STEREOSELECTIVEMULTIPLEBOND-FORMINGTRANSFORMATIONSIN ORGANIC SYNTHESIS

STEREOSELECTIVEMULTIPLEBOND-FORMINGTRANSFORMATIONSIN ORGANIC SYNTHESIS

Edited by

JEAN RODRIGUEZ AND DAMIEN BONNE

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Library of Congress Cataloging-in-Publication Data:

Stereoselective multiple bond-forming transformations in organic synthesis / edited by Jean Rodriguez,Damien Bonne.

pages cmIncludes bibliographical references and index.ISBN 978-1-118-67271-6 (cloth)

1. Organic compounds–Synthesis. 2. Stereochemistry. 3. Chemical reactions. I. Rodriguez, Jean, editor.II. Bonne, Damien, 1979- editor.

QD262.S83 2015547′.2–dc23

2014046406

Cover image courtesy of Jean Rodriguez and Damien Bonne.

Typeset in 10/12pt TimesLTStd by Laserwords Private Limited, Chennai, India

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

1 2015

CONTENTS

List of Contributors xiiiForeword xviiPreface xix

1 Definitions and Classifications of MBFTs 1Damien Bonne and Jean Rodriguez

1.1 Introduction, 11.2 Definitions, 41.3 Conclusion and Outlook, 6

References, 7

PART I STEREOSELECTIVE SYNTHESIS OFHETEROCYCLES 9

2 Five-Membered Heterocycles 11Hanmin Huang and Pan Xie

2.1 Introduction, 112.2 Monocyclic Targets, 12

2.2.1 1,3-Dipolar Cycloaddition, 122.2.2 Michael Addition-Initiated Domino Process, 202.2.3 Multicomponent Reactions, 232.2.4 Carbohalogenation Reactions, 26

vi CONTENTS

2.2.5 Radical Processes, 262.3 Fused Polycyclic Targets, 28

2.3.1 Cycloaddition Reactions, 282.3.2 Domino Cyclization Reactions, 32

2.4 Bridged Polycyclic Targets, 342.5 Conclusion and Outlook, 36

References, 37

3 Six-Membered Heterocycles 45Giammarco Tenti, M. Teresa Ramos, and J. Carlos Menéndez

3.1 Introduction, 453.2 Monocyclic Targets, 47

3.2.1 Nitrogen-Only Heterocycles, 473.2.2 Oxygen-Containing Heterocycles, 58

3.3 Fused Polycyclic Targets, 623.3.1 Nitrogen-Only Fused Polycyclic Targets, 623.3.2 Oxygen-Containing Fused Polycyclic Targets, 703.3.3 Sulfur-Containing Fused Polycyclic Targets, 74

3.4 Bridged Polycyclic Targets, 743.4.1 General Procedure for the Preparation of

2,6-DABCO-Derived Compounds 138, 763.5 Polycyclic Spiro Targets, 773.6 Summary and Outlook, 79

References, 79

4 Other Heterocycles 87Qian Wang and Jieping Zhu

4.1 Introduction, 874.2 Synthesis of Medium-Sized Monocyclic, Fused and Bridged

Polycyclic Heterocycles, 884.2.1 Ring Synthesis by Ring Transformation via

Rearrangements/Ring Expansions, 884.2.2 Ring Synthesis by Annulation, 99

4.3 Summary and Outlook, 109References, 109

PART II STEREOSELECTIVE SYNTHESIS OF CARBOCYCLES 115

5 Three- and Four-Membered Carbocycles 117Renata Marcia de Figueiredo, Gilles Niel, and Jean-Marc Campagne

5.1 Introduction, 1175.2 Cyclopropane Derivatives, 118

CONTENTS vii

5.2.1 Organocatalysis and Related Reactions [Michael-InitiatedRing-Closure (MIRC) Reactions], 118

5.2.2 Organometallics and Metal Catalysis, 1235.2.3 Lewis Acid-Promoted Sequences, 1335.2.4 Pericyclic Domino Strategies, 1345.2.5 Radical Domino Strategies, 135

5.3 Cyclobutane Derivatives, 1365.3.1 Organocatalyzed Cyclobutanations, 1365.3.2 Organometallics and Metal Catalysis, 1375.3.3 Acid- or Base-Promoted Transformations, 1435.3.4 Multicomponent Reactions (MCRs), 145

5.4 Summary and Outlook, 146References, 146

6 Five-Membered Carbocycles 157Vijay Nair and Rony Rajan Paul

6.1 Introduction, 1576.2 Monocyclic Targets, 158

6.2.1 Metal-Catalyzed Reactions, 1586.2.2 Organocatalytic Reactions, 1586.2.3 Miscellaneous Reactions, 167

6.3 Fused Polycyclic Targets, 1696.3.1 Metal-Catalyzed Reactions, 1696.3.2 Organocatalytic Reactions, 1706.3.3 Lewis Acid-Catalyzed Reactions, 1726.3.4 Miscellaneous Reactions, 173

6.4 Bridged Polycyclic Targets, 1776.5 Conclusion and Outlook, 179

References, 179

7 Stereoselective Synthesis of Six-Membered Carbocycles 185Muriel Amatore, Corinne Aubert, Marion Barbazanges, Marine Desage-ElMurr, and Cyril Ollivier

7.1 Introduction, 1857.2 Metal-Catalyzed Stereoselective Multiple Bond-Forming

Transformations, 1867.2.1 Introduction, 1867.2.2 Cycloadditions, 1867.2.3 Metal-Catalyzed Cascades as Formal [2+2+2]

Cycloadditions, 1917.2.4 Metal-Catalyzed Cycloisomerization Cascades, 192

7.3 Enantioselective Organocatalyzed Synthesis of Six-MemberedRings, 195

viii CONTENTS

7.3.1 Organocatalyzed Miscellaneous Reactions, 1957.3.2 Organocatalyzed Cascade and Multicomponent Reactions, 1977.3.3 Polycyclization Cascade Reactions, 201

7.4 Stereoselective Multiple Bond-Forming Radical Transformations, 2027.4.1 Intermolecular Cascade Reactions, 2027.4.2 Intramolecular Cascade Reactions, 203

7.5 Conclusions, 204References, 205

8 Seven- and Eight-Membered Carbocycles 211Gérard Buono, Hervé Clavier, Laurent Giordano, and Alphonse Tenaglia

8.1 Introduction, 2118.2 Cycloheptenes, 2128.3 Cycloheptadienes, 2198.4 Cycloheptatrienes, 2218.5 Cyclooctenes, 2228.6 Cyclooctadienes, 2258.7 Cyclooctatrienes, 2298.8 Cyclooctatetraenes, 2348.9 Concluding Remarks, 235

References, 235

PART III STEREOSELECTIVE SYNTHESIS OF SPIROCYCLICCOMPOUNDS 241

9 Metal-Assisted Methodologies 243Gaëlle Chouraqui, Laurent Commeiras, and Jean-Luc Parrain

9.1 Introduction, 2439.2 Quaternary Spirocenter, 244

9.2.1 Copper-Assisted Methodologies, 2459.2.2 Gold-Assisted Methodologies, 2479.2.3 Palladium-Assisted Methodologies, 2479.2.4 Rhodium-Assisted Methodologies, 2519.2.5 Platinum-Assisted Methodologies, 252

9.3 α-Heteroatom-Substituted Spirocenter, 2529.3.1 Zinc-, Magnesium-, and Copper-Assisted Methodologies, 2539.3.2 Titanium-Assisted Methodologies, 2549.3.3 Gold- and Platinum-Assisted Methodologies, 2559.3.4 Palladium-Assisted Methodologies, 2589.3.5 Rhodium-Assisted Methodologies, 259

CONTENTS ix

9.4 α,α′-Diheteroatom-Substituted Spirocenter, 2619.5 Conclusion and Outlook, 264

References, 265

10 Organocatalyzed Methodologies 271Ramon Rios

10.1 Introduction, 27110.2 Enantioselective Synthesis of All-Carbon Spirocenters, 275

10.2.1 Organocatalytic Enantioselective Methodologies for theSynthesis of Spirooxindoles, 275

10.2.2 Other Spirocycles, 29210.3 Enantioselective Synthesis Spirocenters with at Least One

Heteroatom, 29910.3.1 Synthesis of Spirooxindoles, 29910.3.2 Synthesis of Other Spirocycles, 301

10.4 Conclusion and Outlook, 301References, 302

PART IV STEREOSELECTIVE SYNTHESIS OF ACYCLICCOMPOUNDS 307

11 Metal-Catalyzed Methodologies 309Gabriela Guillena and Diego J. Ramón

11.1 Introduction, 30911.2 Anion Relay Approach, 31011.3 Mannich Reaction, 312

11.3.1 Diastereoselective Approach, 31211.3.2 Enantioselective Approach, 312

11.4 Reactions Involving Isonitriles, 31411.4.1 Diastereoselective Passerini Reaction, 31411.4.2 Enantioselective Passerini Reaction, 31511.4.3 Diastereoselective Ugi Reaction, 316

11.5 1,2-Addition-Type Processes, 31711.5.1 Diastereoselective Approach, 31711.5.2 Enantioselective Approach, 320

11.6 Michael-Type Processes, 32411.6.1 Diastereoselective Approach, 32411.6.2 Enantioselective Approach, 327

11.7 Summary and Outlook, 331References, 332

x CONTENTS

12 Organocatalyzed Methodologies 339Vincent Coeffard, Christine Greck, Xavier Moreau,and Christine Thomassigny

12.1 Introduction, 33912.2 Aminocatalysis, 340

12.2.1 Enamine–Enamine Activation, 34012.2.2 Iminium–Enamine Activation, 343

12.3 N-Heterocyclic Carbene (NHC) Activation, 35412.4 H-Bonding Activation, 35712.5 Phase-Transfer Catalysis, 35812.6 Summary and Outlook, 359

References, 359

PART V MULTIPLE BOND-FORMING TRANSFORMATIONS:SYNTHETIC APPLICATIONS 363

13 MBFTs for the Total Synthesis of Natural Products 365Yanxing Jia and Shiqiang Zhou

13.1 Introduction, 36513.2 Anionic-Initiated MBFTs, 36613.3 Cationic-Initiated MBFTs, 37113.4 Radical-Mediated MBFTs, 37513.5 Pericyclic MBFTs, 37913.6 Transition-Metal-Catalyzed MBFTs, 38513.7 Summary and Outlook, 388

References, 390

14 Synthesis of Biologically Relevant Molecules 393Matthijs J. van Lint, Eelco Ruijter, and Romano V.A. Orru

14.1 Introduction, 39314.2 Organocatalyzed MBFTs for BRMs, 39414.3 Multicomponent MBFTs for BRMs, 40414.4 Palladium-Catalyzed MBFTs for BRMs, 41314.5 Conclusion and Outlook, 418

References, 419

15 Industrial Applications of Multiple Bond-Forming Transformations(MBFTs) 423Tryfon Zarganes-Tzitzikas, Ahmad Yazbak, Alexander Dömling

15.1 Introduction, 42315.2 Applications of MBFTs, 424

CONTENTS xi

15.2.1 Xylocaine, 42415.2.2 Almorexant, 42415.2.3 (−)-Oseltamivir (Tamiflu®), 42715.2.4 Telaprevir (Incivek®), 42915.2.5 Ezetimibe (Zetia®), 43115.2.6 Crixivan (Indinavir®), 43315.2.7 Oxytocine Antagonists: Retosiban and Epelsiban, 43615.2.8 Praziquantel (Biltricide®), 439

15.3 Summary and Outlook, 442References, 442

Index 447

List of Contributors

Muriel Amatore, Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien deChimie Moléculaire (IPCM), Paris, France

Corinne Aubert, Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien deChimie Moléculaire (IPCM), Paris, France

Marion Barbazanges, Sorbonne Universités, UPMC Univ Paris 06, Institut Parisiende Chimie Moléculaire (IPCM), Paris, France

Damien Bonne, Aix Marseille Université, CNRS, Marseille, France

Gérard Buono, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Jean-Marc Campagne, Institut Charles Gerhardt Montpellier, Ecole NationaleSupérieure de Chimie, France

Gaëlle Chouraqui, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Hervé Clavier, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Vincent Coeffard, Institut Lavoisier de Versailles, Université de Versailles-St-Quentin-en-Yvelines, Versailles, France

Laurent Commeiras, Aix Marseille Université, Centrale Marseille, CNRS, Mar-seille, France

xiv LIST OF CONTRIBUTORS

Alexander Dömling, Department of Drug Design, University of Groningen,Groningen, The Netherlands

Renata Marcia de Figueiredo, Institut Charles Gerhardt Montpellier, EcoleNationale Supérieure de Chimie, France

Laurent Giordano, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Christine Greck, Institut Lavoisier de Versailles, Université de Versailles-St-Quentin-en-Yvelines, Versailles, France

Gabriela Guillena, Instituto de Síntesis Orgánica (ISO) and Departamento deQuímica Orgánica, Facultad de Ciencias, Universidad de Alicante, Alicante,Spain

Hanmin Huang, State Key Laboratory for Oxo Synthesis and Selective Oxidation,Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou,China

Yanxing Jia, Peking University Health Science Center, Beijing, China

Matthijs J. van Lint, Department of Chemistry and Pharmaceutical Sciences, VUUniversity Amsterdam, Amsterdam, The Netherlands

J. Carlos Menéndez, Departamento de Química Orgánica y Farmacéutica, Facultadde Farmacia, Universidad Complutense, Madrid, Spain

Xavier Moreau, Institut Lavoisier de Versailles, Université de Versailles-St-Quentin-en-Yvelines, Versailles, France

Marine Desage-El Murr, Sorbonne Universités, UPMC Univ Paris 06, InstitutParisien de Chimie Moléculaire (IPCM), Paris, France

Vijay Nair, Organic Chemistry Section, National Institute of Interdisciplinary Sci-ence and Technology (NIIST), Kerala, India

Gilles Niel, Institut Charles Gerhardt Montpellier, Ecole Nationale Supérieure deChimie, France

Cyril Ollivier, Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien deChimie Moléculaire (IPCM), Paris, France

Romano V.A. Orru, Department of Chemistry and Pharmaceutical Sciences, VUUniversity Amsterdam, Amsterdam, The Netherlands

Jean-Luc Parrain, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Rony Rajan Paul, Department of Chemistry, Christian College, Organic ChemistrySection, National Institute of Interdisciplinary Science and Technology (NIIST),Kerala, India

LIST OF CONTRIBUTORS xv

Diego J. Ramón, Instituto de Síntesis Orgánica (ISO) and Departamento de QuímicaOrgánica, Facultad de Ciencias, Universidad de Alicante, Alicante, Spain

M. Teresa Ramos, Departamento de Química Orgánica y Farmacéutica, Facultad deFarmacia, Universidad Complutense, Madrid, Spain

Ramon Rios, University of Southampton, UK

Jean Rodriguez, Aix Marseille Université, CNRS, Marseille, France

Eelco Ruijter, Department of Chemistry and Pharmaceutical Sciences, VU Univer-sity Amsterdam, Amsterdam, The Netherlands

Alphonse Tenaglia, Aix Marseille Université, Centrale Marseille, CNRS, Marseille,France

Giammarco Tenti, Departamento de Química Orgánica y Farmacéutica, Facultad deFarmacia, Universidad Complutense, Madrid, Spain

Christine Thomassigny, Institut Lavoisier de Versailles, Université de Versailles-St-Quentin-en-Yvelines, Versailles, France

Qian Wang, Laboratory of Synthesis and Natural Products, Institute of ChemicalSciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne,Switzerland

Pan Xie, State Key Laboratory for Oxo Synthesis and Selective Oxidation, LanzhouInstitute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China

Ahmad Yazbak, Synthatex Fine Chemicals Ltd, Israel

Tryfon Zarganes-Tzitzikas, Department of Drug Design, University of Groningen,Groningen, The Netherlands

Jieping Zhu, Laboratory of Synthesis and Natural Products, Institute of ChemicalSciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne,Switzerland

Foreword

Dieter EndersInstitute of Organic Chemistry, RWTH Aachen, Aachen, Germany

It has always been the dream of chemists to imitate nature’s enzyme catalyzedmachinery in the chemo- and stereoselective synthesis of complex molecules undermild conditions in the compartment of a living cell. While nature has neededbillions of years on our planet to reach such a level of elegance and syntheticefficiency, chemists have only had less than two hundred years to develop syntheticmethodologies in the laboratory. In our science “to synthesize” basically meansto form new chemical bonds, and it is, therefore, not surprising that at a ratherearly stage in history scientists tried to create several bonds by development of newone-pot multiple bond-forming transformations (MBFTs) involving one-, two-, andmulticomponent conditions. Famous cases are the pioneer synthesis of amino acidsreported by Adolph Strecker in 1850 or the more recent biomimetic polycyclizationapproach to steroids by Johnson. Other well-known one-pot MBFTs followed,for example, the Hantzsch dihydropyridine synthesis, later used in industry tosynthesize the calcium antagonist Adalat®. However, it took quite a long time untilIvar Ugi reported his four-component reaction in the late 1950s, which became aneye-opener for the chemical community as a fundamental synthetic principle. Oneof its important industrial applications is the synthesis of the piperazine-amide corestructure of the HIV protease inhibitor Crixivan®.

Confronted with the need to develop a sustainable chemistry, we have witnessedan amazing increase in the efficiency and selectivity of synthetic methods in the lastfifty years. In order to solve the problems associated with the traditional step-by-stepprocedures, such as the cumbersome, time-consuming, and expensive isolation ofintermediates, several new criteria have been introduced: atom, redox, step and poteconomy or protecting-group-free synthesis. It is obvious that all variants of one-potdomino and cascade reactions or multicomponent consecutive reactions sequencesmay allow fulfilling these criteria.

xviii FOREWORD

Guided by nature, the asymmetric catalysis (metal catalysis, biocatalysis,and organocatalysis) is the method of choice when it comes to the chemo- andstereoselective synthesis of complex bioactive molecules bearing a number ofstereocenters. Especially the rapid growth of the research area of organocatalysissince the turn of the millennium has enabled us to reach exceptionally high diastereo-and enantioselectivities under very mild catalytic conditions. When in 2006 ourgroup developed a multicomponent organocatalytic triple domino reaction, I did notexpect to see virtually complete asymmetric inductions in almost all the cases wetested. Nowadays, endowed with such powerful protocols and by employing themany technical extensions, such as solid phase and flow syntheses or combinatorialapproaches, our synthesis arsenal offers many options for multiple bond-formingcascades.

The editors Jean Rodriguez and Damien Bonne supported by fourteen interna-tionally renowned experts have done an excellent job in covering all aspects of theexciting achievements in the realm of stereoselective MBFTs of the last decade. Thebook will inspire not only those working in academia to push the forefront of effi-cient stereoselective synthetic chemistry even further but also chemists in industryto develop and use new one-pot multiple bond-forming cascade protocols for thelarge-scale synthesis of biologically active compounds, such as pharmaceuticals andagrochemicals.

PREFACE

“Caminante no hay camino, se hace camino al andar, caminante, son tus huellas elcamino y nada más… ”

Antonio Machado, 1875–1939.

The efficiency of a chemical process is now evaluated not only by the yield butalso by the amount of waste, the human resources, and the time needed. In simplewords, how to make more with less? How to render a synthesis “greener”? In orderto address these emerging difficulties, novel organic syntheses must answer as muchas possible to economic and environmental problems.

On the basis of these considerations, this book focuses on modern tools for efficientstereoselective synthesis proceeding exclusively with multiple bond-forming trans-formations (MBFTs), including selected examples of domino, multicomponent, orconsecutive sequences within the last ten years. These atom-economic reactions makechemical processes more efficient by decreasing the total number of steps while max-imizing the structural complexity and the functional diversity. Moreover, the controlof chirality is essential in academic research and also becomes of primary impor-tance in the industrial context such as medicinal chemistry or agrochemical research.For these reasons, we decided to only focus on stereoselective methodologies involv-ing either metallic or organic catalysis and to present some selected current syntheticapplications in the field of total synthesis or in the elaboration of biologically relevanttargets, including some industrial developments.

We have been particularly exited to embark on this adventure although a bit scaredby the challenge of being editors of a book for the first time! However, this has beenrapidly overcome with the enthusiastic and friendly collaboration of distinguishedexperts who have contributed by writing chapters of high scientific level. We are

xx PREFACE

deeply indebted to all authors and coauthors for their rewarding dedication and timelycontributions that have enhanced the quality of this book. We are also very honored bythe friendly and warm foreword from Dr Dieter Enders. His pioneer achievements andongoing research in the field of MBFTs is internationally recognized and constitutesan outstanding model for many chemists worldwide. We also gratefully acknowl-edge the Wiley editorial staff, in particular, Jonathan Rose for his invaluable help andguidance.

Finally, our modest contribution to the field of MBFTs would not have been pos-sible without the strong implication of brilliant PhD students and postdoctoral asso-ciates combined with the permanent support of all our colleagues from the group, andwe would like here to deeply thank them for their collaboration.

Jean Rodriguez and Damien Bonne, Aix Marseille University, 2015

1DEFINITIONS AND CLASSIFICATIONSOF MBFTs

Damien Bonne and Jean RodriguezAix Marseille Université, CNRS, Marseille, France

1.1 INTRODUCTION

The selective formation of covalent bonds, especially carbon–carbon andcarbon–heteroatom bonds, is at the heart of synthetic organic chemistry. Fromthe very beginning, researchers have developed many ingenious methodologies ableto create one specific chemical bond at a time, and this has led to very significantadvances in the total synthesis of complex natural or nonnatural molecules. Pastdecades have seen an impressive development of this “step-by-step” approach,notably with the help of efficient catalytic systems, allowing the discovery of new,powerful reactions. This huge investment has been recently rewarded with two NobelPrizes in chemistry, in 2005 and 2010 [1]. The arsenal of modern organic synthesis isnow deep enough for answering “yes” to the question: “can we make this molecule?”provided that sufficient manpower, money, and time are available. However, today’ssocietal economic and ecologic concerns have raised the contemporaneous question:“can we make this molecule efficiently?” This small upgrade places the efficiency of

Stereoselective Multiple Bond-Forming Transformations in Organic Synthesis, First Edition.Edited by Jean Rodriguez and Damien Bonne.© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.

2 DEFINITIONS AND CLASSIFICATIONS OF MBFTs

a synthetic pathway in a central position both for academic developments or potentialindustrial applications. The efficiency of a chemical process is now evaluated notonly from the overall yield and selectivity issues but also in terms of the control ofwaste generation, toxicity and hazard of the chemicals, the level of human resourcesneeded, and the overall time and energy involved: in simple words, “how to makemore with less”? How to render a synthesis “greener”?

Clearly, the iterative “step-by-step” approach does not fulfill all these emergingeconomic and environmental concerns, but it appears that significantly reducing theoverall number of synthetic events required to access a defined compound can be asimple strategy to combine together all the above criteria of efficiency. Therefore,“step economy” becomes one of the most important concepts to deal with for thedevelopment of efficient modern organic synthetic chemistry.

Usually, the total synthesis of a target of interest, even if the total number ofsteps is limited (around 10–15), requires the use of multi-gram quantities of start-ing materials to afford milligrams of the desired target. Of course, different strategieshave been employed over the years to reduce the total number of steps in a synthe-sis, such as, for example, the development of highly chemoselective transformations(protecting-group-free syntheses [2] and redox economy [3]). An alternative way toshorten a synthetic plan is the development of new sequences that allow the creationof several covalent carbon–carbon or carbon–heteroatom bonds in a single chemi-cal transformation. This powerful strategy is referred to as “multiple bond-formingtransformations” (MBFTs), which is precisely the topic of this book (Scheme 1.1) [4].

This simple intuitive idea has its roots in Nature, which, with the help of biolog-ical systems and billions of years of practice, can produce high levels of structural

Target

Target

Reaction Reaction Reaction

Work- up andpurification

Work- up andpurification

Work- up andpurification

Work- up andpurification

Traditionalstep by step

synthesis

Reaction

ReactionReaction

[Intermediate ]

[Intermediate ]

Intermediate Intermediate Crude product

Crude product

Startingmaterials

Startingmaterials

Multiplebond-forming

transformations(MBFTs)

1 2 3

1 2

1

1 2 3

1

1

23

2

Scheme 1.1 A three-event process either by a “step-by-step” approach or a MBFT.

INTRODUCTION 3

Squalene Squalene epoxide

Me

Me

H

MeH

NADPH NADP+

Enzyme

O2O

H2O

HO

Me

4 C–C

Cholesterol

Lanesterol

steps

+

Scheme 1.2 Biosynthesis of lanosterol.

complexity and functional diversity by means of elegant and spectacular MBFTs.A magnificent example is the biosynthesis of steroids from squalene epoxides, whichis converted in cells to lanosterol and then to cholesterol (Scheme 1.2) [5]. This trans-formation occurs with high stereoselectivity for the formation of four C–C bonds andsix stereogenic carbon atoms.

MBFTs make chemical processes more efficient by reducing the total numberof steps and improve atom economy while maximizing structural complexity andfunctional diversity. In consequence, the amount of waste generated, money, the man-power needed, and the negative environmental impact are greatly reduced. One of thefirst examples of such a reaction proposed by a synthetic chemist goes back to themiddle of the nineteenth century with the work of Adolf Strecker in 1850. He wasable to synthesize α-amino cyanides, precursors of α-amino acids, by the one-potconcomitant creation of one C–C and one C–N bond from an aldehyde, ammonia,and hydrogen cyanide (Scheme 1.3) [6].

Since then, this field of research has grown rapidly with the help of metal catalysis,and even more in the last decade with the spectacular advent of organocatalysis thatperfectly fits with the criteria of efficiency for a synthesis to be viable.

R

O

H

NH3HCN

R

NH2

CN

H2OH+

R

NH2

COOH

1 C–C1 C–N

Scheme 1.3 The Strecker reaction, one of the first MBFTs.

4 DEFINITIONS AND CLASSIFICATIONS OF MBFTs

1.2 DEFINITIONS

It seems highly desirable to introduce a clear definition of the different types ofMBFTs. First, MBFTs do not include concerted transformations such as cycload-ditions (e.g., Diel–Alder reaction) or metal-catalyzed cycloisomerization (e.g.,Pauson–Khand reaction), even though, strictly speaking, two or more bonds arecreated in these transformations. MBFTs can be roughly categorized according tothe protocol used and the number of functional components involved. Therefore,one-, two-, and multicomponent sequences can be envisioned, and following thedefinitions proposed by Tietze [7], we distinguish domino reactions and consecutivereactions as the two main classes of nonconcerted MBFTs. Domino (or cascade)reactions are MBFTs that take place under the same reaction conditions withoutadding extra reagents and catalysts, and in which the subsequent reactions resultas a consequence of the functionality formed in the previous step. A very elegantexample of a unimolecular transformation is the two-directional epoxide-openingreaction in the total synthesis of the natural product glabrescol reported by Coreyand Xiong, where four C–O bonds were created by simple acidic treatment of atetraepoxide precursor (Scheme 1.4a) [8].

In comparison, consecutive reactions describe MBFTs in which the introductionof the reagent(s) and/or additional solvent(s) and substrate(s) is performed in a step-wise manner to a single reaction mixture from which nothing is removed. Strictlyspeaking, sequences involving even a limited and operationally simple change of thereaction conditions such as an elevation of temperature should not be denoted asdomino reactions but preferably as consecutive reactions. The example displayed inScheme 1.4b has been described by Rueping’s group for the enantioselective synthe-sis of polycyclic heterocycles with the concomitant formation of one C–C and twoC–N bonds [9]. The first step of the sequence involves two components and is cat-alyzed by diarylprolinol silyl ethers. It leads to a transient cyclic hemiacetal, whichis not isolated and can react with a third component, for example, a functionalizedprimary amine, in a second consecutive step via intramolecular capture of an iminiumion intermediate.

Finally, multicomponent reactions (MCRs) are a subclass of domino reactions andcan be defined as processes in which three or more starting materials react to forma product, where basically all or most of the atoms contribute to the newly formedproduct [10]. A recent example reported by our group (Scheme 1.4c) involves thereaction between β-ketoamides, acrolein, and aminophenols, allowing the preparationof an enantioenriched diazabicyclo[2.2.2]octanone (2,6-DABCO) scaffold [11]. Thechemoselective reaction sequence installs five new bonds and three stereocenters,with excellent yields and high levels of stereocontrol.

Practically, the design of new MBFTs requires the use or the synthesis of substratesdisplaying several complementary reactive sites, which can be exploited successivelyin the transformation. Some families of densely functionalized small molecules areparticularly well adapted to serve as substrates for these reactions. We can cite, for

DEFINITIONS 5

O

O R

O

+

1)NH

OTMS

PhPh

DCM, 0 °C

2)

NNH

NH2

CH3CO2H, 50 °C

NH

N

OH

R

1 C–C2 C–N

(10 mol%)

4Å MS, toluene, –10 °C, 24 h

H

O

NH2

OHOR3HN

OR2

R1

NH

N

NH

S

CF3

F3CR4

N

N

O

O

R4

R1R2

R3

1 C–C3 C–N1 C–O

(a)

(b)

(c)

O O

O O

Me

Me

MeMe Me Me

Me Me

Me MeMe

Me

Me

Me Me

HO

HO

HO

OH

OH

OH

OH OH

Me

CSA, CH2C12–94 °C

44 % O O

O OH H

H

4 C–O

Scheme 1.4 (a) Domino MBFTs with one component. (b) Consecutive MBFTs with twocomponents. (c) Domino MBFTs with three components.

example, isocyanides [12] and dicarbonyl compounds [13], which have led to the dis-covery of important MBFTs owing to the presence of multiple reaction sites with bothelectrophilic and nucleophilic characters, which could be modulated by the nature ofthe substituents.

On the basis of these considerations, this book will focus on modern tools forefficient stereoselective synthesis proceeding exclusively with MBFTs includingselected examples of domino, multicomponent, or consecutive sequences that havebeen described in the last 10 years. In this book, we highlight the best of these

6 DEFINITIONS AND CLASSIFICATIONS OF MBFTs

methodologies with criteria of efficiency in terms of chemical yield, selectivity,width of scope, and ease to perform. Moreover, the control of the chirality is essentialin academic research, and is becoming also of primary importance in the industrialcontext such as medicinal chemistry or agrochemical research. For this reason, wedecided to focus only on stereoselective methodologies involving either metallicor organic catalysis and to present some selected current synthetic applications inthe fields of total synthesis or in the elaboration of biologically relevant targets. Inaddition, for practical matters, we feel that an organization by the type of molecules(e.g., carbocycles, heterocycles, spirocycles, acyclic) should be very attractive anduseful for the readers.

We choose an organization in four main parts including 15 chapters classified bystructures of the final product obtained through the chemical process. In all cases,special attention is given to synthetic applications in the fields of total synthesis orin the elaboration of biologically relevant targets, completed with some experimentaldata when appropriate.

After this introductory chapter, Chapters 2–4 are dedicated to the stereoselectivesynthesis of mono and polyheterocycles in the fused and bridged series. The secondpart (Chapters 5–8), in the same way as before, presents the stereoselective synthesisof carbocycles. The third part (Chapters 9 and 10) is devoted to spirocyclic structures,which are privileged scaffolds present in numerous natural products and bioactivemolecules. In recent years, organic chemists have developed original metallic andorganic catalytic methods to synthesize these important molecular backbones. Thefourth part (Chapters 11 and 12) deals with the stereoselective synthesis of acyclicstructures involving metallic and organic catalysis. Finally, the fifth part (Chapters13–15) concerns the synthetic applications of MBFTs in the total synthesis of naturalproducts as well as biologically relevant compounds (Chapters 13 and 14). In thispart, the readers will also find in Chapter 15 some remarkable industrial applicationsof MBFTs.

1.3 CONCLUSION AND OUTLOOK

Despite the considerable advances chemist have made during nearly only in two cen-turies, the limits of synthetic organic chemistry are far from being reached, and webelieve that the discovery of new MBFTs will constitute a significant advance in thisdirection moving closer from the “ideal synthesis,” which is not only an academicholy grail but also a great challenge for industrial applications. This book shouldprove useful for graduate students, faculty members, and industrial scientists withinterests in organic chemistry in general and in new efficient synthetic methodologies(medicinal chemistry, natural product chemistry, biochemistry, and process chem-istry, etc.) in particular. The original layout of this book, which is based on structureswith a clear presentation of concepts and key reactions, should attract and facilitatereading of graduate students but will also constitute a strong support for more spe-cialized readers interested in new synthetic developments and applications.

REFERENCES 7

REFERENCES

1. (a) The Nobel Prize in Chemistry 2010, Heck, R. F., Negishi, E., Suzuki, A. Forpalladium-catalyzed cross couplings in organic synthesis.(b) The Nobel Prize in Chem-istry 2005, Chauvin, Y., Grubbs R. H., Schrock, R. R. For the development of the metathesismethod in organic synthesis.

2. Young, I. S., Baran, P. S. (2009). Protecting-group-free synthesis as an opportunity forinvention. Nature Chemistry, 1, 193–205.

3. Burns, N. Z., Baran, P. S. Hoffmann, R. W. (2009). Redox economy in organic synthesis.Angewandte Chemie International Edition, 48, 2854–2867.

4. (a) This terminology has been introduced by our group in 2010: Coquerel, Y., Boddaert,T., Presset, M., Mailhol, D., Rodriguez, J. (2010). Ideas in Chemistry and Molecular Sci-ences: Advances in Synthetic Chemistry, in Pignataro, B. (Ed.), Wiley-VCH, Weinheim,Germany, pp. 187–202, Chapter 9.(b) For a concept on this type of transformations, see:Bonne, D., Constantieux, T., Coquerel, Y., Rodriguez, J. (2013). Stereoselective multi-ple bond-forming transformations (MBFTs): the power of 1,2- and 1,3-dicarbonyl com-pounds. Chemistry – A European Journal, 19, 2218–2231.(c) For a recent review intro-ducing the term “Multi-Bond Forming Process”, see: Green, N. J., Sherburn, M. S. (2013).Multi-multi-bond forming processes in efficient synthesis. Australian Journal of Chemistry,66, 267–283.

5. (a) Corey, E. J., Russey, W. E., Ortiz de Montellano, P. R. (1966). 2,3-Oxidosqualene, anintermediate in the biological synthesis of sterols from squalene. Journal of the Ameri-can Chemical Society, 88, 4750–4751.(b) Abe, I., Rohmer, M., Prestwich, G. D. (1993).Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. ChemicalReviews, 93, 2189–2206.

6. (a) Strecker, A. (1850). Ueber die künstliche Bildung der Milchsäure und einen neuen,dem Glycocoll homologen Körper. Justus Liebigs Annalen der Chemie, 1, 27–45.(b) Fora review on asymmetric Strecker reaction, see: Wang, J., Liu, X., Feng, X. (2011). Asym-metric Strecker Reactions. Chemical Reviews, 111, 6947–6983.

7. Tietze, L. F. (1996). Domino reactions in organic synthesis. Chemical Reviews, 96,115–136.

8. Xiong, Z., Corey, E. J. (2000). Simple enantioselective total synthesis of Glabrescol, a chi-ral C2-symmetric pentacyclic oxasqualenoid. Journal of the American Chemical Society,122, 9328–9329.

9. Rueping, M., Volla, C. M. R., Bolte, M., Raabe, G. (2011). General and efficient organocat-alytic synthesis of indoloquinolizidines, pyridoquinazolines and quinazolinones through aone-pot domino Michael addition-cyclization-Pictet–Spengler or 1,2-amine addition reac-tion. Advanced Synthesis & Catalysis, 353, 2853–2859.

10. Zhu, J. and Bienaymé, H. (eds) (2005). Multicomponent Reactions, Wiley-VCH VerlagGmbH, Weinheim.

11. Sanchez Duque, M. M., Baslé, O., Génisson, Y., Plaquevent, J.-C., Bugaut, X., Con-stantieux, T., Rodriguez, J. (2013). Enantioselective organocatalytic multicomponent syn-thesis of 2,6-diazabicyclo[2.2.2]octanones, Angewandte Chemie International Edition, 52,14143–14146.

12. (a) van Berkel1, S. S., Bögels, B. G. M., Wijdeven, M. A., Westermann, B., Rutjes, F.P. J. T. (2012). Recent advances in asymmetric isocyanide-based multicomponent reac-tions. European Journal of Organic Chemistry, 3543–3559.(b) Dömling, A. (2006). Recent

8 DEFINITIONS AND CLASSIFICATIONS OF MBFTs

developments in isocyanide based multicomponent reactions in applied chemistry. Chem-ical Review, 106, 17–89.

13. (a) Bonne, D., Coquerel, Y., Constantieux, T., Rodriguez, J. (2010). 1,3-Dicarbonyl com-pounds in stereoselective domino and multicomponent reactions. Tetrahedron: Asymmetry,21, 1085–1109. (b) Raimondi, W., Bonne, D., Rodriguez, J. (2012). Asymmetric transfor-mations involving 1,2-dicarbonyl compounds as pronucleophiles. Chemical Communica-tions, 48, 6763–6775.