Stereoselective Multiple Bond-Forming Transformations in Organic Synthesis

By Dieter Enders

Combining the important research topic of multiple bond-forming transformations with green chemistry, this book helps chemists identify recent sustainable stereoselective synthetic sequences.

•    Combines the important research topic of multiple bond-forming transformations with green chemistry and sustainable development
•    Offers a valuable resource for preparing compounds with multiple stereogenic centers, an important field for synthetic chemists
•    Organizes chapters by molecular structure of final products, making for a handbook-style resource
•    Discusses applications of the synthesis of natural products and of drug intermediates
•    Brings together otherwise-scattered information about a number of key, efficient chemical reactions

• Language: English
• Publisher: Wiley
• Release date: Apr 8, 2015
• ISBN: 9781119006428

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Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved

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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 cm

Includes 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 2015

547′.2–dc23

2014046406

Cover image courtesy of Jean Rodriguez and Damien Bonne.

List of Contributors

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

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

Marion Barbazanges, Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de 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 Nationale Supérieure 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, Marseille, France

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

Renata Marcia de Figueiredo, Institut Charles Gerhardt Montpellier, Ecole Nationale 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 de Química 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, VU University Amsterdam, Amsterdam, The Netherlands

J. Carlos Menéndez, Departamento de Química Orgánica y Farmacéutica, Facultad de 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, Institut Parisien de Chimie Moléculaire (IPCM), Paris, France

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

Gilles Niel, Institut Charles Gerhardt Montpellier, Ecole Nationale Supérieure de Chimie, France

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

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

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

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

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

M. Teresa Ramos, Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, 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 University Amsterdam, Amsterdam, The Netherlands

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

Giammarco Tenti, Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, 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 Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Pan Xie, State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute 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 Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Foreword

Dieter Enders

Institute of Organic Chemistry, RWTH Aachen, Aachen, Germany

It has always been the dream of chemists to imitate nature's enzyme catalyzed machinery in the chemo- and stereoselective synthesis of complex molecules under mild conditions in the compartment of a living cell. While nature has needed billions of years on our planet to reach such a level of elegance and synthetic efficiency, chemists have only had less than two hundred years to develop synthetic methodologies in the laboratory. In our science to synthesize basically means to form new chemical bonds, and it is, therefore, not surprising that at a rather early stage in history scientists tried to create several bonds by development of new one-pot multiple bond-forming transformations (MBFTs) involving one-, two-, and multicomponent conditions. Famous cases are the pioneer synthesis of amino acids reported by Adolph Strecker in 1850 or the more recent biomimetic polycyclization approach to steroids by Johnson. Other well-known one-pot MBFTs followed, for example, the Hantzsch dihydropyridine synthesis, later used in industry to synthesize the calcium antagonist Adalat®. However, it took quite a long time until Ivar Ugi reported his four-component reaction in the late 1950s, which became an eye-opener for the chemical community as a fundamental synthetic principle. One of its important industrial applications is the synthesis of the piperazine-amide core structure of the HIV protease inhibitor Crixivan®.

Confronted with the need to develop a sustainable chemistry, we have witnessed an amazing increase in the efficiency and selectivity of synthetic methods in the last fifty years. In order to solve the problems associated with the traditional step-by-step procedures, such as the cumbersome, time-consuming, and expensive isolation of intermediates, several new criteria have been introduced: atom, redox, step and pot economy or protecting-group-free synthesis. It is obvious that all variants of one-pot domino and cascade reactions or multicomponent consecutive reactions sequences may allow fulfilling these criteria.

Guided by nature, the asymmetric catalysis (metal catalysis, biocatalysis, and organocatalysis) is the method of choice when it comes to the chemo- and stereoselective synthesis of complex bioactive molecules bearing a number of stereocenters. Especially the rapid growth of the research area of organocatalysis since the turn of the millennium has enabled us to reach exceptionally high diastereo- and enantioselectivities under very mild catalytic conditions. When in 2006 our group developed a multicomponent organocatalytic triple domino reaction, I did not expect to see virtually complete asymmetric inductions in almost all the cases we tested. Nowadays, endowed with such powerful protocols and by employing the many technical extensions, such as solid phase and flow syntheses or combinatorial approaches, our synthesis arsenal offers many options for multiple bond-forming cascades.

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

PREFACE

"Caminante no hay camino, se hace camino al andar, caminante, son tus huellas el camino y nada más…"

Antonio Machado, 1875–1939.

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

On the basis of these considerations, this book focuses on modern tools for efficient stereoselective synthesis proceeding exclusively with multiple bond-forming transformations (MBFTs), including selected examples of domino, multicomponent, or consecutive sequences within the last ten years. These atom-economic reactions make chemical processes more efficient by decreasing the total number of steps while maximizing the structural complexity and the functional diversity. Moreover, the control of chirality is essential in academic research and also becomes of primary importance in the industrial context such as medicinal chemistry or agrochemical research. For these reasons, we decided to only focus on stereoselective methodologies involving either metallic or organic catalysis and to present some selected current synthetic applications in the field of total synthesis or in the elaboration of biologically relevant targets, including some industrial developments.

We have been particularly exited to embark on this adventure although a bit scared by the challenge of being editors of a book for the first time! However, this has been rapidly overcome with the enthusiastic and friendly collaboration of distinguished experts who have contributed by writing chapters of high scientific level. We are deeply indebted to all authors and coauthors for their rewarding dedication and timely contributions that have enhanced the quality of this book. We are also very honored by the friendly and warm foreword from Dr Dieter Enders. His pioneer achievements and ongoing research in the field of MBFTs is internationally recognized and constitutes an outstanding model for many chemists worldwide. We also gratefully acknowledge the Wiley editorial staff, in particular, Jonathan Rose for his invaluable help and guidance.

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

Jean Rodriguez and Damien Bonne, Aix Marseille University, 2015

1

DEFINITIONS AND CLASSIFICATIONS OF MBFTs

Damien Bonne and Jean Rodriguez

Aix Marseille Université, CNRS, Marseille, France

1.1 INTRODUCTION

The selective formation of covalent bonds, especially carbon–carbon and carbon–heteroatom bonds, is at the heart of synthetic organic chemistry. From the very beginning, researchers have developed many ingenious methodologies able to create one specific chemical bond at a time, and this has led to very significant advances in the total synthesis of complex natural or nonnatural molecules. Past decades 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 Nobel Prizes in chemistry, in 2005 and 2010 [1]. The arsenal of modern organic synthesis is now deep enough for answering yes to the question: can we make this molecule? provided that sufficient manpower, money, and time are available. However, today's societal economic and ecologic concerns have raised the contemporaneous question: can we make this molecule efficiently? This small upgrade places the efficiency of a synthetic pathway in a central position both for academic developments or potential industrial applications. The efficiency of a chemical process is now evaluated not only from the overall yield and selectivity issues but also in terms of the control of waste generation, toxicity and hazard of the chemicals, the level of human resources needed, and the overall time and energy involved: in simple words, how to make more with less? How to render a synthesis greener?

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

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

c01h001

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

This simple intuitive idea has its roots in Nature, which, with the help of biological systems and billions of years of practice, can produce high levels of structural complexity and functional diversity by means of elegant and spectacular MBFTs. A magnificent example is the biosynthesis of steroids from squalene epoxides, which is converted in cells to lanosterol and then to cholesterol (Scheme 1.2) [5]. This transformation occurs with high stereoselectivity for the formation of four C—C bonds and six stereogenic carbon atoms.

c01h002

Scheme 1.2 Biosynthesis of lanosterol.

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

c01h003

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

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 that perfectly fits with the criteria of efficiency for a synthesis to be viable.

1.2 DEFINITIONS

It seems highly desirable to introduce a clear definition of the different types of MBFTs. First, MBFTs do not include concerted transformations such as cycloadditions (e.g., Diel–Alder reaction) or metal-catalyzed cycloisomerization (e.g., Pauson–Khand reaction), even though, strictly speaking, two or more bonds are created in these transformations. MBFTs can be roughly categorized according to the protocol used and the number of functional components involved. Therefore, one-, two-, and multicomponent sequences can be envisioned, and following the definitions proposed by Tietze [7], we distinguish domino reactions and consecutive reactions as the two main classes of nonconcerted MBFTs. Domino (or cascade) reactions are MBFTs that take place under the same reaction conditions without adding extra reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step. A very elegant example of a unimolecular transformation is the two-directional epoxide-opening reaction in the total synthesis of the natural product glabrescol reported by Corey and Xiong, where four C—O bonds were created by simple acidic treatment of a tetraepoxide precursor (Scheme 1.4a) [8].

c01h004

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

In comparison, consecutive reactions describe MBFTs in which the introduction of the reagent(s) and/or additional solvent(s) and substrate(s) is performed in a stepwise manner to a single reaction mixture from which nothing is removed. Strictly speaking, sequences involving even a limited and operationally simple change of the reaction conditions such as an elevation of temperature should not be denoted as domino reactions but preferably as consecutive reactions. The example displayed in Scheme 1.4b has been described by Rueping's group for the enantioselective synthesis of polycyclic heterocycles with the concomitant formation of one C—C and two C—N bonds [9]. The first step of the sequence involves two components and is catalyzed by diarylprolinol silyl ethers. It leads to a transient cyclic hemiacetal, which is not isolated and can react with a third component, for example, a functionalized primary amine, in a second consecutive step via intramolecular capture of an iminium ion intermediate.

Finally, multicomponent reactions (MCRs) are a subclass of domino reactions and can be defined as processes in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [10]. A recent example reported by our group (Scheme 1.4c) involves the reaction between β-ketoamides, acrolein, and aminophenols, allowing the preparation of an enantioenriched diazabicyclo[2.2.2]octanone (2,6-DABCO) scaffold [11]. The chemoselective 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 substrates displaying several complementary reactive sites, which can be exploited successively in the transformation. Some families of densely functionalized small molecules are particularly well adapted to serve as substrates for these reactions. We can cite, for example, isocyanides [12] and dicarbonyl compounds [13], which have led to the discovery of important MBFTs owing to the presence of multiple reaction sites with both electrophilic and nucleophilic characters, which could be modulated by the nature of the substituents.

On the basis of these considerations, this book will focus on modern tools for efficient stereoselective synthesis proceeding exclusively with MBFTs including selected examples of domino, multicomponent, or consecutive sequences that have been described in the last 10 years. In this book, we highlight the best of these 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 essential in academic research, and is becoming also of primary importance in the industrial context such as medicinal chemistry or agrochemical research. For this reason, we decided to focus only on stereoselective methodologies involving either metallic or organic catalysis and to present some selected current synthetic applications in the fields of total synthesis or in the elaboration of biologically relevant targets. In addition, for practical matters, we feel that an organization by the type of molecules (e.g., carbocycles, heterocycles, spirocycles, acyclic) should be very attractive and useful for the readers.

We choose an organization in four main parts including 15 chapters classified by structures 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 or in the elaboration of biologically relevant targets, completed with some experimental data when appropriate.

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

1.3 CONCLUSION AND OUTLOOK

Despite the considerable advances chemist have made during nearly only in two centuries, the limits of synthetic organic chemistry are far from being reached, and we believe that the discovery of new MBFTs will constitute a significant advance in this direction moving closer from the ideal synthesis, which is not only an academic holy grail but also a great challenge for industrial applications. This book should prove useful for graduate students, faculty members, and industrial scientists with interests in organic chemistry in general and in new efficient synthetic methodologies (medicinal chemistry, natural product chemistry, biochemistry, and process chemistry, etc.) in particular. The original layout of this book, which is based on structures with a clear presentation of concepts and key reactions, should attract and facilitate reading of graduate students but will also constitute a strong support for more specialized readers interested in new synthetic developments and applications.

REFERENCES

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

2. Young, I. S., Baran, P. S. (2009). Protecting-group-free synthesis as an opportunity for invention. 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 Sciences: 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 multiple bond-forming transformations (MBFTs): the power of 1,2- and 1,3-dicarbonyl compounds. Chemistry – A European Journal, 19, 2218–2231.(c) For a recent review introducing 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, an intermediate in the biological synthesis of sterols from squalene. Journal of the American Chemical Society, 88, 4750–4751.(b) Abe, I., Rohmer, M., Prestwich, G. D. (1993). Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chemical Reviews, 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) For a review on asymmetric Strecker reaction, see: Wang, J., Liu, X., Feng, X. (2011). Asymmetric 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 chiral 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 organocatalytic synthesis of indoloquinolizidines, pyridoquinazolines and quinazolinones through a one-pot domino Michael addition-cyclization-Pictet–Spengler or 1,2-amine addition reaction. Advanced Synthesis & Catalysis, 353, 2853–2859.

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

11. Sanchez Duque, M. M., Baslé, O., Génisson, Y., Plaquevent, J.-C., Bugaut, X., Constantieux, T., Rodriguez, J. (2013). Enantioselective organocatalytic multicomponent synthesis 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 reactions. European Journal of Organic Chemistry, 3543–3559.(b) Dömling, A. (2006). Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chemical Review, 106, 17–89.

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

PART I

STEREOSELECTIVE SYNTHESIS OF HETEROCYCLES

2

FIVE-MEMBERED HETEROCYCLES

Hanmin Huang and Pan Xie

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

2.1 INTRODUCTION

A wide variety of natural and synthetic biologically active compounds and pharmaceuticals have five-membered heterocycles as structural motifs. Depending on the substitution pattern and structure of the five-membered heterocycles, they can be grouped into monocyclic, fused-polycyclic, and bridged-polycyclic, which have found applications as effective antitumor, antibacterial, or analgesic agents. Furthermore, some five-membered heterocycles such as pyrrolidines are now considered to be privileged ligand skeletons, and their use has given rise to excellent results in many useful asymmetric transformations. Driven by this prevalence, intense efforts have been devoted to the synthesis of this type of molecules. Among the many stereoselective synthetic routes for these compounds, multiple bond-forming transformations (MBFTs) [1], which allow the creation of several covalent C—C or C—heteroatom bonds in a single chemical operation, are the most promising approaches to the motif because of high atom and step economy. This chapter describes the major advances since 2004 in the area of the stereoselective synthesis of five-membered heterocycles via MBFTs, including domino transformations, multicomponent reactions, and some other consecutive synthetic processes.

2.2 MONOCYCLIC TARGETS

2.2.1 1,3-Dipolar Cycloaddition

The 1,3-dipolar cycloaddition (1,3-DC) is the reaction of a dipolarophile with a 1,3-dipolar compound to form a five-membered ring, which is a kind of MBFT. The earliest 1,3-DC reactions were described in the late nineteenth century to the early twentieth century, following the discovery of 1,3-dipoles. Mechanistic investigations and synthetic applications were established by Rolf Huisgen in the 1960s [2]. Now, the chemistry of the 1,3-DC reaction has thus evolved for more than 100 years, and a variety of different 1,3-dipoles have been discovered, which has significantly advanced the development of the 1,3-DC reactions. After several decades of development, transition-metal-catalyzed, stereoselective 1,3-DC has become one of the most useful synthetic routes to the synthesis of the five-membered heterocycles.

2.2.1.1 Targets with one Heteroatom

Five-membered heterocycles with one heteroatom, such as pyrrolidine and tetrahydrofuran skeletons, exist widely in numerous natural products and bioactive compounds. Therefore, intense efforts have been devoted to the synthesis of these five-membered ring systems. Among the various methods existing for the synthesis of chiral pyrrolidine and proline derivatives, few can match the synthetic potential of 1,3-DC reactions of azomethine ylides with alkenes [3]. Generally, azomethine ylides are unstable species, so they are normally generated in situ and trapped by unsaturated bonds (Scheme 2.1) [2b].

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Scheme 2.1 1,3-DC reactions between azomethine ylides and alkenes.

Nowadays, many methods are available to generate azomethine ylides, but the in situ metalation of iminoesters to form metalloazomethine dipoles has become the most widely used approach. In their cycloaddition, the coordination of iminoester to the metal catalyst happens initially, which can lead to the formation of the metalloazomethine dipole intermediates. Then, this species reacts with dipolarophile to afford the zwitterionic species, from which the cycloaddition product can be obtained via intramolecular cyclization (Scheme 2.2) [4].

c02h002

Scheme 2.2 Mechanism of 1,3-DC reactions of azomethine ylides.

To date, many functional alkenes, such as maleates, fumarates, and vinyl phenyl sulfones, have been employed as dipolarophiles, successfully (Figure 2.1). The attractiveness of 1,3-DC reactions of azomethine ylides with alkenes is due to the fact that pyrrolidine derivatives with up to four stereocenters can be generated in a single operation from readily available starting materials. As a result, the 1,3-DC of azomethine ylides has become one of the most convenient synthesis methods to the highly substituted pyrrolidines. For these transformations, some copper salts [5], silver salts [6], and other metals [7] have demonstrated high catalytic activity.

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Figure 2.1 1,3-Dipole precursors and dipolarophiles applied in 1,3-DC reactions.

The chiral metal complexes play an important role for getting high activity and selectivity. Mechanistically, in the course of these reactions, metalation of an iminoester with a chiral metal complex results in the formation of a well-organized ligand/metal/azomethine ylide complex. In many cases, the intermediate can add to alkenes with high degrees of regio, diastereo, and enantioselectivity by the use of appropriate chiral ligands. Thus, in order to get optically pure pyrrolidine derivatives, various chiral ligands (Figure 2.2) have been applied in the 1,3-DC reactions of azomethine ylides with alkenes, and excellent results have been obtained.

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Figure 2.2 Chiral ligands applied in 1,3-DC reactions between azomethine ylides and alkenes.

Lewis acid-catalyzed [3 + 2] cycloadditions of activated donor–acceptor cyclopropanes with aldehydes/ketones are particularly attractive methods for the synthesis of substituted tetrahydrofurans [8]. The application of 2,3-trans-disubstituted cyclopropane-1,1-diesters 1 in the cycloaddition reactions with aromatic aldehydes 2 achieved 2,5-diaryl-3,3,4-trisubstituted tetrahydrofurans 3 or 4 in moderate to good yields with excellent regioselectivities and diastereoselectivities (Scheme 2.3). Another trans-selective [3 + 2] cycloaddition of cyclopropane was presented by Niggemann. In the presence of a catalytic amount of Ca(NTf2)2/Bu4NPF6, highly substituted tetrahydrofurans were generated by the reaction of 2,2-disubstituted cyclopropanes bearing an alkyne moiety as the sole donor entity with aldehyde [9].

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Scheme 2.3 AlCl3-promoted [3 + 2] cycloadditions of activated cyclopropanes.

Trost and coworkers reported a novel palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane with ketones. This protocol provides access to highly enantioenriched tetrahydrofurans bearing a tetrasubstituted stereocenter (Scheme 2.4). In this process, the use of a C1-symmetric phosphoramidite ligand is critical for establishing this reaction, which demonstrated a uniquely high activity under the reaction conditions [10].

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Scheme 2.4 Palladium-catalyzed [3 + 2] cycloadditions.

2.2.1.2 Targets with Two Heteroatoms

1,3-DC reaction was also widely used in the preparation of five-membered heterocycles with two heteroatoms. For instance, Lewis acid-catalyzed asymmetric 1,3-DC between nitrones and alkenes is of great interest in organic synthesis because the resulting optically active isoxazolidines can be easily converted into a variety of biologically active β-amino acids and β-lactams, as well as other chiral building blocks such as 3-amino alcohols. The first example of the asymmetric cycloaddition with nitrones as 1,3-dipoles was reported independently by Jørgensen and Scheeren in 1994 [11]. In Jørgensen's work, an asymmetric intermolecular cyclization of a nitrone and 3-acyl-1,3-oxazolidin-2-one occurred to give the corresponding isoxazolidines with moderate stereoselectivity when exposed to a chiral dichlorotitanium alkoxide. Although no detailed mechanistic information was obtained, the activation of dipolarophile through the coordination of the Lewis acid with alkene was proved to be essential. Inspired by this result, many other research groups have been engaged in the development of efficient chiral catalysts or dipolarophiles containing suitable coordination sites. Depending on the nature of dipolarophiles, different catalyst and reaction conditions were required. The different catalyst systems can be grouped into Lewis acid and Brønsted acid catalysts, and their applications are presented below.

In 2004, Nishiyama and Iwasa reported that a chiral Lewis acid complex, generated from Mn(ClO4)2 and the chiral xabox ligand 12, could be used as an efficient catalyst for the asymmetric 1,3-DC reactions of nitrones 9 with 3-alkenoyl oxazolidinone 10 [12]. These reactions were typically carried out at room temperature and provided the corresponding isoxazolidines 11 in good to excellent stereoselectivities (Scheme 2.5).

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Scheme 2.5 Catalytic asymmetric 1,3-DC reactions of nitrones.

Next, the chiral Cu and Ce catalysts were also applied in the 1,3-DC of nitrones in succession. By using a similar strategy, the corresponding isoxazolidine products were generated in good to excellent enantioselectivities [13]. Although a number of chiral Lewis acids have been shown to possess high enantioselectivities in the reactions of nitrones with electron-rich and electron-deficient olefins [14], endo cycloadducts with high enantioselectivity were obtained in most cases. In order to get high exo selectivity, an efficient chiral Lewis acid catalyst Ni(II)/(R)-BINIM-DCOH ligand 16 was developed by Suga and coworkers, which showed high exo selectivities and enantioselectivities in the 1,3-DC reactions of nitrones 13 and 3-(2-alkenoyl)-2-thiazolidinethiones 14 [15]. In contrast to many other chiral Lewis acids, this methodology offers extremely high exo selectivities along with high enantioselectivities for a number of nitrones (Scheme 2.6).

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Scheme 2.6 Chiral binaphthyldiimine-Ni(II) complex-catalyzed cycloaddition reactions.

Chiral Brønsted acid catalysis of organic reactions has become a rapidly growing area of research, as it offers operational simplicity together with mild reaction conditions. However, the first Brønsted acid-catalyzed 1,3-DC of diaryl nitrones 17 to ethyl vinyl ether 18 was demonstrated by Yamamoto and coworkers in 2008 [16]. Only 5 mol% of chiral phosphoramide catalyst 20 was enough for this transformation. Similar to some Lewis acid-catalyzed 1,3-DC reaction, this protocol provided the endo products as the major diastereomers (Scheme 2.7).

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Scheme 2.7 Chiral Brønsted acid-catalyzed cycloaddition reactions of nitrones.

The 1,3-DC of nitrile oxides and alkenes leads to the formation of 2-isoxazolines, which are useful building blocks in organic chemistry. While the diastereoselective nitrile oxide cycloadditions have been investigated extensively, the development of enantioselective variants is quite rare.

In 2004, an elegant example of nitrile oxide cycloaddition to pyrazolidinone crotonates catalyzed by a chiral Lewis acid was described by Sibi and coworkers [17a]. Using this protocol, a variety of chiral 2-isoxazolines 23 were synthesized in high enantioselectivities and good yields. In this case, the pyrazolidinone template was crucial for obtaining high regioselectivity and enantioselectivity (Scheme 2.8). Further studies from the same group revealed that α,β-alkyl-disubstituted N-H acrylimides were also suitable substrates for this kind of reaction [17b].

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Scheme 2.8 Mg-catalyzed 1,3-DC reactions of nitrile oxides.

Using [Ru(acetone)(R,R)-BIPHOP-F)Cp][SbF6] 29 as catalyst, the 1,3-DC reaction between aryl nitrile oxides 26 and methacrolein 27 was