane 79. Approximately equimolar mixtures of di- 80 and monomethylation 81 were obtained in about 50% total yield when methyliodide was added to a mixture of 77 and 79 in the presence of ethylene glycol. Scheme 24 CH 3 [(CH 3 O) 2 B] 3 C-+ C H 3 I 76

-

(H3CO)2B^B(OCH3)2 B(OCH3)2 77 HOCH2CH2OH -B(OCH 3 ) 2 /

\

9 H 3 CK

o

O CH3

O

CH 3

(H3CO)2B—|—B(OCH3)2 *• —^-^ CH3 79

(H 3 CO) 2 B-C-B(OCH 3 ) 2

81

78

HOCH2CH2OH

L^ ' I O

N

CH 3 O

^

80

Alkylation of tris(dimethoxyboryl)methane 82 by LiOEt and removal of one dimethxyboryl cation gave bis(dimethoxyboryl)methide ion 83 (Scheme 25) or its borate ester complex [60]. The reaction with allyl bromide lead smoothly to 4,4-bis(l,3,2dioxaborol-2-yl)-l-butene 85. Other alkyl halides reacted with 82 to give B-C-B products: 84, 86, 87, 88-90 [60].

Chapter 2

79

Scheme 25 LiOEt

[(CH 3 O) 2 B] 3 CH

[(CH 3 O) 2 B] 2 CHO

83

82

CH 2 O R

84: R = C H 2 C = C H 85: R = C H 2 C H = C H 2 86: R = n-Bu 87: R = CH 2 C 6 H 5

\ V ,< I

B—\— B -1

CH 2

(

O=C

89

CH 3 90

Also, octamethyl methanetetraboronate 55 and methyllithium in tetrahydrofuran served as a source of tris(dimethoxyboryl)methide ion 76, which reacts with dimethoxyboron chloride to give tetramethyl 2-methylpropane-l,l-diboronate 91 (Scheme 26) [61], reaction of 91 with ethylene glycol forms the geminated boron compound 92. Refluxing benzophenone with 76 for 6 h followed by additional ethylene glycol formed 93 in 48% yield. Benzaldehyde led to styrene-/?,/?-diboronic acid which reacts with catechol in benzene to form the catechol esters 94 and 95 [61]. Scheme 26 B(OCH 3 ) 2 (CH3O)2B—UB(OCH3)2

MeLi

{CH 3 B(OCH 3 ) 2

B(OCH 3 ) 2

+

[(CH 3 O) 2 B] 3 C"}

76

55

1. CH3COCI 2. CIB(OCH 3 ) 2 2(HOCH 2 CH 2 OH)

H3C. H3C

B(OCH 3 ) 2

H3C

B(OCH 3 ) 2

HoC'

91

92 O

O B-O

94. R = C 6 H 5 95. R = CH 3

80

H.AbuAlietal.

Electrophilic displacement of the boronic ester group occured in the reaction of 92 with two equiv of mercuric chloride and sodium acetate in methanol gave 2methylpropene-l,l-dimercuric chloride 96 (Scheme 27) [61]. Scheme 27

H3C

h3C

EKO

h^C^HgCI

3 96

92 6 1 }

Deprotonation of bis(trimethylenedioxyboryl)methane 97 with lithium 2,2,6,6-tetramethylpiperidine yielded the diborylcarbanion 98, which reacts with alkyl halides to give high yields of gew-diboronic esters 99, which also could be deprotonated and alkylated to give 100 (Scheme 28) [62]. Carbanion 98a reacts with aldehydes and ketones to form enol borate intermediates, which hydrolyzed to ketones. Scheme 28 O

H

o—\

/—O

>-H > O

w 97

C

\ >-?-


\ =

H+

147, 65-80% Formation of B - O C - B compounds 150-153 have been demonstrated with the use of 1,3-diynes via platinum(II) anions [91]. The addition of (pin)B-B(pin) and (cat)BB(cat) to 4-MeOC 6 H 4 OCOCC 6 H 4 -4-OMe and S i M e 3 O C O C S i M e 3 proceeded smoothly to gave the novel tetrakis(boronate ester) compounds 154-157, respectively (Scheme 43). An important step in the catalyzed diboration of alkynes appears to be the

Chapter 2

89

dissociation of phosphine from the [(PPh3)nPt(r|-alkyne)] complexes, giving rise to a mono(phosphine)Pt intermediate which serves as the active catalyst in these systems. Scheme 43

148: R = 4-MeO-C6H4 149:R = SiMe3

-VQ

156:R = 4-MeO-CgH4 157:R = SiMe3

The diboration reaction of bis(pinacolato)diborane(4) with diethyl l-hexynylphosphonate 158a, diethyl phenylethynyl phosphonate 158b, 1-hexynylpinacolatoborane, 158c, and phenylethynylpinacolatoborane 158d in the presence of a catalytic amount of Pt(PPh3)4 (3 mol %) in toluene at 80 °C overnight gave the desired novel cis1,2-diboronated vinylphosphonate and trisboronated alkene addition products 159a, 159b, 159c and 159d respectively, in high yields (Scheme 44) [92].

H. Abu Ali et al.

90

Scheme 44

Pt(PPh3)4, toluene 80 °C, 2h

toluene 80 °C, overnight

158a: R 1 = C 4 H 9 , R 2 = P(O)(OC 2 H 5 ) 2 158b: R-, = C 6 H 5 , R2 = P(O)(OC 2 H 5 ) 2 158c: Ri = C 4 H 9 , R2 = Bpinacol 158d: R., = C 6 H 5 , R2 = Bpinacol

C4H9

P-(OC 2 H 5 ) 2

%

9 P-(OC 2 H 5 ) 2

O-B

.o o 159a, 8 2 %

C4H9

B-d

O-B .0

, O

159c, 86%

159d, 8 7 %

Chapter 2

91

The structure of 159d was found to be fully isomorphous to that of 159c, with the C6H5 ring located in place of the C4H9 residue. The reaction was efficiently catalyzed by Pt(PPli3)4 in toluene at 80 °C. The apparent hydroboration followed by deboronation when the B-B and Pt compounds are not preequilibrated may be due to either water or other such protic impurities since it is known that 1-alkynylboronates are very susceptible to cleavage by water. Preequilibration of Pt(PPli3)4 + excess B-B would lead to (PPri3)2Pt(B)2. If excess water were present, (PPli3)Pt(B)2 would react with H2O to give (PPh3)PtH2 + B-O-B. (PPh3)PtH2 would lose H2 and with excess B-B give more (PPh3)Pt(B)2, which, using PPh3 and B-B, by the way, as well as with the (PPh3)Pt(B)2 species. So, in effect, Pt can catalyze the hydrolysis of the B-B bond. The desired products 159a-d were produced in 100% conversion yields and high isolated yields. Unusual diboration of allenes catalyzed by palladium complexes formed novel B-C-C-B compounds 160—167 [93]. A new catalytic pathway other than one involving the oxidative addition of diborane to palladium (0) species operates in this new Pd-catalyzed reaction. The observation that an aryl, alkenyl iodine, or I2 was required to initiate the present catalytic reaction is interesting and vital to the understanding of the catalytic mechanism (Scheme 45).

Scheme 45

Q 0 B-B 0 0 a

q

p

B—B 0

PdCI2(dba)2, toluene 80 °C , 4h

0 b

ratio 5-7% / 93-95% 160: R, = R2 = Me 161: R ^ H , R2 = n-Butyl 162: R} = H, R2 = Ph 163: R-i = H, R2 = cyclohexyl 164: R-, = H, R2 = cyclopentyl 165: R-, = H, R2 = PhO 166: R ^ H , R2 = o-l-PhO 167: R ^ H , R2 = p-l-PhO

Platinum complexes also catalyzed diboration of terminal alkenes with chiral diborane compounds [9,75]. It has recently been shown that addition of certain enantiomerically pure chiral diborane compounds such as B2[(R,R)-OCHPhCHPhO]2, to 4-vinylanisole using the Miyaura [Pt(dba)2] [86], (dba, dibenzylidene acetone), catalyst system provides chiral 1,2-diborane ester 168 with up to 60% diastereometric excess (Scheme 46). Similarly, and based on earlier stoichiometric data (vide supra) Smith [94]

92

H.AbuAlietal.

reported that [Pt(NBE)3] and [Pt(COD)2] catalyzed the addition of B2cat2 to terminal alkenes giving 1,2-diborane ester 169. Also, saturated bisdiborane 170 with 72% enantiomeric excess (13% yield) could be obtained at -20 °C using a catalyst system composed of [Rh(NBD2]C104/S,S-chiraphos), [NBD, norbornadiene; chiraphos, 2,3-bis(diphenylphosphino)butane] [95]. Scheme 46

MeO-

+ B2[(R,R)-OCHPhCHPhO]2

Pt(dba)2, 5 mM —^ • 4 ° C ' t o l u e n e . 3 daYs

//~\ MeO—(/

X

168 80%, yield 60%, diastereomeric excess B(OR)4

jf-^

B(OR)2

Au(l) or Pt(O)

O _ ^O

[Rh*] HBcat

Synthesis of B-C-C-B compounds 173 and 174, and also geminal boron compounds 175 - 177 using rhodium catalysts have been reported [96]. Diboration of the styrylboronate esters with B2cat2 in the presence of a variety of rhodium phosphine catalysts gives predominantly either j?-R-C6H4-CH2C(Bcat)3 177, which contains three boronate ester groups on one carbon atom, or its isomer />R-C6H4-CH(Bcat)CH(Bcat)2 174 (Scheme 47). The formation of 173 apparently involves regiospecific insertion of the vinylboronates into a Rh-B bond followed by /^-hydride elimination, another regiospecific insertion of the 2,2-vinyl bis(boronate) into the remaining Rh-B bond followed by C-H reductive elimination leading to 2,2-diboration and a 2,1-hydrogen shift. Wilkinson's catalyst [Rh(PPh3)3Cl] gives the highest yields of 177 with 75 and 7 1 % yields from 171 and 172, respectively, while [Rh(COE)2(//-Cl)]2 with two equivalents of P(o-Tol)3 gave 174 in best yield with 50 and 49% from 171 and 172, respectively.

Chapter 2

93

Scheme 47 Ar.

'BH 3 ' promoter

Ar-

HBcat N

22 °C

Bcat

171: Ar= Ph 172:Ar = 4-MeO-C 6 H 4 Bcat= B. B2cat2/

Beat

Beat BcatN s / / \ Ar' Beat 174

Beat

A/ 173 Bcat^

[Rh(PPh3)3CI]

Beat

Beat

Beat Beat A r 177

-(-Beat

i—/

A/

Ar

Beat 176

175

Tetra(chloro)diborane reacts with acetylene to bis(dichloroboryl)ethane 178 [97-99] and cyclopentene bis(dichloroboryl)cyclopentene 179 (Scheme 48) [100].

yield forms

(Z)-l,2cis-\,2-

Scheme 48 H

=

CI2B.

H

BCI 2

H 178

o

cl2B B2CI2

CbB

x> 179

Diphenylacetylene reacts with dibromophenylborane to form cis-fibromovinylborane, which when reacts with lithium leads to hexaphenyl-l,4diboracyclohexadiene 180, the deuterolysis of which by deuteroacetic acid leads to cisdideuterostilbene (Scheme 49) [101].

94

H. Abu Ali et al.

Scheme 49 140

Ph

=

Ph + PhBBr2

°C Br

B(Ph)Br

Ph CH3COOD

Ph.

R

.Ph

Ph 180

Singleton and Redman [102] have found that l,2-diborylethylenes 182, 183 and 184 were readily generated from the reaction of fra«s-I,2-bis(tributylstannyl)ethylene 181 with haloboranes (Scheme 50) [103]. Scheme 50

fVo B -O 1 O 184, 70%

140°C

MeoB. H

BBN 183

95

Chapter 2

Formation of B-C-C-B compounds belonging to the bidentate Lewis acid was conducted by Biallas more than 30 years ago [104-106]. The reactions of a bidentate version of the quintessential boron-based Lewis acid (BF3) with simple Lewis bases and anions have been investigated. Thus, F2BCH2CH2BF2 135 was prepared by mixing ethylene and B2F4 at low temperature (Scheme 51) [107]. To obtain diboryl derivative 136 with strongly Lewis acidic boron centers, a weakly basic reagents such as Pl^COMe was required. Scheme 51

e B

BF2

H

H

Ph3COCH3

185

\

OCH3

[Ph3C]

F 186

Treatment of the known compound 1,2-(BCI2)2C6H4 [108] with slightly more than 2 equiv of Zn(C6Fs)2 led to smooth conversion to the desired 1,2-diborane 187 (Scheme 52) [109]. Reaction of 187 with potassium salts of OH" and F" in the presence 18-crown-6 produces borate anions 188 and 189 when X is chelated between the two boron centers. Scheme 52

[(C6F4)Hg]3

BBr,

e\

[K(18-C-6]+

B.,

187

Two different routes, by Piers [109] reported recently, the formation of compound the organotin precursor 1,2-C6F4(SnMe3)2 with 53). For conversion to 191 organotin C6F5 5)2 reagent were used [109].

188:X = OH 189: X = F

and Marks [110] groups independently, 190. Marks and coworkers [110] treated excess BCI3 at high temperatures (Scheme transfer agent [(C6Fs)2SnMe2] [111], or

96

H.AbuAlietal.

Scheme 53

4 BCI

[(C 6 F 4 )Hg] 3

It is known that zirconocenes mediated cyclization [22]. Metzler et al. [112] synthesized c/.s-bis(4,5-phenylmethylidene)-l,3-bis(dialkylamino)-l,3-boranes 198 and 199 with almost quantitative yield (Scheme 54) via zirconocene species 196 and 197. Bis[(dialkylamino)(phenylethynyl)boryl]methanes 194 and 195 were obtained in good yields by reacting lithium phenylacetylide with 192 and 193. Scheme 54 R

Cl

-~B"N2R Cl

LiCCPh hexane, LiCI

192: R = CH 3 193: R = i-Pr 194: R = CH 3 195: R = i-Pr

198: R = CH 3 199: R = i-Pr

Chapter 2

97

The hexaborylbenzene derivatives 202 and 203 have been obtained by transition metal catalyzed {[CpCo(CO)2], [Co2(CO)8], [Ni(cod)2]}cyclotrimerization of bis(l,3,2benzodioxaborol-2-yl)acetylene 200 and bis[l,3,2-(2,3-naphtho)-dioxaborol-2-yl] acetylene 201 (Scheme 55) [113] AlMe3 and AlEt3 were found to react with 202 and 203 to furnish C6(BMe2)6 204 and C6(BEt2)6 205, respectively. With pyridine, the hexafunctional Lewis acid 204 formed the crystalline bis(pyridine)adduct C6(BMe2)6-2(NC5H5) 206. Thermolysis of Ce(BEt2)6 205 resulted in the intramolecular elimination of ethane to give the l,2,3,4-bis(29,39-dihydro-19,39-diborole)-5,6-bis(diethylboryl)-benzene compound 207 (Scheme 55). Scheme 55

hexane

R

R

204: R' = Me 205: R' = Et

BMe2

202: R = H 203: R = C 4 H 4 NC 5 H 5 206

H. Abu Ali et al.

98

Reaction of [Co2(CO)8] with 200 yielded the bis(l,3,2-dioxaborol-2-yl) dicobaltatetrahedron derivative 208. Reaction of stoichiometric amounts of 208 and diphenylacetylene gives the bis(boryl)tetraphenylbenzene derivative 209, while reaction of 208 and mono(l,3,2-benzodioxaborol-2-yl)acetylene gives the tetraborylbenzene derivative 210 (Scheme 56) [113]. Scheme 56

200

toluene

204

Co(CO)3

(OC)3Co 208

Beat

210 209

The catechol-substituted diborane (4) 200 was reacted with diborylacetylene in the presence of [Pt(PPh3)2(C2H4)] to gave 211 in 7 1 % yield (Scheme 57) [114]. Catecholsubstituted diborylacetylenes 200 or 201 in the presence of [Pt(PPh3)2(C2H4)] or [Pt(PPh3)4], gave tetra- and the RHF/3-21G optimized geometries of 212 and 213 and reveal intramolecular stabilization of the boron p-_ orbital. When [Pt(cod)2] is used as catalyst, the tetraborylethene 213 is formed exclusively covers B-O, B-B, and agostic interactions [114].

Chapter 2

99

Scheme 57

200 + Beat

200 + Beat R=H R = t-Bu

200 + Beat

[(Ph3P)2PtC2H4 ———ii— THF, reflux, 24h

[(Ph3P)2PtC2H4 toluene, reflux, 55 °C ,24h

[Pt(cod)2 toluene, 40 °C , 48h

Derivatives of lithium and tin can be used in the preparation of B-C=C-B 215 217, 219, 221, 222 and B-OC-B 214 and 220 compounds (Scheme 58). Preparing monoand bidentate organoboron Lewis acids, the scope and limitations of synthesizing the requisite organoboranes by the Boron-Tin exchange between a boron halide and the appropriate organostannane have been observed [115]. Also organotin derivatives can be obtained either from the corresponding RMgBr or RLi reagent and MeBSnCU_w or from a Barbier procedure using the organic halide, Me3SnCl and magnesium metal: 1,2bis(trimethylstannyl)ethyne, ortho-, meta-, and /?ara-bis(trimethylstannyl) benzenes, a,obis(trimethylstannyl)toluene, a,a-bis-(trimethylstannyl)-o-xylene, and 2,2-dimethyl-2stannaindane [115]. Studies of the properties of these organoboranes have identified the heightened Lewis acidity of l,2-bis(diethylboryl)ethyne and the ^"-electron delocalization involving the 2/?r-boron orbitals in the 9,10-dihydro- 216 and 9,10-diboraanthracene systems 217. Finally, an electronic mechanism for the boron-tin exchange has been developed to account for the selectivity of boron halide attack at unsaturated carbon-tin bonds.

100

H. Abu Ali et al.

Scheme 58 Li

=

Et2BBBr2

Li

THF

B

=

J

B

+

L_

B-O—1

_|

214

Br

U 93%

B(C 2 H 5 ) 2 Br Me3Sn—=—SnMe3 -Me 3 SnBr

tw0

steps

SnMe 3

216

R = Br, Cl

The thermolysis of boranes 214 led variously to definite dimers or ill-defined oligomers with B-OC-B structure 219 (Scheme 59). 1,2-Bis(diethylboryl)ethyne 214 was heated to 120 °C and the evolved liquid permitted to reflux for 2 h. Evaporation of the evolved liquid under reduced pressure allowed the condensation of 1.0 equivalent of EtjB and a red-brown viscous oil remained 218. Subsequent heating up to 700 °C in a TGA apparatus left a shiny black residue of empirical formula of C3B2H4 219 [115].

Chapter 2

101

Scheme 59

THF Lindmar Pd

Et

9

Et'

-i I

H H r I I I

B-C-C-B H H L 222

B— 220

Et

L-Et

o

-3 Et2B AT

Recently, Ishiyama and Miyaura [116] published article were they reviewed the metal-catalyzed borylation of alkenes, alkynes, and organic electrophiles with B-B compounds. Also they reported that the platinum(O)-catalyzed addition of bis(pinacolato)diborane to alkenes and alkynes stereoselectively yielded cisbis(boryl)alkanes or c/s-bis(boryl)alkenes; and the addition of diborane to 1,3-dienes with a platinum(0)complex afforded a new access to the c/s-l,4-bis(boryl)butene derivatives which are a versatile reagent for diastereoselective allylboration of carbonyl compounds. The mechanisms and the synthetic applications of these reactions have also been discussed. Hydrozirconation of 1-alkynyl pinacolboronates 223, with HZrCp2Cl provides gem-bora zirconocenes 224. The latter when treated with CuBr gives the homocoupled (l£,3£)-2,3-dibora-l,3-butadienes 225 in 65% yield (Scheme 60) [117].

102

H. Abu Ali et al.

Scheme 60

We have described the synthesis of a novel class of 1,3- and 1,4-dibory 1-1,3butadienes by zirconocene mediated reductive cyclization of alkynylboronates followed by treatment with acid [117,118]. While Metzler and Noth have prepared similar 1,4diboryl-l,3-butadienes, a structural investigation of this class of compounds has not been reported heretofore [112,119,120]. To obtain detailed structural information an X-ray structure analysis of 2,4-Diphenyl-l,3-A/.v(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)buta-lZ,3£-diene 226 has been determined, Fig. 3 [118].

Fig. 3. Structure of 2,4-Diphenyl-1,3-fc«(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)-butalZ,3£-diene226 The compound consists of a lZ,3£-butadiene moiety substituted by two pinacol boronate functional groups. The molecular structure consist of a 1,3-butadiene moiety

Chapter 2

103

substituted by two pinacol boronate functional groups at C(13) and C(I5) carbon atoms and a two phenyl functional groups at C(14) and C(16) carbon atoms. All bond angles at C(14) and C(l 5) are close to the triangular value. Bond distances and angles are typical [121]. The C14-phenyl and the C15-dioxaborolane groups are twisted out of the plane of the molecule, while the terminal groups are essentially planar. This arrangement is probably due to steric interactions between the dioxaborolane and phenyl groups. Colorless single crystals of 226 suitable for X-ray diffraction analysis were obtained from a saturated pentane solution at ca. -20 °C The X-ray diffraction measurements were carried out at ca. 110 K on a Nonius KappaCCD difractometer, using Mo K« (1 = 0.7107 A) radiation and 1.0° Phi and Omega scans.

C11

C20

Fig. 4. Molecular structure (50 % displacement ellipsoids) of 226. The selected bond distances (A) and angles (°) are: B1-C15 1.578(3), B1-O2 1.370(2), B2-O4 1.371(2), B2-C13 1.552(3), C13-C14 1.350(3), C15-C16 1.350(3), C14-C15 1.488(2); C13-C14-C15 121.71(17), C14-C15Bl 118.04(16), C15-C14-C23 117.26(15), C16-C15-B1 122.30(16) Bis(pinacolato)diborane(4) selectively adds to terminal alkenes and cyclic alkenes having internal strain to provide bis-(boryl)alkanes in 76-86% yields 227-231 in the presence of a catalytic amount of Pt(dba)2 at 50 °C [122] (Scheme 61). It is interesting to mention that Pt(dba)2 directed 1,2-addition to certain conjugated dienes, whereas 1,4addition through a ^-allyl-platinum(II) intermediate is an energetically more favorable process. The 1,4-addition to penta-l,3-diene at 80 °C with Pt(PPh3)4 gives 232, but the same reaction with Pt(dba)2 selectively produced the 1,2-addition product 233 at room temperature (Scheme 61).

104

H. Abu Ali et al.

Scheme 61 CfiH

r

227, 86%

228, 85%

°

229, 85%

B-B

o

\=/

Pt(dba)2, toluene, 50 °C C a H, 230, 82% —B

MeOC 6 H 4

B—

H

231,86%

\•

OMe

r

Pt(PPh 3 ) 4> toluene, 80 °C

232

Pt(dba)2 *toluene, room temp.

Bis(dibenzylideneacetone)platinum Pt(dba)2 catalyzes the diboration of terminal alkenes 234 with bis(pinacolato)diborane(4) to give products 235 in isolated yields of 76-85% (scheme 62 ) [8].

Chapter 2

105

Scheme 62

toluene, 50 °C,1 h Pt(dba)2,3 mol%

*

234 235

235a:R., = CH3(CH2)7, R2 = H 235b: R-, = Ph, R2 = (CH 2 ) 3 235c: R-, = 4-MeOC 6 H 4 , R2 =

It has been reported that bis(cyclooctadiene) platinum Pt(cod)2 catalyzes the addition of bis(catecolato)diborane(4) to terminal alkenes 236 to give products terminal alkenes 237 in 84-95% crude yields (scheme 63 ) [10]. Scheme 63

0

0

toluene, rt, 30 min

d

b

Pt(cod)2, 3 mol%

w

236

237a: R, = H 237b: R, = Bu 237c: R, = 4-MeOC6H4 237d:R1=4-F3CC6H4 237e: R-, = (CH2)4CI 237f: R-, = (CH2)4OAC

Reaction of vinylarenes 238 with Bis(dibenzylideneacetone)platinum Pt(dba)2 and the chiral diborane(4) compound 239 is carried out to give diboronated compounds 240 (scheme 64) [9].

106

H.AbuAlietal.

Scheme 64

Pi B-B

toluene, 4 °C , 4 days : : ' Pt(dba)2, 5 mol%

238 239 240a: R, = 4-MeOC6H4, 80% 240b: R] = 4-PhC6H4 240c: R.| = 2-naphthyl Stannylboranes having one Sn, C and N atom bonded to a boron atom can be prepared from (amino) (chloro) (organo)boranes. For example, the diborylethene 241 on stannylation with trimethylstannyllithium gives a pair of stereoisomers (Z)- and (E)- 242 and 243 respectively, that can be separated by fractional crystallization (Scheme 65) [123]. Scheme 65 Pr'2N 2

pri2N

\==^ >J-B

Pr^N

NPr'2 B-N

Cl Cl'

NPH2

N-B' B-N Me3Sn SnMe3 (Z)-242

LiSnMe3 (2 equiv) *~

+

-2LiCI

Pri2Ns

241

\

/N

F

B—SnMe 3

Me3Sn—E

(E)- 243

Chapter 2

107

Automated parallel screening using a series of in situ generated platinum(O) phosphine complexes has allowed the identification of improved catalysts for the diboration of alkyne 245 using bis(pinacolato)diborane(4). A selection of phosphines were added to [Pt(NBE)3] (NBE = norbornene), which contains only labile mono-olefin ligands, and the activity of the resulting solutions as catalysts for the diboration of 4CF3C6H4C=CCgH4CF3-4' 244 by bis(pinacolato)diborane(4) was investigated by in situ GC-MS and/or NMR spectroscopy (Scheme 66). This allowed the optimum phosphine: platinum stoichiometry to be identified as 1:1, and the large differences in catalyst activity depending on the nature of the phosphine to be quantified. The best phosphines employed in the study, PCy3 and PPh2(o-Tol) (o-Tol = CeFUMe-o), give activities orders of magnitude greater than the worst, such as P(C6Fs)3 and P(t-Bu)3. The monophosphine catalysts function much more efficiently than previous catalysts for a range of alkynes allowing diborations to be performed at ambient temperatures. The diboration of strained cyclic alkenes and some vinyl- and allyl-arenes proceeded well, although the catalysts were inactive for other olefinic systems examined. As a result of these studies, the isolable and stable compound [Pt(PCy3)(r|2-C2H4)2] was identified as an excellent catalyst for alkyne diboration even at room temperature [124]. Scheme 66

F 3 C-('

N

)

=

(\

/KCF3 Pt(NBE)3, 0.5 mol% / PR3, 0.5 mol% toluene, 10 h, rt

A

245

Boronate esters and boronic acids are extremely useful in synthesis [125] and can also display biological activity [126]. It is not possible to introduce boronate groups at a position /?- to a carbonyl using conventional hydroboration methods as the boron would avoid the electrophilic site [125c]. Bis(pinacolato)diborane(4) reacts with a,/?-unsaturated carbonyl compounds to give 1,4- and unprecedented 3,4-additions in the presence of a second generation Pt(O) catalyst at ambient temperature. Pt(BIAN)(DMFU) (BIAN = bis(phenylimino)acenaphthene, DMFU = dimethylfumarate), a platinum(O) diimine species, was employed as the catalyst precursor at 5 mol% loading and a range of «,/?unsaturated carbonyl compounds were successfully diborated using bis(pinacolato)diborane(4) as the diboron reagent (Scheme 67). In situ ]H NMR spectroscopic analysis of reactions carried out in benzene-d6 indicated that two distinct types of primary diborated product arise. Ketone substrates (R3 = alkyl, aryl) show selectivity for the 1,4-diboration products 247a (O-bound boron enolates). Conversely, ester substrates (R3 = alkoxyl) show selectivity for the 3,4-diboration products 247b (Cbound boron enolates) where bis(pinacolato)diborane(4) effectively adds across the C=C double bond of the unsaturated ester. This is unusual as diboration of alkenes [7,8,9,10] with Pt(O) is comparatively difficult except for terminal or strained cyclic systems.

H. Abu Ali et al.

108 Scheme 67

R2 p-q 0. 247a

247b R-, R, R-i R, R-,

Pt(BIAN)(DMFU) =

= = = = = =

H, R2 = H, R3 = Me, 247 a = 100%, 247 b = 0% Ph, R2 = H, R3 = Me, 247 a = 77%, 247 b = 0% Ph, R2 = H, R3 = Ph, 247 a = 89%, 247 b = 0% H, R2 = Me, R3 = OMe, 247 a = 0%, 247 b = 87% Me, R2 = H, R3 = OEt, 247 a = 9%, 247 b = 59% CO 2 Me, R2 = H, R3 = OMe, 247 a = 0%, 247 b = 93%

MeO,C

Novel organoboronate derivatives consisting of BB, BC(RiR2)B, BCCB, CBC, R B O C B B and R B O C B P structures were synthesized and have been investigated invitro as MMP-2 inhibitors [127]. The following groups of boronate and phosphonoboronate inhibitors were synthesized and tested in this study, Fig. 5: BB, BCB, BCCB A, 1, 3, 4; CBC compounds 5a, 5b, 5c; BC(RiR2)B 8a, 8d; vinyl phosphonodiboronates RBC=CBP 159a, 159aa, 159b, 159bb; and vinyl triboronates RBC=CBB 159c, 159d. Bis(pinacolato)diborane(4) A was prepared from tetra(pyrrolidino)-diborane(4) by Wurtz coupling of bis(pyrrolidino)bromoborane, and then obtained by solvolysis of tetra(pyrrolidino)diborane(4) with 2 equivalents of pinacol in benzene solution at room temperature [5]. BCB compound 1 was prepared by the insertion reaction of diazomethane with A [32]. BCCB 3 was prepared by the coupling reaction of (pinacolato)BCH2l with different metals [32]. CBC compounds 5a, 5b, 5c were prepared by addition of A to cyclic enones [32]. Cl-bridged bis(pinacolato)diborane(4) BC(RiR2)B, 8a, 8d were obtained by the insertion reaction of diazoalkane with A [37]. Vinylphosphonodiboronates RBC=CBP, 159a, 159b and vinyl triboronates RBC=CBB, 159c, 159d were prepared by the diboration reaction of 1-alkynylboronates and 1-alkynylphosphonates with A [92]. Hydrolysis of the vinyl phosphonodiboronates esters, 159a, 159b by MesSiBr followed by treatment with methanol gave the free acid derivatives, 159aa, 159bb [128].

109

Chapter 2

°\\ -B.

/

/ BB

o

HO7

H H

OH

O Ph

OMe \

O

5c C4H9

\

/P(OC2H5)2

>=C \—Q /

o.

159a O C4Hg

C

C 4 Hg

O-

159bb Fig. 5. Structure of the tested compounds

B

, X

159c

6H5

^^

B—q O.

O

O.

159d

110

H.AbuAlietal.

Matrix metalloproteinases (MMPs), also called matrixins, are a family of structurally related zinc containing enzymes that mediate the breakdown of connective tissue and are therefore targets for therapeutic inhibitors in many inflammatory, malignant, and degenerative diseases [129-131]. Long before the individual enzymes were isolated and characterized, researchers had been interested in the activity of tissue remodeling, both in physiological and disease processes. The mammalian MMP family is now known to include at least 23 enzymes. There are two type IV collagenases [132,133], now termed gelatinase A (MMP-2) and gelatinase B (MMP-9), which, as described by Liotta and colleagues [134], can degrade type IV collagen of basal laminae as well as other nonhelical collagen domains and proteins such as fibronectin and laminin. There is increasing evidence for a positive correlation between MMP-2 activity and tumor cell invasion [135]. Therefore, there are a growing number of attempts to design and develop active inhibitors that may restore the balance of MMPs in these pathological processes [136]. Over production or misregulation of MMPs has been implicated in a number of pathological processes, including tumor growth and metastasis, bone matrix degradation, rheumatoid, cerebral ischemia, meningitis, atherosclerosis, gastric ulceration, periodontal diseases, multiple sclerosis, wound healing, degradation of aortic wall in aneurysms and other diseases [137]. There are many types of cancers related to MMP-2 among them are liver cancer, gastric carcinomas, colorectal cancer, oral cancers, central nervous system tumors, osteosarcoma, breast cancer, malignant melanoma and chondrosarcoma. Comparison of the structures of the various MMP inhibitor complexes reveals valuable information on the differences in the active sites of the MMPs studied and on the binding modes of inhibitors [138]. The requirement for a molecule to be an effective inhibitor of the MMP class of enzymes is a functional group (e.g., carboxylic acid, hydroxamic acid, and sulfhydryl, etc.) capable of chelating the active-site zinc(II) ion (this will be referred to as zinc binding group or ZBG), at least one functional group which provides a hydrogen bond interaction with the enzyme backbone, and one or more side chains which undergo effective van der Waals interactions with the enzyme subsites. There are a number of disadvantages of most regular MMP inhibitors: low water solubility, no selectivity versus other MMPs, side effects, high toxicity and poor bioavailability and pharmacokinetics. Modification of physical properties, particularly by introduction of non-peptide structures and replacement of the hydroxamate by other zinc ligands, for example by phosphonate, improved pharmacokinetics without a reduction in metabolism [139]. The use of both boronates and phosphonates as transition state analogue inhibitors is well known [140]. In addition, we have recently shown that phosphonoboronates i.e. compounds containing both boronate and phosphonate groups, can serve as MMP-2 inhibitors, Pergament et al [141]. In addition, boronates were show to bind zinc to certain aminopeptidases by X-ray crystallography [142]. Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, novel organoboronate

Chapter 2

111

derivatives, Fig. 5 have been synthesized and investigated in vitro for the ability to inhibit MMP-2 protease. The results are summarized in Fig. 6A-E. The inhibition activity of these compounds varies from not active through moderate to potent. Vinyl trisboronate 159c and 159d showed promising activity as MMP-2 inhibitors, probably due to the double bond character or to the increasing number of boronate groups. Compound 159c which is substituted with aliphatic C4H9 group has more activity than its analogue 159d with a CeH5 aromatic group. The same trend was also observed between compounds 159a and 159b. In principle there are two modes for MMP-2 action: transition state analogue or zinc chelation mechanism. Since MMP-2 contains two Zn(II) groups, we believe that the boronate group can act as a zinc chelator and increase the inhibition activity. The activity of compounds A, 1, 3 and 4 decreased by increasing the chain length of carbon atoms between the BB groups. Compound A showed 70% inhibition at 10 /JM concentration, while the BCB 1 showed only 45% inhibition at the same concentration. BCCB 3 boronate ester compound did not show any activity but its free acid 4 showed 45% inhibition activity. CBC compounds 5a, 5b and 5c with carbonyl group were found to have 66%, 20%, and 75% inhibition activity, respectively. This may be explained by considering the carbonyl group as a functional group capable of cheiating the active site Zn(II) ion. Compound 5c which incorporates isopropyl moiety in the para position possesses more activity than 5b although both have carbonyl group at the same position. This may be attributed to the increased hydrophobicity gained by the isopropyl group, i. e. both of the above mentioned mechanisms should be taken into consideration. 80

n rh

100-

| V

I%

? 40 V

1\ \; V

f

\

20

.a S

"•• 0

"N>

NN

|

V control

01 5 10

A

1 5 10

1 Treatment

10 50 100

5a

10 50 100

51) Treatment

1C 50 100

5c

112

H. Abu Ali et al. 125

I

100

7550

25

HMrol 1 5 10

159a Treatment

1 5 10

1 5 10

1 5 10

15%

159aa

15%b

Treatment

125

§'• 100 -

50-

rte]

250-

1 0 5 0

1 0 0

159 c Treatment Fig. 6. The effect of organonoboronates on cellular invasion of HT-1080 human fibrisarcoma cells: (A) BB, BCB, BCCB A, 1, 3, 4; (B) CBC compounds 5-7; (C) Ci-bridged bis(pinacolato)diborane(4) BC(RiR2)B 8c, 8d; (D) vinyl phosphonodiboronates RBC=CBP 159a, 159b, 159aa, 159bb; and (E) vinyl triboronates RBC=CBB 159c, 159d. All concentrations are in The Cl-bridged bisboronate derivatives 8c and 8d possess significant activity of 82% at 100 /jM for compound 8c and moderate activity of 51 % at the same concentration for 8d. We observed that the pinacol phosphonoboronates 159a and 159b are more active than their corresponding free phosphonic acids 159aa and 159bb which did not show any activity at all. SAR data for MMP-2 and MMP-9 gelatinases showed that these enzymes tolerate hydrophobic side chains of the inhibitor at the active site [143]. These are general explanations for the mode of interaction of these compounds with MMP-2. The exact mode of interaction with these compounds is still not known until now. Therefore, further studies should be done in order to determine the exact mode of interaction e.g. molecular modeling, X-ray and NMR studies.

Chapter 2

113

REFERENCES [I]

[23] [24] [25] [26] [27] [28] [29] [30]

G. Urry, J. Kerrigan, T.D. Parsons and H.I.Schlesinger, J. Am. Chem. Soc. 76 (1954)5299. T. Onak, Organoboron Chemistry, Academic Press: New York, (1975) 38. T.D. Coyle and J.J.Ritter, Adv. Organomet. Chem. 10 (1972) 237. E.L. Muetterlies, The Chemistry of Boron and its Compounds; Wiley: New York, (1967)398. H. Abu Ali, 1. Goldberg and M. Srebnik, Eur. J. Inorg. Chem. (2002) 73. R.J. Brotherton, J.L. McCloskey, L.L. Petterson and H. Steinberg, J. Am. Chem. Soc. 82(1960)6242. R.T. Baker, P. Nguyen, T.B. Marder and S.A.Westcott, Angew. Chem. Int. Ed. Engl. 34(1995) 1336. T. Ishiyama, andN. Miyaura, Chem. Record 3 (2004) 271. T.B Marder, N.C. Norman and C.R. Rice, Tetrahedron Lett. 39 (1998) 155. T. Ishiyama, T. Kitano and N. Miyaura, Tetrahedron Lett. 39 (1998) 2357. M. Suginome, and Y. Ito, J. Organometal. Chem. 680 (2003) 43. C.N. Iverson and M.R. Smith, J. Am. Chem. Soc. 117 (1995) 4403. Q. Cui, D.G.M. Musaev and K. Morokuma, Organometallics 17 (1998) 742. Q. Cui, D.G.M. Musaev and K. Morokuma, Organometallics 17 (1998) 1383. W. Siebert, H. Pritzkow and A. Maderna Angew. Chem. Int. Ed. Engl. 35 (1996) 1501. W. Clegg, A.J. Scott, G. Lesley, T.B. Marder and N.C. Norman, Acta Cryst. C52 (1996) 1989 and 1991. H.Z. Noth, Naturforsch 39B (1984)1463. F.J. Lawlor, N.C. Norman, N.L. Pickett and E.G. Robins Inorg. Chem. 37 (1998) 1777. V.M. Dembitsky, G.A. Tolstikov and M. Srebnik, Eurasian Chem. Tech. J. 4 (2002) 87. EJ. Corey and X. Cheng, The Logic of Chemical Synthesis, Wiley-Interscience: New York. (1989). P.A. Wender (Ed). Frontiers in Organic Synthesis thematic issue. Chem. Rev. 96 (1996)1. V.M. Dembitsky and M. Srebnik, In: Titanium and Zirconium in Organic Synthesis. Marek I. Ed., Wiley-VCH Verlag GMBH, Weinheim, (2002) 230. I. Marek, Chem. Rev. 100 (2000) 2887. B.M. Trost, Z.T. Ball, Synthesis-Stuttgart 6 (2005) 853. M. Zaidlewicz, and J. Meller, Main Group Metal Chem. 23 (2000) 765. G. Zweifel and H. Arzoumanian J. Am. Chem. Sac. 89 (1967) 291. G. Zweifel, R.P. Fischer and A. Horng, Synthesis (1973) 37. A.J. Ill Ashe and P. Shu, J. Am. Chem. Soc. 93 (1971) 1804. G. Cainelli, G. Dal Bello, and G. Zubiani, Tetrahedron Lett. (1966) 4315. T. Mukaiyama, M. Murakami, T. Oriyami and M. Yamaguchi, Chem. Lett. (1981)

[31] [32]

C.K.. Reddy and M. Periasamy, Tetrahedron Lett. 49 (1993) 8877. H. Abu Ali, I. Goldberg and M. Srebnik, Organometallics 20 (2001) 3962.

[2] [3] [4] [5] [6] [7] [8] [9] [10] II1] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

1193.

114

H.AbuAlietal.

[33] [34] [35] [36] [37]

J. Hooz and G.F. Morrison, Can. J. Chem. 48 (1970) 868. J. Hooz, D.M. Gunn and H. Kono, Can. J. Chem. 49 (1971) 2371. J. Hooz and D.M. Gunn, Tetrahedron Lett. (1969) 3455. T. Ishiyama, S. MomotaandN. Miyaura, Synlett 11 (1999) 1790. H. Abu Ali, 1. Goldberg, D. Kaufmann, C. Burmeister and M. Srebnik Organometallics21 (2002) 1870. B. Wrackmeyer and G. Kehr, Polyhedron 10 (1991) 1497. G.E. Herberich, H. Ohst and H. Mayer, Angew. Chem. Int. Ed. Eng. 23 (1983) 969. M. Enders, H. Pritzkow and W. Siebert, Angew. Chem. Int. Ed. Eng. 31 (1992) 606. J.J. Eosch, J. Organomet. Chem. 500 (1995)101. B. Wrackmeyer and G. Kehr, J. Organomet. Chem. 501(1995) 87. P. Greiwe, V. Beez, H. Pritzkov and W. Siebert, Eur. J. Inorg. Chem. (2001) 381. V. Beez, P. Greiwe, H. Pritzkov, M. Hofmann, P. von R. Schleyer and W. Siebert, Eur. J. Inorg. Chem. (1998) 1775. J.C. Colberg, A. Rane, J. Vaquer and J.A. Soderquist, J. Am. Chem. Soc. 115 (1993)6065. R. Dulou and Y. Chretien-Bessiere, Bull.Soc.Chim.Fr. (1959)1362. H.C. Brown and G. Zweifel, J.Am.Chem.Soc. 83 (1961) 3834. R. Soundararajan and D.S.Matteson, J. Org. Chem. 55(1990) 2274. H.C. Brown and S.P. Rhodes, J. Am. Chem. Soc. 91 (1969) 4306. G. Zweifel and H. Arzoumanian, J. Am. Chem. Soc. 89 (1967) 291. G. Cainelli, G. Dal Bello and G. Zubiani, Tetrahedron Lett. (1965) 3429. P. Binder and R. Koster, Angew. Chem. 74 (1962) 652. YuN, Bubnov, V.S. Bogdanov, l.P. Yakovlev and B.M. Michailov, Zh. Obsch. Khim. (SSSR)42(1972) 1313. T. Kurahashi, T. Hata, H. Masai, H. Kitagawa, M. Shimizu and T. Hiyama, Tetrahedron 58 (2002) 6381. M. Sakai, H. Hayashi and N. Miyaura, Organometallics 16 (1997) 4229. R.B. Castle and D.S. Matteson, J. Am. Chem. Soc. 90 (1968) 2194. R.B. Castle and D.S. Matteson, J. Organomet. Chem. 20 (1969) 19. D.S. Matteson and R.J.Wilcsek, J. Organomet. Chem. 57 (1973) 231. D.S. Matteson and G.L. Larson, J. Organomet. Chem. 57 (1973) 225. D.S. Matteson and J.R. Thomas, J. Organomet. Chem. 24 (1970) 263. D.S. Matteson and P.B.Tripathy, J. Organomet. Chem. 21 (1970) 6. D.S. Matteson and R.J. Moody, J. Am. Chem. Soc. 99 (1977) 3196. D.S. Matteson, Stereodirected Synthesis with Organoboranes. Springer, Berlin,! 995. G. Cainelli, G. Dal Bello and G. Zubiani, Tetrahedron Lett. (1966) 4329. M.W. Rathke and R. Kow J. Am. Chem. Soc. 94 (1972) 6854. R. Kow and M.W. Rathke, J. Am. Chem. Soc. 95 (1973) 2715. K. Nozaki, K. Oshima, and K. Utimoto, Bull. Chem. Soc. Japan 64 (1991) 403. D.S. Matteson, L.A. Hagelee and R.J.Wilcsek, J. Am. Chem. Soc. 95 (1973) 5096; (b) D.S. Matteson and P.K. Jesthi, J. Organomet. Chem. 110 (1976) 25. D.S. Matteson and R.J. Moody, Organometallics 1 (1982) 20.

[38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69]

Chapter 2 [70] [71] [72]

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R. Soundararajan and D.S. Matteson, Organometallics 14 (1995) 4157. L. Jia, X. Yang, C.L. Stern and T.J. Marks, Organometallics 13 (1994) 3755. D.J. Parks, R.E. Spence, H. Spence and WE. Piers, Angew. Chem. Int. Ed. Engl. 34(1995)809. [73] K. Kohler, W.E. Piers, A.P. Jarvis, S. Xin, Y. Feng, A.M. Bravakis, S. Collins, W. Clegg, G.P.A. Yap and T.B. Marder, Organometallics 17 (1998) 3557. [74] W.E. Piers, G.J. Irvine and V.C. Williams Eur. J. Inorg. Chem. (2000) 2131. [75] T.B. Marder and N.C. Norman, Topics in Catalysis 5 (1998) 63. [76] C. Wieczorek, J. Allwohn, G. Schimdt-Lukasch, R. Hunold, W. Massa, A. Berndt, Angew. Chem. Int. Ed. Engl. 29 (1990) 398. [77] A. Ziegler, H . Pritzkow and W. Siebert, Eur. J. Inorg. Chem. (2001) 387. [78] A. Berndt, Angew. Chem. Int. Ed. Engl. 32 (1993) 985; (a) A. Hoefner, B. Ziegler, R. Hunold, W. Massa, A. Berndt, Angew. Chem. Int. Ed. Engl. 30 (1991) 594; (c) A. Hoefner, M. Allwohn, W. Massa, P.v.R., Schelyer, A. Berndt, Angew. Chem. Int. Ed. Engl. 28 (1989) 781. [79] D.S. Matteson, and D. Majumdar, J. Organomet. Chem. 170 (1979) 259. [80] B.M. Mikhailov, A. Bezmenov, L.S. Vasil'ev and V.G. Kiselev, Dokl. Akad. NaukSSSR 155 (1964) 141 [81] B.M. Mikhailov, A. Bezmenov and L.S. Vasil'ev, Dokl. Akad. Nauk SSSR 167 (1966)590. [82] H.C. Brown, E, Negishi and S.K.Gupta, J. Am. Chem. Soc. 92 (1970) 2460. [83] P.M. Aronovich, V.S. Bogdanov and B.M. Mikhailov, Izv. Akad. Nauk SSSR, Ser. Khim. (1969)362. [84] Y. Tanigawa, I. Moritaqni and S. Nishida, J. Organomet. Chem. 28 (1971) 73. [85] D.S. Matteson, and J.W. Wilson, Organometallics 4 (1985) 1690. [86] T. Ishiyama, N. Matsuda, N. Miyaura and A. Suzuki, J. Am. Chem. Soc. 115 (1993) 11018. [87] N. Miyaura and A. Suzuki, Chem. Rev. 95 (1995) 2457. [88] T. Ishiyama, M. Yamamoto and N. Miyaura, Chem. Lett. (1996) 1117. [89] T. Ishiyama, N. Matsuda, M. Murata, F. Ozawa, A. Suzuki and N. Miyaura Organometallics 15 (1996) 713. [90] P. Binder and R. Koster Tetrahedron Lett. (1965) 1901. [91] G. Lesley, P. Nguyen, J. Taylor, T.B. Marder, A.J. Scott, W. Clegg and N.C. Norman, Organonetallics 15 (1996) 5137. [92] H. Abu Ali, A.A. Al Quntar, I. Goldberg and M. Srebnik Organometallics 21 (2002) 4533. [93] F.Y. Yang and C.H. Cheng, J. Am. Chem. Soc. 123 (2001) 761. [94] C.N. Iverson and M.R. Smith III, Organometallics 16 (1997) 2757. [95] C. Wiessauer and W. Weissensteiner, Tetrahedron Asymm. 7 (1996) 5. [96] P. Nguyen, R.B. Coapes, A.D. Woodward, N J . Taylor, J.M. Burke, J.A.K. Howard and T.B. Marder J. Organomet. Chem. 652 (2002) 77. [97] R.W. Rudolph, J. Am. Chem. Soc. 89 (1967) 4216. [98] M. Zeldin, A.R. Gatti and T. Wartik, J. Am. Chem. Soc. 89 (1967) 4217. [99] T.D. Coyle and J.J. Ritter, J. Am. Chem. Soc. 89 (1967) 5739. [100] A. Rozen and M. Zeldin, J. Organomet. Chem. 31 (1971)319. [101] J.J. Eisch, and L.J. Gonsior, J. Organomet. Chem. 8 (1967) 53.

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[102] [103] [104] [105] [106] [107]

D.A. Singleton and A.M. Redman, Tetrahedron Lett. 35 (1994) 509. E.J. Corey and R.H. Wollenberg, J. Am. Chem. Soc. 54 (1974) 5581. D.F. Shriver and M.J. Biallas, J. Am. Chem. Soc. 89 (1967) 1078. M.J. Biallas, J. Am. Chem. Soc. 91 (1969) 7290. M.J. Biallas, Inorg. Chem. 10 (1971) 1320. P. Ceron, A. Finch, J. Frey, J.Kerrigan, T. Parsons, G. Urry and H.I. Schlesinger, J. Am. Chem. Soc. 81 (1959) 6368. D. Kaufman, Chem. Ber. 120(1987)901. V.C. Williams, W.E. Piers, W. Clegg, M.R.J. Elsegood, S. Collins and T.B.Marder, J. Am. Chem Soc. 121 (1999) 3244. M.V. Metz, D.J. Schwartz, C.L. Stern, P.N. Nickias and T.J. Marks, Angew. Chem. Int. Ed. Engl. 39 (2000) 1312. D. Chambers and T. Chivers, J. Chem. Soc. (1964) 4782. N. Metzler, H. Noth and M. Thomann, Organometallics 12 (1993) 2423. C. Ester, A. Maderna, H. Pritzkow and W. Siebert, Eur. J. Inorg. Chem. (2000) 1177. M. Bluhm, A. Maderna, H. Pritzkow, S. Bethke, R. Gleiter and W.Siebert, Eur. J. Inorg. Chem. (1999)1693. J. Eisch, B.W. Kotowicz, Eur. J. Inorg. Chem. (1998) 761. T. Ishiyama and N. Miyaura, J. Organometal. Chem. 611 (2000) 392. G. Desurmont, R. Klein, S. Uhlenbrock, E. Laloe, L. Deloux, D.M. Giolando, Y.W. Kim, S. Pereiraand M. Srebnik, Organometallics 15 (1996) 3323. A. Shibli, H. Abu Ali, I. Goldberg, and M. Srebnik, Appl. Organomet. Chem. 19 (2005) 171. A. Pelter, K. Smith and H. C. Brown, Borane Reagents, Academic Press, London, (1988). B. Zheng and M. Srebnik, J. Organomet. Chem., 474 (1994) 49. B. Zheng, L. Deloux, E. Skrzyczak-Jankun, B.V. Cheesman, S. Pereira, M. Sabat and M. Srebnik, J. Mol. Struct. 374 (1996) 291. T. Ishiyama, M. Yamamoto and N. Miyaura, Chem. Commun. (1997) 689. P. Frankhauser, H. Pritzkow and W. Siebert, Z. Naturforsch. B. 49 (1994) 250 R.L. Thomas, F.E.S. Souza and T.B. Marder, J. Chem. Soc., Dalton Trans. (2001) 1650. For a synthetic route to such species see, for example: R. J. Mears and A. Whiting, Tetrahedron Lett. 49 (1993) 177. A. M. Irving, C. M. Vogels, L. G. Nikolcheva, J. P. Edwards, X.-F. He, M. G. Hamilton, M. O. Baerlocher, A. Decken and S. A. Westcott, New J. Chem. 27 (2003) 1419. H. Abu Ali, R. Reich, R. Berkovitz and M. Srebnik, Arch. Pharm. Pharm. Med. Chem. 337 (2004) 183]. Preparation of 159aa and 159bb: BrSiMe3 (5 equiv) was added in one portion to a solution of 159a and 159b respectively, in dried CH2CI2. The reaction mixture was stirred for 1 h and methylenedichloride was then removed in vacuum. The residue was treated with MeOH and the solution was stirred about 10 min followed by evaporation to give 159aa and 159bb as pure solids in (88% yield). T.E. Cawston, Pharm. Ther. 70 (1996) 163.

[108] [109] [110] [Ill] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126]

[127] [128]

[129]

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117

[130] L.L. Johnson, R. Dyer and DJ. Hupe, Curr. Opin. Chem. Biol. 2 (1998) 466. [131] I. Massova, L.P. Kotra, R. Fridman and S. Mobashery, FASEB J. 12 (1998) 1075. [132] I.E. Collier, S.M. Wilhelm, A.Z. Eisen, B.L. Marmer, G. A. Grant, J.L. Seltzer, A. Kronberger, C. He, E.A. Bauer and G. I. Goldberg, J. Biol. Chem. 263 (1988) 6579. [133] S.M. Wilhelm, I.E. Collier, B.L. Marmer, A.Z. Eisen, G.A. Grant and G.I. Goldberg, J. Biol. Chem. 264 (1989) 17213. [134] L.A. Liotta, K. Tryggvason, S. Garbisa, P.G. Robey and S. Abe, Biochemistry 20 (1981) 100. [135] R. Reich, E. Thompson, Y. Iwamoto, G. Martin, J. Deason, G. Fuller and R. Miskin, Cancer Res. 48 (1988) 3307. [136] R.P. Beckett, A.H. Davidson, A.H. Drummond, P. Huxley and M. Whittaker, Drug Discov. Today 1 (1996) 16. [137] M. Whittaker, C D . Floyd, P. Brown and A.J.H. Gearing, Chem. Rev. 99 (1999) 2735. [138] R.E. Babine and S.L. Bender, Chem. Rev. 97 (1997) 1359. [139] B. Lovejoy, B.M. Hassell, M.A. Luther, D. Weigl and S.A. Jordan, Biochemistry 33(1994)8207. [140] J.B. Summers and S.K. Davidsen, Ann. Rep. Med. Chem. 33 (1998) 131. [141] I. Pergament and M. Srebnik, Bioorg. Med. Chem. Lett. 12 (2002) 1215. [142] K. Curley and R.F. Pratt, J. Am. Chem. Soc. 119 (1997) 1529. [143] K..M. Bottomley, W.H. Johnson and D.S. Walter, J. Enzyme Inhib. 13 (1998) 79.

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Chapter 3 Applied Suzuki cross-coupling reaction for syntheses of biologically active compounds V.M. Dembitsky, H. Abu Ali and M. Srebnik Department of Medicinal Chemistry & Natural Products, School of Pharmacy, P.O. Box 12065, Hebrew University of Jerusalem, Jerusalem 91120, Israel

Contents 1. INTRODUCTION 120 2. SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS VIA CROSS COUPLING REACTION CATALYZED BY PALLADIUM 120 3. CROSS-COUPLING OF ARYLBORANE DERIVATIVES WITH HALOARENES 133 4. CROSS-COUPLING OF ALKYNYLBORANE DERIVATIVES 155 4.1. Cross-coupling of alkenylborane derivatives 157 5. CROSS-COUPLING OF ALKYLBORANE DERIVATIVES 166 6. SYNTHESIS OF MACROCYCLES 184 6.1. Macrocycles with endo aryl-aryl and aryl-alkyl ether bond 184 6.2. Macrocycles with endo aryl-aryl bond 185 6.3. Macrocyclo-depsipeptides 186 6.4. Piperidine alkaloids 187 7. MODIFICATION OF NUCLEOSIDES USING SUZUKI-MIYAURA COUPLING 222 8. SYNTHESIS OF SUBSTITUTED PORPHYRINS 236 9. ADDITIONAL APPLICATION OF THE SUZUKI CROSS-COUPLING REACTION 241 10. SYNTHESIS OF MACROCYCLIC COMPOUNDS 243 11. SYNTHESIS OF TETRACYCLIC SYSTEMS 250 11.1. Atropoisomerism in Suzuki coupling 250 12. SYNTHESIS OF POLYCYCLIC ETHERS 261 13. SYNTHESIS OF DISUBSTITUTED FURANS 267 14. SYNTHESIS OF GERANYLGERANYL DIPHOSPHATE DERIVATIVES 270 15. SYNTHESIS OF SPIROQUINOLIZIDINE DERIVATIVES 271 16. SYNTHESIS OF CARBOHYDRATE-SUBSTITUTED PHOSPHINES 273 17. SYNTHESIS OF NOVEL THYROID HORMONE ANALOGUES: 5'-ARYL SUBSTITUTED GC-1 DERIVATIVES 280 REFERENCES 282

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1. INTRODUCTION The palladium-catalyzed cross-coupling reaction between organoboron compounds and organic halides or triflates provides a powerful and general methodology for the formation of carbon—carbon bonds. Recently, this reaction has been called the Suzuki coupling, Suzuki reaction, or Suzuki-Miyaura coupling. The availability of the reagents and the mild reaction conditions all contribute to the versatility of this reaction. The coupling reaction offers several additional advantages, such as being largely unaffected by the presence of water, tolerating a broad range of functional groups, and proceeding generally regio- and stereoselectively. Moreover, the inorganic by-product of the reaction is non-toxic and easily removed from the reaction mixture thereby making the Suzuki coupling suitable not only for laboratories but also for industrial processes [1-4]. 2. SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS VIA CROSSCOUPLING REACTION CATALYZED BY PALLADIUM A strategy to improve the efficiency of Suzuki coupling reactions, by combining fast microwave reaction with easy fluorous separation was reported. Aryl perfluorooctylsulfonates, e.g., 1, derived from the corresponding aryl alcohols were coupled with arylboronic acids to give biaryls, e.g., 2, under general microwave conditions. Application of this tagging strategy to multistep synthesis of substituted biaryl- was also described (Scheme 1) [5]. Scheme 1 HO^

C 8 F 17 SO 2 F +

jj JL

1. K2CO3, DMF 2. F-SPE

2200 >2200 >2200

RAR (Ki, Nm) b 0.5 >2800 >2800 >2800

g 1.4 >6000 >6000 ND

Scheme 123

Reagents and conditions: (a) MOMC1, (/-Pr)2NEt, Bu4NI, CH2C12, 48 h, 83%; (b) Cp,Ti(CH3)2, PhCH3, 70 °C, 18 h, 87%; (c) (i) 9-BBN-H, THF, reflux, 6 h; (ii) PdCl, (dppf), 3 M K3PO4, DMF, l-bromo-4-nitrobenzene, 18 h, 54%; (d) (i) 6N HCI, MeOH, 18 h; (ii) TEMPO, NaOCl, KBr, NaHCO3, 2 h; (iii) HCI (g), MeOH, 40 °C, 5 h; (iv) Ac,O, pyridine, DMAP, 18 h, 84%; (e) Pd/C, H2, 40 psi, EtOAc, 4 h, 98%; (f) retinoic acid, SOC12, pyridine, 4 h, 86%; (g) (i) K2CO3, MeOH, 18 h; (ii) 5 N KOH, MeOH, 18 h, 86%.

Potent and selective EP3 receptor ligands were found by making a library using solid-support chemistry. These compounds can be obtained by a Suzuki coupling reaction of a solid-supported benzyl bromide using various boronic acids.

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213

The yields obtained for this reaction were in the range of 24-95% of arylmethyl cinnamic acid 378 after cleavage from the Wang resin (Scheme 124). Scheme 124. Suzuki coupling of boronic acids and benzyl bromide on solid support

R-B(OH)2 CsF Pd(PPh3)4

0

DME 100 °C , 10 h

378

378c

378a

378b

378d

These compounds were then prepared by standard solution-phase chemistry, purified and fully characterized. They all have activities equal to or less than 110 nM on the EP3 receptor, Table 3. The best activity was achieved when R was 3,4dichlorophenyl and 2-naphthyl with K\ values of 32 nM and 20 nM, respectively (entries 3 and 4). These two compounds were also selective over the EP receptors by a factor of at least 378 and by a factor of 30 over the other prostanoid receptors. Table 3 Full profile of potent EP3 antagonists Entry

R

EP, >100

EP ? 4.1

EP, 0.11

EP4 >40

FP 63

>100

43

0.080

>50

63

13

0.032

>100

12

0.02

DP 2.5

IP 31

0.52

>83 4.1

>76

4.6

10

41

37

0.90

3.1

69 0.53 >100

2.4

TP

10

Syntheses of (7?)-(+)-lasiodiplodin, zeranol and truncated salicylihalamides have been reported. Concise, flexible and high yielding approaches to the orsellinic acid type macrolides lasiodiplodin 379 and zeranol 380 are described which involve only metal-assisted or metal-catalyzed C-C-bond formations. Key steps are the efficient allylation of aryl triflates 385 and 387 either by Stille or by modified Suzuki

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coupling reactions, and the high yield ring closure of the macrocyclic rings by RCM using the ruthenium carbene as the catalyst [255]. One of the synthesis intermediates, /. e. cycloalkene 386, can also be regarded as a truncated analogue of the potent antitumor agent salicylihalamide A. From the in-vitro cytotoxicity data of 386 it is possible to deduce first insights into the structure/activity relationship of salicylihalamide, Fig. 8. OR O

OR O

HO

382

383

384

Fig. 8. (i?)-(+)-Lasiodiplodin, zeranol and truncated salicylihalamides

(R)-(+)-Lasiodiplodin, Lactone 379a together with its de-O-methyl congener 379b have been isolated from the fungus Botrysdiplodia theobromae (formerly Lasiodiplodia theobromae) as well as from the wood of Euphorbia splendens and E. fidjiana [256]. 379b is also one of the secondary metabolites of Arnebia euchroma, plant which serves in traditional Chinese medicine for the treatment of human hepatitis and abdominal oedema. Both macrolides were found to be efficient inhibitors of prostaglandin biosynthesis and exhibit significant antileukemic activity (Scheme 125). Antitumor activity of 386 also has been detected.

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Scheme 125 OMe O

MeCT^OH b,c,d,e OMeO

OMeO

MeO

v

OSO2CF3

385

386 379a

Syntheses of (R)-(+)-lasiodiplodin (379a) and de-O-methyl lasiodiplodin (379b): (a) CuCl(COD) (10 %), THF, -78 °C, r.t, 81%; (b) (i) NaOMe in MeOH; (ii) CO2 (40 atm), 120 °C, 80%; (c) Methyl 2-methoxy-4-(benzyloxy)-6-(oct-7-en-l-yl)benzoate, EtOOCN=NCOOEt, PPh3, Et2O, r.t., 83%; (d) (CF3SO2)2O, pyridine, 0 °C, r.t., 91%; (e) allyltributylstannane, LiCl (3 eq.), Pd2(dba)3 (3 tool%), tris(2-furyl)phesphine (12 tnol%), Nmethyl-2-pyrrolidinone, 40 °C, 93%; (f) CH2C12, reflux, 94%, (E):(Z) = 2.3:1 (GC); (g) H, (1 atm), Pd/C, EtOH, r.t., 94%.

Very recently it has been disclosed that the sponge metabolite salicylihalamide A exhibits a potent and unique differential cytotoxicity profile in the NCI 60-cell line human tumor assay. The mean panel GI50 concentration is = 15 nM, with melanoma cell lines showing the highest sensitivity (GI50 384 + 379b). Since the activity of 384 does not display any significant correlations to the profiles of known antitumor agents, this macrolide constitutes a very attractive new lead structure in the search for anti-cancer drugs. The anabolic, estrogenic and antibacterial properties of zearalenone 381 and related mycotoxins isolated from the fungus Gibberella zeae (Fusarium graminearum) [257,258] have led to a systematic investigation of their activity profile (Scheme 126).

H. Abu Ali et al.

216 Scheme 126 OMeO

OMe 0

MeO'

o

Reagents and conditions: [a] HS(CH2)3SH, BF3"Et2O, MeOH, 87%; [b] (i) sec-BuLi (2 equiv.), THF,-15 °C, 4h; (ii) 4-bromol-butene, 16h, 85%; [c] PCC, CH2C12, 51-62%; [d] MeMgl, Et2O, -30 °C, 97%; [e] 12, EtOOC-N=N-COOEt, PPh,, Et2O, 84%; [f] (CF3SO2)2O, pyridine/CH2Cl2, 0 °C, r.t., 91%; [g] 9-aUyl-9-BBN, KOMe, PdCl2(dppf) (3 mol%), THF, reflux, 86%. Novel C7-aryl pyrrolo[2,l-c][l,4]benzodiazepines (PBDs) have been synthesized [259] via Suzuki coupling between a 7-Iodo NlO-Troc-protected PBD carbinolamine and commercially available boronic acids (Scheme 127). Scheme 127 Trac

Trac B(OH)2

R-n-

389a-f

Reagents and conditions: (a) Pd(Ph3P)4, NaCO3, benzene, H2O; (b) 10% Cd/Pb couple, IN NH4OAc (aq).

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Table 4 Substituent Patterns, Corresponding Yields and Cytotoxicity Values Compound 389a 389b 389c 389d 389e 389f

% Yield

IC50

R H 4'-Me 4'-F 3'-NO2 2'-0Me 4'-0Me

93 35 40 56 77 55

1.15 0.58 0.66 34.5 1.18 0.56

Johnson's Suzuki coupling protocol was employed to prepare C-glycoside analogs of phlorizin 390 [260]. In vitro biological evaluation of these C-glycosides indicated the anomeric oxygen is important to the SGLT inhibitory activity of phlorizin 390 and related agents (Scheme 128). Scheme 128 OH O

OMOM MOMO

OMOM OMOM

1.9-BBN, THF, reflux, 5 h 2. 2-Br-acetophenone Pd(dppf)-CH2CI2, K3PO4 H 2 0, DMF, rt, 18 h

OMOM Substituted 2-methyl-2'-nitro diaryl compounds in the benzo[Z>]thiophene series were prepared by palladium-catalyzed, two-steps, one-pot borylation/Suzuki coupling (BSC) reaction in good to high yields [261]. The borylation reaction was performed on methylated 6-bromobenzo[6]thiophenes using pinacolborane and was followed by in situ Suzuki coupling with substituted (CF3, OMe) 2bromonitrobenzenes. The obtained compounds 391 a,b were cyclized to the corresponding new linear ring A substituted thienocarbazoles which can have biological activity or/and be used as biomarkers due to their fluorescence properties and possible DNA intercalation (Scheme 129).

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Scheme 129

1. Borylation 2. Suzuki coupling

391a: R., = H, R2 = Me 391b: Ri =OMe, R2 = CF 3

New straightforward syntheses for three analogous alkaloids isolated from Cryptolepis sanguinolenta have been elaborated [262-264]. Thus, Cryptosanguinolentine 392 was obtained from 3-bromoquinoline in 5 steps: the Suzuki-coupling to a phenylquinoline was followed by deprotection of the amino moiety and formation of an azide, which at higher temperature {via formation of a nitrene) underwent ring closure to the product in good yield [265] (Scheme 130). Scheme 130

NHCOBu

. H2SO4 2. HNO2, NaN3

392, 75%

Cryptotackieine 393 was synthesized starting from 3-bromoquinoline-N-oxide in 4 steps (Scheme 131). In contrast to the previous reaction, the final ring closure was accomplished by a condensation reaction of the amino moiety and the oxo function of the carbostyryl ring. The third related compound, quindoline 394, was prepared from 2,3-dibromoquinoline via a selective cross-coupling of the 2-bromo atom to an amine followed by deprotection and intramolecular nucleophilic substitution (Scheme 132) [266].

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Scheme 131

NHCOBu

O

NH,

Ring closure methodology has also been successfully applied in the area of indole-fused ring systems. Recently the alkaloid furostifoline 395 can conveniently be synthesized as outlined in (Scheme 133) [267]. In this case the cross-coupling was carried out by the reaction of a heterocyclic boronic acid and o-bromonitrobenzole and, then the nitro group was transformed to a nitrene to yield the tetracyclic end product. Scheme 132

394, 66% Studies on 3-substituted arylisoquinolines were reported [268], also led to the synthesis of a novel indole-fused ring. It was found that o-azidophenylisoquinoline-Noxide, obtained from the corresponding diazonium salt by an aza transfer reaction, undergoes ring closure at position 4 in the isoquinoline ring and, after a spontaneous deoxygenation, yields the indolo[3,2-c]isoquinoline skeleton 396 as shown in (Scheme 134) [269].

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Scheme 133

CH(OEt)2

(HO)2B-

395

Scheme 134

396

As summarized in (Scheme 135), a new synthetic pathway to the indazolo[3,2a]-/?-carboline ring system 397 has been elaborated. In this case the cross-coupling reaction was carried out with /?-carboline-1 -triflate to yield a protected amine, which was transformed similar to some related cases to the new pentacyclic ring system [270].

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Scheme 135

NHpiv

Some iodo and chloro derivatives of 2-alkylpyridazin-3-ones are suitable starting compounds for cross-coupling reactions with halopyridazines. Thus, the starting 5-iodo derivative can be converted in five reaction steps to pyridazino[4,5-6]indoles 398 in good yield (Scheme 136) [271]. Scheme 136

NHCOBu

1.H 2 SO 4 2. NaNO 2 /HCI 3. NaN 3 /NaOAc

N3

398

O

Halomethoxypyridaziones also proved to be suitable derivatives for ring closure reactions as shown in (Scheme 137). Suzuki coupling of the chlorine atom with appropriately substituted phenylboronie acid and subsequent ring closure - i.e. intramolecular nucleophilic substitution — gave rise to new pyridazoquinolinones 399

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[272]. In the case of the N-benzyl substituted derivative, preparation of the unsubstituted pyridazinoquinolinone could also be accomplished. Biological tests on selected polycyclic derivatives revealed that some of these heterocyclic derivatives behave valuable reverse transcriptase inhibitory and intercalating properties [273,274]. Scheme 137 B(OH)2

R = Me R = Bn

Pd(PPh3)4 Na2CO3 DME/H2O

399: R = Bn, 93%

7. MODIFICATION OF NUCLEOSIDES USING SUZUKI-MIYAURA COUPLING Modified nucleosides have been useful in understanding mutagenesis and biological pathways as well as developing new Pharmaceuticals, which has prompted the need for synthetic methods to modify naturally occurring nucleosides for study. Some methodologies to synthesize modified nucleosides in a more efficient way have been reported; Palladium cross-coupling reactions have been used widely to modify nucleosides [275-277]. These reactions were typically carried out in organic solvents. Due to the hydrophilicity of nucleosides, they had to be protected, modified and later deprotected. If these modifications could be carried out in water or aqueous systems, it would eliminate two steps (protection/deprotection) and increase the overall yield. In addition, water is an attractive solvent because it is relatively inexpensive and environmentally benign. For direct modification of oligonucleotides, an aqueous system would be required for solubility. There has been only one other attempt at modifying nucleosides using palladium-assisted couplings in aqueous media [278]. However, they reported modest yields at elevated temperatures (e.g. 47% at 80 °C). The Shaughnessy and Both [279] had found that a Pd(OAc)2/TPPTS system worked well for synthesizing 8-phenyl-2'-deoxyguanosine. To test the generality of this system with other nucleosides and boronic acids, Pd(OAc)2, TPPTS (2.5 ligand:Pd), Na2CC>3, the halonucleoside and arylboronic acid were dissolved in 2:1 watenacetonitrile. The reactions were allowed to stir at 80 °C for 2-4 h before workup, which includes diluting with water, neutralizing the solution and purifying by either recrystallization or reverse-phase column chromatography. Good to excellent yields were achieved with a variety of nucleosides and both electron-donating and electron-withdrawing boronic acids, Table 5. Synthesis of a nucleoside 400 via Suzuki reaction with 8-bromo-2'-deoxyadenosine is shown below in Scheme 138.

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Scheme 138

R B(OH)2 Pd(OAc)2 TPPTS Na2CO3 80 °C , 2 h

Table 5 Percent yields for Suzuki-Miyaura coupling of nucleosides with various boronic acids PhB(OH)2 MeOPhB(OH)2 FPhB(OH)2 Compound 8-Bromo-2'-Deoxyadenosine (8BrdA) 8-Bromoadenosine (8-BrA) 8-Bromo-2'-deoxyguanosine (8BrdG) 8-Bromoguanosine (8-BrdG) 5-Iodo-2'deoxyuridine (5-IdU)

87% 87%

87% 85%

96%

82% 64% 83%

73% 63% 82%

82% 73% 92%

Guanosine and deoxyguanosine consistently gave lower yields and slower rates of conversion than deoxyadenosine and deoxyuridine. Compared reactivities of 8-BrdA, 8-BrdG and 5-IdU by coupling them with phenylboronic acid in the presence of palladium acetate (10 mol%), sodium carbonate and TPPTS or TXPTS at room temperature show in Fig. 9. 8-BrdA and 5-IdU with TXPTS by far give the greatest rates of conversion. 8-BrdA and 5-IdU with TPPTS achieved over 70% conversion but only after 17 h. 8-BrdG did not achieve even 50% conversion in 18 h, Fig. 9.

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9

12

15

18

21

24

Time (h) Fig. 9. Comparison of reactivities of 8-BrdG, 8-BrdA & 5-IdLJ at room temperature: • = 8-BrdA, TXPTS; • = 5-IdU, TXPTS; • = 8-BrdA, TPPTS; T = 5-IdU, TPPTS; . = 8=BrdG, TXPTS; X = 8-BrdG, TPPTS. Adapted by authors [Pd]

0' -Br

HO.

401 I OH

403

Fig. 10. Possible palladium-nucleoside complexation under basic conditions for 8-bromo-2'deoxyguanosine 401 and 5-iodo-2'-deoxyuridine, 402 and 403

One possible explanation for this reactivity difference may be the ability of the nucleoside to coordinate with the metal center itself. Under basic conditions such as these, the N-l of 8-BrdG and N-3 of 5-IdU may be deprotonated, Fig. 10. For the dU system, this results in an anion that is delocalized over the nitrogen and the oxygen of the carbonyl alpha to it. This delocalized anion can theoretically coordinate to the palladium center. For 8-BrdG, the oxygen of the carbonyl becomes anionic and can coordinate with the metal center. A competition experiment was carried out in which 0.10 mmol each of 8-BrdA and 8-BrdG were added to a solution containing only 0.06 mmol phenylboronic acid under typical conditions (Pd(OAc)2, TPPTS, Na2CO3 in 2:1 H2O:CH3CN at 50 °C). The reaction was monitored by HPLC. After 8 h, 8PhdG was less than 1 % area, while 8PhdA accounted for slightly more than 20 %. 8-BrdA obviously was favored over 8-BrdG in this coupling but the presence of 8-BrdG severely decreased the rate of formation of 8PhdA. In an identical experiment, but in the absence of 8-BrdG, 8-BrdA was completely converted and about 88% 8PhdA formed in 90 min. Pd(OAc)2/TPPTS is an excellent general catalyst system for Suzuki arylation of halonucleosides. TXPTS gives a much more reactive catalyst system but is not commercially available. TXPTS allows these coupling reactions to be carried out at

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room temperature and in water alone, eliminating organic solvent waste. Furthermore, if water-soluble sources of palladium(II) are used, both TPPTS and TXPTS may be used in water. Some of the synthesized aryl adducts of nucleosides have been fully characterized [278-280]. A modular synthesis of the lamellarin family of natural products has been developed. This synthesis is based on the application of three iterative halogenation/cross-coupling reaction sequences. The ability to halogenate the pyrrole core in a regioselective fashion, even in the presence of highly electron-rich aryl substituents, has been established. The compatibility of Suzuki coupling conditions with free alcohols and phenols in the boronic acids has been employed to reduce the number of protection/deprotection steps. Indeed, the presence of a free phenol on boronic acid 3 has been determined to be critical for the successful final coupling in route to lamellarin G trimethyl ether, since protected versions fail to undergo coupling, Fig. 11 [281].

MeO

0 H

404 Lamellarin D

HO MeO 406 Lamellarin M

OH

HO MeO 405 Lamellarin L

MeO

, MeO 407 Lamellarin G

0 M e

Fig. 11. Members of the lamellarin family of natural products The lamellarins are a growing family of at least 35 related marine natural products [282-291], the first members of which were isolated in 1985 by Faulkner and co-workers, Fig. 11 [292]. In addition to their interesting structure, members of the lamellarin family have been reported as exhibiting a number of potentially valuable biological activities. For example, virtually all of the lamellarins have been found to be cytotoxic to a wide range of cancer cell lines. The most potent of these compounds (lamellarin D, K, and M) exhibit cytotoxicity values in the mid to high nanomolar range (38-110 nM) [293]. Interestingly, multidmg-resistant cell lines are also affected by the lamellarins, which appear to be not only cytotoxic agents but also single-digit micromolar inhibitors of the P-glycoprotein responsible for the MDR effect [294]. Lamellarin K and L have also been observed to have immunomodulatory effects in the micromolar range [295]. Faulkner and co-workers reported that lamellarin R-20

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sulfate is a selective inhibitor of HIV integrase both in vitro and in vivo. Unlike most other natural product integrase inhibitors, inhibition was not completely regulated by the core domain but also partially by the N- and/or C-terminal domains (IC50 for disintegration for the catalytic core 64 juM, for the intact enzyme 7 juM) indicating that some form of unique multisite binding might be responsible for this inhibition. An efficient solid phase synthesis of the pyrrole-based alkaloids lamellarins Q and O, and derivatives 408a-e and 409a-e using Merrifield resin and iV-protected methyl 3,4-dibromopyrrole-2-carboxylate as a scaffold was recently described (Scheme 139) [296]. Scheme 139 ClZn.

COOMe NTIPS

408a: R: = OMe, R2 = H 408b: R-, = OPr, R 2 = H 408c :R.| = R 2 = O M e 408d: Ri = R 2 = (CH)4 408e: R-, = OH, R 2 = H

MeOOC 409a: 409b: 409c: 409d: 409e:

R = CH 2 CO(p-OMe)C 6 H 4 , R = CH 2 CO(p-OMe)C 6 H 4 , R = Me, R, = H R = O(CH 2 ) 2 o-BrC 6 H 4 , R, R = CH 2 CO(p-OMe)C 6 H 4 ,

R-, = Me R, = H =H R, = H

Reagents: (i) NaOMe, dry DMF, N2, 80 °C, 24 h; (ii) Pd(PPh3)4, dry THF, N2, rt, 24 h; (iii) aq. 2M Na2CO3, Pd(PPh_,)4, dioxane, reflux, 21-48 h; (iv) NH4F, DCM/MeOH (1:1), reflux, 6 h; (v) NaH (or LDA), dry THF, N2, 278 °C, 24 h; or 18-crown-6 (2.5 M in DMF), microwave, 100 °C, 3 0 ^ 0 W, 2 min; (vi) A1C13, dry DCM, rt, 3 h.

Bioactive c o m p o u n d s eupomatilone-1, -2, -3, -4, -5, -6, and -7, Fig. 12 have been isolated from the aerial parts of Australiean plant Eupomatia bennettii [297,298]. The synthesis of eupomatilone-6 410, Fig. 12 has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular HornerWadsworth-Emmons reactions [299]. The spectroscopic studies carried out on synthetic eupomatilone-6 do not agree with those reported for the natural product, and therefore revision of the assigned structure is warranted (Scheme 140).

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410 Eupomatilone-6 O.

MeO

T

\D

MeO'

412 Eupomatilone-4

413 Eupomatilone-7

Fig. 12. Members ofthe eupomatilone family of natural products

Scheme 140

B(OH)2

Br-

MeO

O

y OMe OMe

MeO

y OMe OMe

d-n

410

O

MeO

y OMe OMe

MeO

y OMe OMe

Reagents and conditions: (a) Pd[(PPh3)]4, benzene, ethanol, 2 M Na2CO3, reflux, 24 h, 79%; (b) Ph3PdCHCO2Et, CH2Cl2, rt, 3 h; (c) (DHQD)2PHAL, K2OsO4.2H2O, MeSO2NH2, K2CO3, ;BuOH : H2O (1:1), 0 °C, 18 h, 80% (for two steps); (d) DMP, CH2C12, p-TSA, rt, 94%; (e) LiAlH4, THF, 0 °C, 2 h, 78%; (f) TsCI, Et3N, CH,C12, 0 °C, 6 h, 90%; (g) MeOH, HC1, rt, 1 h, 88%; (h) K2CO3, MeOH, 30 min, rt, 75%; (i) MEMC1, DIPEA, CH2CI2, rt, 8 h, 83%; G) LiAlH4, THF, 0 °C, 3 h, 94%; (k) PDC, CH2C12, 4 A molecular sieves, 4 h, 67%; (I) PPTS, /BuOH, 80 °C, 12 h, 75%; (m) (EtO)2P(O)-CH(Me)-COCl, DIPEA, CH2C12, 0 °C, 3 h 70%; (n) NaH, THF, 0 °C, 30 min., 87%; (o) Rh/Al2O3, H2, 60 psi, 20 h, 60%.

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A convergent and diastereocontrolled total synthesis of eupomatilones-4 and 6 was reported and based on a diastereoselective hydroboration/oxidation sequence and a convergent Lipshutz biarylcuprate cross-coupling reaction. The structure of eupomatilone 6 was revised [300]. Scheme 141

OH

9-BBN, THF H 2 O 2 , NaOH "OM • e OMe n-Bu4NF TEMPO

412

In 1998, Sato and co-workers reported a new cytotoxic natural product (WS9885B), isolated from Streptomyces sp. No. 9885 [301]. WS9885B was later renamed FR182877, and the absolute configuration of this substance was reported to be enantiomeric to the structure illustrated for 414 [302]. FR182877 exhibits potent antitumor activity across a number of susceptible cell lines including MCF-7, A549, HT-29, Jurkat, P388, and B16. Results obtained in morphology studies performed with baby hamster kidney (BHK) cells indicate a mechanism of action involving microtubule stabilization and interruption of the cell cycle in metaphase [302d]. An asymmetric synthesis of the cytotoxic natural product, (-)-FRl 82877 414, has been achieved [303]. Chirality for the entire structure was established using two (4R)-4-benzyl-2-oxazolidinone-mediated boron aldol reactions. A 19-membered macrocarbocycle was synthesized by the coupling of two fragments using a regioselective Suzuki coupling (17 + 23 —> 26; 84%) and macrocyclization of a betaketo ester (30-31; 77%). Oxidation of 31 triggered a sequence of stereoselective transannular Diels-Alder reactions (32 —> 34; 63%) forming four new rings and seven new stereocenters in the pivotal construction event. This pentacyclic intermediate was subsequently transformed to (-)-FRl 82877. Semiempirical calculations of the transannular Diels-Alder cycloaddition cascade were carried out to determine the origins of asymmetric induction.

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Scheme 142 O

O

OTBS

O

OTBS

Br

MeCX

COOEt

'OTBS

414(-)-FR182877

Reagents and conditions: (a) Pd(PPh3)4 (0.05 equiv), T12CO3, H2O-THF (1:3), 23 °C, 84%; (b) D1BAL, CH2CI2, -78 °C; (c) ethyldiazoacetate, SnCI2, 70% (two steps); (d) TBAF, AcOH, DMF, 92%; (e) 12, PPh3, CH,C12; (f) Cs2CO3, THF (0.005 M), 23 °C, 77% (two steps); (g) Ph2Se2O3, SOj-Pyr, TEA, THF, 23 °C then hexanes, 50 °C, 63%; (h) HF-MeCN, 89%; (i) Me3B3O3, Pd(dppf)Cl (0.1 equiv), Cs2CO3, DMF-H2O (2:1), 100 °C, 71%; 0) TMSOK, THF; (k) Mukaiyama's reagent, NaHCO3, CH2C12, 62%.

Epothilones A and B, Fig. 13 are themain representatives of a family of bacterial natural products that exhibit potent antiproliferative activity against a broad range of human cancer cell lines. First isolated in 1993 by Reichenbach, and coworkers [304], these compounds were subsequently shown by Bollag et al. to be microtubule depolymerization inhibitors [305, 306] At the time of this discovery, epothilones A and B, apart from paclitaxel and its analogs, were the only compounds recognized in the literature to act as microtubule-stabilizing agents). However, in distinct contrast to paclitaxel, epothilones were found to be equally effective in vitro against drug-sensitive and multidrug-resistant cell lines [305,307], which immediately suggested that epothilone-derived anticancer agents could eventually be useful for the treatment of drug-resistant tumors.

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HO,

OH 415: Epothilone A, R = H 416: Epothilone B, R = Me

O

415a: Epothilone A, R = H 416a: Epothilone B, R = Me

Fig. 13. Structures of epothilones A 415 and B 416 and of their deoxy variants, 415a and 416a. Deoxyepothilones A 415a and B 416a are also known as epothilones C and D, respectively

The total synthesis of (12,S',13>S')-/ra;K-epotliilone A 415a was achieved based on two different convergent strategies [308]. As part of this strategy, the C(l 1)-C(12) bond was established subsequent to the critical aldol step and was based on B-alkyl Suzuki coupling between the C(l)-to-C(ll) fragment and C(12) to-C(15) trans-vinyl iodide. Both approaches converged at the stage of the 3-0, 7-0-bis-TBS-protected seco acid, which was converted to trans-deoxyepothilone A via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12)-C(13) bond could be achieved by epoxidation with ozone 0 °C in the presence of the catalyst l,2:4,5-di-O-isopropylidene-L-erythro-2,3-hexodiuro-2,6pyranose, which provided an 8:1 mixture of 415 (12R,13R)-epoxide isomers in 27% yield. Compound 415 is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 415a is at least two orders of magnitude lower than that of epothilone A. Schemel43

415a

Reagents and conditions: (i) Zn-Cu, [Pd(Ph3P)4], benzene, 60-80 °C; 69%; (ii) CSA, CH2Cl2/MeOH; 80%; (iii) (COCI)2/DMSO, CH2CI2, -78 °C; 79%; (iv) 1. LDA (lithium diisopropylamide), -78 °C; 2. TBS-OTf, lutidine; 3. K2CO3 , MeOH, 31% (3 steps), (v) Bu4NF, THF, 64%. (vi) 2,4,6-Cl3C6H2C(O)Cl, Et3N, DMAP (N,N-dimethylpyridin-4-amine), THF/toluene; 61%; (vii) CF3COOH/CH2C12 ; 91%. Thiophene oligomers have been proven to be important multifunctional materials [309]. Among their most useful properties are good charge mobility [310]

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and efficient fluorescence [311]. Thiophene oligomers are chemically very stable and easy to functionalize [312]. New dendritic molecular structures have recently been described [313] from which it is reasonable to expect different self-assembly modalities and properties. Thiophene oligomers are currently studied for application in thin film transistors [314], electroluminescent diodes [315], lasers [316], and photovoltaic cells [317] and as fluorescent markers for biological molecules [318]. A rapid, efficient, and environmentally friendly methodology for the synthesis of highly pure thiophene oligomers has been reported [319]. The solvent-free, microwave-assisted coupling of thienyl boronic acids and esters with thienyl bromides, using aluminum oxide as the solid support, allowed to check rapidly the reaction trends on changing times, temperature, catalyst, and base and easily optimize the experimental conditions to obtain the targeted product in fair amounts. This procedure offers a novel, general, and very rapid route to the preparation of soluble thiophene oligomers 418-423 (Schemes 144-146) Thus, for example, quaterthiophene was obtained in 6 min by reaction of 2-bromo-2,2'-bithiophene 417 with bis(pinacolato)diborane(4) (yield 65%), whereas quinquethiophene was obtained in 11 min by reaction of dibromoterthiophene with thienylboronic acid (Scheme 144, yield 74%). The synthesis of new chiral 2,2'-bithiophenes also was reported [319]. The detailed analysis of the byproducts of some reactions allowed us to elucidate a few aspects of reaction mechanisms. While the use of microwaves proved to be very convenient for the coupling between conventional thienyl moieties, the same was not true for the coupling of thienyl rings to thienyl-^S-dioxide moieties. Indeed, in this case, the targeted product was obtained in low yields because of the competitive, accelerated, Diels-Alder reaction that affords a variety of condensation products. Scheme 144. Solvent-free, microwave-assisted synthesis of 2,5':2',5"-terthiophene 418

OH HO-B

Br>

417

-Br-

Base/AI2O3, cat MWIOmin, 100°C

Br

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Scheme 145. Solvent-free, microwave-assisted synthesis of quaterthiophene 421 and quinquethiophene 422

OH

\ Br ^U

Scheme 146. Solvent-free, microwave-assisted synthesis of sexithiophene 423

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The monobrominated monomers 424 and 425 were obtained by condensation of commercial 5-bromo-2-thiophene aldehyde with R(-)- and S(+)-lphenylethylamine (Scheme 147). Afterward they were reacted with bis(pinacolato)diborane(4) using the same experimental conditions employed for the preparation of quaterthiophene. After a few minutes of microwave irradiation, bithiophenes 426 and 427 were recovered in high yield (yield of both compounds:

Scheme 147. Solvent-free, microwave-assisted synthesis of r,r(-)- and s,j-(+)-5,5'[methylene(l-phenylethyl)amine]-2,2'-bithiophenes 426 and 427

^N^N-S.

S^z^N-.

425

Conjugated oligomers with an alternating phenylene-pyrimidine structure 428430 have been synthesized by the successive Suzuki coupling reaction starting from 2-bromo-5-iodopyrimidine [320]. The photoluminescence properties and quasireversible redox behavior of these oligomers make them applicable as an active material for a light-emitting device. Blue light-emitting electroluminescent devices with external quantum efficiency up to 1.8% have been fabricated [320]. The resultant oligomers could serve as an active electron transporting material in the OLED device. A two-step synthesis of phenylene-pyrimidine alternating oligomers by a Pdcatalyzed cross-coupling reaction starting from 2-bromo-5-iodopyrimidine was outlined in (Scheme 148).

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Scheme 148

\= N '

Pd(PPh 3 ) 4 , Na 2 CO 3 toluene, reflux R = H, 82% R = OC 4 H 9 , 93% R = t-Bu, 89% OC 8 H 1 7

Pd(PPh 3 ) 4 , Na 2 CO 3 PhMe, reflux

428: R = H, 66% 429: R = OC 4 H 9 , 70% 430: R = t-Bu, 73%

The poly(ethylene glycol) ester of bromo, iodo-, and triflate-para-substituted benzoates are smoothly cross-coupled with aryl boronic acids (Suzuki reaction) under "ligandless" palladium acetate catalysis in water. The reaction proceeds without organic cosolvent under conventional thermal conditions (70 °C, 2 h) and under microwave irradiation (75 W, 2-4 min). The polymeric support remains stable under both reaction conditions. Whereas conventional thermal conditions induced ester cleavage (up to 45%), this side reaction was suppressed when microwave conditions are employed. Aryl nonaflates gave fair yields under these conditions [321]. Nonpolymer-bound aryl halides form biaryls in good to excellent yields in water/poly(ethylene glycol) mixtures under microwave irradiation (4 min, 75 W) (Scheme 149). The cyclopropyl ketone moiety is not only recognized to exhibit important properties in mechanistic studies [322] but it was also found in a growing class of natural products isolated from a wide spectrum of marine organisms with important physiological properties [323]. The general methods used for the synthesis of cyclopropyl ketones are the cyclopropanation of R, a-unsaturated ketones, or its derivatives by diverse reagents [324], and the reaction of cyclopropane carboxylic acid chlorides with organometallic reagents [325]. The cross-coupling of acid chlorides with cyclopropyltin and zinc reagents in the presence or absence of a palladium catalyst also affords cyclopropyl ketones [326]. Despite the many existing strategies for the construction of cyclopropyl ketones, new and effective methods for stereocontrolled substituted cyclopropyl ketones are still sought. Recently, a novel approach to the synthesis of fram-2-substituted cyclopropyl ketones 436a-q by Suzuki-type coupling of acid chlorides with cyclopropylboronic acids was reported [327] (Scheme 150)

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Scheme 149 O.

PEG-O PEG-0 435

Scheme 150 R

.OH OH

O PdCI2(dppf) Ag2O, K2CO3 80 °C

Y 436 O

436a: R-, =n-Bu, R2 =CICOC6H4, 78% 436b: R, =n-Hex, R2 = 4-MeC6H4, 75% 436c: R-, =n-Bu, R2 =2-MeOC6H4, 77% 436d: R, =n-Bu, R2 = : 3-OMeC6H4, 76% 436e: R1 =n-Bu, R2 =4-MeOC6H4, 70% 436f: R-, =n-Bu, R2 =2-FC6H4, 64% 436g: R-, =n-Bu, R2 = 2,4,6-FC6H3, 60% 436h: R, =n-Bu, R2 = 3-CF3C6H4, 64% 436i: Ri =n-Bu, R2 =4-EtOC6H4, 75% 436j: R^ =n-Bu, R2 =4-BuOC6H4, 74% 436k: R., =n-Bu, R2 =3-CNC6H4, 59% 436I: R-, =n-Bu, R2 =4-PhC6H4, 69% 436m: R., = n-Bu, R2 = 2-Naphthyl, 70% 436n: R-, =n-Hex, R2 = 2-Naphthyl, 59% : 436o: R,= n-Hex, R2 = 2,4,6-CIC6H3 436p: R, =n-Pen, R2 = 2-Thiophene, 49% 436q: R, =n-Pen, R2 = 2-Furyl, 45%

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8. SYNTHESIS OF SUBSTITUTED PORPHYRINS Porphyrin synthesis arouses continuing interests in biological, material and inorganic chemistry. Substitutents at the /^-positions of porphyrins exert much larger sterie and electronic effects on the porphyrin ring than substiutents at the meso-aryl positions [328]. The /^-substitutents also induce the porphyrin ring into a non-planar conformation which may control the biological properties in tetrapyrrole systems like the photosynthetic centers, vitamin B12 [329], coenzyme F430 [330] and the P-450 [331]. In fact, the recent crytallographic studies of iron[IV] oxo cation radical has demonstrated the stabilizing effect of/?-halogen substitutents [331]. As was demonstrated [332] that /?-bromoporphyrins 437,439,441 undergo Suzuki cross coupling reactions with aryl boronic acids gave corresponding /?arylporpyrins 438a-e, 440a,b, and 442a-c in high yields (Scheme 151). Scheme 151

Ph Ph

437: R = Br, H2TPP(Br)

439: R = Br, H2TPP(Br)4

44; R = B r, H2TPP(Br)8

X:a = H b = Me c = MeO Pd(Ph3P)4, K2CO3 d = t-Bu p-X-PhB(OH)2 toluene, 110°C e = Cl 442: R = H2TPP(Ar)8 438: R = H2TPP(Ar) 442a: = 65% 438a: = 84% 442b: = 50% 438b: = 84% 440: R = H2TPP(Ar)4 442c: = 33% 438c: = 70% 438d: = 83% 440a: == 88% 438e: = 79% 440b: == 67%

5,10,15,20-Tetrakis(trifluoromethyl)porphyrin zinc complex 443 has been shown to undergo monobromination and regioselective dibromination gave /?bromoporphyrins 443a-c [333]. The free base /?-bromoporphyrins 445a,b are converted to aryl porphyrins through Suzuki cross-coupling reaction. The free base porphyrins 445a-c were obtained by acid treatment of 443a-c with 35% HC1 and subsequent neutralization (Scheme 152). 445a,b were easily demetallated in high yields of about 90% while 445c was obtained in only 44% yield. The low yield of 445c may be due to its acid lability.

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Scheme 152 3

3

X,

CF

Y2

35% HCI

CF

443a: X! = Br, X 2 = Y^ =Y 2 = H 443b: X! = X 2 = Br, Y-, = Y 2 = H 443c: X., = X 2 = Y, = Y 2 = Br Ar-B(OH) 2

X,

445a: X, = Br, X 2 = Y, =Y 2 = H 445b: X, = X 2 = Br, Y, = Y 2 = H 445c: X-, = X 2 = Y-, = Y 2 = Br

Pd(Ph 3 P) 4 , K 2 CO 3 toluene, 110°C , 4-48 h

Ar = 444a: Ph, 98% 444b: 1-Naphtyl, 76% 444c: 4-CHOC 6 H 5 , 5 1 %

Alos investigating the synthesis of dodecaarylporphyrins using the Suzuki coupling reaction of arylboronic acids (Scheme 153) with octabromotetraarylporphyrins 446 was reported [334]. Variable temperature 1H NMR studies of these new porphyrins 447a-g reveal several dynamic processes including the first examples of /?-aryl rotation. Scheme 153 Br b-position meso position Pd(Ph3P)4, K2CO3 toluene, 90 °C , 7 days Br R 446

447a: R = Ph, 5 8 % 447b: R = 3-MeO-Ph, 4 3 % 447c: R = 2-MeO-Ph, 1 4 % 447d: R = 4-CI-Ph, 4 8 % 447e: R = 3,5-Di-CI-Ph, 3 0 % 447f: R = 2,4-Di-CI-Ph, 0 % 447g: R = 3-thienyl, 1 9 %

Among the synthetic molecular architectures based on substituted (fi- or mesopositions) porphyrins, the welldefined modular organization of the linear mesoporphyrins offers homogeneous structural motifs useful for the construction of supramolecular assemblies. C2-Symmetric weso-porphyrins have been prepared 449 a-g (Scheme 154) in high yields by a palladium-catalyzed cross-coupling reaction involving dibromoporphyrins 448 and arylboronic acids [335].

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meso position Pd(Ph3P)4, K2CO3 DMF, 60 °C

449a: R = R, = Ph, 97% 449b: R = Ph, R, = 4-CHO-Ph, 94% 449c: R = Ph, Ry = 2-CHO-3-thiophenyl, 93% 449d: R = Ph, R-, = 3-CHO-2-thiophenyl, 0% 449e: R = 2,4,6-tri-Me-Ph, R., = Ph, 86% 449f: R = 2,4,6-tri-Me-Ph, R, = 4-CHO-Ph, 90% 449g: R = 2,4,6-tri-Me-Ph, R, = 2-CHO-3-thiophenyl, 93%

A new method for the synthesis of me^o-substituted porphyrins wass described [336]. Reaction of 5,10,15,20-tetrabromoporphine magnesium complex 450 with aryl or heteroaryl boronic acids in the presence of Pd(PPli3)4 gave weso-substituted porphyrins 451a-c in up to 70% yields (Scheme 155). Scheme 155

ArB(OH) 2 Pd(Ph 3 P) 4 , K 2 CO 3 MeOH, 70 °C

451a: Ar = 2-Me-Ph, 70% 451b: Ar = 2-NO 2 -Ph, 42% 451c: Ar = 3-thiophenyl, 52%

A method for synthesizing combinatorial libraries of unsymmetrically substituted tetra-meso-phenyl porphyrins on polystyrene based resin was described [337]. Attachment of 5,15-dibromo-10-(4-hydroxyphenyl)-20-(4nitrophenyl)porphyrin onto brominated Wang resin 452 gave a convenient scaffold for the synthesis of photoactive porphyrin libraries with three points for generating diversity (Scheme 156). An array of nine TPP derivatives 453a-i was prepared by sequential Suzuki coupling/nitro-reduction and acylation protocols.

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Scheme 156

ArB(OH)2 Pd(Ph3P)4, K2CO3 MeOH, 70 °C Tin(ll) chloride dihydrate, DMF/H2O, rt, 1 day R^OCI, DIPEA, DCM TFA/DCM, rt, 2 h 453a: R = 4-COMe-Ph, R, = Ph, 77% 453b: R = 4-COMe-Ph, R, =2-thiopene, 85% 453c: R = 4-COMe-Ph, R, = 4-NO2-Ph, 79% 453d: R = 4-OMe-Ph, R, = Ph, 73% 453e: R = 4-OMe-Ph, R, = 2-thiopene, 80% 453f: R = 4-OMe-Ph, Rf = 4-NO2-Ph, 64% 453g: R = Ph, R, = Ph, 85% 453h: R = Ph, R, = 2-thiopene, 86% 453i :R = Ph, R, = 4-NO2-Ph, 69%

453

Multiporphyrin arrays 454, Fig. 14 with/>-phenylene linkers, aryl groups at the non-linking meso positions, and no /?-substituents are attractive constructs for lightharvesting applications. Condensation of a free base porphyrin-benzaldehyde and 5mesityldipyrromethane in CH2CI2 containing 100 mM TFA at room temperature for 3 0 ^ 0 min followed by oxidation with DDQ afforded a /?-phenylene-linked porphyrin trimer in 36% yield [338a]. Suzuki coupling of an iodo-porphyrin and a bis(dioxaborolane)-porphyrin in toluene/DMF containing K2CO3 at 90-95 °C for ~20 h afforded the same trimer in 66% yield. The former route was used to prepare a diethynyl substituted />-phenylene-linked porphyrin trimer. While the two routes are somewhat complementary in scope, both are convergent and proceed in a rational manner.

Fig. 14. Multiporphyrin arrays 454

The Suzuki cross-coupling methodology provides a facile synthetic approach for the modular preparation of weso-tetraaryl cofacial bisporphyrins anchored by

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xanthene and dibenzofuran (Scheme 157). This synthetic method furnishes cofacial bisporphyrin templates with enhanced steric and electronic protection 454A and 454B from ;-oxo formation and oxidative degradation. The ability of these platforms to support multi-electron oxidation chemistry mediated by proton-coupled electron transfer was demonstrated by their reactivity for the catalytic disproportionation of hydrogen peroxide to oxygen and water, Fig. 15. Mes

t-Bu

Mes Mes

Mes t-Bu

Mes 454A

454B

Mes Mes

Fig. 15. Cofacial bisporphyrin templates with enhanced steric and electronic protection 454A and 454B

Scheme 157 Mes

Mes

Mes

Mes

Mes

Mes

R =H R = Br

e,d| 454A

454B

Reagents and conditions: (a) iV-bromosuccinimide (NBS), chloroform; (b) (1) Zn(OAc)2.2H2O, chloroform/methanol; (2) pinacol borane, Pd(PPh3)2Cl2, Et3N, 1,2dichloroethane, 90 °C; (c) (1) 4,5-dibromo-2,7-di-tert-butyl-9,9-dimethylxanthene, Pd(PPh3)4, Ba(OH),.8H2O, 1,2-dimethoxyethane/water, 95 °C; (2) 6 N HC1; (d) (1) Mn(OAc)2.4H,O, DMF; (2) aq NaCl, HC1; (e) (1) 4,6-dibromodibenzofuran, Pd(PPh3)4, K3PO4, DMF, 100 °C; (2)6NHC1.

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9. ADDITIONAL APPLICATION OF THE SUZUKI CROSS-COUPLING REACTION Application of the Suzuki and the Heck cross-coupling reactions for efficient synthesis of diverse biaryl- and styryl-substituted a-lactams on solid support using an optimized catalyst system was reported [339]. The coupling of phenylboronic acid with the resin-bound 3-phenoxy-4-iodophenyl /Mactam 455a proceeded in 89% isolated yield by employing 20 mol % of the bidentate phosphine-palladium complex, [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride {PdChCdppf}} as catalyst in the presence of triethylamine (TEA in DMF at 65 °C for 12 h. Efficient cross-coupling of the iodophenyl /?-lactam to heterocyclic boronates and aryl boronates substituted with various electron-donating and -withdrawing groups was also demonstrated. The reverse coupling reactions of immobilized arylboronic acid 455c with a variety of substituted aryl iodides were found to proceed in excellent yields using the same catalyst system of H2O:DMF at 40 °C. The use of this catalyst for the vinylation of aryl iodide 455a via the Heck reaction was also examined (Scheme 158). Scheme 158

PhO.

PhO

,>===/

1. RB(OH) 2 orRI DMF, Pd-cat 2. TFA, CH2CI2

PhO,^

455a:X = I 455b: X = Br 455c: X = B(OH) 2

O //H^ J O )" rt, 4 h; (e) 10% Pd(PPh3)4, 3 eq. K3PO4, DMF, 80 °C, 12 h; (f) BBr3, CH2C12, -78 °C, rt, 8 h.

466

467a: R = H 467b: R = Br 467c: R = N O 2

-U

468

469a-d, n = 1,2

Fig. 16. Tricyclic biaryls constitute the framework of naturally occurring antimitotic compounds

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These compounds interact with the mitotic spindle: the former bind to tubulin and inhibit the formation of microtubules [353,354]; rhazinilam induces an inhibition of both polymerization and depolymerization of tubulin via the formation of abnormal spirallike structures [355]. Both classes of molecules are configurationally stable due to the presence of the conformationally restrictive 2,2'-bridge between the two aryl moieties and to the possible or?/zo-substitution of these compounds. Remarkable is the fact that their biological activity is restricted to the naturally occurring atropisomer [353,356]. The palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction was developed to synthesize sterically hindered 2,2'-disubstituted biphenyl and phenyl-indole compounds in a short, simple, and efficient manner from two easily accessible aryl halides. High yields can be obtained by choosing properly both components according to their rough electronic properties. The illustration of the utility of this method was provided by the solution and solid-phase synthesis of sevenor eight-membered biphenyl lactams 469a-d (Scheme 164, and, Fig. 17, as well as paullone 467a (Scheme 165) and 469e (eight-membered biphenyl lactam, Scheme 166). These compounds exhibit moderate albeit significant cytotoxicities and may serve as structural models for future medicinal chemistry developments. Scheme 164

469a: R = H, 56% 469d: R = Et, 0% NHR

CN

c,d,e,f

R = H, 39% R = Et, 70%

R= R1 = H R = H, R1 = Et R = t-Boc, R1 = H

469a: R = R1 = H, 64% 469b: R = H, R1 = Me, 58% 469c: R = H, R1 = Et, 47% 469d: R = R1 = Et, 0%

Reagents and condition: (a) NaOH (10 equiv), MeOH/H2O 2/1, reflux, 3.5 h; (b) aq H2SO4, MeO(CH2)2OH, reflux, 1-4 h; (c) LDA (2.0-3.0 equiv), Mel (1.0 equiv) or EtI (3.0 equiv), THF, -78 °C to 25 °C, 2 h; (d) LDA (6.0 equiv), Etl (6.0 equiv), THF, -78 °C to 25 °C, 2 h; (e) NaOH (10 equiv),EtOH/H2O 2/1, reflux, 3-8 h; (f) concentrated H2SO4, 25 °C, 30 min.

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Scheme 165 NHR

R = H, X = Br R = t-Boc, X = I R = H,X = I

467a, 51%

Scheme 166

O

469e

Reagents and condition: (a) (Ph3P + CH2CN,CI-) (1.05 equiv), aq NaOH, CH2C12, 25 °C, 30 min, 98% (Z/E 86/14); (b) NaBH4 (1.3 equiv), pyridine/MeOH, reflux, 2 h, 86%; (c) Et3N (4.0 equiv), Pd(OAc), (5 mol %), PCy2(o-biph) (0.2 equiv), (pin)BH (3.0 equiv), dioxane, 80 °C, 1 h, then H2O, Ba(OH)2.8H2O (3.0 equiv), 100 °C, 1 h, 98%; (d) NaOH (10.0 equiv), EtOH/H2O, reflux, 8 h; (e) Et,N (2.5 equiv), EDCI.HCI (1.1 equiv), CH2C12, 25 °C, 24 h, 25% EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

Chapter 3

major conformer

249

minor conformer

Fig. 17. Solution conformers of 469c with exchange (+) and NOE (-) correlations observed from NOESY spectra (CDCI,, 20 °C (top); X-ray crystal structure of 469c (bottom). Adapted by authors

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11. SYNTHESIS OF TETRACYCLIC SYSTEMS 11.1. Atropoisomerism in Suzuki coupling Atropoisomerism is a type of stereoisomerism that may arise in systems where free rotation about a single covalent bond is impeded sufficiently so as to allow different stereoisomers to be isolated. Especially, it is present in ortho-substituted biphenyls [359] but it may also appear in sterically hindered substituted styrenes. Unsymmetrical biaryls can easily be made by palladium-catalyzed crosscoupling reactions such as Stille, Suzuki or Heck reactions. Amongst the most important advantages of Suzuki coupling is the fact that boronic acids are largely unaffected by the presence of water and tolerate a wide range of functionalities. Another important advantage is that Suzuki coupling reactions often give good yields even when sterically crowded aromatic rings are involved. A key connection to access to the desired tetracyclic systems is the closure of ring C 470 by formation of the D-lactone (Scheme 167). Another important step is the palladium-catalyzed cross-coupling reaction between /?-chloroacroleins and boronic acids. Scheme 167

R R = H or Me X = O or CH2

/?-Chloroacroleins 473a,b and 474 were prepared with good yields by a VilsmeierHaack-Arnold [360] reaction on the corresponding ketones 471 and 472 (Scheme 168); these /?-chloroacroleins are highly activated substrates and constitute good partners for coupling.

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Scheme 168 CHO

471

473a: R=H,95% 473b: R = Me, 99%

CHO

472

O 474, 96%

Methods for carrying out organic reactions in aqueous media have a heightened interest. Especially, palladium-catalyzed cross-coupling reactions have been imported into aqueous media, but most of the time water was only used as cosolvent [361-364]. Jeffery [365] has shown that palladium-catalyzed cross-coupling reactions can be performed in water alone, without any organic solvent, under mild conditions, in the presence of a tetraalkylammonium salt (Scheme 169). Scheme 169

COOMe

[Pd(OAc)2, PPh3] K2CO3 or Na2CO3 H

It was shown that in this mild procedure the behaviour of a wide variety of /?chloroacroleins in coupling with boronic acids was investigated [366]. Reactions were performed in aqueous media in presence of 2 mol% of palladium (II) acetate, tetrabutylammonium bromide and potassium carbonate and were almost complete after 3 h at 45 °C (Scheme 170).

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Scheme 170

MeO CHO

475a: R = H, 75% 475a: R = Me, 91%

473a: R = H 473b: R = Me

MeO'

CHO

CHO

O 476: 98%

J

Oxidation of aldehydes 475a,b and 476 with sodium chlorite [367] in the presence of 30% H2O2 in acetonitrile at room temperature allowed the formation of acids 477a,b and 478. Treatment of the corresponding acyl chlorides with aluminium chloride in dichloromethane at room temperature lead to the desired tetracyclic systems 470a,b and 470c, respectively (Scheme 171). Scheme 171 MeO

MeO'

,CHO CHO

470a, 40% , 470b, 57% 470c, 96%

Reagents and conditions: i, NaClO2, H2O2 30%, CH3CN, RT; ii, (a) SOC12, Et3N, Et2O, reflux; (b) A1CI3, CH2C12, it.

Easy access to /J-chloroacroleins and use of mild conditions allowed the preparation of tetracyclic compounds with moderate to good yields for this four-step synthesis: 7,8-dihydro-5-oxa-benzo[c]phenanthren-6-one 470a and 7,8-dihydro-7methyl-5-oxa-benzo[c]phenanthren-6-one 470b were prepared with 25% and 27% of global yields respectively based on a-tetralone and 3-methyl-l-tetralone whereas 1H5,8-dioxa-benzo[c]phenanthren-6-one [368] 470c was synthesized with a global yield of 62% based on 4//-chromanone. Although this cross-coupling reaction isn't atropselective, the tetracyclic

Chapter 3

253

compounds synthesized may lead to chiral "biaryls". Indeed, stereocontrolled ring opening of the lactone can be realised by a wide variety of chiral N-, O- and Hnucleophiles. This methodology, known as the "lactone concept", has been used in the synthesis of many axially chiral natural products and is currently under investigation for application [369]. Marine polyether toxins, exemplified by brevetoxins, ciguatoxins and maitotoxin, have attracted a great deal of attention of chemists and biologists due to their unusual molecular architecture as well as their highly potent and diverse biological activity. Numerous and significant efforts directed toward total synthesis of this class of natural products have been reported. A feasible method for the convergent synthesis of polycyclic ether framework is essential for total synthesis. Such method using S-alkyl Suzuki-Miyaura coupling as a key step was established. It was found that use of cyclic ketene acetal phosphate as one of the coupling components greatly improved the generality and feasibility of the present method. It should be noted that this is the first example of B-alkyl Suzuki-Miyaura coupling using phosphate as a leaving group. A variety of polycyclic ether frameworks including 7 to 9-membered ether rings can be constructed in a convergent manner via 5-alkyl Suzuki coupling tactic. Application to total synthesis of (-)-gambierol (vide infra) and syntheses of important fragments of ciguatoxins and gymnocin A have been reported [370]. A new palladium catalysed coupling reactions with the aim of constructing stereodefmed polyene systems with high stereocontrol have been used for several years. This methodology relies on both Heck and Suzuki coupling protocols and has been successfully applied to simple polyene systems. Research is underway to develop this area to encompass natural product synthesis of bioactive compounds, including some of the more complex polyene containing systems such as viridenomycin 479 and the development of vinyl dianion equivalents. This area involves the rational design, synthesis and screening of polyenes related to the retinoids and their analogues to provide new ways of controlling cell differentiation processes, both for application in stem cells and in cancer treatment. Viridenomycin is an antifungal antibiotic that has demonstrated in-vivo activity against cancer, prolonging the lifespan of mice with B16 melanoma [371]. The gross structure of 479 contains a highly functionalized cyclopentenyl A-ring and a 24-membered macrocyclic B-ring. The macrocycle is comprised of two tetraene subunits connected by an amide bond linkage. In addition, one of the tetraenes is conjugated to an unstable enol-ester. Three enantiomerically and geometrically pure building blocks representing fragments of the antifungal antibiotic viridenomycin have been prepared [372]. Retrosynthetic plan for 479 relies on the convergence of three key fragments 480-482 by disconnection of both tetraene subunits and the lactam bond (Scheme 172) was also reported [372]. Total synthesis of fragments 480 and 481 is shown in Scheme 173.

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Scheme 172 HO

-

MeO HO

479

TMS ArO 2 S

482 480 CHO

Scheme 173 COOMe

Et3N, THF TMS

1. DOB ALII THF.-78°C ,,2. DMP, CH2Cl2/pyr 480

NHBoc

1. Pd(MeCN)2CI2, THF 2. NBS, PPh3, CH2C12

PhSO2Na DMF 481 -*-

The first total synthesis of racemic Phthoxazolin A 483 was described [372], involving a convergent series of palladium cross-coupling reactions to stereoselectively construct the Z,Z,£-trienyl unit. The most important steps involve using vinylboronate pinacol ester 484 as a vinyl dianion equivalent, by employing a

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Chapter 3

Heck coupling of a vinyl iodide 486 with the vinyl boronate 484, followed by a deboronation-iodination sequence with inversion of alkene stereochemistry to provide a new alkenyl iodide 485. Final Stille coupling of the vinyl iodide 485 with an oxazolyl alkenyl stannane 487 provided Phthoxazohn A 483 (Scheme 174). Synthesis of fragments is shown in (Scheme 175). Scheme 174

483

B-O

SnBu 3

487

/

484 j

486

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H. Abu Ali et al.

Scheme 175 I

CHO

TiCI4, Et3N, DCM -78 °C , 1h

\

483

In contrast to the thermal Diels-Alder reactions with alkynylboronic esters, the cobalt(I)-catalyzed cycloaddition [373] of alkynylboron compounds 488 with the acyclic 1,3-dienes 489 proceeds under very mild conditions to generate the corresponding dihydroaromatic vinylboron compounds 490 in good yield. A catalyst system consisting of [CoBr2(dppe)] (dppe = bis(diphenylphosphanyl)ethane), Znt, and Zn powder has proven to be very effective for the reaction of the alkynylboron compounds [374]. Regioselective cobalt(I)-catalyzed Diels-Alder reaction of alkynylboronic esters with 1,3-dienes is shown in (Scheme 176). Scheme 176 Ri E B

= -R + -j—R 2

Co-cat

o' 488

490

489

[PdCl2(dppf)] R,-Hal

DDQ -2 492

R

^-^

R2

491

The complexity of the products could be increased significantly by palladium catalyzed Suzuki coupling reactions (Scheme 176). The reaction sequence consisting of the cobalt-catalyzed Diels-Alder reaction, Suzuki coupling giving 491, and mild oxidation with DDQ (2,3-Dichloro-5,6-dicyano-p-benzoquinone) to yield 492 can be

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performed as a one-pot operation without isolation of the intermediates. The dihydroaromatic vinylic boron compounds 490 can be used in sp2/sp2 and sp2/sp coupling reactions with the corresponding halides to generate intermediates 491. Thus building blocks can be connected to give more complex polyfunctionalized structures, Fig. 18. Products

Diene

y

R = Ph

R = Ph

R = Ph

R = MeO

MeO'

490i, 76%

Fig. 18. Results of the Cobalt(l)-catalyzed Diels-Alder reaction with alkynylboronic esters (derivatives of 490)

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Tricyclic compounds can be prepared efficiently when the Suzuki coupling of the isopropenyl substituents building block 493 with alkoxy-functionalized aromatic halides is followed by oxidation with DDQ and cleavage of the ether with trimethylsilyl iodide (Scheme 177). Spontaneous cyclization gives the framework of the family of cannabinoid natural products 494. Structural variations are easily accessible by this modular approach. For example, the Suzuki coupling of 2iodobenzylic alcohol and the following acid-catalyzed cyclization generates the structurally related product 495 in good yield. These and other reactions of dihydroaromatic boron compounds give an indication of the synthetic potential of this new class of compounds. Scheme 177. Synthesis of heterocyclic compounds from polyfunctionalized dihydroaromatic boron compounds. TMS] = trimethylsilyl iodide OMe

MeO

,-OMe

(Pin)B

I.Suzuki 2. DDQ

HO'

Epothilones A 496 and B 497 are cytotoxic macrolides isolated from the myxobacterium Sorangium cellulosum [375]. These compounds exhibit potent antitumor activity, and their mechanism of action is found to be similar to that of Taxol (paclitaxel) [376]. Both epothilones and taxanes kill tumor cells through induction of tubulin polymerization and microtubule stabilization. Moreover, it has been recognized that epothilones are effective against a number of Taxol-resistant tumor cell lines. As a consequence of their remarkable biological activity and unique chemical structure, extensive effort concerning the synthesis of the epothilone class of molecules was initiated and is manifested in the large number of publications in this area [377]. Epothilones A 496 and B 497 are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A 496 was reported, which utilized chiral silane-based bond construction methodology to introduce the key C-6 and C-7 stereocenters of fragment 498. The C-15 stereocenter of fragment 499 was established by a lipase-mediated kinetic resolution. The fragments were assembled with a Suzuki coupling reaction and an aldol condensation and cyclized with a Yamaguchi-type macrolactonization reaction (Scheme 178) [378]. Synthesis of fragment 498 is shown in Scheme 179.

259

Chapter 3 Scheme 178. Retrosynthetic Analysis of Epothilone A 496

.0 OH

496: R = H 497: R = Me

Aldol condensation

OTBS 498

Gilvocarcin M 500 shows the key structural features of a growing class of aryl C-glycoside antibiotics [379] which share a common aromatic nucleus, 6Hbenzo[d]naphtha-[l,2-(3]pyran-6-one, to which various rare sugars are connected through a C-C bond. These compounds are attractive as synthetic targets because of the challenge presented by their unusual C-glycoside structures linked to the highly functionalized skeleta and because some of the members show significant antitumor activity with exceptionally low toxicity [380,381]. Total Synthesis of (+)-gilvocarcin M 500 has been reported (Scheme 180) [382].

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Scheme 179. Synthesis of Fragment 498 OTMS OBn OTB9D _^ EtO H

OEt

a,b,c,d,e,f,g

OBn OTBS OH

498 O

Reagents and conditions: (a) TMSOBn, catalytic TMSOTf, CH2C12, -78 to -50 °C, 16 h; S3, BF3.Et,O, -30 °C, 24 h, 83%, syn/anti) 15:1; (b) O3, MeOH/CH2Cl2 (2:1), pyridine, Me2S, -78 °C to rt, 88%; (c) TiCl4, CH2C12, -78 °C, 30 min, 83%, anti/syn ) 6:1; (d) TBSOTf, 2,6lutidine, CH2C12, 0 °C, 2 h, 95%; (e) BaJMF/AcOH (1:1), THF, rt, 24 h, 92%; (f) (COC1)2, DMSO, Et3N, CH2C12, -78 °C to rt, 95%; (g) Ph3PdCHCO2Et, benzene, reflux, 4 h, 91%; (h) Me2CuLi, TMSCI, THF, -78 °C, 4 h, 94%, anti/syn > 10:1; (i) DIBAL-H, CH2C12, -78 °C, 15 min; (j) TBSC1, imidazole, DMF, 68% for two steps; (k) CH3PPh:,Br, NaN(TMS)2, THF, 0 °C,90%.

Scheme 180 OBn OMe

OBn OMe

OMe

OMe

BnO,

OBn

BnO,

OBn

O

90%

OH OMe OMe HO,,,

Reagents and conditions: (a) (Ph3P)2PdCl2, NaOAc/DMA, 125 °C, 6 h; (a) H2, Raney Ni/EtOH, rt, 3 days. Using the versatile Directed ortho and remote Metalation protocols linked with Suzuki-Miyaura cross coupling, efficient syntheses of defucogilvocarcin M, V, and E, 500-502 have been synthesized (Scheme 181) [383].

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12. SYNTHESIS OF POLYCYCLIC ETHERS Marine polycyclic ethers, such as brevetoxins, ciguatoxins, and maitotoxin, represent formidable and challenging synthetic targets due to their structural complexity and exceptionally potent biological activities [383]. One most critical issue in the synthesis of these large natural products was the development of synthetic methodology for convergent coupling of polyether fragments [384]. A new strategy for convergent synthesis of trans-fused polyethers based on palladium(O)-catalyzed Suzuki cross-coupling reaction of alkylboranes with cyclic enol triflates has been developed [385]. The present method allows to construct polyether frameworks rapidly and efficiently for big bilding blocks synthesis such as 503 (Scheme 182). Scheme 181 OR NEt2 R

Et2N

(HO)2B OMe

OMe Oi-PrOMe

Oi-PrOMe

HO,,, H R 501: R = vinyl 502: R = Et

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Scheme 182

503

Reagents and conditions: (a) 9-BBN (2.6 equiv), THF, reflux, 5 h, then aq. Cs2CO3 (3 equiv), PdCb(dppf) (0.1 equiv), KBr (1.2 equiv), Ph3As (0.4 equiv), DMF, r.t, 20 h; (b): prepared from the corresponding lactone by standard method (1.2 equiv of KHMDS, 1.5 equiv of HMPA, THF, -78 °C; 1.2 equiv of PhNTf2, -78 to 0 °C). (c): prepared from the corresponding lactone with Tebbe reagent (2.2 equiv) in THF-toluene-pyridine at -40 °C (7276%). (d): prepared from the corresponding iodide by base-treatment (t-BuOK, THF, 0 °C, 92%); (e) ThexylBH,, THF, 0 °C; H2O2, NaOH, r.t.; (f) Swem oxidation, 82% (2 steps); (g) CSA, CH2Cl2-MeOH, r.t; (h) Ac,O, Pyr, r.t., 94% (2 steps); (i) Et3SiH, BF3.OEt2, CH,CI2, 10 °C, 83%.

Convergent synthesis of H-I-J-K ring model compound 505 of ciguatoxin 504, Fig. 19 was described [386]. The present synthesis relied on a palladium-catalyzed Suzuki cross-coupling reaction between eight-membered ketene acetal phosphate 506 (Scheme 183) and seven-membered alkylborane 508 (Scheme 184). The described synthesis demonstrated the potential of the Suzuki cross-coupling protocol for a general entry to the convergent synthesis of polyether compounds. Further studies toward the total synthesis of ciguatoxins and related natural products based on the present strategy are currently under investigation and will be reported in due course.

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Chapter 3

504 Ciguatoxin (CTX1B)

Fig. 19. Ciguatoxin 504

Scheme 183

Reagents and conditions: (a) TBSC1, imidazole, DMF, rt, 73%; (b) OsO4, NMO, acetone:H2O (4:1), rt, then NaIO4, rt; (c) NaBH4, MeOH, 0 °C, 95% (two steps); (d) h, Ph3P, imidazole, benzene, rt; (e) KCW-Bu, THF, 0 °C, 96% (two steps).

A synthetic route to the F-G-H ring system of gambierol 509, a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed [387]. The present synthesis features B-alkyl Suzuki coupling of the F and H rings, followed by ring-closure of the G ring and stereoselective installation of 1,3diaxial methyl groups at C21 and C23 [387].

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Scheme 184

TBSO,,.

507

Reagents and conditions: (a) 9-BBN, THF, rt, then 1 M NaHCO3, 506, Pd(PPh3)4, DMF, 50 °C, 86%; (b) thexylborane, THF, 0 °C, H2O2, NaOH, rt, 75%; (c) TPAP, NMO, 4 A MS, CH2C12, rt, quant.; (d) LiHMDS, TMSC1, Et3N, THF, -78 °C; (e) Pd(OAc)2, CH3CN, 60 °C, 77% (two steps); (f) Me2CuLi, Et2O, -20 °C, 71%; (g) p-TsOH, MeOH, rt, 98%; (h) Ac2O, DMAP, CH2C12, 0 °C, 97%; (i) Et3SiH-BF-OEt2, CH2C12-CH3CN (1:1), 0 °C, 90%.

A convergent synthetic approach to gambierol 509 involves construction of two fragments representing the ABC and EFGH ring systems (Schemel85). The latter compound was derived from the precursor FGH ring system 510. The synthesis of 510 was based on 5-alkyl Suzuki coupling of the F and H ring precursors and then ring-closure of the G ring; (512 + 513 —> 511). A formidable challenge in synthesizing 510 appeared to be the introduction of the 1,3-diaxial dimethyl groups at C21 and C23 positions on the F ring. The problem could solve by a preliminary introduction of the C23 methyl group, followed by installation of a quaternary center at C21 (511^510) (Scheme 186 and 187).

265

Chapter 3

Scheme 185

513

512

TIPSO

BnO-^/

yo>)

BnO' -^ 0511 h

H ^ O A c

OAc

510

H

Scheme 186

/A

BnO^/xj^O. BnO*^^

v I^—-> OTBS

BnO BnO

Reagents and conditions: (a) BH3-THF, THF, -30 °C; then H,O2, NaOH, rt.40 °C, 77%; (b) KH, PMBC1, Bu4Nl, THF, rt, 88%; (c) Bu4NF, THF, rt, quant.; (d) TPAP, NMO, 4 A, molecular sieves, CH2CI2, rt, 94%; (e) DDQ, CH2Cl2-phosphate buffer (pH 7), rt; (f) pTsOH-H2O, CHCl3-MeOH, rt, 82% (two steps); (g) Ac,O, DMAP, CH2C12, 0 °C, 97%; (h) DDQ, CH2Cl2-phosphate buffer (pH 7), rt; (i) EtSH, Zn(OTf)2, NaHCO3, CH 2 CI, (Scheme 175, then Ac2O, Et3N, DMAP, 86% (three steps); Q) wCPBA, NaHCO3, CH2CI2, rt, 96%; (k) Me3Al, CH2C12, -78°C, 90%.

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A synthetic route to the E-F-G-H ring system 511 of gambierol 509 a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features convergent coupling of the F and H rings followed by ring-closure of the G ring based on the 5-alkyl Suzuki reaction of lactone-derived enol phosphates. An angular methyl group at C23 was stereoselectively introduced by treatment of respectively sulfone with trimethylaluminum. Finally, formation of the E ring as a lactone form completed the synthesis of 511. Scheme 187 TIPSO

511

a-d

HO'

510

Reagents and conditions: (a) NaOMe, MeOH, rt; (b) Me2C(OMe)2, PPTS, DMF, rt, 98% (two steps); (c) H2, Pd(OH)2:C, EtOAc, rt; (d) TIPSCl, imidazole, CH2Cl2, rt, 89% (two steps); (e) TPAP, NMO, 4 A, molecular sieves, CH2Cl2, rt, 99%; (f) Ph3P + CH3Br-, NaHMDS, THF, -78 °C, rt, 92%; (g) OsO4(3 equiv.), NMO (10 equiv.), f-BuOH-H2O (1:1), rt, 96%; (h) TsCl, DMAP, (CH2CI2, rt, 99%; (i) LiAlH4, THF, 0 °C, rt, 75%.

Synthetic Studies on a Marine Polyether Toxin, Gambierol: Stereoselective Synthesis of the EFGH Ring System 512 via B-Alkyl Suzuki Coupling also has been reported [388] (Scheme 188).

Chapter 3

267

Scheme 188 BnO.

Reagents and conditions: (a) KH, BnBr, THF, rt; (b) «-Bu4NF, THF, rt, 87% (two steps); (c) SOrpyridine, Et,N, DMSO, CH2C12, 0 °C; (d) Ph3P=CHCO2Bn, (CH2C1)2, rt, 86% (two steps); (e) H2, Pd(OH)2/C, EtOAc, rt; (f) 2,4,6-trichlorobenzoyl chloride, Et3N, THF-toluene (1:1), rt, then DMAP, toluene, 110 °C, 93% (two steps).

13. SYNTHESIS OF DISUBSTITUTED FURANS An organosilicon-organoboron protocol directed to the synthesis of 3,4-disubstituted furans was recently established [389,390]. The same method was subsequently extended to the realization of polysubstituted furans [391]. Recently the application of this strategy as a pivotal step in the synthetic study of eudesmanolides, e.g. 11,13dihydrotubiferin 513 [392] and artogallin 514 [393] was reported, Fig. 20. An initial target molecule is furan 515 because the oxidative conversion of furans to butanolides was well documented [394]. By employing a model Ring C—>BC—>ABC approach, the construction of 515 as well as its related compound 516 utilizing the title compound tris(3-methylfuran-4-yl)boroxine as a precursor is delineated below. It is noteworthy that a compound structurally similar to 516 was recently used to synthesize the cyathin core of diterpenes erinacine and scabronine [395].

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,OAc

513

514

515

516

Fig. 20. Eudesmanolides, 11,13-dihydrotubiferin 513 and artogallin 514

A synthetic study of eudesmanolides was performed utilizing a Suzuki coupling reaction of tris(4-methylfuran-3-yl)boroxine as the pivotal step. The other key reactions involved Friedel-Crafts acylation, Wacker-Tsuji reaction and aldol condensation. In this Ring C^BC—>ABC approach, a model compound 515 towards the synthesis of eudesmanolides 11,13-dihydrotubiferin 513 and artogallin 514 was realized. In another model study, the five-membered analog 516 was also obtained (Scheme 189). Scheme 189 EtOOC

1.NaBH 4 , EtOH 2. NaOH, MeOH 3. TFAA, CH2CI2 4. IMNaOH

OH

O

HO(CH2)2OH p-TsOH C 6 H 6 , reflux

Dess-Martin periodinane CHCI2

n = 2, 515, 70% n = 1, 516, 79%

Synthetic routes to the bufadienolide group of steroids are important due to the powerful biological activity of these compounds [397] and their proposed role in controlling the mammalian sodium pump [398]. Bufadienolides are characterised by a 2-pyrone unit connected at the 5-position to the C-17 position of a steroid nucleus and exemplified by the toad venom bufalin 517 [399]. A high yielding route to bufadienolide type steroids using a novel Suzuki coupling reaction between a range of

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steroid vinyl triflates and 2-pyrone-5-boronate 518 was presented (Scheme 190). The Pd(0)-mediated coupling of 2-pyrone-5-boronate 518 to a range of steroid vinyl triflates is an efficient method of preparing bufadienolide type steroids without the use of toxic tin reagents and hence avoids the risk of products contamination with tin residues. Scheme 190 OTf

O

TBDMSO'

518

TBDMSO'

The synthesis of the novel enantiopure B-nor-steroid 519 was described employing a combination of a Suzuki- and a Heck-reaction [400]. As substrates the 2bromobenzylchloride 521 and the boronic ester 522 were used; the latter was prepared from the Hajos-Wiechert ketone derivative in five steps. Noteworthy, the Heckreaction was performed under microwave irradiation, which was much superior compared to the normal thermal reaction. The purpose of the described work was the design of novel estrogens, which bind to the |3-unit of the maxi K+-channel located on the surface of the endothelium without showing the hormonal activity of estradiol. The novel B-nor-estradiol analogue 519 was synthesized using two subsequent Pdcatalyzed reactions as the key steps. Suzuki-coupling of the benzylchloride 521 and the boronic ester 522 led to the seco-B-nor-steroid 520, which was transformed into 519 by an intramolecular Heck-reaction under microwave irradiation (Scheme 191). Suzuki-coupling of 522 and the benzylic chloride 521 with Pd(PPIi3)4 as catalyst and sodium hydroxide as base in THF under reflux gave the seco-B-norsteroid 520 in 72% yield (Scheme 191). The transformation showed a high regioselectivity; thus, the cross-coupling with the boronic ester took place exclusively at the benzyl chloride moiety of 521, whereas the aryl bromide moiety seemed to be inert under these conditions.

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Scheme 191

O-t-Bu

MeC

MeC

O-t-Bu

V MeO

14. SYNTHESIS OF GERANYLGERANYL DIPHOSPHATE DERIVATIVES The Suzuki coupling reaction has been used to introduce a methyl group derived from commercially available methylboronic acid into a vinyl triflate. This has led to a concise synthesis of all-fraws-geranylgeraniol 525, with the key step being the palladium-catalyzed, silver-mediated methylation of triflate (Schemes 192 and 193) to give ethyl geranylgeranoate 526. This coupling protocol has also been used to produce the novel geranylgeranyl diphosphate (GGPP) analogue 3-phenyl-3desmethylgeranylgeranyl diphosphate (3-PhGGPP, 524d). Previously developed organocuprate coupling protocol has been used to introduce the cyclopropyl and tertbutyl moieties into the 3-position of vinyl triflate. The four GGPP analogues 3-vinyl3-desmethylgeranylgeranyl diphosphate (3-vGGPP, 524a), 3-cyclopropyl-3desmethylgeranylgeranyl diphosphate (3-cpGGPP, 524b), 3-?ert-butyl-3-desmethylgeranylgeranyl diphosphate (3-tbGGPP, 524c), and 524d were then evaluated as potential inhibitors of recombinant yeast protein-geranylgeranyl transferase I (PGGTase I). The potential mechanism-based inhibitors 3-vGGPP and 3-cpGGPP did not exhibit time-dependent inactivation of PGGTase I. Instead, both analogues were alternative substrates, in accord with the interaction of the corresponding farnesyl analogues 3-vFPP and 3-cpFPP with PFTase. The tert-buty\ and phenyl analogues were not substrates, but were instead competitive inhibitors of PGGTase I. Note that all four GGPP analogues were bound less tightly by the enzyme than the natural substrate, in contrast to the behavior of the 3-substituted FPP analogues. Scheme 192

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o

o p^

^P-v

o'o • -

^ \

6^°^ 524a: 524b 524c: 524d

524 R = vinyl, 3-vGGPP) R = cyclopropyl, 3-cp-GGPP R = tert-butyl, 3-tbGGPP R = phenyl, 3-PhGGPP

0

R 0

F3 C "0

u

1

RB(OH)2

Pd(AsPh3)4

0

G ^ ^ A ^ ^

^ ^ +

0

G^ G> = /

P

\

OEt

Scheme 193

F3C

O

Far-

PhB(OH) 2 Pd(AsPh 3 ) 4

O OEt

Ph

Ag 2 O, THF

DIBALH PhMe

MeB(OH) 2 Pd(AsPh 3 ) 4 K3PO4

Ph

dioxane

526

O

NCS, Me2S

"OEt

DIBALH PhMe

O

OH2OI2 Ph

0

Fa (Bu) 4 HP 2 O 7 CH 2 CN

525

?h ff 9 o

Far =

524d

15. SYNTHESIS OF SPIROQUINOLIZIDINE DERIVATIVES The C1-C15 spiroquinolizidine subunit 528 of the marine natural product halichlorine 527 was prepared in 12 steps starting from the known 'Meyers-lactam' 529 [402]. The synthesis involves a S-alkyl-Suzuki coupling followed by a highly stereoselective intramolecular Michael addition and an intramolecular Mannich ring closure (Scheme

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194). Scheme 194

HOOC

528 HOOC

Reagents and conditions: (a) PhMe, A (95%); (b) allyltrimethylsilane, TiCI4, CH2C12, -78 °C, rt (99%); (c) Na, NH3, THF, EtOH, -78 °C (92%); (d) Boc2O, DMAP, THF (96%); (e) (i) LiHMDS, THE -40 °C; (ii) Mel, -78 °C-0 °C (90%); (f) LiOH, THF, H,O (89%); (g) (i) CICOOEt, Et3N, THF; (ii) NaBH4, MeOH (82%); (h) TBDPSCI, Et3N, DMAP, CH2C12 (95%); (j) (i) 9-BBN, THF; (ii) Z-I-CH=CH-COOMe, Pd(dppf)Cl2, AsPh3, Cs2CO3, DMF, H2O; (k) (i) TFA, CH2C12; (ii) H2O, K2CO3

The development of a highly enantioselective method for the synthesis of aroylalanines was reported [403]. The described approach employs a protected 2amino-4-bromopent-4-enoic acid, generated via the asymmetric phase-transfer catalyzed alkylation of a glycine imine, as a key intermediate. Suzuki coupling with an aryl boronic acid followed by ozonolysis of the resulting styrene provides efficient access to the aroylalanine derivatives 531a-d. The utility of this methodology was illustrated by the synthesis of L-kynurenine along with several aroylalanine inhibitors of the kynurenine pathway. Application of the asymmetric PTC alkylation of a glycine imine to the synthesis of 3-aroylalanine derivatives, including the natural product L-kynurenine 530, was reported (Scheme 195).

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Scheme 195 N02 COOH

MeO'

NH 2 O NH 2 530, 84%

531a, 87%

531b, 96%

Ar-B(OH)2, Pd, O 3

Br

531 Ar

531c, 58% 531d, 86%

The first total synthesis of dehydroaltenusin 532, a natural enzyme inhibitor, was described [404]. The key step involves Suzuki-coupling reaction of an aryl triflate prepared from 2,4,6-trihydroxybenzoic acid with a catechol-derived boronic acid or boronic ester. The synthetic product was evaluated as a potent inhibitor against eukaryotic DNA polymerase a and other DNA polymerases (Scheme 196 and 197). Scheme 196

MOMO. f

HO

^"-^

MOMO

OMe

R

Reagents and conditions: (a) acetone, SOC12, DMAP, DME, rt, 56%; (b) DIAD, Ph3P, MeOH, THF, rt, 89%; (c) Tf2O, pyridine, 0 °C, 94%; (d) MOMC1, NaH, DMF, 0 °C, 90%; (e) n-BuLi, THF, 278, 240 °C, then (i-PrO)3B, Et2O, 278 °C, rt, 95%; (f) (Ph_,P)4Pd, K3PO4, KBr, dioxane, 100 °C, 93%; (g) 2N KOH, EtOH, 60 °C; (h) 10% HCI-MeOH, CH2C12, rt, 64% (two steps); (i) BCI3 (10 equiv), CH2CI2, 0 °C, rt, 63%; 0) FeCl3, aq. EtOH, rt, 82%.

16. SYNTHESIS OF CARBOHYDRATE-SUBSTITUTED PHOSPHINES Carbohydrate-substituted phosphines are easily obtained in quite good yields by coupling of protected or non-protected D-glucosamine with the corresponding diphenylphosphino acid. These neutral ligands, in association with palladium acetate,

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are very active catalysts in the Suzuki cross-coupling reaction. The polyhydroxy phosphines are more active than the peracetylated phosphines. The process tolerates electron-rich as well as electron-poor substituents. Coupling of D-glucosamine or of the corresponding acetate with various diphenylphosphino acids afforded carbohydrate-substituted phosphines in quite good yields [405]. The catalysts obtained by the association of these ligands with Pd(OAc)2 are very effective in the Suzuki cross-coupling of various iodo- and bromoaryl derivatives with aryl boronic acids in a toluene-ethanol-water mixture. The highest activities were obtained using the polyhydroxy phosphines, turnovers of up to 97000 being obtained. The synthesis of the glucosamine-based phosphines 534a,b-537a,b is shown in (Scheme 198). The reaction of 4-diphenylphosphinobenzoic acid with 2amino-l,3,4,6-tetra-O-acetyl-2-deoxy-(3-D-glucopyranose 535a,b in a CH2CI2/THF mixture in the presence of EDC (or l-[3-dimethylaminopropyl]-3-ethylcarbodiimide) and HOBT (or 1 -hydroxybenzotriazole) afforded the peracetylated phosphine 536a in 50% yield. Deacetylation of 536a with a catalytic amount of sodium methoxide in methanol gave the polyhydroxy phosphine 536b in 80% yield, as a 87:13 mixture of the a- and b-anomers. Scheme 197

.OMe

OMe

Reagents and conditions: (a) bis(pinacolato)diborane(4), PdCI2-(dppf), KOAc, DMF, 80 °C, 81%; (b) PdCl2(dppf), K2CO3, DME, 85 °C, 67%; (c) BCI3, CH2CI2, it, 80%; (d) FeCl3, aq. EtOH, rt, 82%.

Chapter 3

275

Scheme 198

Ph2P 537a, b

Reagents: (i) PPh2Br, C5H5N, Et3N, 20 "C, 12 h; (ii) NaOH, CH3CH2OH, room temperature; (iii) 4-Ph2PC6H4CO2H for 536b, 2-Ph2PC95% diastereomeric purity), (b) TBDPS-C1, excess imidazole, CH2C12, rt, 16 h, 99%. (c) i. AcOH: THF: H2O (3:1:1), rt, 16 h, 99%; ii. NaBH4, EtOH, rt, 15 min, 98%; iii. MsCl, Et3N, CH2C12, 0 °C to rt, 1 h, 99%; iv. KCN, 18crown-6, MeCN, 80 °C, 5 h, 95%; v. DIBA1-H, hexane-toluene (2:1), -78 °C, 40 min, 99%. (d) i. AllMgBr, 'lpc2BOMe, Et2O-THF, 0 °C to rt; ii. -78 °C to rt, 2 h; iii. 6N NaOH, H2O2, rt, 15 h, 55% (>95% diastereomeric purity), (e) Ac2O, cat. DMAP, Py, rt, 94%. (f) CH2C12, rt, 24 h, 80% (100% Z); (g) TBAF, THF, rt, 94-100%. (h) Et,N, DMAP, CH,C12, 50-59%. (i) K2CO3, MeOH, 94%. (j) (COC1)2, DMSO, Et3N, CH2C12, -60 to 0 °C, 90%; (k) Ph3P=CH2, THF, 50 °C, 92%.

Sarcodictyins A 5, B 6 and eleutherobin 7 (the 'eleutheside' family of microtubule-stabilizing agents, Fig. 1 are active against paclitaxel-resistant tumor cell lines and therefore hold potential as second generation microtubule-stabilizing anticancer drugs [15]. The scarce availability of 5, 6 and 7 from natural sources makes their total syntheses vital for further biological investigations [15]. To date, sarcodictyins A and B have been synthesized successfully by Nicolaou et al. [16] who have also exploited a similar route for accessing eleutherobin [17]. A subsequent report by Danishefsky and co-workers shows an elegant alternative access to

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eleutherobin [18]. A number of partial syntheses and approaches have also been described [19].

9

o NMe

TOH 5: Sarcodictyin A, R = Me 6: Sarcodictyin B, R = Et

O' 7: Eleutherobin

OH

Fig. 1. Sarcodictyins A 5, B 6 and eleutherobin 7 (the 'eleutheside' family of microtubulestabilizing agents The synthesis of a number of novel, simplified, C-7 substituted eleutheside analoges with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the same fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 8 via multiple stereoselective Hafner—Duthaler allyltitanations and/or Brown allylborations. 'Second generation' RCM catalyst gave the desired ring closed tenmembered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) is likely reflecting thermodynamic control. Molecular mechanics and semi-empirical calculations also show that the Z stereoisomers of these ten-membered carbocycles are consistently more stable than theE. The crucial role of the homoallylic and allylic substituents and of their protecting groups for the efficiency of the RCM reactions is discussed. One of the simplified analogues of the natural product (9, lacking inter alia the C-4/C-7 ether bridge) retains potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma, human colon carcinoma and human leukemia cell lines, IC50 in the mM range), approximately two orders of magnitude less than paclitaxel (IC50 in the nM range). The mechanism of cell cycle arrest induced by compound 9 is similar to that obtained with paclitaxel.

2.2. Synthesis of tetrahydrofuraneglycine isomers The first enantiodivergent synthesis of all four possible yl)-glycine stereoisomers 11 and 12 was described (Scheme 3) the route is the highly stereocontrolled allylboration of the aldehydes 10 to give four chiral homoallylalcohols. Starting compounds are obtained in five steps.

2-(tetrahydrofuran-2[21]. The key step of (S)- or (^)-Garner's from them, the title

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Scheme 2 MOMOO,,

Reagents and conditions: (a) (i) 2-ButenylMgCl, (S,S)-TaddolCpTiCl [(S,S)-4], Et2O, -78 to 0 °C; (ii) solution of 3 in Et,O, -78 °C, 16 h; (iii) NH4F (45% aqueous solution), rt, 4 h, 85% (~ 95% diastereomeric purity), (b) MOMCI, DIPEA, TBAI, CH2CI2, rt, 16 h, 82%. (c) (i) LiBF4, CH3CN/H,0 (98/2), rt, 1 h; (ii) NaBH4, EtOH, rt, 20 min, 60% over two steps, (d) MsCl, Et3N, CH2CI2, 0 °C to rt, 1 h, quant, (e) KCN, 18-crown-6, MeCN, 80 °C, 5 h, 91%. (f) DIBAL-H, n-hexane/toluene (2/1), -78 °C, 40 min, quant, (g) (i) AllMgBr, dIpc2BOMe, Et2OTHF, 0 °C to rt; (ii) solution of 10 in Et,O, -78 °C 15 h, -78 to -20 °C 8 h; (iii) 6 N NaOH, H2O2, rt, 16 h, 48% (11/12Z3:1). (h) (i) AllMgBr, Hpc2BOMe, Et2O-THF, 0 °C to rt; (ii) solution of 10 in Et2O, -78 °C 15 h, -78 to -20 °C 15 h; (iii) 6 N NaOH, H2O2, rt, 16 h, 54%

Scheme 3

b,c,d

b,c,d

10

HOOC

o-

Reagents and conditions: (a) (4i?,5i?)-2-allyl-l,3,2-dioxaborolane-4,5-dicarboxylic acid bisisopropyl ester, toluene, -78 °C, 3 h; (b) BH3-THF, THF, 0-5 °C, 1 h then 30% H2O2, 2 M NaOH; 0-5 °C, 30 min; (c) (i) TsCl, Et3N, DMAP, CH2C12, rt, 48 h, (ii) MPLC; (d) (i) 0.01 N pTsOH in MeOH, 5-7 h, then NaHCO3, 30 min, (ii) PDC, DMF, rt, 15 h, (iii) 4.5 N HC1 in dioxane, rt, 2 h, (iv) Dowex 50WX2-200, 10% NH4OH; (e) (45',55)-2-allyl-l,3,2dioxaborolane-4,5-dicarboxylic acid bis-isopropyl ester toluene, -78 °C, 3 h.

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2.3. Synthesis of O-lactone rings Lactone rings constitute a structural feature of many natural products [22,23]. Many naturally occurring lactones, most particularly those being a,/?-unsaturated [24], display pharmacologically relevant properties (e.g. antitumoral or else tumorpromoting activity). Among the latter, the a,/?-unsaturated 30 meg B/g tissue) and high tumor/blood ratios were achieved (> 5). The most favorable results were obtained with the polyhedral borane. Liposomes encapsulating this species produced a tumor boron concentration of 45 meg/g tissue at 30 hr post-injection, at which time the tumor/blood boron ratio was 9.3 [120]. Polyhedral borane ions has been also encapsulated in small, unilamellar liposomes, which are capable of delivering their contents selectively to tumors in vivo, and investigated as a potential agent for boron neutron capture therapy. The biodistribution of boron was determined after intravenous injection of the liposomal suspension into BALB/c mice bearing EMT6 mammary adenocarcinoma. At low injected doses, the tumor boron concentration increased throughout the time-course experiment, resulting in a maximum observed boron concentration of 46.7 meg B/g of tumor at 48 h and a tumor to blood boron ratio of 7.7, Fig. 11. The boron concentration obtained in the tumor corresponds to 22.2% injected doses/g of tissue, a value analogous to the most promising polyhedral borane anions investigated for liposomal delivery and subsequent application in boron neutron capture therapy [121].

10

20

30

40

50

Time (hours)

Fig. 11. Murine tissue boron concentrations from the liposomal delivery of Na4-B2oHi7SH, 210 mg of B (10.5 mg of B per kg of body weight): empty squares, tumor; full squares, skin; empty triangles, liver; full triangles, kidney; empty circles, brain; and full circles blood [121]

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BPA was encapsulated into liposomes as a complex with fructose, but also as a free drug in two different pH buffers. The influence of critical variables (cholesterol content, drug:lipid molar ratio, osmotic stress of liposomes containing hyperosmotic drug solution) on liposome morphology and drug content was evaluated. The drug content and dissolution profile of different BPA loaded liposomes were also studied. The encapsulation efficiencies of all formulations were always satisfactory, being between 20-48%; even when the liposomes were exposed to high osmotic stress, the particle size was below 200 nm. The BPA-fructose complex loaded liposomes showed a slower drug release profile [122]. Conventional vesicles were composed of a 1:1 molar ratio of phosphatidylcholine and cholesterol. To obtain stealth liposomes, GM1 or PEG was included in the lipid bilayer at a concentration of 6.67 or 5-mol%, respectively. Large unilamellar vesicles were formulated encapsulating BPA in the liposome aqueous compartment as a complex with fructose; BPA freebase also was embedded into the lipid bilayer. In vivo experiments were carried out after intravenous injection of liposome suspensions in rats in which liver metastases had been induced. Alpha particle spectroscopy associated with histological analysis was performed to visualize boron spatial distribution in liver, Fig. 12. Simultaneously, tissue boron concentrations were determined using inductively coupled plasma-mass spectroscopy. Results showed that PEGmodified liposomes accumulated boron in therapeutic concentrations (> 30 micrograms boron/g tissue) in metastatic tissue, consequently, the PEG-liposomes could be considered as a successful boron delivery system for BNCT [123].

Fig. 12. Histological and radiography slides of metastatic tissue: A and B experiment using BPA-loaded conventional liposomes (sacrifice time 3 h); C and D experiment using BPA-loaded PEG-stabilized liposomes (sacrifice time 6 h) [123]

Chapter 5

353

4.3. Targeting by entrapping into targeted liposomes The use of targeted liposome (bound to recognition factors) has advantageous delivery properties over non-targeted liposomes. Small, unilamellar BSH-encapsulating, transferrin (TF)conjugated polyethyleneglycol liposomes (TF-PEG liposomes) were used for specific targeting to tumor cells. When TF-PEG liposomes were injected at a dose of 35 mg 10B/kg. A prolonged residence time in the circulation and low uptake by the reticuloendothelial system (RES) in colon 26 tumor-bearing mice was observed. This enhanced accumulation of B into the solid tumor tissue (e.g., 35.5 mcg/g). TF-PEG liposomes maintained a high IOB level in the tumor, with concentrations over 30 mcg/g for at least 72 h after injection. This high retention of B in tumor tissue indicates that binding and concomitant cellular uptake of the extravasated TF-PEG liposomes occurs by TF receptor and receptor-mediated endocytosis, respectively. On the other hand, the plasma level of B decreased, resulting in a tumor/plasma ratio of 6.0 at 72 h after injection. Therefore, 72 h after injection of TF-PEG liposomes was selected as the time point of BNCT treatment. TF-PEG liposomes at a dose of 5 or 20 mg IOB/kg and irradiation with 2 x 1012 neutrons/cm for 37 min produced tumor growth suppression and improved long-term survival compared with PEG liposomes, bare liposomes and free BSH. Intravenous injection of TF-PEG liposomes increased the tumor retention of IOB atoms, which were introduced by receptormediated endocytosis of liposomes after binding, causing tumor growth suppression in vivo upon thermal neutron irradiation, suggesting that BSH-encapsulating TF-PEG liposomes as an intracellular targeting carrier in BNCT [31]. Two hundred to three hundred microliters of BSHTF-PEG liposomes, BSH-PEG liposomes, BSH bare liposomes or BSH solution were injected into tumor-bearing mice via the tail vein at a dose of 35 mg l0 B/kg. TF-PEG liposomes, with an average of 20 TF molecules per liposome, were used. The area under the concentration-time curve (AUC) was calculated by applying the trapezoidal rule, Table 2. In order to achieve an accurate measurement of IOB concentrations in the biological samples, a technique of neutron capture autoradiography (NCAR) of the sliced whole-body samples of tumor bearing mice using CR-39 plastic track detectors was employed. NCAR images for mice injected intravenously by IOB-PEG liposome, IOB-TF-PEG liposome, or l0B-bare liposome was obtained. The B concentrations in the tumor tissue of mice were estimated by means of alpha-track density measurements. The accumulation of B atoms in the tumor tissues was increased by binding polyethylene-glycol chains to the surface of liposome, which increase the retention in the blood flow and escape the phagocytosis by reticulo-endothelial systems, Table 2. Therefore, it will be possible to apply NCAR technique for selection of effective B carrier in BNCT for cancer [124], Table 2 AUC values of ' B in plasma and tumor, and the tumor-to-plasma B ratio at 24, 48 and 72 h after injection of liposomal BSH and BSH solution in Colon 26 tumor-bearing mice [31] AUS plasma AUC tumor Tumor/Plasma (mg*h/ml) (mg*h/ml) 24 h 48 h 72 h BSH solution 0.11 0.07 0.4 0.5 0.3 Bare liposomes 3.83 0.83 0.4 1.5 1.1 PEG liposomes 7.56 2.43 0.1 2.0 2.5 TF-PEG liposomes 7.36 3.31 0.1 2.5 6.0

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Folate receptor (FR) is amplified in a variety of human tumors. Folate-derived liposomes have been shown to selectively deliver entrapped agents into tumor cells via receptor-mediated endocytosis. The biodistribution of FR-targeted liposomes were evaluated as a potential delivery agent for Naj^oHnNH^) for BNCT of FR(+) tumors. N a j ^ o H n N F b ) was incorporated into liposomes by passive entrapment, following which they were administered intravenously into BALB/c mice bearing subcutaneous implants of FR(+) Ml09 murine lung carcinoma. Tumor and normal tissue boron content was measured by direct current plasma atomic emission spectroscopy. Mice that received FR-targeted and non-targeted control liposomes showed indistinguishable levels of tumor boron uptake (up to 85 mcg/g tumor), which reached a maximum at the 24 h time-point, while the tumor: blood ratio continued to rise until the 72 h time-point [67]. Two highly ionized boron compounds, IS^BnHuSH and Na3B2oHi7NH3, were incorporated into liposomes by passive loading with encapsulation efficiencies of 6% and 15%, respectively. In addition, five weakly basic boronated polyamines were incorporated into liposomes by a pH-gradient-driven remote-loading method; two were the spermidine derivatives: SPD-5, and ASPD-5 and three were the spermine derivatives: SPM-5, ASPM-5, and SPM-5,10. The in vitro uptake of folate-derivatized, boronated liposomes was investigated using human KB squamous epithelial cancer cells, which have amplified FR expression. Higher cellular boron uptake (up to 1584 meg/10 cells) was observed with FR-targeted liposomes than with nontargeted control liposomes (up to 154 microg per 10(9) cells), irrespective of the chemical form of the boron and the method used for liposomal preparation. KB cell binding of the FR-targeted liposomes was saturable and could be blocked by 1 mM free folic acid, Fig. 13 [125]. Folate receptor (FR)-targeted liposomes as carriers for a lipophilic boron agent, nido-7CH3(CH2)15-7,8-C2B9Hii, in FR-overexpressing tumor cells were evaluated. Boron-containing, FR-targeted liposomes readily bound to KB cells, an FR-overexpressing cell line, and were internalized via FR-mediated endocytosis. The boron uptake in cells treated with these liposomes was approximately 10 times of those treated with control liposomes. In contrast, FR-targeted and non-targeted liposomes showed no difference in boron delivery efficiency in F98 cells, which do not express the FR [126]. The delivery of Na.^oHiyNH}, which has been loaded into FRtargeted liposomes, in mice bearing xenograft implants of FR (+) KB subcutaneous tumor was evaluated. Mice that received FR-targeted liposomes containing boron showed the highest tumor boron levels at 24 h (6.1 mcg/g) and tumor/blood boron ratios continued to rise for up to 120 h [127]. Boron delivery via FR-targeted liposomes is feasible and can potentially improve tumor uptake compared to non-targeted liposomes. Additionally, it improve cellular and sub-cellular

355

Chapter 5

10 I 1 Noo-Tujeud ^ ^ FR-Tirffled HS • U FRTirjc(£j+ imM Fi«Frlile

II

2*

36

Boron Co ocoitradon 85% overall diastereoselectivity) was accomplished [14b]. Synthesis demonstrated the power of substrate-based anti-selective aldol reactions via the chiral ketone building blocks and the utility of the Liebeskind Cu-promoted protocol for the Stilletype coupling of complex polyoxygenated fragments. Important to the synthetic plan was the late installation of the C17 side chain via the stereocontrolled aldol coupling of methyl ketone 21 with the aldehyde 22 that afforded a protected version of concanamycin F 23 and potentially providing access to novel glycoside analogues.

375

Chapter 6

SiEt2iPr Et

10. SYNTHESIS OF AN ISOMER OF MEMBRENONE C An isomer of membrenone C was prepared in 8 steps (17% yield) with 93% overall ds starting from the ethyl ketone (S)-EtCOCH(/?-Me)CH2OCH2Ph. Key steps are the boron-mediated aldol coupling followed by anti selective reduction, giving the C6C10 stereochemistry, the two direction chain extending double titanium aldol coupling of dialdehyde 24 and enolate MeCH=CH(OTiCl3)Et to give 25 and the TFA promoted double cyclization/dehydration giving an isomer of membrenone C 26 [15].

OHC

CHO (X

.0

Si But' vtBu 24

376

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11. SYNTHESIS OF DOLICULIDE The total synthesis of doliculide 27, a potent cytotoxic cyclodepsipeptide from the Japanese sea hare, has been achieved. The key step of the synthesis is the construction of the stereogenic centers of a 15-carbon polyketide-derived dihydroxy acid moiety by a combination of the Evans aldol reaction and the Barton deoxygenation reaction [16].

OH

27

12. SYNTHESIS OF TRI- AND TETRAPEPTIDE S: THE EXTENDED CTERMINUS OF BLEOMYCIN A2 Concise diastereocontrolled syntheses of tri- and tetrapeptide S (28; R = H, Q), key subunits of the antitumor antibiotic bleomycin A2, were detailed. A stereocontrolled preparation of hydroxyhistidine fragment 29 was also reported [17].

SMe,

HQHQ

H

28

311

Chapter 6

13. SYNTHESIS OF A (9S)-MACROLIDE INTERMEDIATE FOR OLEANDOMYCIN The (9S)-macrolide 30 was prepared in 14 steps (5% yield) with 63% overall ds starting from (S)-MeCH2COCHMeCH2OCH2Ph [18]. The C(l)-C(7) and C(8)-C(13) segments, 31 and 32, were obtained via boron enolate aldol reactions mediated by (+)and (-)-(Ipc)2BOTf, respectively.

Me3CMe2Si0.

—Si— 32

14. SYNTHETIC STUDIES ON ANTITUMOR ANTIBIOTIC BLEOMYCIN Comparison of the DNA cleavage activity of synthetic bleomycins 33 [Z = (2S,3S,4R)-NHCHMeCH(OH)CHMeCO (II), (4S)-NHMeCH2CH2CO] demonstrates that bleomycins are small enzymes comprised of a catalytic site and a binding site. The linker moiety is significant for DNA binding and inversion of its stereochemical results in a dramatic decrease in the DNA cleaving efficiency. Synthetic bleomycin II shows excellent cytotoxicity against cancer cells L1210 [19]. H

H HU2

u. A«-?V O

NMe,

/k/N.

^-NH

33

H. Abu Ali et al.

378

Erythro-/?-Hydroxy-L-histidine 34 was efficiently synthesized in organic solvents from the aldol reaction of (R)-3-bromoacetyl-4-isopropyl-l,3-oxazolidin-2-one 35 and l-triphenylmethylimidazole-4-carbaldehyde 36 followed by SN2 reaction with L1N3 and hydrogenation [20]. O

OH

15. SYNTHESIS OF THE ESTERASE INHIBITOR (±)-EBELACTONE A The /2-lactone (±)-ebelactone A 37 has been prepared in 12 steps from Et2CO (9% overall yield) using a series of three boron enolate aldol reactions coupled with the Ireland ester enolate Claisen rearrangement [21].

OH

16. SYNTHESIS OF THE OVIPOSITION-DETERRING PHEROMONE IN RHAGOLETIS CERASI The preparation of the possible stereoisomers of compound 38 from (R)- and (S)was reported [22]. Thus, (R)and (S)MeCH(OH)CO2Et (Me3CMe2SiO)CHMe(CH2)3CHO were prepared and condensed with boron enolates (R)- and (S)-PhSCOCH2CH2CH(OCH2Ph)(CH2)7OC6H4OMe-4, followed by decarboxylative dehydration to give all stereoisomers of Glycosylation of the latter compounds with 2,3,4,6-tetra-O-pivaloyl-a-Dglucopyranosyl fluoride followed by taurine amide formation and deprotection gave (8R,15R)-, (8S,15R)-, (8R,15S)- and (8S,15S)- 38.

Chapter 6

379

OH

HO1' OCHMe(CH 2 )6CH(OH)(CH2)6CONHCH2SO 3 H

38

17. SYNTHESIS OF (±)-HERNANDULCIN Treating 3-(trimethylsilyloxy)-l -methyl- 1,3-cyclohexadiene (39, R = Me3Si) with Bu2BBr gave 39 (R = Bu2B) which was condensed with Me2C:CHCH2CH2COMe to give an intermediate borane followed by treatment with H2NCH2CH2OH to give 30% (±)-hernandulcin 40, a sweet substance of Lippia dulcis, using boron and silicon enolates [23]. O

40

18. SYNTHESIS OF y?-LACTAM ANTIBIOTICS The asymmetric synthesis of (+)-PS-5 41 was prepared from the enolate 42 and 3MeOCH2OC6H4CH2CHO via lactamization of 3MeOCH2OC6H4CH2CH(OH)CHEtCONHOMe, oxidative ring cleavage of the benzene ring, and ring closure of the diazo ketene 43 [24]. NHAc

O"

-NH N2 4 3

OCH 2 OMe

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19. SYNTHESIS OF (+)-PSEUDOMONIC ACID C The convergent enantiospecific total synthesis of (+)-pseudomonic acid C 44 has been completed from D-glucose [25]. Construction of the chiral tetrahydropyranyl system utilized a condensation of the preformed Z(0)-Boron enolate of Me2C:CHCH2CH2COSPh with aldehyde 45. The high diastereofacial selectivity is consistent with enolate attack from the re-face of 45 through that chair-like transition state which also affords a Felkin conformer model. Selective nucleophilic C-0 bond formation leads to the complex tetrahydropyran 46. Convergency by reductive coupling via elimination of /?-sulfonyl xanthates with BujSnH gave alkene 47. Subsequent introduction of the a,/?-unsaturated ester of 44 was feasible by addition of the organocerium reagent available from 2-bromo-4-tetrahydropyranyloxy-2-butene.

(CH 2 ) 8 COOH

OCH

45 44 OSiPh 2 CMe 3 OCH 2 Ph O

46

OCH 2 OCH 2 Ph 47

381

Chapter 6

20. SYNTHESIS OF MASAMUNE NOREPHEDRINE ESTERS Highly selective synthesis of glycolate aldol reactions with boron enolates of Masamune norephedrine esters was reported [26]. Boron enolates of norephedrinebased glycolate esters (48; Mes = mesityl, Bn = benzyl; P = Me, CH2PI1, tertbutyldimethylsilyl) reacted with various aldehydes 49 of formula RCHO (R = cyclohexyl, Bu, i-Pr, Et, Ph, trans-2-phenylethenyl, phenylethynyl, 1-methylethenyl, trans-MeCH:CMe, /rara-PhCHrCMe, Me2C:CH) to produce syn aldol products, 2,3dihydroxyalkanoic acid esters (50; P, R = same as above) in high yield and selectivity (Scheme 1). The outcome is consistent with a Z enolate reacting through a closed transition state with reversal of the enolate facial selectivity relative to the propionate enolates. Scheme 1

o p

48

c-Hex2BOTf, CH2CI2, Et3N

9 +

R

A

H

-78 °C/H 2 O 2

49

21. SYNTHESIS OF L-DAUNOSAMINE AND D-RISTOSAMINE DERIVATIVES A new route to 3-amino sugars via a concise synthesis of L-daunosamine and Dristosamine derivatives was reported [27]. An asymmetric aldol strategy has been developed for the synthesis of L-daunosamine and D-ristosamine derivatives starting from noncarbohydrate precursors. Lithium and boron enolate mediated aldol reactions of 51 with O-TBS lactaldehyde gave non-Evan syn and Evans syn aldol products, respectively, with high selectivity. The chemical efficiency of the lithium enolate reactions was higher than the corresponding reactions with the boron enolates. Curtius rearrangement of lactone acid 52 gave the corresponding N-BOC amino lactones III in 64% and 62%, respectively, with complete retention of configuration. Lactone 53 was converted to N-benzoyldaunosamide and N-benzoylristosamide with an overall yield of 18%.

o,,. TBSO 52

COOH

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22. SEMI-SYNTHESIS OF TAXOL A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere) side chains was developed using the imine addition reaction of thioester-derived boron enolates bearing chiral ligands [28]. The addition reaction was studied extensively, using a combination of different thioesters (YOCH2COSPI1, YOCH2COSt-Bu), oxygen protecting groups (Y = Bn, TBDMS, COPh, EE, TMS), chiral boron ligands [derived from both (-)- and (+)-menthone], imines (PhCH:NSiMe3, PhCH:NCOPh), and in the presence or in the absence of addnl. Lewis acids (BF3-OEt2, Et2AlCl, TiCU). The side chain was assembled in a few steps with the correct relative (syn) and abs. stereochemistry (2R,3S). The stereochemistry outcome of the boron-mediated reaction was rationalized using chair vs boat transition state structures. A new direct route for attachment of the side chains to the baccatin nucleus using thioester chem. has also been developed. By treatment of a mixture of a thioester, e.g. 54 (R = PhCO, Boc) or 55, and protected baccatin 56 (III; Ri = SiEt3, R2 = Ac; R, = R2 = CO2CH2CC13) with LHMDS, the 13-O acylated compounds were obtained in high yield (up to 90%). Hydrolysis of 57 gave Paclitaxel in 80% yield.

AcO

O

PSiEt,

23. SYNTHESIS OF THE PYRROLIZIDINE RING SYSTEM The boron enolate derived from Evans' chiral imide 58 was utilized to control the C-l stereochemistry during addition to a-acetoxy lactam in the synthesis of the pyrrolizidine alkaloid, (+)-hastanecine. Thus, the boron enolate was formed in situ by the addition of Bu2BOTf to a solution of 58 and subsequent addition of iP^NEt. Addition of 59 to this boron enolate stereoselectively afforded the hastanecine precursor 60, which was converted to (+)-hastanecine in five steps [29].

383

Chapter 6

58

OCH 2 Ph

W-V

q

6

O

O AcO1

60

24. SYNTHESIS OF (-)-BRANCHED UNUSUAL AMINO ACIDS A new method for the asymmetric synthesis of key intermediates of unusual amino acids has been established by utilizing /^-carbon chirality for asymmetric induction in allylic-strained boron enolates. Thus, treatment of acyloxazolidinones 61 (R = Me, Et, Ri = Ph, 4-MeOC6H4, R2 = H) with dibutylboron triflate and Et2NCHMe2 in CH2C12 to form the boron enolate, followed by treatment with NBS gave c/s-bromides 61 (R2 = Br) in 50-82% purified yields and >99% diastereoselectivity [30].

P O

61

o

25. SYNTHESIS OF a-AMINO ACIDS Two complementary approaches to the asymmetric synthesis of a-amino acids have been achieved [31]. In the initially investigated reaction sequence, the diastereoselective bromination of the boron enolates 62 (Bn = benzyl; R = CH2Ph, CH2CHMe2, CH2CH:CH2, Ph, CHMe2) with N-bromosuccinimide was followed by stereospecific azide displacement by tetramethylguanidinium azide. The resulting aazido carboximides 63 may be readily purified to high diastereomeric purity by chromatography on silica gel. In the second reaction sequence, the potassium enolates 64 R = CH2Ph, Me, CH2CH:CH2, Ph, CHMe2, CMe3) were treated with 2,4,6triisopropylbenzenesulfonyl azide, and then quenching sulfonyl triazene intermediates with acetic acid gave the a-azido carboximides 65. The diastereoselection of the reaction as a function of R is as follows: R = Me, CH2Ph, 97:3, R = CHMe2, 98:2; R = CMe3, > 99:1, R = Ph, 91:9. The important parameters of this azidation process were evaluated, and experiments were conducted to help elucidate the mechanism of the reaction. The a-azido carboximide products have been shown to be versatile a-amino acid synthons that may be readily converted to a-amino acids as well as to N-

H. Abu Ali et al.

384

protected a-amino acid derivatives. The racemization-free removal of the chiral auxiliary was achieved in high yield both by saponification and frans-esterification, either before or after reduction and acylation of the azide functionality.

Bu/Bu

N 3 Bri Bn

62

63

65

26. SYNTHESIS OF 1-/£METHYLCARBAPENEM ANTIBIOTICS The diastereoselective synthesis of the 1 -/?-methylcarbapenems 66 and 67 (R = Ri, R2) has been achieved [32]. The key step was an aldol reaction of the achiral boron enolate generated from BU2BO3SCF3 and 3-propionyl-2-oxobenzoxazoline, with (3R,4R)-4-acetoxy-3-((R)-l-hydroxyethyl)azetidin-2-one. 66: R =

67: R

=

\— S.

385

Chapter 6

27. SYNTHESIS OF NAKADOMARIN A (-)-Nakadomarin A 68 is a member of manzamine alkaloid isolated from a marine sponge and has a unique hexacyclic structure. The first total synthesis of (+)nakadomarin A 69, an enantiomer of natural product, has been accomplished from stereochemistry defined 4-oxopiperidin-3-carboxylic acid derivatives [33]. The synthesis established the structure of nakadomarin A including absolutely configuration.

69

28. SYNTHESIS OF ll-/?,17-/?-DIARYL-18A-HOMO-19-NORSTEROIDS In a highly diastereoselective fashion novel 11/?, 17-/5- intermediate -diaryl steroids 70 (R = OMe, NMe2) were synthesized via Birch-type reduction of styrylic precursors. Both precursors were readily available by Suzuki-type coupling of aromatic boronates and the corresponding enol triflates. Regioselective 17-enol triflate formation in presence of a 11-keto function could be demonstrated in case of steroid 71. The remarkably high stereoselectivity obtained showed parallel results from the natural series and demonstrated a broader applicability of such single-electron transfer reductions in stereoselective transformations on the steroid skeleton [34].

O

386

H. Abu Ali et al.

29. SYNTHESIS OF THE CENTRAL C18-C30 CORE OF THE PHORBOXAZOLE A direct synthesis of the central C18-C30 core 72 of the phorboxazole B 73 natural products has been developed [35]. This involves construction of an acyclic acrylate using Paterson's (E)-enol boronate aldol methodology followed by an intramolecular hetero-Michael addition to form the central pyran ring of the natural products [35]. H

H

COOMe

Bo

30. SYNTHESIS OF A C17-C32 SUBUNIT OF SCYTOPHYCIN C The C17-C32 subunit 74 (R = Me; R, = CHO) of scytophycin C was prepared in 11 steps (19% yield, 83% ds) from (S)-EtCOCHMeCH2OCH2Ph [36]. Key features include the dipropionate aldol construction of the stereopentad 75, the Brown asymmetric crotylboration leading to 76, followed by their Ba(OH)2-induced HornerEmmons coupling, debenzylation, oxidation and then BF3.OEt2-promoted allylation to give 74 (R = H, R, = CH:CH2). OSi(Me2CH)3

OMe O

CXO ,0 74

A CMe

Me

OR 3

76

(X

O

Ov

Chapter 6

387

31. SYNTHESIS OF THE ARCHAEBACTERIAL C40 DIOL A synthetic strategy was developed wherein the high 1,2-stereoselection obtainable from aldol reaction of an a,/?-unsaturated aldehyde is parlayed by a subsequent Claisen rearrangement into 1,4- or 1,5-stereoselection. Thus, (E,2S*,3S*)MeCH:CHCH(OH)CHMeCH2OR (R = Ph3C, Me3CMe2Si) gave (E,3R*,6R*)ROCH2CHMeCH:CHCHMeCH2CORi (R = Ph3C, Rt = Me2N, OEt; R = Me3CMe2Si, Ri = Me2N) via Claisen rearrangement. In contrast (2S*,3R*)H2C:CMeCH(O2CEt)CHMeCH2OSiMe2CMe3 gave (E,2S*,6R*)Me3CMe2SiOCH2CHMeCH:CMeCH2CHMeCO2H. The 1,4-stereoselection strategy was used in the preparation of (13S*,16R*)Me(CH2)iiCHMeCH2CH2CHMe(CH2)iiMe. This stereorational synthesis establishes the relative stereochemistry of the C30 diol from Messel shale kerogen. The 1,5stereoselection strategy was used in the preparation of (+)Me2CH(CH2CH2CH2CHMe)2CH2OH and 2 diastereomers of H2OH. More recently, the structure of tetraether 77, an archaebacterial membrane substance was fully defined [37].

77

32. SYNTHESIS OF ANTHRACYCLINE GLYCOSIDES Anthracycline glycosides 78 [X = CH2, CHMe, CH2CH2; R = H, alkyl, aryl, aralkyl, heterocyclyl, (CH2)nCOR3; R,, R2 = H, OH, alkoxy, OCH2Ph; R3 = OH, (un)substituted NH2, alkoxy; n = 1-4] and some alkylene bis(carbamates) were prepared [38]. Thus, 78 (X = CH2, R = Ph, R, = OH, R2 = H) was prepared by treating naphthacene 79 (R4 = CONHPh) with the protected lyxo-hexopyranosyl chloride and deblocking. 79 (R4 = CONHPh) was prepared from 79 (R4 = Ac) by deacetylation, reaction with PhB(OH)2, followed by PhNCO, and hydrolysis of the boronate. At 0.5 //g/kg I.P. in mice infected with lymphocytic leukemia 78 (X = CH2, R = Ph, R] = OH, R2 = H) doubled the survival time. O

O

78

R R

OH

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REFERENCES [I] [2] [3]

[4] [5] [6]

[7]

[8] [9] [10] II1] [12] [13] [14]

[15] [16]

A. Abiko, Ace. Chem. Res. 37 (2004) 387. A. Abiko, J. Synth. Org. Chem. Japan, 61 (2003) 24. (a) C. Gennari, Pure & Applied Chem. 69 (1997) 507; (b) I. Paterson, V.A. Doughty, G. Florence, K. Gerlach, M.D. McLeod, J.P. Scott and T. Trieselmann, ACS Symposium Series, (Organoboranes for Syntheses) 783 (2001) 195. (a) AW. Lloyd, Drug Discovery Today, 1 (1996) 84; (b) C.J. Cowden and I. Paterson, Organic Reactions (New York) 51 (1997) 1. T. Mukaiyama, Angew. Chem. Int. Ed. 43 (2004) 5590. S.J. Mickel, G.H. Sedelmeier, D. Niederer, R. Daeffler, A. Osmani, K. Schreiner, M. Seeger-Weibel, B. Berod, K. Schaer, R. Gamboni, S. Chen, W. Chen, C.T. Jagoe, F.R.Jr. Kinder, M. Loo, K. Prasad, O. Repic, W.-C. Shieh, R.-M. Wang, L. Waykole, D. David, and X.S. Xue, Organic Proc. Res. Develop. 8 (2004) 92. S.J. Mickel, D. Niederer, D. Niederer, R. Daeffler, A. Osmani, E. Kuesters, E. Schmid, K. Schaer, R. Gamboni, W. Chen, E. Loeser, F.R.Jr. Kinder, K. Konigsberger, K. Prasda, T.M. Ramsey, O. Repic, R.-M. Wang, G. Florence, I. Lyothier and I. Paterson, Organic Proc. Res. Develop. 8 (2004) 122. M.T. Crimmins and P. Siliphaivanh, Org. Lett. 5 (2003) 4641. C.H. Heathcock, M. McLaughlin, J. Medina, J.L. Hubbs, G.A. Wallace, R. Scott, M.M. Claffey, C.J. Hayes and G.R. Ott, J. Am. Chem. Soc. 125 (2003) 12844. C. Schneider, F. Tolksdorf and M. Rehfeuter, Synlett 12 (2002) 2098. M.T. Crimmins, J.D. Katz, D.G. Washburn, S.P. Allwein and L.F. McAtee, J. Am. Chem. Soc. 124 (2002) 5661. I. Paterson, C. De Savi and M. Tudge, Org. Lett. 3 (2001) 3149. D. E. DeMong and R. M. Williams, Tetrahedron Lett. 42 (2001) 183. (a) I. Paterson, V.A. Doughty and M.D. McLeod, Book of Abstracts, 218th ACS National Meeting, New Orleans, Aug. 22-26 (1999), Publisher: Am. Chem. Soc, Washington, D. C; (b) I. Paterson, V.A. Doughty, M.D. McLeod and T. Trieselmann, Angew. Chem. Int. Ed. 39 (2000) 1308. M.V. Perkins and R.A. Sampson, Tetrahedron Lett. 39 (1998) 8367. H. Ishiwata, H. Sone, H. Kigoshi, and K. Yamada, J. Org. Chem. 59 (1994) 4712.

[17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]

D.L. Boger and F.J. Menezes, J. Org. Chem. 57 (1992) 4331. I. Paterson, M.A. Lister and R.D. Norcross, Tetrahedron Lett. 33 (1992) 1767. T. Owa, A. Haupt, M. Otsuka, S. Kobayashi, N. Tomioka, A. Itai, M. Ohno, T. Shiraki and M. Uesugi, Tetrahedron 48 (1992) 1193. T. Owa, M. Otsuka and M. Ohno, Chem. Lett. 11 (1988) 1873. I. Paterson and A.N. Hulme, Tetrahedron Lett. 31 (1990) 7513. B. Ernst and B. Wagner, Helvetica Chimica Acta 72 (1989) 165. Yu.N. Bubnov and M.E. Gurskii, Izvest. Akad. Nauk SSSR, Ser. Khim. 6 (1986)1448. D.A. Evans and E.B. Sjogren, Tetrahedron Lett. 27 (1986) 3119. D.R. Williams, J. L. Moore and M. Yamada, J. Org. Chem. 51 (1986) 3916. M.B. Andrus, B.B. Soma, B. B.V. Sekhar, T.M. Turner and EX. Meredith, Tetrahedron Lett. 42 (2001) 7197. M.P. Sibi, J. Lu and J. Edwards, J. Org. Chem. 62 (1997) 5864.

Chapter 6 [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]

389

C. Gennari, M. Carcano, M. Donghi, N. Mongelli, E. Vanotti and A. Vulpetti, J. Org. Chem. 62 (1997) 4746. R.A. Pilli and D. Russowsky, J. Org. Chem. 61 (1996) 3187. G. Li, D. Patel and V.J. Hruby, Tetrahedron Lett. 35 (1994) 2301. D.A. Evans, T.C. Britton, J.A. Ellman and R.L. Dorow, J. Am. Chem. Soc. 112(1990)4011. T. Shibata and Y. Sugimura, J. Antibiot. 42 (1989) 374. T. Nagata, M. Nakagawa and A. Nishida, J. Am. Chem. Soc. 125 (2003) 7484. E. Ottow, A. Cleve, G. Neef, W. Schwede and J. Prakt. Chem./Chem.-Zeit. 339(1997)365. C.S. Lee and C.J. Forsyth, Tetrahedron Lett. 37 (1996) 6449. I. Paterson and K.S. Yeung, Tetrahedron Lett. 34 (1993) 5347. C.H. Heathcock, B.L. Finkelstein, E.T. Jarvi, P.A. Radel and C.R. Hadley, J. Org. Chem. 53(1988) 1922. M.J. Broadhurst, C.H. Hassall, G.J. Thomas, (Hoffmann-La Roche, F., und Co. A.-G., Switz.). Eur. Pat. Appl. (1984) 109.

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391

Chapter 7 Boronated saccharides: potential applications R. S mo urn and M. Srebnik Department of Medicinal Chemistry & Natural Products, School of Pharmacy, P.O. Box 12065, Hebrew University of Jerusalem, Jerusalem 91120, Israel

Contents 1. INTRODUCTION 393 2. BORONIC ACIDS-SACCHARIDE INTERACTION; THE BASICS 393 3. CHEMOSENSING 396 3.1. CD receptors 396 3.2. Fluorescent receptors 399 3.2.1. PET receptors 399 3.2.2. Non-PETsensors (ICTsystems) 413 3.3. Colored receptors 419 3.4. Porphyrin-based receptors 422 3.5. Metal co-ordinated receptors 424 3.6. Electrochemical receptors 429 3.7. Receptors at the air-water interface 430 3.8. Receptors at the lipid-water interface 431 3.9. Polymeric receptors 432 3.10. Imprinted receptors 433 4. TRANSPORT 434 4.1. Membrane transport of sugars using boronic acid carriers 435 4.2. Transport selectivity for D-glucose 442 4.3. Further insights into boronic acid-promoted transport of monosaccharides through lipophilic membranes 443 4.4. Chemical and physical factors that control transport rate 444 5. BORON AND PLANTS 446 5.1. Borate esters and borate complexes 446 5.2. Speciation of boron in plants 447 5.2.1. Boron in cell walls 447 5.3.2. Sugar transport 450 5.3.3. Enzyme interactions 451 6. CHROMATOGRAPHY 451 6.1. Glycohemoglobin measurement 452 6.1.1. Boronate affinity 453 6.7.2. Boronate acid affinity chromatography 453 6.2. Saccharide separation 460 7. BORON AND DIABETES 461 7.1. Recent advances in artificial receptors for diabetes diagnosis 462 7.2. Glycemia control and glycated hemoglobin measurement 463 7.2.7. Glycated hemoglobin tests 463 8. BORON AND CANCER 465

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8.1. Boron neutron capture therapy 8.2. Fluorescent probes for cells expressing sialyl Lewis X 8.3. Synthetic polymers with lectin-like function 9. DRUG DELIVERY 10. MISCELLANEOUS BIOLOGICAL APPLICATIONS OF BORON SACCHARIDE INTERACTIONS 10.1. Modification of enzyme activity 10.2. Inhibition of enzymes 10.3. Control of the conformation of poly(L-lysine) 10.4. Boronic acid SAMs 10.5. Blocking adhesion to cell and tissue surfaces 10.6. As a novel entry for photochemical DNA cleavage 10.7. Myglobin-phenylboronic acid conjugates 10.8. Boron compound/complexes to control hair growth 10.9. Compositions and method for steroid hemostasis REFERENCES

465 468 469 470 472 472 473 474 474 476 477 478 478 478 479

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393

1. INTRODUCTION The reaction of boronic acids with polyols to form boronate esters has been known for over 50 years, but it is still the subject of considerable research [1]. Ferrier pioneered the application of this process in synthetic chemistry [2], and this aspect of boronic acid chemistry continues to blossom [3]. Boronic acids bind with the diol containing moieties with high affinity through reversible ester formation. Such tight binding allows boronic acids to be used as biochemical sensors [4-13], carbohydrate transporters [14-21], affinity ligands for the separation of carbohydrates and glycoproteins [22-29], boron neutron capture therapy (BNCT) agents [30], feedback controlled drug delivery polymers [31], and as antibody mimics targeted on cell-surface carbohydrates [32,33]. This broad interest in boronic acids results from their relatively low toxicity and the unique interactions they have with diols, namely, they form cyclic esters with diols in water much more readily than many other acids [34]. This chapter will discuss the interaction of boronic acids with saccharides and the usefulness of this kind of interaction in chemosensing, transport, chromatography, diabetes, cancer, drug delivery and few other miscellaneous applications. 2. BORONIC ACIDS-SACCHARIDE INTERACTION; THE BASICS Boeseken [35] was among the first to predict an interaction between D-glucose and boric acid and he deduced the formation of a complex in water between boric acid and the a-furanose form of glucose. In 1954, Foster [36] concluded that glucose could interact with two boric acid units when in the furanose form and he suggested an «-Dglucofuranose-l,2:3,5,6-bis(borate) complex. Complex formation between an aromatic boronic acid and different polyols was first mentioned in 1954 by Kuivila and co-workers [la] and several papers on the subject followed [lb-d]. In 1959, Lorand and coworkers [Id] published the first quantitative evaluation of the interaction between various diol containing compounds and phenylboronic acid using the so-called pH-depression method. This method is based on the phenomenon that diol binding to a boronic acid usually lowers the pATa of the boron containing functional group [ld,37]. Boronic acids react covalently and reversibly with 1,2- or 1,3-diols to form five- or six-membered cyclic esters in non-aqueous or basic aqueous media (Scheme 1). The adjacent rigid cis diols of saccharides form stronger cyclic esters than trans diols. The formation of cyclic ester of saccharides is complicated by the possibility of pyranose to furanose isomerization of the saccharide moiety. On saccharide binding and formation of a cyclic boronate ester, the pKa of the boronic acid is enhanced and the 'ester' is more acidic than the 'acid'. The enhanced acidity is due to a bond angle compression on formation of a cyclic boronate ester. Boronic acids have a 120° (sp2) bond angle but in a cyclic ester the bond angle is reduced to 108°. The change in the bond angle from 120° to 108° facilitates the change in hybridization from sp to sp on deprotonation.

394

H.AbuAlietal.

Scheme 1. Formation of trigonal and tetrahedral boronate esters from boronic acid and polyol.

2H2O

R

_ B ' 0 H + Cdi^T)

bH HC?

aqueous solvent

bH ^ = ^ ^

+

~yC RX

H

3°+

OH

Although the formation of boronic acid derivatives of diols have been known for almost 50 years, structures of these complexes in solution are poorly characterized and still a matter of debate [4,38-45]. Boric and boronic acids, however, are known to interact with the furanose form of glucose under alkaline aqueous conditions [46-50]. In several studies, Shinkai and co-workers [40,42-45,50], nevertheless conclude that a pyranose complex is formed both in nonaqeous and in alkaline aqueous solution. Drawber et al. [51] also concluded that the pyranose form of glucose interacts with a solution of sodium borate. The binding constants determined using the pH-depression method [ld,37] was much higher than those determined later using spectroscopic methods. For example, the binding constant between phenylboronic acid and fructose was found to be 4370 M"' when using the pH depression method whereas the binding constant of the structurally similar anthrylboronic acid and fructose was found to be 270 M~' when determined by the fluorescent method [52]. Therefore, a new method was developed for examining boronate ester stability using the fluorescent reporter Alizarin Red S. This system was used to determine the binding constants of a series of diols and as a basis from which to derive a number of relationships that correlate the various equilibrium constants in the literature [37]. Boronic acids can react with water to go from the trigonal form A to the anionic tetrahedral form B (Scheme 2) and this is true for the diol-boronic acid complex of the boronate ester C. Therefore, boronic acids and their esters can exist in two different ionization states, hence, three different binding constants have to be considered. The first one is Ktr;g which refers to the conversion of the trigonal boronic acid A to the trigonal ester C. The second one refers to the conversion of tetrahedral boronate B to its ester counterpart D, termed Ktet. The third binding constant describes the overall binding strength regardless of the ionization state of the boron species, Keq (Scheme 3). After several studies, it was found that the binding constant determined using the pH depression method was the Ktet, whereas spectroscopic methods tend to give the Keq [8,37]. In general, boronic acids with lower pA^'s tend to have higher affinities for diols [52] , although the optimal binding also depend on the pA"a's of the boronic acid and diol and the pH [53].

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Scheme 2. The relationships between phenylboronic acid and its diol ester.

B(OH)2

H20

Diol

Diol

/

V2H 2 O

2H2O

HQ rf ^OAR2

Scheme 3. Overall binding process between phenylboronic acid and a diol.

Diol

Keq

E

The interest in the recognition of biologically important species by synthetic molecular receptors has gained momentum recently. The function of many of these receptors, including several that recognize carbohydrates is based on hydrogenbonding interactions [6]. The efficiency of such interactions has been well demonstrated in nonaqueous systems, but in aqueous media competitive hydrogen bonding by the solvent is a serious drawback. Boronic acids readily form covalent interactions with saccharides in aqueous media, and these represent an important alternative binding force in the recognition of saccharides and related molecular species. Since the chemistry of saccharides plays a significant role in the metabolic pathways of living organisms, the detection of the presence and concentration of biologically important sugars (glucose, fructose, galactose, etc ) in aqueous solution is necessary in a variety of medicinal and industrial contexts. The recognition of D-glucose is of particular interest, since the breakdown of glucose transport in

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humans has been correlated with certain diseases: renal glycosuria [54,55], cystic fibrosis [41], diabetes [43] and human cancer [56]. The enzymatic detection methods of sugars were used specifically for only a few saccharides and the enzyme based sensors are unstable at harsh conditions. Stable boronic acid-based saccharide receptors offer the possibility of creating saccharide sensors which are selective and sensitive for the chosen saccharide. 3. CHEMOSENSING Chemical sensors are devices that transform chemical information into analytically useful signals. Chemosensors are molecules of abiotic origin that signal the presence of matter or energy [57]. Analyte binding must occur reversibly, and hence, this allows analyte concentration to be measured at equilibrium by optical detection of either the chemosensor-bound species or the analyte-free chemosensor. It also permits continuous measurements to be made with dynamic optical response to changing analyte concentration. An optical chemosensor incorporates a binding site, a chromophore or fluorophore, and a mechanism for communication between the two [58]. Analyte binding thus produces a change in chemosensor optical properties (absorption or fluorescence). The chemosensor binding must be an artificial receptor. Artificial receptors can, in principle, be tailored for various analytes, and their physical properties can be adjusted to meet specific sensor requirements. Many approaches have been used to design artificial receptors capable of selectively binding organic analytes with optical response. The result is a wide range of molecular structures constituting the binding and signal-generating components of chemosensors. A variety of different host-guest interactions have been employed to stabilize the complex and varying degrees of preorganization have been used to enhance analyte selectivity [59]. Boronic acids readily form reversible covalent interactions with saccharides in aqueous media, and these represent an important alternative driving force in the recognition of saccharides and related molecular species. Stable boronic acid based saccharide receptors offer the possibility of creating saccharide sensors which are selective and sensitive for a specific saccharide [6]. This section summarizes the progress in the development of chemosensors for saccharides based on artificial receptors. 3.1. CD receptors Optical activity stemming from chirality is manifested by practically allnatural products such as nucleic acids, sugars, proteins, etc Chiroptical properties are among the most important physical properties for both the food and drug related industries. The induced CD (circular dichroism) properties of molecular complexes with chiral guest species such as saccharides upon chiral induction are important in providing a method to determine the chirality of the guest. This is significant for non-chromophoric host molecules. When two boronic acid units are arranged in a specific orientation, a saccharide may be bound in a 1:1 fashion. The co-operative binding of two boronic acids creates a rigid cyclic complex. The asymmetric immobilization of two chromophoric benzene rings by ring closure can be read out by CD-spectroscopy.

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Bis-(6-methoxyphenyl)methane-3,3'-diboronic acid 1 forms 1:1 complexes with mono-and di-saccharides and gives circular dichroism (CD) spectra specific to each saccharide (Scheme 4) [41,43,56]. Based on 'H NMR spectroscopy, the complex with D-glucose is a macrocyclic compound formed by the reaction of the two boronic acids with cis 1,2-diol and trans-4-OH,5-CH2OH moieties. The association constants were in the following order: D-glucose (19000 dm3mol"') » D-talose > D-galactose > D-mannose > D-fructose (= 0 dm3mor') for monosaccharides and D-maltose (100 dm3mol"') > D-cellobiose > D-lactose > D-sacchrose (= 0 dm mol" ) for disaccharides. The absolute configuration of saccharides can be conveniently predicted from the sign and strength of the CD spectra of their complex with compound 1. OCH

OCH,

A HO

A OH

HO

OH

Scheme 4. Formation of a 1:1 saccharide:diboronic acid 1 CD active complex

OCH3

OCH

For the development of new receptor molecules that can recognize sugar molecules, the biphenyl-3,3'-diboronic acid 2 was synthesized. The distance between the two boronic acids is designed so it can selectively form cyclic 1:1 complexes with disaccharides [45,56]. It forms 1:1 complexes with several disaccharides and gives the characteristic exciton coupling in CD spectroscopy owing to immobilization of the two phenyl rings. Thus, the absolute configuration was successfully predicted from the sign of the exciton coupling. On the other hand, the association constants for disaccharides were much less than those for the complex of monosaccharides and 1.

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CPK models revealed that the distance between the two boronic acids in 2 is shorter than the distance between the head and tail hydroxyl groups of disaccharides; therefore, the CD activity was much weaker and inadequate for the estimation of association constants. B(OH)2

(HO)2B.

Another class of artificial receptors that respond to sugar substrates with two binding sites was reported. The molecular sensor trans-3,3'-stilbenediboronic acid 3 gave enhanced fluorescence upon disaccharide complexation whereas no response was found for monosaccharides [60]. The fluorescence increase was attributed to the formation of a cyclic complex of diboronic acid with the disaccharide and subsequent freezing of ethylenic bond rotation in the excited state (Scheme 5). Existence of such a cyclic complex was supported by the CD activity of the complex under the same condition used for fluorescence measurements.

Scheme 5. Formation of a dissacharide:trans-3,3'-stilbenediboronic acid CD active complex

B-OH i OH OH

OH OH V 7

OH OH -4H?O

On the other hand, diboronic acid 4 gave better complexes with disaccharides since it has a larger spacer between the two boronic acid moieties [61] B(OH)2 (HO)2B.

Helical chiral aggregates are found when aggregates of a non-chiral tetraboronic acid porphyrin 5 are treated with monosaccharides [62]. CD spectroscopy can monitor the induced chirality of the aggregates. In addition, the sign of the exciton

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coupling of the sugar complexed aggregate can be predicted by the structural orientation of the complex. The chromophoric boronic acid derivative 6 was also found to aggregate in mixed solvents (H^OiDMF) [63,64]. When glucose was added to the aggregate, the aggregate was CD active. The aggregative properties of other di- and tetra-boronic acid porphyrins system have been also investigated [65,66]. Inspite of the usefulness of CD spectroscopic measurements for the detection and identification of optically pure saccharides, this method is only appropriate for these compounds only. B(OH)2

(HO)2B

3.2. Fluorescent receptors 3.2.1. PET receptors Photoinduced electron transfer (PET) has been widely used as a tool in the design of fluorescent sensors for saccharides. PET sensors generally consist of a fluorophore and a receptor linked by a short spacer. The changes in redox potential of the receptor upon guest binding can alter the PET process and generate changes in the fluorescence. The fluorescent sensors based on the boronate ester complex between carbohydrate and boronic acid receptor typically display signals through changes in the fluorescence intensity either through chelation-enhanced quenching (CHEQ) or chelation-enhanced fluorescence. Yoon and Czarnik reported the first fluorescence photoinduced electron transfer (PET) sensors for saccharides. The anthryboronic acid 7 and 8 showed significant fluorescence intensity changes upon binding with saccharide. The intensity change was lower for glucose than fructose, i.e. (/ (in the presence of saccharide)//« (in the absence of saccharides) = ca. 0.6) [8]. Upon ester formation, the boron functionality exists in the anionic tetrahedral because of a decreased pKa (about 4.6 and 6.8 for the fructose and glucose esters, respectively) [37]. This hybridization change abolishes the excited state PET and therefore removes the fluorescence quenching mechanism, which consequently causes increased fluorescence. Later studies have also shown that 5-indolylboronic acid 9 undergoes fluorescence quenching upon complexation with oligosaccharides [67]. The stability

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constants of monosaccharides were similar to the inherent selectivity of phenylboronic acid [Id]. On the other hand, the response to oligosaccharides was generally lower than predicted on the basis, although higher oligomers proved to be better at quenching fluorescence because of a secondary interaction with the indole N(HO)2B B(OH)2

Until now, facile boronic acid saccharide complexation occurs at the high pH required to create a boronate anion. Therefore, molecular fluorescence sensors that contain a boronic acid group and an amine group were developed. In addition to the fact that boronic acids with a neighboring amine will bind strongly with sugars at neutral pH, the fluorescence intensity is controlled by the amine. With no sugar, the free amine reduces the intensity of the fluorescence, and this is the "off state of the fluorescent sensor. When sugar is added, the amine becomes 'bound' to the boron centre. The boron bound amine cannot quench the fluorescence and hence a strong fluorescence is observed. This is the 'on' state of the fluorescent sensor. This is the concept of an 'off-on' fluorescent sensor for sugars. The first of these fluorescent PET 'off-on' saccharide sensors was prepared in 1994 [50]. The saccharide probe utilizes a benzylic amine appended to an anthracene in the form of a sensor 10. This probe could provide fluorescence detection (420 nm) at pH conditions as low as 6.4. In addition, the photoinduced electron transfer, normally a quenching response with boronic acids has been reversed to become a chelation enhanced fluorescence response due to an interaction between amine lone pairs and boron (Scheme 6). As with other monoboronic acid probes, this sensor displayed the greatest fluorescence enhancement with fructose. (HO)2B

10

Scheme 6. Illustration of an anthracene-based photoinduced electron transfer system.

Boronic acid weakly fluorescent

Boronic ester strongly fluorescent

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The simple 'off-on' PET system was improved with the help of molecular modeling by the introduction of a second boronic acid group [68,4]. Compound 11 has two appropriately spaced boronic acid and is particularly selective and sensitive for glucose due to the formation of intramolecular moieties 1:1 complex between the two boronic acids and the 1,2- and 4,6-hydroxyls of glucose (Scheme 7). It shows a maximum fluorescence intensity change of about 7-fold upon binding with glucose (i.e. the binding constant of 11 with glucose is 3980 M"1 in aqueous methanol buffer at pH 7.8, while it shows much weaker binding for fructose (Keq = 316 M~ )). This indicates that the spacing and orientation of the two boronic acid moieties are complementary to that of two diol pairs on glucose. Norrild and coworkers [39] found that 11 initially binds with the pyranose form of D-glucose and then slowly converts to the thermodynamically more stable furanose form. Addition of water facilitates this process since faster mutarotation of glucose occurs in water than in methanol.

N

B(OH) 2

Scheme 7. The effect of saccharide complexation and pH changes on the fluorescence of the diboronic acid 11

( HO fluoresenct

) fluoresenct

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In 1995, asymmetric fluorescent platforms were introduced in the form of (R)and (S)-l,l'-binaphthyl (binap) ligands. Chiral recognition of saccharides by 12 utilizes both steric and electronic factors. It gave an enhanced fluorescent signal (358 nm) in the presence of sugars by a combination of twist angle effects and a reduction in the quenching efficiency of the amino lone pairs. At pH 7.7, the PET quenching of (R)-12 was affected more strongly by D-fructose, D-glucose and L-galactose; the least by L-fructose, L-glucose, and D-galactose. The opposite trend in fluorescence response was found in the case of (S)-12 [69]. More investigations into the effects of positional isomers provided additional insight into the electron transfer process. Eight aromatic boronic acids have been screened and it was determined that 13 and 14 were more suitable candidates for saccharide detection [40].

,B(OH)2 ,B(OH)2

13

14

A novel phenanthroline diboronic acid PET sensor 15 has been designed and could detect a range of saccharides at neutral pH in aqueous media. Due to large spacing of the boronic acid groups, this PET sensor looses selectivity and sensitivity. It was dubbed as a "sweet toothed" sensor since it only forms 2:1 saccharide to sensor complexes. This system may be useful for the detection of saccharides in concentrated solutions, such as those encountered in the brewery and confectionary industries [70].

15 Bifunctional receptor components were introduced onto an anthracene fluorescent platform in the form of a crown ether/boronic acid combination. The novel allosteric diboronic acid 16 has been prepared where the formation of metal crown sandwich causes the release of bound saccharide. This system mimics the action of the Na+/D-glucose cotransport protein in nature. D-glucose binds in the 'cleft' of 16 as

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a 1:1 complex in the presence of 0.03 mol dm"3 sodium and released from the 'cleft' at the same concentration for potassium [71].

16

Efforts to develop a three-dimensional fluorescent chemosensor yielded a novel calixarene diboronic acid 17. This "sugar bowl" can detect saccharides at neutral pH in aqueous media; the binding events are sensitively monitored by changes in the fluorescence intensity. It displayed an optimal enhanced fluorescence emission for fructose at 337 nm. The presence of a 1:1 binding complex with monosaccharides was confirmed by mass spectral data [72]

17

In continuing efforts to design glucose sensors, a series of potential glucose sensors that use an appropriate spacer to link two fluorescent boronic acid moieties were developed. Among them, compound 18 with a hexamethylene spacer between the two phenylboronic acid moieties has high selectivity for D-glucose (Keq = 1995 M"1), whereas it binds to glucose in a 1:2 ratio [73]. The rigidification imposed on a bis-pyrene system that is separated by a hexamethylene spacer competes with the hydrophobic effect that typically forces these two fluorophores to form excimers. The decrease in excimer emission (475 nm) occurs in a cooperative manner to increase monomer fluorescence at 376 nm. Given the spacer length and bis-boronic acid geometry, a preference for glucose was observed with the sensor. As a reference probe, a similar monoboronic/monopyrene

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system was synthesized 19 and the anticipated monomer emission was the only fluorescence signal observed.

N

B(OH)2

19

18

A dendritic saccharide "sponge" 20 displayed high sensitivity to galactose and fructose at 423 nm in methanol. The complexity of the system and the large number of the binding sites prevented from assigning the binding mode as either 1:1 boronic acid:sugar or 2:1 boronic acids:sugar. The sensitivity of this system observed with galactose was attributed to the apparent flexibility of this system relative to preorganized clefts [74].

B(OH) 2

20

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The selectivity of the diboronic acid cleft towards saccharides can be modified in a controlled manner by the correct spacing of two boronic acid units. The small binding pocket of compound 21 can exclude 'large' saccharides such as D-glucose, whereas 'small' saccharides such as D-sorbitol are strongly bound as 1:1 complexes; the binding event can be sensitively monitored by changes in the fluorescence intensity. This approach offers the possibility of monitoring the concentrations of biologically important saccharides which are less important than D-glucose in a variety of industrial and medicinal applications [75]. The bifunctional chemosensory designs were used as new and selective receptors for targeting fluorescence detection of important biological molecules such as glucosamine. A fluorescent photoinduced electron transfer sensor 22 with monoaza-18-crown-6-ether and boronic acid receptor units shows selective fluorescent enhancement with D-glucosamine hydrochloride in aqueous solution at pH 7.18. The monoaza-18-crown-6-ether binds the ammonium terminal of Dglucosamine hydrochloride, while a boronic acid serves as a binding site for the diol (carbohydrate) part of D-glucosamine hydrochloride. The nitrogen of the azacrown ether unit can participate in PET with the anthracene fluorophore; ammonium ion binding can then cause fluorescence recovery. This recovery is due to hydrogen bonding from the ammonium ion to the nitrogen of the azacrown ether. The strength of this hydrogen bonding modulates the PET from the amine to the anthracene [76].

B(OH)2

21 22

In sensor 23, a boronic acid binding site and biphenyl fluorophore were used to create a fluorescent PET sensor for saccharides in aqueous solution at pH 7.77. The large HOMO-LUMO gap for the biphenyl system was chosen to investigate the B-N interaction which is required to suppress PET from nitrogen to fluorophore. The fluorescence results imply that a cyclic boronate ester formed with a furanose-(l,2)diol results in strong B-N interaction (high fluorescence recovery) and the cyclic boronate ester formed with a pyranose-(l,2)-diol results in a weak B-N interaction (low fluorescence recovery). Therefore, monoboronic acids bind preferentially with saccharides in the furanose form [77]. In another study, a chemosensing system for the selective recognition of fructose based on a reverse photoinduced electron transfer process was developed. The fluorescent boronic acid, m-dansylaminophenylboronic acid 24 reacts with

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fructose to produce an electron transfer, which results in the fluorescence quenching of the dye. The sensor proved to be directly applicable in the fructose concentration determination of jam, fruit juice and shole biscuit giving values quite similar to enzymatic test kits [78]. B(OH)2

VJ 24 (DAPA) binding a sugar

23

For the development of efficient glucose sensors, these sensors must be biocompatible. This means that these sensors must have water solubility, low toxicity, high chemical and photochemical stability, and long excitation and emission wavelengths. Most fluorescence sensors contain fluorophores that are hydrophobic polyarene molecules that limit their water solubility. The application of such hydrophobic sensors in biological systems could be severely hindered by this low water solubility problem as well as other issues. New designs in water soluble saccharide sensors appeared in 1999 with the use of naphthalic carboximide fluorophore which serves to lower the working pH of the sensor to near physiological conditions. The new water-soluble saccharide receptor 25 represented the first receptor design to feature a Co spacer. The extensive fluorescence quenching observed upon saccharide complexation was attributed to the Co design which is sensitive to conformational changes. This sensor exhibited the highest selectivity towards fructose followed by galactose and glucose [9]

25

The longest wavelength fluorescence signal reported for a carbohydrate probe was found in the squaraine derived sensor 26. The so called "red to near IR" signaling displayed a 25% increase in fluorescence enhancement with fructose in ethanol/aqueous solution buffered at pH 10. This probe exhibited 1:2 squaraine /fructose selectivity [79]. In another study, a new twist was introduced with the development of a novel 'on-off PET system 27 which behaves contrastingly to the conventional 'off-on' PET system [80]. In this system steric crowding on saccharide binding breaks the B-N bond found in the 'free' receptor.

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B(OH)2

26 27

New cleft designs were considered in 2001. With the use of computer aided design, a glucopyranose sensor 28 was developed. This fluorescent probe was designed to form cyclic boronates between the a-1,2 and 4,6-hydroxy groups of the pyranose form of glucose. In agreement with computational predictions, this probe displayed the largest binding affinity for glucose. Compared to previously reported glucose probes, 28 exhibited a 400-fold greater affinity relative to other sugars [12]. On the otherhand, boron-dipyrronmethane dyes (BODIPY™) present several advantages as fluorescent probes. They possess high extinction coefficients, high emission quantum yield and narrow emission bands. In addition, their building block synthesis allows for the development of many different analogues with emission ranges from 500 to 700 nm. For example, probe 29 that has a very narrow emission band at 510 nm displayed an enhanced fluorescence response in the presence of fructose [81]. B(OH)2 B(OH)2

28

29

The two pyrene groups in compound 18 cause complications in emission fluorescence spectra due to stacking of the two pyrene units. Therefore, the unsymmetrical modular and modular polymer supported fluorescence photoinduced electron transfer (PET) sensors 30 and 31 with two boronic acid receptor units, a pyren-1-yl fluorophore, and the hexamethylene linker show selective saccharide binding in aqueous methanolic solution at pH 8.21. Compound 30 showed higher

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selectivity for glucose (Keq = 962 M") whereas the polymeric compound 31 showed higher selectivity for fructose (Keq = 1124 M"1) [82].

CH 2 -CH ) ' J x

(CH2-CH2] \COO CHONH2/V

31

Inclusion complexes previously studied as hydrophobic effects between cyclodextrins and pyrene were aptly transformed into a fluorescence saccharide sensing system. Tong et al. demonstrated that a boronic acid fluorophore complex 32 binds sugars and produces increased fluorescence emission in water. The fluorescence quantum yield is greatly enhanced by forming an inclusion complex of sugar-/?-CyD. A pH-fluorescence profile for the complex reveals that the fluorescence intensity increases upon formation of the boronate conjugate base (pKa = 7.95). The fluorescence emission response of the complex upon sugar binding appears to be due to suppression of the photoinduced electron transfer (PET) from a pyrene donor to a trigonal arylboronic acid receptor. The 1:1 binding constants of the complex decrease in the order: D-fructose » L-arabinose > D-galactose > D-glucose, which is consistent with the known binding selectivity of phenylboronic acid [83]. In order to promote charge-transfer excited states that display dual fluorescence, a monoboronic acid fluorescent sensor 33 has been synthesized from 3nitrophthalic anhydride and 3-aminophenylboronic acid. This novel saccharide probe exhibits dual emission suitable for ratiometric sensing and displays a remarkable sensitivity for glucose relative to fructose and galactose [84]. B(OH) 2

H2)4OB(OH) 2

O O,N 33

32

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Recently, a D-glucose selective competition assay has been devised using Alizarin Red S (ARS) and diboronic acid 34 in buffered aqueous solution. Sensor 34 was designed without any fluorescent signaling unit, so that ARS would serve as the only reporter. In this chemosensing ensemble, the ARS remains fluorescent at 464 nm so long as boronic acid is bound to its aromatic diol functionality. Upon addition of glucose, the sugar competes for the boronic acids of 34 in a 1:1 complex and a concomitant decrease of ARS fluorescence occurs [85]. In another study, several boronic acids were screened for their ability to bind to diols and the binding was determined by a competition assay using ARS as an indicator. 3-Methoxycarbonyl-5-nitrophenyl boronic acid 35 bound to both a catechol dye as well as fructose with a comparable affinity to that of an ort/zo-methylamino substituted boronic acid. Therefore, there is a great role for appropriately functionalized electron deficient boronic acids in diol and carbohydrate recognition [86]. B(OH)2

MeOOC

NO2 35

34

Phytophysical effects of positional isomers involving phenylboronic acid were investigated with the use of sensors 36 and 37. The incorporation of the boronic acid group in the meta or ortho position does not lead to significant spectroscopic and phytophysical changes in comparison with the unsubstitute TV-phenyl analogue. Both derivatives show larger decreases of their fluorescence emission at high pH while no effect of the pH was observed on the fluorescence lifetime. This suggests the presence of a static quenching resulting from the formation of the anionic form of the boronic acid group. Both compounds show important decrease of their fluorescence intensity in the presence of sugar. A significant increase of the fluorescence lifetime was observed for the ortho derivative in the presence of sugar while relatively small effect was obtained for the meta derivative. The increase of the fluorescence seems to be correlated to a steric hindrance effect. Important change in the phase angle and modulation in the presence of sugar show the potential of the ortho derivative for its use as a sugar probe for fluorescence lifetime-based sensing [87]. (HO)2B O

36

B(OH)2

37

In a continuing research for an optical glucose sensor, it was found that the combination of pyranine and a boronic acid 4,4'-iV,jV-bis(benzyl-2-boronic acid)bipyridinium dibromide (o-BBV) results in a sensor 38 that signals monosaccharides in the range of 0-1800 mg/dL. The quenching ability of o-BBV is modulated upon

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sugar binding, which in turn alters the fluorescence of pyranine. The system utilizes a dye that is active in the visible spectrum, operates in aqueous solution at pH 7.4, and is highly sensitive to glucose in the physiological range [88]. e B(OH)2

(HO)2B'

Further studies showed the development of a fluorescent resonance energy transfer (FRET) saccharide sensor 39 with two different fluorophores, phenanthrene as the donor and pyrene as the acceptor. Titration experiments with monosaccharides indicated that energy transfer for the phenanthrene donor to pyrene acceptor in a rigid 1:1 cyclic glucose complex is more efficient than in a flexible 2:1 acyclic fructose complex. The more efficient energy transfer leads to an enhanced fluorescence response to D-glucose [89]. B(OH)2

(HO)2BX

Five modular photoinduced electron-transfer (PET) sensors 40a-e bearing two phenyl-boronic receptors, a hexamethylene linker and different fluorophores have been prepared. Fluorescence spectroscopy was used to assess the sensor's interaction with saccharides. Results have shown that monosaccharide selectivity and sensitivity displayed by fluorescent sensors is fluorophore dependent. As well as considering solubility, minimizing the steric repulsions from peri-hydrogens not only increases the relative stability but can be used to fine tune sensitivity toward specific saccharides

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Further developments with fluorescent chemosensors continued with the development of novel boronic acid-substituted 4,7-phenanthrolinium viologens 41 that have the ability to quench the fluorescence of 8-hydroxypyrene-l,3,6-trisulfonic acid trisodium salt (pyranine). The quenching is suppressed in aqueous buffer solution at pH 7.4 upon binding to saccharides. A spectroscopic study reveals a ground-state complexation between the viologens and pyranine. In the presence of monosaccharides, the complex dissociates, resulting in the relative increase in fluorescence. This sensor shows a great fluorescence quenching as well as sensitivity to and an unusual selectivity for glucose [91]. More studies showed that a number of water soluble, fluorescent boronic acids could be used as building blocks for the design of selective glucose sensors in the future [37]. 8-Qinoline boronic acid (8-QBA) 42 that has good water solubility and chemical and photochemical stability, responds to the binding of a carbohydrate with over 40-fold increases in fluorescence intensity. This sensor is nonfluorescent at pH above 5 and weakly flurescent at lower pH in aqueous solution. Upon addition of fructose, the fluorescence intensity increases significantly to provide a simple "off-on" probe. It appears to signal in the presence of saccharides with a mechanism other than PET since the boron atom in this sensor exists primarily in a tetrahedral geometry and no B-N interaction can be readily formed with the quinoline nitrogen. A phytophysical change that occurs with 8-QBA wherein the non-emissive n7r* state is perturbed and gives rise to an emissive iun* excited state was attributed to this large fluorescence enhancement [92].

B(OH)2

e

(HO)2B

41 Recently, the development of new glucose-sensing polymerized crystalline colloidal array (PCCA), which utilizes phenylboronic acids as the glucose recognition element has been reported. This phenylboronic acid PCCA could sense glucose due to the decrease in the boronic acid pKa upon glucose binding. The glucose binding induced the formation of boronate anions, which resulted in a Donnan potential that in give rise to an osmotic pressure and in turn swelled the PCCA and red-shift the diffraction. Unfortunately, this glucose-sensing material does not operate at the high ionic strengths of bodily fluids [93]. Later, a more sophisticated boronic acid complextation motif designed for glucose sensing at physiological salinities has been described. This colorimetric glucose recognition material consists of a crystalline colloidal array embedded within a polyacrylamide-poly(ethylene glycol) (PEG) hydrogel, or a polyacrylamide-15crown-5-hydrogel, with pendent phenylboronic acid groups. In this new molecular recognition motif in which boronic acid and PEG (or crown ether) functional groups are propositioned in a photonic crystal hydrogel, the glucose self assembles these functional groups into a supramolecular complex, Fig. 1. The formation of the complex is associated with an increase in the hydrogel cross-linking, which blueshifts the photonic crystal diffraction. The visually evident diffraction color shifts

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across the visible spectral region, from red to blue over physiologically important glucose concentration ranges. These materials respond to glucose at physiological ionic strengths and are selective in their mode of response for glucose over galactose, mannose and fructose. This motif shows promise for the fabrication and noninvasive in vivo glucose sensing for patients with diabetes mellitus [94]

Fig. 1. Bis-bidentate complex formation between glucose (in Furanose form) and two boronates stabilized by PEG-Na + complex [94].

The anthracene-based fluorescent boronic acid system 10 developed by Shinkai group has been widely used for the preparation of fluorescent sensors of carbohydrates. Such application is based on significant fluorescence intensity increase of this system upon binding with a carbohydrate. The mechanism through which this fluorescence intensity change happens was originally proposed to go through a B-N bond formation mechanism, which masks the nitrogen lone pairs. However, new fluorescence studies suggest a possible alternative mechanism for the fluorescence change upon the formation of the boronic acid 10 complex with diols. In this new proposed mechanism, complex formation induces solvolysis, which results in the protonation of the amine nitrogen if the reactions are carried out in a protic solvent such as water. This protonation prevents the photoinduced electron transfer, resulting in a reduced quenching of the anthracene fluorescence [95]. As already known, carbohydrate chemosensors consist of three parts: fluorophore, spacer and receptor. Since fluorescent probes without spacers are fewer in number, Gao et al. synthesized a series of monoboronic acid fluorescent sensors with Co spacers on the basis of N-phenyl naphthalimide fluorophore 43. These carbohydrate sensors exhibit interesting photochemical and photophysical properties that provided useful insight into the relatively limited area of Co design chemosensors. Sensor 43a displays features typical of PET monoboronic acid sensors and shows high selectivity to fructose. Sensor 43b exhibits a novel dual emission and remarkable sensitivity for glucose relative to fructose and galactose through subtle changes in pH. Sensor 43c displays significantly enhanced fluorescence in the presence of galactose at low pH. Probes 43d-f gave poor signal response upon titration with

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monosaccharides; however, their substituent effects lend support to the chelationenhanced quenching model proposed for these systems [96].

a: b: c: d: e: f:

R-, = H, R2 = H, R 3 = H R-i = H, R 2 = H, R3 = NO2 R ^ H , R2=H, R3=NH2 R-, = H, R2 = H, R3 = CH 3 CONH 2 R., = H, R2 = OCH 2 , R3 = H R., = SO 3 K, R2 = NH 2 , R3 = SO3K

D-Glucarate is a biologically active carbohydrate that exists in human serum, vegetables, and fruits. It has been used as a chemopreventive agent in certain cancers. A new fluorescent sensor 44 with a recognition unit consisting of boronic acid moiety and a guanidinium unit shows selective binding of D-glucarate in aqueous solution. Formation of a salt-bridge between the carboxylic acids of glucarate and a guanidinium recognition unit from the sensor were key design elements in sensor 44. The diols of the carbohydrates were addressed with a benzylic amine derived boronic acid. This strategy allowed for the suppression of the PET phenomena which give rise to fluorescence enhancement upon glucarate complexation. The receptor can discriminate well between D-glucarate and other structurally similar carbohydrates and the binding event results in significant fluorescence changes [97]. (HO)2E5

44

3.2.2. Non-PET sensors (ICTsystems) The internal charge transfer (ICT) mechanism has been employed in a number of fluorescent boronic acid glucose sensing compounds. An ICT system contains an electron donor group and an electron acceptor group in the same fluorophore. In its neutral form, the boronic acid acts as an electron acceptor. When the boronic acid is in its anionic form upon binding with a sugar, it is no longer an electron acceptor. This in turn leads to the spectral changes due to the perturbation of the charge transfer nature of the excited state [98].

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The search for higher quantum yields from the fluorescensing reporter group yielded amino coumarine boronic acid dyes as potential saccharide probe components. This is an example of the first internal charge transfer (ICT) chromophore 45 [99] as an approach toward longer wavelength signals. Here, both the fluorescence intensity and wavelength is affected since the nitrogen is directly connected with the chromophore. However, this system shows only a small shift in intensity and wavelength. In neutral pH, Stokes shift of 100 nm was found for sensor 45. This probe shows the largest xhelation enhancing quenching response to fructose at 452 nm.

45

Molecular rigidification has been used to generate a fluorescence increase with cyanine diboronic-acid 46 on saccharide binding. The rigidification of the cyanine skeleton by macrocyclization and the adjustment of the distance between the two boronic acids to the size of monosaccharides caused an induced saccharidefluorescence increase. The largest association constant K was observed for D-fructose (1.3xl05 M~') and the next for D-arabinose (l.OxlO4 M"1). The increased fluorescence at 579 nm in the presence of sugar is attributed to a reduction in the rotational freedom in the ethylenic double bond [100]. In 1997, a "rigid" diboronic-acid-based saccharide receptor 47 was designed in order to obtain high chiral discrimination ability. Two boronic acid groups were directly connected with a chiral binaphthyl skeleton. Among monosaccharides tested, xylose showed a 8.7-fold difference, the highest chiral discrimination ability achieved so far. Therefore, this high selectivity stems from the rigidified structure of the host molecule (R)-47 [101].

(R)-47

(R)-47-D-glucose complex (assuming the pyranose form immobilization)

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A new bisboronic acid that combines low pKa values and water solubility with a structurally optimized design for selective glucose binding was synthesized. This system works by reducing the quenching ability of the pyridine groups of 48 on saccharide binding. It combines low pK& values and water solubility with a structurally optimized design for selective glucose binding. Binding studies in aqueous solution evidence a strong binding of glucose as the a-D-glucofuranosel,2:3,5-bisboronate complex at physiological pH (Scheme 8). A selective fluorescence response to glucose compared to fructose and galactose is observed which may suggest a similar design for a future sensor of glucose in blood or subcutaneous tissue [5].

48

Scheme 8. Equilibrium between 48 and glucose to give 48.Glu. The equilibrium constant K refers to the measured value. HOHOS .OH -B-OH

HO, OH HO-B-

O o O \=N

V

/

N=

glucose

[48.Glul [48(OH)2]. [glucose] The use of ICT as an effective tool in ratiometric sensing was further elaborated with the synthesis of the fluorescent saccharide sensor 49 that has been prepared from 2-formyl benzeneboronic acid and aniline. When saccharides interact with sensor 49 in aqueous solution at pH 8.21, the emission maxima at 404 nm shifts to 362 nm. It displayed the largest dynamic change in fluorescence at pH 8 in 50:50 methanol water with fructose [10].

49

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In an attempt to extend the usefulness of fluorescent probes for saccharides based on the boronic acid group, DiCeasare et al. investigated the possibility of using excited state charge transfer (CT) between the boronic acid moiety and a donor and/or acceptor groups. The study was conducted on trans-stilbene derivatives 50a-d of phenylboronic acid. The combination of electron withdrawing and/or electron donating group and the boronic acid group both directly linked to a fluorophore could lead to the formation of an excited CT state. The anionic form of the boronic acid acts as an electron donor group and a photoinduced CT state can be formed when an electron withdrawing group is present on the fluorophore. After sugar addition, the emission spectra of DSTBA and MSTBA showed a blue shift and an increase shift whereas a red shift and a decrease in the intensity are observed in the emission spectra of CSTBA. A change from the neutral to the anionic form of the boronic acid group is used to explain these changes (Scheme 9). The emission spectra of DSTBA display a large solvent-polarity dependence showing the formation of a photoinduced charge transfer state (CT). This state is weakly present in MSTBA and not present for CSTBA and STBA in the neutral form of the boronic acid group. The combination of electron donor or withdrawing groups with the boronic acid group is a new and promising way to develop ratiometric fluorescent probes for glucose and other saccharides [102].

/-B(OH)2

OCH

50a (STBA)

50b (MSTBA)

(H 3 C) 2 N-\ 50c (CSTBA)

1

50d(DSTBA)

Scheme 9. Equilibrium and conformation of the different forms of the boronic acid group with and without sugar.

pKa = 5.4-5.9 with fructose

Similarly, long wavelength and ratiometric probes for sugars have been synthesized. They are based on donor-acceptor diphenylbutadiene and

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diphenylhexatriene derivatives involving a boronic acid group 51a,b. The changes of the electron-withdrawing property between the boronic acid group and its anionic form induce useful shifts and intensity changes in the emission spectra of these compounds. Both compounds show high affinity for fructose but it decreases for galactose and glucose respectively [103].

51a (1,4-diphenylbuta-1,3-diene)

51b (1,6-diphenylbuta-1,3, 5-triene)

Continuing research in developing high fluorescent probes resulted in synthesis of sensor 52 that uses diphenyloxazole as reported components. The donoracceptor derivatives of these fluorophores are well known to show high fluorescence quantum yields, long wavelength emission and to be very sensitive to small variations that affect the ICT properties of the excited state. The ICT state of 52 is between the electron withdrawing boronic acid group and the electron donating N,Ndimethylamino group. In the presence of saccharides, the boronic acid group changes to its anionic form, thus giving a blue shift in fluorescence from 557 nm in the uncomplexed form to 488 when complexed to saccharides [104]. More efforts in this field resulted in the preparation of an efficient D-glucose selective internal charge transfer (ICT) fluorescent sensor 53. When D-glucose was added to this sensor in aqueous solution at pH 8.21, the emission maximum at 405 nm shifts to 360 nm [105].

52

53

Advances in ICT based fluorescent probes for saccharides continued with the development of two new chalcone-analogue platforms. The two new fluorescent probes that are based on l,3-diphenylprop-2-en-l-one and on 1,5-diphenylpenta-2,4dien-1-one structures posses one electron-donating dimethylamino group and one electron-withdrawing boronic acid group 54a,b. The change between the neutral and the anionic form of the boronic acid group induced at high pH and/or in presence of sugar induces optical changes for both probes (Scheme 10) [106]. The feasibility of tear glucose sensing using a daily, disposable contact lens embedded with boronic

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acid-containing fluorophores such as compounds 54a,b and 50c as a potential alternative to current invasive glucose-monitoring techniques has been tested. It was found that this approach may indeed, be suitable for the continuous monitoring of tear glucose levels in the range 50-500 //M, which track blood glucose levels that are ~510-fold higher. Both the pH and the polarity within the contact lens need to be considered with respect to choosing/designing and optimizing glucose-sensing probes for contact lenses [107].

,CH3 (HO)2B'

N

(HO)2B'

CH 3

54a

54b

Scheme 10. Ground and excited state electronic distributions involved in the neutral and anionic forms of the boronic acid group for 54a.

A new water-soluble fluorescent on-off saccharide sensor 55 that shows large fluorescence intensity increases upon binding with a diol was conveniently synthesized. An ICT process is responsible for the low fluorescence intensity before addition of a sugar and the removal of an ICT process upon addition of a sugar is the reason of the increased fluorescence of compound 55. This is an on-off system. Binding studies showed that fructose and sorbitol induce a 40-fold fluorescence intensity increase at 50 mM whereas glucose showed a 17-fold increase at 1M. These water soluble boronic acids can be used to make bis- or multiboronic acid sensors to detect glucose and other carbohydrates with high selectivity and specificity [108]. Recently, three boronic acid saccharide sensors 56a-c with an aniline fluorophore have been prepared. 56a contains an intramolecular boron-nitrogen bond (B-N) and displays fluorescence due to both locally excited (LE) and twisted internal charge transfer (TICT). On the other hand, 56b and 56c have no B-N bond and only shows fluorescence due to the LE state [109].

w r\T^ B(OH)2

HO

56a DMANBA 55 4-(Dimethylamino)naphthalene boronic acid

OH

'6H 56b

56c

OH

Chapter 7

419

Fluorescent species that form aggregates do not exhibit fluorescence due to concentration quenching. However, molecular forces that deaggregate such systems can cause an increase in the fluorescence intensity. In 1993, bis-boronic acid was prepared when 3-aminophenylboronic acid was appended to protoporphyrin system [110,111]. The aggregates of porphyrin 57 that forms in DMF:water could be dispersed by the introduction of saccharides into the system. When saccharides form complexes with the boronic acids, they solubilize the porphyrin into the bulk phase leading to a very large fluorescence increase. This fluorescent probe displayed a remarkable 215 nm Stokes shift and the largest fluorescence enhancement to fructose at pH 10.5. Some selectivity in this process has been observed.

(HO)2B" "

B(OH)2

3.3. Colored receptors Boronic acid azo dyes were used in the 1940's for investigations in the treatment of cancer by boron neutron capture therapy (BNCT) [112,113]. However, only in 1991 a boronic acid azo dye has been synthesized from maminophenylboronic acid and was found to be sensitive for a selection of saccharides [114]. In 1994, a molecular internal charge transfer (ICT) sensor 58 was synthesized. The design was based on the intramolecular interaction between the tertiary amine and the boronic acid group. The electron-rich amine creates a basic environment around the electron-deficient boron centre, therefore, inducing the boronic acidsaccharide interaction and reducing the working pH of the sensor. This decrease in the pKa of the boronic acid moiety on saccharide complexation was shown to be transmitted to the neighboring amine. This creates a spectral change in the connected ICT chromophore which can be detected spectrophotometrically. The pK^ related to the boron nitrogen interaction of 58 shifts on the addition of saccharides. The largest pATa shift was found for D-Fructose and the smallest for simple diols as ethylene glycol. The drawbacks of this system are the relatively small shifts in the absorption bands of the chromophore upon saccharide binding [115]. In another study, the addition of saccharides causes changes in the absorption spectra of boronic acid appended spirobenzopyrans 59. The added saccharide changes the color of the system due to the change in the position of the merocyanine (MC) to spyropyran (SP) equilibrium. The SP structure is favored due to a stronger B-N interaction in the saccharide complex [116].

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58

59

A tetraboronic resorcinarene 60 for the visual sensing of saccharides has been prepared. However, for a color change to be observed, the saccharide must be heated at90°CinDMSO[117]. (HO) 2 B

B(OH) 2

OH

HO

B(OH) 2

B(OH) 2

60

Recently, two systems based on boronic acid receptors have been reported. Both systems involve a competitive spectrophotometric assay. The first system is a tris-boronic acid receptor 61 that showed selectivity for glucose-6-phosphate. It was used to determine glucose-6-phosphate concentrations in the micromolar range using 5-carboxyfluorescein as an indicator [11]. The second system is a receptor of tartrate or malate 62. The binding of tartrate or malate is measured through the competitive displacement of alizarin complexone [118].

62 61

It was found that on the addition of monoscacharides in aqueous solutions, the boronic acid color sensor 63 undergoes a large visible color change from purple to red. The color change arise from a change in the environment of the anilinic nitrogen

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Chapter 7

that leads to a change in the energy levels of the n and K* orbitals of the azo chromophore and hence to a change in the absorption energy and wavelength [119]. Another new boronic acid color sensor 64 undergoes visible color change from purple to pink, on the addition of monosaccharides at pH 8.21 [120].

63

Therefore, the use of better chromophores and better receptors will help to develop selective and sensitive color sensors that will have widespread applications in industry. Binding of sugars to nitrophenolboronic compounds 65a,b results in very significant spectroscopic changes in both intensity and wavelength. Manipulation of the pKa values of the boronic acid affect the equilibrium among different chromophoric species (Scheme 11). These compounds can be used as colorimetric reporters functioning as both recognition and a signaling unit for the construction of polyboronic acid spectroscopic sensors for monocarbohydrates and complex carbohydrates, many of which are biomarkers for important biological and pathological results [121]. B(OH) 2

65a

B(OH) 2

65b

Scheme 11. Equilibrium among different species of 65a,b in the presence and absence of D-fructose.

?'

9"

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H. Abu Ali et al.

422

Liquid crystals composed of chiral molecules may possess chiral helical structures in which the length of the pitch determines the color of the liquid crystal. Influence on the pitch by inclusion species can result in visible color changes and the spectral shifts can reflect the absolute structure of such species. The Cholesterylboronic acid 66 complexes of monosaccharides alter the color of a composite chiral cholesteric liquid crystal membrane. The direction of the color change is indicative of the absolute configuration of the monosaccharides. For example, the green color of the uncomplexed composite was changed to red upon introduction of D-glucose and to blue by L-glucose [44,122]. (HO)2B.

66

3.4. Porphyrin-based receptors The combination of metalloporphyrins and boronic acids is very potential for molecular design of novel receptor molecules. Imada et al. showed that 67, a Zn(II) prophyrin bearing an intramolecular boronic acid group is capable of discriminating D-glucose-6-phosphate (G-6-P) from ec-D-glucose-1 -phosphate (G-l-P) through the two point interaction [123]. Therefore, it can selectively bind guest molecules bearing both a diol group and a metal ligand group in an appropriate distance. When the guest is optically active, the resultant complex is turned into a CD active species. It binds glucose-6-phosphate (G-6-P) in a two point interaction, one between the 1,2-diol moiety and the boronic acid moiety and the other between the phosphate moiety and Zn(II) [124]. In addition, a novel porphyrin assembly has been constructed using monoboronic acid pyridine unit 68 and dicatechol porphyrin [125]. Later, Takeuchi et al. reported another example for sugar sensing using a boronic acid-porphyrin selfassembly system. A mixture of boronic-acid-appended Zn (II) porphyrin and 3pyridyylboronic acid self organizes to create a novel diboronic acid system for saccharide (S) recognition [126].

// W ° H \)H

68

67

423

Chapter 7

A highly selective and sensitive "sugar tweezer" can be designed utilizing the self-assembling nature of bis[porphinatoiron(III)] to form the //-oxo dimmer 69 (Scheme 12). This molecule shows high and selective binding with D-glucose and Dgalactose [127,128]. Scheme 12. Saccharide 'tweezer' formed from an iron porphyrin //-oxodimer.

= saccharide

(HO) 2 B'

69

B(OH) 2

Novel dimeric system using cationic pophyrins 70 or 71 have been used with 1,5- or 2,6-anthraquinonedisufonates (ADS) as a competitive system for the fluorescence detection of D-fructose. 1,5- or 2,6-ADS binds with 70 or 71 and quenches the fluorescence; addition of D-fructose causes the decomplexation and fluorescence recovery [129]. Porphyrin 70 has been also used in saccharide controlled intercalation with DNA [130]. With no added saccharides 70 intercalates with DNA but when saccharides are added 70 dissociates from DNA [131]. B(OH)2

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H.AbuAlietal.

Kijima developed a diboronic acid porphyrin system 72 that showed high selectivity for the disaccharide D-lactulose. The special disposition of the two boronic acids in 72 produces the perfect 'cleft' for D-lactulose [132].

72

Other novel porphyrin dimmers using monoboronic acid and saccharides have been developed. These systems show saccharide controllable electron-transfer efficiency [133,134]. 3.5. Metal co-ordinated receptors The bipyridine (bpy) diboronic acid 73 and its iron (II) complex produce CD active saccharide complexes. The asymmetric immobilization of the two pyridine units on saccharide binding produces the CD activity of 73. The copper (II) complex gave a CD band in the region of the metal to ligand charge transfer band. A or A complexes were found depending on the complexed saccharide [135]. Later, the diaza 18-crown-6 diboronic acid 74 was synthesized. The saccharides and the calcium ions interact competitively for the receptor 74 [136].

B(OH)2

73 74 Similar complexes have also been prepared with cobalt (II) and bipyridine (bpy) diboronic acid 73. The A- and A-[Co(bpy)3]3+ saccharide-binding ligands, 2,2'bipyridine-4-boronic acid (bpymb) and 2,2'-bipyridine-4,4'-diboronic acid (bpydb) were synthesized. Most D-saccharides form cyclic 1:1 complexes with bpydb to afford a CD-active species with the two pyridine rings twisted in a clockwise direction ((R)-chirality), while such a CD-active species was not yielded from bpymb. The treatment of the bpydb-D-saccharide complexes with Co(OAc)2 gave the substitution active {[Co(bpybd)3]-saccharide}4" complexes, which were oxidized to the substitution -inactive {[Co(bpybd)3]-saccharide}3~ complexes (Scheme 13). In this stage A vs. A ratio was fixed. The complexes were converted to [Co(bpy)3]3+ and the e.e. was determined by complexation with authentic A- or A-[Co(bpy)3]3+. The Aisomer was obtained in excess from most D-saccharides but the A-isomer was

425

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obtained from D-fructose and D-fucose. Therefore, the saccharide-temptated synthesis is useful as a new concept for the preparation of chiral tris(2,2'-bipyridine)-metal complexes. The A vs. A equilibrium can be shifted in either direction by the selection of saccharide enantiomers [137,138]. Scheme 13. Formation of {[Co(bpybd)3]-saccharide}4" complex.

(HO)2B

bpydb

bpydb-saccharide complex Co(OAc)2

{[Co(bpybd)3]-saccharide}3" complex

{[Co(bpybd)3]-saccharide}

complex

A D-glucouronic acid-selective fluorescent system based on a boronic acid and a metal chelate has been developed. Sensor 75 incorporated a phenanthroline ligand along with phenylboronic acid to give a design that is specific for metal chelation and diol complexation. The addition of Zn(II) in the form of Zn(NC>3)2.6H2O provided a cooperative effect for the carboxylates of several saccharides such as glucuronic, galactouronic and sialie acids. The probe displayed the highest affinity for the glucouronic acid at 375 nm in pH 8.0. The saccharides interact with the receptor at two points to form a cyclic structure 76, thus giving circular dichroism active chiral complex [139]. More investigation [140] indicates that the association for commonly occurring monosaccharides is little affected by Zn(II) addition whereas for uronie acids or sialie acid is enhanced in the presence of Zn(II) owing to the two points interactions.

75

76

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The boronic acid 77 together with saccharides have been used to transcribe chirality into metal complexes [141]. Moreover, the Cu(I) complex of 78 gave different CD spectra reflecting the helicity, which is regulated by the absolute configurational structure of saccharides. Thus, the P versus M helicity of the complex can be controlled by the boronic-acidsaccharide interaction [142,143].

B(OH)2

77 78a: R = H 78b: R = Me

Two chiral salen-Co(II) complexes, (R)-79 and (R)-80 bearing two boronic acid groups were synthesized. Since the distance between the two boronic acid groups is shorter than the other diboronic acid-based receptors, the saccharide selectivity is different from the other systems: the largest association constant was observed for fructose and next for talose. In addition, chiral recognition was achieved for certain saccharides: the largest discrimination was 2.1 observed for (R)-79 with D/L-allose. Therefore salen-metal complexes provide an excellent basic skeleton for designing the chiral sugar sensing system [144].

B-OH HO-B' I OH OH

(R)-79

B-OH

HO-B

OH

OH

(R)-80

Yam and Kai reported a Re1 complex bearing two boronic acids 81a,b which changed electronic absorption characteristics in response to saccharide binding. The pKa of the boronic acid groups was estimated to be 5.9 and large spectral changes for 81-saccharide complexation were observed. They suggested the formation of cyclic 1:1, and noncyclic 1:2 complexes on the basis of mass spectrometric data. The interaction of saccharides and deprotonated amide anions was proposed to occur at pH This work was reexamined by another group. They synthesized compounds 81a,b and extensively studied their saccharide binding properties. The results showed that they have pA"a-values of 8.4-8.9 and that the saccharide-binding mode at pH

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Chapter 7

above the pKd is totally different from that at pH below the pKa. The absorption spectral change which reflects sp2-lo sp1 boron hybridization change induced by the saccharide complexation, was observed only at pH below the pKa, and the CD band, which reflects the formation of 1:1 cyclic complexes, appeared only at pH above the pK&. Therefore, the optimum pH should be carefully selected for the precise optical sensing of saccharides [146]. B-OHHO-B

N-R

R-N

OC-Re—Cl

oc 7 x co old! R — H

81b: R = C 2 H 5

Later, a prochiral salen-Co(II) complex 82 was synthesized and its excitoncoupling-type CD spectra for saccharide binding was compared to the chiral salenCo(II) complexes (R)-79 and (R)-80. The monosaccharides which are selectively bound to (R)-79 and (R)-80 with P helicity generate the P helicity CD spectra in prociral 82. This means that the two boronic acid groups in (R)-79 and (R)-80 are chirally preorganized suitable to the binding of these monosaccharides. 82 show high selectivity for talose which has all OH groups arranged on the same side of the pyranose ring because of the short distance between the two boronic acid groups. Therefore 82 is useful for sugar 'chirality' sensing at visible wavelength region and prediction of D/L selectivity for (R)-79 and (R)-80 [147]. In another study, the fluorescence detection of phosphorylated sugars in water was made possible with a luminescent ruthenium(II) bipyridyl receptor 83. This system provided adjacent binding sites via acidic NH amide groups as phosphate binding sites and phenylboronic acid as saccharide binding components. Fructose-6phosphate in its disodium salt displayed the highest affinity for this probe relative to glucose, galactose or glycerolphosphate analytes. This receptor simultaneously binds saccharide/phosphate with positive cooperativity [148]. HO

B-OH

HO-B

OH

OH 82

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H. Abu Ali et al.

428

Recently, a diaza-18-crown-6-based saccharide receptor 84 bearing two boronic acid receptors has been developed. In 84, boronic acid groups in the side arms interact as Lewis acids with amines and boron atoms are changed to sp3 hybridization through the B... .N interaction. Because of this hybridization, the boronic acid groups can bind saccharides even in a neutral pH region. 84 forms 1:1 cyclic complexes with glucose and allose as confirmed by CD spectroscopy. UV photometric titration studies showed that the boronic acid group and metal cation bound to the crown cavity competitively interact as Lewis acids with crown amines. As a result, the saccharides and metal cations "communicate" with each other in an allosteric manner. Therefore, added metal cations can affect the saccharide binding ability of 84 through the competitive interaction with the crown amines and conformational change of the crown ether ring. This is a novel example for the design of artificial saccharide receptors in which saccharide and metal cation interact with the binding site competitively. Consequently, metal and saccharide binding sites couple in a negative allosteric manner, and metal cations make the saccharide and association constants smaller, Table 1 [149].

84

Table 1. Saccharide association constants in the absence and presence of metal cations a Metal cation none

Kass (D-glucose) (10 4 mor'dm 3 ) 2.65(1.00) b

Kass (D-allose) (10 2 mol"'dm 3 ) 1.95 (1.00) b

Ca2+

1.65(0.62) b

1.48(0.76) b

Sr2+

1.43 (0.54) b

1.07 (0.55) b

2+

b

1.13 (0.58) b

Ba

2.25 (0.85)

[84] = I.OxlO"3 inol dm"3, [metal cation] = 2.0x10"2 inol dm"3 in methanol-water (9:1) containing 0.05 mol dm"3 choline, pH = 8.5, 25 °C; b values in parenthesis are relative values[149].

a

In addition, a diboronic acid-appended chiral ferrocene derivative (R)-85 was designed and synthesized. (R)-85 show D/L selectivity for specific monosaccharides since the chiral ferrocene scaffold was obtained by resolution of the diasteriomer with a monosaccharide derivative. The CD spectral changes (A[0]) induced by added monosacchrides was chiroselective: in particular, D/L-alloses and D/L-galactoses induced the 8.0- and 7.0- differences in the magnitude of the CD spectral change. The association constants for D- and L-saccharides (KD and KL, respectively) were determined, (R)-85 showed a significant discrimination ability for mannose (K L /KD = 2.6) and arabinose (KL/KD = 1/2.4). D/L selectivity was discussed on the basis of computational studies on (R)-85 saccharide complexes [150].

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B(OH)2

B(0H) 2 (R)-85

New promising glucose sensors 86a-c based on boronic acid-appended ferrocenes were synthesized. Their design includes an intramolecular B-N bonding motif in order to facilitate binding at physiological pH. The three sensor molecules form mixtures of glucofuranose complexes; however, determination of detailed structures of the complexes and their stability constants was precluded by the very broad lines observed. The line broadening phenomenon was ascribed to internal equilibria (via B-N bond breaking/formation) between various complexes or between similar structures with inverted nitrogen atoms [151].

86a

86c

3.6. Electrochemical receptors Electrochemical detection of saccharides by enzymatic decomposition of sugars is well known [152]. Boronic acid based electroactive saccharide receptors could provide selectivity for a range of saccharides. Chiral ferroceneboronic acid derivatives (-)-87 and (+)-87 have been synthesized and tested for chiral electrochemical detection of monosaccharides. DFructose, D-mannitol, D-sorbitol, L-sorbitol and L-iditol gave stability constants with (+)-87 and {(-)-87} of 15{14}, 28{27}, 110(70} and 76(120} (mol"1 dm3) respectively at pH 7.0 in 0.1 mol dm3 phosphate buffer solution [153]. Recently, the redox switching of carbohydrate binding with commercial ferrocene boronic acid has been explored. Studies have shown that binding constants of saccharides with the ferrocenium form are about two orders of magnitude greater

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than for the ferrocene form. The increased stability is ascribed to the lower pKd of the ferrocenium (5.8) than ferrocene (10.8) boronic acid [154]. A study showing the efficiency of a boronic acid-substituted 2,2'-bipyridine 88 Fe(II) complex for electrochemically sensing analytes such as a Lewis base, like F-, and D-fructose was demonstrated. The voltammetric behavior of [Fe(II) 88]2+ was investigated in the presence of various sugars at a pH value enabling the conversion of boronic acid groups into OH" adducts, i.e. pH > 6.4 (Scheme 14). The strongest modifications were observed with D-fructose and the selectivity of the complex was in the order: D-fructose » D-glucose, D-galactose > D-mannose > D-xylose [155]. B(OH)2

87

88

Scheme 14: The different eqiulibria involved in the sugar complexation (pH > by [Fe(II) 88]2+ HOX OH HO—Be

HOX OH HO—B0

Ve

(III)

HO HCT

HO

OH ,

HO^

^QH .OH

OH

'OH HO—BQ

OH ^QH

OH

HO—Be

W // ^ Fe (II)

Eo' comp ~^~\ Fe (III)

3.7. Receptors at the air-water interface Molecular assemblies of monolayers and their properties have been well established [156]. The unique characteristics of Langmuir-Blodgett (LB) films have drawn particular attention. The pressure of an LB film sensitively reflects the interaction between its individual constituents on the surface and the guests in the aqueous subphase. m- and p-Hexadecyloxyphenyl boronic acids, 89 and 90 respectively, selectively extract saccharides, the monolayer of 89 at the air-water interface selectively responds to these saccharides, the order of the change in it-A isotherm being similar to that of the extractability. The order of extractability is D-fructose >

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431

D-glucose > D-maltose > D-sacchrose, with the order of extractability rationalized on the basis of the ring-formation mode [42].

B HO' OH

90

The chiral cholesterylboronic acid derivative 66 behaved in a similar manner with selectively recognizing chiral isomers of fructose [158]. Quaternized amines were found to facilitate the saccharide detection by the monolayer at neutral pH. The source of this enhancement is due to the assistance of the ammonium cations in the formation of boronate anion [159]. The amphiphilic diphenylmethane-3,3'-diboronic acids 1 and 91a-c form stable monolayers which selectively bind monosaccharides. The selectivity is determined by the stoichiometry of the complexes at air-water interface and the configuration of the saccharide molecules. The selectivity order expressed as a difference in the collapse pressure between the uncomplexed and complexed boronic acid monolayer is governed by the formation of complexes consisting of two diboronic acid molecules bridged by one sugar molecule. The selectivity can be changed to correlate with the order of association constants of the 1:1 complexes in homogeneous solution by adding polycations to the subphase by diluting the monolayer with amphiphilic quaternized ammonium ions [159,160]. B(OH) 2

B(OH) 2

OR 1: R = methyl 91a: R = 2-octyldodecyl 91b: R = 4-tert-butylbenzene 91c: R = -CH 2 CH=C(CH 3 )CH 2 CH 2 CH=C(CH 3 ) 2 (Geranyl)

3.8. Receptors at the lipid-water interface Molecular recognition at the lipid-water interface is quite essential in various phenomena (for example, reproduction, formation of tissues and organs, immunological protection system) in living bodies [161]. Recognition of sugars on membrane surfaces is very important [162] because sugars are essential constituents in living bodies not only as essential sources and architecture-forming materials but also as participants in many essential biological processes including recognition and response to outer signals. Kitano et al. constructed a three-dimensional molecular recognition system at lipid membrane surfaces by utilizing many functional groups organically. Novel amphiphiles which carry several boronic acid groups in their polar head regions were

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prepared by copolymerization of 3-(acrylamido)phenylboronic acid (APBA) and ((A',Af-dimethylamino)propyl)methacrylamide (DMAPMA) using a lipophilic radical initiator. The amphiphiles obtained 92 (Lipid AD) formed a stable monolayer, and the surface-pressure-molecular area (JI-A) profile of the monolayer was changed by addition of sugars in the subphase. The effect was dependent on the structure of the sugars added, that is consistent with the effect of the sugars on the viscosity of aqueous solution of the copolymer of APBA and DMAPMA. The monolayer of Lipid AD was expanded by a sugar-carrying protein, ovalbumin, and the expansion was inhibited by the addition of low-molecular weight sugars. Similarly, monomeric sugars inhibited the ovalbumin-mediated aggregation of liposomes composed of Lipid AD and dioctadesyldimethylammonium bromide [163]. C18H37

\

C18H37

o

C=N II N-C-(CH2)2-C— (-CH2-CH)—(-ChU-CH)— CH3

1.3

9.6

c=o NH (CH2)3

I

B(OH)2 N(CH3)2

92

3.9. Polymeric receptors Boronic acids appended to the amine residue of poly(lysine) polymers have been used as saccharide receptors. These polymers are converted from neutral sp2 boron to anionic sp3 hybridized boron on saccharide complexation. The resulting anionic polymer interacts with added cyanine dye. Saccharide binding can then be 'read out' by changes in the absorption and the ICD spectra of the cyanine molecule [164-166]. In addition, poly(vinylalcohol) (PVA) polymers containing boronic acids and tertiary amines have been used to prepare membrane coated platinum electrodes. It was shown that glucose responsive swelling produced measurable current changes [167]. In 1999 Wang et al. prepared the first polymerizable chemosensor for carbohydrates. The fluorescent monomer 93 was polymerized using molecular imprinting methods in the presence of fructose. The fluorescence enhancement for the polymer at 446 nm indicated good selectivity for fructose compared with the monomer [7]. CH2OOCC(Me)=CH2

93

Chapter 7

433

3.10. Imprinted receptors The boronic acid ligand was often used to imprint molecular recognition sites in polymers for the specific binding [168,169] and separation [170,171] of sugars. One of the early examples of molecular imprinting was shown by Wulff in 1977, where boronic acid was used as a receptor and sugars as target molecules [172]. In addition, imprinted sites for phenyl ec-D-mannopyranoside were generated in an acrylic acid copolymer [173]. Molecular imprinting of [60]fullerene 94 has been used to create homogeneous chiral selective saccharide receptors. The 2:1 complex of a boronic acid of the l,2-bis(bromomethyl)benzene: sugar was allowed to react with [60]fullerene in a homogeneous solution. The chiroselectivities attained in this method ranged from 44-82% e.e. [174]. The obtained diboronic acid/[60]fullerene receptors showed a good memory for templated sugars (44-48 d.e) [175]. In addition, a novel form of molecular imprinting in polyion complexes has been used to detect AMP using a QCM system. Polyanion polymer 95 containing boronic acid units can sustain AMP by a boronic acid-diol interaction. When this polyanion forms a polyion complex with polycation according to 1:1 anion-cation stoichometry, the phosphate anionic charges introduced into the polyanion by the AMP complexation are also counted. After removal of AMP from the precipitated polyion complex a "cleft" which has the memory for the AMP template is created [176]. This cleft shows high affinity with AMP and the precipitate (gel) shows the reversible swelling-shrinking transformation in response to the AMP binding. When this gel is deposited on a QCM resonator, it responds to a slight change in the AMP concentration [177].

-©-

e COO

e e B(OH)3COO

[60]Fullerene 95

Gao et al. designed and synthesized the fluorescent monomer 93 that allows for the preparation of fluorescent sensors of cis diols using molecular imprinting methods. This monomer has been used for the preparation of imprinted polymers as sensitive fluorescent sensors for D-fructose. The imprinted polymers prepared showed significant fluorescence intensity enhancement upon binding with the template carbohydrate [178]. A D-glucose-selective QCM resonator was designed by a simple imprinting method. A poly(L-lysine) derivative 96 appending 70 mol% of the B(OH)2 group and 30 mol% of the SH group was synthesized. After induction of conformational change by the sugar-boronic acid interaction, the polymeric complex was immobilized on Au surface, and this keeps a memory for the templated sugar. When D-glucose is used as a template sugar, the polypeptide backbone tends to adopt a unique /?-turn structure [179].

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B(OH) 2

The specific recognition sites for /?-D(+)-glucose, D(+)-galactose, and fS-D()fructose were imprinted in an acrylamide-acrylamidephenylboronic acid copolymer membrane associated with an ion-sensitive field-effect transistor (ISFET) device. Selective sensing of the respective monosaccharides is accomplished in the presence of the imprinted membrane-functionalized ISFET devices [180]. In 2003, Deore et al. developed a new approach for the electrosynthesis of saccharide-imprinted poly (aniline boronic acid). The saccharide-aminophenylboronic acid complex was formed in the presence of fluoride to allow the electropolymerization of a self-doped, molecularly imprinted polyaniline. The formation of the anionic monomer complex enables electrochemical polymerization at near neutral pH (5-7) ensuring the incorporation of saccharide in the resulting, self doped polymer. Films were imprinted with D-fructose where saccharideaminophenylboronic acid complexation occurred in the presence of one equivalent of fluoride. The selectivity of D-fructose over D-glucose showed an increase of over 25% as a result of imprinting [181]. 4. TRANSPORT Over the last thirty-five years, a large number of artificial carriers have been developed for membrane transport [182]. Most have been ionophores that are selective for cations [183,184]; however, more recently there has been increased emphasis on carriers for anions and neutral hydrophilic solutes [185]. There are a variety of potential applications for such carriers including small and large scale separations, electrode sensing, drug delivery and controlled-releases technology [182]. Boronic acids have been known to form covalent complexes with a range of bidentate compounds [la,d]. This reversible interaction has enabled them to facilitate the transport of reducing monosaccharides [186], ribonucleosides [14,187], aryl glycosides [188], catechol amines [189], a-amino acids [190] and riboflavin [191]. The transport can be either passive (down a solute concentration gradient) or active (against a solute concentration gradient). In the transport experiments, either bulk liquid membranes (BLMs) or supported-liquid membranes (SLMs) were used. BLMs consist of a source and receiving phase separated by an immiscible membrane phase. In most cases, the source and receiving phase are aqueous and the membrane organic, but the reverse configuration can also be used [192]. The thickness of the diffusion layer / is of the order of magnitude of the Nernst layer [193], which is dependent on the experimental conditions, but is typically in the order of 50-500 //m. The ease of operation, low cost,

Chapter 7

435

and the less stringent requirement for the carriers to be highly lipophilic [194] are the main advantages of BLMs. However, the need for large amounts of carrier, the relatively low transport fluxes and the poor reproducibility are its disadvantages. Therefore, BLMs are not practical on the industrial scale. On the contrary, SLMs are used. These have essentially the same configuration as BLMs, but now the organic phase is contained in the pores of a macroporus (pore size 0.1-1.0 //m) polymer sheet, of which the thickness is in the range of 10-100 ftm. For practical applications, the SLM-concept has been developed into practical hollow fiber modules [195]. The SLMs require low quantities of carrier and are more industrially relevant than BLMs [34]. 4.1. Membrane transport of sugars using boronic acid carriers As mentioned in the introduction, boronic acids readily condense with diolcontaining compounds to form trigonal boronate esters in anhydrous aprotic solvents, while in aqueous solution, the trigonal boronates are unstable and either hydrolyze back to starting compounds or ionize to form anionic tetrahedral boronates. Although covalent bonds are formed, the associated activation energy is low, so the process is rapid and reversible. In this context, boronic acids can be employed as membrane transport agents. Lipophilic boronic acids are known to promote the transport of hydrophilic monosaccharides, such as fructose and glucose, across bilayer and liquid organic membranes [11,12,196-198]. Depending on conditions, transport proceeds via one of two related pathways. First, the 'trigonal' mechanism by which a trigonal boronate ester facilitates transport and this is the most relevant to physiological applications. Second, the 'tetrahedral' mechanism in which the added stability of the tetrahedral boronates [37] as well as their ability to ion-pair with lipophilic cations makes the sugar fluxes greater (scheme 15). This mechanism dominates when the pH of the departure phase is greater than the pKa of the boronic acid (pKa of the phenylboronic acid is 8.8) [15]. Since the tetrahedral boronate is anionic, a lipophilic tetraalkylammonium cation (Q+) is included in the membrane so that the transported species is a membrane-soluble ionpair. In addition, a hydroxide is also transported with the sugar, so a pH gradient can be used to derive the sugar into the receiving phase. Since the formation of the boronate ester is rapid and reversible, it is their passage across the aqueous/organic interfaces, as well as through the membrane, that are thought to be the main ratelimiting steps in the sugar transport process [199]. In 1986, Shinbo and coworkers demonstrated that the combination of phenylboronic acid (PBA) with trimethyloctylammonium (TOMA) chloride could facilitate the passage of mononsaccharides through a lipophilic liquid membrane. Transport was pH sensitive, in that active saccharide transport could be achieved from a basic departure phase into an acidic receiving phase (scheme 15: bottom) [186]. Later studies [187,188] showed that aryl glycosides could be transported by this ion-pair process. Under low extraction conditions, the order of transport enhancement reflected the known order of boronic acid affinities for cyclic diols which is cis-a,/?-diol > cis- «,y-diol > trans-a,y-diol » trans-a,/?-diol. Thus, the order of transport enhancements for glucopyransosides was galactoside> mannoside >glucoside> xyloside, and for monosaccharides, fructose~mannose> galactose> glucose [186].

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Scheme 15. Top: Trigonal boronate transport mechanism, Bottom: tetrahedral boronate transport mechanism.

(sugarj) HO

OH

,OH Ar—B. 'OH

(sugar) HO

v°

2H,0

X

2H 2 O

BX

A/ Aqueous departure phase

OH

OH

organic membrane

Aqueous receiving phase

OH sugar ) HO'

7

X"

+ OH

0H

\>H

+ 2H 2 O

'HO

\ / Ar

Aqueous departure phase

A

Q+

X" +

"

OH

2H 2 O

OH

organic membrane

Aqueous receiving phase

In this series, however, the order of sugar selectivity is more difficult to rationalize because reducing sugars are known to isomerize in the presence of boronic acids making the identity of the sugar/boronate complex less certain [188b]. It was shown, that phenylboronic acid A and 3-(l-admantylcarboxamido) phenylboronic acid 97 can mediate selective glycoside transport (galactoside) through a liquid organic membrane by forming a reversible triagonal boronate ester with a glycoside diol. The apparent order of diol selectivity for the trigonal boronate transport pathway was observed to be cis-a,y-diol > cis-ec,/?-diol ~ trans-«,y-diol » trans-«,/i-diol, which differs from the selectivity of the tetrahedral boronate pathway. Extraction of a glycoside as its trigonal boronate ester and its subsequent transport through an organic layer is maximal when the aqueous phase is at neutral pH and is enhanced by increasing the lipophilicity of the boronic acid [188b].

97

Chapter 7

437

The ion-pair transport mechanism has been extended in an alternative direction. It was reasoned that another way of producing a lipophilic cation to ion-pair with the diol-boronate anion would be to complex a metal cation inside a lipophilic ionophore. The first attempt using a PBA-[2.2.2]cryptand admixture produced a modest transport enhancement of glucoside transport [188a]. The design was improved by covalently linking the boronic acid and the ionophore together (Scheme 16). An arylboronic acid and benzo-15-crown-5 were fixed together in a preorganized cleft arrangement to give 98. Compound 98 was found to act as a functionally biomimetic sodium-saccharide co-transporter. A liquid membrane containing 1 mm of 98 transported an aryl glucoside five times faster than the background rate, however, 98 was less than half as effective as glucoside transport as PBA-TOMA reflecting among other things the inherent difficulty for a heterotopic receptor like 98 to simultaneously bind and cotransport two different solutes (Scheme 16). Carrier 98 represents the first artificial sodium-saccharide cotransported to mimic, at least functionally, the way nature uses the ubiquitous inward indirect Na+ gradient to actively transport sugars into cells [188a,d]. Scheme 16. Simultaneous binding of Na+ and aryl glycosides by a carrier.

The transport of D-sucrose, D-glucose, and D-fructose, promoted by PBA and an ammonium salt, through a bulk dichloroethane membrane was investigated [13]. It was found that there is a preference for boronic acids to transport D-fructose, and the presence of the highly lipophilic ammonium salt is required to achieve high fluxes, as well as a pH gradient, which serves to prevent build up of sugars in the membrane. In addition, an important finding was that the results of non-competitive extraction experiments were not be used to predict the outcome of competitive transport experiments. Several studies were performed to determine the boronate ester structures formed within the membrane and their relative stabilities. Using labeled D-[ C] frustose, D-glucose and I3C NMR spectroscopy, the structures of the major tetrahedral p-polylboronates formed with D-fructose and D-glucose have been identified. The most stable of these structures are shown in Scheme 17. In both its pyranose and furanose forms, D-fructose contains several cis-l,2-diols and convergent triols, and hence readily forms the stable boronate complexes 100 and 101 [39,200]. Recently, it was confirmed by using alizarin red S (ARS) to determine aqueous polyol association constants, that out of a group of ten common monosaccharides, D-fructose forms the most stable boronate ester with PBA (Kass 560

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H.AbuAlietal.

M~' at pH 8.5). The qualitative order of transport of three main natural sweeteners is in the order: fructose >glucose » sucrose and this matches the order of PBA binding strength in water [37]. Scheme 17. The equilibrium distribution of the cyclic isomers of D-fructose and Dglucose in an aqueous solution, and their most stable arylboronates in alkaline media (Ar = p-tolyl). Ar

HOS

- .nu

ArB(OH) 2

OH

OH

D-fructose

100

g

101

LV0H

Ar

'

" D-glucose

;6?OH

^%

fi

b62%

102

Recently, Supported liquid membranes (SLM) were made in the pertraction of fructose from a mixture of sugars contained in a fermentation broth. Specifically, a hollow filter supported liquid membrane (HFSLM) using boronic acid 103 as a carrier was able to extract fructose selectively from a fermentation broth. Simulation results showed that the HFSLM coupled to a bioreactor is capable of decreasing microorganism inhibition by fructose accumulation in the medium and increase the system performance, although further improvement in membrane stability and fluxes are still necessary [201]. B(OH) 2

fV(CH 2 ) 8 -O

o

4-[8-2-nitrophenoxy)acetoxycarbonyl] benzeneboronic acid 103.

In their development of boronic acid-based D-glucose sensors, Shinkai and coworkers demonstrated that the incorporation of more than one boronic acid in a sugar receptor could lead to improved binding constant for the desired analyte [52]. In addition, fluxes with the diboronic acid carriers are slightly lower than those observed with monoboronic acids; however, fructose selectivity can be improved slightly by using appropriately designed diboronic acids that are capable of forming macrocyclic complexes [12]. The o-Phenylene linked diboronic acid 104 in combination with Aliquat 336 (mainly trioctylmethylammonium chloride), gave a D-fructose/D-glucose transport

439

Chapter 7

selectively of 6.2:1.0. On the otherhand, the monoboronic acid reference 105 was found to have a selectivity of only 4.5:1.0. Molecular modeling results suggest that 104 is able to bind /?-D-fructopyranose to form the 1:1 macrocyclic diester. The formation of such macrocyclic esters with 104 could enhance D-fructose flux by significantly reducing the sugar's hydrophobic surface area. This should lead to improved extraction into the membrane and promote the smooth passage of the Dfructose boronate through the hydrophobic membrane medium. Later, diboronic acid 106, which was designed with the aid of molecular modeling to be a better binder for /?-D-fmctopyranose than 104, was prepared and its sugar transport properties were tested. This new diboronic acid did promote improved D-fructose fluxes relative to 104, it also induced significant D-glucose transport such that the D-fructose/Dglucose selectivity was quite poor [202]. It is likely that the structural features of diboronic acids that encourage the formation of macrocyclic /?-D-fructopyranose esters with D-fructose are only slightly different to those that promote the formation of macrocyclic a-D-glucofuranose diesters with D-glucose. Therefore, although this approach is likely to lead to higher D-fructose fluxes, it is unlikely to lead to very high D-fructose/D-glucose selectivity. (HO)2B B(OH)2 MeO

y B(OH) 2

(HO)2BX

( /

^OMe

X //

B(OH)2

106

105

The leaching of the carriers out of the membrane was one of the most concerns in this issue. Therefore, to solve this problem, more lipophilic membrane-bound boronic acids were prepared. Cholesterol was attached to an arylboronic acid 107 to give a compound that is more lipophilic than the free boronic acid. This compound did not leach from the membrane but the results with the sugar fluxes and selectivity were not promising [11,13,203]. It is thought that cholesterol self-assembles at the membrane-aqueous phase interfaces, and thus, inhibits transport. This interpretation appears reasonable, given that 107 displays liquid crystalline characteristics [44]. B(OH)2

107

Following this approach, a series of lipophilic boronic acids were constructed [11,203]. The mono- and diboronic acids 108 and 109 were highly lipophilic with an overall tetrahedral shape, and hence, they had good sugar transport properties. On the otherhand, the triboronic acid 110 was insoluble in the membrane and could not be used in transport. Compound 109 showed high preference for D-fructose. Molecular

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H. Abu Ali et al.

modeling experiments showed that 109 forms two intramolecular hydrogen bonds with intratomic distances of less than 1.2 A. In addition, 13C experiment using I3C labeled D-fructose showed that under conditions similar to those present in SLMs, this tetrahedral-shaped diboronic acid has a strong preference to bind D-fructose as the 2,3,6-/?-D-fructofuranose ester 111 [203]. B(OH)2

(OH)2B

B(OH)2

(OH)2B

110

Recently, the diboronic acids 112 and 113 were prepared to examine their sugar transport properties. With preference for D-fructose transport, both compounds show similar D-fructose fluxes, however, the ether linked diboronic acid 113 displayed a D-fructose/D-glucose selectivity that was less than half of that shown by the ester-linked diboronic acid 112. Presumably the extra stability of the ether linkages, and the larger angle and distance between the boronic acids in 113 makes its D-fructose esters less stable than those formed in 112 [204].

441

Chapter 7 (OH)2B

B(OH)2

B(OH)2

(OH)2B

112

113

The results obtained so far suggest that carriers bearing more than two boronic acids projected in an appropriate way from the same side of a relatively rigid scaffold will have higher fructose selectivities and fluxes. Some compounds such as 100 favor the binding of D-fmctose as 2,3,6-/?-D-fmctofuranose esters, and therefore will result in the transport of multiple fructose molecules through the membrane by a single carrier. In addition, intramolecular hydrogen bonding between the 2,3,6-/?-Dfructofuranose esters can occur, and this would further minimize the hydrophilic surface area of the fructose boronate and thus minimize aggregation within the hydrophobic membrane and keep diffusion constants high. A family of five cavitand rim-appended boronic acids 114-118 was prepared. These conformotionally rigid compounds were not observed to leach out of lipophilic membranes, and they exhibit unprecedented fructose to glucose transport selectivities and give higher fluxes than other neutral boronic acids. The A,C-diboronic acids 116 exhibits the highest fructose to glucose selectivity reported thus far (10.6:1). The triboronic acid promotes remarkably high fluxes of both fructose and glucose: although the selectivity for fructose is not as high as other carriers, flux rates for 117 are almost four times higher than the neutral monoboronic acids. The tetraboronic acid 118 exhibits fluxes lower than those of the triboronic acid 117. This behavior of 118 relates to the physical properties of this compound and may indicate a limitation to the multi-boronic acid approach to better fructose transporters [197].

H11C5 114: 115: 116: 117: 118:

A=B(OH) 2 , B, C, D = H A,B = B(OH)2, C, D =H A,C = B(OH)2; B, D = H A, B, C = B(OH)2, D = H A, B, C, D = B(OH) 2

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4.2. Transport selectivity for D-glucose Researchers have reported that although the binding constant for fructose is about 50 times that of glucose [37], the selectivity of monoboronic acids for Dfructose is only about 4:1. Strong glucose binding can be achieved upon Dglucopyranose being isomerized to D-glucofuranose [13], but since the rate of this isomerization is at least as fast as the rate for D-glucopyranose mutarotation, which is extremely rapid at pH > 9 [205], it is unlikely that this can be rate-limiting for Dglucose transport from high pH departure phases. In addition, the need to form 2:1 diboronates with D-glucose before the extraction makes the transport more problematic for D-glucose transport. The formation of such diboronates would have entropic disadvantages and their greater molecular weight should lead to diffusion rates that are lower than those of the tridentate monoboronates, which are formed with D-fructose. One explanation [206] for the promoted D-glucose transport by boronic acids is that D-glucose is being transported through the membrane by a competing, boronic acid independent 'mobile fixed site relay' mechanism [207]. In this process, the sugar is extracted into the membrane by hydrogen bonding to membrane- bound anions, and then diffuses through the membrane by a series of 'hops', Fig. 2 [208]. Aliquat 336 was used as the ammonium salt in the SLMs that contain the boronic acid. It promotes D-glucose transport through NPOE at rates that are largely unaffected upon addition of a monoboronic acid. The relay process does not distinguish between different monosaccharides, and so has the effect of lowering the D-fructose/D-glucose selectivity. This effect on stability is likely to be pronounced when the boronic acid promoted D-fructose flux is low, which is typical when monoboronic acids is used.

sugar

1 OH

OH

Receiving phase

Departure phase Organic membrane

Fig. 2. 'Mobile fixed site relay' mechanism in which lipophilic salts assist the passage of sugars through a lipophilic organic membrane

Another explanation for D-glucose transport is the fact that the D-glucose transport should be enhanced when boronic acid carriers that bind D-glucose strongly are used. Studies with the diboronic acid 1 showed that this compound bind Dglucose preferentially [52] as the macrocyclic a-D-glucofuranose diester 119 [39] and that the D-glucose transport promoted by 1 is enhanced relative to monoboronic acids. Therefore, molecular modeling performed for the analogous boronate 120 [34], suggest that it may have similar stability. Therefore, the lower D-fructose selectivities shown by 115, 117, and 118, all of which have adjacent boronic acids, results from stronger D-glucose binding.

443

Chapter 7

(OH)2B

B(OH)2

H-MC,

CH,0

119

120

4.3. Further insights into boronic acid-promoted transport of monosaccharides through lipophilic membranes. The rate limiting steps in the transport of monosaccharides through a lipophilic membrane from an alkaline aqueous medium into a separate, lower pH aqueous medium by the transient formation of the tetrahedral boronate-ammonium ion pairs include: (a) Covalent binding of boronic acids to sugars at the aqueous/organic interface; (b) Association of sugar boronates with the lipophilic cation; (c) Diffusion through the organic membrane; or (d) Hydrolysis of sugar boronates at the receiving interface. Most of the attempts in research have been focused on improving D-fructose flux and selectivity by achieving a more favorable outcome in process (a). With respect to process (b), higher D-fructose fluxes are obtained when the departure phase is higher than the pK3 of the boronic acid carrier rather than the pKa of the saccharide boronate ester [37]. Hence, this implies that there is a significant kinetic advantage in having the boronic acid ionized within the membrane. Such an advantage could be entropic in nature and may result from pre-association of the ammonium cation with the boronate carrier before sugar binding. This proposal is supported by a study done later that the conjugated monoboronic acid-quaternary ammonium carrier 121 facilitates fructose transport about 20 times better than an analogous monoboronic acid/quaternary ammonium mixture [12]. Studies [209] with similar boronic acid/ammonium conjugate showed that 122 promoted enhanced rates of glycosidic extraction into organic media. B(OH) 2

e

B(OH) 2

Br N(C 8 H 1 7 ) 3 ®

N(C 8 H 1 7 ) 3 '0

e

Br

121

122

Process (c) is thought to be one of the main rate-limiting steps in the transport process. In order to investigate this step extensively, a procedure for the measurement of diffusion constants for supramolecular complexes, namely, pulsed-gradient spin echo (PGSE) NMR spectroscopy has been used [210,211]. Initial results suggest [212] that increasing the size of the boronate carrier will have a detrimental effect on sugar boronate diffusion constant, and hence SLMs fluxes, but a similar effect any not be observed when the size of the ammonium ion is increased.

444

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When a pH gradient is used, the last process (d) is not rate limiting because boronate esters are much less stable at lower pH [37,196,13]. 4.4. Chemical and physical factors that control transport rate Studies by Smith et al. [188c] found that transport was dependent on the extraction ability of the boronic acid carrier. An extraction constant, Kcx, was calculated using the following expression: G + (aq)

B , (org)

GB (org)

where: G = uncomplexed glycoside B = uncomplexed boronic acid C = glycoside-boronic complex A plot of Transport rate verses log Kex exhibited an approximate bell-shaped curve with maximal transport occurring when the carrier had an extraction constant, Kex(max) ~2.2. The most likely, that this bell-shaped relationship can be explained by a diffusion-controlled process. This diffusion controlled model assumes rapid kinetics for the carrier complexation and a rate determining step which is diffusion of the solutes through the unstirred layer of the three-phase system [183]. Transport flux through the unstirred layers is in turn determined by the carrier extraction equilibrium constant KeX. The observed bell-shaped correlation is rationalized in the following way [2]. Transport is a multistep process involving extraction of the solute from the departure phase, movement of the carrier/solute complex through the organic layer, and subsequent stripping of the complex into the receiving phase. Under conditions of weak extraction, transport is slow due to the low amounts of solute moving from the departure phase into the organic layer. Under conditions of high extraction, it is the low solute concentrations moving from the organic layer into the receiving phase that is the rate determining step. Being the critical variable determining the transport rate in the diffusion-controlled process [183], analysis of the factors that control transport can be reduced to an analysis of the factors that change K«x relative to Kex(maX) Although the diffusion-controlled mechanism has only been proven in the case of glycopyranoside transport, it is likely that other boronic acid transport systems are also diffusion controlled. In addition, according to Fick's first law, transport flux is proportional to the rate of diffusion through the stagnant layers associated with the membrane [183,213]. Thus attempts to fme-tune the design of membrane transport carriers to produce high fluxes must consider the structural factors that govern the rates of carrier diffusion. In this context, a recent study [214] showed that the design of boronic acid carriers (123127) can be fine-tuned to produce higher transport fluxes. Larger boronate carriers may reduce the problem of carrier leaching from the membrane, but they also lead to slower transport fluxes, Table 2. Similarly, Q+/boronate ion-pairing and ion-pair aggregation will also lead to slower membrane fluxes. Therefore, ion-pairing effects within a liquid organic membrane should always be considered when developing carrier-mediated transport system.

Chapter 7

445

V Me 123

124

0 0 + HO-BN(C8H17)4

Me 127

Table 2. Molecular weights (Da) and diffusion coefficients, D (l