Retrosynthetic analysis and synthesis of natural products 1: synthetic methods and applications 9781119663324, 1119663326

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Retrosynthetic Analysis and Synthesis of Natural Products 1

Series Editor Max Malacria

Retrosynthetic Analysis and Synthesis of Natural Products 1 Synthetic Methods and Applications

Olivier Piva

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address: ISTE Ltd 27-37 St George’s Road London SW19 4EU UK

John Wiley & Sons, Inc. 111 River Street Hoboken, NJ 07030 USA

www.iste.co.uk

www.wiley.com

© ISTE Ltd 2019 The rights of Olivier Piva to be identified as the author of this work have been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. Library of Congress Control Number: 2019943838 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-349-3

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi

Chapter 1. Total Synthesis: Some Elements to Contemplate . . . . . . . . .

1

1.1. Total synthesis – why and for what purpose? . 1.2. The different approaches . . . . . . . . . . . . 1.3. Efficiency, selectivity . . . . . . . . . . . . . . 1.4. The essential reactions . . . . . . . . . . . . . 1.5. Towards a sustainable total synthesis . . . . . 1.6. What about tomorrow? . . . . . . . . . . . . . 1.7. References . . . . . . . . . . . . . . . . . . . .

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Chapter 2. Squamostolide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

2.1. Structure, isolation and properties . . . . . . . . . . . . . . 2.2. Bond disconnections. . . . . . . . . . . . . . . . . . . . . . 2.3. Approach according to M.J. Wu . . . . . . . . . . . . . . . 2.3.1. Bond disconnections . . . . . . . . . . . . . . . . . . . 2.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Key reaction: Claisen–Ireland rearrangement . . . . . 2.3.4. Key reaction: functionalization of true alkynes . . . . 2.3.5. Supporting synthetic transformations . . . . . . . . . . 2.4. Approach according to K.J. Quinn . . . . . . . . . . . . . . 2.4.1. Bond disconnections . . . . . . . . . . . . . . . . . . . 2.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3. Key reaction: alkene metathesis and tandem processes 2.4.4. Supporting synthetic transformations . . . . . . . . . . 2.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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21 21 23 23 24 27 29 31 33 33 34 37 43 44

vi

Retrosynthetic Analysis and Synthesis of Natural Products 1

Chapter 3. Rubrenolide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . . . . . 3.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Approach according to H. Fujioka . . . . . . . . . . . . . . . . . . . . . 3.3.1. Disconnection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Synthesis, developed by the Fujioka group . . . . . . . . . . . . . . 3.3.3. Key reaction: iodoetherification . . . . . . . . . . . . . . . . . . . . 3.3.4. Key reaction: oxidation of aldehydes to carboxylic acids . . . . . . 3.3.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . 3.4. Approach according to B. Zwanenburg . . . . . . . . . . . . . . . . . . 3.4.1. Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Synthesis, Zwanenburg’s approach . . . . . . . . . . . . . . . . . . 3.4.3. Key reaction: Wolff rearrangement . . . . . . . . . . . . . . . . . . 3.4.4. Key reaction: dehydration of alcohols according to Grieco . . . . . 3.4.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . 3.5. Approach according to N. Kommu . . . . . . . . . . . . . . . . . . . . . 3.5.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3. Key reaction: diastereoselective alkylation of oxazolidinones . . . 3.5.4. Key reaction: enantioselective reduction of ketones – CBS method 3.5.5. Key reaction: alkyne formation according to Ohira–Bestmann . . . 3.5.6. Supporting synthetic transformations . . . . . . . . . . . . . . . . . 3.6. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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51 52 53 53 54 56 57 58 59 59 60 62 63 64 65 65 66 68 71 73 74 75

Chapter 4. Bipinnatin J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

4.1. Structure, isolation and properties . . . . . . . . . . . . . . . . 4.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Approach according to D. Trauner (racemic synthesis) . . . . 4.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Key reaction: ene reaction between alkynes and alkenes . 4.3.3. Key reaction: Stille coupling . . . . . . . . . . . . . . . . . 4.3.4. Key reaction: Nozaki–Hiyama–Kishi reaction . . . . . . . 4.3.5. Supporting synthetic transformations . . . . . . . . . . . . 4.4. Approach according to V.H. Rawal . . . . . . . . . . . . . . . 4.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Key reaction: Negishi coupling . . . . . . . . . . . . . . . 4.4.3. Supporting synthetic transformations . . . . . . . . . . . . 4.5. Enantioselective approach according to G. Pattenden . . . . . 4.5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2. Supporting synthetic transformations . . . . . . . . . . . . 4.6. Approach according to D. Trauner – enantioselective version . 4.6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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51

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81 82 83 83 86 88 90 93 94 94 97 98 99 99 102 102 102

Contents

vii

4.6.2. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . . 4.7. Comparison of the four syntheses . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

105 106 107

Chapter 5. Tubingensin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111

5.1. Structure, isolation and properties . . . . . . . . . . . . . . . . 5.2. Bond disconnections. . . . . . . . . . . . . . . . . . . . . . . . 5.3. Approach according to N.K. Garg . . . . . . . . . . . . . . . . 5.3.1. Bond disconnections . . . . . . . . . . . . . . . . . . . . . 5.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3. Key reaction: Sonogashira reaction . . . . . . . . . . . . . 5.3.4. Key reaction: Suzuki coupling . . . . . . . . . . . . . . . . 5.3.5. Key reaction: cycloaddition [2+2] of arynes . . . . . . . . 5.3.6. Key reaction: radical cyclization and Baldwin’s rules . . . 5.3.7. Key reaction: enantioselective hydrogenation of ketones . 5.3.8. Supporting synthetic transformations . . . . . . . . . . . . 5.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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111 112 113 113 114 116 118 120 122 122 124 125

Chapter 6. Polygonatine A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

127

6.1. Structure, isolation and properties . . . . . . . . . . . 6.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . 6.3. Synthesis according to S.M. Allin . . . . . . . . . . . 6.3.1. Disconnection . . . . . . . . . . . . . . . . . . . . 6.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . 6.3.3. Key reaction: radical cyclization of selenoesters . 6.3.4. Supporting synthetic transformations . . . . . . . 6.4. Synthesis by J.P. Michael . . . . . . . . . . . . . . . . 6.4.1. Disconnections . . . . . . . . . . . . . . . . . . . 6.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . 6.4.3. Key reaction: Vilsmeier–Haack–Arnold reaction 6.4.4. Supporting synthetic transformations . . . . . . . 6.5. References . . . . . . . . . . . . . . . . . . . . . . . .

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143

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Chapter 7. (+)-Intricatetraol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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127 127 128 128 129 130 133 133 133 134 135 137 139

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7.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . 7.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Approach according to Morimoto . . . . . . . . . . . . . . . . . 7.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2. Key reaction: epoxidation according to Katsuki–Sharpless . 7.3.3. Key reaction: asymmetric epoxidation according to Shi. . . 7.3.4. Supporting synthetic transformations . . . . . . . . . . . . . 7.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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viii

Retrosynthetic Analysis and Synthesis of Natural Products 1

Chapter 8. Enigmazole A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Approach according to T. Molinski . . . . . . . . . . . . . . . . . . . . . . . 8.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3.3. Key reaction: 1,2-enantioselective addition of dialkylzinc to aldehydes . 8.3.4. Key reaction: reduction of β-aldols to 1,3-diols . . . . . . . . . . . . . . 8.3.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . 8.4. Approach according to A. Fürstner. . . . . . . . . . . . . . . . . . . . . . . . 8.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4.3. Key reaction: diastereoselective alkylation according to Myers . . . . . 8.4.4. Key reaction: Yne-yne ring-closing metathesis (RCAM) . . . . . . . . . 8.4.5. Key reaction: sigmatropic rearrangement [3,3] of propargyl esters . . . 8.4.6. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . 8.5. Approach according to A.B. Smith III . . . . . . . . . . . . . . . . . . . . . . 8.5.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5.3. Key reaction: dithiane, umpolung and relayed reactions . . . . . . . . . 8.5.4. Key reaction: Petasis–Ferrier rearrangement . . . . . . . . . . . . . . . . 8.5.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . 8.6. Approach according to H. Fuwa . . . . . . . . . . . . . . . . . . . . . . . . . 8.6.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6.3. Key reaction: Tishchenko–Evans reaction . . . . . . . . . . . . . . . . . 8.6.4. Key reaction: Meyer–Schuster and Rupe rearrangement . . . . . . . . . 8.6.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . 8.7. Comparative assessment of the different syntheses . . . . . . . . . . . . . . . 8.8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

159

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159 160 160 160 161 166 168 169 172 172 173 177 179 180 181 183 183 183 189 191 191 194 194 195 199 201 203 205 206

Chapter 9. Biyouyanagin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

213

9.1. Structure, isolation and properties . . . . . . . . . . 9.2. Synthesis according to K.C. Nicolaou . . . . . . . . 9.2.1. Disconnections . . . . . . . . . . . . . . . . . . 9.2.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . 9.2.3. Key reaction: 1,4-addition and organocatalysis 9.2.4. Shapiro reaction . . . . . . . . . . . . . . . . . . 9.2.5. Supporting synthetic transformations . . . . . . 9.3. References . . . . . . . . . . . . . . . . . . . . . . .

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Contents

Chapter 10. Elatol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Structure, isolation and properties . . . . . . . . . . . . . . . . 10.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Approach according to B. Stoltz . . . . . . . . . . . . . . . . . 10.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . 10.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3.3. Key reaction: Tsuji–Trost reaction . . . . . . . . . . . . . . 10.3.4. Key reaction: ring-closing metathesis of hindered olefins . 10.3.5. Key reaction: reduction of enones according to Luche . . . 10.3.6. Supporting synthetic diagrams . . . . . . . . . . . . . . . . 10.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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233 234 234 234 235 237 241 242 243 245

Chapter 11. Thiomarinol H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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273

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Chapter 12. Oblongolides A and C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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249 250 250 250 252 254 256 258 258 260 262 264 268 270

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12.1. Structures, isolation and properties . . . . . . . . . . . . 12.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . 12.3. Synthesis of oblongolide A according to Shing . . . . . 12.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . 12.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . 12.3.3. Key reaction: intramolecular Diels–Alder reaction . 12.3.4. Supporting synthetic transformations . . . . . . . . 12.4. Shishido’s approach to oblongolide C . . . . . . . . . . 12.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . 12.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . 12.4.3. Key reaction: intramolecular [3+2] cycloadditions . 12.4.4. Supporting synthetic transformations . . . . . . . . 12.5. References . . . . . . . . . . . . . . . . . . . . . . . . .

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11.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . 11.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3. Approach according to D.G. Hall . . . . . . . . . . . . . . . . . . 11.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3.3. Key reaction: hetero-Diels–Alder enantioselective reaction . 11.3.4. Supporting synthetic transformations . . . . . . . . . . . . . 11.4. Approach according to S. Raghavan . . . . . . . . . . . . . . . . 11.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4.3. Key reaction: Kirmse–Doyle rearrangement . . . . . . . . . 11.4.4. Key reaction: Julia–Lythgoe and Julia–Kocienski reaction . 11.4.5. Supporting synthetic transformations . . . . . . . . . . . . . 11.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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ix

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273 274 275 275 275 278 280 281 281 283 287 288 291

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Retrosynthetic Analysis and Synthesis of Natural Products 1

List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

295

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

301

Preface

Through a dozen molecules isolated from living organisms, the field of total synthesis is presented to the reader by analyzing for each target compound: – its structure and known biological properties; – the retrosynthesis envisaged; – the various syntheses completed, briefly discussed step-by-step and compared with one other. An overview of several key steps is found at the end of each chapter, explaining the mechanisms and describing various applications. Similarly, the set of reactions involved in each synthesis are grouped together in a text box and thus form a compendium of practical methods, mostly referring to the publications referenced in the original articles. Learning about retrosynthesis can certainly be based on the monitoring of laws and general rules, most often gathered in difficult studies. We have chosen to avoid this limitation and instead favor an approach using examples, which we hope is nevertheless pleasant to read and follow. Other examples will follow… Olivier PIVA June 2019

1 Total Synthesis: Some Elements to Contemplate

1.1. Total synthesis – why and for what purpose? Nature is an immeasurable source of rather complex molecules, which have always attracted the curiosity of chemists. Since Friedrich Wöhler prepared urea from ammonium cyanate in 1828, vital force theory has been challenged, allowing the synthesis of organic compounds from the simplest to the most complex, such as spongistatin 1 [HUD 07, HUA 18], and thereby the emergence of organic synthesis. In less than two centuries, this branch of chemistry has reached a certain degree of maturity that has made it possible to prepare a considerable number of the most complex compounds, whose exact structures have been revealed as a result of the concomitant development of purification, analysis or characterization techniques (HPLC and UPLC, 1D and 2D NMR, mass spectrometry, X-ray diffraction, etc.). The isolation and structural determination of natural products is most often guided by the existence of biological properties of interest to human health. In order to confirm or invalidate the proposed structures [NIC 05, MAR 17a] and also to identify the functional groups responsible for, or even essential to, these activities, it is necessary to carry out structure-activity studies. This assumes there are significant quantities of these natural compounds as well as different analogues with regard to their structure or even the spatial arrangement of these same functional groups; it is also one of the roles assigned to chemical synthesis [WIL 07]. Does this mean that organic synthesis becomes a simple tool available to researchers in the life sciences? No, of course not [HOF 13, NIC 18].

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

2

Retrosynthetic Analysis and Synthesis of Natural Products 1 OH AcO

Cl OH

O

O

H

H

O OH

AcO H

O H

HO

O H

O H2N

Urea

O

HO HO NH2

H

O

O O

OMe

OH Spongistatin 1

(F. Wöhler)

1828

Syntheses: D.A. Evans, A.B. Smith III, I. Paterson, Y. Kishi, S. V. Ley

Figure 1.1. Evolution of target complexity in just over 150 years. For a color version of the figures in this chapter, see www.iste.co.uk/piva/analysis1.zip

With increasing ecological awareness, organic synthesis can also indirectly dispose of the required molecules, in order to preserve certain endemic species and their biotopes. To minimize the impact of chemical synthesis on the environment, it is also important to develop new methods and concepts that produce less waste; this is all the more true since those generated using so-called fine chemistry are generally very numerous. This trend is commendable but remains difficult to achieve; the E factor, defined as the ratio of kg of waste per kg of product formed, is between 25 and 100 for the most advanced products (pharmaceuticals), while for base chemicals, this number is closer to 1 [SHE 07, ROS 15]. Industry

Annual tonnage as Factor E products

Number of Annual tonnage as people of waste steps

Petrochemical

106–108 t

0.1

107 t

separation

Heavy chemistry

10 –10 t

6

Pharmaceutical

5

6

10–1000 t

25–> 100

10 t

Table 1.1. Environmental impact factors across chemical industries

Total Synthesis: Some Elements to Contemplate

3

1.2. The different approaches There are two distinct conflicting approaches: the approach developed in the academic world and that recognized in industry. Of course, the effectiveness criterion, which can be correlated to the number of steps and overall performance, remains common to both. For academic syntheses, in addition to these efficiency criteria, there is the primacy of experiment, which is often reflected in publications by the words “first total synthesis of…”. In many cases, to reach the target, teams use methodologies that they have developed themselves. The choice of target may be the result of: – direct application of this method; – interest in the compound’s properties, or its unique and even fascinating structure. Last but not least, training young researchers through research is obviously a factor. A thesis in total synthesis undoubtedly makes it possible to “see” more chemistry and probably to test one’s character by being faced with a challenge at each stage [NIC 11]. The success and effectiveness criteria for the approaches implemented in industry are: cost reduction (in reagents and human resources), a minimum number of operations (for processing and purification), the reduction in associated waste and risks. For complex targets, particularly stereochemistry control can be performed:

those

with

several

stereocenters,

– By hemisynthesis: one of the most well-known cases is that of taxol, a diterpene initially isolated from the bark of Taxus baccata and known for its highly cytotoxic properties. To collect sufficient quantities, Françoise Guéritte and Pierre Potier’s team at the ICSN in Gif-sur-Yvette succeeded in isolating 10-deacetylbaccatin III from yew tree needles, a precursor with the same taxane skeleton; it was possible to regioselectively graft the appropriate side chain onto the hydroxy group at the C-13 position of the taxane skeleton [DEN 88, DAN 96].

4

Retrosynthetic Analysis and Synthesis of Natural Products 1 R1O NHR2

O

HO

OH

O

OH

10

O

Ph O

HO

H OBz OAc

HO

HO

O

13

HO

Taxol (R1 = Ac, R2 = Bz) Taxotere (R1 = H, R2 = tBu-CO)

O

H OBz OAc

10-Deacetylbaccatine III

Figure 1.2. Taxol and Taxotere® from 10-deacetylbaccatin III

– According to a chiron approach: it is a question of benefiting from molecular platforms and carrying out various selective transformations. Stephen Hanessian is one of the researchers who has made the most out of this concept [HAN 12, BRI 17]. In the synthesis of dihydromevinolin, L-glutamic acid was used as a molecular block to prepare the lactone synthon with two stereogenic centers, which after several steps, gives rise to the key precursor of cycloaddition according to Diels–Alder [HAN 87, HAN 90]. O HO

O

R1O O-PG

O

O

O O

H

D1

R2O

H Dihydromevinolin

D3

R2O D2

O

OTBS

O

H D4

CO2H

O OMOM

NH2 CO2H

O

H

H

H

H

O O

H

NO2

+

L-glutamic acid

Figure 1.3. Dihydromevinolin from L-glutamic acid

LEGEND OF FIGURE 1.3.– D1: ring enlargement (Baeyer–Villiger reaction). D2: introduction of the cyclopentanone unit (1,4-addition of a nitronate anion).

Total Synthesis: Some Elements to Contemplate

5

D3: functionalization of the tricyclic lactone. D4: formation of the tricyclic structure (intramolecular Diels–Alder reaction in exo mode). De novo syntheses are generally based on well-established processes but are also an impetus to the discovery of new reactions or catalysts [MEN 16]. In addition to the expected formation of the carbon skeleton and the functional groups present, it is necessary to master the configuration of the stereogenic centers by addressing the 3D aspect. There are a plethora of diastereoselective and enantioselective asymmetric syntheses which make it possible to reach selectivities close to those in biocatalysis (e.g. > 99%). Natural products represent a significant source of inspiration in the genesis of drug candidates. Thanks to structure-activity studies, it is possible to identify sub-units responsible for the expected activity. Eribulin is exemplary in this respect. This anti-cancer molecule, now marketed by Eisai in Japan, has a common fragment with halichondrin B, itself isolated from marine sponges. Its synthesis requires no less than 62 steps and is currently one of the most successful examples of a pharmaceutical synthetic molecule on the market [BAU 16].

Figure 1.4. Marine polyethers for cancer treatment

6

Retrosynthetic Analysis and Synthesis of Natural Products 1

Establishing a retrosynthetic scheme is the first step in the long journey to the synthesis of any target molecule. A convergent synthesis from fragments obtained in parallel pathways is preferred over a linear synthesis, which will take longer to implement and has a lower overall yield. In the event that the proposed scheme fails, a linear synthesis may prove to be ineffective; it will then be necessary to reconsider the overall strategy rather than just that of a fragment. Linear synthesis w% S"1

w%

S"2

w% w%

S"3

S"4

t%

Linear sequence : Yield = (w%)4 x t%

S"5

Convergent synthesis S1

S2

x%

S4 t'% S'1

S'2 y%

S'3

z%

y%

The shortest convergent sequence : S1 -S2 -S4 -> Target : Yield : x% x z% x t% The longest convergent sequence : S'1 -S'2 -S'3 -S4 -> Target : Yield :( y%)2 x z% x t'%

Figure 1.5. Convergent or linear synthesis

Even though very recently some syntheses have been effectively carried out without the involvement of protective groups, this solution is uncommon; the higher the number of functional groups present the truer this statement [YOU 09, SAI 14]. Introduction and deprotection can lead to a significant number of steps, which can however be reduced by simultaneously cutting off some of them in a single process. A very large number of protective groups have been defined [WUT 14]; the most commonly used ones meet the following criteria: – their accessibility (cost); – obtaining the highest possible yields when attaching them; – the possibility of avoiding the creation of new stereogenic centers; – stability under reaction conditions; – their selective and effective deprotection. In order to minimize the number of steps to obtain a given target molecule, performing multiple transformations in the same reactor is highly tempting (Figure 1.6). Such processes avoid dealing with unstable or volatile intermediates; they also avoid one or more time-consuming solvent purifications. A distinction should be made here:

Total Synthesis: Some Elements to Contemplate

7

– sequential reactions for which different reagents are introduced as the starting substrates are transformed and consumed to create a new entity capable of reacting itself. This process is automatically retained since the second reagent involved R2 could itself interact with the substrate S [EPP 15]; – tandem, domino or cascade reactions, which allow a high level of complexity to be reached, by deliberately placing all reagents in the same reactor, will ideally react step-by-step until the target compound is obtained [NIC 06, LU 12, PEL 13a, PEL 13b, HON 15, SZÖ 18]. If competitive reactions were to take place, it would then be possible to modulate the reactivity by altering the physical parameters, such as temperature (heating/cooling) or the possibility of generating excited species (photochemical activation). R1

Classical synthesis In two distinct stages : - Action of reagent R1 - Isolation of Pi - Action of reagent R2

Pi

S R2 Pi

Pf

R1 S

R2 Pi

Pf

R1 + R2 S

Pi

Pf

One-pot sequential approach : R1 reacts at first with S to deliver the intermediate Pi then R2 is added to furnish product Pf One-pot cascade approach : R1 and R2 are introduced simultaneously : R2 doesn't interfere and R1 reacts first. Once formed in situ, Pi reacts with R2 leading to Pf

Figure 1.6. Classic, sequential or cascade synthesis

1.3. Efficiency, selectivity For an author, the synthetic pathway he has conceived and carried out will probably always be preferred. An external examiner has a less subjective view to compare different reaction pathways leading to the same target molecule and measure their effectiveness. The number of steps and overall performance are two important criteria, but they can also be weighted by negatively considering the use of protective groups or changes in the degree of oxidation of specific functional groups [HEN 75, GAI 10]. Thus, the percentage towards the ideality of a synthesis can be expressed in the form:

8

Retrosynthetic Analysis and Synthesis of Natural Products 1

Ideality (%) =

[No. Of constructive reactions] + [No. Of strategic redox processes] [Nr. of total steps]

To obtain. the highest possible percentage, the chemist can and must rely on the extraordinary number of reactions at his disposal, allowing him to control the regio-, diastereo- and enantioselectivity. An ideal synthesis must be possible to carry out a large-scale synthesis, while minimizing the production of by-products (always selectivity) and the quantity of waste. As such, reactions with atomic economy (cycloadditions, condensation (aldolic), isomerizations) are of great help [TRO 91]. In order to reduce the number of steps, cascade reactions will also be an asset to move closer to absolute ideality. To achieve this, the combination of catalytic reactions (organometallic(s), organocatalyzed and/or involving biocatalysis) is essential [XIO 10, WEN 13, VOL 14, BIE 18, IND 18, BAR 19, REE 13]. Benefiting from the symmetry of a substrate, for a more advanced stage, to achieve desymmetrization using a chiral or non-chiral reagent, is also an interesting strategy, often leading to spectacular results [HO 95, ZEN 16, MER 17, YOS 17].

PG N O O

N

N

OH

O PG N

Br Br

Br

KHCO3 AcOEt, r.t. Desymmetrization

O

O

HN HO2C

N O

OH

Actinophyllic acid

Figure 1.7. Desymmetrization and synthesis of actinophyllic acid [YOS 17]

Planning the synthesis of a single target molecule or achieving an intermediate structure that will allow different targets to be synthesized is the challenge of target-oriented synthesis (TOS) rather than a divergent approach (DOS) [LI 18, SZP 10, SER 13]. Figure 1.9 shows the interesting nature of the DOS approach; from diketone I, itself obtained by ozonolysis of a cyclohexenone, it has been possible through the set of post-functionalizations to obtain no less than 11 indole alkaloids, differing by the size of the adjacent rings and the nature of the grafted substituents [XU 15].

Total Synthesis: Some Elements to Contemplate

9

Target oriented synthesis (TOS) : Diversification by parallel synthesis Target 1 Target 2 Target 3 Target n

Divergent oriented synthesis (DOS) : Implication of a common intermediate I Target 1

I

Target 2

Target n

Figure 1.8. Target-oriented or divergent-oriented synthesis

N

O

OH

HO N

N

N

(-)-Mersicarpine O (-)-Scholarisine G

O

N3

N3

O CO2Me H N N

O O NO2 Key intermediate I O

OMe

NO2

(+)-Arboloscine O

Figure 1.9. Route to different indole alkaloids from the same diketone I [XU 15]

1.4. The essential reactions The chemist has an ever-increasing arsenal of methods that allow him to consider multiple transformations accompanied by the control of selectivities (regio-, diastereo- and enantioselectivities). It would be unrealistic to want to create an

10

Retrosynthetic Analysis and Synthesis of Natural Products 1

exhaustive list of them. However, some of them are unavoidable and widely involved in synthesis. Thus, since the late 1970s, pallado-catalyzed C-C coupling reactions (Stille, Suzuki, Heck, Sonogashira or Negishi) have greatly facilitated access to complex targets, requiring only a small quantity of organometallic complexes and always with very high selectivities [BAT 12, WU 10]. Moreover, due to the availability of unsaturated compounds, the metathesis reactions ene-ene, ene-yne, yne-yne and their variants have allowed the formation of very diverse structures, whether cyclic or not, and always highly functionalized. Moreover, extremely mild operational conditions have led to their association with subsequent transformations in sequential processes [GRU 15, COS 10, HAN 15, CHE 18, TUR 19]. Olefinization reactions of carbonyl compounds are also strongly present in the construction of carbon units, obtained via the reactions of Wittig, Wittig–Horner [ROC 18], Peterson [VAN 02], Julia–Kocienski [BLA 02], Tebbe [HAR 07], etc. The same is true for achieving alkynes (Corey–Fuchs or Ohira–Bestmann reaction). In addition to organometallic cycling processes (e.g. RCM), thermal or photochemical cycling reactions [HOF 08, BAC 11, KÄR 16, LIU 17] often remain popular routes to produce cyclic structures, while also allowing relative and absolute control of the created stereogenic centers. Asymmetric synthesis is now essential. Here too, spectacular advances have been made thanks to the development of chiral copulas (Evans’ oxazolidinones [HER 16, HER 13], amides derived from ephedrine [LAR 79, MYE 94], Enders’ hydrazones [JOB 02] and many others) and their involvement in alkylation, addition-1,4 or aldolization reactions. The 1,2-addition is also one of the most important. In this field, reactions using organozinc compounds are very attractive both from a compatibility point of view and in terms of asymmetric induction [KIT 99, NUG 02, TRO 06], chirality amplification or asymmetric autocatalysis [KAG 11, SOA 96, SOA 17]. The reactivity of allyl metals is also a key factor in processes, widely used to access exceptional synthons such as homoallylic alcohols [BRO 87, ROU 85, DEN 03]. Since the 2000s, the chemistry of enamines has been brought back to the forefront and organocatalysis, in the broad sense, is an effective way to form C-C or C-heteroelement bonds [BER 05, GRO 10]. A dual catalysis approach has recently emerged through the combination of these organocatalyzed reactions with other processes, in particular involving metals [AFE 16]. Finally, more recently, C-H activation involving noble metals [JAZ 10, PIN 17] as well as photoredox catalysis has been added to this panel [NAR 11]. Also worth mentioning are all selective reduction or oxidation methods, including:

Total Synthesis: Some Elements to Contemplate

11

– reductions via oxazaborolidines (CBS method) [COR 98]; – enantioselective hydrogenations [MAR 17b]; – the selective oxidation of alcohols to carbonyl derivatives [COR 75, MAN 78, LEY 94, DES 91]; – enantioselective epoxidation processes [HER 15, WAN 97, ZHA 90]; – enantioselective dihydroxylation of alkenes [HER 17, KOL 94]. and all esterification and macrocyclization methods [PAR 13]. The applications of any of the reactions mentioned and their mechanisms will be described in detail in the following chapters but can also be found in various books [KÜR 05].

1.5. Towards a sustainable total synthesis

Preventing the risk of accidents e tim r al- is fo e s R l y on a ti an ollu ntion p ve e pr

Designing degradable products

Promoting atom economy

Avoiding waste

les Favo s rin ch haza g e rd m sy nth ical ous es is

12 Principles of green chemistry

Promoting catalytic processes Minimizing the number of steps

Designing safer products

Achieving less noxious solvents Using renewable feedstocks

Minimizing the energy requirements

Figure 1.10. The 12 principles of green chemistry

12

Retrosynthetic Analysis and Synthesis of Natural Products 1

The 12 principles of green chemistry are now at the heart of the concerns of all chemists [ANA 10, FED 09]. Still, it is not easy to follow them throughout the entire multi-step sequence. However, some of these principles are now well established (involvement of catalysis, development of bioresources into synthons, waste minimization, involvement of flow chemistry, etc.); this development is going strong and will undoubtedly dictate the strategies deployed to achieve future targets [NOY 09]. The combination of chemical and biological processes (biocatalysis) is also an underestimated approach, at least in academic research. 1.6. What about tomorrow? With the invention of artificial intelligence and by integrating thousands of referenced reactions into databases, it is possible by mobilizing powerful computers to obtain retrosynthetic pathways for targets of moderate complexity, with a certain degree of success [SCH 18, MAR 18]. What about the future? If machines replace chemists not only on the bench but also in the design of synthesis pathways, then the discipline would lose a little more of its soul. By relying solely on the relative intelligence of a brain, whose neurons are silicon-based, there is a risk that we will no longer be able to detect fortuitous results, which only experienced or insightful – human – minds can detect. This source of unpredictable discoveries related to serendipity is, however, at the basis of considerable progress in the recent past in many fields, from therapeutic chemistry (penicillin, Viagra, etc.) [MON 14] to the development of new materials (Teflon, post-it®, etc.). In conclusion, total synthesis, like chemistry as a whole, remains a promising field with a societal demand that remains as strong as ever in terms of products and applications. It is up to chemists to make it more efficient, always as elegant and with as little impact on the environment as possible [NOY 05, NOY 18].

1.7. References [AFE 16] AFEWERKI S., CORDOVA A., “Combinations of aminocatalysts and metal catalysts: A powerful cooperative approach in selective organic synthesis”, Chemical Reviews, vol. 116, pp. 13512–13570, 2016. [ANA 10] ANASTAS P., EGHBALI N., “Green chemistry: Principles and practice”, Chemical Society Reviews, vol. 39, pp. 301–312, 2010. [BAC 11] BACH T., HEHN J.P., “Photochemical reactions as key steps in natural product synthesis”, Angewandte Chemie: International Edition, vol. 50, pp. 1000–1045, 2011.

Total Synthesis: Some Elements to Contemplate

13

[BAR 19] BARRETT A.G.M., MA T.-K., MIES T., “Recent developments in polyene cyclizations and their application in natural product synthesis”, Synthesis, vol. 51, pp. 67–82, 2019. [BAT 12] BATES R., Organic Synthesis Using Transition Metals, 2nd ed., John Wiley & Sons, Chichester, 2012. [BAU 16] BAUER A., “Story of eribulin mesylate: Development of the longest drug synthesis”, in CASAR Z. (ed.), Synthesis of Heterocycles in Contemporary Medicinal Chemistry, Springer, pp. 209–270, 2016. [BER 05] BERKESSEL A., GRÖGER H., Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005. [BIE 18] BIEMOLT J., RUIJTER E., “Advances in palladium-catalyzed cascade cyclizations”, Advanced Synthesis & Catalysis, vol. 360, pp. 3821–3871, 2018. [BLA 02] BLAKEMORE P.R., “The modified Julia olefination: Alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds”, Journal of the Chemical Society: Perkin Transactions 1, pp. 2563–2585, 2002. [BRI 17] BRILL Z.G., CONDAKES M.L., TING C.P. et al., “Navigating the chiral pool in the total synthesis of complex terpene natural products”, Chemical Reviews, vol. 117, pp. 11753–11795, 2017. [BRO 87] BROWN H.C., BHAT K.S., RANDAD R.S., “B-Allyldiisopinocampheylborane: A remarkable reagent for the diastereoselective allylboration of α-substituted chiral aldehydes”, The Journal of Organic Chemistry, vol. 52, pp. 319–320, 1987. [CHE 18] CHENG-SANCHEZ I., SARABIA F., “Recent advances in total synthesis via metathesis reactions”, Synthesis, vol. 50, pp. 3749–3786, 2018. [COR 75] COREY E.J., SUGGS J.W., “Pyridinium chlorochromate. An efficient reagent for oxidation of primary and secondary alcohols to carbonyl compounds”, Tetrahedron Letters, vol. 16, pp. 2647–2650, 1975. [COR 98] COREY E.J., HELAL C.J., “Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: A new paradigm for enantioselective catalysis and a powerful new synthetic method”, Angewandte Chemie: International Edition, vol. 37, pp. 1986–2012, 1998. [COS 10] COSSY J., ARSENIYADIS S., MEYER C., Metathesis in Natural Product Synthesis, Wiley-VCH, Weinheim, 2010. [DAN 96] DANISHEFSKY S.J., MASTERS J.J., YOUNG W.B. et al., “Total synthesis of baccatin III and taxol”, Journal of the American Chemical Society, vol. 118, pp. 2843–2859, 1996. [DEN 03] DENMARK S.E., FU J., “Catalytic enantioselective addition of allylic organometallic reagents to aldehydes and ketones”, Chemical Reviews, vol. 103, pp. 2763–2793, 2003.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

[DEN 88] DENIS J.-N., GREENE A.E., GUENARD D. et al., “A highly efficient, practical approach to natural taxol”, Journal of the American Chemical Society, vol. 110, pp. 5917–5919, 1988. [DES 91] DESS D.B., MARTIN J.C., “A useful 12-I-5-triacetoxyperidinane for the selective oxidation of primary and secondary alcohols and a variety of related 12-I-5”, Journal of the American Chemical Society, vol. 113, pp. 7277–7287, 1991. [EPP 15] EPPE G., DIDIER D., MAREK I., “Stereocontrolled formation of several carboncarbon bonds in acyclic systems”, Chemical Reviews, vol. 115, pp. 9175–9206, 2015. [FED 09] FEDERSEL H.-J., “Chemical process research and development in the 21st century: Challenges, strategies, and solutions from a pharmaceutical industry perspective”, Accounts of Chemical Research, vol. 42, pp. 671–680, 2009. [GAI 10] GAICH T., BARAN P.S., “Aiming for the ideal synthesis”, Journal of Organic Chemistry, vol. 75, pp. 4657–4673, 2010. [GRO 10] GRONDAL C., JEANTY M., ENDERS D., “Organocatalytic cascade reactions as a new tool in total synthesis”, Nature Chemistry, vol. 2, pp. 167–178, 2010. [GRU 15] GRUBBS R.H., WENZEL A.G., O’LEARY D.J. et al., Handbook of Metathesis, 2nd ed, vols 1–3, Wiley-VCH, Weinheim, 2015. [HAN 12] HANESSIAN S., “The enterprise of synthesis: From concept to practice”, Journal of Organic Chemistry, vol. 77, pp. 6657–6688, 2012. [HAN 15] HAN J.-C., LI C.-C., “Collective synthesis of natural products by using metathesis cascade reactions”, Synlett, pp. 1289–1304, 2015. [HAN 87] HANESSIAN S., MURRAY P.J., “Stereochemical control of nature’s biosynthetic pathways: A chemical strategy for the synthesis of polypropionate-derived structural units from a single chiral progenitor”, Tetrahedron, vol. 43, pp. 5055–5072, 1987. [HAN 90] HANESSIAN S., ROY P.J., PETRINI M. et al., “Synthetic studies on the mevinic acids using the chiron approach: Total synthesis of (+)-dihydromevinolin”, Journal of Organic Chemistry, vol. 55, pp. 5766–5777, 1990. [HAR 07] HARTLEY R.C., LI J., MAIN C.A. et al., “Titanium carbenoid reagents for converting carbonyl groups into alkenes”, Tetrahedron, vol. 63, pp. 4825–4864, 2007. [HEN 75] HENDRICKSON J.B., “Systematic synthesis design. III. The scope of the problem”, Journal of the American Chemical Society, vol. 75, pp. 5763–5784, 1975. [HER 13] HERAVI M.M., ZADSIRJAN V., “Oxazolidinones as chiral auxiliaries in the asymmetric aldol reactions applied to total synthesis”, Tetrahedron: Asymmetry, vol. 24, pp. 1149–1188, 2013. [HER 15] HERAVI M.M., LASHAKI T.B., POORAHMAD N., “Applications of Sharpless asymmetric epoxidation in total synthesis”, Tetrahedron: Asymmetry, vol. 26, pp. 405–495, 2015.

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[HER 16] HERAVI M.M., ZADSIRJAN V., FARAJPOUR B., “Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis”, RSC Advances, vol. 6, pp. 30498–30551, 2016. [HER 17] HERAVI M.M., ZADSIRJAN V., ESFANDYARI M. et al., “Applications of Sharpless asymmetric dihydroxylation in the total synthesis of natural products”, Tetrahedron: Asymmetry, vol. 28, pp. 907–943, 2017. [HO 95] HO T.-L., Symmetry- A Basis for Synthesis Design, John Wiley & Sons, New York, 1995. [HOF 08] HOFFMANN N., “Photochemical reactions as key steps in organic synthesis”, Chemical Reviews, vol. 108, pp. 1052–1103, 2008. [HOF 13] HOFFMANN R.W., “Natural product synthesis: Changes over time”, Angewandte Chemie: International Edition, vol. 52, pp. 123–130, 2013. [HUA 18] HUANG P.-Q., YAO Z.-J., HSUNG R.P., Efficiency in Natural Product Total Synthesis, John Wiley & Sons, Hoboken, 2018. [HUD 07] HUDLICKY T., REED J.W., The Way of Synthesis, Wiley-VCH, Weinhiem, 2007. [HON 15] HONG B.-C., RAJA A., SHETH V.M., “Asymmetric synthesis of natural products and medicinal drugs through one-pot-reaction strategies”, Synthesis, vol. 47, pp. 3257–3285, 2015. [IND 18] INDU S., KALIAPPAN K.P., “A new and informative [a,b,c,d] nomenclature for one-pot multistep transformations: A simple tool to measure synthetic efficiency”, RSC Advances, vol. 8, pp. 21292–21305, 2018. [JAZ 10] JAZZAR R., HITCE J., RENAUDAT A. et al., “Functionalization of organic molecules by transition-metal-catalyzed C(sp3)-H activation”, Chemistry – A European Journal, vol. 16, pp. 2654–2672, 2010. [JOB 02] JOB A., JANECK C.F., BETTRAY W. et al., “The SAMP/RAMP-hydrazone methodology in asymmetric synthesis”, Tetrahedron, vol. 58, pp. 2253–2329, 2002. [KAG 11] KAGAN H.B., “Practical consequences of non-linear effects in asymmetric synthesis”, Advanced Synthesis & Catalysis, vol. 343, pp. 227–233, 2011. [KÄR 16] KÄRKÄS M.D., PORCO Jr J.A., STEPHENSON C.R.J., “Photochemical approaches to complex chemotypes: Application in natural product synthesis”, Chemical Reviews, vol. 116, pp. 9683–9747, 2016. [KIT 99] KITAMURA M., OKA H., NOYORI R., “Asymmetric addition of dialkylzincs to benzaldehyde derivatives catalyzed by chiral β-amino alcohols. Evidence for the monomeric alkylzinc aminoalkoxide as catalyst”, Tetrahedron, vol. 55, pp. 3605–3614, 1999. [KOL 94] KOLB H.C., VANNIEUWENHZE M.S., SHARPLESS K.B., “Catalytic asymmetric dihydroxylation”, Chemical Reviews, vol. 94, pp. 2483–2547, 1994.

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[KÜR 05] KÜRTI L., CZABO B., Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Amsterdam, 2005. [LAR 79] LARCHEVÊQUE M., IGNATOVA E., CUVIGNY T., “Asymmetric alkylation of chiral N,N-disubstituted amides”, Journal of Organometallic Chemistry, vol. 177, pp. 5–15, 1979. [LEY 94] LEY S.V., NORMAN J., GRIFFITH W.P. et al., “Tetrapropyl ammonium perruthenate, Pr4N+RuO4-, TPAP: A catalytic oxidant for organic synthesis”, Synthesis, pp. 639–666, 1994. [LI 18] LI L., CHEN Z., ZHANG X. et al., “Divergent strategy in natural product total synthesis”, Chemical Reviews, vol. 118, pp. 3752–3832, 2018. [LIU 17] LIU W., LI C.-J., “Recent synthetic applications of catalyst-free photochemistry”, Synlett, vol. 28, pp. 2714–2754, 2017. [LU 12] LU L.-Q., CHEN J.-R., XIAO W.-J., “Development of cascade reactions for the concise construction of diverse heterocyclic architectures”, Accounts of Chemical Research, vol. 45, pp. 1278–1293, 2012. [MAN 78] MANCUSO A.J., HUANG S.-L., SWERN D., “Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide “activated” by oxalyl chloride”, The Journal of Organic Chemistry, vol. 43, pp. 2480–2482, 1978. [MAR 17a] MARTIN S.F., “Natural products and their mimics as targets of opportunity for discovery”, The Journal of Organic Chemistry, vol. 82, pp. 10757–10794, 2017. [MAR 17b] MARGARITA C., ANDERSSON P.G., “Evolution and prospects of the asymmetric hydrogenation of unfonctionalized olefins”, Journal of the American Chemical Society, vol. 139, pp. 1346–1356, 2017. [MAR 18] MARYASIN B., MARQUETAND P., MAULIDE N., “Machine learning for organic synthesis: Are robots replacing chemists”, Angewandte Chemie: International Edition, vol. 57, pp. 6978–6980, 2018. [MEN 16] MENDOZA A., COLAS K., SUAREZ-PANTIGA S. et al., “Chemical innovation through ligand total synthesis”, Synlett, vol. 27, pp. 1753–1759, 2016. [MER 17] MERAD J., CANDY M., PONS J.-M. et al., “Catalytic enantioselective desymmetrization of meso compounds in total synthesis of natural products: Towards an economy of chiral reagents”, Synthesis, vol. 49, pp. 1938–1954, 2017. [MON 14] MONNERET C., “La sérendipité, un chemin de traverse à suivre…”, L’actualité Chimique, vol. 385, pp. 7–8, 2014. [MYE 94] MYERS A.G., YANG B.H., CHEN H. et al., “Use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis”, Journal of the American Chemical Society, vol. 116, pp. 9361–9362, 1994.

Total Synthesis: Some Elements to Contemplate

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[NAR 11] NARAYANAM J.M.R., STEPHENSON C.R.J., “Visible light photoredox catalysis: Applications in organic synthesis”, Chemical Society Reviews, vol. 40, pp. 102–113, 2011. [NIC 05] NICOLAOU K.C., SNYDER S.A., “Chasing molecules that were never there: Misassigned natural products and the role of chemical synthesis in modern structure elucidation”, Angewandte Chemie: International Edition, vol. 44, pp. 1012–1044, 2005. [NIC 06] NICOLAOU K.C., EDMONDS D.J., BULGER P.G, “Cascade reactions in total synthesis”, Angewandte Chemie: International Edition, vol. 45, pp. 7134–7186, 2006. [NIC 11] NICOLAOU K.C., “Invigorating education”, Angewandte Chemie: International Edition, vol. 50, pp. 63–74, 2011. [NIC 18] NICOLAOU K.C., “The emergence and evolution of organic synthesis and why it is important to sustain it as an advancing art and science for its own sake”, Israel Journal of Chemistry, 58, pp. 104–113, 2018. [NOY 05] NOYORI R., “Pursuing practical elegance in chemical synthesis”, Chemical Communications, vol. 14, pp. 1807–1811, 2005. [NOY 09] NOYORI R., “Synthesizing our future”, Nature Chemistry, vol. 1, pp. 5–6, 2009. [NOY 18] NOYORI R., “Converging and integrating our knowledge to sustain humanity”, Chemistry: An Asian Journal, vol. 13, pp. 5–6, 2018. [NUG 02] NUGENT W.A., “An amino alcohol ligand for highly enantioselective addition of organozinc reagents to aldehydes: Serendipity rules”, Organic Letters, vol. 4, pp. 2133–2136, 2002. [PAR 13] PARENTY A., MOREAU X., NIEL G. et al., “Update 1 of: Macrolactonizations in the total synthesis of natural products”, Chemical Reviews, vol. 113, pp. PR1–PR40, 2013. [PEL 13a] PELISSIER H., “Stereoselective domino reactions”, Chemical Reviews, vol. 113, pp. 442–524, 2013. [PEL 13b] PELISSIER H., “Recent developments in enantioselective multicatalyzed tandem reactions”, Tetrahedron, vol. 69, pp. 7171–7210, 2013. [PIN 17] PING L., CHUNG D.S., BOUFFARD J. et al., “Transition metal catalyzed site- and region-divergent C-H bond functionalization”, Chemical Society Reviews, vol. 46, pp. 4299–4328, 2017. [REE 13] REETZ M.T., “Biocatalysis in organic chemistry and biotechnology: Past, present, and future”, Journal of the American Chemical Society, vol. 135, pp. 12480–12496, 2013. [ROC 18] ROCHA D.H.A., PINTO D.C.G.A., SILVA A.M.S., “Applications of the Wittig reaction on the synthesis of natural and natural analogue heterocyclic compounds”, European Journal of Organic Chemistry, vol. 2018, pp. 2443–2457, 2018. [ROS 15] ROSCHANGAR F., SHELDON R.A., SENANAYAKE C.H., “Overcoming barriers to green chemistry in the pharmaceutical industry – the green aspiration levelTM concept”, Green Chemistry, vol. 17, pp. 752–768, 2015.

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[ROU 85] ROUSH W.R., WALTSA E., HOONG L.K., “Diastereo- and enantioselective aldehyde addition reactions of 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic esters, a useful class of tartrate ester modified allylboronates”, Journal of the American Chemical Society, vol. 107, pp. 8186–8190, 1985. [SAI 14] SAICIC R.N., “Protecting group-free syntheses of natural products and biologically active compounds”, Tetrahedron, vol. 70, pp. 8183–8218, 2014. [SCH 18] SCHWALLER P., GAUDIN T., LANYI D. et al., “Found in Translation: Predicting outcomes of complex organic reactions using neural sequence-to-sequence models”, Chemical Science, vol. 9, pp. 6091–6098, 2018. [SER 13] SERBA C., WINSSINGER N., “Following the lead from Nature: Divergent pathways in natural product synthesis and diversity-oriented synthesis”, European Journal of Organic Chemistry, vol. 2013, pp. 4195–4214, 2013. [SHE 07] SHELDON R.A., “The E factor: Fifteen years on”, Green Chemistry, vol. 9, pp. 1273–1283, 2007. [SOA 17] SOAI K., ARIMASA M., “Asymmetric autocatalysis and the origin of homochirality”, in ACS Symposium series, 1258, Stereochemistry and global connectivity: The legacy of Ernest L. Eliel, 2, chap. 3, pp. 27–47, 2017. [SOA 96] SOAI K., INOUE Y., TAKAHASHI T. et al., “Asymmetric synthesis of chiral diols by the catalytic enantioselective dialkylation of tere-, iso-, and phtalaldehydes and by a catalytic enantioselective autoinductive reaction”, Tetrahedron, vol. 52, pp. 13355–13362, 1996. [SZÖ 18] SZÖLLÖSI G., “Asymmetric one-pot reactions using heterogeneous chemical catalysis: Recent steps towards sustainable processes”, Catalysis Science & Technology, vol. 8, pp. 389–422, 2018. [SZP 10] SZPILMAN A.M., CARREIRA E.M., “Probing the biology of natural products: Molecular editing by diverted total synthesis”, Angewandte Chemie: International Edition, vol. 49, pp. 9592–9628, 2010. [TRO 06] TROST B.M., WEISS A.H., JACOBI VON WANGELIN A., “Dinuclear Zn-catalyzed asymmetric alkynylation of unsaturated aldehydes”, Journal of the American Chemical Society, vol. 128, pp. 8–9, 2006. [TRO 91] TROST B.M., “The atom economy – A search for synthetic efficiency”, Sciences, vol. 254, pp. 1471–1477, 1991. [TUR 19] TURCZEL G., KOVACS E., MERZA G. et al., “Synthesis of semiochemicals via olefin metathesis”, ACS Sustainable Chemistry & Engineering, vol. 7, pp. 33–48, 2019. [VAN 02] VAN STADEN L.F., GRAVESTOCK D., AGER D.J., “New developments in the Peterson olefination reaction”, Chemical Society Reviews, vol. 31, pp. 195–200, 2002. [VOL 14] VOLLA C.M.R., ATODIRESEI I., RUEPING M., “Catalytic C-C bond forming multi-component cascade or domino reactions: Pushing the boundaries of complexity in asymmetric organocatalysis”, Chemical Reviews, vol. 114, pp. 2390–2431, 2014.

Total Synthesis: Some Elements to Contemplate

19

[WAN 97] WANG A.-X., TU Y., FROHN M. et al., “An efficient catalytic asymmetric epoxidation method”, Journal of the American Chemical Society, vol. 119, pp. 11224–11235, 1997. [WEN 13] WENDER P.A., “Toward the ideal synthesis and transformative therapies: The roles of step economy and function oriented synthesis”, Tetrahedron, vol. 69, pp. 7529–7550, 2013. [WIL 07] WILSON R.M., DANISHEFSKY S.J., “Applications of total synthesis toward the discovery of clinically useful anticancer agents”, Chemical Society Reviews, vol. 36, pp. 1207–1226, 2007. [WU 10] WU X.-F., ANBARASAN P., NEUMANN H. et al., “From Noble metal to Nobel prize: Palladium-catalyzed coupling reactions as key methods in organic synthesis”, Angewandte Chemie: International Edition, vol. 49, pp. 9047–9050, 2010. [WUT 14] WUTS P.G.M., Greenes’s Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons, Hoboken, 2014. [XIO 10] XIONG Z., BUSCH R., COREY E.J., “A short total synthesis of (+)-omaezakianol via an epoxide-initiated cationic cascade reaction”, Organic Letters, vol. 12, pp. 1512–1514, 2010. [XU 15] XU Z., WANG Q., ZHU J., “Total syntheses of (-)-mersicarpine, (-)-scholarisine G, (+)-melodinine E, (-)-leuconoxine, (-)-leuconolam, (-)-leuconodine A, (+)-leuconodine F, and (-)-leuconodine C: Self-induced diastereomeric anisochronism (SIDA) phenomenon for scholarisine G and leuconodines A and C.”, Journal of the American Chemical Society, vol. 137, pp. 6712–6724, 2015. [YOS 17] YOSHII Y., TOKUYAMA H., CHEN D.Y.-K., “Total synthesis of actinophyllic acid”, Angewandte Chemie: International Edition, vol. 56, pp. 12277–12281, 2017. [YOU 09] YOUNG I.S., BARAN P.S., “Protecting-group free synthesis as an opportunity for invention”, Nature Chemistry, vol. 1, pp. 193–205, 2009. [ZEN 16] ZENG X.-P., CAO Z.-Y., WANG Y.-H. et al., “Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters”, Chemical Reviews, vol. 116, pp. 7330–7396, 2016. [ZHA 90] ZHANG W., LOEBACH J.L., WILSON S.R. et al., “Enantioselective epoxidation of unfunctionalized olefins catalyzed by(salen)manganese complexes”, Journal of the American Chemical Society, vol. 112, pp. 2801–2803, 1990.

2 Squamostolide

2.1. Structure, isolation and properties Squamostolide belongs to acetogenins, a class of polyoxygenated compounds, typified by a fatty long chain, with a terminal γ-lactone subunit [XIE 03]. These compounds, isolated from tropical plants, have various biological activities such as antimalarial, antibiotic or antitumor [BER 05].

OH

O

O O

O Figure 2.1. Structure of squamostolide. For a color version of the figures in this chapter see, see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– γ-Valerolactone substituted at α position by a long chain of 13 carbon atoms. Its tip has a secondary alcohol functional group and a second saturated lactone unit.

2.2. Bond disconnections For each of the two approaches, bond disconnections are carried out along the carbon chain linking the two butyrolactones. The first is based on a Sonogashira

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

22

Retrosynthetic Analysis and Synthesis of Natural Products 1

coupling between a terminal alkyne and a vinyl iodide catalyzed by palladium (0) [LEE 05, MAK 06]. For the second, a tandem process of cyclization and cross-coupling by metathesis allows both the formation of one of the lactone units and the formation of the carbon chain linking them [QUI 07]. To finalize the syntheses, a selective reduction of double bonds is required while preserving or regenerating the one present in butenolide.

OH

O +

I

( )5

O

H

O O

Sonogashira coupling OH

O ( )5

O

O O

RCM / CM OBn + O

PhS ( )5

O

Figure 2.2. Key disconnections

O O

Squamostolide

2.3. Approach according to M.J. Wu 2.3.1. Bond disconnections OH

O

D1 ( )5

O

O O

OH

O I

( )5

O

+

O O

1-A1

1-B1

D2

D5

I CO2Et

( )5

I

SiMe3 1-C1

1-E

D3

1

+

O

PhS

OH

O 1-D1 D4

SiMe3

1-F1

OH 4-pentyn-1-ol

Figure 2.3. Disconnections recommended by Wu

LEGEND OF FIGURE 2.3.– D1: ene/yne coupling (Sonogashira reaction followed by reduction). D2: formation of a hydroxy-butyrolactone (dihydroxylation/lactonization).

23

24

Retrosynthetic Analysis and Synthesis of Natural Products 1

D3: formation of an γ,δ-unsaturated ester (Claisen rearrangement). D4: allyl alcohol (1,2-addition of vinylmagnesium to an aldehyde). D5: butenolide (coupling of an anion stabilized by a thiophenyl group and an alkyl iodide/elimination). 2.3.2. Synthesis 2.3.2.1. Access to hydroxylactone 1-A1 OH OH

a

b

OHC

SiMe3 OH

SiMe3 EtO2C

c

d SiMe3 SiMe3 SiMe3

e

f O

O

O

O

OH

OH 1-A1

Figure 2.4. Synthesis of hydroxylactone 1-A1

LEGEND OF FIGURE 2.4.– a. Triple bond protection – 71%: (i) n-BuLi, THF, 0°C; (ii) TMS-Cl, 0°C -> r.t. b. Oxidation of primary alcohol to aldehyde – 96%: Complex SO3.py, Et3N, DMSO, CH2Cl2, −10°C, 1 h. c. 1,2-Addition of vinylmagnesium chloride – 98%: CH2=CH-MgCl, THF, 0°C. d. Claisen rearrangement – 64%: CH3-C(OEt)3, propionic acid, 150°C. e. Asymmetric dihydroxylation and lactonization – 94%: AD-mix-β, CH3SO2NH2, t-BuOH/H2O, 0°C. f. Deprotection at the terminal position of the alkyne – 95%: TBAF, THF, 0°C.

Squamostolide

25

2.3.2.2. Access to vinyl iodide 1-B1 OH

OH g

OH

OTHP

OTHP

j

k OTHP

I

l

I

h, i

OTs

I OH

m

I I 1-E1

O

O

PhS

I O

n, o

1-F1

O

1-B1

Figure 2.5. Synthesis of vinyl iodide 1-B1

LEGEND OF FIGURE 2.5.– g. Monoprotection of 1,6-hexandiol – 67%: dihydropyran, TsOH. h. Tosylation of a primary alcohol: TsCl, pyridine, CH2Cl2. i. Formation of a primary iodide – 81% (two steps): NaI, NaHCO3, acetone. j. Introduction of the alkyne functional group by nucleophilic substitution – 83%: lithium acetylide, ethylenediamine, DMSO. k. Hydrozirconiation/iodination/deprotection of THP ether – 81%: (i) Cp2ZrHCl, THF; (ii) I2, THF, 0°C; (iii) Conc. HCl, MeOH. l. Protection of the primary alcohol function – Tosylation: Ts-Cl, pyridine. m. Substitution of the tosyl group by iodide – 79% (two steps): NaI, NaHCO3, acetone. n. Coupling – 45%: (i) NaHMDS, THF/HMPA; (ii) 1-E1. o. Generation of the double bond by sulfoxide elimination – 67%: (i) m-CPBA, CH2Cl2; (ii) Ph-Me, Δ.

26

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.3.2.3. Coupling of the two fragments – termination of the synthesis OH

O

O

I

O

O

+

1-A1

1-B1 p

OH O

O

O

O q OH

O

O O

O

Figure 2.6. Sonogashira coupling and finalizing the synthesis

LEGEND OF FIGURE 2.6.– p. Sonogashira reaction – 58%: PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N, Ph-H, 8 h. q. Reduction of both unsaturated bonds – 62%: Ts-NH-NH2, AcONa, EtOCH2CH2CH2OEt. Number of steps: 11 (from 1.6-hexandiol) – Overall yield: 3.1%. A Sonogashira reaction between a true acetylene and a vinyl iodide makes it possible to build the carbon skeleton; the hydroxy group tolerates the conditions of this coupling and avoids the use of a protective group. The selective reduction of enyne, without affecting the unsaturation present on a lactone unit, is ensured by diimide.

Squamostolide

27

2.3.3. Key reaction: Claisen–Ireland rearrangement The Claisen rearrangement of allylic esters allows direct access to γ,δ-unsaturated acids. It is a concerted sigmatropic process [3,3] that takes place in an acyclic series, according to a 6-membered chair transition state. From esters derived from cyclic unsaturated alcohols, the transition state for this transformation is of boat type [CHA 02, MAJ 07, FER 13]. In order to decrease the activation energy of the reaction, deprotonation of the ester by a lithiated base was recommended by R.E. Ireland, thus generating enolate, trapped by trimethylsilyl chloride [IRE 72]. From the ketene acetal thus formed, the rearrangement of Claisen–Ireland takes place at room temperature. O

R1

1) LDA, THF

R2

O

-78°C R1

O

R2

2) TMS-Cl

OTMS Enolate (E) R1

R1 R2

OH

O H

R2

OH

O

anti

Figure 2.7. Claisen rearrangement of acyclic allylic esters

The process has been successfully applied many times in total synthesis. The acid can then be trapped by diazomethane to make the methyl ester easier to handle [RED 13]. O

O 1) LiHMDS, TMSCl

O

THF, -78°C -> r.t., 15h

CO2H

H3CO

2) CH2N2, Et2O

OPMB

0°C, 30 min BnO

N H Kainic acid

OPMB BnO 79%

Figure 2.8. Claisen rearrangement, a key step towards kainic acid

CO2H

28

Retrosynthetic Analysis and Synthesis of Natural Products 1

The mild conditions of this reaction made it possible to combine it with other reactions conducted sequentially and generate the required intermediate in situ [ERN 17, ERI 95, SER 16]. F

Ph

FSO2CF2CO2-SiMe3

Ph

Ph

(3 equiv.) O

Ph O

NaF (0.1 equiv.)

OPMB

F

OPMB

Diglyme, 120°C

O

O

F

Ph 1) KHMDS

(4 equiv.)

H

O

TMS-Cl (4 equiv.)

F

[3,3]

F

Ph

-78°C -> r.t. OTMS

O

Ph PMB

2) NH4Cl 3) CH2N2

MeOH, PhMe

F Ph

PMBO

CO2Me

73% (d.r. >96/4)

Figure 2.9. Difluorocyclopropanation and Claisen–Ireland rearrangement [ERN 17]

O-TMS 1) Me2CuLi, Li-I

O

TMS-Cl, Et2O -78°C, 4h

3) HCl (3M)

Ketene acetal (Z)

O

CO2H

2) Et3N, r.t.

93% syn Major d.r. = 82 : 18

O O-TMS O 1) MeCu, Li-I

CO2H

2) Et3N, r.t. 3) HCl (3M)

TMS-I, Et2O -78°C, 4h

68% anti Major Ketene acetal (E)

d.r. = 83 : 17

Figure 2.10. Tandem Michael addition/Claisen rearrangement [ERI 95]

Squamostolide

29

2.3.4. Key reaction: functionalization of true alkynes Before the advent of palladium catalyzed reactions, the coupling of aromatic or vinyl derivatives with alkynes, known as Castro–Stephens reactions, could be carried out under fairly harsh conditions (involvement of strong bases, high temperatures, reactions under inert atmosphere) requiring stoichiometric quantities of copper acetylides [STE 63]. I +

Cu

pyridine

Ph

Ph

125°C, 7h

OH

O 88%

Figure 2.11. Castro–Stephens coupling

From an application point of view, the reaction has some disadvantages: the instability of copper acetylides gives them potential explosion risks, as well as the homocoupling of alkynes leading to diynes (Eglinton–Glaser reaction). As for the exact mechanism, it is still controversial; the most commonly accepted model is the one involving a transition state with four centers, although the possible involvement of Cu(III) species is not totally excluded [ROV 14]. Cu-I

R

L L

Cu L

I

R' L

L L

Cu

R

L

I

Cu L

R

R' L R'

I

L

Cu

L R

Figure 2.12. Mechanism of the Castro–Stephens reaction

30

Retrosynthetic Analysis and Synthesis of Natural Products 1

The reaction can be carried out intramolecularly to produce enynes [COL 01, HAA 03]. The coupling studied in the synthesis of oximidine II led to low yields and was accompanied by the isomerization of the E double bond to Z; thanks to the presence of sodium formate, enyne can be reduced stereoselectively and form the expected triene with very significant yields. The effectiveness of the second step depends on the phosphine present in the medium; further studies have shown that phanephos allows a better stabilization of the reductive species, copper hydride (Cu-H) [LI 15]. OTBDPS OMe

OMOM

O O

K2CO3, CuI PPh3, DMF 120°C

OTBDPS OMe

Z 18%

O OMOM

O E

I

OTBDPS OMe

K2CO3, CuI H-CO2Na PPh3, DMF 120°C

OMOM

O O

H

H 67%

Figure 2.13. Intramolecular coupling sequence and alkyne reduction

Since its discovery, the Sonogashira reaction has superseded the Castro– Stephens reaction. Catalyzed by palladium Pd(0), it eliminates the need for stoichiometric quantities of copper acetylides, is produced at a lower temperature and tolerates the presence of many functional groups [MIL 97].

O O

+

I

O

Pd(Ph3)2Cl2 (5% mol.) CuI (10% mol.)

O

iPr2NH, THF, 0°C OTBS

OTBS

54%

Figure 2.14. Sonogashira reaction – Harveynone synthesis

Squamostolide

31

The Sonogashira reaction creates a C-C bond between an alkyne and an aryl or vinyl halide. Like most pallado-catalyzed processes, it involves three classic steps: oxidative addition, transmetalation and reductive elimination.

Pd(0)L2

L

R1-X

R2

L Pd R1 R1

L 1

L

R2

1

R

R 2

Pd

R

Pd X L

L Cu+

X-

R2

Cu

R2

H

Base 2

H

R

Cu X +

Figure 2.15. Catalytic cycle of the Sonogashira reaction

2.3.5. Supporting synthetic transformations 2.3.5.1. Oxidation of alcohols to aldehydes according to Parikh–von Doering [BOU 10, CAR 06, PAR 67]

MeO2C

SO3, pyridine

O OMe

DMSO, Et3N OH

MeO2C

O OMe H 90%

O

32

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.3.5.2. Asymmetric dihydroxylation according to Sharpless [AHM 06] OH AD-mix β (2 mol%) MeO

MeSO2NH2 (1 equiv.)

C11H23

O

O

t-BuOH / H2O (1 : 1)

O

C11H23 86%

e.e. > 95%

2.3.5.3. Preparation of phenylsulfonyl butyrolactone 1-F1 [IWA 77] CO2H

O

2)

1) LDA (2 equiv.)

CO2H

THF, -78°C OH

SPh

SPh

SPh Ni Raney

TsOH (cata.) Ph-H, Δ

O

O

O

O

MeOH

82%

78%

2.3.5.4. Sulfoxide removal – access to butenolides [REN 01, MOG 96]

O Ar

O

LDA

O

S

Ph H THF, Δ

Ph

H

Ar

THF, -78°C

O

H2SO4 (2M)

Ph H

O

Ar

S O

OH

S

O

O

O O

O

O O

PhMe, Δ

O

OH Ph 79% e.e. = 93%

Squamostolide

33

2.4. Approach according to K.J. Quinn 2.4.1. Bond disconnections OH

O O

O O

D1 OBn

PhS ( )7

O

O O

O

1-A2 D2

OBn

PhS ( )8

O

O

+

O 1-B2

O

1-C2

D3

D4 O

OH

OH

PhS

OH

O

D5 OH

OH

OH

D-mannitol

Propylene O oxide

1-D2

Figure 2.16. Disconnections recommended by K. J. Quinn [QUI 07]

LEGEND OF FIGURE 2.16.– D1: reduction of two C=C bonds and the regeneration of one C=C bond (reduction by hydrogenation/elimination of a sulfoxide).

34

Retrosynthetic Analysis and Synthesis of Natural Products 1

D2: formation of the carbon (RCM)/cross-metathesis (CM)).

skeleton

(tandem

ring-closing

metathesis

D3: C2 symmetric chiral 1-B2 synthon (functionalization of D-mannitol). D4: α-alkylated butyrolactone (enolate anionic coupling with an iodoalkyl derivative). D5: chiral lactone 1-D2 (functionalization of propylene oxide).

2.4.2. Synthesis 2.4.2.1. Access to ester 1-B2 OH

OH

OH

OAc

OAc

Br

a OH

OH

OH

OAc b

Br

OAc

OAc

OAc

D-Mannitol OBn OBn

OH d

c

e O

OH

OH 1-B2

O

Figure 2.17. Synthesis of polyunsaturated ester 1-B2

LEGEND OF FIGURE 2.17.– a. Bromoacetylation – 67%: AcBr, Ac2O, pyridine. b. β-Elimination: Zn, AcONa, AcOH. c. Saponification – 80% (two steps): MeONa, MeOH. d. Monoetherification – 88%: (i) Bu2SnO, nBu4NI, Ph-H, Δ; (ii) PhCH2-Br, Δ. e. Esterification – 83%: acryloyl chloride, iPr2Net, CH2Cl2.

Squamostolide

35

2.4.2.2. Synthesis of dodec-11-en-1-ol triflate 1-E2 O ( )8

H

f

g, h

OMe

( )8

OTf

( )8 1-E2

Figure 2.18. Access to triflate (trifluoromethanesulfonate) 1-E2

LEGEND OF FIGURE 2.18.– f. Wittig reaction: Ph3P=CHOMe, THF. g. Hydroxymercuration and reduction of enol ether – 44% (two steps): (i) Hg(OAc)2, THF; (ii) NaBH4, MeOH. h. Protection of alcohol in triflate – 84%: Tf2O, 2,6-lutidine, CH2Cl2. 2.4.2.3. Access to butyrolactone 1-A2 O PhS O 1-D2

i OBn PhS ( )8

O O

1-B2

O O

1-C2 j

OBn

OBn

+

O O

1-F2

PhS

O

O O

O

1-A2

Figure 2.19. Access to lactone 1-A2 by RCM/CM coupling

36

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 2.19.– i. Alkylation of α-phenylthiobutyrolactone – 80%: (i) KHMDS, THF, 0°C; (ii) 1-E2, 0°C -> r.t., 16 h. j. Tandem RCM/CM – 77%: Hoveyda–Grubbs catalyst (10 mol%), CH2Cl2, 40°C. 2.4.2.4. Termination of the synthesis OBn

PhS

O O

O O

1-A2 k-m

OBn

O O

O O

1 Figure 2.20. Termination of the synthesis

LEGEND OF FIGURE 2.20.– k. Hydrogenation of the two double bonds and hydrogenolysis of the benzyl ester: H2, Pd/C, AcOEt. l. Conversion of α-phenylthiolactone to butenolide (oxidation to sulfoxide): m-CPBA, CH2Cl2, 0°C. m. Thermal β-elimination of sulfoxide – 53% (three steps): PhCH3, 110°C. Number of steps: 9 (from D-mannitol) – Overall yield: 12.7%.

Squamostolide

37

The synthesis is convergent and uses as a key reaction a double metathesis process (RCM and CM) carried out in tandem [QUI 07, QUI 05, SCH 18]; the most efficient catalyst here is that of Hoveyda–Grubbs which minimizes the formation of non-functionalized 1-F2 butenolide. Chirality is controlled by using D-mannitol as a synthon. The appropriate choice of benzyl group to protect the hydroxy group – allows, during the double bond reduction step, to regenerate at the same time as the free alcohol functional group. The presence of the phenylsulfanyl group in the 1-D2 compound is also essential to introduce butenolide unsaturation (by oxidation to sulfoxide and β-elimination); it also helps to stabilize the anion during the alkylation step with triflate 1-E2.

2.4.3. Key reaction: alkene metathesis and tandem processes Since the discovery of catalysts, capable of reacting in the presence of many functional groups, the metathesis reaction has taken off and is no longer restricted to the field of petrochemistry or polymerization processes [LIU 18]. The metathesis of alkenes is declined in several modes [YET 16]. Cross-coupling is a key tool but remains the most difficult to control in terms of regio- and E or Z stereo-selectivity. Ring-closing metatheses, on the contrary, have undergone extraordinary development and have truly revolutionized the strategy for the synthesis of macrocyclic compounds. Instead of breaking the bonds at or near well-established functional groups, it is quite easy and now common to cleave the molecule between two sp3 carbon atoms of an alkyl chain, even though it means subsequently reducing (by selective hydrogenation) the newly created double bond. Over the past two decades, significant progress has been made. Now even tetrasubstituted alkenes can be achieved with highly active catalysts; control of selectivity to Z alkenes is also possible with other well-defined catalysts. Regio-selectivity can also be controlled by involving either tether groups (silylated or phosphate) or by implementing relayed reactions. In order to reduce the steps of a synthesis, the combination of different metathesis reactions (CM, RCM or ROM) through cascade or domino processes allows access to complex structures [ZIE 16]. In addition, the extremely mild conditions also lend themselves to the implementation of tandem reactions combining at least two distinct transformations and resulting in the formation of molecules produced in a single vessel.

38

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.4.3.1. Cross-metathesis – access to tetrasubstituted alkenes [WHI 08, CHU 08, PAE 12] N

N

Cl Ru Cl

O

O

O 5 mol% Cl

Cl O

Ph-H, 60°C, 18h

O 97%

Figure 2.21. Key step in the synthesis of elatol

2.4.3.2. Cross-metathesis – Z selectivity [MEE 11, END 11, WER 15] adamantanamine or 2,6-dimethylaniline NH2

N

.. N Mo

O

Br

Br

R O

R1 R2

N

Rotation around C-O

.. N Mo

R1

O

Br

R2 Br

RO

(OR = OTBS)

R1 N Br

.. N Mo

O RO

R2

.. N

R1 R2 Br

.N Mo CH2

O

Br TBS O

Selectivity Z/E > 96 /4 Figure 2.22. Cross-coupling and Z selectivity

Br

Squamostolide

39

2.4.3.3. Ring-closing metathesis and silylated ethers [EVA 16, CUS 12]

GBII (2 x 1 mol%)

PMPO

O

Si

i-Pr

O

OBn

PMPO

O

CH2Cl2, 40°C

Si

i-Pr

i-Pr

O

OBn

i-Pr

86% (Z / E > 19:1)

Figure 2.23. Silylated ethers allowing Z-selective metathesis coupling

2.4.3.4. Ring-closing metathesis and ether phosphates [VEN 12] O P

O

O

O

1) HGII (4 mol%)

benzoquinone CH2Cl2, reflux

O 2)

H

O

P

OTBS

O

O

OTBS H

HGII (6 mol%)

52%

3) Diimide

Figure 2.24. RCM/CM and selective hydrogenation

2.4.3.5. Domino process: RCM/CM [VIR 03, DRA 06, CRO 10] O O

Mes Cl Cl

+ C11H23

O

N Mes

N Ru

Ph

PCy3

(5% mol.)

CH2Cl2, 40°C, 4h

O C11H23 75%

Figure 2.25. Domino reaction RCM/CM

40

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.4.3.6. Domino process: RCM/CM and transfer of alkenyl groups [VIR 04] Mes Cl

O

Cl

O C5H11

O

N Mes

N Ru

Ph

PCy3

(5% mol.)

O

O

+

O

CH2Cl2, 40°C, 4h C5H11

65%

16%

Figure 2.26. Metathesis cyclization and transfer of alkenyl groups

2.4.3.7. Domino process: ROM/Double RCM [HAL 14]

O 1) GBI

O ( )4 O-Li

(10mol%) then

O THF, -78°C -> r.t.

O

O

2) GBII (5 mol%) PhMe, Δ

O

O

79%

42%

Figure 2.27. Access to bicyclic macrolides

2.4.3.8. One-pot synthesis: CM/hydrogenation [ZIE 18] O O

H

O

1) GBII (4 mol%)

THF, 40°C, 2h + CO2Me (3 equiv.)

O

CO2Me

2) NaH (0.2 equiv)

HCO2H (50 equiv.) 80°C, 90h

H

62%

Figure 2.28. Tandem cross-metathesis and reduction of the alkene formed

Squamostolide

41

2.4.3.9. Migration of C=C double bonds induced by ruthenium hydrides [CLA 13, SCH 13] Mes Cl

OTBS

OC

N

N Ru

Mes H

OTBS

PCy3

OH

OH n-BuOH Ph-Me, 95°C, 8h

Mes Cl Cl

76%

N Mes

N Ru

Ph + OSiMe3

PCy3

Figure 2.29. Isomerization induced by a ruthenium hydride complex

2.4.3.10. Sequential process: RCM/Oppenauer oxidation/hydrogenation [LOU 01] (R)-Citronellal OH OH

GBII (7 mol%) DCE 50°C, 12h c = 3,4 10-4M O

O O

NaOH (1.5 equiv.) OH

H2 (800 psi) 80°C, 24h (R)-Muscone 57%

Figure 2.30. One-pot synthesis of (R)-muscone

42

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.4.3.11. Domino process: RO–double RCM [MAO 14] Mes Cl 1) Cl

Boc N N

H

N Mes

N Ru

H

N

Ph

CF3CO2

PCy3

(15% mol.)

TFA

CH2Cl2, r.t.

CH2Cl2, r.t.

N

Boc

H

H CF3CO2

54%

Figure 2.31. Access to bipiperidines

2.4.3.12. Alkylation/RCM/Claisen rearrangement [CHA 14] O Ph

1) LiTMP ( 3 equiv.)

S O

O

O

Br

O

Ph

Ph

GBII THF reflux

S

(2 equiv.), THF

O O

S O O

O

S O

O

55%

Figure 2.32. Formation of vinylcyclopropanes

2.4.3.13. CM/oxa-Michael reaction [WAL 13, SAN 17] OH

Et OH

OH

O

O (20 equiv.) HG (10 mol%) DCE (0.2M), 80°C

Et

O O 76% (d.r. = 10:1)

Figure 2.33. Tandem CM double reaction and oxa-Michael monoaddition

Et

Squamostolide

43

2.4.3.14. CM/aza-Michael reaction [FUS 12, SAN 17] PMB O

N

F F

O

PMB

HG (5 mol%)

H

+

O

( )n

Ti(OiPr)4 (10 mol%) OMe

N F F

CH2Cl2, reflux, 8h

O OMe

( )n n = 1 - 61% n = 2 - 51%

Figure 2.34. Tandem cross-metathesis (CM) reaction/aza-Michael addition

2.4.3.15. Alkane group cross-metathesis (AGCM) by dual catalysis [DOB 13, HAI 12] R

R

+

+ CH3-CH3 [Ir]

[Ir] Dehydrogenation

Hydrogenation [Ir]H2

[Ir]H2

R +

R

Cross-metathesis

+ CH2=CH2

Metathesis catalyst [W]

[Ir] :(tBuPCP) Ir (C2H4) [W] : W(NAr)(C3H6)(py)(OHIPT)

Figure 2.35. Tandem dehydrogenation/metathesis/hydrogenation reaction

2.4.4. Supporting synthetic transformations 2.4.4.1. Selective reduction of enol ethers [CRO 99, TOH 83] Hg(OAc) OCH3

Hg(OAc)2

CHO

THF,H2O C4H9

C4H9

NaBH4 K2CO3 aq.

OH

C4H9 82%

44

Retrosynthetic Analysis and Synthesis of Natural Products 1

2.4.4.2. Bromoacetylation [BEN 92, EL 93] OH

OH

OH

OH

OH

1) Ac-Br (3 equiv.)

2) Ac2O

Br

OAc

Br

py

1,4-dioxane r.t., 16h

OAc

OAc

74% OH

Br

Br

O

O O

O

2.4.4.3. Mono-etherification of 1,2-diols [RAM 87] n-Bu OH

Sn O

Bu2SnO

n-Bu O

OH Bn-Br

DMF, 100°C

OH

OBn 77%

2.4.4.4. Reduction of alkenes by diimide [SIN 10]

O

O

NH2-NH-COO NH2-NH3 H2O2

O

O

EtOH, THF, r.t., 12h 72%

2.5. References [AHM 06] AHMED MD. M., CUI H., O’DOHERTY G.A., “De novo asymmetric syntheses of muricatacin and its analogues via dihydroxylation of dienoates”, Journal of Organic Chemistry, vol. 71, pp. 6686–6689, 2006. [BEN 92] BENAZZA M., UZAN R., BEAUPERE D. et al., “Direct regioselective chlorination of unprotected hexitols and pentitols by Viehe’s salt”, Tetrahedron Letters, vol. 33, pp. 3129–3132, 1992.

Squamostolide

45

[BER 05] BERMEJO A., FIGADERE B., ZAFRA-POLO M.-C. et al., “Acetogenins from annonaceae. Recent progress in isolation, synthesis, and mechanisms of action”, Natural Product Reports, vol. 22, pp. 269–303, 2005. [BOU 10] BOURCET E., FACHE F., PIVA O., “Synthesis of the macrolactone structure of the aurisides”, Tetrahedron, vol. 66, pp. 1319–1326, 2010. [CAR 06] CARON S., DUGGER R.W., RUGGERI S.G. et al., “Large-scale oxidations in the pharmaceutical industry”, Chemical Reviews, vol. 106, pp. 2943–2989, 2006. [CHA 02] CHAI Y., HONG S.-P., LINDSAY H.A. et al., “New aspects of the Ireland and related Claisen rearrangements”, Tetrahedron, vol. 58, pp. 2905–2928, 2002. [CHA 14] CHANG M.-Y., CHEN Y.-C., CHAN C.-K., “Synthesis of vinylcyclopropanes by allylation/ring-closing metathesis/Claisen rearrangement”, Tetrahedron, vol. 70, pp. 8908–8913, 2014. [CHU 08] CHUNG C.K., GRUBBS R.H., “Olefin metathesis catalyst: Stabilization effect of backbone substitutions of N-heterocyclic carbine”, Organic Letters, vol. 10, pp. 2693– 2696, 2008. [CLA 13] CLARK J.R., GRIFFITHS J.R., DIVER S.T., “Ruthenium hydride-promoted dienyl isomerization: Access to highly substituted 1,3-dienes”, Journal of the American Chemical Society, vol. 135, pp. 3327–3330, 2013. [COL 01] COLEMAN R.S., GARG R., “Stereocontrolled synthesis of the diene and triene macrolactones of oximidines I and II: Organometallic coupling versus standard macrolactonization”, Organic Letters, vol. 3, pp. 3487–3490, 2001. [CRO 99] CROUCH R.D., MEHLMANN J.F., HERB B.R. et al., “Selective conversion of enol ethers into alcohols in the presence of alkenes using Hg(OAc)2 – NaBH4”, Synthesis, pp. 559–561, 1999. [CRO 10] CROS F., PELOTIER B., PIVA O., “Regioselective tandem ring-closing/cross metathesis of 1,5-hexandien-3-ol derivatives: Application to the total synthesis of rugulactone”, European Journal of Organic Chemistry, pp. 5063–5070, 2010. [CUS 12] CUSAK A., “Temporary silicon-tethered ring-closing metathesis: Recent advances in methodology development and natural product synthesis”, Chemistry: A European Journal, vol. 18, pp. 5800–5824, 2012. [DOB 13] DOBEREINER G.E., YUAN J., SCHROCK R.R. et al., “Catalytic synthesis of n-alkyl arenes through alkyl group cross-metathesis”, Journal of the American Chemical Society, vol. 135, pp. 12572–12575, 2013. [DRA 06] DRAGUTAN V., DRAGUTAN I., “A resourceful new strategy in organic synthesis: Tandem and stepwise metathesis/non metathesis catalytic processes”, Journal of Organometallic Chemistry, vol. 691, pp. 5129–5147, 2006. [EL 93] EL ANZI A., BENAZZA M., FRECHOU C. et al., “Bromation régiosélective d’itols non protégés”, Tetrahedron Letters, vol. 34, pp. 3741–3744, 1993.

46

Retrosynthetic Analysis and Synthesis of Natural Products 1

[END 11] ENDO K., GRUBBS R.H., “Chelated ruthenium catalysts for Z-selective olefin metathesis”, Journal of the American Chemical Society, vol. 133, pp. 8525–8527, 2011. [ERI 95] ERIKSSON M., HJELMENCRANTZ A., NILSSON M. et al., “Addition of organocopper reagents to allylic acrylates – the preparation of γ,δ-unsaturated acids and subsequent functionalization to γ-lactones”, Tetrahedron, vol. 51, pp. 12631–12644, 1995. [ERN 17] ERNOUF G., BRAYER J.-L., FOLLEAS B. et al., “Synthesis of alkylidene(gemdifluorocyclopropanes) from propargyl glycolates by a one-pot difluorocyclopropenation / Ireland-Claisen rearrangement sequence”, Journal of Organic Chemistry, vol. 82, pp. 3965–3975, 2017. [EVA 16] EVANS P.A., CUSAK A., GRISIN A. et al., “Medium-ring stereocontrol in the temporary silicon tethered ring-closing metathesis approach to the synthesis of polyketide fragments”, Synthesis, vol. 48, pp. 2402–2412, 2016. [FER 13] FERNANDES R.A., CHOWDURY A.S., KATTANGURU P., “The orthoester Johnson-Claisen rearrangement in the synthesis of bioactive molecules, natural products, and synthetic intermediates – Recent advances”, European Journal of Organic Chemistry, pp. 2833–2871, 2013. [FUS 12] FUSTERO S., BAEZ C., SANCHEZ-ROSELLO M. et al., “A new tandem cross-metathesis-intramolecular aza-Michael reaction for the synthesis of α,αdifluorinated lactams”, Synthesis, vol. 44, pp. 1863–1873, 2012. [HAA 03] HAACK T., KURTKAYA S., SNYDER J.P. et al., “Studies toward the synthesis of oximidines I and II”, Organic Letters, vol. 5, pp. 5019–5022, 2003. [HAI 12] HAIBACH M.C., KUNDU S., BROOKHART M. et al., “Alkane metathesis by tandem alkane-dehydrogenation-olefin metathesis catalysis and related chemistry”, Accounts of Chemical Research, vol. 45, pp. 947–958, 2012. [HAL 14] HALLE M.B., FERNANDES R.A., “A relay ring-opening/double ring-closing metathesis strategy for the bicyclic macrolide-butenolide core structures”, RSC Advances, vol. 4, pp. 63342–63348, 2014. [IRE 72] IRELAND R.E., MÜLLER R.H., “Claisen rearrangement of allyl esters”, Journal of the American Chemical Society, vol. 94, pp. 5897–5898, 1972. [IWA 77] IWAI K., KOSUGI H., UDA H. et al., “New method for synthesis of various types of substituted 2(5H)-furanones”, Bulletin of the Chemical Society of Japan, vol. 50, pp. 242–247, 1977. [LEE 05] LEE C.-L., LIN C.-F., LIN W.-R. et al., “Design, syntheses, and biological evaluations of squamostolide and its related analogs”, Bioorganic & Medicinal Chemistry, vol. 13, pp. 5864–5872, 2005. [LI 15] LI W., SCHNEIDER C.M., GEORG G.I., “Synthesis of strained 1,3-dienes macrocycles via copper-mediated Castro-Stephens coupling/alkyne reduction tandem reactions”, Organic Letters, vol. 17, pp. 3902–3905, 2015. [LIU 18] LIU P., AI C., “Olefin metathesis reaction in rubber chemistry and industry and beyond”, Industrial & Engineering Chemistry Research, vol. 57, pp. 3807–3820, 2018.

Squamostolide

47

[LOU 01] LOUIE J., BIELAWSKI C.W., GRUBBS R.H., “Tandem catalysis: The sequential mediation of olefin metathesis, hydrogenation, and hydrogen transfer with single-component Ru complexes”, Journal of the American Chemical Society, vol. 123, pp. 11312–11313, 2001. [MAJ 07] MAJUMDAR K.C., ALAM S., CHATTOPADHYAY B., “Catalysis of the Claisen rearrangement”, Tetrahedron, vol. 64, pp. 567–643, 2007. [MAK 06] MAKABE H., KIMURA Y., HIGUCHI M. et al., “Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin, squamostolide, and their inhibitory action with bovine heart mitochondrial complex I”, Bioorganic & Medicinal Chemistry, vol. 14, pp. 3119–3130, 2006. [MAO 14] MAOUGAL E., DALENCON S., PEARSON-LONG M.S.M. et al., “An efficient synthesis of 3,3’-bipiperidines using an ROM/RCM metathesis sequence: Extension to oxygenated analogues”, European Journal of Organic Chemistry, pp. 3268–3272, 2014. [MEE 11] MEEK S.J., O’BRIEN R.V., LLAVERIA J. et al., “Catalytic Z-selective olefin cross-metathesis for natural product synthesis”, Nature, vol. 471, pp. 461–466, 2011. [MIL 97] MILLER M.W., JOHNSON C.R., “Sonogashira coupling of 2-iodo-2-cycloalkenones: Synthesis of (+)- and (-)-harveynone and (-)-tricholomenyn A”, Journal of Organic Chemistry, vol. 62, pp. 1582–1583, 1997. [MOG 96] MOGHADDAM F.M., GHAFFARZADEH M., “Rapid dehydrosulfenylation of sulfoxides under microwave irradiation”, Tetrahedron Letters, vol. 37, pp. 1855–1858, 1996. [PAE 12] PAEK S.-M., “Synthesis of tetrasubstituted alkenes via metathesis”, Molecules, vol. 17, pp. 3348–3358, 2012. [PAR 67] PARIKH J.R., VON E. DOERING W., “Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide”, Journal of the American Chemical Society, vol. 89, pp. 5505–5507, 1967. [QUI 05] QUINN K.J., ISAACS A.K., DECHRISTOPHER B.A. et al., “Asymmetric total synthesis of rollicosin”, Organic Letters, vol. 7, pp. 1243–1245, 2005. [QUI 07] QUINN K.J., SMITH A.G., CAMMARANO C.M., “Convergent total synthesis of squamostolide”, Tetrahedron, vol. 63, pp. 4881–4886, 2007. [RAM 87] RAMA RAO A.V., MYSOREKAR S.V., GURJAR M.K. et al., “Synthesis of (3R,4R)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: Application to (R)-(+)-α−lipoic acid”, Tetrahedron Letters, vol. 28, pp. 2183–2186, 1987. [RED 13] REDDY N.K., CHANDRASEKHAR S., “Total synthesis of (-)-α−kainic acid via chirality transfer through Ireland-Claisen rearrangement”, Journal of Organic Chemistry, vol. 78, pp. 3355–3360, 2013. [REN 01] RENARD M., GHOSEZ L.A., “A convergent asymmetric synthesis of γ-butenolides”, Tetrahedron, vol. 57, pp. 2597–2608, 2001.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

[ROV 14] ROVIRA M., FONT M., ACUNA-PARES F. et al., “Aryl-copper(III)-acetylides as key intermediates in Csp2-Csp model couplings under mild conditions”, Chemistry: A European Journal, vol. 20, pp. 10005–10010, 2014. [SAN 17] SANCHEZ-ROSELLO M., MIRO J., DEL POZZO C., “Cross-metathesis/intramolecular (hetero)-Michael addition: A convenient sequence for the generation of carbo- and heterocycles”, Synthesis, vol. 34, pp. 2787–2802, 2017. [SCH 13] SCHMIDT B., HAUKE S., “Cross-metathesis of allyl alcohols: How to suppress and how to promote double bond isomerization”, Organic & Biomolecular Chemistry, vol. 11, pp. 4194–4206, 2013. [SCH 18] SCHMIDT B., PETERSEN M.H., BRAUN D., “Bidirectional synthesis of 6-acetoxy-5hexadecanolide, the mosquito oviposition pheromone of Culex quinquefasciatus, from a C2-symmetric building block using olefin metathesis reactions”, Journal of Organic Chemistry, vol. 83, pp. 1627–1633, 2018. [SER 16] SERRANO-MOLINA D., MARTIN-CASTRO A.M., “Tandem sequences involving Michael additions and sigmatropic rearrangements”, Synthesis, vol. 48, pp. 3459–3469, 2016. [SIN 10] SINGH C., SINGH A.S., NAIKADE N.K. et al., “Hydrazinium carbazate-H2O2: An ideal combination for diimide reduction of base-sensitive unsaturated peroxides”, Synthesis, pp. 1014–1022, 2010. [STE 63] STEPHENS R.D., CASTRO C.E., “The substitution of aryl iodides with cuprous acetylides. A synthesis of tolanes and heterocyclics”, Journal of Organic Chemistry, vol. 28, pp. 3313–3315, 1963. [TOH 83] TOH T.H., OKAMURA W.H., “Studies on a convergent route to side-chain analogues of vitamin D: 25-Hydroxy-23-oxavitamin D8”, Journal of Organic Chemistry, vol. 48, pp. 1414–1417, 1983. [VEN 12] VENUKADASULA P.K.M., CHEGONDI R., SURYN G.M. et al., “A phosphate tethermediated, one-pot, sequential ring-closing metathesis/cross-metathesis/chemoselective hydrogenation protocol”, Organic Letters, vol. 14, pp. 2634–2637, 2012. [VIR 03] VIROLLEAUD M.-A., BRESSY C., PIVA O., “A straightforward synthesis of (E)-δalkenyl-β,γ-unsaturated δ-lactones by a tandem ring-closing/cross-coupling metathesis process”, Tetrahedron Letters, vol. 44, pp. 8081–8084, 2003. [VIR 04] VIROLLEAUD M.-A., PIVA O., “Domino ring-closing metathesis/intramolecular transfer of an alkenyl subunit: A direct formation of functionalized butenolides and pyrenes from α,β- and β,γ-unsaturated esters”, Synlett, pp. 2087–2090, 2004. [WAL 13] WALDECK A.R., KRISCHE M.J., “Total synthesis of cyanolide A in the absence of protecting groups, chiral auxiliaries, or premetalated carbon nucleophiles”, Angewandte Chemie: International Edition, vol. 52, pp. 4470–4473, 2013. [WER 15] WERREL S., WALKER J.C.L., DONOHOE T.J., “Application of catalytic Z-selective olefin metathesis in natural product synthesis”, Tetrahedron Letters, vol. 56, pp. 5261–5268, 2015.

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49

[WHI 08] WHITE D.E., STEWART I.C., GRUBBS R.H. et al., “The catalytic asymmetric total synthesis of elatol”, Journal of the American Chemical Society, vol. 130, pp. 810–811, 2008. [XIE 03] XIE H.H., WEI X.Y., WANG J.D. et al., “A new cytotoxic acetogenin from the seeds of Annona squamosal”, Chinese Chemical Letters, vol. 14, pp. 588–590, 2003. [YET 16] YET L., “Olefin ring-closing metathesis”, Organic Reactions, vol. 89, pp. 1–1303, 2016. [ZIE 16] ZIELINSKI G., GRELA K., “Tandem catalysis utilizing olefin metathesis reactions”, Chemistry: A European Journal, vol. 22, pp. 9440–9454, 2016. [ZIE 18] ZIELINSKI G.K., MAJTCZAK J., GUTOWSKI M. et al., “A selective and functional group-tolerant ruthenium-catalyzed olefin metathesis/transfer hydrogenation tandem sequence using formic acid as hydrogen source”, Journal of Organic Chemistry, vol. 83, pp. 2542–2553, 2018.

3 Rubrenolide

3.1. Structure, isolation and properties Rubrenolide 1 and rubrynolide 2 are two isolated metabolites of Nectandra rubra, the red louro, a tree endemic to the Amazonian and Guyanese forests. These butyrolactones differ from each other only by the nature of the unsaturation at the end of the chain and have insecticidal (larvicidal) properties [FRA 71]. The relative and absolute configuration of the centers (2S, 4R, 2R') was confirmed by total synthesis [THI 04].

HO

O

2'R

HO 2S

HO

O

2S

HO

O 4R

4R

1

O

2'R

2

Figure 3.1. Structure of rubrenolide 1 and rubrynolide 2. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– A molecule with 17 carbon atoms with a disubstituted butyrolactone moiety: a long chain of carbon 10 atoms, fixed at position 5; a chain of three carbon atoms with a 1,2-diol unit is bonded at the α position of the carboxylic group.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

52

Retrosynthetic Analysis and Synthesis of Natural Products 1

3.2. Disconnections The butyrolactone unit is common in a large number of natural compounds, some of which are shown in Figure 3.2 and which have a variety of properties such as anti-cancer, antiviral, antibacterial, antifungal or anti-inflammatory. O

O O

O

O O

( )3

( )3

N H

γ-Decalactone

Dubiusamine

H HO2C

H

O

O

O O

O Cephalosporolide I

O

H H

H

O Arglabin

Figure 3.2. Examples of natural compounds possessing a butyrolactone framework

As a result, a significant number of methods to prepare the butyrolactone unit have been reported in the literature [MAO 17, KIT 09]. This diversity is also reflected in the three approaches described to synthesize rubrenolide.

Figure 3.3. Key disconnections for the lactone structure

Rubrenolide

53

3.3. Approach according to H. Fujioka [FUJ 05, FUJ 08] 3.3.1. Disconnection The synthesis is based on the involvement of a chiral cyclic ketal 3-C1 in a double iodoetherification, allowing the stereo-controlled formation of a new bicyclic ketal 3-B1 whose regioselective cleavage leads to the formation of a butyrolactone precursor. 1,2-Diphenyl ethanediol (hydroxybenzoin) was chosen for various reasons: – easy access by Sharpless asymmetric dihydroxylation of (E)-stilbene; – the selective cleavage which allows the formation of both a lactol, easily oxidized to lactone, and also an epoxide, facilitating the subsequent introduction of an unsaturated carbon chain. OH

I 2'R

OH 2'R

O

Ph

O 2R

D1

2S

H

O

O

O

D2 O

4S

4R

I

1

3-A Ph

1

( )8

3-B

O

4S 1

5

I

Ph O

D3

O H

MT

Ph

2'R

5

( )8

O

O

3-C1

H

D4 3-D1

Figure 3.4. Disconnection involving double iodoetherification

LEGEND OF FIGURE 3.4.D1: lactone cleavage and functionalization to the diol (tandem epoxide ring opening/translactonization and further reformation of an epoxide on the lateral chain).

54

Retrosynthetic Analysis and Synthesis of Natural Products 1

D2: terminal epoxide from a β-iodoether and a lactone from a lactol (epoxide cyclization and oxidation). D3: ketal cleavage and concomitant formation of a five- and eight-membered ring (bis-etherification and desymmetrization). D4: ketalization (from a diol of C2 symmetry). 3.3.2. Synthesis, developed by the Fujioka group Ph

Ph

Ph

H

CHO

I O

O

O

O

Ph O

b

a

H 3-C1 I

OH

O

c

OH

H

O

O

I

I

OH

O

( )7

3-C1 O

O

g

O

O O

Ph

O

O

f

e

OH

O

d

O

I

Ph

Ph

I

O

I

Ph O

I

3-B1

h ( )7

HO OH

( )7

Figure 3.5. Synthesis according to Fujioka

LEGEND OF FIGURE 3.5.– a. Ketalization – 83%: (R,R)-hydroxybenzoin, TMS-OTf, TMS-OMe, THF. b. Bisiodoetherification – 62%: NIS (2.5 equiv.), H2O, CH3CN, -40°C, 3 h.

Rubrenolide

55

c. Ketal cleavage: DDQ, CH3CN, H2O. d. Oxidation of lactol – 84% (two steps): NaClO2, NaH2PO4, 2-methylbutene, t-BuOH/H2O. e. Formation of a benzyl radical at the terminal position/β-elimination/epoxidation – 80%: (i) CAN, CH3CN, H2O; (ii) K2CO3, CH3CN. f. Ring opening of the epoxide: CH2=CH2-(CH2)7-MgBr, CuI. g. Relactonization – 63% (two steps): K2CO3, AcOEt. h. Ring opening of the epoxide by water – 75%: Bi(OTf)3, CH3CN, H2O. Number of steps: 8 – Overall yield: 16.3%. The overall yield of the synthesis is more than appreciable. The crucial step is a double iodoetherification. The first cyclization stereoselectively delivered a transient bicyclic oxonium species I, which is directly attacked by water. The free hydroxyl group of the remaining ketal II further reacts with a second iodonium intermediate. This second cyclization is assumed to be faster than the cleavage of the hemiketal which would result in the formation of an aliphatic γ-hydroxyaldehyde. Ph O

Ph

Ph

O I+

H2O

Ph H

+ O

Ph

I+

O

I O

I

I

O Ph H-O

H Ph

O H

I I

Ph

O

+

II

O H

O

I

Figure 3.6. Mechanism of bisiodoetherification

The transformation of the bicyclic diiodo compound requires three successive oxidation steps to produce a butyrolactone 3C1 possessing two additional electrophilic sites. Organocuprate reacts mainly with the terminal epoxide. The alcoholate formed under these conditions is then able to open the existing lactone ring; a new lactonization occurs and is accompanied by the formation of an epoxide. This strained three-membered ring is finally opened by water in the presence of bismuth triflate as a catalyst. It is interesting to note that the (potentially competitive) attack of the same cuprate on carbon linked to the iodine atom, followed by the opening of the terminal epoxide ring, would have led to a very similar structure (in fact the enantiomer) of the expected product (Figure 3.7).

56

Retrosynthetic Analysis and Synthesis of Natural Products 1 O

O

O

O

I R-MT

I

O R

O

O

O

R

O R-MT

R

O

O

O

O O O R

Figure 3.7. Epoxy ring opening versus direct alkylation

3.3.3. Key reaction: iodoetherification Haloetherification of alkenes allows the functionalization at the vicinal positions of a double bond. In intermolecular mode, regioselectivity depends on steric hindrance and electronic effects related to the nature of the substituents present on the double bond. The intramolecular process is much more attractive because the formation of cyclic structures can be predicted by Baldwin’s rules [BAL 76, ALA 13]. Out of all the processes involving halogens, iodoetherification (and lactonization) has developed most strongly [FUJ 12, SIM 94, ROU 97]. The electrophilic species may be the diiode itself, as well as more elaborate complexes such as Rousseau’s reagent (bis(sym-collidine)iodonium perchlorate or hexafluorophosphate). Hydroiodic acid is most often neutralized by sodium carbonate, in order to avoid any subsequent reaction. In addition to its ease of implementation, the reaction is most attractive because of its stereospecificity; by controlling the E or Z configuration of the double bond that will be activated, the relative stereochemistry of the two new contiguous centers can be predicted. These different aspects reflect the interest in accessing tetrahydrofuran or tetrahydropyran subunits widely present in natural products. Ph O

Ph O

Ph I(coll)2ClO4

O

Ph

Ph

O

O+

Bn-OH, CH2Cl2

I

-78°C -> r.t.

-

ClO4 Ph

OH

Figure 3.8. Ketal-assisted iodoetherification

Ph O

O I Ph 74% (dr 90/10)

Rubrenolide

57

3.3.4. Key reaction: oxidation of aldehydes to carboxylic acids The direct oxidation of primary alcohols to carboxylic acids very often requires drastic conditions that are difficult to reconcile with the presence of labile functions. The conversion of alcohol into aldehyde followed by a second oxidation step into the expected acid is nowadays the most commonly applied strategy in synthesis. The use of sodium chlorite (NaClO2) was initially reported by B. O. Lindgren for the oxidation of vanillin to vanillic acid [LIN 73]. G. A. Kraus significantly improved the modus operandi by associating 2-methyl-2-butene, an electron-rich alkene, to trap hypochlorous acid formed in situ [KRA 80]. Na+ ClO2- +

NaH2PO4

H-O-Cl=O

+ Na2HPO4

H O R

O

H O

R

H + Cl

H

H R

O

O

Cl

O O

O

Cl

H

O Cl O R

OH O

H + HO-Cl

Figure 3.9. Oxidation mechanism according to Lindgren–Kraus–Pinnick

The subsequent work of H. W. Pinnick, whose contribution somewhat evaded that of the first inventors, showed the general nature of the process, which has since been very widely applied to the synthesis of molecules of interest and in total synthesis [BAL 81, MAT 11, ZHA 15]. OMe Cl

O

OMe H

BnO Cl

NaClO2 (3 equiv.) NaH2PO4 (3 equiv.)

Cl

2-methyl-2-butene (4 equiv.)

BnO

THF/t-BuOH/H2O 25°C, 3h

O OH

Cl

Figure 3.10. Oxidation of an aldehyde to benzoic acid

95%

58

Retrosynthetic Analysis and Synthesis of Natural Products 1

NaClO2 (3 equiv.) NaH2PO4 (3 equiv.)

H

OHC

O

H

H

2-methyl-2-butene (4 equiv.)

HO2C

t-BuOH/H2O 25°C, 3h

O

H

91%

Figure 3.11. Access to spiculoic acid

3.3.5. Supporting synthetic transformations 3.3.5.1. Ketalization [FAU 01, TSU 80] O

O TMSO

O

OTMS

TMSOTf O

O

CH2Cl2, -30°C

O

O

82%

3.3.5.2. Hydrolysis of ketals under oxidizing conditions [FER 95, TAN 92] HO

O O

HO

O

DDQ (1 equiv.) O O

HO

HO

O O

CH3CN / H2O, 20°C, 48h

O 100%

3.3.5.3. Opening of epoxides by zinc compounds [DEL 03, PIN 04] (CH3)2Zn OH O

O O

P

65% Cu(OTf)2 PhMe, -78°C -> 0°C (1.5 mol%)

e.e. > 90%

Rubrenolide

59

3.3.5.4. Opening of epoxides catalyzed by Bi(OTf)3 [OLL 04, MOH 00] NH2 O

OH

Bi(OTf)3 10% mol. in water

+

hexanes or Et2O

NHPh

25°C, 7-9h

83%

3.4. Approach according to B. Zwanenburg 3.4.1. Retrosynthesis The retrosynthesis envisaged involves a post-functionalization at α of the lactone functional group [THI 04]. In order to control the relative stereochemistry between the substituents at position 3 and 5, a three-step process has been chosen: it requires an aldolization, crotonization and hydrogenation reaction of the double bond on the less cluttered side, the aldehyde used during condensation being the appropriately protected glyceraldehyde. Access to the five-membered heterocyclic compound results from the lactonization of the γ-hydroxyester 3'C. The latter is derived from the Wolff photochemical rearrangement of an α'-diazo-α, β-epoxyketone. This diazo reagent is obtained by the Arndt–Eistert reaction, from the α,β-epoxy acid 3'-F, itself derived from the trans epoxy alcohol 3'-G. OH OH 8(

)

HO D1

D1

O

O

O

O

D2

D2 ( )8

O

O 3-A2

OR

RO

OR

D4

D3 ( )8

O

D5

( )8

O

CO2Et

O

OH 2

3-B

3-C

OR

2

3-D2

OR N2

D6

OR

D7

D8

( )8

( )8 O

O

2

3-E

O

( )8

X O 3-F

O 2

( )8

OH O 3-G

2

Figure 3.12. Retrosynthesis envisaged by the Zwanenburg group

LEGEND OF FIGURE 3.12.– D1: generation of the terminal double bond (elimination).

60

Retrosynthetic Analysis and Synthesis of Natural Products 1

D2/D3: cleavage of α- of the lactone functional group (introduction of the side chain via an alkenylation followed by the reduction of the double bond). D4: butyrolactone formation (hydrogenation/cyclization under acidic medium). D5: formation of unsaturated γ-hydroxyester (epoxyketene alcoholysis). D6: epoxyketene (Wolff rearrangement of an epoxy α-diazoketone). D7: generation of epoxy-α-diazoketone (action of CH2N2 on an activated ester). D8: obtaining an acid from an epoxy alcohol (Pinnick’s oxidation). 3.4.2. Synthesis, Zwanenburg’s approach 3.4.2.1. Access to lactone 3-B2 ( )8

HO

c

e

h

OH

a

( )8

Br

OH

THPO

( )8

THPO

( )8

O

THPO

( )8

O

OH

b

( )8

Br

OTHP

THPO

( )8

f,g

THPO

( )8

O

i

THPO

( )8

O

d

OH

OH

O

CO2H

O

O i-Bu-O

N2

3-E2

O

OH j

HO

()

8

OEt 2

3-C

O

()

k, l, m THPO

8

O

O

2

3-B

Figure 3.13. Synthesis of lactone 3-B2

LEGEND OF FIGURE 3.13.– a. Bromination – 73%: HBr (48% aq.), hexanes, 80–100°C, 60 h. b. Protection of alcohol as a THP ether – 94%: DHP, TsOH, CH2Cl2, 0°C, 2 h. c. Nucleophilic substitution – 99%: LiNH2 (6 equiv.), 2-propyn-1-ol (1,3 equiv.), THF, -40°C then r.t. d. Reduction of the triple bond – 99%: LiAlH4, Et2O/THF, -60°C -> r.t. -> 40°C, 12 h.

Rubrenolide

61

e. Sharpless epoxidation – 69%: (-)-DET, Ti(OiPr)4, t-BuOOH, CH2Cl2, −25°C, 12h. f. Oxidation according to Swern: (i) Oxalyl chloride, DMSO, CH2Cl2, −60°C; (ii) Et3N, CH2Cl2, -60°C r.t. g. Oxidation of the aldehyde into acid according to Lindgren–Kraus–Pinnick process: NaClO2, t-BuOH, isobutene, NaH2PO4, H2O, r.t. h. Activation of acid by formation of mixed anhydride: Isobutyl chloroformate, Et3N, Et2O, 0°C. i. Formation of diazoketone 3-E2 – 68% (four steps): CH2N2, Et2O, −30°C. j. Photorearrangement of diazoketone 3-E2: hν (300 nm), EtOH (10-2 M), 4 h. k. Reduction of conjugated double bond – 57% (two steps): Ni(OAc)2, NaBH4, EtOH. l. Lactonization – 99%: TsOH (cat.), PhH, Δ. m. Protection of primary alcohol: DHP, TsOH, CH2Cl2, 0°C, 2 h. 3.4.2.2. Completion of the synthesis O

O

HO

O

O 3-B2

n

o

O

( )8

O

( )8

O

O

OTHP

OTHP OH

O

OH p

O

( )8 OH

O q, r

O

O

( )8

O

OH

3-A2 O

OH

O s, t

O 8(

)

O

OH u

8(

)

O

O 1

Figure 3.14. Completion of the synthesis

LEGEND OF FIGURE 3.14.– n. Aldolization – 26%: (i) LDA, HMPA, THF, -70°C; (ii) (S)-isopropylidene glyceraldehyde, 16 h.

62

Retrosynthetic Analysis and Synthesis of Natural Products 1

o. Elimination via mesylate – 72%: (i) Ms-Cl, Et3N, CCl4; (ii) DBU, ether, r.t. p. Deprotection of the acetonide group and THP – 70%: MeOH, TsOH, r.t. q. Diastereoselective hydrogenation – quantitative: H2, Pd/C, MeOH. r. Reprotection of the 1,2-diol as an acetonide – 73%: acetone, TsOH, 30 min. s. Arylselenation – 91%: o-nitrophenyl-selanyl cyanide, PBu3, THF, 2 h, r.t. t. Oxidation/β-elimination of selenoxide: H2O2, THF, r.t. u. Acetonide deprotection – 60% (two steps): p-TsOH, MeOH, r.t. Number of steps: 21 – Overall yield: 0.93%. Butyrolactone is obtained via the acid-catalyzed cyclization of a chiral γ-hydroxyester. The control of this center is ensured from the fifth stage thanks to the Sharpless epoxidation of a trans-allyl alcohol. A second center at the base of a hydroxy group and located on the side chain at position 3 comes from the chiral pool (glyceraldehyde). The step with the lowest yield (aldolization with only 26% yield) is followed by crotonization. The presence of the side chain at position 5 allows a diastereoselective hydrogenation to be carried out, which leads to a product that is mainly syn. The terminal unsaturated bond is generated from an alcohol and the use of selenium derivatives that are quickly removed under mild conditions (Grieco’s reaction). The major disadvantage of this synthesis is that it is totally linear, which results in a very low overall yield. 3.4.3. Key reaction: Wolff rearrangement The Wolff rearrangement allows the formation of a ketene from an α-diazo ketone. Its decomposition can be thermally initiated by UV light or by organometallic catalysis (silver salts); the intermediate is most often trapped by a nucleophilic species, such as ethanol, used as a solvent [KIR 02, FOR 15, FUS 17]. O

O

hν R2

R1 N

or Δ or Ag+

O

R2

R1

R1

N

R2

N

N

O R1 C R2

O

Nu-H

R2

Nu

R1 H

Figure 3.15. The Wolff rearrangement

Rubrenolide

63

Diazoketones from α,β-epoxyacids similarly lead to epoxyketenes, which after nucleophilic attack by an alcohol result in unsaturated γ-hydroxyesters [THI 90]. H 1) iBuCO-Cl

O R

Et3N, ether

O

N2

O

hν

R

CO2H 2) CH2N2

C

R

EtOH

O

Et O

O OH EtOH

OEt

R H

1,5-2h

46-63%

O

Figure 3.16. The Wolff rearrangement of α,β-epoxyacids

3.4.4. Key reaction: dehydration of alcohols according to Grieco NO2

NO2 Se

CN

R

OH

Se PBu3

PBu3

CN H-CN

H Se-Ar

R

O

R O

H2O2

H R

Bu

PBu3

Se

P

Bu Bu

NO2

O Se-Ar

R

+ Ar-Se-OH

Figure 3.17. The Grieco elimination mechanism

A very effective method of forming terminal alkenes from the corresponding primary alcohols was reported by Paul Grieco in 1976 [GRI 76]. It consists of the formation of an aryl selenide with the irreversible formation of a tributylphosphine oxide. At room temperature, the selenide is oxidized by hydrogen peroxide or m-CPBA to produce a selenoxide, which is immediately syn-eliminated and results in the formation of the expected alkene. This efficient method is far preferable to acid eliminations that may be accompanied by migration or Wagner–Meerwein-type

64

Retrosynthetic Analysis and Synthesis of Natural Products 1

rearrangements. It can also be highly regioselective; all of these factors have contributed to its reputation as a total synthesis [MAR 79, ZHO 02]. OH O

SeAr

O O

OH

O

O OH

Ar-SeCN H

PBu3

O OH

H 2 O2 (30%) r.t.

H

H

THF MeO2C

MeO2C

MeO2C

86%

98%

O

O N

OH 1)

Se-CN NO2

N

O

H

PBu3, THF, r.t.

CH3

N

2) NaIO4

NaHCO3 CH3OH 50°C

N

O

H

CH3 86%

Figure 3.18. Applications of Grieco’s reaction in total synthesis

3.4.5. Supporting synthetic transformations 3.4.5.1. Formation of bromoalcohols from 1,n-diols [KAD 03, END 91, CHO 00] HO

( )n

HBr aq. 48%

OH

n-Bu4NBr, μυ, 5min

n = 1-8

HO

( )n

Br

75-80%

3.4.5.2. Enantioselective epoxidation according to Sharpless [KON 07, KAT 80, HER 15] HO

CO2iPr

HO

CO2iPr

(-)DIPT OH

Ti(OiPr)4, t-BuOOH CH2Cl2, -30°C, 3h

OH O 75% (e.e. = 93.6%)

Rubrenolide

65

3.4.5.3. Reduction of α,β-unsaturated esters [RUS 71] Ni(OAc)2, EtOH, H2 CO2Et

CO2Et

NaBH4 100%

3.5. Approach according to N. Kommu [MAD 14] 3.5.1. Disconnections The synthesis is based on the direct construction of a lactone subunit by oxidation of a 1,4-diol. The two stereogenic centers present on the five-membered ring are created respectively by an alkylation reaction involving an Evans oxazolidinone, and by a stereo-controlled reduction of a ketone. The terminal 1,2-diol group on one of the two side chains results from a chironic approach from ascorbic acid. The terminal double bond is generated by partial hydrogenation of a triple bond, itself accessible from an aldehyde by the Ohira–Bestmann reaction, an alternative to the Corey–Fuchs reaction. RO

HO

RO

HO O

O

( )8

HO

( )8

HO

3-A3 RO

RO RO

RO

R'O

R'O

O

O P

( )7 CHO

3-B3

O

O 3-C3

O O

3-D3

O

OMe OMe

O

NX*

3-E3

Figure 3.19. Disconnection according to N. Kommu

CO2H

66

Retrosynthetic Analysis and Synthesis of Natural Products 1

3.5.2. Synthesis 3.5.2.1. Access to β-ketophosphonate 3-C3 O

O CO2H O

a, b

N

O

O

3-D3

O

e

O

Ph OTPS

OTPS c, d

O

O

O

H

O O

f, g

O

O

OMe P OMe O TPSO

O 3-C3

O

HN Ph

O

P

OMe OMe

O

XN*

3-F3

Figure 3.20. Synthesis of β-ketophosphonate 3-C3

LEGEND OF FIGURE 3.20.– a. Formation of acyl oxazolidinone – 88%: Piv-Cl, Et3N, XN*, LiCl, THF, −20°C. b. Diastereoselective alkylation – 65%: (i) NaHMDS, THF, -78°C, 1 h; (ii) Allyl bromide, -45°C, 4 h. c. Reduction in primary alcohol – 88%: LiBH4, MeOH, ether, 0°C - r.t., 3 h. d. Protection of the alcohol as a silyl ether – 94%: TPS-Cl, imid., CH2Cl2, 0°C. e. Ozonolysis in reducing medium – 85%: O3, CH2Cl2, -78°C, then Me2S, r.t., 14 h. f. Addition of methylphosphonate to the aldehyde: 3-F3, n-BuLi, THF, −78°C. g. Oxidation of β-hydroxyphosphonate to ketone – 84% (two steps): DMP, NaHCO3, CH2Cl2, r.t., 1 h.

Rubrenolide

67

3.5.2.2. Continuation of the synthesis ()6

HO

h

OH

HO

()6

()6

H

i

OBn

OBn

O 3-G3 O

O

O

O

j

k-m

()6 O

TPSO

( )7

OBn

OTBS

TPSO

O MeO MeO

O

O n

O

P

O

O

OH

OMe N2

3-H3

o ( )7

( )7 OTBS CHO

TPSO

OTBS

TPSO 3-I3

Figure 3.21. Access to alkyne 3-I3

LEGEND OF FIGURE 3.21.– h. Mono-etherification – 84%: NaH, BnBr, DMF, -10°C -> r.t., 6 h. i. Oxidation of primary alcohol according to Swern – 87%: (i) (COCl)2, DMSO, CH2Cl2, -78°C; (ii) Et3N, CH2Cl2, -78°C, 1 h. j. Wittig–Horner condensation – 76%: (i) phosphonate 3-C3, Ba(OH).8H2O, THF, 2 h; (ii) aldehyde 3-G3, THF/H2O (40: 1), r.t., 6 h. k. Enantioselective reduction of enone to allyl alcohol – 83% (d.r. = 95:5): (R)-CBS (1 equiv.), BH3. Me2S (1.5 equiv.), THF, -40°C, 8 h. l. Alcohol protection – 93%: TBS-OTf, 2,6-lutidine, CH2Cl2, 0°C, 2 h. m. Hydrogenation of the double bond and hydrogenolysis of benzyl ether – 86%: H2, Pd/C (10 mol%), AcOEt, r.t., 6 h. n. Oxidation of alcohol to aldehyde: DMP, NaHCO3, CH2Cl2, 0°C, 2 h. o. Ohira–Bestmann reaction – 78% (two steps): Reagent 3-H3, MeOH, K2CO3, r.t., 1 h.

68

Retrosynthetic Analysis and Synthesis of Natural Products 1

3.5.2.3. Termination of the synthesis O

O O

O ( )8

p

OTBS

TPSO

HO

3-I3

HO

O q

OH 3-A3

O

r, s O

O

( )8

HO O

O

( )8

Figure 3.22. Termination of the synthesis

LEGEND OF FIGURE 3.22.– p. Deprotection of the two silylated ethers – 76%: TBAF, THF, 0°C -> r.t., 12 h. q. Oxidation of diol to lactone – 90%: TEMPO, BAIB, CH2Cl2, r.t., 6 h. r. Ketal cleavage – 92%: HCl (2 M), THF, r.t., 2 h. s. Reduction of alkyne to alkene according to Lindlar – 90%: H2, Pd/ BaSO4, quinoline, r.t., 9 h. 3.5.3. Key reaction: diastereoselective alkylation of oxazolidinones Evans’ oxazolidinones are the chiral auxiliaries of choice for the creation of stereo-controlled centers in α-position of a carboxylic group [EVA 82]. Prepared from β-aminoalcohols from (2S)-amino acids such as valine, or alkaloids (norephedrine) and trisphogen, they are easily grafted onto an acid chain. The deprotonation of acyloxazolidinones results in enolate structures with Z configuration, the metal being chelated to the oxo group. This conformation favors the selective approach at low temperature of an electrophile to one of the two sides of the enolate. The highest selectivities are achieved with methyl iodide, allyl or benzyl bromides and are in the range of 90–99%; with other less activated or more cluttered electrophiles, higher reaction temperatures are required to collect products with similar yields, but at the expense of selectivities.

Rubrenolide

69

O NH2

O

NH2 LiAlH4

HO

THF

trisphosgene

O

O N

H

2) 1) n-BuLi

H

N

HO

O O

O

R1

Cl

O

O R1

N

THF, -78°C

O O

O

O N

R1

LDA THF -78°C

O

Li

N

O

O R1

E THF -30°C

O

O R1

N E

76% < d.e. < 98%

Figure 3.23. Alkylation involving an Evans oxazolidinone from (S)-valinol

During the deprotection step of the chiral auxiliary, the lithium hydroxide associated with H2O2 makes it possible to generate a nucleophilic reagent that is less basic than hydroxide ions, thus minimizing the risk of racemization of the new center created. Alternatively, direct product reduction allows access to primary alcohols without a significant variation in selectivity. In order to obtain the α-substituted carboxylic derivative with the opposite configuration, two complementary methods can be considered: – Use a chiral auxiliary with the opposite configuration; instead of involving unnatural (2R)-amino alcohols, the simplest way is to consider commercial derivatives of norephedrine, whose use is sadly regulated because of their potential precursors to synthetic drugs. – Do not change the initial auxiliary, but modify the order of electrophile introduction, i.e. first graft the R2 group on the acid chain, and then introduce the R1 group via a suitable electrophile.

70

Retrosynthetic Analysis and Synthesis of Natural Products 1

O O

O

O R1

N

a

Li

O

O

O R1

N

b

O

O

O R1

N

+

R2

O

O O

O

O R2

N

a

O

O

O R2

N

c

R2

8

O

O

R1

N

92 Li

O

O R2

N R1

+

O

O

R2

N R2

92

8

Conditions: (a) LiHMDS, THF, -78°C then 0°C; (b) R2-X (1.1 equiv.) or (c) R1-X (1.1 equiv.)

Figure 3.24. Reversal of the configuration of the new center from the same Evans oxazolidinone

O

O

O Ph

O

N

a

Li

O

O Ph

O

N

b

O

O

N

O

O N

+

O

O

N

a

O

N

8

O

O

Ph

Ph O

Li

O Ph

O

92

(S)-valinol series

O

O Ph

O

Ph b

O

Ph

N

O

N

+

98.5

(S)-t-leucinol series

1.5

Li O

O

O

O

Ph O

N

O

O

Ph a

O

N

O

O

Ph b

O

N

(S)-dimethylvalinol series

Ph +

97

O

N

3

Conditions: (a) LiHMDS, THF, -78°C then 0°C. (b) Me-I (1.1 equiv.) .

Figure 3.25. Evans’ oxazolidinones from (S)-valinol and SuperQuat®

Rubrenolide

71

In the case of β-amino alcohols, it is expected that the excesses will be greater the bulkier the grouping fixed to α- of the nitrogen atom. Thus, the selectivities obtained from t-leucine derivatives are very impressive, the disadvantage being to the detriment of the precursor. D. Seebach and S. Davies have in turn developed chiral reagents called “SuperQuat®” derived from the same inexpensive amino acids, but with almost as good a selectivity as with the t-leucine derivative [HIN 98, BUL 00, BUL 06, DAV 19]. The significant difference in selectivity between the valinol derivative and the one with two additional methyl groups (without creating a new stereogenic center) could be explained by measuring NOE effects in 1H-NMR spectrometry from lithium enolate structures. In valinol series, in order to minimize interactions with the enolate part, the hydrogen atom Ha is placed in the bisector plane derived from the two methyl groups of the isopropyl group. In SuperQuat series, due to the presence of the two methyl groups at the base of the oxygen atom, it is the hydrogen atom Hb which is placed in the median plane with the effect of bringing the isopropyl group closer to the nucleophilic site, thus allowing a better facial discrimination of an electrophile. Li O H O H O N H3C Ha H NOE

H3C Valinol series

H

H3C O O H3C Hb NOE

Li O H N

H CH3

CH3

Super Quat series

Figure 3.26. Change in conformation due to the introduction of a gem-dimethyl group on the heterocycle compound

3.5.4. Key reaction: enantioselective reduction of ketones – CBS method The CBS method – Corey–Bakshi–Shibata – allows the enantioselective reduction of ketones by the action of a chiral oxazaborolidine (most often derived from diphenylprolinol) and borane [COR 98, CHO 06]. The catalyst can be prepared in situ from amino alcohol and an alkylboronic acid in toluene and using a Dean–Stark apparatus [COR 87]. The reaction is extremely efficient when the carbonyl substrate has a very marked substitution difference, ideally bonded at α to a hybridized carbon atom sp3 and in α’ to a hybrid carbon atom sp2.

72

Retrosynthetic Analysis and Synthesis of Natural Products 1

Enantiomer excess (ee) can be increased by altering the nature of the group fixed to the boron atom, that of the associated reducing reagent (Borane–THF, catecholborane, etc.), and also the temperature. Selectivity at the transition state level results from the minimization of interactions (typically of a steric nature) between the substituent attached to the boron atom of the chiral auxiliary and the least bulky group Rs of the carbonyl compound. H N H

H Ph Ph

+

HO

B

OH

Δ Ph-Me

Alk

HO

B Alk

Ph

H BH3

N+

(S)-CBS

Ph

O

-

O

(S)-CBS O RL

RS

B

H 3B

Ph Ph

N

Alk

OH RS

RL H

N

H O

+

B Alk

H

+ N H 2B

Ph

-

BO H

H

RL C RS

Ph

O B

#

Ph Ph

-

H O

RL RS

CH3

Figure 3.27. Enantioselective reduction of ketones via the CBS method

This method published in 1987 by Corey et al. is similar to a process published a few years earlier by Itsuno and his team on the reduction of ketones and imines, involving an acyclic aminoalcohol derived from (S)-valine [ITS 83]. Nevertheless, the very large excesses and ease of implementation of this reaction have led to its very high profile and widespread use in total synthesis.

Rubrenolide

73

3.5.5. Key reaction: alkyne formation according to Ohira–Bestmann The Ohira–Bestmann reaction allows access to a terminal alkyne from an aldehyde with an additional unit at the end of the carbon chain. Initially described in 1989 by Ohira, the reaction was carried out in two stages: (i) preparation of the reagent from 2-oxopropylphosphonate; (ii) action of the reagent on an aldehyde in a basic medium [OHI 89]. The modifications made by Bestmann allowed the reagent to be generated in situ and access the alkyne in one step with a similar yield [ROT 04, PIE 06]. O

O

O 1) NaH, PhMe

MeO P MeO

MeO MeO

2) Ar-SO2-N3

O

P N

THF, 0°C

N

77%

Figure 3.28. Ohira–Bestmann reaction

From a mechanistic point of view, a retro-Claisen reaction by the action of sodium methoxide leads to a phosphonium ylide which immediately interacts with an aldehyde to give an oxaphosphetane whose decomposition leads to an acetylide, which is reprotonated using a protic solvent. O O MeO P MeO

O

O MeO-K

N

MeO MeO

MeOH

N

O MeO MeO

H

O P

R

O H

P

R

R

R H

N

N

N

N H

R

C

C

N

N

N

N

N

N

H

MeO MeO

O

P

N2

R

R MeO-K

H

K+

Figure 3.29. Ohira–Bestmann reaction mechanism

It is also possible to prepare the carbonyl compounds from benzyl alcohols using MnO2, then subjecting them to the Ohira–Bestmann reaction to directly access the expected alkynes [QUE 06].

74

Retrosynthetic Analysis and Synthesis of Natural Products 1

OH

O

CHO Br

Br

MnO2, THF

MeO MeO

O

P

Br N2

THF, 4-24h

MeOH, K2CO3 r.t., 12h

94%

Figure 3.30. Tandem oxidation reaction/Ohira–Bestmann reaction

3.5.6. Supporting synthetic transformations 3.5.6.1. The Swern oxidation [MAN 78, TID 90] O OH

1) Cl

O

Cl + DMSO O CH2Cl2, - 65°C

H

2) Base, - 65°C

72% 85%

Et3N iPr2NEt

3.5.6.2. Wittig–Horner reaction [PAT 93] O

O

P MeO MeO

Ba(OH)2

+

THF (40:1) 60°C, 20h

OBn

t-Bu

CHO OBn

O

Si

t-Bu

O

Si

O

O t-Bu 72%

O t-Bu

3.5.6.3. Oxidation of 1,4-diols by TEMPO/DAIB [NOM 14, HAN 03]

O

HO HO

OTPS

O OTPS

TEMPO, BAIB CH2Cl2 / H2O (1:1) 0°C -> r.t., 5h

81%

Rubrenolide

75

3.5.6.4. Oxidation of 1,4-diols to butyrolactones [LEY 94] O

TPAP

OH

(Pr4N)[RuO4] (5 mol%)

O

NMO (1.5 equiv.) CH3CN / CH2Cl2 (9:1)

OH

90%

3.5.6.5. Controlled hydrogenation of alkynes to alkenes [UEM 07] O O MPMO

H2

O OBn O

Lindlar catalyst AcOEt

MPMO

OBn

O O 99%

3.6. References [ALA 13] ALABUGIN I.V., GILMORE K., “Finding the right path: Baldwin “rules for ring closureˮ and stereoelectronic control of cyclizations”, Chemical Communications, vol. 49, pp. 11246–11250, 2013. [BAL 76] BALDWIN J.E., “Rules for ring closure”, Journal of the Chemical Society, Chemical Communications, pp. 734–736, 1976. [BAL 81] BAL B.S., CHILDERS Jr. W.E., PINNICK H.W., “Oxidation of α,β-unsaturated aldehydes”, Tetrahedron, vol. 37, pp. 2091–2096, 1981. [BUL 00] BULL S.D., DAVIES S.G., KEY M.-S. et al., “Conformational control in the SuperQuat chiral auxiliary 5,5-dimethyl-4-iso-propyloxxazolidin-2-ones induces the iso-propyl group to mimic a tert-butyl group”, Chemical Communications, pp. 1721–1722, 2000. [BUL 06] BULL S.D., DAVIES S.G., GARNER A.C. et al., “SuperQuat 5,5-dimethyl-4-isopropyloxazolidin-2-one as a mimic of Evans 4-tert-butyloxazolidin-2-one”, Organic & Biomolecular Chemistry, vol. 4, pp. 2945–2964, 2006. [CHO 00] CHONG J.M., HEUFT M.A., RABBAT P., “Solvent effects on the monobromination of α,ω-diols: A convenient preparation of ω-bromoalkanols”, Journal of Organic Chemistry, vol. 65, pp. 5837–5838, 2000. [CHO 06] CHO B.T., “Recent advances in the synthetic applications of the oxazaborolidinemediated asymmetric reduction”, Tetrahedron, vol. 62, pp. 7621–7643, 2006.

76

Retrosynthetic Analysis and Synthesis of Natural Products 1

[COR 87] COREY E.J., BAKSHI K., SHIBATA S., “Highly enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. Mechanism and synthetic implications”, Journal of American Chemical Society, vol. 109, pp. 5551–5553, 1987. [COR 98] COREY E.J., HELAL C.J., “Reduction of carbonyl compounds with chiral oxazaborolidine catalysts: A new paradigm for enantioselective catalysis and a powerful new synthetic method”, Angewandte Chemie: International Edition, vol. 37, pp. 1986–2012, 1998. [DAV 19] DAVIES S.G., FLETCHER A.M., ROBERTS P.M. et al., “SuperQuat chiral auxiliaries: Design, synthesis, and utility”, Organic & Biomolecular Chemistry, vol. 17, pp. 1322–1735, 2019. [DEL 03] DEL MORO F., CROTTI P., DI BUSSOLO V. et al., “Catalytic enantioselective desymmetrization of COT-monoepoxyde. Maximum deviation from coplanarity for SN2’-cuprate alkylation”, Organic Letters, vol. 5, pp. 1971–1974, 2003. [END 91] ENDERS D., BARTZEN D., “Stereoselective synthesis of racemic elemanolide dilactones related to vernolepin”, Liebigs Annalen der Chemie, pp. 569–574, 1991. [EVA 82] EVANS D.A., ENNIS M.D., MATHRE D.J., “Asymmetric alkylation reactions of chiral imide enolates. A practical approach to enantioselective synthesis of a-substituted carboxylic acid derivatives”, Journal of the American Chemical Society, vol. 104, pp. 1737–1739, 1982. [FAU 01] FAURE S., PIVA O., “Application of chiral tethers to intramolecular [2+2] photocycloadditions: Synthetic approach to (-)-italicene and (+)-isoitalicene”, Tetrahedron Letters, vol. 42, pp. 255–259, 2001. [FER 95] FERNANDEZ J.M.G., MELLET C.O., MARIN A.M. et al., “A mild and efficient procedure to remove acetal and dithiocetal protecting groups in carbohydrate derivatives using DDQ”, Carbohydrate Research, vol. 274, pp. 263–268, 1995. [FOR 15] FORD A., MIEL H., RING A. et al., “Modern organic synthesis with α−diazocarbonyl compounds”, Chemical Reviews, vol. 115, pp. 9981–10080, 2015. [FRA 71] FRANCA N.C., GOTTLIEB O.R., COXON D.T. et al., “Chemistry of Brazilian Lauraceae. XVII. Constitution of rubrenolide and rubrynolide, an alkene-alkyne pair of Nectandra rubra”, Anais da Academia Brasileira de ciéncias, vol. 43, pp. 123–125, 1971. [FUJ 05] FUJIOKA H., OHBA Y., HIROSE H. et al., “A double iodoetherification of σ-symmetric diene acetals for installing four stereogenic centers in a single operation: Short asymmetric total synthesis of rubrenolide”, Angewandte Chemie, International Edition, vol. 44, pp. 734–737, 2005. [FUJ 08] FUJIOKA H., OHBA Y., HIROSE H. et al., “Facile formation of tetrahydrofurans with multiple chiral centers using double iodoetherification of σ-symmetric diene acetals: Short asymmetric total synthesis of rubrenolide and rubrynolide”, Tetrahedron, vol. 64, pp. 4233–4245, 2008.

Rubrenolide

77

[FUJ 12] FUJIOKA H., “Intramolecular haloetherification of ene- and diene-acetals: Asymmetric synthesis involving chiral oxonium ion intermediates”, Synlett, vol. 23, pp. 825–836, 2012. [FUS 17] FUSE S., OTAKE Y., NAKAMURA H., Integrated micro-flow synthesis based on photochemical Wolff rearrangement”, European Journal of Organic Chemistry, pp. 6466–6473, 2017. [GRI 76] GRIECO P.A., GILMAN S., NISHIZAWA M., “Organoselenium chemistry. A facile one-step synthesis of alkyl aryl selenides from alcohols”, Journal of Organic Chemistry, vol. 41, pp. 1485–1485, 1976. [HAN 03] HANSEN T.M., FLORENCE G.J., LUGO-MAS P. et al., “Highly chemoselective oxidation of 1,5-diols to d-lactones with TEMPO/BAIB”, Tetrahedron Letters, vol. 44, pp. 57–59, 2003. [HER 15] HERAVI M.M., LASHAKI T.B., POORAHMAD N., “Applications of Sharpless asymmetric epoxidation in total synthesis”, Tetrahedron: Asymmetry, vol. 26, pp. 405–495, 2015. [HIN 98] HINTERMANN T., SEEBACH D., “A useful modification of the Evans auxiliairy: 4-Isopropyl-5,5-diphenyloxazolidine-2-one”, Helvetica Chimica Acta, vol. 81, pp. 2093–2126, 1998. [ITS 83] ITSUNO S., HIRAO A., NAKAHAMA S. et al., “Asymmetric synthesis using chirally modified borohydrides. Part 1. Enantioselective reduction of aromatic ketones with reagent prepared from borane and (S)-valinol”, Journal of the Chemical Society, Perkin Transactions 1, pp. 1673–1676, 1983. [KAD 03] KAD G.L., KAUR I., BHANDARI M. et al., “Functional group transformations of diols, cyclic ethers and lactones using aqueous hydrobromic acid and phase transfer catalyst under microwave irradiation”, Organic Process Research & Development, vol. 7, pp. 339–340, 2003. [KAT 80] KATSUKI T., SHARPLESS K.B., “The first practical method for asymmetric epoxidation”, Journal of the American Chemical Society, vol. 102, pp. 5974–5976, 1980. [KIR 02] KIRMSE W., “100 Years of the Wolff rearrangement”, European Journal of Organic Chemistry, vol. 2002, pp. 2193–2256, 2002. [KIT 09] KITSON R.R.A., MILLEMAGNI A., TAYLOR R.J.K., “The renaissance of α-methyleneγ-butyrolactones: New synthetic approaches”, Angewandte Chemie, International Edition, vol. 48, pp. 9426–9451, 2009. [KON 07] KONG L., ZHUANG Z., CHEN Q. et al., “A facile asymmetric synthesis of (+)-eldanolide”, Tetrahedron: Asymmetry, vol. 18, pp. 451–454, 2007. [KRA 80] KRAUS G.A., ROTH B., “Synthetic studies toward verrucarol. 2. Synthesis of the AB ring system”, Journal of Organic Chemistry, vol. 45, pp. 4825–4830, 1980. [LEY 94] LEY S.V., NORMAN J., GRIFFITH W.P. et al., “Tetrapropylammonium perruthenate, Pr4N+ RuO4-, TPAP: A catalytic oxidant for organic synthesis”, Synthesis, pp. 639–666, 1994.

78

Retrosynthetic Analysis and Synthesis of Natural Products 1

[LIN 73] LINDGREN B.O., NILSSON T., “Preparation of carboxylic acids from aldehydes (including hydroxylated benzaldehydes) by oxidation with chlorite”, Acta Chemica Scandinavica, vol. 27, pp. 888–890, 1973. [MAD 14] MADDA J., KHANDREGULA S., BANDARI S.K. et al., “Stereoselective total synthesis of rubrenolide and rubrynolide”, Tetrahedron: Asymmetry, vol. 25, pp. 1494–1500, 2014. [MAN 78] MANCUSO A.J., HUANG S.L., SWERN D., “Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide activated by oxalyl chloride”, Journal of Organic Chemistry, vol. 43, pp. 2480–2482, 1978. [MAO 17] MAO B., FANANAS-MASTRAL M., FERINGA B.L., “Catalytic asymmetric synthesis of butenolides and butyrolactones”, Chemical Reviews, vol. 117, pp. 10502–10566, 2017. [MAR 79] MARSHALL J.A., FLYNN G.A., “Stereoselective synthesis of racemic elemanolide dilactones related to vernolepin”, Journal of Organic Chemistry, vol. 44, pp. 1391–1397, 1979. [MAT 11] MATSUMURA D., TAKARABE T., TODA T. et al., “Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin”, Tetrahedron, vol. 67, pp. 6730–6745, 2011. [MOH 00] MOHAMMADPOOR-BALTORK I., TANGESTANINEJAD S., ALIYAN H. et al., “Bismuth(III) chloride; an efficient catalyst for mild, region- and stereoselective cleavage of epoxides with alcohols, acetic acid and water”, Synthetic Communications, vol. 30, pp. 2365–2374, 2000. [NOM 14] NOMULA R., RAJU G., KRISHNA R., “Total synthesis of two g-butyrolactone containing compounds (Z, 11S)-3,4-trans-11-hydroxy-3-methyldodec-cis-6-en-4-olide and (Z)-3,4-trans-11-oxo-3-methyldodec-cis-6-en-4-olide”, Tetrahedron Letters, vol. 55, pp. 5976–5978, 2014. [OHI 89] OHIRA S., “Methanolysis of dimethyl-(1-diazo-2-oxopropyl) phosphonate: Generation of dimethyl (diazomethyl)phosphonate and reaction with carbonyl compounds”, Synthetic Communications, vol. 19, pp. 561–564, 1989. [OLL 04] OLLEVIER T., LAVIE-COMPIN G., “Bismuth triflate-catalyzed mild and efficient epoxide opening by aromatic amines under aqueous conditions”, Tetrahedron Letters, vol. 45, pp. 49–52, 2004. [PAT 93] PATERSON I., YEUNG K-S., SMAILL J.B., “The Horner-Wadsworth-Emmons reaction in natural products synthesis: Expedient construction of complexe (E)-enones using barium hydroxide”, Synlett, pp. 774–776, 1993. [PIE 06] PIETRUSKA J., WITT A., “Synthesis of the Bestmann-Ohira reagent”, Synthesis, pp. 4266–4268, 2006. [PIN 04] PINESCHI M., “Copper-catalyzed enantioselective allylic alkylation ring-opening reactions of small-ring heterocycles with hard alkyl metals”, New Journal of Chemistry, vol. 28, pp. 657–665, 2004.

Rubrenolide

79

[QUE 06] QUESADA E., RAW S.A., REID M. et al., “One-pot conversion of activated alcohols into 1,1-dibromoalkenes and terminal alkynes using tandem oxidation processes with manganese dioxide”, Tetrahedron, vol. 62, pp. 6673–6680, 2006. [ROT 04] ROTH G.J., LIEPOLD B., MÜLLER S.G. et al., “Further improvements of the synthesis of alkynes from aldehydes”, Synthesis, pp. 59–62, 2004. [ROU 97] ROUSSEAU G., HOMSI F., “Preparation of seven and larger membered heterocycles by electrophilic heteroatom cyclization”, Chemical Society Reviews, vol. 26, pp. 453–461, 1997. [RUS 71] RUSSELL T.W., HOY R.C., “A facile reduction of unsaturated compounds containing oxygen”, Journal of Organic Chemistry, vol. 36, pp. 2018–2019, 1971. [SIM 94] SIMONOT B., ROUSSEAU G., “Oxygen effect in the iodo lactonization of unsaturated carboxylic acids leading to 7- to 12-membered ring lactones”, Journal of Organic Chemistry, vol. 59, pp. 5912–5919, 1994. [TAN 92] TANEMURA K., SUZUKI T., HORAGUCHI T., “2,3-Dichloro-5,6-p-benzoquinone as a mild and efficient catalyst for the deprotection of acetals”, Journal of Chemical Society, Chemical Communications, pp. 979–980, 1992. [TID 90] TIDWELL T.T., “Oxidation of alcohols to carbonyl compounds via alkoxysulfonium ylides: The Moffat, Swern, and related oxidations”, Organic Reactions, vol. 39, John Wiley & Sons, Hoboken, 1990. [THI 04] THIJS L., ZWANENBURG B., “Rubrenolide, total synthesis and revision of its reported stereochemical structure”, Tetrahedron, vol. 60, pp. 5237–5252, 2004. [THI 90] THIJS L., DOMMERHOLT F.J., LEEMHUIS F.M.C. et al., “A general stereospecific synthesis of γ-hydroxy-α,β-unsaturated esters”, Tetrahedron Letters, vol. 31, pp. 6589–6592, 1990. [TSU 80] TSUNODA T., SUZUKI M., NOYORI R., “Trialkylsilyl triflates. VI. A facile procedure for acetalization under aprotic conditions”, Tetrahedron Letters, vol. 21, pp. 1357–1358, 1980. [UEM 07] UEMURA T., SUZUKI T., ONODERA N. et al., “Total synthesis of (+)-obtusenyne”, Tetrahedron Letters, vol. 48 pp. 715–719, 2007. [ZHA 15] ZHANG A., XIE H., LI H. et al., “Total synthesis of (-)-exiguolide”, Organic Letters, vol. 17, pp. 4706–4709, 2015. [ZHO 02] ZHOU S.-Z., BOMMEZIJN S., MURPHY J.A., “Formal total synthesis of (+/-)vindoline by tandem radical cyclization”, Organic Letters, vol. 4, pp. 443–445, 2002.

4 Bipinnatin J

4.1. Structure, isolation and properties Isolated from gorgonians of the genus Pseudopterogorgia, bipinnatin J 1 belongs to the furanocembrane family of natural products and has cytotoxic activities against colon cancer or certain melanomas. It is considered a biosynthetic precursor of other complex polycyclic compounds such as intricarene 2 [TAN 06, ROE 06b].

OH O

O O

H H

O

O O

O 1

2

Figure 4.1. Structures of bipinnatin J 1 and intricarene 2. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– Fourteen-membered macrocycle with a butenolide moiety, a furan ring and a trisubstituted double bond. The molecule has three stereogenic centers, two of which are contiguous, one united in a homoallylic alcohol subunit characteristic of cembranoids. Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

82

Retrosynthetic Analysis and Synthesis of Natural Products 1

4.2. Disconnections The four syntheses described are all based on two main disconnections: the closure of the large cyclic ring from the same 4-A substrate via a Nozaki–Hiyama–Kishi reaction, on the one hand, and the stereo-controlled formation of a Z-trisubstituted C=C double bond directly linked to the furan unit, on the other hand.

OH

CHO

O

O

Br

D1 O

O

O

O

4-A

D2

X OR M

CHO

O

O O

4-C

4-B Figure 4.2. Key disconnections included for the four approaches

LEGEND OF FIGURE 4.2.– D1: ring closure (intramolecular Nozaki–Hiyama–Kishi reaction). D2: stereo-controlled fixation of a furan to a double bond with Z configuration (organopalladium coupling).

Bipinnatin J

83

4.3. Approach according to D. Trauner (racemic synthesis) [ROE 06a] 4.3.1. Synthesis The synthesis of this cembranoid is based on the construction of the 14-membered ring, by intramolecular Nozaki coupling between an aldehyde and an allyl bromide involving chromium (II) salts. The triple-substituted double bond of configuration (Z) is obtained by the carboalumination of butynol, the alcohol functional group being involved in the control of selectivity. The butenolide subunit is achieved by the ene reaction catalyzed by ruthenium salts between a γ-hydroxy ester propiolic and an alcohol. A Stille coupling is also involved to synthesize the precursor of macrocyclization. This is accompanied by selectivity in favor of the expected compound. Number of steps: 9 – Overall yield: 6.8%. 4.3.1.1. Access to 4-B1 lactone H a

OH

OH

b

O

I

I

OH

OH c

CO2Et

d I

CO2Et

I

OH O e

CHO

O

O f, g

I

OH

O

I

Figure 4.3. Formation of the lactone pattern 4-B1

4-B1

84

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 4.3.– a. Carboalumination/iodination of butynol – 60%: (i) Me3Al, Cp2ZrCl2, CH2Cl2; (ii) I2. b. Oxidation according to Dess–Martin: (i) Periodinane DMP (1.05 equiv.), CH2Cl2, 15 min.; (ii) NaHCO3 aq. c. Addition of an acetylide to aldehyde – 66% (two steps): ethyl propiolate, LDA, THF, −78°C. d. Ene reaction: allyl alcohol, catalyst A-2 (5%), THF/acetone, 50°C. e. In situ Lactonization – 52%: CSA, THF/acetone. f. Wittig reaction – 71%: Ph3P=CH(CH3)CHO, PhH. g. Reduction of unsaturated aldehyde to allyl alcohol – 99%: NaBH4, MeOH, r.t. + Catalyst A-2 :

Ru(N

C-CH3)3

PF6

4.3.1.2. Access to the synthon 4-C1

OLi

a' O

Li

CHO

O N

OMe

Bu3Sn

CHO

O 4-C

1

Figure 4.4. Synthesis of the synthon 4-C1

LEGEND OF FIGURE 4.4.– a'. Protection and ortholithiation of 3-methylfurfural – 85%: (i) n-BuLi, MeONHMe, THF, −40°C; (ii) Me3Sn-Cl; (iii) NH4Cl aq.

Bipinnatin J

85

4.3.1.3. Termination of the synthesis

O

O 4-B1

Br

O

OH

O

h

i

O O

O

10

O

H

H

4-A1 O O O O

O

OH 1'

j +

O

O

OH

O

1 O OH 1"

Figure 4.5. Termination of the synthesis

LEGEND OF FIGURE 4.5.– h. Stille coupling – 92%: 4-C1 (1.3 equiv.), Pd(Ph3)4 (4%), CuI (8%), CsF (2 equiv.), DMF, r.t., 20 min. i. Conversion of alcohol to bromide – 87%: NBS (1.1 equiv.), PPh3 (1.1 equiv.), CH2Cl2, −5°C, 20 min. j. Nozaki–Hiyama–Kishi reaction – 59%: CrCl2 (12 equiv.), NiCl2 (3 equiv.), 4 Å sieves, THF, 12 h, r.t. Ratio (1/1'/1'' = 73/12.7/5.8).

86

Retrosynthetic Analysis and Synthesis of Natural Products 1

4.3.2. Key reaction: ene reaction between alkynes and alkenes H

R1

+ H

+

R1

R1

R3

E' Ru L

R3 R2

E

R2

+

R3

R2

L

L

R1 > R2

A

Reductive elimination

+ Ru

H

+ R3

R2

+

Ru

H

+ R3

R1

R1

+ R3

Ru

+ R2

R2 R1

R2

D'

Hydride

D Ru

R1

β-elimination

B'

H R3

R2

R3

R1

B

+

Ru

C

Oxidative cyclization

+ + H Ru

R2

R3 R1

C'

Figure 4.6. An ene reaction involving an alkyne and an olefin

The ene reaction between an alkyne and an olefin results in the formation of 1,4-dienes. Trost et al. showed that cationic ruthenium complexes were able to catalyze the reaction. This is accompanied by high regio- and stereoselectivity, which makes it an attractive method, particularly for the synthesis of trisubstituted olefins. The proposed catalytic cycle includes four steps: (1) an exchange of ligands around the metal; (2) the formation of a metallacycle by oxidative cyclization; (3) a β-elimination leading to a ruthenium-hydride complex; (4) an irreversible reductive elimination step, regenerating the catalyst and leading to dienes E and E' [TRO 99, TRO 02]. Regioselectivity in favor of alkene E depends on the favored obtaining of metallacycle C rather than C' which corresponds to a minimization of interactions between the largest substituent R1 and the terminal site of the alkene [TRO 02]. The catalyst A-2 [CpRu-MeCN)3]PF6 is much more active than A-1 CpRu(COD)Cl and

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allows the desired transformation to be carried out at room temperature instead of at 65°C, in a polar solvent such as DMF. In the case of propiolic acid derivatives, regioselectivity is reversed and the carbon chain is fixed on α-position to the ester subunit. OH Ru(N

C-CH3)3

H H

H

PF6

A-2 (10% mol.)

+ ( )7

OH

( )7

H

DMF, r.t.

CO2Me

CO2Me 91%

OH O

( )14

OH

O

CO2Me

A-2 (10% mol.)

H

( )14

DMF, r.t.

OH

83%

Figure 4.7. Separate regioselectivities according to alkyne substitution

R3

R3

R2 +

HO

HO

R2

(10% mol.) R1

DMF, r.t.

R2

R3

A-3 Ru

R1

O H

Ru R1

O

H

O

H

O

H R3 A-3 :

Cp* Ru(N C-CH3)3

R2 R1

PF6

OHC 68-92%

OH

Figure 4.8. An ene reaction between an allyl alcohol and a propargyl alcohol

88

Retrosynthetic Analysis and Synthesis of Natural Products 1

The coupling between two alcohols makes it possible, via hydrogen bonds, to promote the regioselective formation of hydroxyaldehydes (reduced in situ by NaBH4) [RUM 17]. 4.3.3. Key reaction: Stille coupling The synthetic interest of coupling halogenated (or pseudohalogenated) aryl and vinyl derivatives with organotin compounds, catalyzed by palladium salts, was demonstrated by the Stille group in 1978 [MIL 78]. O

O Cl +

NC

Me3Sn-Me (1.01 equiv.)

Ph-CH2Pd(PPh3)2Cl (0.0005 equiv.) HMPA, 65°C

Me NC 99%

Figure 4.9. Initial Stille reaction: ketone formation

The reaction tolerates the presence of many functional groups and despite the relative toxicity of tin salts, it has been widely used for the synthesis of bioactive molecules, with various procedures now available to ensure that the final products are minimally contaminated with stannylated residues [COR 15, HER 18]. Using proven methods, whether through the ortholithiation of aromatic derivatives, or the regio- and stereoselective hydrostannylation of terminal alkynes, the synthesis of precursors is relatively easy and controlled. All these factors have contributed to its development. The (simplified) reaction mechanism can be represented according to a conventional catalytic cycle for palladocatalyzed reactions involving an oxidative addition step, a trans-metalation followed by isomerization, and then a reductive removal to regenerate the catalyst. It seems that depending on the nature of the starting group, that of the reaction medium (solvent, presence of additives), several reaction paths must be considered. A synergistic effect of copper(I) salts and fluoride ions has been demonstrated when the Stille reaction is carried out in a polar solvent such as DMF. Copper(I) iodide participates in transmetalation with the stannyl derivative to give a more reactive organocopper derivative, while the fluoride ion participates in the precipitation of tin salts in the medium, making the transmetalation reaction irreversible [MEE 04, MEE 05]. These same fluorides also affect the reducing elimination step [GRI 17].

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PdLn

R1-R2

89

Oxidative addition Reductive elimination

Isomerization

R1 R2

R1

Pd

L

L

Pd

L

X

L

Isomerization

Transmetalation R1 L

Pd

R2-SnBu3 X-SnBu3

L

R2

Figure 4.10. Catalytic cycle of the Stille reaction

L

(II)

R1

L

Pd R2

(II)

R1

Pd L

X

L

R2-Cu

Cu-X

Cu-I

CsF F-Sn(R3)3

I-Sn(R3)3

+ Cs-I Figure 4.11. Synergy of copper(I) salts and fluoride ions during the transmetalation step

R2-Sn(R3)3

90

Retrosynthetic Analysis and Synthesis of Natural Products 1

OPMB

OH

OPMB

Me4Sn (7.6 equiv.) Pd(PPh3)4 (0.05 equiv.)

CO2Me

OH CO2Me

CuI (0.2 equiv.) CsF (2.0 equiv.)

I

Me 75%

DMF, 45°C, 1h

Figure 4.12. Stille reaction: introduction of a methyl group [HAL 14]

OMe

OMe Br O Ac

N H

Pd(Ph3)4, CsF OMe

O

O

Bu3Sn

O

Ac

CH3CN, 100°C, 6h

N H

OMe

O

O

88%

Figure 4.13. Stille reaction: key step in the synthesis of clavilactones I

SnBu3 O

O

Pd2(dba)3, LiCl

O

O

DMF, r.t. OTBS

OMe

OTBS

OMe 94%

Figure 4.14. Stille reaction: macrocyclization [SAT 16]

4.3.4. Key reaction: Nozaki–Hiyama–Kishi reaction The nucleophilic addition of alkenylchromium reagents to carbonyl compounds was initially described by the Nozaki and Hiyama group in 1977 [OKU 77].

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OH R2

R1 OH

OH

R1

R2 R1

OH

R1

O H

R2

OH

R1

R1 R2

R2

OH R1 R2

Figure 4.15. Access to allyl, homoallyl and propargyl alcohols

The success of the coupling depends on the quality of the chromium salts used. The presence of catalytic quantities of nickel (II) chloride is essential to achieve effective coupling [TAK 83, TAK 86, JIN 86]. Its role is explained in the catalytic cycle shown below. The nickel (0) generated in situ contributes to the oxidative addition in the C-X bond. The alkenyl nickel undergoes transmetalation with chromium (III) salts to provide the species responsible for the 1,2-addition.

Ni X

Cr(III)

X

R

Cr(III)

NHTK

X = I, Br, OTf

R-CHO

OH

Ni(II)

Ni(0) (III)

2 Cr

(II)

2 Cr

Figure 4.16. Dual catalysis of the Nozaki–Hiyama–Takai–Kishi reaction

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Retrosynthetic Analysis and Synthesis of Natural Products 1

To control the configuration of the new stereocenter, the enantioselective version was studied. Of all the ligands tested, the one described by White and Shaw gives excellent results [WHI 11, TIA 16].

N

N R1

Cr O

O

O

OH

t-Bu

+

t-Bu t-Bu Mn (3 equiv.)

t-Bu

Br

R1 e.e. > 97%

THF

Figure 4.17. Enantioselective version of the Nozaki–Hiyama–Takai–Kishi reaction

TBSO

H

MeO

TBSO

O

O

O

OTBS

H

O

TBSO

O

OTBS I

O CHO

CrCl2 /NiCl2 THF / DMF

TBSO

H

MeO

TBSO

O O O

O

O

OTBS

H TBSO

OTBS O

OH

95%

Figure 4.18. Eribulin synthesis – a key macrocyclization step

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The reaction was widely used in total synthesis in both intermolecular and intramolecular modes to access macrocyclic structures [FÜR 99, GIL 17]. Researchers at Eisai in Japan used this reaction to synthesize eribulin, a complex anti-cancer molecule inspired by halichondrin B [YU 13]. 4.3.5. Supporting synthetic transformations 4.3.5.1. Carboalumination of homopropargyl alcohols [MA 97]

H

CH3

Me3Al Cp2ZrCl2 (1 equiv.)

H

CH2Cl2

OH

I2

HO

O Al

I 60%

4.3.5.2. Dess–Martin oxidation [THO 05, WIR 99, ZHD 02] I

Oxone

CO2H

OH

(0.2 equiv.)

OH

1.3 equiv.

acetonitrile/H2O, 70°C, 6h

O 94%

4.3.5.3. Ortholithiation of furans [DON 94]

n-BuLi O

THF, -80°C -> 0°C, 2h

O

Li

94

Retrosynthetic Analysis and Synthesis of Natural Products 1

4.3.5.4. Lithium–tin exchange [HUC 98, GRA 02]

1) n-BuLi (2.5 equiv.)

S

S

TMEDA / THF, -60°C

O

SnMe3

O

2) Me3Sn-Cl

95%

S

S

SnMe3

4.4. Approach according to V.H. Rawal [HUA 06] 4.4.1. Synthesis Macrocycle formation always involves an intramolecular Nozaki reaction (with the same selectivities). Different couplings, in particular that of Negishi and that between a butenolide enol ether and an allylic iodide, lead to the key precursor of macrocyclization [HUA 06]. Number of steps: 9 – Overall yield: 6.8%. 4.4.1.1. Access to butenolide 4-B2 4.4.1.1.1. Synthesis of 5-iodo-2-methyl-pent-2-enol protected 4-D2 Br

Br a

OH

OMOM

I b, c

4-D2

Figure 4.19. Access to the synthon 4-D2

LEGEND OF FIGURE 4.19.– a. Allylic oxidation – 67%: SeO2 (0.5 equiv.), t-BuOOH (2 equiv.), r.t., 6 h. b. Protection of the alcohol function – 91%: MOM-Cl (1.5 equiv.), iPrNEt2 (1.1 equiv.), 0°C -> r.t., CH2Cl2, 3 h. c. Bromine/iodine exchange – 99%: NaI/acetone, r.t., 12 h.

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4.4.1.1.2. Butyrolactone alkylation and access to 4-B2 O

O d

O

O

MOMO e, f

O

MOMO

O

O TBSO

OMOM

g

h

O

MOMO

O

I 4-B2

Figure 4.20. Synthesis of the precursor 4-B2

LEGEND OF FIGURE 4.20.– d. Deprotonation and alkylation of butyrolactone – 72%: (i) LDA, THF, HMPA (0.2 M), −78°C, 1.5 h; (ii) 4-D2. e. α-Selenation – 66%: (i) LDA, THF, −78°C; (ii) PhSeCl, 10 min. f. Oxidation and elimination of selenoxide – 82%: H2O2, THF, 10 min. g. Formation of 2-silyloxyfuran – 99%: (i) LDA, THF, −78°C; (ii) TBDMS-Cl, 20 min. h. Alkylation of enol ether – 60%: 3-Iodo-2-methyl-1-bromopropene (1.3 equiv.), Ag(O2CCF3) (1.2 equiv.), −40°C -> r.t. CH2Cl2, 4 h. 4.4.1.2. Preparation of the zinc reagent 4-E2 O

O O O

a'

ClZn

O O 4-E2

Figure 4.21. Ortholithiation – access to the reagent 4-E2

LEGEND OF FIGURE 4.21.– a’. Formation of the organozinc: (i) t-BuLi, THF, −78°C, 1.5 h; (ii) ZnCl2.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

4.4.1.3. Finalization of the synthesis MOMO

Br

O

O

O 4-B2

i

O O

O

j, k

O

10

O

O

H

O O O O

O

OH l

1'

+

O

O

OH O 1 O

OH 1"

Figure 4.22. Access to bipinnatin J 1

LEGEND OF FIGURE 4.22.– i. Negishi coupling – 99%: 4-E2, PdCl2(dppf), THF, 0°C, 2 h. j. Acid hydrolysis of dioxolane and MOM ether – 81% (two steps): PPTS, t-BuOH, 60–80°C, 18 h. k. Conversion of alcohol to bromide – 68%: CBr4, PPh3, CH2Cl2, 0°C, 5 min. l. Nozaki–Hiyama–Kishi reaction – 91.5% (1/1'/1''= 73/12.7/5.8): CrCl2 (20.6 equiv.), THF, 4 Å sieve.

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4.4.2. Key reaction: Negishi coupling In its initial form, the Negishi reaction corresponded to the coupling between an unsaturated halide (aromatic or vinyl) and an organozinc compound, a process catalyzed by palladium (0) salts. The accessibility of organozinc reagents as well as their low toxicity have made this reaction highly prized in synthesis. The catalytic cycle is very similar to that described for other palladocatalyzed reactions (Stille, Kumada–Corriu or Suzuki); it has been shown that the transmetalation step was faster with organozinc compounds than with organomagnesium compounds without the significant formation of products resulting from dehalogenation or β-elimination [NEG 80, NEG 11]. n-Bu-MT I

Pd(Ph3)4 (5 mol %)

n-Bu

THF, r.t., 2h

H

+

MT = ZnCl

76

2

MT = MgCl

25

51

Figure 4.23. Formation of 1,5-dienes according to Negishi

The use of lithium chloride is now recommended to improve the solubility of the organometallic compound, as well as to remove oxides from the zinc surface. In addition, other catalysts based on iron, cobalt, nickel or copper instead of palladium may also be involved, making it possible to extend the scope of cross couplings while reducing the cost of the overall process [HAA 16]. (2 mol%) I

ZnI +

N N

N

NiCl2.glyme (2 mol%) THF, 60°C, 20h

96%

Figure 4.24. Coupling involving a secondary organozinc derivative [JOS 11]

Particular attention was also given to couplings between aryl halides and primary [HAU 18, PAN 18] or secondary [JOS 11] zinc species. The efficiency of the coupling depends particularly on the polarity of the solvent medium as well as on the nature of the metal and the ligands that stabilize it.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

Bn

O

N

OMe

I

Bn N

H

OMOM

I

t-BuLi, ZnCl2 TBSO

O

MeO

OMOM

THF, -78°C

Pd-SPhos THF, DMA, 40°C

H

TBSO 49%

Figure 4.25. Coupling from a primary organozinc derivative [HAU 18]

The creation of new stereogenic centers has been studied. G. Fu’s work has thus provided access to coupling products with excellent yields and enantioselectivities. The C2 symmetric PyBox complexes have proven extremely successful [SON 08, QUR 17]. O O

O

ZnBr 1.2 equiv. + Cl

NiCl2 glyme

N Bn

O

N N (5.5%)

O

Bn

O

(S)-BnCH2-PyBox

NaCl (4.0 equiv.), DMA/DMF (1:1), -10°C

93% e.e. = 90%

Figure 4.26. Asymmetric coupling of allylic chlorides and organozinc compounds

4.4.3. Supporting synthetic transformations 4.4.3.1. Allylic oxidation by SeO2 [ZOU 07, FUJ 02] O

O SeO2 (3 equiv.) dioxane, μν 110°C, 10 min.

HO

83%

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4.4.3.2. Formation and elimination of selenoxides [RÜE 82] H

PhSe

H2O2, pyridine CO2Me

N

CO2Me

N

CH2Cl2, 0°C -> r.t.

Cbz

Cbz

87%

4.5. Enantioselective approach according to G. Pattenden [TAN 06] 4.5.1. Synthesis 4.5.1.1. Access to 4-B3 O

OH

OH

a, b

OH

OH

c

OH I

OH O

d

O S

O

I

O

e I

4-B3

Figure 4.27. Synthesis of butenolide 4-B3

LEGEND OF FIGURE 4.27.– a. Opening of (R)-glycidol – 97%: TMS-acetylene, n-BuLi, BF3.OEt2, THF, −78°C -> −30°C. b. Regeneration of the terminal alkyne – 92%: K2CO3, MeOH/THF, r.t. c. Carboalumination: (i) Cp2ZrCl2, AlMe3, Cl-CH2-CH2-CH2-Cl, r.t., then reflux, 3 days; (ii) I2, THF, −30°C −> 0°C. d. Tosylation of primary alcohol – 48% (two steps): TsCl, pyridine, 0–3°C. e. Formation of the epoxide – 73%: K2CO3, MeOH.

100

Retrosynthetic Analysis and Synthesis of Natural Products 1

4.5.1.2. Precursor synthesis 4-A3 SePh MeO

f, g

OH

MeO

O

O O

SePh

MeO2C

OTBS

h

i

O

SePh

OTBS

HO

I

I

O

j

TBSO

O

TBSO

O

k

OH

O

I

I 4-A3

Figure 4.28. 4-A3 Precursor synthesis of 4-A3

LEGEND OF FIGURE 4.28.– f. Protection of primary alcohol – 90%: TBS-Cl, imidazole, DMF, 0°C. g. α-Phenylselenation – 97%: (i) LDA, THF, −78°C; (ii) PhSe-Br, TMS-Cl, −78°C -> r.t. h. Epoxide ring opening 4-B3 – 60%: (i) NaHMDS, THF, −78°C; (ii) 4-B3, BF3.OEt2, -> r.t. i. Lactonization: TsOH cata. CH2Cl2, r.t. j. Formation and elimination of phenylselenoxide: H2O2, THF, 0°C -> r.t. k. Deprotection of TBS ether – 62% (three steps): PPTS (cata.), CH2Cl2/MeOH.

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4.5.1.3. Termination of the synthesis O O

Br

O

OH O

l, m

CHO

O

I 4-A3 O

O

O

O

n +

O

O

OH 1

OH 1' / 1"

Figure 4.29. Termination of the synthesis

LEGEND OF FIGURE 4.29.– l. Stille coupling: 4-C1, Pd(PPh3)4, CuI, CsF, DMF. m. Conversion of primary alcohol to bromide – 72% (two steps): NBS, PPh3. n. Cyclization by Nozaki–Hiyama–Kishi reaction – 70%: CrCl2 (10 equiv.), 4 Å MS, THF, r.t. Number of steps: 9 – Overall yield: 16.3%. Pattenden’s synthesis was the first enantioselective synthesis. The source of chirality is (R)-glycidol whose stereogenic center is in the five-membered lactone. The macrocycle closure process is based, as with other approaches, on an intramolecular Nozaki reaction.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

4.5.2. Supporting synthetic transformations 4.5.2.1. Epoxy ring opening [HEA 03, MAC 01] O

OH

SiMe3 n-BuLi

PPTS

K2CO3

BF3.OEt2

MeOH / THF

MeOH / THF

OTES

OH

THF, -78°C

73%

4.5.2.2. Stille coupling [ELO 08] Br NO2 +

NO2

Pd(Ph3)4

SnBu3

PhMe, 80°C, 16h

NO2

NO2 65%

4.6. Approach according to D. Trauner – enantioselective version 4.6.1. Synthesis [ROE 06b] 4.6.1.1. Access to butenolide 4-B4 H

OH OH

a

b

O I

I

OH

OH d, e

c I

I

SiMe3

SiMe3 O

CHO

OH j

f-i I

O

CO2Et I

Figure 4.30. Synthesis of butenolide 4-B4

4-B4

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LEGEND OF FIGURE 4.30.– a. Carboalumination/iodization of butynol – 60%: (i) Me3Al, Cp2ZrCl2; (ii) I2. b. Dess–Martin Oxidation: Periodinane, CH2Cl2, NaHCO3, 15 min, r.t. c. Addition of an acetylide to the aldehyde: Li-C=C-TMS, THF, −78°C, 15 min. d. Dess–Martin Oxidation – 60% (two steps): Dess–Martin periodinane, CH2Cl2, NaHCO3, 30 min. e. Enantioselective reduction of ynone – 91% (two steps): (i) (S)-Alpine borane, THF, 0°C -> r.t., 22 h; (ii) propionaldehyde, NaOH, H2O2, 16 h, r.t. f. Deprotection of the alkyne TMS group: MeOH, K2CO3. g. Protection of the hydroxy group: TES-OTf, lutidine, THF, 20 min. h. Functionalization of the terminal position of the alkyne: (i) LiHMDS, THF, −78°C; (ii) Cl-CO2Et, −50°C -> r.t. i. Deprotection of the TES group – 85% (four steps): HF aq., MeCN, 0°C. j. Ene alkyne/alkene reaction according to Trost and in situ lactonization – 52%: (i) allyl alcohol, 4-R catalyst (5%); (ii) CSA, THF/acetone. 4.6.1.2. Finalization of the synthesis OH

OH O

OH O

k, l

4-B4

m, n

O

10

I

I

Br

OH O

O

O

O

o

p

O O

O O

H

H

4-A4 O

O

O

O

q +

O

O

OH 1

OH 1' / 1"

Figure 4.31. Termination of the synthesis

104

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 4.31.– k. Wittig reaction – 84%: Ph3P=CH(CH3)CO2Et, CH2Cl2, r.t. l. Reduction of the unsaturated ester to allyl alcohol and lactone to lactol: DIBAL-H, CH2Cl2, −78°C. m. Oxidation to lactone and unsaturated aldehyde: PDC, CH2Cl2. n. Reduction of aldehyde to allyl alcohol – 70% (three steps): NaBH4, MeOH. o. Stille coupling – 92%: 4-C4 (1.3 equiv.), Pd(Ph3)4 (4 mol.), CuI (0.8 equiv.), CsF (2 equiv.), DMF. p. Conversion of alcohol to bromide – 87%: NBS (1.1 equiv.), PPh3 (1.1 equiv.), CH2Cl2, −5°C, 20 min. q. Nozaki–Hiyama–Kishi reaction – 72%: CrCl2, NiCl2, THF, 4 Å MS, r.t., 16 h. 4.6.1.3. Access to the synthon 4-C4

a' O

CHO

OLi Li

O N

Bu3Sn OMe

O

CHO

4-C4

Figure 4.32. Synthesis of the synthon 4-C4

LEGEND OF FIGURE 4.32.– a'. Protection and ortholithiation of 3-methylfurfural – 85%: (i) n-BuLi, MeONHMe, THF, −40°C; (ii) Me3Sn-Cl; (iii) NH4Cl aq. Number of steps: 18 – Overall yield: 4.9%. In this synthesis, stereochemistry control is achieved through the enantioselective reduction of an ynone by Alpine borane®. The strategy is similar to the first synthesis described by the same team (see the synthesis in section 4.3).

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4.6.2. Supporting synthetic transformations 4.6.2.1. Enantioselective reduction of ynones by Alpine borane® [MID 84, BRO 95]

B H

O

H OH

Alpine borane (2.2 equiv.) THF, r.t., 48h 72% (e.e. = 85%)

# B H CH3

+ pinene

O RL

Rs

4.6.2.2. Appel reaction [BER 07]

+ OH

Ph Ar

P

(+/-)

O

CCl4 Me

Cl

PhMe, 4Å MS -78°C -> r.t., 12h

+

Ph Ar

P

Me

e.e. = 50% > 95%

2006

2006 2006

2006

V.H. Rawal Univ. of Chicago

G. Pattenden Univ. of Nottingham

D. Trauner Univ. of California, Berkeley

4.4

4.5

4.6

Year

4.3

Corresponding author (University)

D. Trauner Univ. of California, Berkeley

Section

18

12

9

9 4.3.4. Nozaki reaction 4.3.4. Nozaki reaction

4.3.4. Nozaki reaction

4.3.3. Stille reaction

4.3.2. Ene reaction catalyzed by ruthenium

4.3.4. Nozaki reaction

4.3.3. Stille reaction

Key reaction 2, Key reaction 3

4.4.2. Negishi reaction

4.3.2. Ene reaction catalyzed by ruthenium

Key reaction 1

Table 4.1. Syntheses

4.9%

5.8%

11.5%

6.8%

Number Overall of steps yield

Enantioselective reduction with Alpine borane®

– stereo-controlled synthesis:

(R)-glycidol = chiron

– stereo-controlled synthesis:

– racemic synthesis

– racemic synthesis

Source of chirality

Racemic or stereocontrolled synthesis

106 Retrosynthetic Analysis and Synthesis of Natural Products 1

4.7. Comparison of the four syntheses

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4.8. References [BER 07] BERGIN E., O’CONNOR C.T., ROBINSON S.B. et al., “Synthesis of P-stereogenic phosphorous compounds. Asymmetric oxidation of phosphines under Appel conditions”, Journal of the American Chemical Society, vol. 129, pp. 9566–9567, 2007. [BRO 95] BROWN H.C., RAMACHANDRAN P.V., “Versatile α−pinene-based borane reagents for asymmetric syntheses”, Journal of Organometallic Chemistry, vol. 500, pp. 1–19, 1995. [COR 15] CORDOVILLA C., BARTOLOME C., MARTINEZ-ILARDUYA J.M. et al., “The Stille reaction, 38 years later”, ACS Catalysis, vol. 5, pp. 3040–3053, 2015. [DON 94] DONDONI A., JUNQUERA F., MERCHAN F.L. et al., “Addition of 2-lithiofuran to chiral α-alkoxy nitrones; a stereoselective approach to α-epimeric β-alkoxy-α-amino acids”, Synthesis, pp. 1450–1456, 1994. [ELO 08] ELOY N., PASQUINET E., GRECH E. et al., “A one-step safe synthesis of 2,4-dinitrostyrene and related (Di)nitrodivinylbenzenes via Stille coupling”, Synthesis, pp. 1805–1807, 2008. [FUJ 02] FUJIOKA H., KOTOKU N., SAWAMA Y. et al., “Concise asymmetric synthesis of a model compound (4S,5S,6S)-6-(2,2-dimethoxy)ethyl-4,5-epoxy-6-hydroxy-2 -cyclohexenone for the cyclohexanone core of scyphostatin”, Tetrahedron Letters, vol. 43, pp. 4825–4828, 2002. [FÜR 99] FÜRSTNER A., “Carbon-carbon bond formations involving organochromium(III) reagents”, Chemical Reviews, vol. 99, pp. 991–1046, 1999. [GIL 17] GIL A., ALBERICIO F., ALVAREZ M., “Role of the Nozaki-Hiyama -Takai-Kishi reaction in the synthesis of natural products”, Chemical Reviews, vol. 117, pp. 8420–8446, 2017. [GRA 02] GRANA P., PALEO M.R., SARDINA F.J., “A relative organolithium stability scale derived from tin-lithium exchange equilibria. Substituent effects on the stability of α−oxy- and α−aminoorganolithium compounds”, Journal of the American Chemical Society, vol. 124, pp. 12511–12514, 2002. [GRI 17] GRIMAUD L., JUTAND A., “Role of fluoride ions in palladium-catalyzed cross-coupling reactions”, Synthesis, vol. 49, pp. 1182–1189, 2017. [HAA 16] HAAS D., HAMMANN J.M., GREINER R. et al. “Recent developments in Negishi cross-coupling reactions”, ACS Catalysis, vol. 6, pp. 1540–1552, 2016. [HAL 14] HALE K.J., GRABSKI M., MANAVIAZAR S. et al., “Asymmetric total synthesis of (+)-inthomycin C via O-directed free radical alkyne hydrostannation with Ph3SnH and catalytic Et3B: Reinstatement of the Zeeck-Taylor (3R)-structure for (+)-inthomycin C”, Organic Letters, vol. 16, pp. 1164–1167, 2014. [HAU 18] HAUT F.-L., SPECK K., WILDERMUTH R. et al., “A Negishi cross-coupling reaction enables the total synthesis of (+)-stachyflin”, Tetrahedron, vol. 74, pp. 3348–3357, 2018.

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[HEA 03] HEATHCOCK C.H., MCLAUGHLIN M., MEDINA J. et al., “Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)”, Journal of the American Chemical Society, vol. 125, pp. 12844–12849, 2003. [HER 18] HERAVI M.M., MOHAMMADKHANI L., “Recent applications of Stille reaction in total synthesis of natural products: An update”, Journal of Organometallic Chemistry, vol. 869, pp. 106–200, 2018. [HUA 06] HUANG Q., RAWAL V.H., “Total synthesis of (+/−)-bipinnatin J”, Organic Letters, vol. 8, pp. 543–545, 2006. [HUC 98] HUCKE A., CAVA M.P., “Synthesis of mixed thiophene/furan oligomers by Stille coupling”, Journal of Organic Chemistry, vol. 63, pp. 7413–7417, 1998. [JIN 86] JIN H., UENISHI J.-I., CHRIST W.J. et al., “Catalytic effect of nickel(II) chloride and palladium (II) acetate on chromium(II)-mediated coupling reaction of iodo olefins on aldehydes”, Journal of the American Chemical Society, vol. 108, pp. 5644–5646, 1986. [JOS 11] JOSHI-PANGU A., GANESH M., BISCOE M.R., “Nickel-catalyzed Negishi cross-coupling reactions of secondary alkylzinc halides and aryl iodides”, Organic Letters, vol. 13, pp. 1218–1221, 2011. [MA 97] MA S., NEGISHI E.-I., “Anti-carbometallation of homopropargyl alcohols and their higher homologues via non-chelation controlled syn-carbometalation and chelation-controlled isomerization”, Journal of Organic Chemistry, vol. 62, pp. 784–785, 1997. [MAC 01] MACMILLAN D.W.C., OVERMAN L.E., PENNINGTON L.D., “A general strategy for the synthesis of cladiellin diterpenes: Enantioselective total syntheses of 6-acetoxycladiell-7(16),11-dien-3-ol, cladiell-11-ene-3,6,7-triol, sclerophytinA, and the initially purposed structure of sclerophytin A”, Journal of the American Chemical Society, vol. 123, pp. 9033–9044, 2001. [MEE 04] MEE S.P.H., LEE V., BALDWIN J.E., “Stille coupling made easier – The synergic effect of copper(I) salts and the fluoride ion”, Angewandte Chemie International Edition, vol. 43, pp. 1132–1136, 2004. [MEE 05] MEE S.P.H., LEE V., BALDWIN J.E., “Significant enhancement of the Stille reaction with a new combination of reagents – copper(I) iodide with cesium fluoride”, Chemistry: A European Journal, vol. 11, pp. 3294–3308, 2005. [MID 84] MIDLAND M.M., TRAMONTANO A., KAZUBSKI A. et al., “Asymmetric reductions of propargyl ketones”, Tetrahedron, vol. 40, pp. 1371–1380, 1984. [MIL 78] MILSTEIN D., STILLE J.K., “A general, selective, and facile method for ketone synthesis from acid chlorides and organotin compounds catalyzed by palladium”, Journal of the American Chemical Society, vol. 100, pp. 3636–3638, 1978. [NEG 80] NEGISHI E.-I., VALENTE L.F., KOBAYASHI M., “Palladium-catalyzed cross-coupling reaction of homoallylic or homopropargylic organozincs with alkenyl halides as a new selective route to 1,5-dienes and 1,5-enynes”, Journal of the American Chemical Society, vol. 102, pp. 3298–3299, 1980.

Bipinnatin J

109

[NEG 11] NEGISHI E., “Magical power of transition metals: Past, present, and future (Nobel lecture)”, Angewandte Chemie: International Edition, vol. 50, pp. 6738–6764, 2011. [OKU 77] OKUDE O., HIRANO S., HIYAMA T. et al., “Grignard type carbonyl addition of allyl halides by means of chromous salt. A chemospecific synthesis of homoallyl alcohols”, Journal of the American Chemical Society, vol. 99, pp. 3179–3181, 1977. [PAN 18] PANTIN M., BRIMBLE M.A., FURKERT D.P., “Total synthesis of (-)-peniphenone A”, Journal of Organic Chemistry, vol. 83, pp. 7049–7059, 2018. [QUR 17] QURESHI Z., TOKER C., LAUTENS M., “Secondary alkyl groups in palladium-catalyzed cross-coupling reactions”, Synthesis, vol. 49, pp. 1–16, 2017. [ROE 06a] ROETHLE P.A., TRAUNER D., “Expedient synthesis of (+/-)-bipinnatin J”, Organic Letters, vol. 8, pp. 345–347, 2006. [ROE 06b] ROETHLE P.A., HERNANDEZ P.T., TRAUNER D., “Exploring biosynthetic relationships among furanocembranoids: Synthesis of (-)-bipinnatin J, (+)-intricarene, (+)-rubifolide, and (+)-isoepilophodione B”, Organic Letters, vol. 8, pp. 5901–5904, 2006. [RÜE 82] RÜEGER H., BENN M.H., “The preparation of (S)-3,4-dehydroproline from (2S,4R)-4-hydroxyproline”, Canadian Journal of Chemistry, vol. 60, pp. 2918–2920, 1982. [RUM 17] RUMMELT S.M., CHENG G.-J., GUPTA P. et al., “Hydroxy-directed ruthenium-catalyzed alkene/alkyne coupling: Increased scope, stereochemical implications, and mechanistic rationale”, Angewandte Chemie: International Edition, vol. 56, pp. 2599–3604, 2017. [SAT 16] SATO E., TANABE Y., NAKAJIMA N. et al., “Total synthesis of biselyngbyolide B”, Organic Letters, vol. 18, pp. 2047–2049, 2016. [SON 08] SON S., FU G.C., “Nickel-catalyzed asymmetric Negishi cross-couplings of secondary allylic chlorides with alkylzincs”, Journal of the American Chemical Society, vol. 130, pp. 2756–2757, 2008. [TAK 83] TAKAI K., KIMURA K., KURODA T. et al., “Selective Grignard-type carbonyl addition of alkenyl halides mediated by chromium (II) chloride”, Tetrahedron Letters, vol. 24, pp. 5281–5284, 1983. [TAK 86] TAKAI K., TAGASHIRA M., KURODA T. et al., “Reactions of alkenylchromium reagents prepared from alkenyl trifluoromethanesulfonates with chromium (II) chloride under nickel catalysis”, Journal of the American Chemical Society, vol.108, pp. 6048–6050, 1986. [TAN 06] TANG B., BRAY C.D., PATTENDEN G., “A biomimetic total synthesis of (+)-intricarene”, Tetrahedron Letters, vol. 47, pp. 6401–6404, 2006. [THO 05] THOTTUMKARA A.P., BOWSHER M.S., VINOD T.K., “In situ generation of o-iodobenzoic acid (IBX) and the catalytic use of it in oxidation reactions in the presence of oxone as a co-oxidant”, Organic Letters, vol. 7, pp. 2933–2936, 2005.

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[TIA 16] TIAN Q., ZHANG G., “Recent advances in the asymmetric Nozaki-Hiyama-Kishi reaction”, Synthesis, vol. 48, pp. 4038–4049, 2016. [TRO 02] TROST B.M., SHEN H.C., PINKERTON A.B., “A synthesis of trisubstituted alkenes by a Ru-catalyzed addition”, Chemistry: A European Journal, vol. 8, pp. 2341–2349, 2002. [TRO 99] TROST B.M., TOSTE F.D., “A new Ru catalyst for alkene-alkyne coupling”, Tetrahedron Letters, vol. 40, pp. 7739–7743, 1999. [WHI 11] WHITE J.D., SHAW S., “cis-2,5-Diaminobicyclo[2.2.2]octane, a new scaffold for asymmetric catalysis via salen-metal complexes”, Organic Letters, vol. 13, pp. 2488–2491, 2011. [WIR 99] WIRTH T., HIRT U.H., “Hypervalent iodine compounds: Recent advances in synthetic applications”, Synthesis, pp. 1271–1287, 1999. [YU 13] YU M.J., ZHENG W., SELETSKY B.M., “From micrograms to grams: Scale-up synthesis of eribulin mesylate”, Natural Product Reports, vol. 30, pp. 1158–1164, 2013. [ZHD 02] ZHDANKIN V.V., STANG P.J., “Recent developments in the chemistry of polyvalent iodine compounds”, Chemical Reviews, vol. 102, pp. 2523–2584, 2002. [ZOU 07] ZOU Y., CHEN C.-H., TAYLOR C.D. et al., “Formal synthesis of (+/−)-platensimycin”, Organic Letters, vol. 9, pp. 1825–1828, 2007.

5 Tubingensin B

5.1. Structure, isolation and properties Tubingensin B 1 was isolated in 1989 from the fungus Aspergillus tubingensis and its structure was confirmed by X-ray diffraction [TEP 89]. This secondary metabolite appears to play a role in protecting the fungus when predatory organisms attack. It has some cytotoxicity to HeLa cancer cells with an IC50 of 4μg. mL−1.

OH

N H 1 Figure 5.1. Structure of tubingensin B. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– A hexacyclic structure comprising a carbazole unit fused with a bicyclo[3.2.2]nonane structure. Five stereogenic centers including three quaternary centers, two of which are contiguous. An alcohol functional group fixed to a six-membered ring.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

5.2. Bond disconnections The synthesis of tubingensin B 1 and its isomer 2 were both carried out by Neil K. Garg et al., taking advantage of a cyclization between a silylated enol ether and a carbazolyne species generated from an aryl brominated derivative [COR 17, GOE 14]. In parallel, the synthesis of compound 2 was carried out by K.C. Nicolaou et al. on the basis of the electrocyclization of a triene [BIA 12]. OH OH

N H

N H

1

2 Electrocyclization

Aryne OSiR3

OH

( )n N R

Gp

N Gp

Figure 5.2. Key disconnections for tubingensin 1 and 2

These syntheses highlight the recently revived interest in the potential of arynes to form polycyclic molecules. In particular, these successes are based on the way in which these intermediates are generated from ortho-silylated aromatic triflates by treatment with fluoride ions.

Tubingensin B

5.3. Approach according to N.K. Garg 5.3.1. Bond disconnections O

OH

Y D1 N

N H

Gp

1

5-A OSiR3

OH D2

D3

Y

Y

N

N

Gp

Gp

5-B

5-C X

X

O

N

D4

N

X' D5

5-E Gp

O +

Gp OH 5-D

5-F

Figure 5.3. Disconnection according to Garg

LEGEND OF FIGURE 5.3.– D1: formation of the bicyclo[3.2.2]nonane structure by radical cyclization. D2: opening of benzocyclobutanol. D3: cycloaddition [2+2] between an aryne and an enol ether. D4: formation of an enol ether by 1,4-addition and trapping. D5: formation of the 5-D enone by two successive cross couplings.

113

114

Retrosynthetic Analysis and Synthesis of Natural Products 1

5.3.2. Synthesis Br Br a

N

N

TfO

HO

MOM

MOM

Br

Br I

b

I

c, d

N

N MOM

MOM

HO

Figure 5.4. Functionalization of carbazole

LEGEND OF FIGURE 5.4.– a. Sonogashira reaction – 84%: Propargyl alcohol, Pd(PPh3)4, CuI, Et3N, DMF, 60°C. b. Cupromethylation/iodination – 71%: (i) MeMgBr, CuI, THF, −78°C, then 23°C; (ii) I2, THF, −78°C, then 23°C. c. Alcohol mesylation: Ms-Cl, Et3N, CH2Cl2, 0°C, then r.t. d. Mesylate reduction – 81% (two steps): LiBHEt3, THF, −78°C, then 23°C. ODMIPS

O e, f

ODMIPS g B

DMIPSO h

Br N MOM

Figure 5.5. Suzuki coupling

Tubingensin B

115

LEGEND OF FIGURE 5.5.– e. 1,4-Addition: VinylMgBr, CuI, THF, −78°C. f. Enolate trapping – 92% (two steps): DMIPS-Cl, HMPA, −78°C, then r.t. g. Hydroboration of the vinylic double bond: 9-BBN, THF, −78°C, then 50°C. h. Suzuki coupling – 76% (two steps): Pd2(dba)3, AsPh3, K3PO4, DMF, 23°C. O

ODMIPS

Br

Br i, j

MOM

N

MOM

N

OTES

SePh OH k

Br

l SePh

N MOM

MOM

N

Figure 5.6. Generation of the aryne and [2+2] cycloaddition

LEGEND OF FIGURE 5.6.– i. Access to dimethylaminoketone: [Me2N=CH2]+ I-, 18-Cr-6, KF, THF, 35°C. j. Oxidation/Cope elimination – 62% (two steps): m-CPBA, CH2Cl2, 0°C. k. 1,4-Addition of the PhSeCH2 fragment/enolate trapping – PhSe-CH2-SePh, n-BuLi, CuCN.2 LiCl, TES-Cl, THF, −78°C, then 23°C.

61%:

116

Retrosynthetic Analysis and Synthesis of Natural Products 1

l. Formation/cycloaddition of aryne – 47%: NaNH2, t-BuOH, THF, 1.5 h, 23°C. O

OH

SePh

m SePh

N

N

MOM

MOM

O

OH

n

o, p N

N H

MOM 1

Figure 5.7. Completion of the synthesis by Garg

LEGEND OF FIGURE 5.7.– m. Regio-controlled opening of benzocyclobutenol – 53%: [Rh(OH)cod]2, Ph-Me, 100°C. n. 6-exo-trig radical cyclization – 54%: Bu3SnH, AIBN, Ph-Me, 110°C. o. Stereoselective reduction of ketone – 43%: (S)-Ru(OAc)2(DM-SEGPHOS), H2, KOH, i-PrOH, 23°C. p. Deprotection of the MOM ether – 67%: HCl (3 N), ethylene glycol/THF, 55°C. The synthesis requires 13 steps for the longest sequence and is carried out with an overall yield of 0.53%. It combines both palladium-catalyzed coupling reactions, a cyclization reaction via an aryne, and a 6-exo-trig radical cyclization process to reach the bicyclo[3.2.2]nonane structure with a good yield of 47%. 5.3.3. Key reaction: Sonogashira reaction The Sonogashira reaction creates a C-C bond between an alkyne and an aryl or vinyl halide. The pallado-catalyzed process involves three classical steps for this type of coupling.

Tubingensin B

Pd(0)L2

L

1

R

R1-X

R2

L Pd R

1

L 1

L

2

R

117

R

R1 Pd

R2

Pd X L

L Cu+

H

X-

R2

Cu

R2

Base H

R

2

Cu X +

Figure 5.8. Catalytic cycle of the Sonogashira reaction

An oxidative addition step results in the formation of an organopalladium complex of oxidation degree (2), stabilized by two ligands, most often phosphines. It undergoes transmetalation involving copper acetylide generated by pre-complexing the terminal alkyne with copper (I) salts and in the presence of a base (a tertiary amine, for example). The final step is a reductive elimination, leading to the creation of the disubstituted alkyne and the regeneration of the Pd(0) catalyst. This reaction is widely used to create alkynes as well as alkenes of controlled configurations, by the selective reduction of the double bond, to the Z-isomer by hydrogenation in the presence of the Lindlar catalyst or the E alkene by reduction with LiAlH4. For safety reasons and ease of use, acetylene is often replaced by the trimethylsilyl derivative, a liquid for which the protective group can be selectively removed by fluoride ion action or in a basic medium. SiMe 3 F 3C

Br Cl

TMS Pd(Ph 3)4 Cu-I, Et 3N

F3C Cl

Figure 5.9. Regioselectivity for the Sonogashira reaction

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Retrosynthetic Analysis and Synthesis of Natural Products 1

O

O

Ar I

HN

NH

Ar O

N

N Pd(PPh3)4

O

O

Cu-I, Et3N

Si

O

Si

O

DMF, 25°C

O

O Si

O

Si

O

70%

Figure 5.10. Sonogashira coupling [SKO 06]

5.3.4. Key reaction: Suzuki coupling R1-X R1-R2 Pd(0) Oxidative addition

Reductive elimination

R1-Pd-R2

R1-Pd-X NaOH

B(OR)2

transmetallation R1-Pd-OH

(OH)2 R2

B(OR)2

NaX

OH

R2-B(OR)2

NaOH

Figure 5.11. Suzuki reaction catalytic cycle

O

Tubingensin B

119

The Suzuki coupling is currently the most popular pallado-catalyzed reaction for creating C-C bonds between a boron derivative and an aryl or vinyl halide/pseudohalide. Its main advantages are mild conditions, low catalyst loading, (E) or (Z) stereoselectivity maintained when vinyl compounds of established configuration are used. The reaction takes place in three phases: (1) generation of the organopalladium species of oxidation degree (II) by oxidative addition of the Carbon-Halogen bond; (2) transmetalation of the boron derivative involving anions that forms a chelate with the boron atom; and (3) reductive elimination resulting in the expected bond and regeneration of the catalyst to oxidation degree (0). Since its discovery in 1979, many developments have been reported for Suzuki coupling. Today, this reaction can be conducted from crowded boranes for Csp3-Csp2 couplings. In order to overcome their tendency to form trimeric boroxins, potassium trifluoroborates or MIDA derivatives are preferred over boronic acids, which are deprotected just before coupling.

MgBr

B(OMe)3

KHF2, H2O

THF

CHO Br

BF3K CHO

BF3K

PdCl2(dppf) (2% mol.) Et3N, n-PrOH, Δ, 3h 65%

Figure 5.12. Suzuki reaction involving potassium trifluoroborates

In addition to the very classical Friedel–Crafts reactions involving the nucleophilic properties of the aromatic ring with respect to electrophilic species such as carbocations, the functionalization of aromatic rings via arynes is now an alternative route. These highly constrained intermediates are likely to interact with different nucleophiles (Grignard reagents, enolates, alcoholates, etc.) or to perform thermal [4+2] or [2+2] cycloadditions. Access to these structures required extreme conditions until recently (use of strong bases such as sodium amide and/or use of high temperatures) [GRE 86].

120

Retrosynthetic Analysis and Synthesis of Natural Products 1

Recently, o-silylaryl triflates have been shown to be excellent precursors. The action of potassium fluoride in the presence of a crown ether to enhance the nucleophilic properties of the F ion results in the formation of an aryne, which can undergo cocyclization [2+2+2], for example [SAT 07]. 5.3.5. Key reaction: cycloaddition [2+2] of arynes [HUT 11, GRE 86, TDA 12] OTBS

OTBS

H

H NaNH2 (10.5 equiv) t-Bu-OH (3.5 equiv.)

O Br

O

THF, 23°C N

N

Me

Me

TBSO

OTBS H

H

O O

+ N

33%

Me

N 13%

Me

Figure 5.13. Cyclization of benzyne/enolate

These same fluoride ions are capable of generating the carbanion of a β-ketoester; a cycloaddition between the two species leads to benzocyclobutane which then opens spontaneously after protonation to form a disubstituted aromatic compound.

Tubingensin B

O

SiMe3

O

OTf

F

O

-

O

OMe

+ MeO

121

O

N

N

O O

O

O [Pd2(dba)3] (5 mol %) P(o-tol)3

O

Cs-F (6 equiv.) O

MeCN, r.t., 4h O

O

O

61%

Figure 5.14. Co-cyclization between an aryne and a diyne R1 SiMe3

O +

OTf

O

R1

O R2 O

R2

KF, 18-Cr-6 DME

R1

R1 O

O-M

M

+

R2

O R2

Figure 5.15. Cyclization of an aryne and β-ketoester

O

122

Retrosynthetic Analysis and Synthesis of Natural Products 1

5.3.6. Key reaction: radical cyclization and Baldwin’s rules Long overlooked in synthesis, radical reactions are now part of the synthetic chemist’s arsenal to access specific (poly)cyclic structures. The propensity of a radical to cyclize depends on many factors related to operational conditions as well as to the very structure of the starting products (sp or sp2 hybridization of the attacked centers, size of the cyclic compound formed, etc.). Professor Jack Baldwin defined rules that make it possible to consider the preference to form a cyclic compound by considering the two competitive exo or endo attacks [BAL 76]. The ratio observed 98:2 following the cyclization of a hexenyl radical is directly related to the kinetics of these two processes [BEC 92, ALA 13]. k6-endo = 4. 103 s-1

k5-exo = 2. 105 s-1

2

98

6-endo trig

5-exo trig

Figure 5.16. Radical cyclization of the 5-hexenyl radical

5.3.7. Key reaction: enantioselective hydrogenation of ketones The enantioselective hydrogenation of ketones to secondary alcohols in the presence of ruthenium complexes is a preferred alternative to reactions involving hydrides. The success of this method is largely linked to the discovery of highly efficient ligands both in terms of enantiomeric excesses and consequent turnover number (TON). In addition, its ease of implementation, operating conditions and low cost have made it possible to scale it up to industrial scales [SHI 07]. Axial symmetrical ligands, such as BINAP, have proven their effectiveness [OHK 98]. Subtle variations in the biphenyl system have allowed the design of new and even more active derivatives. Among them, SEGPHOS has proven to be very effective in reducing many ketones, possessing a second chelating group [SAI 01].

Tubingensin B

H2

O

OH

[NH2Me2] [{RuCl (R)-segphos)}2(u-Cl]3]

OH

123

OH

(S/C = 10000)

e.e. = 98.5% O

PPh2

PPh2

MeO

PPh2

O

PPh2

PPh2

PPh2

MeO

PPh2

O

PPh2

O BINAP

BIPHEMP

MeO-BIPHEP

SEGPHOS

θ

73.5°

72.0°

68.6°

65.0°

e.e.

89%

92.5%

96.0%

98.5%

θ

P

P

θ' P

P

M

M

O

O Y

Y

R

R

a)

b)

Figure 5.17. Enantioselective hydrogenation of hydroxyketone

This increase in selectivity is correlated with a decrease in angle θ, which then leads to stronger interactions between the aryl substituents attached to the phosphorus atoms and the substrate to be reduced.

124

Retrosynthetic Analysis and Synthesis of Natural Products 1

5.3.8. Supporting synthetic transformations 5.3.8.1. Access to α-methylene ketones according to Eschenmoser [DUD 01] O

1) LHMDS (1.5 equiv.) 2)

O H

N (3 equiv.)

I

N

THF, -78°C then r.t.

O m-CPBA (2 equiv.)

N

+

CH2Cl2, NaHCO3 (2:1)

OH

70%

5.3.8.2. Opening of benzocyclobutenols catalyzed by Rh(OH)(cod)2 [ISH 12] Rh

[Rh(OH)(cod)]2

OH Ph

O

(2.5 mol %)

Rh

Ph

O

Ph-Me, 100°C

Ph

Ph Ph O Rh

Ph

Ph

82%

Ph OH

5.3.8.3. 5-exo-trig radical cyclization [UYE 96]

Br

Bu3Sn-H O

(1.6 equiv.)

O

O

+

AIBN (0.1 equiv.) Ph-H, 80°C, 2h

42%

25%

Tubingensin B

125

5.3.8.4. Enantioselective reduction of ketones [TRA 97, TAN 03] O

(P*P)RuBr2 (2 mol %) SPh

H2 (30 bars), r.t. MeOH, 24h

MeO

P(Ph)2

(S)-MeO-Biphep MeO

P(Ph)2

P*P :

OH SPh Quantitative (e.e. = 98%)

5.4. References [ALA 13] ALABUGIN I.V., GILMORE K., “Finding the right path: “Baldwin Rules for ring closure” and stereoelectronic control of cyclizations”, Chemical Communications, vol. 49, pp. 11246–11250, 2013. [BAL 76] BALDWIN J.E., “Rules for ring-closure”, Journal of Chemical Society, Chemical Communications, pp. 734–736, 1976. [BEC 92] BECKWITH A.L.J., “The pursuit of selectivity in radical reactions”, Chemical Society Reviews, pp. 143–151, 1992. [BIA 12] BIAN M., WANG Z., XIONG X. et al., “Total syntheses of anominine and tubingensin A”, Journal of the American Chemical Society, vol. 134, pp. 8078–8081, 2012. [COR 17] CORSELLO M.A., KIM J., GARG N.K., “Total synthesis of (-)-tubingensin B enabled by the strategic use of an aryne cyclization”, Nature Chemistry, vol. 9, pp. 944–949, 2017. [DUD 01] DUDLEY G.B., TAN D.S., KIM G. et al., “Remarkable stereoselectivity in the alkylation of a hydroazulenone: Progress towards the total synthesis of guanacastepene”, Tetrahedron Letters, vol. 42, pp. 6789–6791, 2001. [GOE 14] GOETZ A.E., SILBERSTEIN A.L., CORSELLO M.A. et al., “Concise enantiospecific total synthesis of tubingensin A”, Journal of the American Chemical Society, vol. 136, pp. 3036–3039, 2014. [GRE 86] GREGOIRE B., CARRE M.-C., CAUBERE P., “Arynic condensation of ketone enolates. New general access to benzocyclobutene derivatives”, Journal of Organic Chemistry, vol. 51, pp. 1419–1427, 1986. [HUT 11] HUTERS A.D., QUASDORF K.W., STYDUHAR E.D. et al., “Total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate”, Journal of the American Chemical Society, vol. 133, pp. 15797–15799, 2011.

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[ISH 12] ISHIDA N., SAWANO S., MASUDA Y. et al., “Rhodium-catalyzed ring opening of benzocyclobutenols with site-selectivity complementary to thermal ring opening”, Journal of the American Chemical Society, vol. 134, pp. 17502–17504, 2012. [OHK 98] OHKUMA T., KOIZUMI M., DOUCET H. et al., “Asymmetric hydrogenation of alkenyl, cyclopropyl, and aryl ketones. RuCl2(xylbinap)(1,2-diamine) as a precatalyst exhibiting a wide scope”, Journal of the American Chemical Society, vol. 120, pp. 13529–13530, 1998. [SAI 01] SAITO T., YOKOZAWA T., ISHIZAKI T. et al., “New chiral diphosphine ligands designed to have a narrow dihedral angle in the biaryl backbone”, Advanced Synthesis & Catalysis, vol. 343, pp. 264–267, 2001. [SAT 07] SATO Y., TAMURA T., KINBARA A. et al., “Synthesis of biaryls via palladium-catalyzed [2+2+2] cocyclization of arynes and diynes: Application to the synthesis of aryl-naphtalene lignans”, Advanced Synthesis & Catalysis, vol. 349, pp. 647–661, 2007. [SHI 07] SHIMIZU H., NAGASAKI I., MATSUMURA K. et al., “Developments in asymmetric hydrogenation from an industrial perspective”, Accounts of Chemical Research, vol. 40, pp. 1385–1393, 2007. [SKO 06] SKOROBOGATYI M.V., USTINOV A.V., STEPANOVA I.A. et al., “5-Arylethynyl-2’ -deoxyuridines, compounds active against HSV-1”, Organic & Biomolecular Chemistry, vol. 4, pp. 1091–1096, 2006. [TAD 12] TADROSS P.M., STOLTZ B.M., “A comprehensive history of arynes in natural product total synthesis”, Chemical Review, vol. 112, pp. 3550–3577, 2012. [TAN 03] TANG W., ZHANG X., “New chiral phosphorous ligands for enantioselective hydrogenation”, Chemistry Review, vol. 103, pp. 3029–3069, 2003. [TEP 89] TEPASKE M.R., GLOER J.B., WICKLOW D.T. et al., “The structure of tubingensin B: A cytotoxic carbazole alkaloid from the sclerotia of Aspergillus tubingensis”, Tetrahedron Letters, vol. 30, pp. 5965–5968, 1989. [TRA 97] TRANCHIER J.-P., RATOVELOMANANA-VIDAL V., GENET J.-P. et al., “Asymmetric hydrogenation of phenylthio ketones with chiral Ru(II) catalysts”, Tetrahedron Letters, vol. 38, pp. 2951–2954, 1997. [UYE 96] UYEHARA T., MURAYAMA T., SAKAI K. et al., “Formal substitution at both bridgeheads of a bicyclo[2.2.2]oct-5-en-2-one and its application to a synthesis of modhephene”, Tetrahedron Letters, vol. 37, pp. 7295–7298, 1996.

6 Polygonatine A

6.1. Structure, isolation and properties Polygonatine A is an alkaloid isolated in 1997 from Polygonatum sibiricum of the lily family [SUN 05]. It is used in traditional Chinese medicine to treat bronchial diseases. It has a low activity against different microorganisms, suggesting that its real effectiveness needs to be weighed up. O

N OH

Figure 6.1. Structure of polygonatine A. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– An alkaloid with a 6,7-dihydro-8(5H)-indolizinone skeleton; the presence of a hydroxymethyl group on the pyrrole ring.

6.2. Disconnections Access to the indolizinone skeleton was considered starting from the same pyrrole precursor substituted on the nitrogen atom by an appropriate side chain, possessing a free carboxylic acid group; one approach is based on the cyclization of an acyl radical on the aromatic ring [ALL 01] while the other involves a Friedel–Crafts reaction via Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

128

Retrosynthetic Analysis and Synthesis of Natural Products 1

an acylium ion [DIN 06]. The hydroxymethyl group results from the reduction of an aldehyde group, introduced by a Vilsmeier–Haack reaction. O D2

O

O

N

O

D1

OH

R

N

N

O

N

CHO

HO

R D2'

N R

Figure 6.2. Key disconnections

LEGEND OF FIGURE 6.2.– D1: hydroxymethyl group derived from an aldehyde (Reduction). D2: formation of indolizinone (Radical cyclization). D2': formation of indolizinone (Intramolecular Friedel–Crafts acylation). 6.3. Synthesis according to S.M. Allin 6.3.1. Disconnection O

O

O D1

SePh

D2

N

N

N CHO

OH

CHO

O OCH3 D3

D4 N

CO2Me Br

CHO

Figure 6.3. Disconnection

+

H

N CHO

Polygonatine A

129

LEGEND OF FIGURE 6.3.– D1: obtaining the hydroxymethyl group from an aldehyde (reduction). D2: formation of the cycle with six centers adjacent to the pyrrole ring (radical cyclization and rearomatization). D3: access to the precursor of radical cyclization (conversion of the ester to acyl selenide). D4: functionalization of the nitrogen atom of the pyrrole ring (N-alkylation). 6.3.2. Synthesis The key reaction is the formation of the six-membered ring from pyrrole carboxaldehyde by radical cyclization according to a 6-exo-trig process. In the absence of carbon monoxide, the acyl radical leads to the expected product with a yield of only 20%. The intermediate is also likely to undergo decarbonylation resulting in the production of a new primary alkyl radical that can be cyclized to pyrrolizidine. The reaction conducted in a carbon monoxide atmosphere avoids decarbonylation and leads to the expected bicyclic compound. It should also be noted that the rearomatization of the pyrrole is accompanied by the reduction of the formyl group. CO2H

CO2Me a

N

H

CHO

N CHO

CHO

O O

b

N

H N

CHO

O

SePh d

c

N

N CHO

O

O

H N

Figure 6.4. Synthesis of polygonatine A and radical cyclization

HO

130

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 6.4.– a. Alkylation of the nitrogen atom of the pyrrole: (i) NaH, DMF, 30 min, r.t.; (ii) Br-(CH2)3-CO2Me, 0°C, 2 h, then r.t. b. Saponification of methyl ester – 95% (two steps): LiOH/EtOH/H2O, r.t., 4 h. c. Access to acyl selenide – 57%: Bu3P (2.5 equiv.), PhSe-SePh (1.5 equiv.), CH2Cl2, r.t. d. Reducing radical cyclization – 65%: Bu3SnH (2.2 equiv.) slow addition over 5–6 h, 80°C, CH3CN/cyclohexane in CO atmosphere (sealed tube). Number of steps: 4 – Overall yield: 35.2%. 6.3.3. Key reaction: radical cyclization of selenoesters Phenylselenoesters are excellent precursors of acyl radicals by homolytic cleavage of the C-Se bond [BOG 92]. When the substrate includes a substituted or unsubstituted C=C double bond, the addition takes place and results in the formation of a new cycle. The regioselectivity in favor of the observed 5-exo, 6-exo or even 7-exo-trig process obeys Baldwin’s rules. The reaction is usually not disrupted by decarbonylation, except when the resulting radical would be highly stabilized (benzyl, for example). O

O Bu3Sn-H (1.2 equiv.) AIBN (0.1 equiv.)

SePh ( )n

R

R ( )n

Ph-H, 80°C

n=0,R=H

81% (5-exo-trig)

n=1,R=H

76% (6-exo-trig)

n = 1 , R = CO2Me

84% (6-exo-trig)

n=2,R=H

74% (7-exo-trig)

Figure 6.5. Radical cyclization and exo-trig process

Polygonatine A

131

O O

SePh Bu3Sn-H (1.2 equiv.) CO2Me

CO2Me

37% +

AIBN (0.1 equiv.) Ph-H, 80°C

42% 6-exo-trig

O

CO2Me

5-exo-trig

CO CO2Me

CO2Me benzyl radical

Figure 6.6. Decarbonylation/cyclization versus direct radical cyclization

Conversely, with all other things being equal, the cyclization of acyl radicals on a triple bond is less favorable in terms of trajectory; in this case, reduction takes precedence over cyclization [CRI 89, BOG 92]. O

O SePh

Bu3Sn-H (1.2 equiv.) AIBN (0.1 equiv.)

H

Ph-H, 80°C Ph

Ph 61%

Figure 6.7. Reduction versus radical cyclization

These cyclizations could be carried out in tandem mode on polyunsaturated compounds. The studies conducted show that cyclizations are irreversible processes under kinetic control, preferably in an exo mode and not involving rearrangements of the newly formed radical. In the case of relatively crowded substrates at position 5, cyclization in the exo mode is more difficult for steric reasons and may be replaced by the endo mode, involving the formation of a more stable tertiary radical [BOG 92].

132

Retrosynthetic Analysis and Synthesis of Natural Products 1

Bu3Sn-H (1.2 equiv.)

PhSe O

O

O

H

AIBN (0.1 equiv.) Ph-H, 80°C

5-exo-dig

Me

6-endo-trig

Ph

Ph

Ph

H

80% (cis/trans 97/3)

Figure 6.8. Radical tandem reaction

Finally, these selenium-containing substrates were exploited during the total synthesis of indole alkaloids and the formation of bridged structures [BEN 08, ZAI 12]. MeO2C N

O

N MeO2C

H 6-endo-trig

N SePh N H

O

Bu3SnH Et3B C = 0.07M Ph-H, r.t. 71% (ratio: 1:1)

MeO2C

N

H

N

O

H 5-exo-trig Figure 6.9. Non-regioselective radical cyclization in indole series

Polygonatine A

133

6.3.4. Supporting synthetic transformations 6.3.4.1. Formation of acyl selenide [NIC 85] O O N SePh + Bu3P

CO2H

SePh

O

O

O

CH2Cl2, -20 -> 25°C O

O 75%

6.3.4.2. Carbonylation and radical cyclization [MIR 99, KIM 04] H

n-Bu3SnH + AIBN (addition in small portions)

N O

H N O

CO (80 atm.), PhH, 100°C C = 0.02M

I

C

30%

6.4. Synthesis by J.P. Michael 6.4.1. Disconnections O

O

O

D1

D2

N

N

N CHO

OH O

MeO

OH D3

D4

CO2Me

N

+ NH2

Figure 6.10. Disconnections

O OMe

O

134

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 6.10.– D1: obtaining the hydroxymethyl group from a formyl group (reduction). D2: introduction of a formyl group on an aromatic ring (Vilsmeier–Haack reaction). D3: formation of the six-membered ring (Friedel–Crafts acylation). D4: formation of the N-substituted pyrrole ring (condensation of a primary amine and a bis-acetal – Clauson-Kaas reaction). 6.4.2. Synthesis

CO2H + NH3

+

O

+ O C

MeO a

O

N

-

Cl

N

OMe O

Cl

O

c

b N

d N

CHO

N CHO HO

Figure 6.11. Synthesis of polygonatine A and Friedel–Crafts acylation

LEGEND OF FIGURE 6.11.– a. Formation of pyrrole – 61%: polyphosphoric acid, r.t., 16 h. b. Vilsmeier–Haack reaction – 54%: DMF, POCl3, PhMe, 0°C, then 4 h. c. Hydrolysis of vinyl chloride – 100%: HClO4 (60%)/HCO2H. d. Reduction of aldehyde to alcohol – 78%: Zn(BH4)2, THF, -10°C, 30 min. Number of steps: 4 – Overall yield: 25.7%. Condensation between a primary amine (γ-substituted by a carboxylic acid group) and 2,5-dimethoxytetrahydrofuran gives a pyrrole which by simple heating in an acid medium undergoes intramolecular acylation according to Friedel–Crafts. The introduction of the hydroxymethyl group could not be carried out successfully

Polygonatine A

135

via a SEAR reaction with formaldehyde or its equivalent. A Prins reaction via an azafulvenium intermediate then takes place to give bis-arylmethyl structures. 6.4.3. Key reaction: Vilsmeier–Haack–Arnold reaction The formylation of aromatic and heteroaromatic molecules has attracted the interest of chemists since the end of the 19th Century. Like the reactions of Reimer–Tiemann, Gattermann–Koch or Duff, the Vilsmeier–Haack reaction, initially reported in 1925, represents a very effective method for obtaining aromatic aldehydes from electron-rich aromatic hydrocarbons [BEN 15]; it was later extended to certain alkenes such as enol ethers by the Czech chemist Z. Arnold [REI 99]. The Vilsmeier–Haack reagent is prepared by the action of an acid chloride (most often phosphoryl chloride (POCl3) or oxalyl chloride) against an N,N-disubstituted formamide, typically DMF. It then interacts in an aromatic electrophilic substitution reaction (SEAR) to produce an intermediate iminium chloride which is hydrolyzed at the end of the reaction. O Cl

P

O N

Cl

Cl Cl

O + N

H O

-

O

P

Cl

P

O

Cl

Cl N

H

POCl2 H Cl

N

O

Cl

H Cl

Cl

-

N

O-POCl2

Cl

N

H -

Cl

H

Vilsmeier-Haack reagent

Cl OH

H

N

OH

OH

Cl

H

-

Cl

H

N

NMe2 Cl

OH H2O

OH N H H Cl

H-NMe2, HCl

OH

-

O H

Figure 6.12. Mechanism of the Vilsmeier–Haack reaction applied to phenol

136

Retrosynthetic Analysis and Synthesis of Natural Products 1

The reaction has been widely applied in the synthesis of natural products, particularly in indole series. Thus, access to CDE cycles of aspidospermatan-type alkaloids could be achieved by combining a Vilsmeier–Haack reaction with a 1,3-dipolar cycloaddition involving an azomethine ylide [HAU 17]. TfO

O H

CN

N

O

TfO

1) Tf2O

O

DTBMP

OAc

OAc

CH2Cl2, t.a.

CO2Me

CO2Me

O

CN

N

TfO

TfO

CN

N

OAc

TfO

CN

N

OAc

O

CO2Me

CO2Me OMe CN

N 2) i-Pr2NEt

OAc

O

PhCl 125°C

N

NC

CO2Me

OAc O

O OMe

NC N

N

OMe

MeO2C

NC O

OAc O

AcO

47%

N

N

N H

MeO2C

N Condylocarpine

Condyfoline

Figure 6.13. Tandem Vilsmeier–Haack/[3+2] cycloaddition reaction

Polygonatine A

137

More traditionally, the introduction of a formyl group was carried out as the last step in the synthesis of indiacen A [ANA 17].

+ N

1) POCl3, DMF

H Cl

-

O

0°C, 15 min 2) H2O

N

H

Cl

N

H

H

Indiacen A 58%

Figure 6.14. Last step in the synthesis of indiacen A

6.4.4. Supporting synthetic transformations 6.4.4.1. Pyrrole formation – Clauson-Kaas reaction [ELM 52, ROC 06, MÜL 98] CO2Me Cl

HN NH2

CO2Me HN

OMe +

N N+ Cl H

O

MeO

1,4-dioxane 100°C

F

F

90%

6.4.4.2. Alkylation according to Friedel–Crafts [ERK 90, BAN 04] OH

OH

O CO2Me

CH2Cl2, -10°C

Me OH

* CO2Me

56% e.e. = 84% ZrCl3

138

Retrosynthetic Analysis and Synthesis of Natural Products 1

6.4.4.3. SEAR involving an azafulvenium ion [DIN 06, ABE 99] O

OEt

N

Cl SnCl4

O

O

N +

N

EtO O PhH

N Ph

6.4.4.4. Vilsmeier–Haack reaction [MIK 06, JON 97, TAS 03] O H N 1) POCl3, DMF

+ N

H Cl

-

N

Cl

Cl OMe

2) H2O

Cl , -78°C OMe

82%

6.4.4.5. Aromatic hydrocarbon formylation – Gattermann–Koch reaction [CRO 49]

Polygonatine A

139

6.4.4.6. Aromatic hydrocarbon formylation – Duff reaction [GHO 13, GRI 16] N

OH N N

OH N

CHO

HMTA CO2Me

CO2Me

TFA, 75°C, 8h 85%

6.4.4.7. Aromatic hydrocarbon formylation – Reimer–Tiemann reaction [VUO 12] OH

OH CHO CHCl3, NaOH

Cl

N H

H2O, 80°C, 20h

O

Cl

N H

O

46%

6.4.4.8. Chemo-selective reduction by Zn(BH4)2 [TAK 80, CRA 73, OIS 99] O

O

O

O

CCl3

O

O

CCl3

O

O O

O

O

Zn(BH4)2

O

ether, r.t. O

OH 73%

6.5. References [ABE 99] ABELL A.D., NABBS B.K., “Properties and reactions of ring-deactivated deuterated hydroxymethylpyrroles”, Organic Letters, vol. 1, pp. 1403–1405, 1999. [ALL 01] ALLIN S.M., BARTON W.R.S., BOWMAN W.R. et al., “Acyl radical cyclisation onto pyrroles”, Tetrahedron Letters, vol. 42, pp. 7887–7890, 2001. [ANA 17] ANANTOJU J.K., MOHD B.S., MARINGANTI T.C., “An efficient and concise synthesis of indiacen A and indiacen B”, Tetrahedron Letters, vol. 58, pp. 1499–1500, 2017.

140

Retrosynthetic Analysis and Synthesis of Natural Products 1

[BAN 04] BANDINI M., MELLONI A., UMANI-RONCHI A., “New catalytic approaches in the stereoselective Friedel-Crafts alkylation reaction”, Angewandte Chemie: International Edition, vol. 43, pp. 550–556, 2004. [BEN 08] BENNASAR M.-L., ROSA T., GARCIA-DIAZ D., “A new acyl radical-based route to 1,5-methanoazocino[4,3-b]indole framework of uleine and strychnos alkaloids”, Journal of Organic Chemistry, vol. 73, pp. 9033–9039, 2008. [BEN 15] BENIWAL M., JAIN N., “Review article on Vilsmeier Haack reaction and its applications”, European Journal of Biomedical and Pharmaceutical Sciences, vol. 2, pp. 1340–1374, 2015. [BOG 92] BOGER D.L., MATHVINK R.J., “Acyl radicals: Intermolecular and intramolecular alkene addition reactions”, Journal of Organic Chemistry, vol. 57, pp. 1429–1443, 1992. [CRA 73] CRABBÉ P., GARCIA A., RIUS C., “Synthesis of novel bicyclic prostaglandins by photochemical cycloaddition reactions”, Journal of Chemical Society, Perkin Transaction vol. 1, pp. 810–816, 1973. [CRI 89] CRICH D., FORTT S.M., “Acyl radical cyclizations in synthesis. Part 1. Substituent effects on the mode and efficiency of cyclization of 6-heptenoyl radicals”, Tetrahedron, vol. 45, pp. 6581–6598, 1989. [CRO 49] CROUNSE N.N., “The Gattermann-Koch reaction. The formylation of isopropylbenzene under pressure”, Journal of the American Chemical Society, vol. 71, pp. 1263–1264, 1949. [DIN 06] DINSMORE A., MANDY K., MICHAEL J.P., “Total synthesis of two novel 5,6,7,8-tetrahydroindolizine alkaloids, polygonatines A and B”, Organic & Biomolecular Chemistry, vol. 4, pp. 1032–1037, 2006. [ELM 52] ELMING N., CLAUSON-KAAS N., “The preparation of pyrroles from furans”, Acta Chemica Scandinavica, vol. 6, pp. 867–874, 1952. [ERK 90] ERKER G., VAN DER ZEIJDEN A.H., “Enantioselective catalysts having a new zirconium trichloride-Lewis acid with dibornaneannulated cyclopentadienyl ligand”, Angewandte Chemie: International Edition, vol. 29, pp. 512–514, 1990. [GHO 13] GHOSH K., KARMAKAR R., MAL D., “Total synthesis of neo-tanshinlactones through a cascade benzannulation-lactonisation as the key step”, European Journal of Organic Chemistry, pp. 4037–4046, 2013. [GRI 16] GRIMBLAT N., SAROTTI A.M., KAUFMAN T.S. et al., “A theoretical study of the Duff reaction: Insights into its selectivity”, Organic & Biomolecular Chemistry, vol. 14, pp. 10496–10501, 2016. [HAU 17] HAUDUC C., BELANGER G., “General approach toward aspidospermatan-type alkaloids using one-pot Vilsmeier-Haack cyclization and azomethine ylide cycloaddition”, Journal of Organic Chemistry, vol. 82, pp. 4703–4712, 2017. [JON 97] JONES G., STANFORTH S.P., “The Vilsmeier reaction of fully conjugated carbocycles and heterocycles”, Organic Reactions, vol. 49, pp. 1–330, 1997.

Polygonatine A

141

[KIM 04] KIM S., “Free radical-mediated acylation and carboxylation reactions”, Advanced Synthesis & Catalysis, vol. 346, p.19–32, 2004. [MIK 06] MIKHALEVA A.I., ZAITSEV A.B., IVANOV A.V. et al., “Expedient synthesis of 1-vinylpyrrole-2-carbaldehydes”, Tetrahedron Letters, vol. 47, pp. 3693–3696, 2006. [MIR 99] MIRANDA L.D., CRUZ-ALMANZA R., PAVON M. et al., “A tandem carbonylation/cyclization radical process of 1-(2-iodoethyl)indoles and pyrrole”, Tetrahedron Letters, vol. 40, pp. 7153–7157, 1999. [MÜL 98] MÜLLER P., POLLEUX P., “Synthessis of a ketorolac model via aromatic carbenoid insertion”, Helvetica Chemica Acta, vol. 81, pp. 317–323, 1998. [NIC 85] NICOLAOU K.C., PETASIS N.A., CLAREMON D.A., “N-phenylselenophtalimide (NPSP), a valuable selenenylating agent”, Tetrahedron, vol. 41, pp. 4835–4841, 1985. [OIS 99] OISHI T., Handbook of Reagents for Organic Synthesis – Oxidizing and Reducing Agents, BURKE S.D., DANHEISER R.L. (eds.), Wiley, pp. 513, 1999. [REI 99] REICHARDT C., “Vilsmeier-Haack-Arnold formylation of aliphatic substrates with N-chloromethylene-N,N-dimethylammonium salts”, Journal für Praktische Chemie, vol. 341, pp. 609–615, 1999. [ROC 06] ROCHAIS C., LISOWSKI V., DALLEMAGNE P. et al., “Synthesis and biological evaluation of novel pyrrolopyrrolizinones as anticancer agents”, Bioorganic & Medicinal Chemistry, vol. 14, pp. 8162–8175, 2006. [SUN 05] SUN L.-R., LI X., WANG S.-X., “Two new alkaloids from the rhizome of Polygonatum sibiricum”, Journal of Asian Natural Products Research, vol. 7, pp. 127–130, 2005. [TAK 80] TAKANOBU N., NAKATA T., AKITA H. et al., “Synthesis of (+/−)-cinnamodial and (+/−)-cinnamosmolide”, Chemistry Letters, vol. 9, pp. 445–446, 1980. [TAS 03] TASNEEM, “Vilsmeier-Haack reagent”, Synlett, pp. 138–139, 2003. [VUO 12] VUONG S., BRONDEL N., LEN C. et al., “Formal synthesis of TMC-69-6H via a onepot enantioselective domino proline-mediated aldol/olefin homologation procedure”, Tetrahedron, vol. 68, pp. 433–439, 2012. [ZAI 12] ZAIMOKU H., TANIGUCHI T., ISHIBASHI H., “Synthesis of the core of actinophyllic acid using a transannular acyl radical cyclization”, Organic Letters, vol. 14, pp. 1656–1658, 2012.

7 (+)-Intricatetraol

7.1. Structure, isolation and properties (+)-Intricatetraol is a triterpenic polyether member of the oxasqualenoid family. It was isolated in 1993 by Suzuki et al. from the red sponge Laurencia intricata, harvested from the coasts of Hokkaido. This tetraol has moderate cytotoxic activities against P388 leukemic cells with an IC50 of 12.5 μg.mL-1. The synthesis described here confirmed the allocation of all stereogenic centers initially based on a biogenesis study [SUZ 93]. Br

OH 12

Cl HO

H

O

O

H

OH Cl

13

OH

Br

Figure 7.1. Structure of intricatetraol. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– A molecule with a C2 axis of symmetry between the C12 and C13 carbon atoms, characterized by 2 x 5 stereogenic centers. The presence of halogen atoms (bromine and chlorine) indicates its marine origin. Two identical syn-2,5disubstituted tetrahydrofuran units are present on this compound containing, as its name indicates, four hydroxyl groups (two tertiary and two secondary). 7.2. Disconnections The retrosynthesis envisaged by Morimoto is extremely convergent, based on the intrinsic symmetry of the target [MOR 07]. By breaking the bond between the two carbon atoms C12 and C13, it is possible to consider a metathesis homodimerization of the alkene 7-B, followed by the selective reduction of the new double bond while preserving the halogenated substituents.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

144

Retrosynthetic Analysis and Synthesis of Natural Products 1 Cl

Br Cl

HO

Br

H O 12

D1

OH

HO

2

RO

H O

13

O H

OH

RO

1

7-A

Br

Cl OR'

O R'O D3

D2 RO

H

OH

O OR

HO

7-B

H

OH 7-C

R'O D4

O

OAc

R'O

D5 O

O

OH 7-D

7-E

Figure 7.2. Key disconnections

LEGEND OF FIGURE 7.2.– D1: symmetric molecule (homodimerization by metathesis and reduction). D2: 1,2-dihalogenated derivative from an epoxide (regioselective opening and functional transformations). D3: terminal alkene from a primary alcohol (oxidation/methylenation). D4: THF from a Payne rearrangement (cascade cyclization from a bis-epoxy alcohol). D5: polyoxygenated sesquiterpene structure enantioselective dihydroxylation of farnesyl acetate).

(double

epoxidation

and

The challenge is to prepare tetrahydrofuran 7-C by controlling the configuration of four centers, two of which are quaternary. This was achieved by taking advantage of the stereospecific opening of a bis-epoxide via a Payne reaction followed by a

(+)-Intricatetraol

145

Wittig reaction to reach the required alkene. The two epoxide functional groups were introduced respectively by means of an asymmetric Sharpless epoxidation of an allyl alcohol and a Shi epoxidation of a trisubstituted alkene. The bromine atom results from the ring opening of a third epoxide generated from a 1,2-diol. Farnesyl acetate 7-E, a commercial terpene, was used as a starting material. 7.3. Approach according to Morimoto 7.3.1. Synthesis 7.3.1.1. Synthesis of fragment 7-C p-MeOC6H4 O O a,b OAc

OAc

7-E p-MeOC6H4 O O c,d

O

e OH

p-MeOC6H4 O

O

O

O

O

O

O

O

O

O

D-Fructose

OH

7-D f

p-MeOC6H4 O

p-MeOC6H4

O

O

HO

H

OH

O

+

O

O

O

OH 7-C

Figure 7.3. Synthesis of fragment 7-C

OH

7-C'

146

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 7.3.– a. Regioselective asymmetric dihydroxylation – 34%: AD-mix-β, 0°C, 24 h. b. Ketalization: p-MeO-C6H4-CH(OMe)2, PPTS, CH2Cl2, 0°C -> r.t., 16 h. c. Methanolysis of the ester – 99% (two steps): MeOH, K2CO3, r.t., 7 h. d. Regio- and enantioselective epoxidation according to Sharpless – 95% (d.r. > 20/1): t-BuOOH, Ti(OiPr)4, L-(+)-DET, 4 Å MS, CH2Cl2, -20°C, 21 h. e. Enantioselective epoxidation according to Shi – 87% (r.d. > 6/1): Shi reagent, oxone, Bu4NHSO4, CH2(OMe)2/CH3CN/H2O, pH = 10.5, 0°C, 2.5 h. f. Payne rearrangement and 5-exo-tet cyclization – 7-C (67%) and 7-C' (23%): LiOH aq. (1 M), 1,4-dioxane, 100°C, 7 h. 7.3.1.2. Synthesis of fragment 7-F Ar

Ar

O

O O

O OH

OTBS

g,h HO

H

O MOMO

OH

H

O OMOM

7-C Ar HO

O O k-m

i,j H

MOMO

O

HO

CHO OMOM

MOMO

H

O OMOM

7-F Ar = p-MeO-Ph

Figure 7.4. Synthesis of fragment 7-F

LEGEND OF FIGURE 7.4.– g. Protection of the primary hydroxy group – 96%: TBDMS-Cl, Et3N, DMAP, CH2Cl2, r.t., 26 h. h. Protection of the two secondary alcohols as MOM ethers – 96%: MOM-Cl, iPr2NEt, CH2Cl2, 0°C, then r.t., 36 h.

(+)-Intricatetraol

147

i. Deprotection of silyl ether – 99%: nBu4NF, THFaq, 0°C -> r.t., 15 h. j. Oxidation of primary alcohol to aldehyde according to Parikh–von Doering – 99%: SO3.pyr, Et3N, DMSO/CH2Cl2, 0°C, 30 min. k. Methylenation – 90%: Ph3P=CH2, THF, 0°C, 1 h. l. Conversion of ketal to p-methoxybenzoate: DDQ, H2O, CH2Cl2, r.t., 2 h. m. Reduction of benzoate to alcohol – 96% (two steps): LiAlH4, THF, 0°C, 1.5 h. 7.3.1.3. Access to fragment 7-A 7-F n Br

O

HO

H

MOMO

o

O

MOMO

OMOM

H

O OMOM

7-B p,q

Br Cl

HO

H

O OH 7-A

Figure 7.5. Synthesis of fragment 7-A

LEGEND OF FIGURE 7.5.– n. Conversion of 1,2-diol to epoxide – 90%: (i) Ms-Cl, pyridine, CH2Cl2, 0°C, then r.t., 14 h; (ii) MeOH, K2CO3, r.t., 3 h. o. Regioselective opening of epoxide in bromohydrin – 76%: Li2[NiBr4], THF, r.t. p. Conversion of tertiary alcohol to chloride: SOCl2, DMPU, 0°C, 30 min. q. MOM ether deprotections – 55% (two steps): HCl, MeOH, r.t., 1 h.

148

Retrosynthetic Analysis and Synthesis of Natural Products 1

7.3.1.4. Homologous coupling and finalization of the synthesis Br Cl

HO

H

O OH 7-A r

OH

Br Cl HO

H

H

OH O

Cl

O Br

OH s

OH

Br Cl HO

H

H

OH O

Cl

O Br

OH 1

Figure 7.6. Finalization of the synthesis of intricatetraol

LEGEND OF FIGURE 7.6.– r. Metathesis – 86%: GBII, CH2Cl2, 40°C, 7 h. s. Reduction of double bond by diimide – 56%: KOOC-N=N-COOK, AcOH, MeOH, MeOH, r.t., 70 h Number of steps: 19 – Overall yield: 2.6%. The symmetry of the molecule led the authors to favor metathesis coupling between two identical 7-A subunits. The reduction of the double bond is subsequently achieved by diimide action in the absence of transition metals that would interact with bromine or chlorine atoms. These two steps were carried out on substrates without protective groups demonstrating the catalyst’s action spectrum and synthetic power. The different stereogenic centers were controlled by a Sharpless dihydroxylation step and two successive epoxidation reactions, respectively: first, a reaction involving only allyl alcohols (enantioselective Sharpless epoxidation) and then an organocatalyzed epoxidation reaction initially

(+)-Intricatetraol

149

developed by Shi. From bisepoxyalcohol 7-D, a Payne rearrangement leads, in a single step, to the formation of the 7-C syn-disubstituted five-membered ring, including the functionalities necessary for the elaboration of the unsaturated synthon. During this step, by-product 7-C' with a 7-cycle is also isolated with a significant yield. It results from the intramolecular attack of the alcoholate formed during the crucial 5-exo-tet cyclization stage. In order to minimize its formation, a high concentration of lithium oxide (1 M), initiating the Payne rearrangement, was recommended. 7.3.2. Key reaction: epoxidation according to Katsuki–Sharpless The enantioselective epoxidation reaction of allyl alcohols was developed by K. B. Sharpless et al. in the 1980s and has been very successful in both academia and industry [RAM 06, HER 15]. Its impact in synthesis is such that it earned Professor Sharpless the Nobel Prize in Chemistry in 2001 (with W. S. Knowles and R. Noyori) [SHA 2002]. It is usually carried out in dichloromethane at -20°C in the presence of Ti(OiPr)4, t-butyl hydroperoxide as oxidizing agent and a tartaric acid diester (ethyl ester, or even better, isopropyl ester) as chiral inducer. Since both enantiomers are available at non-prohibitive costs, it is possible to access epoxyalcohols in their two enantiomeric forms. Selectivities are generally very high, exceeding 90% or even 95% in the case of allyl alcohols of configuration E. The reaction requires anhydrous conditions; when carried out in the presence of 4 Å molecular sieves, the kinetics are faster and it can therefore take place with clear substoichiometric quantities of reactants [HIE 08]. It has been widely used for region- and enantioselective access to many synthons: the presence of the alcohol functional group allows many post-functionalizations, while the oxirane pattern can easily undergo a regio- and stereoselective ring opening. O HO

(-)-DET, Ti(OiPr)4 t-BuOOH, 4Å MS CH2Cl2, -20°C, 3h

HO

81% (e.e. = 96%)

Figure 7.7. Regioselective epoxidation according to Sharpless

A predictive model has been proposed to anticipate synthesis one of the two enantiomers, the “L model”, depending on the tartrate used.

150

Retrosynthetic Analysis and Synthesis of Natural Products 1

Figure 7.8. Mnemonic: epoxidation and configuration of tartrates

Various mechanistic models have been proposed for this transformation, including one using a dimeric structure where a titanium atom is bound to both the substrate by a metal-oxygen bond and to the oxidant. The chiral environment created by tartrate entities allows the highly selective approach of one of the two sides of the C=C double bond. HO (+)-DET (R' = Et) R'O2C

RO RO Ti

O

CO2R' O

R'O

O R'O2C RO CO2R' RO O Ti Ti O O

O OR

Ti O

R1

R2 R1

OR

O

R3

C

OR'

O R'O

O

R3 O O-O C

Activation of peroxide

O R1

R1 R2 R3

R'O2C O CO2R' O O Ti Ti O CO2R' O

RO RO O R'O

O

t-Bu

t-Bu

O

R1 O

OR'

R3

HO R2

R2

transfer of an oxygen atom

R2 O R'O2C RO CO2R' R3 RO O O Ti Ti O O O O CO2R' R'O

O

t-Bu

Figure 7.9. Enantioselective epoxidation – model

(+)-Intricatetraol

151

On the basis of the same model, with a considerable difference in reactivity rate, the kinetic resolution of racemic allyl alcohols could be established to access one of the two enantiomers of the starting product. Deriving from these studies, a regioselective epoxidation reaction was used in the synthesis of (-)-laulimalide by both Ian Paterson’s team in Cambridge and Johann Mulzer’s team in Vienna [PAT 01, MUL 01, MUL 01, MUL 04]. The two allylic alcohol subunits differ in the configuration of the stereogenic center at the base of the hydroxy group and are considered as pseudoenantiomer subunits. In the presence of diisopropyl (+)-tartrate as a chiral ligand, only one of the two alkenes reacts (match), the other remaining unchanged (mismatch). OH

OH H

O

O

H

O

O

H

TBHP, Ti(OiPr)4 (+)-DIPT CH2Cl2, -27°C, 15h

OH

O

OH H

O

O

O

H

O

H

73% (one sole diasteromer)

Figure 7.10. Regioselective epoxidation: match and mismatch effect

7.3.3. Key reaction: asymmetric epoxidation according to Shi The epoxidation of alkenes can easily be carried out by dioxiranes, formed in situ by the action of an oxidant such as potassium persulfate (KHSO5) on a ketone. Once the transfer of an oxygen atom has been completed, the ketone is regenerated, the latter being most often the solvent itself (acetone or trifluoromethyl ketone).

152

Retrosynthetic Analysis and Synthesis of Natural Products 1

R

R1

R

HSO5-

O

O

R2

in situ R1 R

R

R2

O

HSO4

O

-

Figure 7.11. Transfer of an oxygen atom from dioxirane to an alkene

In order to achieve an asymmetric reaction, different chiral ketones could be tested including fluoroketones derived from terpenes as well as sugar derivatives such as D-fructose duly protected by different groups. The reactions are carried out in a polar solvent such as acetonitrile by introducing quantities between 5 and 300% of chiral dioxirane precursor [ZHU 14]. The reaction performed on 1,2-disubstituted alkenes of E configuration results in a very high enantiomeric excess (ee) greater than 93%, unlike Z-isomers for which the ee does not exceed 60% at best. In the “spiro” transition state leading to the major enantiomer, the most favorable approach is the one, which as a first approximation places the largest substituent (R2) furthest from the rest of the oxidizing species, then involving the weakest possible interaction between the “small” substituent R1 and the axial hydrogen atom attached to C2 of the sugar. This model can be transposed to trisubstituted alkenes of E configuration. R2

R2

R1

O

#

O O

R1

O O H R1

e.e. > 93 %

R2 O

O

O

Figure 7.12. Epoxidation according to Shi of alkenes with E configuration

By taking advantage of the nature of the protective groups attached to the chiral ketone, the epoxidation of different classes of alkenes can be achieved always with high selectivities. Thus, 1,1-disubstituted olefins undergo effective oxidation in terms of yields and enantiomeric excesses in the presence of the required catalyst. A planar transition state was assigned to reflect the selectivities and configuration observed [WAN 08].

(+)-Intricatetraol O

O N O

O O

O

(0.3 equiv.)

OH

OH

Oxone (1.6 equiv.) 1,4-dioxane, -10°C, 2h K2CO3 / AcOH pH = 9.3 #

O O

O

O O

O O

#

O

Ar Ph R

N

O

47% ( e.e. = 72%)

O

O

planar T.S.

R O

Ar

N

O Ph O

spiro T.S.

Figure 7.13. Epoxidation of 1,1-disubstituted alkenes

7.3.4. Supporting synthetic transformations 7.3.4.1. Enantioselective dihydroxylation [VID 93, SHA 92, COR 93] OAc

OH

OH OAc

34% AD-mixβ + acetone/water

OH

OAc

0°C, 24h conversion 80%

OH

16% +

tetrol 27%

153

154

Retrosynthetic Analysis and Synthesis of Natural Products 1

7.3.4.2. Payne rearrangement [MOR 02] NaOH (1M) HO

O

O

O

1,4-dioxane 100°C, 1h

OH

HO

O

O

HO HO HO

H

O

HO

O

H

H

HO

O

OH

H

OH

94%

7.3.4.3. Wittig reaction [HAN 09] OTBS

OTBS O

O

O H

O

CH2=PPh3

O

PhMe -40°C -> 0°C, 30 min.

57%

7.3.4.4. Protection of ketals by DDQ [OIK 82] O

O DDQ (1.5 equiv.)

O

O

HO

CH2Cl2 / H2O OMe

(17/1), r.t., 1h

OMe 74%

7.3.4.5. Formation of bromohydrins [DAW 84, MOH 03] HO O

Li2NiBr4, THF NC

25°C, 5h CN

Br NC

CN 99%

(+)-Intricatetraol

155

7.3.4.6. Synthesis of chlorides from alcohols [CHE 02] H

H SOCl2

OH

O

Cl

O

DMAP, THF 0°C -> r.t.

71%

7.3.4.7. Cross-metathesis [YAM 08] H

N

Boc

P OCbz

OMe OMe

Mes Cl

N

Mes

Ru

Cl

O

N

Ph

H

PPh3

Boc OMe P OMe

C13H27

(3% mol.)

+

(E) OCbz

CH2Cl2, 40°C, 7h C13H27

N

(4 equiv.)

O

68%

7.3.4.8. Reduction of alkenes by diimide [ARM 05] H

H

H2O2 + N2H4 N

N O

H

H

N

N

N +

H

O

O 15

1

7.4. References [ARM 05] ARMSTRONG P., O’MAHONY G., STEVENSON P.J. et al., “Stereoselective synthesis of (8R,8S)-8-methylhexahydroindolizin-5-one”, Tetrahedron Letters, vol. 46, pp. 8109–8111, 2005. [CHE 02] CHEN B., KO R.Y.Y., YUEN M.S.M. et al., “A tandem metal carbene cyclizationcycloaddition approach to the pseudolaric acids”, Journal of Organic Chemistry, vol. 68, pp. 4195–4205, 2002. [COR 93] COREY E.J., NOE M.C., SHIEH W.-C., “A short and convergent enantioselective synthesis of (3S)-2,3-oxidosqualene”, Tetrahedron Letters, vol. 34, pp. 5995–5998, 1993. [DAW 84] DAWE R.D., MOLINSKI T.F., TURNER J. V., “Dilithium tetrabromonickelate (II) as a source of soft nucleophilic bromide: Reaction with epoxides”, Tetrahedron Letters, vol. 25, pp. 2061–2064, 1984.

156

Retrosynthetic Analysis and Synthesis of Natural Products 1

[HAN 09] HANDE S., M., UENISHI J.-I., “Total synthesis of aspergillide B and structural discrepancy of aspergillide A”, Tetrahedron Letters, vol. 50, pp. 189–192, 2009. [HER 15] HERAVI M.M., LASHAKI T.B., POORAHMAD N., “Applications of sharpless asymmetric epoxidation in total synthesis”, Tetrahedron: Asymmetry, vol. 26, pp. 405–495, 2015. [HIE 08] HIEBEL, M.A., PELOTIER B., LHOSTE P. et al., “Synthesis of bistramide A and analogues: Stereoselective access to normethyl tetrahydropyran subunit”, Synlett, pp. 1202–1204, 2008. [MOH 03] MOHR P.J., HALCOMB R.L., “Total synthesis of (+)-phomactin A using a B-alkyl Suzuki macrocyclization”, Journal of American Chemical Society, vol. 125, pp. 1712–1713, 2003. [MOR 02] MORIMOTO Y., IWAI T., NISHIKAWA Y. et al., “Stereospecific and biomimetic synthesis of CS and C2 symmetric 2,5-disubstituted tetrahydrofuran rings as central building blocks of biogenetically intriguing oxasqualenoids”, Tetrahedron: Asymmetry, vol. 13, pp. 2641–2647, 2002. [MOR 07] MORIMOTO Y., OKITA T., TAKISHI M. et al., “Total synthesis and determination of the absolute configuration of (+)-intricatetraol”, Angewandte Chemie: International Edition, vol. 46, pp. 1132–1135, 2007. [MUL 01] MULZER J., ÖHLER E., “An intramolecular case of Sharpless kinetic resolution: Total synthesis of laulimalide”, Angewandte Chemie: International Edition, vol. 40, pp. 3842–3846, 2001. [MUL 04] MULZER J., MARTIN H.J., “Lessons learned from macrolide synthesis”, The Chemical Record, pp. 259–270, 2004. [OIK 82] OIKAWA Y., YOSHIOKA T., YONEMITSU O., “Protection of hydroxyl groups by intramolecular oxidative formation of methoxybenzylidene acetals with DDQ”, Tetrahedron Letters, vol. 23, pp. 889–892, 1982. [PAT 01] PATERSON I., DE SAVI C., TUDGE M., “Total synthesis of the microtubule-stabilizing agent (-)-laulimalide”, Organic Letters, vol. 34, pp. 3149–3152, 2001. [RAM 06] RAMON D.J., YUS M., “In the arena of enantioselective synthesis, titanium complexes wear the laurel wreath”, Chemical Reviews, vol. 106, pp. 2126–2208, 2006. [SHA 02] SHARPLESS K.B., “Searching for new reactivity”, Angewandte Chemie: International Edition, vol. 41, pp. 2024–2032, 2002. [SHA 92] SHARPLESS K.B., AMBERG W., BENNANI Y.L. et al., “The Osmium-catalyzed asymmetric dihydroxylation: A new ligand class and a process improvement”, Journal of Organic Chemistry, vol. 57, pp. 2768–2771, 1992. [TU 96] TU Y., WANG Z.-X., SHI Y., “An efficient asymmetric epoxidation method for transolefins mediated by a fructose-derived ketone”, Journal of American Chemical Society, vol. 118, pp. 9806–9807, 1996.

(+)-Intricatetraol

157

[SUZ 93] SUZUKI M., MATSUO Y., TAKEDA S. et al., “Intricatetraol, a halogenated triterpene alcohol from the red alga Laurencia intricata”, Phytochemistry, vol. 33, pp. 651–656, 1993. [VID 93] VIDARI G., DAPPIAGGI A., ZANONI G. et al., “Asymmetric dihydroxylation of geranyl, neryl and trans, trans-farnesyl acetates”, Tetrahedron Letters, vol. 34, pp. 6485–6488, 1993. [WAN 08] WANG B., WONG O.A., ZHAO M.-X. et al., “Asymmetric epoxidation of 1,1disubstituted terminal olefins by chiral dioxirane with a planar-like transition state”, Journal of Organic Chemistry, vol. 73, pp. 9539–9543, 2008. [YAM 08] YAMAMOTO T., HASEGAWA H., ISHII S. et al., “Syntheses of sphingomyelin methylene, aza, sulfur analogues by the versatile olefin cross-metathesis method”, Tetrahedron, vol. 64, pp. 11647–11660, 2008. [ZHU 14] ZHU Y., WANG Q., CORNWALL R.G. et al., “Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic applications”, Chemical Reviews, vol. 114, pp. 8199–8256, 2014.

8 Enigmazole A 8.1. Structure, isolation and properties Enigmazole A is an 18-membered macrolactone isolated from the sponge Cinachyrella enigmatica, collected in Papua New Guinea by Gustafson and his team at the University of San Diego [OKU 10]. It showed cytotoxic activity against a panel of 60 cancer cell lines. It is a target for the development of new cancer therapies for gastrointestinal tumors and certain leukemias. O HO P O HO

O

OMe O N

O OH

O

Figure 8.1. Structure of enigmazole A. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– An 18-membered macrolactone with a THP subunit included in the ring, a disubstituted oxazole unit attached to C17, two hydroxy groups on the C5 (one of which is esterified with phosphoric acid) and C15 carbon atoms. The molecule has eight stereogenic centers and an exo-methylene group.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

160

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.2. Disconnections The most obvious construction for the enigmazole consists of creating the lactone structure in the last step by intramolecular esterification according to, for example, a Steglich–Keck or Yamaguchi reaction [SKE 10, AI 15, AI 18]. Alternatively, the same large cycle can be achieved via a ring-closing metathesis of a diene ester [SAK 18] or with two alkyne units [AHL 16], followed by the reduction of unsaturated bonds, by hydrogenation. The tetrahydropyran subunit, in most cases, was created before macrocyclization; in only one case, it was obtained via a transannular process [AHL 16]. D1 : Ene-ene RCM C13-C14

D1 : Macrolactonization C1-O17 D2 : Wittig reaction C12-C13 D3 : THP via Hetero-Diels-Alder

D2 : Esterification C1-O17 D3 : THP : Tandem CM/Oxa-Michael C7-C8 H. Fuwa (2018)

T. Molinski (2010) O

HO P O HO

O OMe

5

6

1 7

O

O 17 N

7

13

OH 12

D1 : Macrolactonization C1-O17 D2 : THP via Ferrier-Petasis rearrangement

O

14

D1 : THP via transannular sigmatropic rearrangement D2 : Yne-yne ring-closing metathesis C12-C13

A. B Smith III (2015)

A. Fürstner (2016)

Figure 8.2. The four disconnections reported for enigmazole

8.3. Approach according to T. Molinski 8.3.1. Disconnections The first synthesis of enigmazole A was published by T. Molinski and his team at the University of San Diego, directly following K.R. Gustafson’s article on determining its structure [OKU 10, SKE 10].

Enigmazole A

161

O HO P O HO

O

OMe O N

O

O

OH O-Gp

O D1 OH

D3

OMe OH

O

D2

TBSO

N O

OH

Ph3P

O

Figure 8.3. Key disconnections

LEGEND OF FIGURE 8.3.– D1: simplification into two acid and alcohol subunits (regioselective esterification). D2: creation of a C-C bond (Wittig reaction and hydrogenation). D3: formation of the THP heterocycle (hetero Diels–Alder reaction). 8.3.2. Synthesis 8.3.2.1. Functionalization of oxazole by the Negishi reaction O HO

a, b

OMe

I

H

H

I

c,d

H

8-A1 OMe O

O I EtO2C

N

e

O

ZnI EtO2C

N

LiCl

EtO2C

N

8-B1

Figure 8.4. Synthesis of disubstituted oxazole 8-B1

162

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 8.4.– a. Formation of 2-methyl-3-iodo-propenol – 38%: (i) MeMgBr, CuI, Et2O, 0°C -> r.t.; (ii) I2, 0°C -> r.t. b. Oxidation of allyl alcohol to aldehyde – 82%: MnO2, CH2Cl2, r.t., 1 h. c. Enantioselective addition of dimethylzinc – 60%: (+)-MIB, Me2Zn, hexanes, 0°C -> r.t., 12 h. d. O-Methylation of alcohol – 80%: (i) NaH, THF, imidazole (cat.), 0°C -> r.t., 2 h; (ii) Me-I, 1 h 30. e. Negishi reaction – 86%: (i) Zn, LiCl, THF, r.t., 10 min; (ii) 8-A1, Pd(PPh3)4, r.t., 1 h. 8.3.2.2. Synthesis of Wittig reaction precursor 8-C1 OMe

OMe

O EtO2C

OBz

N 8-B

O

f, g

N

1

OH OMe

OBz

OMe OBz

O

h

O

i N

O

N

OH

OH

OH

OMe

OMe I

I

+ PPh3

O

j-l

m

N

O

O

O

N

O

O

Ph 8-C BzO

SnBu3 8-D1

Ph

1

Ts R-1

N

B Br

Figure 8.5. Synthesis of Wittig reaction precursor 8-C1

N

Ts

Enigmazole A

163

LEGEND OF FIGURE 8.5.– f. Reduction of the ester to aldehyde – 89%: DIBAL, CH2Cl2/PhMe, -90°C, 2 h. g. Enantioselective allylation according to Corey – 88% (ratio 24:1): (i) Reagent R-1, allylstannane 8-D1, 0°C -> r.t., 16 h; (ii) addition to aldehyde, -78°C, 1 h 30. h. Oxidative cleavage of the alkene – 60%: (i) OsO4, K3Fe(CN)3, K2CO3, NaHCO3, DABCO, t-BuOH/H2O, r.t., 2 h 30; (ii) NaIO4, THF/H2O, 0°C -> r.t., 30 min. i. Reduction of β-aldol to syn-1,3-diol: Et2BOMe, NaBH4, THF, MeOH, -78°C, 4 h. j. Diol protection – 89% (two steps): 2,2-Dimethoxy-propane, CSA, r.t., 1 h. k. Benzoate reduction – 80%: DIBAL, DCM, toluene, -78° -> -10°C, 2 h. l. Conversion of primary alcohol to iodide – 89%: PPh3, imid. THF, 0°C, 1 h. m. Phosphonium salt formation – 75%: PPh3, Li2CO3, MeCN, toluene, microwave, 130°C, 30 min. 8.3.2.3. Synthesis of aldehyde 8-E1 HO2C

CO2H

b'

a' O

O

HO2C

O O

c'

CO2Me

HO

d'

CO2Me

RO2C

CO2Me

H

CO2R

O

B

O

R-2 OTBS

O CO2Me

e', f'

OTBS

g'

(R = i-Pr)

CO2Me

H 1

8-E

Figure 8.6. Synthesis of aldehyde 8-E1

LEGEND OF FIGURE 8.6.– a’. Conversion of diacid to anhydride – 99%: AcCl, 50°C, 30 min. b’. Opening of symmetric anhydride C2 – 87%: MeOH, py, CH2Cl2, 3 h. c’. Reduction of acid to alcohol – 82%: BH3.DMS, B(OMe)3, THF, 0°C, 3 h. d’. Swern oxidation – 85%: (i) Cl(CO)2Cl, DMSO, CH2Cl2, -78°C, 30 min.; (ii) alcohol, -78°C, 30 min.; (iii) Et3N, -78°C -> 0°C, 2 h.

164

Retrosynthetic Analysis and Synthesis of Natural Products 1

e’. Allylation according to Roush – 85% (d.r. 9:1): allylboronate R-2, PhMe, -78°C, 2 h. f’. Alcohol protection – 90%: TBS-Cl, imidazole, DMF, 17 h. g’. Oxidative cleavage of the double bond – 99%: (i) O3, CH2Cl2, -78°C; (ii) PPh3, CH2Cl2, -78°C -> r.t., 1 h. 8.3.2.4. Construction of the tetrahydropyran pattern O

OMe

O

TBSO

TBSO OBn O

O

OMe

OBn

n

TBSO

OBn

+

O

OMe

O

8-E1 MeO

OTBS

MeO

OMe 8-F

1

OMe 8-G

1

OMe CO2Me TBSO TBSO

8-G

1

o, p

N

CHO OMe

O

q

O

MeO

CO2Me

O

MeO MeO

O O

8-H1

Figure 8.7. Hetero Diels–Alder reaction and Wittig coupling

LEGEND OF FIGURE 8.7.– n. Cycloaddition[4+2] and hydrolysis of enol ether – 81% (ratio cis-8-F1/trans8-G1: 4.2/1): (i) BF3.OEt2 (0.2 equiv.), CH2Cl2, -78°C, 40 min.; (ii) MeOH, CH(OMe)3, CSA, -78°C -> r.t., 1 h. o. Hydrogenolysis of benzyl ether – 94%: H2, Pd/C, AcOEt, 3 h. p. Swern oxidation – 99%: (i) Cl(CO)2Cl, DMSO, CH2Cl2, -78°C, 30 min.; (ii) alcohol, -78°C, 30 min.; (iii) Et3N, -78°C -> 0°C, 2 h. q. Wittig coupling – 71%: (i) Phosphonium salt 8-C1, LHMDS, THF, -78°C, 30 min.; (ii) Aldehyde 8-H1, -78°C, 1 h 15, then 0°C, 45 min.

Enigmazole A

8.3.2.5. Macrolactonization and finalization of the synthesis R

O

CO2Me

CO2H N

TBSO

MeO MeO

N

TBSO

r, s

O O

R

O

OH O

O

OH

MeO MeO

8-I1 R

R

N

N

O

O

O

O

O

O

OAc

OAc TBSO

TBSO

t

u, v

O

MeO

O

OMe

O R

O

w, x

HO

O

N O OAc

O

y, z

O KO P O HO

O OMe O

H2 C

N

O OH

O

1

Figure 8.8. Macrolactonization and access to enigmazole 1

165

166

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 8.8.– r. Saponification of methyl ester 8-I1: LiOH, MeOH/H2O, 80°C, 1 h. s. Ketal cleavage: CSA, MeOH, r.t., 1 h. t. Regioselective macrolactonization according to Keck/Acylation of alcohol in position C-15 – 35% (three steps): (i) DCC, DMAP, DMAP.HCl, CHCl3, reflux, 15 h 30; (ii) AcOH, MeOH. u. Hydrogenation of the double bond – 70%: H2, Rh(PPh3)3Cl, THF/t-BuOH (1:1), 50°C, 5 h. v. Ketal cleavage 82%: CSA, acetone, r.t., 4 h 30. w. Takai–Lombardo methylenation – 78%: (i) Zn, CH2Br2, TiCl4, THF, -78°C -> 0°C, 2 days. (ii) Ketone, CH2Cl2, 0°C -> r.t., 30 min. x. Deprotection of silyl ether – 72%: HF/MeCN/H2O (5/86/9), r.t., 2 days. y. Phosphatation – 61%: (i) i-Pr2N(OFm)2, 1H-tetrazole, MeCN/CH2Cl2, r.t.; (ii) H2O2 30%, 0°C, 10 min. z. Hydrolysis of phosphate and acetate – 98%: K2CO3, MeOH, H2O, r.t., 25 h. The synthesis requires 26 steps for the longest sequence (from propargyl alcohol) with an overall yield of 0.1%. 8.3.3. Key reaction: 1,2-enantioselective addition of dialkylzinc to aldehydes The addition reaction of organozinc compounds on aldehydes is a much slower process than the action of organolithium or organomagnesium compounds. However, the kinetics can be significantly increased when a β-aminoalcohol is added to the reaction medium. In order to distinguish between one of the two enantiotopic faces of the substrate, the involvement of such non-racemic chiral compounds (derived from amino acids or alkaloids) has nevertheless proved very promising. The reaction is all the more effective when two equivalents of the organometallic species are used. Aminoalcohols are deprotonated by the zinc species to generate a chiral zinc complex in situ that can then enhance like a Lewis acid and enhance the electrophilic character of the substrate. A second molecule of the organozinc species bonds to the oxygen atom. The chiral environment thus created by this complex induces a selective attack on one side of the carbonyl group. Soai’s work has shown that proline derivatives can achieve very high selectivities [SOA 87].

Enigmazole A

167

Figure 8.9. Enantioselective addition of organozinc compounds

By using aminoalcohols prepared from camphor, enantioselectivities can reach values close to the detection limit [KIT 89, NUG 99]. The 1,2-addition process was also combined with a cyclopropanation reaction according to Simmons–Smith, itself controlled by the new stereogenic center. Cyclopropane alcohols are isolated with high yields and high stereoselectivities [KIM 05]. O 1)

N OH

F3C O

O H

(-)-MIB (4 mol%) + Me2Zn

O

ZnMe

Me

2)

3)

Zn I (2 equiv.)

HO Me

H2O 76% e.e. = 99% d.r. > 20:1

Figure 8.10. Tandem addition/cyclopropanation reaction

In addition, when non-optically pure aminoalcohols are used, a chirality amplification phenomenon has been observed [KAG 01]. This can be explained by the formation of different dimeric species; the heterochiral species would have a slower rate of dissociation than the predominant homochiral species too. The minor amino alcohol would thus be trapped (reservoir tank model) and would not be able to catalyze the reaction, with the opposite effects that could be expected. The transition state proposed by R. Noyori and D.A. Evans has been refined through molecular modeling [KIT 89, EVA 88, GOL 98]. Unlike Grignard’s reagents, organozinc compounds are less easy to manipulate: few are commercial and must therefore be prepared in situ, while the simplest (Me2Zn) is pyrophoric. Despite these limitations, the addition reaction of organozinc compounds remains a process particularly adapted to the synthesis of chiral secondary alcohols.

168

Retrosynthetic Analysis and Synthesis of Natural Products 1

NMe2 O

OH

Ph

+

H

OH

ee 15%

Et2Zn

Ph

(8% mol)

e.e. 95%

NMe2

NMe2 OH

Me2N

OH

15%

Et

HO

42.5%

42.5% Et2Zn

Et2Zn

N

N

Et Zn

O

Et Zn

O

O

N

Et

Zn

Et Homochiral dimeric species

O

Zn N

Non reactive dimeric heterochiral species

rapid

N O

Minimization of # steric interactions Et2Zn Zn

N

Zn

O

Zn Et

H O

Et

Ph

Figure 8.11. Catalysis by aminobornanols and nonlinear effects

8.3.4. Key reaction: reduction of β-aldols to 1,3-diols The reduction of β-hydroxyketones to 1,3-diols can be controlled to selectively obtain either the anti compound or the syn compound; Narasaka and Pai reported access to the latter by precomplexing the two oxygen atoms with a trialkyl borane [NAR 84, KAT 86, BOD 06]. The species, doubly chelated at the two oxygen atoms, adopts a chair conformation by minimizing 1,3-diaxial interactions. A hydride added into the reaction medium is then able to selectively attack the less hindered face.

Enigmazole A

O

HO H

OH

OH

OH

OH

169

H

1) n-Bu3B

H

THF, r.t. 2) NaBH4 -100°C

O

H

+

R1 H

O

Bu B

Bu

5% (anti)

86% (syn)

Figure 8.12. Diastereoselective reduction according to Narasaka and Pai

8.3.5. Supporting synthetic transformations 8.3.5.1. Oxidation of allyl alcohols by MnO2 [GRA 69, TAY 05, PAR 11] HO

OHC MnO2 CHCl3, r.t. OH

OH 80%

8.3.5.2. Negishi reaction [DUT 06] F

Br

MeO-Ph

H +

Ph Pd(OAc)2, (2.5 mol. %)

OEt

THF, 10°C

OEt

HCl (1N) r.t.

MeO-Ph

Ph

ClZn

F

O F

MeO-Ph

H

H

Ph

93%

8.3.5.3. Alkylation/iodination of alkynes [DUB 79, NEG 79, LU 06] n-C5H11

OH 92

1)

OH

-78°C -> r.t.

+ n-C5H11MgBr (3.5 equiv.)

CuI (0.5 equiv.)

2)

I

+

I2 (3 equiv.), THF -40°C, 30 min.

I

OH 8

n-C5H11 66%

170

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.3.5.4. Desymmetrization of meso anhydrides [CHE 00] O

DHQD

O

DHQD

OMe

O

CO2H

(5 mol %)

O

MeOH (10 equiv.)

N

CO2Me

Et2O, -20°C

O

OH

N

DHQD

97% (e.e. = 97%)

8.3.5.5. Enantioselective allylation according to Roush [ROU 90, HOF 89] OH

CO2iPr

OTBDPS

O O

B

OTBDPS

O

CO2iPr syn : 89

(1 equiv.)

H

° MS Ph-Me, -78°C, 4 A

71%

OH

OTBDPS anti : 11

8.3.5.6. Enantioselective allylation according to Singaram [HIR 05] Br

In

+ pyridine

O

(2 equiv.) Ph

HO

NHMe

Ph

Ph

OH

(2 equiv.)

H

Ph THF / n-hexane, -78°C, 1h30 Conversion > 99% e.e. = 93%

8.3.5.7. Enantioselective hetero Diels–Alder reaction [DOS 99] Ad

1)

Ad N

OSiEt3

O

H OTBS

O

Cr

O +

O SbF6

Me

(3 mol %) acetone, r.t. 2) TBAF, AcOH, THF

Me

O

OTBS

97% (d.e. > 97%)

Enigmazole A

8.3.5.8. Esterification according to Steglich [BOD 85] O

O DCC (2 equiv.)

OH HO

O

DMAP (3 equiv.) DMAP.HCl (2 equiv.) CHCl3 : THF (5:1) 95%

In the absence of DMAP.HCl, the yield is only 4%.

8.3.5.9. Transesterification [PAT 98] PMB O

O

O 1

OMe

O

OTIPS

25

MeO

OH

Ti(OiPr)4 CH2Cl2, 20°C, 24h PMB O

O

O 1

MeO

O

HO

TIPSO

23

MeO macrolide 24 / macrolide 26 = 3 : 1

8.3.5.10. Methylenation – Takai–Lombardo reagent [TAK 80] O C7H15

CH2

CH2Br2 (3 equiv.) Zn (9 equiv.) - TiCl4 (1 equiv.) THF, r.t., , 25°C

C7H15 89%

171

172

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.3.5.11. Phosphate synthesis [WAT 97] N

P

Fm

O O

R

R-OH

P

O

O O

Tetrazole

H

Fm H

CH2Cl2

O R

P

O

m-CPBA

O

Fm

O O

R

DBU H

CH2Cl2 95%

O

P

OH OH

90-95%

8.4. Approach according to A. Fürstner 8.4.1. Disconnections With a view to developing a DOS approach, Aloïs Fürstner et al. carried out the synthesis of the enigmazole based on their very fruitful experience of ring-closing metatheses, particularly those involving diynes [AHL 16]. The THP cycle is constructed by a transannular reaction requiring prior sigmatropic rearrangement [3,3]. MeO

MeO

N O

N

D3

O

O

O

O

O 17

1

OH

R

OR

O 5

D2 6

O 7

D1

R"O 11

D4 OR'

1

8-A2

O 1

OH

OMe 8-C2

+

R'O

O

MT

10

8-B2

H

11

OH 17

OR

N O

8-D2

Figure 8.13. Disconnections retained by A. Fürstner

Enigmazole A

173

LEGEND OF FIGURE 8.13.– D1: C7-O11 bond cleavage (tetrahydropyran formation by transannular cyclization). D2: disconnection C5-C6: ring-closing metathesis of diyne and reduction. D3: disconnection of the C1-O17 bond: esterification. D4: homoallyl alcohol: stereoselective allylation of aldehyde 8-D2. 8.4.2. Synthesis 8.4.2.1. Synthesis of aldehyde 8-D2 OMe

MeO OMe

I

O a

b-d

N EtO2C

2

8-E

N

O OBoc OMe

OMe O

I e O

O

f, g

N

N

O

O

OTBS

O O

OMe

O O

h, i

O j N

N OTPS OTBS

OMe

CHO

OTPS OTBS 2

8-D

Figure 8.14. Synthesis of aldehyde 8-D2

LEGEND OF FIGURE 8.14.– a. Coupling by C-H activation – 74%: 8-E2, Pd(OAc)2 (5 mol%), Ligand CyJohnPhos (10 mol%), Cs2CO3, 1,4-dioxane, 110°C. b. Reduction of ethyl ester to aldehyde – 80%: DIBAL, CH2Cl2, -90°C. c. Keck allylation – 98% (diastereomeric ratio > 95: 5): AllylSnBu3, Ti(OiPr)4 (10 mol%), (S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C.

174

Retrosynthetic Analysis and Synthesis of Natural Products 1

d. Protection of alcohol as a t-butyl carbonate – 92%: (Boc)2O, DMAP, CH3CN. e. Iodocarbonation – 54–73%: IBr, toluene, -90°C. f. Carbonate removal and SNi – 79% (d.r. > 95: 5): K2CO3, MeOH. g. Alcohol protection – 98%: TBS-Cl, imid. DMAP (10 mol%), THF. h. Regioselective epoxide opening – 92%: Reagent 8-F2, CuI (20 mol%), THF, -78°C -> -40°C. i. Protection of secondary alcohol as TPS ether – 88%: TPS-OTf, 2,6-lutidine, CH2Cl2, 0°C. j. Deprotection of the ketal – 97%: TMS-OTf, 2,4,6-trimethylpyridine, CH2Cl2, 0°C. O O

MgBr

Cy2P Ligand CyJohnPhos

Reagent 8-F2

Figure 8.15. Reagent 8-F2 and Ligand CyJohnPhos

8.4.2.2. Conversion of aldehyde 8-D2 to acetylenic alcohol 8-G2 AcO Cl

Cl

AcO

a'

Bu3Sn

Cl

Cl

b', c'

OMe

CHO

SnBu3

d', e'

O k-m N

Ph TsN

OTPS OTBS

Ph

B

8-D2

NTs

Br R-1

OMe AcO

O N OTroc

OTPS OH 8-G2

Figure 8.16. Access to alcohol 8-G2

Enigmazole A

175

LEGEND OF FIGURE 8.16.– a’. Access to stannane by nucleophilic substitution – 49%: (i) LDA, Bu3SnH, THF/pentane, 0°C; (ii) 3-chloro-2(chloromethyl)-1-propene, pentane, -78°C. b’. Enantioselective 1,2-addition – 84%: butynal, Ti(OiPr)4 (10 mol%), (S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C. c’. Acylation of propargyl alcohol – 93%: Ac2O, Et3N, DMAP (10 mol%), CH2Cl2. d’. Conversion of allyl chloride to allyl iodide – 88%: NaI, acetone, 70°C. e’. Stille Coupling with a bistannane – 73%: Bu3Sn-SnBu3, [Pd2(dba)3] (2 x 1.7 mol%), THF, 55°C. k. Allylation according to Corey – 95% (d.r. > 10: 1): 8-D2, Reagent R-1, CH2Cl2, -78°C. l. Protection of homoallyl alcohol in trichloromethylcarbonate – 99%: Troc-Cl, DMAP (10 mol%), pyridine, CH2Cl2. m. Cleavage of TBS ether – 61%: CSA (20 mol%), CH2Cl2/MeOH (3:1), 0°C -> r.t. 8.4.2.3. Access to diyne 8-A2 O Ph

O

N OH

Ph

n

2

N

8-H I

OTBS

OH OTBS

O o, p

H

OTBS

q, r

OTBS

O s, t OH u O

O

OMe O

O

N

TrocO OTPS

8-A2

Figure 8.17. Access to diyne 8-A2

O

176

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 8.17.– n. Alkylation according to Myers – 98% (d.r. = 96:4): (i) 8-H2, LDA, LiCl, THF, -78°C -> r.t.; (ii) alkyl iodide. o. Reduction of amide by LAB – 89%: (i) LDA, THF; (ii) BH3.NH3, 0°C. p. Oxidation of alcohol to aldehyde – 88%: TPAP, NMO, 4 Å MS, CH2Cl2. q. Formation of 1,1-dibromoalkene – 74%: CBr4, PPh3, Zn, CH2Cl2. r. Corey–Fuchs alkylating reaction – 97%: (i) n-BuLi (2 equiv.), THF; (ii) MeI, THF, -78°C -> r.t. s. Deprotection of silyl ether – 96%: TBAF, THF. t. Oxidation of alcohol to acid – 92%: TPAP (10 mol%), NMO, H2O, MeCN. u. Esterification according to Yamaguchi – 99%: (i) 8-G2, 2,4,6-trichlorobenzoyl chloride, Et3N; (ii) DMAP, toluene, 0°C. 8.4.2.4. Cyclization of diyne 8-A2 by metathesis O

OMe O

AcO

C6H4OMe

N

TrocO OTPS

8-A2

Ph3SiO

O

Ph3SiO

K

OSiPh3 OSiPh3

R-3

v, w O

Mo

O

O

OMe O

TPSO HO

N O

8-I

2

Figure 8.18. Access to cycloalkyne 8-I2

LEGEND OF FIGURE 8.18.– v. Yne-yne ring-closing metathesis – 79%: Molybdenum catalyst R-3 (0.31 equiv.), 4Å MS, toluene, Δ. w. Deprotection of trichloromethylcarbonate – 93%: Zn, AcOH, ultrasound.

Enigmazole A

177

8.4.2.5. Termination of the synthesis O

O

O

OMe O

TPSO

N

HO

OAc

O

8-I2

x

Ar

O

OMe O

MeO

P

MeO

P Ar

N

O OTPS

Ar AuCl

AuCl Ar t-Bu

O

Ar :

OMe

y-z, aa-ab

O HO P O HO

R-4 O

t-Bu

OMe O N

O

O

OH

1

Figure 8.19. Formation of tetrahydropyran subunit and access to 1

LEGEND OF FIGURE 8.19.– x. Sigmatropic rearrangement [3,3] – 91%: Gold (R)-R4 complex (17 mol%), AgSbF6 (34 mol%), CH2Cl2. y. Saponification of enol acetate – 95%: MeOH, K2CO3. z. Reduction of carbonyl to alcohol – 61% (+ epimer C5: 33%): NaBH4, MeOH, -40°C. aa. Formation of protected phosphate – 99%: (i) (FmO)2PNiPr2, tetrazole, MeCN; (ii) H2O2 aq., 0°C. ab. Deprotection of the Fmo groups and the TPS group – 82%: TBAF, AcOH, THF, 40°C. This synthesis requires 28 steps for an overall yield of 2.2%. 8.4.3. Key reaction: diastereoselective alkylation according to Myers The α-alkylation of a carboxylic acid derivative may be accompanied by very high stereoselectivities when carried out successfully from esters or amides derived

178

Retrosynthetic Analysis and Synthesis of Natural Products 1

from alcohols or chiral amines. Following the work of Larchevêque and Husson, the Myers group reported various stereoselective functionalizations by using pseudoephedrine as a chiral auxiliary [MYE 97]. By the action of two equivalents of a lithiated base, the enolate from the amide reacts with an electrophile to give the α-substituted derivative after hydrolysis, with excellent stereoselectivities. O

O 1) LDA (2 equiv.)

Cl

N

N

LiCl 2) Ph-CH2-Br,

OH

OH

-45°C

Cl

Ph

88% d.e. = 90%

Figure 8.20. Myers alkylation

The cleavage of amides into acids requires often drastic conditions that could lead to a partial racemization of the α-center. The action of the LAB allows the amide to be easily reduced to aldehyde without loss of selectivity [SU 09]. O Ph

N OH

O O

OTPS

O

O

O

BH3.NH3, LDA H

THF 0°C -> r.t., 2h

TPSO

97%

Figure 8.21. Non-epimerizing reduction by LBA

Selectivities and easy access to carbonyl derivatives make this asymmetric process very attractive, even though an excess of base is required compared to other well-established asymmetric alkylations. A model has been proposed to rationalize the approach of the electrophile species towards the (Z)-enolate of the amide. O-Li H

H H3C N H3C

E

O H

Li R

+

Figure 8.22. Enantioselective alkylation according to Myers: model

Enigmazole A

179

8.4.4. Key reaction: Yne-yne ring-closing metathesis (RCAM) The metathesis of alkynes is a catalytic process that allows cyclic alkynes to be synthesized from diynes [FÜR 13]. Initially developed on relatively simple compounds, it is now possible to involve substrates with multiple functionalities. Most probably inspired by the classic catalytic cycle of alkene metathesis, published by Chauvin, Katz and McGinnis proposed a mechanism for the cross-metathesis of alkynes involving a carbyne [KAT 75]. This was confirmed by the detection of metallacyclobutadiene structures by the Schrock group using spectroscopic methods. The process is in equilibrium; in order to move it towards the formation of the expected alkyne, the addition of 5 Å molecular sieves is necessary. The but-2-yne is trapped in the cavity which has the optimal size; this method is preferable to vacuum evaporation, which can also affect the solvent used and contribute to an increase in concentration that is detrimental to the reaction. Since Mortreux’s initial work on homogeneous catalysis [MOR 74], an impressive number of catalysts have been synthesized based around tungsten or molybdenum. In the presence of dichloromethane, the molybdenum complex leads to the formation of a new Mo-carbyne species in the reaction medium, which has proven to be very effective and widely used in total synthesis. The major disadvantage, however, is its very high sensitivity to air oxidation or hydrolysis. It therefore requires working exclusively under argon and not under molecular nitrogen, to which the complex can react, leading to nitrides.

[M]

R

R

N N Ar Ar Mo-complex

Ar

N Mo

CH2Cl2

R

[M]

R

[M]

R

[M]

[M]

H

R

Ar

N

Mo

R

R

R

N N

Ar

[M]

Ar

R

Mo-carbyne

R

Figure 8.23. Yne-yne ring-closing metathesis

R

180

Retrosynthetic Analysis and Synthesis of Natural Products 1

A very important step forward in the development of air-stable catalysts has been made by the Fürstner group, the ate complex intermediates prepared in a few steps from Mo(CO)6 can be transformed into pre-catalysts bound by 1,10-phenanthroline. Decomplexing, carried out under mild conditions in the presence of MnCl2 or ZnCl2 at 80°C, results in the release of the true catalyst into the reaction medium [HEP 12]. Mo(CO)6

5 steps

Ar

Ar

Ph3SiO

Mo

Ph3SiO K

Ph3SiO OSiPh3 OSiPh3 Phenanthroline

Mo

Ph3SiO N

stable

Ar

Ph3SiO Ph3SiO

OSiPh3 N

MnCl2 or ZnCl2 Toluene, 80°C

Mo

OSiPh3

Ar = Ph, p-MeOPh

Figure 8.24. Access to air-stable molybdenum-based catalysts

The cyclization process has been extended to the direct formation of cyclic 1,3-diynes by the intramolecular reaction of bis(diynes) and has found an application for the convergent synthesis of the ivorenolide carbon skeleton [UNG 15]. OMe

TBSO

OTBS O O

Ph3SiO Ph3SiO

Mo OSiPh3

(40 mol%)

Toluene, 4Å/5Å MS

O O

82%

Figure 8.25. Ring-closing metathesis of a bis(diyne)

8.4.5. Key reaction: sigmatropic rearrangement [3,3] of propargyl esters The rearrangement of propargyl esters known as Saucy and Marbet reaction allows access to the corresponding allenic isomers. Silver tetrafluoroborate (AgBF4)

Enigmazole A

181

as well as platinum (PtCl4) or gold (HAuCl4) salts used as catalysts considerably reduce the reaction temperature (35–95°C) [SCH 73, KUS 11, MAR 07, MER 11]. From cyclopropane analogues and in the presence of gold salts, the Nevado group showed that sigmatropic migration could be accompanied by ring enlargement and lead to cyclopentenones [ZOU 08, GAR 10]. R2

R1 R3 O

O

R1 R2

+ Ag

R3 C O O R4

R4

O 1) Au(PPh3)SbF6

O O

1 mol% CH2Cl2, r.t., 5 min 2) K2CO3, MeOH

r.t., 4h 88%

AcO

OAc

AcO

Au

Au

Figure 8.26. Rearrangement of propargyl cyclopropane acetates

8.4.6. Supporting synthetic transformations 8.4.6.1. C-H activation – direct functionalization of oxazoles [VER 09]

EtO2C

Br

N + O

(1 equiv.)

Pd(OAc)2 (5 mol%)

EtO2C

N PCy2

Cs2CO3 (2 equiv.)

O

L, dioxane 110°C, 18h

92% L

182

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.4.6.2. Enantioselective allylation according to Keck [KEC 93] 1) (R)-BiNOL

2)

SnBu3

Ti(OiPr)4 CHO

OH

-78°C -> -20°C, 70h

CH2Cl2 reflux, 1h

89% (e.e. = 96%)

8.4.6.3. Iodocarbonation [DUA 93] O

O-t-Bu O

O

O OBn

O

I

I-Br

OBn

Ph-Me -85°C, 70h

syn, syn 85% 13,9

anti, syn 1

8.4.6.4. Enantioselective allylation according to Corey [COR 89, WIL 98, WIL 04] Ts Ph

N B

Ts

Br

Ph

N

Ph +

N B

Ts CH2Cl2 0°C

Bu3Sn

Ts

OH

R2-CHO

N

Ph

CH2Cl2 -78°C

R1

R1

R2 95% e.e. > 96%

R1

#

# Ts Ph

N

B N

Ts

R2

O H Ts

N

Ph R1

B N

R2

O R1 Ts H

Ph

Ph The most favorable

8.4.6.5. Deprotection of trichloromethylcarbonates [NEU 14] O

O O

Cl

Cl

Cl

O O

Zn, DMF / AcOH

HO

0°C, 45 min

84%

Enigmazole A

183

8.5. Approach according to A.B. Smith III 8.5.1. Disconnections MeO

OMe

N O

N

OH

O

O

O

OH

O

OH O P OH

OH

PMBO

O RO O

1

O

CH2

CH2

8-A3

OMe MeO

OTPS N

OR

O

OR

X

N OTIPS

PMBO

O

+ O

TIPSO

HO

PMB

O

3

8-C

O

HO

O O

8-B3

HO2C

8-D3

Figure 8.27. Disconnections according to A.B. Smith III

LEGEND OF FIGURE 8.27.– D1: breakdown of the lactone functional group (macrolactonization). D2: formation of dihydropyran (Petasis–Ferrier rearrangement). D3: dioxanone disconnection (Condensation of a β-hydroxy acid and an aldehyde). 8.5.2. Synthesis The approach envisaged by A. B. Smith and his team is based on a lactonization step, according to Yamaguchi, to synthesize the macrocycle while methylene tetrahydropyran results from the combination of Petasis and Ferrier reactions. The linear fragments were prepared by the application of anionic reactions from a 2-trialkylsilyl-1,3-dithiane [AI 15, AI 18].

184

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.5.2.1. Access to epoxide 8-E3

OH

SS S

H

H

OH

S b'

a' TBS

OPMB

TBS-O

OPMB

TBSO OTBS

OTBS OTBS c'

OH

OTBS d'

TBSO

O

TBSO

OH

8-E3 O

OTBS

OPMB

O 3

8-F

8-G

3

Figure 8.28. Synthesis of epoxide 8-E3

LEGEND OF FIGURE 8.28.– a’. Double alkylation of dithiane involving Brook rearrangement – 90%: (i) n-BuLi, Et2O, 0°C; (ii) epoxide 8-F3, Et2O, -30°C; (iii) epoxide 8-G3, DMPU, 78°C -> r.t. b’. Reduction of dithiane by Raney nickel – 95%: Ni(Ra), H2, EtOH, 80°C. c’. PMB ether cleavage – 87%: Ni(Ra), H2, EtOH, 80°C. d’. Epoxide formation from 1,2-diol – 99%: NaH, Tris-imid., THF, 0°C. 8.5.2.2. Synthesis of dithiane 8-H3 OMe OH

a, b

N c

MeO2C

O

OMe

I S d, e

H

MeO2C O

8-H3

Cl

N

N

S

OMe

8-I3

Figure 8.29. Access to dithiane 8-H3

O

Enigmazole A

185

LEGEND OF FIGURE 8.29.– a. Copper–magnesium iodination: (i) MeMgBr, Cu-I, toluene. (ii) I2, -78°C -> r.t. b. O-Methylation – 77% (two steps): NaH, 15-Cr-5, Me-I, Et2O, r.t. c. Negishi coupling – 80%: (i) t-BuLi, ZnCl2, pentane, Et2O, THF, -78°C -> r.t.; (ii) Pd(PPh3)4, 8-I3, THF, 65°C. d. Reduction of the ester to aldehyde – 87%: DIBAL, CH2Cl2, -78°C. e. Conversion of aldehyde to dithiane – 96%: 1,3-propanedithiol, BF3.OEt2, CH2Cl2. 8.5.2.3. Synthesis of acid 8-D3 OMe S

S

H

OMe OTBS

O 8-H

HO

f

N

S

S

N O

OTBS

3

OMe OTBS

O

HO

N

g

h, i

O

OTBS

PMB OTBS

OMe

O

O

N j, k

O

OTBS PMB O

OTBS

O

OMe

O N

HO

O

l, m

OMe

PMB O

OH

O

OH N

HO 8-D3

O

Figure 8.30. Synthesis of acid 8-D3

186

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 8.30.– f. Condensation of the dithiane anion on epoxide 8-E3 – 77%: (i) n-BuLi, Et2O, 0°C; (ii) epoxide 8-E3, Et2O, -78°C. g. Dithiane deprotection – 75%: Fe(acac)2, NaI, H2O2, AcOEt. h. Selective syn reduction – 95% (20:1): Et2BOMe, NaBH4, THF/MeOH, -78°C. i. Protection of 1,3-diol: p-Anisaldehyde dimethylacetal, CSA, CH2Cl2. j. Deprotection of primary silyl ether – 88% (two steps): TBAF, AcOH, THF. k. Oxidation of alcohol to acid – 95%: TEMPO, NaClO, NaClO2, THF, H2O, CH3CN, r.t. l. Regioselective ketal opening – 93%: DIBAL, CH2Cl2, hexanes, -78°C. m. Deprotection of silyl ether – 88%: TBAF, AcOH, THF. 8.5.2.4. Access to aldehyde 8-C3 O Ph

N

OTPS

OH

OTPS

OH

p, q

n, o

OH 8-J3 OTPS

OTPS

OTIPS

r-t

I

O 8-C3

8-K3

Figure 8.31. Synthesis of aldehyde 8-C3

LEGEND OF FIGURE 8.31.– alkylation according to Myers: (i) Amide 8-J3 (2.1 equiv.), LDA (4 equiv.), LiCl (12.6 equiv.), THF, -78°C; (ii) iodide 8-K3 (1 equiv.), -78°C -> r.t. N. Diastereoselective

O. Reduction of amide to alcohol – 99% (two steps, d.r. > 20:1): LDA (3.9 equiv.), BH3.NH3 (4 equiv.), THF, -78°C -> r.t. P. Oxidation

of primary alcohol: SO3.pyr, iPr2Net, DMSO, CH2Cl2.

q. Allylation according to Brown – 91% (two steps, d.r. > 20:1): (-)-Ipc2BOMe, allyl-MgBr, Et2O, -78°C. r. Alcohol protection – 91%: TIPS-OTf, lutidine, CH2Cl2.

Enigmazole A

187

s. Dihydroxylation of the double bond: K2OsO4 (8 mol%), NMO (3 equiv.), t-BuOH, H2O, acetone. t. Oxidative cleavage of 1,2-diol – 75% (two steps): NaIO4, acetone, r.t. 8.5.2.5. Formation of the 4-methylene tetrahydropyran structure OMe

MeO

OTPS

OTIPS

+

O

O

O

HO

PMB

N

OTPS

N

OTMS

PMBO

O u, v

3

8-C

TIPSO O

HO O HO2C

8-D3

O OMe

OMe

N

OTPS

O

TMS

N

OTPS

O

O

PMBO

w

TIPSO

TMS O

PMBO

x,y

TIPSO

O

O

CH2

CH2

O 8-L3

Figure 8.32. Access to the 4-methylene tetrahydropyran structure 8-L3

LEGEND OF FIGURE 8.32.– u. Silylation of the oxygenated functions of 8-D3: HMDS, THF. v. Dioxanone condensation – 95%: 8-C3, TMS-OTf, H2O, CH2Cl2, -78°C. w. Enol ether formation – 87%: Tebbe reagent, toluene, THF, microwave, 100°C, 3 h. x. Ferrier rearrangement: Me2AlCl, CH2Cl2, -78°C, 30 sec. y. Wittig reaction methylenation – 84% (two steps, d.r. > 20:1): Ph3P=CH2.

188

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.5.2.6. Access to acid 8-A3 OMe

OMe

N

OTPS

N

OH

O

OTMS

O

OH

O

PMBO

PMBO

TIPSO

TIPSO z, aa

O

O

CH2

CH2

8-L3

8-A3

Figure 8.33. Access to acid 8-A3

LEGEND OF FIGURE 8.33.– z. TMS and TPS ether removal – 84%: KOH, 18-CR-6, H2O, THF. aa. Oxidation of primary alcohol to acid – 75%: TEMPO, NaClO, NaClO2, t-BuOH, CH3CN, H2O, r.t. 8.5.2.7. Termination of the synthesis MeO

MeO

N

N O

O

O

O O

OPMB

ab, ac

OH OH

O

CH2

ad-af

O OH

O

HO 8-A3

P

O

O

CH2 1

Figure 8.34. Termination of the synthesis

Enigmazole A

189

LEGEND OF FIGURE 8.34.– ab. Esterification according to Yamaguchi – 89%: 2,4,6-trichlorobenzoyl chloride, iPr2Net, DMAP, toluene, Δ. ac. Deprotection of TIPS ether – 70%: HF/pyr (1:6), THF. ad. Formation of bisfluorenylmethyl phosphate: (i) iPr2NP(OFm)2, 1H-tetrazole, CH3CN, CH2Cl2; (ii) H2O2. ae. Deprotection of PMB ether – 61% (two steps): DDQ, pH =7, CH2Cl2. af. Cleavage of fluorenylmethyl groups: (i) Na2CO3, H2O, MeOH; (ii) TFA, CH3CN, H2O. 8.5.3. Key reaction: dithiane, umpolung and relayed reactions 1,3-Dithiane, a commercial reagent, can undergo a deprotonation reaction in the presence of a strong organometallic base, thus leading to a stabilized carbanion by delocalizing the charge in the free d orbitals of sulfur atoms. This species formally constitutes a “formyl carbanion” synthon whose potential was revealed in 1972 by E.J. Corey and D. Seebach, which since then has been widely used in synthesis [SEE 72, BUL 88, KIR 07]. S

S

S

O

O

R3

R3

R2

S R2

R1 R2 R2

X

O S

S

R2

Cl

S

R2

R1

R2-CHO

S

R1

O

S

R2

R1 NHTs

N Ts

S R2 HO

R2 S

S R1

R2 O

R2

S

S R1

HO

Figure 8.35. Reactivity of 1,3-dithiane

Many deprotection methods to release the carbonyl derivative have been reported. Compared to the initial use of mercuric chloride (HgCl2) or other heavy metal-based reagents, more eco-friendly processes are now preferred, such as activation by methyl iodide, the use of oxidants or photochemical methods. While the monofunctionalization of dithiane is easily achieved, the introduction of a

190

Retrosynthetic Analysis and Synthesis of Natural Products 1

second group is sometimes more difficult. Amos B. Smith III and his team were able to overcome this barrier by developing a strategy based on the regeneration of the base through a Brook rearrangement [SMI 97]. O SiR3 H

R

SiR3

Base

GSA

SiR3

GSA

O

GSA

R

ASG : Anion stabilizing group O

Brook rearrangement 1,4-migration

GSA

SiR3

O

E

SiR3

E+ GSA

R

R

Figure 8.36. Principle of relayed anionic reactions

This very elegant strategy has been successfully used to access many natural products and extrapolated to other methodological umpolung procedures.

O S

S OTBS

TBS t-BuLi

O

TBS

BnO

S

TBS

S

O

S

S

OTBS

OTBS

Et2O BnO

BnO

O

OTBS

HMPA/Et2O

TBS

TBS O O

TBS S

S

OH

O

OBn 69%

Figure 8.37. Synthesis of polyols by multicomponent coupling of a silyl dithiane

Enigmazole A

191

8.5.4. Key reaction: Petasis–Ferrier rearrangement The methylenation of 1,3-dioxan-4-ones by the Tebbe reagent results in exocyclic enol ethers. In the presence of a Lewis acid such as trialkylaluminum salts, they undergo a σ-1,3-sigmatropic rearrangement to generate, after a series of steps, a tetrahydropyranone, whose ketone function is finally reduced stereoselectively by transfer of a hydride [PET 96, SMI 01, SMI 06, SMI 08]. CH2

O

OH

R2

R2 O R1

O

O

Cp2TiMe2 R3

THF, 65°C

O

R1

R1

R3

PhMe

R3

O

R1

R1 R2

O Al(i-Bu) 3 R3

O

H H R2 O

Al

R1 R2

R3

O O H

(i-Bu)3Al

H R3

R3

R1 R2 O

H

O HO H

R3

H

H

(i-Bu)3Al

O

Al(i-Bu)3 -78°C

H R 1 R2

R2

R2

R1

Al(i-Bu)3

O O

O H

R3 H

Figure 8.38. Petasis–Ferrier rearrangement

8.5.5. Supporting synthetic transformations 8.5.5.1. Reduction of sulfides, disulfides and dithianes [MOZ 43] Ni(Ra) MeS

CO2H

H MeOH, reflux, 5h

CO2H 95%

192

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.5.5.2. Deprotection of para-methoxybenzyl ethers [HOR 86] O OMe O

NC

Cl

NC

Cl DDQ

O

O

O O

(1.5 equiv.)

O

OBn

HO

CH2Cl2/H2O/i-PrOH

OBn

5°C, 40 min. 97%

8.5.5.3. Direct conversion of 1,2-diols to epoxides [HIC 74] H Ph

H

H O O HO

H O H OH

H

OCH3 H

Ph

N-Tosyl imidazole

Ph

H O O

NaH / DMF

O

O

H

H

OCH3 78%

H O O HO

H O

H

H OTs OCH3

8.5.5.4. Deprotection of dithianes [KIR 13]

S

THPO

S

O

Fe(acac)3 (0.1 equiv.) NaI (1 equiv.) H2O2 (30%) - 4 equiv.) AcOEt/Buffer (1 : 1) r.t., 20 min

S +

THPO 93%

S

Enigmazole A

193

8.5.5.5. Oxidation of primary alcohols to carboxylic acids [HIR 09] OH

OH O HO

O O HO

4-acetamidoTEMPO

O

NaClO/NaClO2

O

OH

O

n

O

OH

pH = 6.8 40°C, 3d

n

84%

8.5.5.6. Access to the synthon 8-K3 from Roche ester [Li 10]

MeO

OH

MeO

1) Ts-Cl, DMAP, Et3N

CH2Cl2, r.t.,12h

O

OTs O

98%

+ 3) CH3P(Ph)3 Br

H

2) DIBAL

Ph-Me, -90°C

OTs n-BuLi, THF, 0°C

I

4) Li-I, Et2O

O

reflux, 4h

78% (3 steps)

8.5.5.7. Brown enantioselective allylation [NZO 05, BRO 82] t-BuOK/n-BuLi

(+)-Ipc2B-OMe

THF, -78°C -> -45°C 20 min

Et2O, -78°C

OH

O TBSO

B(+Ipc)2

B(+Ipc)2 H

TBSO Et2O, -78°C 80% (e.e. > 95%)

8.5.5.8. Oxidative breakdown of alkenes according to Lemieux and Johnson [PAP 56] Ph

Ph

O

1) OsO4, dioxane 2) NaIO4, dioxane

1h30

Ph

H 85%

194

Retrosynthetic Analysis and Synthesis of Natural Products 1

8.6. Approach according to H. Fuwa 8.6.1. Disconnections The most recent synthesis carried out jointly by M. Sasaki and H. Fuwa involves a ring-closing metathesis reaction to reach the macrocycle [SAK 18]. The precursor 8-D4 results from the combination of a cross-metathesis reaction and an oxa-Michael reaction, performed in the same pot. MeO O

OGp N

O

P

O

O

O

OMe O N

O

OH OH

OH

O

O

GpO

O

8-A4 O OMe O

OGp

OH N

OH

CH2 1

+

O

O

GpO X 4

8-C

8-B

4

OGp OGp

O

OH

S

S

+ CHO

GpO 4

8-D

GpO 8-E4

8-F4

Figure 8.39. Disconnection according to H. Fuwa

OGp

Enigmazole A

195

8.6.2. Synthesis 8.6.2.1. Access to tetrahydropyran 8-D4 OH

OH CO2Me

S

OTPS f-g

a-e

OTPS

S

8-G4 Bz OPMB OH

S

OPMB O

OTPS

S

OH

TPSO

OH

TPSO

i, j

h

OH

TPSO

OH

k

O

l

CHO

PMBO

PMBO OTBS

OH

OTBS

OH O

O

m-o

O

p, q PMBO

PMBO

8-D4 O 8-E4

OPMB

Figure 8.40. Synthesis of tetrahydropyran 8-D4

LEGEND OF FIGURE 8.40.– a–e. Synthesis of 8-G4 – 77% (five steps): see, sections 8.5.2.4 and 8.5.5.6. f. Swern oxidation: (i) (COCl)2, DMSO, CH2Cl2; (ii) Et3N, CH2Cl2, -78°C, then -30°C, 30 min. g. Dithiane formation – 85% (two steps): HS-(CH2)3-SH, BF3.OEt2, CH2Cl2 -78°C, then 0°C, 1 h. h. Alkylation of dithiane – 76%: (i) t-BuLi, HMPA, THF, -78°C; (ii) 8-E4 -78°C -> -50°C, 2 h.

196

Retrosynthetic Analysis and Synthesis of Natural Products 1

i. Oxidative deprotection of dithiane – 78%: NaClO2, NaH2PO4, Me2CH=CHMe, EtOH/H2O (10:1), 0°C, 50 min. j. Evans–Tishchenko reaction – 99% (d.r. > 20:1): SmI2, PhCHO, THF, -10°C, 2 h. k. Benzoate reduction – 95%: DIBAL, CH2Cl2, -78°C, 2 h. l. Tandem cross-metathesis/oxa-Michael reaction – 77% (d.r. > 20): HGII, CSA, crotonaldehyde, 1,2-DCE, r.t., 14 h. m. Olefin according to Wittig – 78%: CH3-PPh3+ Br-, NaHMDS, THF, 0°C, 1 h 30. n. Protection of secondary alcohol – 96%: TBS-OTf, 2,6-lutidine, CH2Cl2, 0°C, 1 h 20. o. Deprotection of primary silyl ether – 77%: TBAF, AcOH, THF, 0°C, 17 h. p. Oxidation of alcohol to aldehyde: SO3.py, Et3N, DMSO, CH2Cl2, 0°C, 35 min. q. Oxidation of aldehyde to acid – 88% (two steps): NaClO2, NaH2PO4, Me2CH=CHMe, t-BuOH/H2O (5:1), 0°C, 2 h. 8.6.2.2. Access to oxazole 8-C4 OMe

OMe a'

EtO2C

N O

I

OMe

OMe O

OTBS e', f'

N

b'-d '

OTBS N

H

O

O OH

OMe OTBS g'

OMe OTBS

N

h'

N

O

O

O-Bz

OMe OH

i', j'

EtO2C

N

8-H4

O

N 4

8-C

O

Figure 8.41. Synthesis of oxazole 8-C4

Enigmazole A

197

LEGEND OF FIGURE 8.41.– a’. Coupling by C-H activation – 74%: Ester 8H4, Pd(OAc)2 (5 mol%), Ligand CyJohnPhos (10 mol%), Cs2CO3, 1,4-dioxane, 110°C. b’. Reduction of ethyl ester to aldehyde – 80%: DIBAL, CH2Cl2, -90°C. c’. Keck allylation – 98% (diastereomeric ratio > 95: 5): AllylSnBu3, Ti(OiPr)4 (10 mol%), (S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C. d’. Protection of silyl ether alcohol – 97%: TBS-Cl, imidazole, DMF, 0°C. e’. Dihydroxylation of the double bond: OsO4, NMO, THF/H2O (1:1), r.t., 3 h. f’. 1,2-Diol cleavage – 99% (two steps): NaIO4, THF/H2O (1:1), r.t., 2 h. g’. Corey–Fuchs reaction – 88%: (i) CBr4, PPh3, Et3N, CH2Cl2, 0°C, 1.5 h; (ii) n-BuLi (2.1 equivalent), THF, -78°C, 2 h. h’. Alkylation of alkyne – 67%: n-BuLi, CH3-CHO, THF, -78°C -> 0°C, 1 h 30. i’. Protection of alcohol to benzoate: BzCl, py, DMAP, CH2Cl2, 0°C -> r.t. j’. Deprotection of silyl ether – 92% (two steps): TBAF, AcOH, THF, 0°C. 8.6.2.3. Coupling of fragments 8-C4 and 8-D4 and formation of the macrocycle O

OTBS

OMe OH

OMe O

N

N

O O

r

O

PMBO

OBz

OBz

8-C4

s O

OTBS

OMe O N

O

O

O

PMBO 8-A4

t OTBS

O

OMe O N

O PMBO

O

O

Figure 8.42. Formation of macrolactone by ring-closing metathesis

198

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 8.42.– r. Esterification according to Yamaguchi – 96%: (i) 8-D4, 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0°C, then r.t., 1 h 30; (ii) DMAP, toluene, r.t., 15 h. s. Meyer–Schuster rearrangement – 82%: iPrAuCl, AgSbF6, THF/H2O (10:1), microwave, 80°C, 7 h. t. Ring-closing metathesis – 81% (E/Z: 20/1): GBII, toluene, 40°C, 11 h. 8.6.2.4. Termination of the synthesis MeO

MeO

O

O

TBSO

N

O O

O

N

O

O

TBSO

u-x

OAc

O

O

HO

PMBO

MeO

MeO

O

TBSO

O

N

N O

O

O

OH

OAc aa-ac

y-z O

O

O

P

O

HO OH

O

H2C

1 CH2

Figure 8.43. Termination of the synthesis

Enigmazole A

199

LEGEND OF FIGURE 8.43.– u. Hydrogenation of the double bond – 91%: H2, RhCl(PPh3)3, toluene, 50°C, 1 h. v. Reduction of ketone function – 86% (d.r. = 3:1): L-selectride, THF, -78°C, 2 h. w. Protection of alcohol as acetate – 90%: Ac2O, py. 0°C -> r.t., 11 h. x. Deprotection of PMB ether – 93%: DDQ, CH2Cl2, pH 7 buffer, 0°C. y. Oxidation of alcohol to ketone – 88%: DMP, NaHCO3, 1,2-DCE, 0°C, 1 h 20. z. Ketone methylenation – 83%: CH2Br2, Zn, TiCl4, CH2Cl2, 0°C -> r.t., 30 min. aa. Deprotection of silyl ether – 48%: HFaq, CH3CN, 0°C -> r.t., 20 h. ab. Formation of fluorenylmethyl phosphate – 77%: (i) iPr2NP(OFm)2, 1Htetrazole, CH3CN/CH2Cl2 (7:1); (ii) H2O2, 0°C, 30 min. ac. Access to free phosphate and cleavage of the acetate – 87%: K2CO3, MeOH/H2O (10:1), r.t., 16 h. Number of steps: 29 – Overall yield: 1.4%. The synthesis is based on the potential of two metathesis reactions: a cross-coupling reaction associated with an oxa-Michael reaction and a ring-closing metathesis to reach the macrocycle. All the processes implemented are accompanied by excellent yields, except for the step aa of deprotection of a silyl ether at the end of the sequence. 8.6.3. Key reaction: Tishchenko–Evans reaction Stereo-controlled access to 1,3-diols is of primary importance because this pattern is found in many cyclic and acyclic natural products. To achieve them, the stereoselective reduction of β-hydroxyketones was considered by taking advantage of the proximal stereogenic center already present. The required substrates are easily reached via a diastereoselective aldolization reaction involving, for example, Evans’ oxazolidinones followed by transamidation with the Weinreb amine and finally the addition of an organometallic species [EVA 03]. At low temperature, in the presence of an aldehyde and a catalytic amount of samarium (II) salts, the β-aldols yield protected 1,3-diols in the form of monoesters in less than one hour. The reaction is accompanied by very high selectivities in favor of the anti-derivative. These values are not affected by the presence of a methyl group at α-, which significantly increases its potential [EVA 90, RAL 12].

200

Retrosynthetic Analysis and Synthesis of Natural Products 1 BHex2 O R1

OH

O N

R2-CHO

O

O

O

R2

N

O

R1

OH AlMe3

R2

HNMe(OMe)

OH

O OMe

N R1

R3-MT

O R3

R2 R1

Me

O OH

O

R2

R4-CHO SmI2 (15 mol%)

R3 R1

R4

O HO R2

THF, -10°C

H R3

R1

Figure 8.44. Tishchenko reaction

The mechanism accepted for this transformation is based on the prior formation of a hemiketal between the aldehyde and the substrate, a reaction catalyzed by the samarium salts possibly brought to the oxidation degree +3, via a pinacolization reaction of the aldehyde introduced in excess (the disappearance of the intense blue color of the solution clearly indicates the disappearance of the samarium (II) salts). The carbonyl group chelated by the metal is then activated and can be attacked intramolecularly by a hydride. This mechanism, supported by isotopic studies, is to be compared with the Verley– Meerwein–Ponndorf reduction [CHA 07]. It should also be noted that such a transformation was developed by the Heathcock group using nickel salts [BUR 90]. O OH

O R1

R2-CHO SmI2 (15 mol%)

R2

O

OH R1

THF, -10°C

O H

R1 O

H Sm

R2 O

Figure 8.45. Transition state for Evans–Tishchenko reaction

Enigmazole A

201

The reaction was applied in synthesis including on highly functionalized substrates [END 07, RAL 15].

O

OH

OTBS

OH

O H

OAc

OTBS

SmI2

THF, -15°C 90% - d.e. > 96%

Figure 8.46. Application of the Evans–Tishchenko reaction to the synthesis of pironetin

8.6.4. Key reaction: Meyer–Schuster and Rupe rearrangement The Meyer–Schuster rearrangement corresponds to the conversion of a propargyl alcohol (secondary or tertiary) into an α,β-unsaturated carbonyl compound. It is made possible by the use of Bronsted or Lewis acid catalysts [ENG 09]. Mechanically, the reaction carried out in a protic medium takes place via alcohol protonation followed by a σ-1,3 sigmatropic rearrangement, to form an allenol, which is tautomerized into the corresponding carbonyl compound [ZHU 14, ROY 18]. Depending on the substitution of alkyne, the reaction leads either to unsaturated aldehydes (R3 = H) or enones (R3 = alkyl, aryl). OH R1

R2

R1

H R1

O

R2

R3

H

R3

+

H

H R1

R2

O

H O + C

R3

R2

R1 C R2

R3

allenol

H+

Figure 8.47. Meyer–Schuster rearrangement mechanism

R3 OH

202

Retrosynthetic Analysis and Synthesis of Natural Products 1

The rearrangement can be assisted by a nucleophile such as an ester function; the allenic structure can then interact with an internal nucleophile such as an aromatic ring to form bicyclic structures [THA 17, FÜR 07, FÜR 14]. EtO

O

EtO O

TsOH (cat.)

RO2C

C

CH2Cl2 55°C

O

H

O

R = Et : 80% and R = H : 10%

H+

Figure 8.48. Cascade Meyer–Schuster and Friedel–Crafts reactions

A very close rearrangement, that of Rupe can take place from tertiary propargyl alcohols with at least one hydrogen atom on one of the carbon atoms in position α. H

R1

OH

H H

R1 H

R1 H

O

H2 O

H

+

H +

R2 H

O

R2

H

R2

H

H

R1

R1 H

R1 H R2

H

R2

H

R2 enyne

Figure 8.49. Rupe rearrangement mechanism

Instead of Bronsted acids, Gold and Silver salts catalyzed these isomerizations which can be combined in a sequential process with other reactions such as 1,4additions catalyzed by rhodium [HAN 13].

Enigmazole A

203

OH O IPrAuNTf2 (3 mol%) MeOH/H2O

Rh-L* (2.5 mol%)

1-3h, r.t. O

p-Tol-B(OH)2 (2 equiv.)

p-Tol

KOH (0.05 equiv.)

CO2-(2-Naphtyl) RhCl/2

97% (e.e. = 93%)

Rh-L*

2-3h, 50°C

Figure 8.50. Tandem process Meyer–Schuster rearrangement/1,4-addition

8.6.5. Supporting synthetic transformations 8.6.5.1. Deprotection of dithianes [ICH 04]

S

S

NaClO2 (6 equiv.)

OH

O

NaH2PO4 (2 equiv.)

TBSO

OH

TBSO

OPMB

OPMB 87%

(10 equiv.) MeOH : H2O (3:1), r.t.

8.6.5.2. Tandem metathesis reaction/oxa-Michael addition [FUW 10] OTIPS

OTIPS O

O (1.5 equiv.) OH OTPS

HG-II (10 mol %) CH2Cl2, 100°C (μν)

O OTPS 94% cis/trans : 7/1

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Retrosynthetic Analysis and Synthesis of Natural Products 1

8.6.5.3. Corey–Fuchs reaction [GRA 94, DUM 17, PAR 11, COR 72] CBr4 (2 equiv.)

OTBS CHO

OTBS

Br NaHMDS

PPh3 ( 2 equiv.) Et3N ( 1 equiv.)

O

Br

THF, -100°C

O

CH2Cl2, -60°C

OTBS

O

80%

92%

O Boc N

O

O Boc N

( )7

Br

O ( )6

CBr4 / PPh3 H

n-BuLi (2 equiv.)

Boc N

( )6

THF, -90°C Br

Br

90%

8.6.5.4. Relayed ring-closing metathesis [WAN 04, GRA 06]

OPMB OTBS O O

N Mes Mes N Cl Ru Cl

10% mol. O

OPMB OTBS O

O

O

O

DCE 50°C [Ru]

OPMB OTBS O O

71%

O

Year

2010

2016

2015

2018

Section Corresponding author (University)

T.F. Molinski Univ. of California, San Diego

A. Fürstner Max Planck Institute, Mülheim

A. B. Smith III Univ. of Pennsylvania

H. Fuwa Tohoku University

8.3

8.4

8.5

8.6

29

31

28

27

Key reaction 2, Key process Key reaction 3

8.4.3. Alkyne metathesis 8.4.5. Rearranged [3,3] propargyl esters

8.4.4. Gold cycling

8.6.3. Tishchenko– Evans reaction

Table 8.1. Syntheses

1.4%

8.6.4. Meyer– Schuster and Rupe’s reagent

- ene-ene RCM - THP: crossmetathesis and oxaMichael

- Macrolactonization - THP: Ferrier–Petasis rearrangement

- Yne-yne RCM – THP: transannular sigmatropic rearrangement

8.3.3. Enantioselective 8.3.4. Reduction - Macrolactoniztaion - Wittig addition of organozinc of β-aldols to - THP: Hetero Diels– compounds 1,3-diols Alder

Key reaction 1

8.5.4. Petasis– 1.95% 8.5.3. Dithiane, umpolung and relayed Ferrier Retreat reactions

2.2%

0.1%

Number Global of steps report

Enigmazole A

8.7. Comparative assessment of the different syntheses 205

206

Retrosynthetic Analysis and Synthesis of Natural Products 1

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[TAY 05] TAYLOR R.J.K., REID M., FOOT J. et al., “Tandem oxidation processes using manganese dioxide: Discovery, applications, and current studies”, Accounts of Chemical Research, vol. 38, pp. 851–869, 2005. [THA 17] THARRA P., BAIRE B., “A coherent study on the Z-enoate assisted Meyer-Schuster rearrangement”, Organic & Biomolecular Chemistry, vol. 15, pp. 5579–5584, 2017. [UNG 15] UNGEHEUER F., FÜRSTNER A., “Concise total synthesis of ivorenolide B”, Chemistry: A European Journal, vol. 21, pp. 11387–11392, 2015. [VER 09] VERRIER C., HOARAU C., MARSAIS F., “Direct palladium-catalyzed alkenylation, benzylation and alkylation of ethyl oxazole-4-carboxylate with alkenyl, benzyl- and alkyl halides”, Organic & Biomolecular Chemistry, vol. 7, pp. 647–650, 2009. [WAN 04] WANG X., BOWMAN E.J., BOWMAN B.J. et al., “Total synthesis of the salicylate enamide macrolide oximidine III: Application of relay ring-closing metathesis”, Angewandte Chemie: International Edition, vol. 43, pp. 3601–3605, 2004. [WAT 97] WATANABE Y., NAKAMURA T., MITSUMOTO H., “Protection of phosphate with 9-fluoromethyl group. Synthesis of unsaturated-acyl phosphatidylinositol 4,5bisphosphate”, Tetrahedron Letters, vol. 38, pp. 7407–7410. [WIL 04] WILLIAMS D.R., KIRYANOV A.A., EMDE U. et al., “Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A”, Proceedings of the National Academy of Sciences, vol. 101, pp. 12058–12063, 2004. [WIL 98] WILLIAMS D.R., BROOKS D.A., MEYER K.G. et al., “Asymmetric allylation. An effective strategy for the convergent synthesis of highly functionalized homoallylic alcohols”, Tetrahedron letters, vol. 39, pp. 7251–7254, 1998. [WUT 14] WUTS P.G.M., GREENE T.W., Greene’s Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, 2014. [ZHU 14] ZHU Y., SUN L., LU P. et al., “Recent advances on the Lewis acid-catalyzed cascade rearrangements of propargylic alcohols and their derivatives”, ACS Catalysis, vol. 4, pp. 1911–1925, 2014. [ZOU 08] ZOU Y., GARAYALDE D., WANG Q. et al., “Gold-catalyzed cycloisomerization of cyclopropyl alkynyl acetates: A versatile approach to 5-, 6-, and 7-mebered carbocycles”, Angewandte Chemie: International Edition, vol. 47, pp. 10110–10113, 2008.

9 Biyouyanagin A

9.1. Structure, isolation and properties Biyouyanagin A was isolated in 2005 from St. John’s Wort (Hypericum chinense L.) and has inhibitory activity against HIV virus replication in H9 lymphocytes [TAN 05]. Its synthesis and that of analogues was carried out by K. C. Nicolaou and his group [NIC 07, NIC 08, SAV 16].

H

H

H

O

O

O H

O

Figure 9.1. Structure of biyouyanagin A. For a color version of the figures in this chapter, see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– Pentacyclic structure including three rings linearly joined respectively six-membered, four-membered and five-membered and a butyrolactone entity linked to the last cycle by a spiranic center. The molecule has eight stereogenic centers, four of which are around the cyclobutane, according to a cis/anti/cis sequence.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

214

Retrosynthetic Analysis and Synthesis of Natural Products 1

9.2. Synthesis according to K.C. Nicolaou 9.2.1. Disconnections [NIC 07, NIC 08]

H

H

O

H

O

H

H

D1

O

O

+

O

O

Ph

O

O 9-B

9-A

H

D2

H

D3 +

9-A

O

O

(R)-citronellal

O OR O

Ph O

D5

D4 9-B Ph

D6

O

O 9-C

OR

OR

O

HO 9-D

O

O O

9-E

O O

OH L-malic acid

HO2C

CO2H

Figure 9.2. Key disconnections

LEGEND OF FIGURE 9.2.– D1: disconnection of cyclobutane (intermolecular [2+2] photocycloaddition between two known compounds: sesquiterpene 9-A and hyperolactone C 9-B). D2: formation of a trisubstituted alkene from a ketone (Shapiro reaction). D3: synthesis of a cyclohexenone (1,4-addition/crotonization).

Biyouyanagin A

215

D4: double bond from β-elimination (R=H) (Grieco elimination). D5: disconnection of the spiranic subunit (Pallado-catalyzed rearrangement of a propargyl alcohol into furanone). D6: formation of propargyl alcohol (1,2-addition on an α-ketolactone from malic acid). 9.2.2. Synthesis 9.2.2.1. Synthesis of cyclohexadiene 9-A

CHO

H a'

H

O

Ph

+ N

Ph OMe

H

H

H

c', d'

b' O

H

H

O O

Ph N H

Ph OMe

9-A CO2Et

R1 (S)-Diphenyl(methoxy) methyl-pyrrolidine

R2 HO OH

Ethyl 3,4-dihydroxybenzoate

Figure 9.3. Synthesis of precursor 9-A

LEGEND OF FIGURE 9.3.– a’. Formation of enamine from citronellal and 1,4-addition: (i) Reagent R1 (5 mol %), methylvinyl ketone (1.5 equiv.); (ii) Reagent R2 (20 mol %), 0°C, 24 h.

216

Retrosynthetic Analysis and Synthesis of Natural Products 1

b’. Aldol reaction/crotonization – 68% (two steps) d.e. = 86%: KOH [0.1 N aq.], (1.0 equiv.), nBu4N+OH- [40% aq.] catalytic, Et2O/THF/H2O (3/1/3). c’. Formation of enol triflate: (i) KHMDS, THF, −78°C, 3 h; (ii) Comins’ reagent (1.5 equiv.), THF, −78°C, 1 h. d’. Functionalization of the double bond C=C – 80% (two steps): CH3MgI: [3.0 M in ether] (1.5 equiv.), CuI (2 mol %), THF, 0°C, 15 min. 9.2.2.2. Synthesis of the precursor ketolactone 9-E

HO2C

MeO2C

MeO2C OH

OH

OH

a, b

CO2H

c CO2Me

CO2Me

OBn

HO

O

d, e O

O

OBn

f O

OBn

O 9-E

Figure 9.4. Synthesis of ketolactone 9-E

LEGEND OF FIGURE 9.4.– a. Esterification of malic acid – 98%: MeOH, BF3, OEt2, r.t. b. Diastereoselective methylation – 86% (anti/syn = 12/1): (i) LHMDS (2 equiv.), THF, −78°C; (ii) MeI. c. Enolate alkylation and creation of the quaternary center – 58%: (i) LDA (2 equiv.), THF, −78°C; (ii) BnOCH2CH2CH2-I. d. Regioselective saponification – 97%: KOH, MeOH, H2O. e. Selective acid reduction and lactonization – 75%: LiEt3BH (Superhydride®), THF, −78°C. f. Oxidation of α-hydroxylactone – 92%: DMP (2 equiv.), CH2Cl2, r.t., 5 h.

Biyouyanagin A

217

9.2.2.3. Synthesis of the spiranic precursor 9-B O

Ph

g

9-E

HO O

h O

HO

OBn

O

OBn

O

9-D Ph O O

Ph

O

O

O O O

O

O

OBn

OBn

O 9-C O

O i, j

Ph

Se O O

O

Ph k

O2N

O O

O 9-B

Figure 9.5. Synthesis of the spiranic precursor 9-B

LEGEND OF FIGURE 9.5.– g. Diastereoselective addition of acetylene – 79% (d.r. = 3:1): acetylene, n-BuLi, THF, −78°C, 1 h. h. Pallado-catalyzed carbonatation and rearrangement of a propargyl alcohol into furanone – 77%: Pd(Ph3)4 (5 mol %), Ph-I, CO (200 psi), CO2 (200 psi), Et3N, 100°C, 5 h. i. Deprotection of benzyl ether: BBr3 (1.5 equiv.), CH2Cl2, −78°C, 30 min. j. Selenation: o-NO2PhSe-CN, P(n-Bu)3, THF, 25°C, 4 h. k. Generation of the double bond by oxidation of the selenide and

β-elimination/Grieco’s reaction – 73% (three steps): H2O2 (30% aq.) in excess, THF, 25°C, 1 h.

218

Retrosynthetic Analysis and Synthesis of Natural Products 1

9.2.2.4. Completion of the synthesis

H

9-A

+

l

H

H

H

O Ph O

O

O H

O

O

Ph

O

1 O

9-B

Figure 9.6. Intermolecular [2+2] cycloaddition: final step of synthesis

LEGEND OF FIGURE 9.6.– l. Photosensitized [2+2] cycloaddition – 46%: 9-A (4 equiv.), 9-B (1 equiv.), 2-acetonaphthone (1 equiv.), CH2Cl2, 25°C, 5 h. Number of steps: 12 – Overall yield: 6.7%. The synthesis made it possible to determine the relative and absolute configuration of numerous stereogenic centers, in particular the cis/syn/cis arrangement initially assumed for cyclobutane had to be revised. Two molecules from the “chiral pool” (R)-citronellal and L-malic acid were chosen for the control of the absolute configuration of two target centers. Thanks to a suitable proline derivative, an organocatalyzed 1,4-addition allowed the stereocontrol of a new center crucial for the key diastereoselective intermolecular cycloaddition. A tandem carbonylation reaction of a propargyl alcohol followed by an oxa-Michael reaction and then the rearrangement of a cyclic carbonate into furanone results in the expected spiro derivative 9-B.

Biyouyanagin A

O

R2

H R1

HO O

R2

O

R2

O R1

O

O

O

O

R1

O

O

O

O

R2

O O

R1

Pd O

O O

Pd O

O

O O

R1

O

R1

+

O

R2

-

R2 O

O

O

O

+

Pd O-

CO2

219

R2

R1 O O

O

Figure 9.7. Formation of a furanone by pallado-catalyzed coupling

The formation of cyclobutane by the photochemical route could be considered according to an exo- or endo-approach. Based on NMR studies (NOE effect), the exo-approach has to be considered to minimize interactions between the side chain attached to the 9-A cyclohexadiene and the 9-B butyrolactone subunit. According to this approach, the adduct obtained has the relative configuration cis/anti/cis, that of the natural product. The photochemical process is carried out in the presence of a sensitizing agent, in this case 2-acetonapthone, which makes it possible to reach the triplet stage of hyperolactone C 9-B by intersystem crossing, thus avoiding the formation of by-products from the singlet state (reached in the case of direct irradiation). The reaction is performed at 320 nm, which does not require the use of special quartz glassware.

220

Retrosynthetic Analysis and Synthesis of Natural Products 1

H H

O O

O O

O

O

O O Endo approach

Exo approach

Figure 9.8. Facial discrimination during [2+2] cycloaddition

9.2.3. Key reaction: 1,4-addition and organocatalysis The functionalization at β-position of α,β-unsaturated carbonyl or carboxylic compounds gives access to important synthons. The introduction of alkyl groups is generally carried out via a Michael reaction involving organocopperlithium compounds. Enamines, on the contrary, lead to 1,5-dicarbonyl derivatives, in particular precursors of cyclohexenones, from the same substrates. The first enantioselective study was reported by Yamada and Otani and required the prior formation of nucleophilic species and therefore stoichiometric quantities of chiral amines [YAM 69]. Modest ee up to 37% have significantly increased thanks to D’Angelo’s work involving α-methylbenzylamine, both enantiomers of which are commercially available [PFA 85, DAN 92]. Ph N O O

Ph

Ph NH2

NH

N

H+, H2O O

Ph 88% O e.e. = 91%

Figure 9.9. 1,4-Addition of a chiral enamine to methylvinyl ketone

Biyouyanagin A

221

With the renaissance of organocatalysis in the 2000s [PEL 07, MUK 07], catalytic versions have been reported by Jorgensen, Gellman or List involving reagents derived from proline or cyclic derivatives (imidazolidinones) from (S)-phenylalanine [MEL 03, FRA 05, CHI 05, PEE 05, FON 04, JEN 12]. Ph Ph O

N H

O +

H

OMe (5 mol%)

O

O

H

neat, 4°C, 24h

Bn

Bn conversion 90% e.e. = 98%

Figure 9.10. Enantioselective addition of an aldehyde to methylvinyl ketone

O O H

O

Ph

N

N H2 (10 mol%)

O Cl

-

O

H

THF, r.t. 15-24h 99% (e.e. = 97%) anti / syn : 20:1

Figure 9.11. Organocatalyzed intramolecular Michael addition

Two activation processes have been proposed: – one involving the formation of an enamine, a nucleophilic species likely to attack the electrophilic position of the enone; in this case, the accepting character of the latter can be enhanced by the use of additives such as Bronsted acids (e.g. phenols). – the other involving the formation of an iminium ion from the unsaturated carbonyl compound increasing the accepting character of the substrate.

222

Retrosynthetic Analysis and Synthesis of Natural Products 1

E+

Nu-H

Ar

Ar

Ar

Ar OTMS

OTMS N

N

R

R'

E+

Nu-H

Figure 9.12. Possible activation modes for the organocatalyzed 1,4 addition

9.2.4. Shapiro reaction The Shapiro reaction, initially described in 1967, makes it possible to create an unsaturation from a carbonyl compound (aldehyde or ketone) via the initial formation of an arylsulfonyl hydrazone [SHA 67, ADL 83], which undergoes double deprotonation using a lithium base, to generate a dianion, stable below −65°C. By allowing the temperature to rise, it irreversibly decomposes to generate a vinyl anion, which can then be hydrolyzed or used to attack an electrophilic E+ species (I2, Me3Si-Cl, aldehyde). R3

R3

R3

O

O O N

R3

O

S N

H

R3

R-Li, THF

Li R3

N

-30°C

Ar

S

O

O

R1

Li R2

R2

R-H

+

N

R-Li

H

R1

R2

+

N Li

-78°C

H

R1

N

S

R-H

+

Li

Ar-SO2-Li

N

N

N2

E

Li +

E R1

R1 R2

R2

Figure 9.13. Mechanism of the Shapiro reaction

R1 R2

+

Biyouyanagin A

223

In order to limit the risks of ortholithiation during the deprotonation step, a trisyl group substituted at positions 2, 4 and 6 of the aromatic ring will be preferred over the phenyl or toluyl group not substituted at the ortho and ortho’ positions. In addition, with such a crowded sulfonylhydrazone, a better E/Z selectivity is observed, which is crucial to control the regioselectivity of the second deprotonation, which is performed on the same side as the nitrogen branch [CHA 79, FUN 15]. This reaction has undergone many developments in total synthesis, as shown by the following example to generate a key synthon for taxoid synthesis [LET 16, NIC 93].

OMe 2)

OMe

O

O 1) t-BuLi

N NHTris

THF -78°C

TMSO (+/-) 3) HCl aq

CHO

OH OH 70% (2 diastereo - isomers)

Figure 9.14. Shapiro reaction – a key step in taxoid synthesis

The dianion, at very low temperature, can react with an initial electrophile to achieve a first functionalization at position 2. The action of one equivalent of a base allows the regeneration of the dianion; by slowly increasing the temperature to −30°C, its decomposition with loss of a dinitrogen molecule provides the expected vinyl anion [CHA 79]. Nakai and Mimura used this reaction sequence to perform the 1,2-transposition of a keto group from different cyclohexanones and terpene derivatives [NAK 79].

224

Retrosynthetic Analysis and Synthesis of Natural Products 1

SO2Ar O

N

SO2Ar

SO2Ar (2 equiv.)

N

H H

1) NH2-NHSO2Ar

2) n-BuLi

N

N

N

N

3) CH3S-S-CH3

Li+ SCH3 H

T < -30°C

SO2Ar N

N

Li+

N

N

Li+ SCH3

SCH3 4) BuLi

SCH3

48%

O

H+/H2O

98%

Figure 9.15. 1,2-Transposition of oxo groups by the Shapiro reaction

As the Shapiro reaction allows the synthesis of vinyllithium compounds, these can be easily transformed into their boronic derivatives by adding a trialkylborate. These can then sequentially undergo a Suzuki coupling catalyzed by palladium [PAS 96, COR 97].

Biyouyanagin A

O2S N N

B(OiPr)2

H H

1) n-BuLi (3 equiv.)

2) B(OiPr)3

TMEDA/hexane -78°C -> 0°C (5 min)

1h

Br Pd(OAc)2 (5 mol%) Na2CO3, P(Ph)3 (10 mol%) Ph-Me, reflux, 14h

55%

Figure 9.16. Sequential process: Shapiro reaction and Suzuki coupling

9.2.5. Supporting synthetic transformations 9.2.5.1. Formation of enol triflates [GHO 06, COM 92] Cl

O

2) CF3SO2 1) KHMDS

N Boc

THF, -78°C

OSO2CF3 N

N

SO2CF3

-30°C

N Boc 92%

225

226

Retrosynthetic Analysis and Synthesis of Natural Products 1

9.2.5.2. Coupling [KAR 98]

triflates

with

organocoppermagnesium

compounds Me

OTf Me-MgBr (1.5 equiv.) Cu-I (10 mol %), 0°C, THF

Ph Ph

Ph Ph 95%

9.2.5.3. Dess–Martin oxidation [BAC 01, DES 83, TOH 04] AcO OAc I OAc

OH

O

O

O

O

O

DMP O (1.3 equiv.)

O

O O

CH2Cl2, 25°C

98%

9.2.5.4. 1,2-Addition of acetylides – chelation control [MEA 87, GUI 06] OH CHO

Li

OH

Ph OBn

OBn

Ph

Ph

OBn

1,2-syn

1,2-anti

THF, -78°C

45

55

Et2O, -78°C + ZnBr2

95

5

9.2.5.5. Palladium-catalyzed carbonylation [FUK 05, SAN 06] I

(1 mol %) +

F

O

PdCl2(PPh3)2

CO Ph

(bmim)PF6, Et3N 120°C, 1h, 20 atm.

Ph

F 81%

Biyouyanagin A

227

9.2.5.6. Deprotection of p-methoxybenzyl ethers [ONO 97, KIM 03] OMe MgBr2, OEt2 (3 equiv.) Me2S (10 equiv.) O

CH2Cl2, r.t.

OH OMe 76%

OMe

9.2.5.7. Grieco elimination [HAY 04, GRI 76] NO2

1)

H

H

HO

SeCN N

N

(n-Bu)3P, THF, r.t. 2) m-CPBA

PMBO

PMBO

THF, r.t.

86%

9.2.5.8. Intermolecular photocycloaddition [ZHO 15, BAC 11] MeO2C

MeO2C H O

O

O

H

hν = 313 nm H

CO2Me

H

(15 equiv.)

H

CH3CN, acetone r.t., 5h 98% ratio:

5

2

+ 0,2 (head-to-tail regioisomer)

228

Retrosynthetic Analysis and Synthesis of Natural Products 1

9.2.5.9. Intramolecular photocycloaddition [HAT 94, BAC 11] O

CO2Me

O

O

MeO2C

hν (350 nm)

O

MeO2C

hexane

O

O

(c = 4. 10-3M)

64%

9.2.5.10. Asymmetric photocycloaddition and ether groups [FAU 02] O

H O

O

hν (366 nm)

O

CH2Cl2, 20°C

O

MeONa O

O

MeOH O

O

O

H

O 81% (d.e. = 94%)

O

O

69% (e.e. = 94%)

9.2.5.11. Enantioselective intermolecular photocycloaddition [POP 18] Ar N

O

Br3Al F

B

Ar

O

O F

hν (366 nm)

+

CH2Cl2 F

H

-75°C, 24h

(0.5 equiv.) (Ar : 2,3-dimethylphenyl)

H 72% - e.e. = 93%

Biyouyanagin A

229

9.3. References [ADL 83] ADLINGTON R.M., BARRETT A.G.M., “Recent applications of the Shapiro reaction”, Accounts of Chemical Research, vol. 16, pp. 55–59, 1983. [BAC 01] BACH T., KIRSCH S., “Synthesis of 6-substituted 4-hydroxy-2-pyrones from aldehydes by addition of an acetoacetate equivalent, Dess-Martin oxidation and subsequent cyclization”, Synlett, pp. 1974–1976, 2001. [BAC 11] BACH T., HEHN J.P., “Photochemical reactions as key steps in natural product synthesis”, Angewandte Chemie: International Edition, vol. 50, pp. 1000–1045, 2011. [CHA 79] CHAMBERLIN A.R., BOND F.T., “Regiochemical control in alkenyllithium generation from arenesulfonylhydrazones”, Synthesis, pp. 44–45, 1979. [CHI 05] CHI Y., GELLMAN S.H., “Diphenylprolinol methyl ether: A highly enantioselective catalyst for Michael addition of aldehydes to simple enones”, Organic Letters, vol. 7, pp. 4253–4256, 2005. [COM 92] COMINS D.L., DEGHANI A., “Pyridine-derived triflating reagents: An improved preparation of vinyl triflates from metallo enolates”, Tetrahedron Letters, vol. 33, pp. 6299–6302, 1992. [COR 97] COREY E.J., ROBERTS B.E., “The application of a Shapiro reaction – Suzuki coupling sequence to the stereoselective synthesis of E-trisubstituted olefins”, Tetrahedron Letters, vol. 38, pp. 8919–8920, 1997. [DAN 92] D’ANGELO J., DESMAELE D., DUMAS F. et al., “The asymmetric Michael addition reactions using chiral imines”, Tetrahedron: Asymmetry, vol. 3, pp. 459–505, 1992. [DES 83] DESS D.B., MARTIN J.C., “Readily accessible 12-I-51 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones”, Journal of Organic Chemistry, vol. 48, pp. 4155–4156, 1983. [FAU 02] FAURE S., PIVA-LE BLANC S., BERTRAND C. et al., “Asymmetric intramolecular [2+2] photocycloadditions: α− and β−hydroxy acids as chiral tether groups”, Journal of Organic Chemistry, vol. 67, pp. 1061–1070, 2002. [FON 04] FONSECA M.T.H., LIST B., “Catalytic asymmetric intramolecular Michael reaction of aldehydes”, Angewandte Chemie: International Edition, vol. 43, pp. 3958–3960, 2004. [FRA 05] FRANZEN J., MARIGO M., FIELENBACH D. et al., “A general organocatalyst for direct a-substitution of aldehydes: Stereoselective C-C, C-N, C-F, C-Br, and C-S bond-forming reactions. Scope and mechanistic insights”, Journal of the American Chemical Society, vol. 127, pp. 18296–18304, 2005. [FUK 05] FUKUYAMA T., YAMAURA R., RYU I., “Synthesis of acetylenic ketones by a Pd-catalyzed carbonylative three-component coupling reaction in [bmim]PF6”, Canadian Journal of Chemistry, vol. 83, pp. 711–715, 2005.

230

Retrosynthetic Analysis and Synthesis of Natural Products 1

[FUN 15] FUNES-ARDOIZ I., LOSANTOS R., SAMPEDRO D., “On the mechanism of the Shapiro reaction: Understanding the regioselectivity”, RCS Advances, vol. 5, pp. 37292–37297, 2015. [GHO 06] GHOSH S., KINNEY W.A., GAUTHIER D.A. et al., “Convenient preparation of aryl-substituted nortropanes by Suzuki-Miyaura methodology”, Canadian Journal of Chemistry, vol. 84, pp. 555–560, 2006. [GRI 76] GRIECO P.A., GILMAN S., NISHIZAWA M., “Organoselenium chemistry. A facile one-step synthesis of alkyl aryl selenides from alcohols”, Journal of Organic Chemistry, vol. 41, pp. 1485–1486, 1976. [GUI 06] GUILLARME S., PLE K., BANCHET A. et al., “Alkynylation of chiral aldehydes: Alkoxy-, amino-, and thio-substituted aldehydes”, Chemical Reviews, vol. 106, pp. 2355–2403, 2006. [HAT 94] HATAKEYAMA S., KAWAMURA M., TAKANO S., “Total synthesis of (-)-paeoniflorin”, Journal of the American Chemical Society, vol. 116, pp. 4081–4082, 1994. [HAY 04] HAYAKAWA I., ARIMOTO H., UEMURA D., “Synthesis of the tricyclic core of halichlorine”, Chemical Communications, pp. 1222–1223, 2004. [JEN 12] JENSEN K.L., DICKMEISS G., JIANG H. et al., “The diarylprolinol silyl ether system: A general organocatalyst”, Accounts of Chemical Research, vol. 45, pp. 248–264, 2012. [KAR 98] KARLSTRÖM A.S.E., RÖNN M., THORARENSEN A. et al., “A versatile route to 2-substituted cyclic 1,3-dienes via a copper(I)-catalyzed cross-coupling reaction of dienyl triflates with Grignard reagents”, Journal of Organic Chemistry, vol. 63, pp. 2517–2522, 1998. [KIM 03] KIM J.D., HAN G., JUNG Y.H., “Deprotection of benzyl and p-methoxybenzyl ethers by chlorosulfonyl isocyanate-sodium hydroxide”, Tetrahedron Letters, vol. 44, pp. 733–735, 2003. [LET 16] LETORT A., DE-LIANG L., PRUNET J., “Study of cascade ring-closing metathesis reactions en route to an advanced intermediate of taxol”, Journal of Organic Chemistry, vol. 81, pp. 12318–12331, 2016. [MEA 87] MEAD K.T., “Syn-selective additions of acetylide anions to α-alkoxyaldehydes”, Tetrahedron Letters, vol. 28, pp. 1019–1022, 1987. [MEL 03] MELCHIORRE P., JORGENSEN K.A., “Direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by chiral amines”, Journal of Organic Chemistry, vol. 68, pp. 4151–4157, 2003. [MUK 07] MUKHERJEE S., YANG J.W., HOFFMANN S. et al., “Asymmetric enamine catalysis”, Chemical Reviews, vol. 107, pp. 5471–5569, 2007. [NAK 79] NAKAI T., MIMURA T., “A facile procedure for regioselective 1,2-carbonyl transposition. One-pot conversion of ketone tosylhydrazones to enol thioethers of transposed ketones”, Tetrahedron Letters, vol. 20, pp. 531–534, 1979.

Biyouyanagin A

231

[NIC 07] NICOLAOU K.C., SARLAH D., SHAW D.M., “Total synthesis and revised structure of biyouyanagin A”, Angewandte Chemie: International Edition, vol. 46, pp. 4708–4711, 2007. [NIC 08] NICOLAOU K.C., WU T.R., SARLAH D. et al., “Total synthesis, revised structure and biological evaluation of biyouyanagin A and analogues thereof”, Journal of the American Chemical Society, vol. 130, pp. 11114–11121, 2008. [NIC 93] NICOLAOU K.C., YANG Z., SORENSEN E.J. et al., “Synthesis of ABC taxoid ring systems via a convergent strategy”, Journal of the Chemical Society, Chemical Communications, pp. 1024–1026, 1993. [ONO 97] ONODA T., SHIRAI R., IWASAKI S., “A mild and selective deprotection of p-methoxybenzyl (PMB) ether by magnesium bromide diethyl etherate-methyl sulfide”, Tetrahedron Letters, vol. 38, pp. 1443–1446, 1997. [PAS 96] PASSAFARO M.S., KEAY B.A., “A one-pot in situ combined Shapiro-Suzuki reaction”, Tetrahedron Letters, vol. 37, pp. 429–432, 1996. [PEE 05] PEELEN T.J., CHI Y., GELLMAN S.H., “Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones: Cocatalyst effects and evidence for an enamine intermediate”, Journal of the American Chemical Society, vol. 127, pp. 11598–11599, 2005. [PEL 07] PELISSIER H., “Asymmetric organocatalysis”, Tetrahedron, vol. 63, pp. 9267–9331, 2007. [PFA 85] PFAU M., REVIAL G., GUINGANT A. et al., “Enantioselective synthesis of quaternary carbon centers through Michael type alkylation of chiral imines”, Journal of the American Chemical Society, vol. 107, pp. 273–274, 1985. [POP 18] POPLATA S., BACH T., “Enantioselective intermolecular [2+2] photocycloaddition reaction of cyclic enones and its application in a synthesis of (-)-grandisol”, Journal of the American Chemical Society, vol. 140, pp. 3328–3231, 2018. [SAN 06] SANS V., TRZECIAK A.M., LUIS S. et al., “PdCl2(P(OPh)3)2 catalyzed coupling and carbonylative coupling of phenylacetylenes with aryl iodides in organic solvents and in ionic liquids”, Catalysis Letters, vol. 109, pp. 37–41, 2006. [SAV 16] SAVVA C.G., TOTOKOTSOPOULOS S., NICOLAOU K.C. et al., “Selective activation of THFR1 and NF-κB inhibition by a novel biyouyanagin analogue promotes apoptosis in acute leukemia cells”, BMC Cancer, vol. 16, pp. 279/1–279/14, 2016. [SHA 67] SHAPIRO R.H., HEATH M.J., “Tosylhydrazones. V. Reaction of tosylhydrazones with alkyllithium reagents. A new olefin synthesis”, Journal of the American Chemical Society, vol. 89, pp. 5734–5735, 1967. [TAN 05] TANAKA N., OKASAKA M., ISHIMURA Y. et al., “Biyouyanagin A, an anti-HIV agent from Hypericum chinense L. var salifolium”, Organic Letters, vol. 7, pp. 2997–2999, 2005.

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[TOH 04] TOHMA H., KITA Y., “Hypervalent iodine reagents for the oxidation of alcohols and their application to complex molecule synthesis”, Advanced Synthesis & Catalysis, vol. 346, pp. 111–124, 2004. [YAM 69] YAMADA S.-I., OTANI G., “Asymmetric synthesis with amino acids. II. Asymmetric synthesis of optically active 4,4-disubstituted-2-cyclohen-1-one”, Tetrahedron Letters, pp. 4237–4240, 1969. [ZHO 15] ZHOU M., LI X.-R., TANG J.-W. et al., “Scopariusicides, novel unsymmetrical cyclobutanes: Structural elucidation and concise synthesis by a combination of intermolecular [2+2] cycloaddition and C-H functionalization”, Organic Letters, vol. 17, pp. 6062–6065, 2015.

10 Elatol

10.1. Structure, isolation and properties Elatol is a dihalogenated spirosesquiterpene, initially isolated from the red alga Laurencia elata collected from the coasts of New South Wales in Australia [SIM 74] and whose structure has been determined by studying the R-X-ray diffraction of its acetate. Tests on biological targets revealed cytotoxic activity and also against leishmaniasis [CAM 12, DOS 10].

Cl HO Br Elatol

α-Chamigrene

Figure 10.1. Elatol structure. For a color version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– Elatol is a spiro dihalogenated molecule (spiro[5.5]undecane); one of the two six-membered rings has a chlorine atom attached to a tetrasubstituted endocyclic double bond. The second cycle includes an exo methylene group, two cis hydroxy and bromo groups and also two methyl groups in a geminal position.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

10.2. Disconnections The key reaction to form the six-membered unsaturated cycle is a ring-closing metathesis from a diene [WHI 08, WHI 10].

O

B Cl

A

Cl

HO RO

Br

Figure 10.2. Key disconnections

10.3. Approach according to B. Stoltz 10.3.1. Disconnections

O

B Cl

A HO

D1

Cl

D2 Cl

O RO

Br

O O D3

X

butenone O

D4 RO

A

+ dimedone

HO

Figure 10.3. Disconnection according to Stoltz

LEGEND OF FIGURE 10.3.– D1: functional arrangement around cycle A (α and γ’-halogenation, reduction of carbonyl group and SN' by hydride). D2: cycle B with six disconnected bonds at the tetrasubstituted double bond (RCM between two terminal double bonds including one substituted by a chlorine atom).

Elatol

235

D3: stereo-controlled introduction of an allylic chain (enantioselective Tsuji–Trost reaction). D4:introduction of a chain of four carbon atoms (Michael reaction between an enolate from dimedone and butenone (methylvinyl ketone)). 10.3.2. Synthesis O

O

O

a, b HO

i-Bu-O 10-C O

Cl

O c

O

d

O

i-Bu-O i-Bu-O

O

O e

f

Cl

Cl i-Bu-O

i-Bu-O 10-B

10-A

Figure 10.4. Formation of the spiranic structure 10-A

LEGENDS OF FIGURE 10.4.– a. Protection of 1,3-dione to enol ether – 90%: isobutanol, TsOH cat. PhH, Δ. b. α-Alkylation of the ketone – Michael reaction: (i) LDA, THF, −78°C; (ii) methylvinyl ketone. c. Methylenation of non-conjugated carbonyl – Wittig reaction – 74% (two steps): CH3PPh3Br, t-BuOK, THF, 0-> 70°C. d. Formation of enol carbonate – 73%: (i) LDA, THF, −78°C; (ii) TMEDA, Cl-CO-O-CH2(CCl=CH2).

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Retrosynthetic Analysis and Synthesis of Natural Products 1

e. Enantioselective alkylating decarboxylation – 82%: Phosphinooxazoline PHOX-2 (12.5 mol%), Pd(dmdba)2 (10 mol%), PhH, 11°C. f. Ring-closing metathesis – 97%: Stewart–Grubbs catalyst (5 mol%), PhH, 60°C. The selected process requires from dimedone (including the gem-dimethyl group present on ring A) the introduction of two unsaturated chains at a position adjacent to the first quaternary center. The chain with four carbon atoms is easily introduced via a Michael addition involving methylvinyl ketone. The chloroallylic chain is attached via an enantioselective Tsuji–Trost reaction involving a PHOX ligand, a phosphinooxazolidine derived from t-leucine. Ring-closing metathesis allows the formation of the B cycle. If the Grubbs II catalyst (2.5 mol%) is effective, it only results in an incomplete conversion of the substrate (85% after 22 hours of heating at 60°C). The so-called Stewart–Grubbs catalyst (5 mol%) has been used here and leads to better results (total conversion in only 5 hours). OH 10-A

g

h

Cl

Cl

i-Bu-O

O

Br

i

Cl

j

Cl HO

O

Br

Br

CF3

N O

(p-CF3-C6H4)2-P

Cl Cl

N [Ru] O

N

PHOX-2

1

Stewart-Grubbs catalyst

Figure 10.5. Synthesis of elatol

Elatol

237

LEGENDS OF FIGURE 10.5.– g. 1,2-Addition: MeLi, CeCl3, THF, −78°C -> 0°C. h. Deprotection of enol ether and dehydration – 89% (two steps): HCl aq. (10%), 0–23°C. i. Double α-bromination of the carbonyl and at the allylic position: Br2, HBr 48%, AcOH, 23°C. j. Diastereoselective reduction of carbonyl group and SN2' – 32% (two steps): DIBAL (2 equiv.), THF, −78°C -> 60°C. Number of steps: 9 – Overall yield: 11%. For the functionalization of ring A, the addition of methyllithium followed by acid hydrolysis conventionally generates the corresponding enone. In a single step, two brominations are then carried out: the first, the α-bromination of the carbonyl group with a stereoselectivity of 6 to 1; the second, at the allylic position. Chemo- and stereo-selective reduction (syn/anti = 3.9/1) of the ketone is possible by treatment with DIBAL at low temperatures. In the same step, the bromine atom in allyl position is substituted mainly by a hydride ion from the same reducing agent (SN'/SN = 11/1) according to an SN' process. 10.3.3. Key reaction: Tsuji–Trost reaction The Tsuji–Trost reaction discovered in the 1970s was widely used to create a C-C bond as well as a carbon-heteroatom bond from compounds with a leaving group (bromide, acetate, carbonate, etc.) in the allylic position. Depending on the nature of the nucleophile and the operating conditions, regiocontrol and diastereoselectivity now place this reaction at the forefront of coupling processes. It involves a π-allyl-palladium complex whose formation is conditioned by the stereocenter of the leaving group. Depending on the nature of the nucleophile, the nucleophilic attack can be carried out on the opposite side to that coordinated to the metal (with soft nucleophiles such as malonates); conversely, in the presence of harder nucleophile (hydrides from ammonium formate, stannanes, etc.), a pre-coordination with the metal leads to the nucleophilic attack on the same side (Figure 10.6).

238

Retrosynthetic Analysis and Synthesis of Natural Products 1

R1

Pd0L2

Nu

R1

X

Coordination

Decoordination L2Pd(0) R1

Nu

L2Pd(0) R1

Oxidative addition

Nu (soft reagents)

R1 II

Pd L

X

R1

Nu Nucleophilic attack

II

Pd L

Nu

L X

R1 (hard reagents)

PdII L

X

L

Figure 10.6. Catalytic cycle of the Tsuji–Trost reaction

In order to further increase the potential of this reaction, different groups have focused on developing an enantioselective version. Some of the most effective ligands grouped together in Figure 10.7 belong to classes including phosphinooxazolines PHOX [LOI 00], C2-symmetric diphosphines or atropoisomeric biaryl structures [LEB 16].

Elatol

239

CF3

O (C6H5)2-P

N

O N

(p-CF3-C6H4)2-P

PHOX-2

PHOX-1

O P

O NH

P

HN

PPh2 Ph2P

(R,R)-Me-DUPHOS

OMe O

(S,S)-Trost-stilbene

O

O

O

O

Me

Ph2P PPh2 (R,R)-MeO-BIPHEP

(Ar)2 P

P (Ar)2

(S)-DTBM-SEGPHOS

Figure 10.7. Chiral ligands associated with the enantioselective Tsuji–Trost reaction

PHOX ligands, derived from t-leucine and initially developed by the Pfaltz group at the University of Basel, were taken over by the group of B. Stoltz (Caltech) to synthesize elatol [WHI 10]. A reaction conducted on the dechlorinated compound showed that the process was possible with the PHOX-1 ligand. Transposed to the derivative with a chlorine atom, the reaction was slower and less effective in terms of yield. Additional studies have shown that the decisive step was alkylation; in the presence of the PHOX-2 ligand, possessing very strongly electroattractive fluorinated groups on aromatic rings, the electrophilic character of the complex

240

Retrosynthetic Analysis and Synthesis of Natural Products 1

π-allyl palladium (II) was largely increased leading to a very significant improvement in yield. Thus, under optimal conditions (PHOX-2 ligand (11–13 mol%), benzene, 13°C), the alkylation product is formed with an excellent yield of 90% and an ee of 87%. O

Cl Cl

PHOX-1 (12 mol%) O

O

O

Pd(dmba)2 (10 mol%) Ph-H, 40°C, 7h

i-BuO

i-BuO

53% - e.e. = 78% O

Cl O

O

O

HCO2H Pd(OAc )2 (10 mol%) i-BuO

H

PHOX-1 (12 mol%)

Ph-H, 40°C, 4Å MS, 3h

i-BuO

Total conversion (NMR)

O

PHOX-1 (12 mol%) O

O

O

Pd(dmba)2 (10 mol%) Ph-H, 40°C, 1h

i-BuO

i-BuO

Total conversion (NMR)

Figure 10.8. Optimization and control of allyl transfer

The catalytic cycle of the reaction as well as the stereochemical course of the reaction are explained in Figure 10.9.

Elatol

241

(PHOX-2) Pd(dmdba) O

Cl O

CF3

90% e.e. = 87%

i-BuO

Cl

O

O

O

i-BuO N

P(Ar)2 Pd

C-C Coupling

Coordination

CF3

CF3 O N

O

P(Ar)2

N

Pd O

P(Ar)2 Pd

Cl

Cl O O O

CF3

i-BuO CO2

O-iBu

O

Decarboxylation

N O O

P(Ar)2

Oxidative addition

Pd O

Cl

i-BuO

Figure 10.9. Enantioselective Tsuji–Trost reaction

10.3.4. Key reaction: ring-closing metathesis of hindered olefins The formation of tri- and tetra-substituted double bonds has been considered by metathesis but has long suffered from low conversions and yields. The development of second-generation ruthenium catalysts substituted by NHC ligands has opened a new path towards more reactive species. In 2008, Caltech’s R. H. Grubbs and his team developed a new catalyst for which the mesityl group attached to each of the two nitrogen atoms is replaced by a less cumbersome tolyl group (Figure 10.9).

242

Retrosynthetic Analysis and Synthesis of Natural Products 1

This new reagent (called Stewart–Grubbs reagent) has proven to be extremely effective in reaching highly substituted alkenes while supporting the presence of many functionalities [STE 07, STE 10]. This field remains very active as evidenced by recent work published by Cazin and Grela and their groups [URB 13, ABL 14]. E

E

E [Ru]

E

CH2

C = 0.1M, Ph-H, 60°C

N [Ru]

CH2 :

Cl Cl

N

95%

[Ru] O

Figure 10.10. Ring-closing metathesis to tetrasubstituted alkenes

10.3.5. Key reaction: reduction of enones according to Luche Controlling the reduction of enones to allyl alcohols is an important issue in synthesis. The conditions described by Luche et al. of the University of Grenoble, combining NaBH4 and lanthanide chloride in methanol, allow very high selectivities to be achieved by minimizing the formation of possible by-products (ketones or saturated alcohols). Of all the salts tested, cerium salts were the most effective [GEM 81].

O

OH

Me

OH

Ce3+ O H O

NaBH4 + CeCl3

R2

+

MeOH (0.4M) 97

3

R3

Figure 10.11. Luche reduction of cyclopentenone

H R1 B OMe R4 MeO OMe

#

Elatol

243

The selectivity in favor of the observed 1,2-reduction would result from the in situ formation of alkoxyborohydrides associated with the Ce3+ cation considered as a “hard” species. A protic solvent, most often methanol, is essential to activate the carbonyl group by hydrogen bonding. To be effective, the process requires more than one equivalent of relatively expensive cerium salts, which is a major drawback for large-scale implementation. Variants have been reported combining NaBH4 with calcium triflate or rehydrated alumina respectively [FOR 12, JON 16]. An enantioselective variant has been developed involving potassium borohydride and a scandium (III)/chiral L N,N'-dioxide complex derived from (S)-proline (Figure 10.12) [HE 12].

Figure 10.12. Enantioselective reduction of enones

10.3.6. Supporting synthetic diagrams 10.3.6.1. Organocatalyzed 1,4-addition [PER 00, JHA 02, IKU 07] Cl-

O

CO2Me MeO2C K2CO3

H

N + OH

N OMe Quinine salt

O

*

CO2Me

MeO2C e.e. -> 90%

244

Retrosynthetic Analysis and Synthesis of Natural Products 1

10.3.6.2. Organocatalyzed addition – Rauhut–Currier reaction [ARO 07, RAU 63, MEL 08] O

O O

O

Ph

O

NHAc

MeO

SH 0.2 equiv.

Ph

Ph

Ph

t-BuOK (6 equiv.), CH3CN, -40°C C = 0.05M, 24h 70% e.e. = 95%

10.3.6.3. Wittig methylenation [CHA 08] O

TBDPSO

+

-

PPh3-CH3 , I H

TBDPSO

t-BuOK, THF, 0°C -> -78°C 83%

10.3.6.4. Enantioselective alkyl decarboxylation according to Tsuji–Trost [MOH 05, TAN 07, MOH 08] O O

O

O

O

PPh2 N t-Bu

90% e.e. 89%

[Pd2(dba)3], THF, 12°C

10.3.6.5. Tsuji–Trost decarboxylation and enantioselective protonation [ABO 94, KUK 08, DUH 04]

O

NH2 OH

O O

(0.3 equiv.) H2, 5% Pd/C CH3CN, r.t., 5h

O *

79% e.e. = 50%

Elatol

245

10.3.6.6. Formation of spiranic compounds by double RCM [WYB 04, KOT 07] C5H11 N

CF3

N Mes Mes N . Cl Ru Ph Cl 10% PCy3 PhMe, 80°C

O

N

C5H11

CF3

O

Quantitative (ratio dia. 1.5/1)

10.3.6.7. Radical allylic bromination [FUC 07] O

Br

N Br O

AIBN cata.

CCl4, Δ, 3h

72%

10.4. References [ABL 14] ABLIALIMOV O., KEDZIOREK M., MALINSKA M. et al., “Synthesis, structure, and catalytic activity of new ruthenium(II) indenylidene complexes bearing unsymmetrical N-heterocyclic carbenes”, Organometallics, vol. 34, pp. 2160–2171, 2014. [ABO 94] ABOULHODA S.J., HENIN F., MUZART J. et al., “ Production of optically active ketones by a Palladium-induced cascade reaction from racemic β-ketoesters”, Tetrahedron: Asymmetry, vol. 5, pp. 1321–1326, 1994. [ARO 07] AROYAN C.E., MILLER S.J. “Enantioselective Rauhut-Currier reactions by protected cysteine”, Journal of the American Chemical Society, vol. 129, pp. 256–257, 2007. [CAM 12] CAMPOS A., BORGES SOUZA C., LHULLIER C. et al., “Anti-tumor effects of elatol, a marine derivative compound obtained from red algae Laurencia microcladia”, Journal of Pharmacy and Pharmacology, vol. 64, pp. 1146–1154, 2012. [CHA 08] CHANDRASEKHAR S., YARAGORLA S.R., SREELAKSHMI L. et al., “Formal total synthesis of (-)-spongidepsin”, Tetrahedron, vol. 64, pp. 5174–5183, 2008. [DOS 10] DOS SANTOS A.O., VEIGA-SANTOS P., UEDA-NAKAMURA T. et al., “Effect of elatol, isolated from red seaweed Laurencia dendroidea, on Leishmania amazonensis”, Marine Drugs, vol. 8, pp. 2733–2743, 2010.

246

Retrosynthetic Analysis and Synthesis of Natural Products 1

[DUH 04] DUHAMEL L., DUHAMEL P., PLAQUEVENT J.-C. et al., “Enantioselective protonations: Fundamental insights and new concepts”, Tetrahedron: Asymmetry, vol. 15, pp. 3653–3691, 2004. [FOR 12] FORKEL N.V., HENDERSON D.A., FUCHTER M.J., “Lanthanide replacement in organic synthesis: Luche-type reduction of α,β-unsaturated ketones in the presence of calcium triflate”, Green Chemistry, vol. 14, pp. 2129–2132, 2012. [FUC 07] FUCHS S., BERL V., LEPOITEVIN J.-P., “A highly stereoselective divergent synthesis of bicyclic models of photoreactive sesquiterpene lactones”, European Journal of Organic Chemistry, pp. 1145–1152, 2007. [HE 12] HE P., LIU X., ZHENG H. et al., “Asymmetric 1,2-reduction of enones with potassium borohydride catalyzed by chiral N,N’-dioxide-Scandium(III) complexes”, Organic Letters, vol. 14, pp. 5134–5137, 2012. [IKU 07] IKUNAKA M., “Catalytic, asymmetric carbon-carbon formations: Their evolution from biocatalysis to organocatalysis over the millennium”, Organic Process Research & Development, vol. 11, pp. 495–502, 2007. [JHA 02] JHA S.C., JOSHI N.N., “Catalytic enantioselective Michael addition reactions”, Arkivoc, vol. 7, pp. 167–196, 2002. [JON 16] JONES-MENSAH E., NICKERSON L.A., DEOBALD J.L. et al., “Cerium-free Luche reduction directed by rehydrated alumina”, Tetrahedron, vol. 72, pp. 3748–3753, 2016. [KOT 07] KOTHA, LAHIRI K., “Synthesis of diverse polycyclic compounds via catalytic metathesis”, Synlett, pp. 2767–2784, 2007. [KUK 08] KUKULA P., MATOUSEK V., MALLAT T. et al., “Enantioselective decarboxylation of β-ketoesters with Pd/amino alcohol systems: Successive metal catalysis and organocatalysis”, Chemistry: A European Journal, vol. 14, pp. 2699–2708, 2008. [LEB 16] LE BRAS J., MUZART J., “Production of Csp3-Csp3 bonds through palladium-catalyzed Tsuji-Trost-type reactions of (hetero)benzylic substrates”, European Journal of Organic Chemistry, pp. 2565–2593, 2016. [LOI 00] LOISELEUR O., ELLIOTT M.C., VON MATT P. et al., “Pd-Catalyzed allylic substitution with enantiomerically pure catalysts and chiral non-racemic substrates: A new approach to catalyst-based regiocontrol”, Helvetica Chimica Acta, vol. 83, pp. 2287–2294, 2000. [MEL 08] MELCHIORRE P., MARIGO M., CARLONE A. et al., “Asymmetric aminocatalysis gold rush in organic chemistry”, Angewandte Chemie: International Edition, vol. 46, pp. 6138–6171, 2008. [MOH 05] MOHR J.T., BEHENNA D.C., HARNED A.M. et al., “Deracemization of quaternary stereocenters by Pd-calatyzed enantioconvergent decarboxylative alkylation of racemic β-keto esters”, Angewandte Chemie: International Edition, vol. 44, pp. 6924–6927, 2005. [MOH 08] MOHR J.T., STOLTZ B.M., “Enantioselective Tsuji Allylations”, Chemistry: An Asian Journal, vol. 2, pp. 1476–1491, 2008.

Elatol

247

[PER 00] PERRARD T., PLAQUEVENT J.-C., DESMURS J.-R. et al., “Enantioselective synthesis of both enantiomers of methyl dihydrojasmonate using solid-liquid asymmetric phase-transfer catalysis”, Organic Letters, vol. 2, pp. 2959–2962, 2000. [RAU 63] RAUHUT M.M., CURRIER H., “Dialkyl 2-methylglutarates”, Brevet U.S. 3074999 19630122, American Cyanamid Co., 1963. [SIM 74] SIMS J.J., LIN G.H.Y., WING R.M., “Marine natural products X: Elatol, a halogenated sesquiterpene alcohol from the red sea Laurencia elata”, Tetrahedron Letters, vol. 15, pp. 3487–3490, 1974. [STE 07] STEWART I.C., UNG T., PLETNEV A.A. et al., “Highly efficient ruthenium catalysts for the formation of tetrasubstituted olefins via ring-closing metathesis”, Organic Letters, vol. 9, pp. 1589–1592, 2007. [STE 10] STEWART I.C., KELTZ B.K., KUHN K.M. et al., “Nonproductive events in ring-closing metathesis using ruthenium catalysts”, Journal of the American Chemical Society, vol. 132, pp. 8534–8535, 2010. [TAN 07] TANI K., BEHENNA D.C., MCFADDEN R.M. et al., “A facile and modular synthesis of phosphinooxazoline ligands”, Organic Letters, vol. 9, pp. 2529–2531, 2007. [URB 13] URBINA-BLANCO C.A., BANTREIL X., WAPPEL J. et al., “Mixed N-heterocyclic carbine/phosphite ruthenium complexes: The effect of a bulkier NHC”, Organometallics, vol. 32, pp. 6240–6247, 2013. [WHI 08] WHITE D.E., STEWART I.C., GRUBBS R.H. et al., “The catalytic asymmetric total synthesis of elatol”, Journal of the American Chemical Society, vol. 130, pp. 810–811, 2008. [WHI 10] WHITE D.E., STEWART I.C., SEASHORE-LUDLOW B.A. et al., “A general enantioselective route to the chamigrene natural product family”, Tetrahedron, vol. 66, pp. 4668–4686, 2010. [WYB 04] WYBROW R.A.J., EDWARDS A.S., STEVENSON N.G. et al., “A diastereoselective tandem RCM approach to spiropiperidines”, Tetrahedron, vol. 60, pp. 8869–8880, 2004.

11 Thiomarinol H

11.1. Structure, isolation and properties Thiomarinol H 1 was isolated from Alteromonas rava bacteria – strain SANK 73390 [STI 92]. Its structure is close to pseudomonic acids, in particular the C analogue 2 with a similar carbon skeleton. It is an antibacterial agent that is just as active against Staphylococcus aureus as streptomycin [MAR 09]. OH

OH

HO O

O

H N

HN

O O

O OH

1

OH

OH

HO O

O

HO

O

O

2

Figure 11.1. Structure of thiomarinol 1 and pseudomonic acid C 2. For a color version of the figures in this chapter, see www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– A polyhydroxy molecule comprising an amide functional group connected to an α-cyclic-aminoamide, an α,β unsaturated ester functional group, a THP unit, four hydroxy groups including one in the homoallyl position, one in the allyl position and a 1,2-diol subunit. Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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Retrosynthetic Analysis and Synthesis of Natural Products 1

11.2. Disconnections Dihydroxylation HO Esterification O R

O

DR

OH

DH

O

DR 5

2

HO

Allylation

NHK

O

Julia - Kociensky reaction OH

DG X

R2O

B

O

X

5

R3-CHO

+

2

O

PhS RO

OR2

OR1 HDA

O

R2O RCM

B

OR2 X

PhS RO

+ O

OR1

O

Figure 11.2. Disconnections considered for thiomarinol H

The two syntheses known to date are based on the functionalization of dihydropyran entities obtained respectively by ring-closing metathesis (DR pathway) or by a hetero-Diels–Alder reaction (DG pathway) [RAG 17, GAO 05]. The functionalization of position 5 is ensured in both cases via a Julia–Kocienski reaction, while the introduction of the side chain in position 2 involves either a Nozaki–Hiyama–Takai–Kishi (NHTK) reaction [TIA 16] or an allylation conducted in sequential mode with a cyclic allylboronate. 11.3. Approach according to D.G. Hall 11.3.1. Disconnections The first synthesis of the target molecule was carried out by D. G. Hall and his team, focusing on the classic disconnections D1, D2 and D3 leading to three distinct

Thiomarinol H

251

fragments [GAO 05]. The synthesis of the intermediate dihydropyran 11-F was considered via an original sequential reaction combining a hetero Diels–Alder cycloaddition reaction/allylation involving an allylboronate. D3 HO

OH

HO O

D1 O

H N

HN

D2 O O

O HN

O OH

1

O

H N

( )7 O

OH

OR'

N

OHC

N

RO2C

+

O S

H OGp

11-A

N

O

Ph

+

N

11-C

11-B

D4

O RO

CHO 11-E

RO2C OH

H

O

D5

OEt

R'O +

B

OR'

D6

11-D R'O

B

O

OR'

+

11-G O

OEt

11-F

11-H OEt

Figure 11.3. Key disconnections

LEGEND OF FIGURE 11.3.– D1: simplification into two acid and alcohol subunits (esterification). D2: disconnection at the double bond level (Julia–Kocienski olefination). D3: 1,2-diol obtained from an alkene (asymmetric dihydroxylation). D4: sulfone from an alkene (oxidative cleavage/reduction/substitution). D5: disconnection of homoallyl alcohol (allylboration of an aldehyde). D6: formation of dihydropyran (hetero-Diels–Alder).

252

Retrosynthetic Analysis and Synthesis of Natural Products 1

11.3.2. Synthesis 11.3.2.1. Synthesis of sulfone 11-B

O

B

O

O

O

O 11-G

EtO

OEt

O

11-H

( )2

O

OH c-f H OTIPS

b

OEt

11-F

O EtO

CHO 11-E

a

+ H

B

O

O

OEt

EtO OH O

H

OEt 11-D

O S

g-i

O

N N

EtO2C H OTIPS

N

O

Ph

N

11-B

Figure 11.4. Synthesis of sulfone 11-B

LEGEND OF FIGURE 11.4.– a. Enantioselective hetero-Diels–Alder reaction: Jacobsen catalyst (3 mol%), 20°C. b. Allylation – 76% (2 steps): aldehyde 11-E, 110°C, 36 h. c. Protection of allyl alcohol – 93%: TIPS-OTf, 2,6-lutidine, CH2Cl2. d. Regioselective dihydroxylation: AD-mix-β, t-BuOH, H2O, 0°C, 2 h. e. Oxidative cleavage of 1,2-diol: NaIO4, THF, H2O f. Reduction of aldehyde to alcohol – 88%: NaBH4, EtOH. g. Ketal reduction – 85%: TiCl4, Et3SiH, CH2Cl2, −50°C. h. Conversion of alcohol to sulfide by the Mitsunobu reaction: 1-phenyl-1Htetrazole-5-thiol, PPh3, DIAD, THF. i. Oxidation of sulfide to sulfone – 91%: (NH4)2MoO4, H2O2, EtOH.

Thiomarinol H

253

11.3.2.2. Julia olefination – functionalization of the side chain O

ArO2S O

O S

N N

EtO2C H OTIPS

N

O

Ph

N

O j,k

O EtO

H OTIPS

11-B OTIPS

OTIPS

O

OHC

O

O

11-C EtO2C

l

H OTIPS

O 11-I

Figure 11.5. Julia–Kocienski coupling involving sulfone 11-B

LEGEND OF FIGURE 11.5.– j. Dihydroxylation of the less hindered double bond: OsO4, NMO, acetone–water. k. 1,2-Diol protection – 91% (2 steps): Me2C(OMe)2, TsOH cata., AcOEt. l. Julia–Kocienski reaction – 76%: (i) KHMDS, THF, −78°C; (ii) 11-C, −78°C -> r.t. 11.3.2.3. Completion of the synthesis OTIPS

O O EtO2C H OTIPS

m

O 11-I

O

OTIPS

O HO2C H OTIPS

n-p

O

OH O HN

O

H N

( )5

HO

O

O

O

OH 1

Figure 11.6. Final steps of the synthesis

OH

254

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 11.6.– m. Saponification – 96%: KOSiMe3, Et2O, THF, 45°C. n. DIC-mediated esterification – 95%: hydroxyamide 11-A, DIC, DMAP, CH2Cl2. o. Silylether cleavage – 81%: TBAF, THF, r.t. p. Acetonide deprotection – 90%: AcOH aq., r.t. Number of steps: 15 – overall yield: 22%. The key step in the synthesis is the formation of dihydropyran via an enantioselective hetero-Diels–Alder reaction resulting in an allylboronate directly involved in a tandem addition process on an aldehyde, here 11-E. The introduction of the unsaturated carbon chain is achieved by a Julia–Kocienski olefination between an arylsulfone and a duly protected chiral β-hydroxyaldehyde. 11.3.2.4. Access to fragment 11-A Hydroxyamide 11-A was prepared in four steps from 1,8-octanediol with an overall yield of 30%. OH

HO

a'

OH

BnO H

b'

BnO

( )5

CO2H

c',d'

HO

N

( )5

O N

H

O 11-A

Figure 11.7. Access to the synthon 11-A

LEGEND OF FIGURE 11.7.– a’. Monoetherification – 56%: (i) NaH, DMF, 0°C; (ii) Bn-Br, THF/DMF. b’. Oxidation of primary alcohol to acid – 78%: PDC, DMF/H2O, 0°C c’. Amidation – 72%: CDI, (S)-3-aminopiperidinone, THF, r.t. d’. Benzyl ether cleavage – 96%: H2, Pd/C, AcOEt, r.t. 11.3.3. Key reaction: hetero-Diels–Alder enantioselective reaction The hetero-Diels–Alder reaction (HDA) with inverse demand between an α,β-unsaturated aldehyde and an electron-rich alkene – typically an enol ether – allows synthesis of the corresponding dihydropyrans with high regio- and

Thiomarinol H

255

stereoselectivities [WEI 82, HER 15]. In order to control the approach of the alkene to one of the two sides of the unsaturated aldehyde, the reaction was carried out in the presence of a catalytic amount of a salen derivative, cis-1-amino-2-indanol as the chiral unit [GAD 02, PEL 09, JOR 00].

(S) N

O Cr

CO2Et

CO2Et

Cl

(R) O

(5 mol %)

+ O

4Å MS, no solvent

OEt

OEt

O

90% e.e. = 95 %

Figure 11.8. Enantioselective hetero-Diels–Alder reaction according to Jacobsen

By using 3-boronoacrolein 11-G, cycloaddition results in a dihydropyran with an allylboronate chain capable of reacting with an aldehyde in a three-component sequential reaction [GAO 06].

O

B

O n-C7H15

n-C7H15

n-C7H15 R-CHO

OEt

O

H

H O

OR

OR' B

OR'

C7H15 OEt ET-1

OEt

R OH

H

O

OEt

# R'O R'O O B C7H15 H

# OEt R O

ET-2

(R'O)2B H

O R

C7H15 O OEt

H ET-3

Figure 11.9. Hetero Diels–Alder reaction/allylation

#

256

Retrosynthetic Analysis and Synthesis of Natural Products 1

The effectiveness of the reaction, however, is highly dependent on the substrate. When the process is conducted at 20°C in the presence of ethyl vinyl ether, only a very small amount of catalyst is required (1 mol%) and for a reaction time of 2 h. With a 2-substituted ether in position 2 of configuration Z, the reaction time exceeds 5 h and the amount of catalyst is tripled. The second allylation step also requires higher than usual temperatures of 45°C with saturated linear aldehydes or 110°C with 11-C aldehyde required for target synthesis. The presence of the chiral catalyst is harmful during the allylation reaction and requires elimination by rapid filtration, which does not allow the process to be carried out in a stricto sensu sequential manner. To account for the relative cis,cis stereochemistry observed, different transition states have been proposed. The ET-1 state appears to be excluded due to steric interactions between the 6-chain ring and the aldehyde. The second state of transition of the ET-2 chair results in placing the ethoxy and boronate groups in a pseudo-axial position, which is prohibitive; on the other hand, with ET-3 adopting a boat conformation, and for which the alkoxy group is then placed in a pseudo-equatorial position, it clearly reflects the stereochemistry of the reaction. 11.3.4. Supporting synthetic transformations 11.3.4.1. Enantioselective crotylation [BRO 86, YAM 93] O 1) H3C

(Ipc)2B

OH H THF, -78°C

CH3

2) NaOH, H2O2

75%

prepared from (-)-pinene

d.r. = 99% - e.e. = 95%

11.3.4.2. Dihydroxylation/oxidative cleavage [YU 04] CH3

OPMB CH3

OTBS

CH3 OsO4 (0.02 eq.) NaIO4 (4 eq.) Dioxane/water (3:1) no base : 2,6-lutidine (2 eq.)

CH3 O

CH3

OPMB

H OTBS

OPMB

O

CH3

+ OH

OTBS

A : 60-64%

B : 30-25%

A : 90%

B : 6%

Thiomarinol H

257

11.3.4.3. Reduction of ketals [CRA 95] OSitBuPh2

OSitBuPh2 Et3SiH, TMSOTf

EtO

CH2Cl2

O

O 70%

11.3.4.4. Mitsunobu reaction in FBS mode [DAN 02, DEM 04] O O2 N

CO2H

O

C6F13 O

O N N

C6F13

O2 N

C6F13

NO2

NO2

C6F13

+ Et-OH

OEt

O

92% P Ph

After extraction by MeOH/H2O

THF

11.3.4.5. Julia–Kocienski reaction [BEL 96] S S

2)

N

OTBS

O 1) Li-HMDS

S

SO2

THF, -78°C

H

OMe

H

S

O

H

CHO

OTBS

S OMe

68% (E,E,E) 5% (E,E,Z)

258

Retrosynthetic Analysis and Synthesis of Natural Products 1

11.3.4.6. Dess–Martin oxidation [NIC 07] O

O

O

O OAc AcO OAc I

(1.2 equiv.)

OH

NaHCO3 ( 3 equiv.)

Br

OHC

Br

CH2Cl2, 45°C, 4h

95%

11.3.4.7. Selective saponification [LAG 84, MIN 05] O Bn2N

O O-t-Bu

Bn2N

O O-t-Bu

TMSO-Na

OCH3

O-t-Bu

THF, r.t. 2) NaBH4

THF r.t., 16h O

1) BOP,

Bn2N

O

ONa

THF 0°C -> r.t.

OH 74%

11.3.4.8. Esterification of tertiary alcohols mediated by DCI [ZHA 98]

O2N

+

HO

O

DCI, DMAP

CO2H CO2Et

Sc(OTf)3 (0.6 equiv.) CH2Cl2, -8°C

O

CO2Et

O2N 92%

11.4. Approach according to S. Raghavan 11.4.1. Disconnections The synthesis of the precursor 11-J, common to thiomarinols, was carried out by S. Raghavan and his team [RAG 17]. The construction of dihydropyran is based particularly on a ring-closing metathesis followed by the introduction of a carbon chain in position 2 via a Kirmse–Doyle reaction involving a diazoester and an allylic sulfide.

Thiomarinol H

259

Figure 11.10. Key disconnections to synthesize acid 11-J

LEGEND OF FIGURE 11.10.– D1: functionalization of the chain in position 2 (Nozaki–Hiyama coupling). D2: cis-1,2-diol obtained from an alkene (diastereoselective dihydroxylation). D3: disconnection at the double bond level (Julia olefination reaction). D4: sulfone from a chiral β-hydroxyester (asymmetric hydrogenation of a

β-ketoester according to Noyori and post-functionalization). D5: migration of the double bond and introduction of the carbon chain in position 5 (Kirmse–Doyle rearrangement). D6: formation of dihydropyran (ring-closing metathesis).

260

Retrosynthetic Analysis and Synthesis of Natural Products 1

11.4.2. Synthesis 11.4.2.1. Synthesis of sulfone 11-N O

OMOM

OH a

CO2Et

OMOM

OMOM d

CO2Et

b,c

CO2Et

N

N

e,f

OH

N N

S O

O

Ph

11-N

Figure 11.11. Synthesis of sulfone 11-N

LEGEND OF FIGURE 11.11.– a. Enantioselective hydrogenation according to Noyori – 95%: (S)-BINAP-RuCl2 (0.1 mol%), H2 (50 psi), EtOH, 80°C, 8 h. b. Stereoselective alkylation – 82%: (i) LDA (2.1 equiv.), THF, HMPA, −78°C then -40°C, 20 min.; (ii) MeI (1.25 equiv.), −78°C then 0°C, 3 h. c. Alcohol protection – 85%: TBAI (0.05 equiv.), MOM-Cl, DIPEA, CH2Cl2. d. Ester reduction – 94%: LiAlH4, THF, 0°C then r.t., 3 h 30. e. Mitsunobu reaction – 76%: 1-phenyl-1H-tetrazole-5-thiol, P(Ph)3, DEAD, Ph-Me, 0°C then r.t., 20 min. f. Oxidation of sulfide to sulfone – 86%: m-CPBA, CH2Cl2, -30°C, 3 h. 11.4.2.2. Formation of dihydropyran 11-P SPh HO

Cl OH

PhS

SPh i

g,h OH

O

OTPS

Cl

j

OTPS

PhS

PhS

k

l

O OTPS

O OTPS

O OTPS 11-P

Figure 11.12. Synthesis of dihydropyran 11-P

Thiomarinol H

261

LEGEND OF FIGURE 11.12.– g. Substitution of chloride by thiophenol – 86%: PhSH, DBU, MeCN, r.t. h. Protection of primary alcohol – 92%: TPS-Cl, imid. DMF, 0°C – r.t., 4 h. i. Allylation of secondary alcohol – 83%: Allyl-Br, NaH, 0°C then r.t., 8 h. j. Formation of a chlorosulfide (non-isolated): NCS (1.1 equiv.), PhH, r.t., 15 min. k. Substitution of the chloride by a vinyl group – 65%: vinylMgBr, ZnCl2, THF, r.t. l. Ring-closing metathesis – 81%: GBII (3 mol %), PhMe, reflux, 8 h. 11.4.2.3. Access to acid 11-J SPh O

CO2Et

CO2Et

n,o

m

O

O

OTPS 11-P

SO2Ph

O

PhS

O

OTPS

OTPS

O

O

O

O CO2Et

p

CHO

q O

O OTPS

OTPS

OMOM

O

11-M OMOM

O

O

O s,t

r O

OHC

O

OTPS

11-L OMOM

O O u,v

OTBS O

w-z

O OMOM

O O OH O

O OTBS

Figure 11.13. Access to acid 11-J

11-J

262

Retrosynthetic Analysis and Synthesis of Natural Products 1

LEGEND OF FIGURE 11.13.– m. Kirmse–Doyle rearrangement – 71%: N2CHCO2Et, Rh2(OAc)4, PhMe. n. Double oxidation of sulfide to sulfone and alkene to diol – 79%: OSO4, NMO, aqueous acetone. o. Protection of the 1,2-diol – 84%: Me2C(OMe)2, TsOH. p. Desulfonation – 80%: Na(Hg), Na2HPO4, MeOH. q. Reduction of the ester to aldehyde – 92%: DIBAL-H, CH2Cl2. r. Julia–Kocienski reaction – 75% (E/Z = 3/1): (i) Sulfone 11-N, KHMDS, THF, −78°C, 15 min; (ii) Aldehyde 11-L, −78°C then return r.t., 12 h. s. Deprotection of silylated ether – 88%: TBAF, THF, r.t., 3 h. t. Oxidation of alcohol to aldehyde – 73%: TEMPO (0.1 equiv.), BAIB (1.2 equiv.), CH2Cl2, 0°C. u. Nozaki–Hiyama–Kishi coupling – 81%: iodoalkene 11-K, NiCl2, CrCl2, DMSO, r.t., 7 h. v. Oxidation of allyl alcohol to ketone – 84%: DMP, NaHCO3, CH2Cl2, 30 min. w. Stereoselective reduction of enone to allyl alcohol – 93%: Noyori catalyst, HCO2Na, n-Bu4NBr, CH2Cl2/H2O. x. Protection of secondary allyl alcohol in silyl ether – 81%: TBSOTf, 2,6-lutidine, CH2Cl2, -20°C, 3 h. y. Selective deprotection of silyl ether to primary alcohol – 77%: HF.pyridine, THF, 0°C. z. Direct oxidation of primary alcohol to carboxylic acid – 92%: BAIB (30 equiv.), TEMPO (2.1 equiv.), CH3CN/H2O (1:1), 0°C then r.t., 2 h.

11.4.3. Key reaction: Kirmse–Doyle rearrangement The decomposition of diazo derivatives catalyzed by copper (I) or rhodium (II) salts and carried out in the presence of allyl sulfide generates a sulfur ylide, which can then undergo sigmatropic rearrangement [2,3]. Initially highlighted by Kirmse and Kapps in 1968 and reinvested by the Doyle group, it provides access to functionalized homoallyl sulfides [KIR 68, DOY 84].

Thiomarinol H

R1

R1 N2 +

Ph

R2

S

MLn

Ph + S

R1 R2

Ph

263

R2 R3

S

R3

R3

Figure 11.14. General mechanism of the Kirmse–Doyle rearrangement

More recently, in order to minimize the risks associated with the handling of diazo derivatives, their in situ generation has been carried out in water by the action of nitrous acid on amino acetonitrile hydrochloride. In the presence of the iron (III) dihydroporphyrin complex (FeTPPCl), the intermediate diazo decomposes into a carbene, which immediately interacts with an allyl and aryl sulfide, already present. The ylide formed is rearranged into the corresponding α-arylmercapto valeronitrile in excellent yields [HOC 17]. CN S

FeTPPCl (1 mol%)

+ + H3 N Cl

CN

-

S

NaNO2 (3 equiv.) (Slow addition) H2O/ CH2Cl2

96%

Figure 11.15. Kirmse–Doyle rearrangement from aminoacetonitrile

In the presence of chiral catalysts such as Rh2(S-DOSP)4, enantioselective variants have been reported in particular for the genesis of quaternary stereogenic centers containing a trifluorosulfanyl unit [ZHA 17].

N2

O Rh

CO2Et Ph

N SO2Ar

+

(0.13 mol%) S-CF3

S-CF3

O Rh

n-pentane, -30°C, 24h

Ph

CO2Et

95% - e.e. = 91% Ar = p-C12H25C6H4-

Figure 11.16. Enantioselective Kirmse–Doyle rearrangement

264

Retrosynthetic Analysis and Synthesis of Natural Products 1

11.4.4. Key reaction: Julia–Lythgoe and Julia–Kocienski reaction Initially reported by Marc Julia and Jean-Marc Paris in 1973, the condensation reaction of an arylalkylsulfone on a carbonyl compound followed by a reductive elimination, makes it possible to synthesize di-, tri- or even tetrasubstituted alkenes [CHA 14].

LiO

Li Ph

n-BuLi S O2

R1

Ph

S O2

THF, -78°C

Ac

Ac-Cl

Ph

O

R2

S O2

R1

R2-CHO

R1

Na (Hg)

Ph

R2

S O2

R1

R1

R2

EtOH

Figure 11.17. Mechanism of the Julia olefination reaction involving phenylsulfones

The reaction is carried out in two steps; after trapping the lithiated intermediate as an acyloxysulfone, reduction can be achieved using sodium amalgam. After removal of the acetate group, the vinyl sulfone is reduced to a vinyl radical with the E configuration; this is then reduced to the corresponding anion to finally give the alkene after protonation. Na + MeOH H PhO2S R1

Ph -

MeO Na

+

R2

O R1

OAc

S

O Na(Hg) R2 - PhSO2Na

R1

H Na(Hg) R1

R2

R1

R2

Figure 11.18. Reduction of β-acyloxysulfones by sodium amalgam

R2

Thiomarinol H

265

Alternatively, samarium(II) iodide can be used to synthesize the same alkenes, according to two consecutive single electron transfer. Ph O

S

Ph

O Sm2+

O

R2

R1

O

S

R2 H

H

R2

R1

SET

Ph-SO2 SmIII

R1

OAc

OAc

OAc

free rotation

Sm2+

R2 H

H R1

SET

R2

R1

OAc

Figure 11.19. Reduction of β−acyloxysulfones by samarium diiodide

The Sylvestre Julia group developed an approach involving a benzothiazol-2-yl group directly linked to a sulfone, allowing the formation of an alkene, without the use of an additional reduction step.

S

S

N n-BuLi

S

O O

N

O

THF

S R2-CHO

S

Li

N OLi

O

S

R2

O

O

R1

R1

R1

S

N

O2S

O

R1

Li

R2

R2

R1

O

N Smiles Rearrangement

R2 R1

O2S

S

N +

+ SO2

HO S

Figure 11.20. Modified Julia olefination reaction

266

Retrosynthetic Analysis and Synthesis of Natural Products 1

The intermediate lithium alcoholate is added onto the carbon-nitrogen double bond to give a spiro intermediate, which undergoes a Smiles rearrangement for which the SO2 group directs the opening of the five-membered ring leading to the rearomatization of the benzothiazole ring. The cleavage of the carbon-sulfur bond is accompanied by the release of a gaseous SO2 molecule and 2-hydroxybenzothiazole in the form of its anion, which is neutralized at the end of the reaction. The stereochemistry of the alkene depends on many factors including steric hindrance and operating conditions (solvent, temperature, nature of the base and cation involved). With lithiated and apolar bases, selectivity is in favor (weakly) of compounds with Z configuration; the latter can be correlated with the transition states represented in Figures 11.21 and 11.22 from anti and syn alcoholates respectively. In the case of the anti derivative, the chelation of the small lithium cation with the heteroatoms O and N leads to the development of a gauche interaction between the substituents R1 and R2, which does not promote an easy ring-closing to the spiro intermediate. After rearomatization and adoption of a conformation for which the BTO and SO2Li substituents are anti, the elimination leads to the compound with E-configuration.

S OLi R1

S

Li

N

R1

SO2Ar anti

O

H H R1

SO2Li

S R2

O

Li

O

R2

slow

O

R1 R2

H

R2

SO2

H H

H R1 R1

C BT-O

N

R2 H

R2

H

Figure 11.21. Justification of the E stereochemistry from the anti adduct

With the synderivative, the situation is more favorable to the formation of the spiro intermediate, the two substituents R1 and R2 being in anti. In this way, elimination gives the Z stereoisomer.

Thiomarinol H

S

OLi R1

S R1

SO2Ar

O

S

Li

Li

O

fast

O

R1

SO2

R2

H

syn

N

N O

R2

267

H

H

R2 H

R2 R1

R R12

SO2Li

R2 R1

C BT-O

H H

H

Z

H

Figure 11.22. Justification of Z stereochemistry from the syn adduct

By modifying the nature of the sulfone-bound heterocycle, Kocienski et al. showed that tetrazoles substituted by a t-butyl or phenyl group made it possible to free themselves, just like the BT derivatives, from the reduction step but with much greater selectivity, in favor of the E derivative, including with lithiated derivatives. These sulfones now represent the most commonly used reagents for this method of olefination [SPE 15]. O

Ph N

O TBSO

N O CHO

H OTBS

O

H

O

S

N N KHMDS, THF

TBSO

O H

-78°C -> r.t.

H

OTBS 70% E/Z > 95/5

Figure 11.23. Application of tetrazolylsulfones in total synthesis

Usually performed using aldehydes and ketones, the reaction has more recently been extended to lactones, lactams and imides to synthesize, in the latter case, bicyclic nitrogen structures [TRI 16, GUE 18].

268

Retrosynthetic Analysis and Synthesis of Natural Products 1

N

O S

O

O 1) LiHMDS, -78°C

S

N

BF3.OEt2, THF O

2) DBU (2.5 equiv.)

N O

BF3.OEt2, THF

79%

Figure 11.24. Intramolecular Julia reaction involving an imide

11.4.5. Supporting synthetic transformations 11.4.5.1. Ring-closing metathesis [RAG 11, JAC 16] HO

C10H21

( )2

O

OBn

HO

GBII (5 mol%) OR

CH2Cl2, Δ

OBn

C10H21

( )2

O

OBn

R=H R = TES

OR OBn

76% 85%

11.4.5.2. Desulfonation under reductive conditions [TRO 76]

O O

S

H

NC

Na(Hg)

NC

Na2HPO4 MeOH, -10°C 7 min.

66%

11.4.5.3. Reduction of β-ketoesters according to Noyori [NOY 87] O

O

RuCl2[(R)-BINAP] OMe

Substrate/catalyst : 2000

H2 (100 atm.) MeOH, 23°C

OH

O OMe

99% - e.e. > 99%

Thiomarinol H

11.4.5.4. Nozaki–Hiyama–Kishi reaction [STI 83] OCH2OBn

O

O

Ph HO

O Br CHO

4

CrCl2 (5 equiv.)

O

+

THF, 25°C, 6h

OCH2OBn

1

64%

HO

O

11.4.5.5. Oxidation of alcohols to aldehydes by TEMPO [DEM 97] AcO

I

OAc

N O TEMPO (0.1 equiv.)

OH

BAIB (1.1 equiv.)

O

CH2Cl2, r.t., 1h30 95%

11.4.5.6. Oxidation of alcohols to carboxylic acids [EPP 99] NH2

NH2 N N

HO

O

N

N N

N

OH TEMPO (0.2 equiv.)

N

O

N

O

BAIB (2.2 equiv.) O

O

O CH3CN/H2O

O 90%

269

270

Retrosynthetic Analysis and Synthesis of Natural Products 1

11.5. References [BEL 96] BELLINGHAM R., JAROWICKI K., KOCIENSKI P. et al., “Synthetic approaches to rapamycin: Synthesis of a C10-C26 fragment via a one-pot Julia olefination reaction”, Synthesis, pp. 285–296, 1996. H.C., BHAT K.S., “Enantiomeric (Z)and (E)[BRO 86] BROWN crotyldiisopinocampheylboranes. Synthesis in high optical purity of all four possible stereoisomers of β-methylhomoallyl alcohols”, Journal of the American Chemical Society, vol. 108, pp. 293–294, 1986. [CHA 14] CHATTERJEE B., BERA S., MONDAL D., “Julia-Kocienski olefination: A key reaction for the synthesis of macrolides”, Tetrahedron: Asymmetry, vol. 25, pp. 1–55, 2014. [CRA 95] CRAWLEY G.C., BRIGGS M.T., “Asymmetric syntheses of (S)-2-methyl-3,4,5,6tetrahydro-2H-pyran-4-one and (2S,6S)-trans-dimethyl-3,4,5,6-tetrahydropyran-2Hpyran-4-one which employ a common lactol intermediate”, Journal of Organic Chemistry, vol. 60, pp. 4264–4267, 1995. [DAN 02] DANDAPANI S., CURRAN D.P., “Fluorous Mitsunobu reagents and reactions”, Tetrahedron, vol. 58, pp. 3855–3864, 2002. [DEM 04] DEMBINSKI R., “Recent advances in the Mitsunobu reaction: Modified reagents and the quest for chromatography-free separation”, European Journal of Organic Chemistry, pp. 2763–2772, 2004. [DEM 97] DE MICO A., MARGARITA R., PARLANTI L. et al., “A versatile and highly selective hypervalent iodine (III)/2,2,6,6-tetramethyl-1-piperidinyloxyl-mediated oxidation of alcohols to carbonyl compounds”, Journal of Organic Chemistry, vol. 62, pp. 6974–6977, 1997. [DOY 84] DOYLE M.P., GRIFFIN J.H., CHINN M.S. et al., “Rearrangements of ylides generated from reactions of diazo compounds with allyl acetals and thioketals by catalytic methods. Heteroatom acceleration of the [2,3]-sigmatropic rearrangement”, Journal of Organic Chemistry, vol. 49, pp. 1917–1925, 1984. [EPP 99] EPP J.B., WIDLANSKI T.S., “Facile preparation of nucleoside-5’-carboxylic acid”, Journal of Organic Chemistry, vol. 64, pp. 293–295, 1999. [GAD 02] GADEMANN K., CHAVEZ D.E., JACOBSEN E.N., “Highly enantioselective inverseelectron demand hetero-Diels-Alder reactions of α,β−unsaturated aldehydes”, Angewandte Chemie: International Edition, vol. 41, pp. 3059–3061, 2002. [GAO 05] GAO X., HALL D.G., “Catalytic asymmetric synthesis of a potent thiomarinol antibiotic”, Journal of the American Chemical Society, vol. 127, pp. 1628–1629, 2005. [GAO 06] GAO X., HALL D.G., DELIGNY M. et al., “Catalytic enantioselective threecomponent hetero-[4+2] cycloaddition/allylboration approach to α−hydroxyalkyl pyrans: Scope, limitations and mechanistic proposal”, Chemistry European Journal, vol. 12, pp. 34–45, 2006.

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271

[GUE 18] GUEYRARD D., “Extension of the modified Julia olefination on carboxylic acid derivatives: Scope and applications”, Synlett, pp. 293–295, 2018. [HER 15] HERAVI M.M., AHMADI T., GHAVIDEL M. et al., “Recent applications of the hetero Diels-Alder reaction in the total synthesis of natural products”, RSC Advances, vol. 5, pp. 101999–102075, 2015. [HOC 17] HOCK K.J., MERTENS L., HOMMELSCHEIN R. et al., “Enabling iron catalyzed DoyleKirmse rearrangement reactions with in situ generated diazo compounds”, Chemical Communications, vol. 53, pp. 6577–6580, 2017. [JAC 16] JACQUES R., PAL R., PARKER N.A. et al., “Recent applications in natural product synthesis of dihydrofuran and pyran- formation by ring-closing alkene metathesis”, Organic and Biomolecular Chemistry, vol. 14, pp. 5875–5893, 2016. [JOR 00] JORGENSEN K.A., “Catalytic asymmetric hetero Diels-Alder reactions of carbonyl compounds and imines”, Angewandte Chmie: International Edition, vol. 39, pp. 3558–3588, 2000. [KIR 68] KIRMSE W., KAPPS M., “Reaktionen des diazomethans mit diallylsulfid un allyläthern unter kupfersalz-katalyse”, Chemische Berichte, vol. 101, pp. 994–1003, 1968. [LAG 84] LAGANIS E.D., CHENARD B.L., “Metal silanolates: Organic soluble equivalents for O2”, Tetrahedron Letters, vol. 25, pp. 5831–5834, 1984. [MAR 09] MARION O., GAO X., MARCUS S. et al., “Synthesis and preliminary antibacterial evaluation of simplified thiomarinol analogs”, Bioorganic & Medicinal Chemistry, vol. 17, pp. 1006–1017, 2009. [MIN 05] MINTA E., BOUTONNET C., BOUTARD N. et al., “Easy saponification by metal silanolates: Application in SPPS and in (S)-5-hydroxyvaline preparation”, Tetrahedron Letters, vol. 46, pp. 1795–1797, 2005. [NIC 07] NICOLAOU K.C., TANG Y., WANG J., “Formal synthesis of (+/-)-platensimycin”, Chemical Communications, pp. 1922–1923, 2007. [NOY 87] NOYORI, R., OHKUMA T., KITAMURA M. et al., “Asymmetric hydrogenation of β-keto-carboxylic esters. A practical purely chemical access to β-hydroxy esters in high enantiomeric purity”, Journal of the American Chemical Society, vol. 109, pp. 5856–5858, 1987. [PEL 09] PELISSIER H., “Asymmetric hetero-Diels-Alder reactions of carbonyl compounds”, Tetrahedron, vol. 65, pp. 2839–2877, 2009. [RAG 11] RAGHAVAN S., SUBRAMANIAN S.G., “Toward a modular, bidirectional synthesis of (-)-mucocin”, Tetrahedron, vol. 67, pp. 7529–7539, 2011. [RAG 17] RAGHAVAN S., RAVI A., “Synthesis of an advanced intermediate enroute to thiomarinol antibiotics”, Tetrahedron, vol. 73, pp. 2814–2823, 2017. [SPE 15] SPECKLIN S., BOISSONNAT G., LECOURT C. et al., “Synthetic studies toward the C32C46 segment of hemicalide. Assignment of the relative configuration of the C36-C42 subunit”, Organic Letters, vol. 17, pp. 2446–2449, 2015.

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[STI 83] STILL W.C., MOBILIO D., “Synthesis of asperdiol”, Journal of Organic Chemistry, vol. 48, pp. 4786–4788, 1983. [STI 92] STIERLE D.B., STIERLE A.A., “Pseudomonic acid derivatives from a marine bacterium”, Experientia, vol. 48, pp. 1165–1169, 1992. [TIA 16] TIAN Q., ZHANG G., “Recent advances in the asymmetric Nozaki-Hiyama-Kishi reaction”, Synthesis, vol. 48, pp. 4038–4049, 2016. [TRI 16] TRINH H.V., PERRIN L., GOEKJIAN P.G. et al., “Development of a modified Julia olefination of imides for the synthesis of alkaloids”, European Journal of Organic Chemistry, pp. 2944–2953, 2016. [TRO 76] TROST B.M., ARNDT H.C., STREGE P.E. et al., “Desulfonylation of aryl alkyl sulfones”, Tetrahedron Letters, vol. 27, pp. 3477–3478, 1976. [WEI 82] WEINREB S.M., STAIB R.R., “Synthetic aspects of Diels-Alder cycloadditions with heterodienophiles”, Tetrahedron, vol. 38, pp. 3087–3128, 1982. [YAM 93] YAMAMOTO Y., ASAO N., “Selective reactions using allylic metals”, Chemical Reviews, vol. 93, pp. 2207–2293, 1993. [YU 04] YU W., MEI Y., KANG Y. et al., “Improved procedure for the oxidative cleavage of olefins by OsO4-NaIO4”, Organic Letters, vol. 6, pp. 3217–3219, 2004. [ZHA 17] ZHANG Z., SHENG Z., YU W. et al., “Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides”, Nature Chemistry, vol. 9, pp. 970–976, 2017. [ZHA 98] ZHAO H., PENDRI A., GREENWALD R.B., “General procedure for acylation of tertiary alcohols: Scandium triflate/DMAP reagent”, Journal of Organic Chemistry, vol. 63, pp. 7559–7562, 1998.

12 Oblongolides A and C

12.1. Structures, isolation and properties The oblongolides are a family of sesquiterpenes (C15) and norsesquiterpenes (C14) isolated from the fungus Phomopsis oblonga itself growing on halophyte forage plants such as sweet clover (Melilotus dentata) [BEG 85, DAI 05, BUN 10]. This family has 26 members (A-Z), and only two of them have been synthesized to date. They differ only in their substitution in position 3a.

O

O

O

H 9b

O

H

3a

9b

3a

OH

H H 1 Oblongolide A

H 2 Oblongolide C

Figure 12.1. Structure of oblongolides A and C. For a color version of the figures in this chapter see, www.iste.co.uk/piva/analysis1.zip

ANALYSIS.– Oblongolides A and C have an octahydronaphthalene (trans decalin) core structure with a butyrolactone group attached. They share an unsaturated bond present on cycle B and five stereogenic centers including a quaternary center at α on the carboxylic group.

Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications, First Edition. Olivier Piva. © ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.

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12.2. Disconnections The decalin skeleton is found in many natural products, and its access has been the subject of many investigations [DHA 15]. Two approaches have been considered here to reach the carbon skeleton common to both targets: – first, involving an intramolecular (or even transannular) Diels–Alder reaction between a diene and an α,β-unsaturated ester to simultaneously construct cycles A and B [SHI 95]; – second, according to a [3+2] dipolar cycloaddition between a nitrile oxide and an alkene already combined on synthon 12-C already containing cycle A [INO 13]. Both intermediates 12-A and 12-C can be prepared from the same natural compound (-)-citronellol. A [4+2] cycloaddition was also carried out using a transannular approach based on the macrolactone prepared from 12-A; this approach is then likely to lead directly to oblongolide A 1.

CO2R OH O O H A

C B

H

12-A

OH

R

(-)-citronellol

O H

1/2

N

H N

12-B

OH

12-C

Figure 12.2. Key disconnections: Diels–Alder or [3+2] cycloaddition

Citronellol and the corresponding aldehyde are key substrates for the synthesis of natural products: the alcohol/aldehyde and alkene functional groups can be selectively modified while preserving the stereogenic center bearing a methyl group, and lead to chiral synthons of real importance [LEN 07, HAN 15].

Oblongolides A and C

275

12.3. Synthesis of oblongolide A according to Shing 12.3.1. Disconnections O O CO2R D1

OH

D2

CHO

H

CHO

H 12-A

1

12-D

D3 OH

(-)-Citronellol

Figure 12.3. Disconnection according to Shing

LEGEND OF FIGURE 12.3.– D1: formation of the B cycle (intramolecular [4+2] cycloaddition). D2: double olefinization of bisaldehyde 12-D (classic and vinylogous Wittig– Horner reaction). D3: access to dialdehyde (oxidative division of the double bond/oxidation of the primary alcohol of (-)-citronellol).

12.3.2. Synthesis 12.3.2.1. Intramolecular Diels–Alder reaction The outcome of the Diels–Alder reaction varies significantly depending on the reaction time and temperature applied. When 12-A is subjected to heat treatment at 155°C in toluene (Figure 12.5), cycloaddition provides the target structure 1 as well as the diastereoisomers 12-E and 12-F in a ratio of 12: 24: 38. In 1,2-dichlorobenzene at 210°C and after 56 h, compounds 1 and 12-E are isolated with respective yields of 38.8 and 17.2%. By extending the heating by 20 h, only 1 is isolated with a yield of 55%. It therefore appears that the formation of

276

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the minor diastereoisomer 12-E is reversible at 210°C and that lactonization takes place at this temperature. It should be noted that the use of Lewis acids as a catalyst in the last step did not lead to convincing results, as the 12-A substrate was found to be unstable under acidic conditions. O

CO2t-Bu

b

a OH

OH

CO2t-Bu

c

OH

CO2t-Bu

d

CO2Me

O O

O CO2t-Bu

e

f

H

OH H

12-A

1

Figure 12.4. Synthesis of oblongolide A by Diels–Alder reaction

LEGENDS OF FIGURE 12.4.– a. Oxidative cleavage: OsO4 (cat.), NaIO4, dioxane/water, r.t. b. Wittig reaction – 71.3% (2 steps): Ph3P=C(CH3)-CO2t-Bu, CH2Cl2. c. Oxidation of primary alcohol: PDC, 3Å MS, CH2Cl2. d. Wittig–Horner homologous reaction – (MeO)2P(O)CH2CH=CHCO2Me, THF, −78°C.

47%

(2

steps):

NaHMDS,

Oblongolides A and C

277

e. Regioselective reduction of methyl ester to alcohol – 70%: DIBAL-H (2 equiv.), THF, −78°C. f. Intramolecular Diels–Alder reaction – 55%: 1,2-dichlorobenzene, sealed tube, 210°C, 76 h. Number of steps: 6 – Overall yield: 13%.

CO2t-Bu OH 12-A f' O O

CO2t-Bu

H

CO2t-Bu

H OH

H +

+ H

H 1

OH

12-E

H 12-F

Figure 12.5. Optimization of the intramolecular Diels–Alder reaction

LEGENDS OF FIGURE 12.5.– f’. Intramolecular Diels–Alder reaction – 71% (1: 12-E12-F = 12: 24: 38): toluene, sealed tube, 155°C. 12.3.2.2. Transannular Diels–Alder reaction The transannular version requires two additional steps from the same precursor 12-A. While the cycloaddition reaction is more effective, the overall yield is strongly affected by the low efficiency of the lactonization step performed under Yamaguchi conditions (27%). The other methods tested (esterification according to Mukaiyama or Steglich involving DCC) proved to be even less successful with respective yields of 12 and 6%.

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CO2H

CO2t-Bu

a OH

OH 12-A

12-G O

O O O

b

c

H H

12-H

1

Figure 12.6. Synthesis of oblongolide A by transannular Diels–Alder reaction

LEGENDS OF FIGURE 12.6.– a. Saponification of the ester 12-A – 68.5%: NaOH (0.1 equiv.), EtOH, H2O. b. Esterification according to Yamaguchi – 27%: (i) 2,4,6-trichlorobenzoyl chloride, Et3N, THF; (ii) DMAP, PhMe. c. Transannular cycloaddition – 80%: PhMe, reflux.

12.3.3. Key reaction: intramolecular Diels–Alder reaction Of all the orbital-controlled cycloadditions, the Diels–Alder reaction between a diene and an electron-depleted dienophile is probably the one that has experienced the strongest developments in synthesis [JUH 09, PAR 14, HER 15]. Its intramolecular IMDA version is no exception to the rule and continues to be applied to the production of complex molecules. By considering the different transition states, it is possible to rationalize the course of such cycloadditions and predict the formation of the majority stereoisomer. In the synthesis of oblongolide A from substrate 12-A, four transition states can be described. Various factors must be taken into consideration in favor of the endo approach (1), in particular the presence of the methyl group on the sole stereogenic center which adopts a pseudo-equatorial position as well as the existence of secondary orbital interactions.

Oblongolides A and C

CO2t-Bu

H

CO2t-Bu OH (1)

OH

eq. endo

279

H

CO2t-Bu

H

CO2t-Bu OH (2)

OH

eq.

H

exo OH

ax.

H

CO2t-Bu OH (3)

E

H

endo

H OH

ax.

CO2t-Bu OH (4)

E

exo

H

Figure 12.7. Possible transition states during the cycloaddition of 12-A

However, the formation of the compound 12-E characterized by a relative cis configuration at the ring junction, resulting from the exo approach (2), should not be disregarded. IMDA reactions have been successfully applied in total synthesis, particularly for the synthesis of (-)-himandrine [MOV 09] and salvinorin A [WAN 18].

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OMe

OMe H

N H

BHT

O OHC

Et

N

TBSO

Et

N O

OHC CH3CN 95°C

TBSO 75%

Endo approach

Figure 12.8. Intramolecular Diels–Alder reaction – towards (-)-himandrine

O

O

O O H

H Ph-Cl, 200°C

conv. 88%

O

O

BHT (1.2 equiv.) MeO2C 3.5 days MeO2C

O

O

O

+ MeO2C

66% (Via endo approach )