Table of Contents

Related Titles

Title page

Copyright page

Foreword

Preface

List of Contributors

Abbreviations

Volume 1: Privileged Catalysts

Part I: Amino Acid-Derived Catalysts

1: Proline-Related Secondary Amine Catalysts and Applications

1.1 Introduction

1.2 Prolinamide and Related Catalysts

1.3 Prolinamine and Related Catalysts

1.4 Proline Tetrazole and Related Catalysts

1.5 Prolinamine Sulfonamide and Related Catalysts

1.6 Prolinamine Thiourea and Related Catalysts

1.7 Miscellaneous

1.8 Conclusions

Acknowledgments

2: TMS-Prolinol Catalyst in Organocatalysis

2.1 Introduction

2.2 Enamine Activation

2.3 Iminium-Ion Activation

2.4 Cascade Reactions

2.5 Dienamine Activation

2.6 Trienamine Activation

2.7 Summary and Conclusions

3: Non-Proline Amino Acid Catalysts

3.1 Introduction

3.2 Primary Amino Acids in Amino Catalysis

3.3 Primary Amino Acid-Derived Organic Catalysts

3.4 Applications of Non-Proline Primary Amino Acid Catalysts

3.5 Conclusions

Acknowledgments

4: Chiral Imidazolidinone (MacMillan's) Catalyst

4.1 Introduction

4.2 Enamine Catalysis

4.3 Iminium Catalysis

4.4 Cascade Reaction–Merging Iminium and Enamine Catalysis

5: Oligopeptides as Modular Organocatalytic Scaffolds

5.1 Introduction

5.2 C–C Bond Forming Reactions

5.3 Asymmetric Acylations

5.4 Asymmetric Phosphorylations

5.5 Enantioselective Oxidations

5.6 Hydrolytic Reactions

5.7 Summary and Conclusions

Part II: Non-Amino Acid-Derived Catalysts

6: Cinchonas and Cupreidines

6.1 Introduction

6.2 Cinchona Alkaloid Derivatives

6.3 Natural Cinchona Alkaloids, Cupreine, and Cupreidine

6.4 Cinchona Alkaloids with an Ether or Ester Group at C9

6.5 Cinchona Alkaloid Derivatives with a Sulfonamide, Urea, Thiourea, Squaramide, or Guanidine Function

6.6 Cinchona Alkaloids with a Primary Amine Group at C9

6.7 Cinchona Alkaloids in Phase-Transfer Catalysis

6.8 Ether Bridged Dimers

6.9 Some Novel Cinchona Alkaloid Derivatives

6.10 Prospects

7: Chiral C₂ Catalysts

7.1 Introduction

7.2 Chiral Lewis Base Catalysts

7.3 Phosphines

7.4 Chiral C₂-Symmetric Secondary and Primary Amines

7.5 Chiral C₂-Symmetric Brønsted Bases: Guanidines

7.6 Chiral C₂-Symmetric Brønsted Acids

7.7 Chiral C₂-Symmetric Bis-Thioureas

7.8 Chiral C₂-Symmetric Aminophosphonium Ions

7.9 Summary and Conclusions

8: Planar Chiral Catalysts

8.1 Introduction

8.2 Lewis/Brønsted Bases

8.3 Lewis/Brønsted Acids

8.4 Redox Reactions

8.5 Summary and Conclusions

9: Dynamic Approaches towards Catalyst Discovery

9.1 Introduction

9.2 Self-Assembly

9.3 Self-Selected Catalysts

9.4 Conclusions

Acknowledgments

Appendix

Proline Derivatives and Proline Analogs

Non-Proline Amino Acids

Chiral Imidazolidinones (MacMillan's Catalysts and Analogs)

Di- and Oligopeptide Catalysts

Cinchonas

Planar Chiral Catalysts

Biaryl Catalysts

1,2-Diamines

1,2-Aminoalcohols

1,2-Aminophosphines

TADDOL-Derived Catalysts

Carbohydrate-Derived Catalysts

Terpene-Derived Catalysts

Chiral Sulfoxides

Miscellaneous

Volume 2: Activations

Part I: Asymmetric Catalysis with Non-Covalent Interactions

10: Brønsted Acids

10.1 Introduction

10.2 Chiral Alcohol Catalysts

10.3 Chiral Squaramides as Hydrogen-Bond Donor Catalysts

10.4 Guanidines/Guanidiniums

10.5 Miscellaneous Brønsted Acids

10.6 Addendum

11: Brønsted Acids: Chiral Phosphoric Acid Catalysts in Asymmetric Synthesis

11.1 Introduction

11.2 Reaction with Imines

11.3 Friedel–Crafts Reaction

11.4 Intramolecular Aldol Reaction

11.5 Ring Opening of meso-Aziridines

11.6 Future Prospects

12: Brønsted Acids: Chiral (Thio)urea Derivatives

12.1 Introduction

12.2 Important Chiral (Thio)urea Organocatalysts

12.3 Summary

13: Brønsted Bases

13.1 Introduction

13.2 Cinchona Alkaloids

13.3 Brønsted Base-Derived Thiourea Catalysts

13.4 Chiral Guanidine Catalysts

13.5 Conclusion

14: Chiral Onium Salts (Phase-Transfer Reactions)

14.1 Introduction

14.2 Phase-Transfer Catalysis

14.3 Onium Fluorides

14.4 Onium Phenoxides and Related Compounds

14.5 Conclusions

15: Lewis Bases

15.1 Introduction

15.2 Allylation Reactions

15.3 Propargylation, Allenylation, and Addition of Acetylenes

15.4 Aldol-Type Reactions

15.5 Cyanation and Isonitrile Addition

15.6 Reduction Reactions

15.7 Epoxide Opening

15.8 Conclusion and Outlook

16: Lewis Acids

16.1 Introduction

16.2 Silyl Cation Based Catalysts

16.3 Hypervalent Silicon Based Catalysts

16.4 Phosphonium Cation Based Catalysts

16.5 Carbocation Based Catalysts

16.6 Ionic Liquids

16.7 Miscellaneous Catalysts

16.8 Conclusion

Part II: Asymmetric Catalysis with Covalent Interactions

17: Rationalizing Reactivity and Selectivity in Aminocatalytic Reactions

17.1 Introduction

17.2 Secondary Amine Catalysis

17.3 Stereoselectivity in Proline-Catalyzed Reactions

17.4 Mechanism and Stereoselectivity in Organocatalytic Cascade Reactions

17.5 Rational Design of Catalysts

17.6 Summary and Conclusions

Acknowledgments

18: Carbene Catalysts

18.1 Introduction

18.2 Reactions of Acyl Anion Equivalents

18.3 Extended Umpolung

18.4 Umpolung of Activated Olefins

18.5 Nucleophilic Catalysis

18.6 Conclusion

19: Oxides and Epoxides

19.1 Alkene Epoxidation

19.2 Hypervalent Iodine-Catalyzed Oxidations

19.3 Oxidation of Thioethers and Disulfides

19.4 Resolution of Alcohols by Oxidation

20: Ylides

20.1 Introduction

20.2 Enantioselective Sulfur Ylide Catalysis

20.3 Enantioselective Phosphorus and Arsenic Ylide Catalysis

20.4 Enantioselective Nitrogen Ylide Catalysis

20.5 Enantioselective Selenium and Tellurium Ylide Catalysis

20.6 Summary and Conclusions

Part III: Tuning Catalyst Activity and Selectivity by the Reaction Medium and Conditions

21: “Non-Classical” Activation of Organocatalytic Reactions (Pressure, Microwave Irradiation.)

21.1 Introduction

21.2 Asymmetric Organocatalysis under High-Pressure Conditions

21.3 Asymmetric Organocatalysis under Microwave Irradiation–Thermal Effect

21.4 Asymmetric Organocatalysis under Ultrasound Irradiation

21.5 Asymmetric Organocatalysis under Ball Milling Conditions

21.6 Summary and Conclusions

22: Ionic Liquid Organocatalysts

22.1 Introduction

22.2 Ionic Liquids as Recyclable Solvents for Asymmetric Organocatalytic Reactions

22.3 “Non-Solvent” Applications of Ionic Liquids and Their Congeners in Asymmetric Organocatalysis

22.4 Conclusion

23: Polymer and Mesoporous Material Supported Organocatalysts

23.1 Introduction

23.2 Polymer-Supported Organocatalysts

23.3 Mesoporous-Supported Organocatalysts

23.4 Conclusions and Outlook

24: Water in Organocatalytic Reactions

24.1 Introduction

24.2 Aldol Reactions

24.3 Michael Reactions

24.4 Mannich Reaction

24.5 Diels–Alder Reaction

24.6 Miscellaneous Examples

Volume 3: Reactions and Applications

Part I: Alpha-Alkylation and Heteroatom Functionalization

25: S_N2-Type Alpha-Alkylation and Allylation Reactions

25.1 S_N2-Type Alkylation under Homogenous Conditions

25.2 Domino Reactions Including S_N2-Type Alkylations

25.3 Intermolecular S_N2′ Alkylations under Homogenous Conditions

25.4 Summary

26: Alpha-Alkylation by S_N1-Type Reactions

26.1 Introduction

26.2 S_N1-Type Nucleophilic Reaction by Generation of Carbocations

26.3 Organocatalytic Stereoselective S_N1-Type Reactions with Enamine Catalysis

26.4 Asymmetric S_N1-Type α-Alkylation of Ketones

26.5 Combination of Enamine Catalysis and Lewis Acids in S_N1-Type Reactions

26.6 Organocatalytic S_N1-Type Reactions with Brønsted Acids

26.7 S_N1-Type Reaction Promoted by Chiral Thioureas

26.8 S_N1-Type Organocatalytic Reaction of Iminium, Oxonium, and Aziridinium Intermediates

26.9 Conclusions and Perspectives

27: Alpha-Heteroatom Functionalization of Carbonyl Compounds

27.1 Introduction

27.2 Enantioselective α-Pnictogenation of Carbonyl Compounds

27.3 Enantioselective α-Chalcogenation

27.4 Enantioselective α-Halogenation of Carbonyl Compounds

27.5 Summary and Conclusions

Part II: Nucleophile Addition to C=X Bonds

28: Aldol and Mannich-Type Reactions

28.1 Introduction

28.2 Enamine Catalysis

28.3 Brønsted Acid Catalysis Including Hydrogen-Bond Catalysis

28.4 Brønsted Base Catalysis Including Bifunctional Catalysis

28.5 Phase-Transfer Catalysis

28.6 N-Heterocyclic Carbene (NHC) Catalysis

28.7 Supported Organocatalysis

28.8 Summary and Conclusions

29: Additions of Nitroalkyls and Sulfones to C=X

29.1 Organocatalytic Addition of Nitroalkanes to C=O (The Henry Reaction)

29.2 Addition of Nitroalkanes to C=NR (The Aza-Henry or Nitro-Mannich Reaction)

29.3 Organocatalytic Addition of Sulfones to C=X

29.4 Summary and Outlook

30: Hydrocyanation and Strecker Reactions

30.1 Introduction

30.2 Amino-Acid Containing Catalysts for Carbonyl Hydrocyanation

30.3 Thiourea Catalysts for Carbonyl Hydrocyanation

30.4 C₂-Symmetrical Guanidines and N,N′-Dioxides

30.5 Diketopiperazines as Catalysts for the Strecker Reaction

30.6 (Thio)urea Catalysts for the Strecker Reaction

30.7 Guanidines as Catalysts for the Strecker Reaction

30.8 N,N′-Dioxides and Bis-Formamides as Catalysts for the Strecker Reaction

30.9 Chiral Quaternary Ammonium Salts as Catalysts for the Strecker Reaction

30.10 BINOL-Phosphates as Catalysts for the Strecker Reaction

30.11 Other Catalysts for the Strecker Reaction

31: The Morita–Baylis–Hillman (MBH) and Hetero-MBH Reactions

31.1 Introduction

31.2 Recent Mechanistic Insights into the MBH/aza-MBH Reaction and Its Asymmetric Version

31.3 Recent Developments of Essential Components

31.4 Recent Developments of Asymmetric MBH/aza-MBH Reactions

31.5 Conclusions

32: Reduction of C=O and C=N

32.1 Introduction

32.2 Hantzsch Ester as the Hydride Source

32.3 Trichlorosilane as the Reducing Reagent

32.4 Other Hydrogen Sources

32.5 Summary and Conclusions

Part III: Nucleophile Addition to C=C Bonds

33: Addition to α,β-Unsaturated Aldehydes and Ketones

33.1 Introduction

33.2 Nucleophilic Addition to Enals and Ketones

33.3 Conclusion

34: Addition to Nitroolefins and Vinyl Sulfones

34.1 Introduction

34.2 Addition to Nitroolefins

34.3 Addition to Vinyl Sulfones

34.4 Addition to Vinyl Selenones

34.5 Summary and Conclusions

Acknowledgments

35: Organocatalyzed Asymmetric Arylation and Heteroarylation Reactions

35.1 Introduction

35.2 Representative Classes of Electrophiles

35.3 Friedel–Crafts in Organocascade Transformations

35.4 Application in Biologically Interesting and Natural Product Syntheses

35.5 Miscellaneous

35.6 Conclusion

Part IV: Ring-Forming Reactions

36: Intramolecular Reactions

36.1 Introduction

36.2 Intramolecular Ring-Forming Reactions via Covalent Catalysis

36.3 Intramolecular Ring-Forming Reactions by Non-Covalent Catalysis

36.4 Conclusion

37: Formation of 3-, 4- and 5-Membered Cycles by Intermolecular Reactions

37.1 Introduction

37.2 Organocatalytic Asymmetric Synthesis of Five-Membered Cycles

37.3 Organocatalytic Asymmetric Synthesis of Four-Membered Cycles

37.4 Organocatalytic Asymmetric Synthesis of Three-Membered Cycles

37.5 Conclusion

38: Diels-Alder and Hetero-Diels–Alder Reactions

38.1 Introduction

38.2 Organocatalytic Diels–Alder Reaction

38.3 Organocatalysis of Oxa-Hetero-Diels–Alder Reaction

38.4 Organocatalysis of Aza-Hetero-Diels–Alder Reaction

38.5 Conclusion

Part V: Increasing Complexity

39: Organocatalytic Radical and Electron Transfer Reactions

39.1 Introduction

39.2 Chemically Induced Oxidative Electron-Transfer Reactions

39.3 Photoredox Catalysis

39.4 Photochemical Asymmetric Synthesis

39.5 Conclusion

40: Organocatalytic Sigmatropic Reactions

40.1 Introduction

40.2 Steglich and Related Rearrangements

40.3 1,3-Sigmatropic Rearrangements

40.4 1,4-Sigmatropic Rearrangements

40.5 2,3-Sigmatropic Rearrangements

40.6 3,3-Sigmatropic Rearrangements

40.7 Aza-Petasis–Ferrier Rearrangement

40.8 Pinacol and Related Rearrangements

Acknowledgments

41: Regio- and Position Selective Reactions and Desymmetrizations

41.1 Introduction

41.2 Kinetic Resolution of Alcohols

41.3 Kinetic Resolution of Amines

41.4 Concluding Remarks

42: Three or More Components Reactions (Single Catalyst Systems)

42.1 General Introduction

42.2 Covalent Modes of Catalysis–Developing MCRs by Asymmetric Aminocatalysis

42.3 Non-Covalent Modes of Catalysis

42.4 Merging Covalent and Non-Covalent Activation Modes

42.5 Summary and Outlook

Acknowledgments

43: Multi-Catalyst Systems

43.1 Introduction

43.2 Combinational Use of Dual Brønsted Acids

43.3 Combinational Use of Chiral Brønsted Acid and Chiral or Achiral Lewis Base

43.4 Carbene-Based Dual Organocatalysis

43.5 Amino Catalyst-Based Cooperative Catalysis with Multifarious Co-Catalysts

43.6 Conclusions

Acknowledgments

44: Organocatalysis in Total Synthesis

44.1 Introduction

44.2 Aminocatalysis in Natural Product Synthesis

44.3 Hydrogen Bond Catalysis in Total Synthesis

44.4 Cinchona Alkaloids in Total Synthesis

44.5 Phase-Transfer Catalysis in Target Molecule Synthesis

44.6 Industrial Applications of Organocatalysis

44.7 Conclusions

Index

The Editor

Dr. Peter I. Dalko

Université Paris-Descartes

PRES Sorbonne Paris Cité, CNRS

45, rue des Saints-Pères

75270 Paris Cedex 06

France

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The enthusiasm and dedication with which chemists have embraced the field of organocatalysis after its inauguration in 2000 has been spectacular and somewhat resembled the quick opening of a bottle of champagne under pressure. So much catalysis needed to be rapidly discovered and revealed by an ever increasing number of researchers with so little time. First dozens, soon hundreds and later thousands of publications appeared describing the power and potential of organic catalysis. But why did all those ideas and catalysis concepts appear in such a burst? In my opinion, the organocatalysis explosion was fueled by the deeper understanding of the reactivity of organic compounds, which chemists have accumulated during the last two centuries. Without doubt, in their slow but steady advancement, organic chemists significantly benefited from the inclusion of physical methods such as kinetics, theory, and spectroscopy. The new understanding had served them very well towards the sophistication of organic synthesis, enabling chemists to make many interesting and useful molecules and materials such as drugs, dyes, polymers, and natural products. But for some reason, this understanding had hardly been applied to advancing organic catalysis. The science of catalysis had been a domain of organometallic chemistry and possibly of biochemistry but certainly not of organic chemistry. Once the first examples of rationally designed reactions catalyzed by organic molecules were disclosed though, the situation quickly became an entirely different one. All of a sudden, the accumulated knowledge of the principles of organic reactivity could immediately be applied to the design of novel catalysis concepts. For organic chemists, entering the catalysis domain by facilely illustrating that organic compounds can be active and selective catalysts very much like metals and proteins was an exciting adventure.

Now, a dozen years later, the discovery phase of organocatalysis continues relentlessly but another phase is also beginning and that is the phase of understanding and structuring organocatalysis. I think these times are equally exciting and valuable for the field. For example, many mechanistic details are still to be elucidated, including the exact nature of reactive intermediates in organocatalysis. But for me, it is also time to define the logics of organocatalysis and to give the field a certain structure. In my experience, making the effort to classify and structure an area is highly rewarding as one can easily identify uninvestigated territories, which in turn are valuable windows of opportunities for further breakthrough research.

It appears to be in this spirit that the present book is edited. I think these efforts are highly laudable and the editor has tried very hard to organize organocatalysis in a rational manner. He also has put a lot of effort on identifying the leading people in the field and on recruiting them as authors. What a massive and impressive task! Efforts such as the present one are of great value in encouraging further studies from the next generation of chemists. I hope they will be stimulated to conduct exciting new research in areas where nobody else had been before, possibly opening up another bottle …

This book is the new edition of the earlier published Enantioselective Organocatalysis manual, which appeared six years ago. Over the past six years the organocatalysis field has progressed considerably; many new more and more powerful methods were discovered, and a new edition of this book appeared to be necessary. The aim of this multiauthor book was to recollect efficient organocatalytic reactions around clear principles that meet actual standards in asymmetric synthesis. Chapters were written in a concise way, and this condensed treatment is supported by more than 1400 schemes and figures, providing condensed visual information at a glance. The book was kept updated with the literature until spring/summer 2012. Considering the historically broad interest in the field, the book wishes to address a large audience: academic or industrial researchers, students, and teachers who are interested in synthetic organic chemistry at an advanced level.

The difficulty of discussing organocatalytic reactions in a comprehensive way lies in the dichotomy of the catalyst/reaction approach: looking at the chemistry from the catalyst side, which is usually more suitable for researchers who are developing new reactions, or discussing the topic by reaction types, which is more useful for those who wish to apply these new reactions in synthesis. The book explores a novel type of treatment by merging different approaches (catalysts, activation types, and applications), giving readers an opportunity to examine the same transformation from different points of view, allowing for some overlaps between parts. In order to give the most useful insight into this large and fast progressing field, frontline leaders who pioneered the field of organocatalysis were requested to contribute to this work. I wish to acknowledge all of the 96 authors for participating in this venture despite their already heavy responsibilities, yielding a manual of a high standard. I wish also to acknowledge the important lecture and advice of many of my colleagues and friends who assisted me in the evaluation and correction process: I am indebted to Prof. Jose L. Vicario, Prof. Helma Wennemers, Prof. Ryan Gilmour, Prof. Viresh H. Rawal, Prof. Frank Glorius, Prof. Yoshiji Takemoto, Prof. Stephen Connon, Dr. Tirayut Vilaivan, Dr. Pablo Domínguez de María, Dr. Vinod Kumar Singh, and Prof. Jieping Zhu. Also, I wish to acknowledge the help and the professionalism of Dr. Anne Brennführer and Mrs Bernadette Anna Gmeiner of STM Books, Wiley-VCH Verlag GmbH & Co. KGaA, who worked tirelessly to keep all deadlines on time. I had a sincere pleasure to work on this project with you.

1.1 Introduction

Since the reappearance of L-proline (1) at the forefront of organocatalysis, tremendous efforts have been made to devise new catalysts based on a proline core structure. In this field, the chirality of a pyrrolidine fragment plays a critical role, and the principal concept that underlies the development of new catalysts can be simply explained as the attachment of acidic sites in place of a carboxylic acid group to the side chain. Accordingly, several catalysts with various acidic functionalities have been developed [1]. In general, proline-based organocatalysts can be classified into six major categories: (A) prolinamides, (B) prolinamines, (C) proline tetrazoles, (D) prolinamine sulfonamides, (E) prolinamine thioureas, and (F) diarylprolinols (Figure 1.1). Representative pK_a values of these catalysts are listed in Figure 1.2 [2]. A subtle change in the side-chain assembly may change the pK_a value in the range 8–20, which would have a significant effect on the strength of hydrogen bonding, and thus the catalytic activity and selectivity may be affected.

In this chapter we will deal with organocatalytic asymmetric transformations using these catalysts, mainly focusing on the significant and major achievements in this area published from 2000 to 2011. However, due to space constraints, this chapter will not cover the great utility of diarylprolinol catalysts (category F); for convenience, only references are given [3].

1.2 Prolinamide and Related Catalysts

Owing to the ready availability of prolinamide derivatives through the condensation of proline with amines, prolinamide-based compounds constitute a large family of organocatalysts [4]. Figure 1.3 lists representative examples of these catalysts.

These catalysts are very useful in a wide range of asymmetric syntheses. Asymmetric aldol reactions have been investigated by several research groups; selected examples are compiled in Scheme 1.1.

In this context, prolinamide 2 [5–8] and its aryl-substituted homologs such as 3–5 have been developed [9–14]. Analogous to these examples, binaphthyldiamine-derived compounds such as 6 and 7 have been introduced for use in aqueous systems and as recoverable catalysts [15–18]. For example, Benaglia and coworkers reported that the prolinamide catalyst 7 with a lipophilic side chain showed efficient catalytic activity in water [16b]. Chiral spiro diamine-derived catalysts have also been designed, albeit in moderate enantioselectivity [19]. Owing to the increased acidity of an NH group of thioamide relative to a normal amide, proline-thioamide catalysts such as 8 have been shown to be more effective [20–23].

A successful approach in this field is the design of multifunctionalized catalysts such as 9 and 10 through the incorporation of chiral aminoalcohol and related species onto the side chain [24–35]. The high catalytic activity and enantioselec­tivity of catalyst 9 can be explained by considering the favorable assembly of donor and acceptor molecules via double hydrogen-bonding stabilization, as depicted in the transition state model 15 [24h]. In these examples, to gain satis­factory results, it is important to match the chirality between the proline core and the attachment.

Several other related systems containing a prolinamide or proline-thioamide core have also been reported [36–42].

In some cases, a chiral diamine assembly can serve as an effective scaffold for the design of multiply functionalized catalysts like 11 and 12 [43–49]. Proline hydrazides [50], dipeptides [51–57], or other small peptides [58–63] bearing a prolinamide core have been shown to be useful in asymmetric aldol reactions.

Catalyst 13 was introduced for use in aqueous systems in the presence of surfactant Brønsted acids as co-catalysts [64], and several other catalysts such as 14 containing a heteroaromatic system have also been reported [65–67].

There has been important progress in the use of proline sulfonamides (pK_a = 8–11) [2] as efficient organocatalysts, and Yang and Carter provided an excellent review [68]. Therefore, only a few important aspects are addressed here. Figure 1.4 lists representative examples of these catalysts.

Various N-arylsulfonyl-substituted prolinamides such as 16 have been used in asymmetric aldol reactions [69–78]. Carter and coworkers actively sought new efficient catalysts of this type, and found that 17 could serve as an efficient catalyst for asymmetric aldol reactions, even in the absence of any organic solvent, with excellent diastereo- and enantioselectivity (Scheme 1.2) [79].

Recently, Ellman and coworkers have shown that chiral sulfinate 18 can catalyze asymmetric aldol reactions of acetone, whereas proline (1) itself gave poor results [80]. Nakamura and coworkers also explored this field, and found that 19 can promote the asymmetric cross-aldol reaction of acetone with activated ketones, to generate a quaternary carbon stereogenic center bearing an OH function [81].

With regard to aldol chemistry, Mannich or domino-Mannich–Michael reactions can also be promoted by N-arylsulfonyl-substituted prolinamide catalysts such as 17 with high levels of enantioselectivity [82, 83].

Importantly, prolinamide catalysts work well in Michael addition reactions using nitroolefins as acceptors [58, 64, 84–95]. For example, Nájera and coworkers used bifunctional catalyst 20 by virtue of the synergistic effect of double hydrogen-bonding activation, as depicted in the transition state model 21 (Scheme 1.3) [90]. For the same purpose, prolinamides containing a heteroaromatic system like 14 have also been reported [96].

Analogously to these examples, proline-derived peptide catalysts can also efficiently promote Michael addition reactions [97–99]. Prolinamide or prolyl sulfonamide catalysts are also effective for intramolecular Michael addition reactions [100–102]. Recently, Yang and Carter reported a short-cut strategy to construct an all-carbon substituted quaternary carbon stereogenic center on a cyclohexenone framework via Robinson-type annulation using the 17-type catalyst (Scheme 1.4) [103].

While some examples of prolinamide-catalyzed enantioselective Biginelli condensation [104, 105] and other types of C–C bond formation [106, 107] are known, their synthetic utility is unclear. Finally, for convenience, with regard to asymmetric heteroatom functionalization and transfer hydrogenation using prolinamides as catalysts, only references are given [108–114].