Development of direct asymmetric aldol reactions mediated by primary amino acid derived organocatalysts exploring DNA cleaving activities of varacin b and varacin c

1.3.1.3 Intermolecular Aldol Reactions 10 1.3.2 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline Derivatives 12 1.4 Direct Asymmetric Aldol Reactions Catalyzed by Primary Amino A

PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL REACTIONS MEDIATED BY PRIMARY AMINO

ACID-DERIVED ORGANOCATALYSTS

PART Ⅱ: EXPLORING DNA-CLEAVING ACTIVITIES

OF VARACIN B AND VARACIN C

JIANG ZHAOQIN

NATIONAL UNIVERSITY OF SINGAPORE

2009

ALDOL REACTIONS MEDIATED BY PRIMARY AMINO

ACID-DERIVED ORGANOCATALYSTS

PART Ⅱ: EXPLORING DNA-CLEAVING ACTIVITIES

OF VARACIN B AND VARACIN C

JIANG ZHAOQIN

(M.Sc., Soochow Univ.)

A THESIS SUBMITTED FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY OF SCIENCE

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

2009

Acknowledgements

I would like to express my wholehearted gratitude to my supervisor, Dr Lu Yixin for his profound knowledge, invaluable guidance, constant support, inspiration and encouragement throughout my graduate studies He is not only an extraordinary supervisor, a complete mentor, but a truly friend The knowledge, both scientific and otherwise, that I accumulated under his supervision, will aid me greatly throughout

I also give my sincere thanks to my colleagues: Choo En, Liang Zhian, Dr Wu Xiaoyu, Dr Cheng Lili, Dr Xu Liwen, Dr Wang Youqing, Dr Yuan Qing, Han Xiao, Zhu Qiang, Luo Jie and other labmates for their cordiality and friendship

I wish to express my deepest appreciation to my family and my husband for their love and support Without their help, I can not complete this work

I want to express my appreciation to the members of instruments test in NMR, Mass Lab They gave me too much help for my research work

Last but not least, my acknowledgement goes to National University of Singapore for the research scholarship and the financial support

Table of Contents

Acknowledgements i

Table of Contents ii

Summary ix

List of Tables xi

List of Schemes xiii

List of Figures xv

List of Abbreviations xvi

List of Publications xix

PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL R E A C T I O N S M E D I A T E D B Y P R I M A R Y A M I N O ACID-DERIVED ORGANOCATALYSTS 1

Chapter 1 Introduction and Literature Survey 1

1.1 Asymmetric Synthesis 1

1.2 Asymmetric Organocatalysis 2

1.2.1 Introduction 2

1.2.2 Enamine Catalysis and Iminium Catalysis 4

1.3 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline and its Derivatives 7 1.3.1 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline 8

1.3.1.1 Introduction 8

1.3.1.2 Intramolecular Aldol Reactions 9

1.3.1.3 Intermolecular Aldol Reactions 10

1.3.2 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline Derivatives 12 1.4 Direct Asymmetric Aldol Reactions Catalyzed by Primary Amino Acids and their Derivatives as Organocatalysts 15

1.4.1 Primary versus Secondary Amino Acids in Intermolecular Aldol Reactions: Mechanistic Considerations 15

1.4.2 Intramolecular Aldol Reactions 17

1.4.3 Intermolecular Aldol Reactions 18

1.5 Organocatalytic Reactions in Aqueous Media 21

1.6 Objectives of Research 24

Chapter 2 Direct Asymmetric Aldol Reactions Catalyzed by L-Tryptophan and its Derivatives in the Presence of Water 28

2.1 Introduction 28

2.2 Organocatalysts Based on Primary Amino Acids 30

2.2.1 Selection of Organocatalysts 30

2.2.2 Catalyst Preparation 31

2.3 Results and Discussion 32

2.3.1 Aldol Reaction Catalyzed by Primary Amino Acids and Tryptophan Analogues 32

2.3.1.1 Investigation of the Reaction Parameters 32

2.3.1.1.1 Effects of Different Catalysts 32

2.3.1.1.2 Effects of Different Solvents 34

2.3.1.1.3 Effects of Water 36

2.3.1.1.4 Substrate Ratio and Catalyst Loading 37

2.3.1.2 Scope of Substrates 39

2.3.1.2.1 Various Ketones as Donor 39

2.3.1.2.2 Aldehyde Acceptors 42

2.3.1.3 Theoretical Calculations and Proposed Mechanism 45

2.3.2 Exploration of Reaction Pathway for Tryptophan-Catalysed Aldol Reactions in Aqueous Media 52

2.3.2.1 Aldol Reactions Catalyzed by Tryptophan with Various ee Values 54

2.3.2.2 The Mass and ee Distribution of Tryptophan in Different Phases 56

2.3.2.3 Formation of Enamine Intermediate in Water 57

2.3.2.4 The Influences of the Tryptophan-Catalysed Aldol Reactions in the Mixture of Surfactant Sodium Dodecyl Sulfate and Water 59

2.4 Conclusion 60

2.5 Experimental Section 61

2.5.1 Experimental Materials and General Methods 61

2.5.2 Representative Experiment for Aldol Reaction 63

2.5.3 Synthesis and Characterization of Substrate 64

2.5.4 Synthesis and Characterization of Tryptophan Derivatives 65

2.5.5 Characterization of Aldol Products 69

Chapter 3 High Efficient Threonine-Derived Organocatalysts for Direct

Asymmetric Aldol Reactions in the Presence of Water 83

3.1 Introduction 83

3.2 Synthesis of Catalysts 84

3.2.1 Catalyst Design 84

3.2.2 Catalyst Preparation 85

3.3 Results and Discussion 87

3.3.1 The Aldol Reactions of Cyclohexanone 87

3.3.1.1 Catalyst Screening 87

3.3.1.2 Aldehyde Acceptors 90

3.3.1.3 The Practical Synthetic Value of 3-1a-Catalysed Aldol Reaction 91

3.3.2 The Aldol Reaction of Functional Hydroxyacetones 92

3.3.2.1 Catalyst Screening 92

3.3.2.2 Effects of Catalyst Loading 94

3.3.2.3 Effects of Water 95

3.3.2.4 Derivatization of Hydroxyacetone 96

3.3.2.5 Aldehyde Acceptors 98

3.3.3 Synthesis of Chiral 1,2-Diols 101

3.3.4 Effects of Catalysts with Different ee Values 102

3.3.5 Proposed Mechanism and Transition State 105

3.4 Conclusion 106

3.5 Experimental Section 106

3.5.1 Experimental Materials and General Methods 106

3.5.2 Catalysts Synthesis and Characterization 107

3.5.3 Synthesis and Characterization of Functional Hydroxyacetones 122

3.5.4 Experimental Procedure for the Aldol Reactions 124

3.5.5 Characterization of Aldol Products 126

Chapter 4 Direct Asymmetric Aldol Reactions of Acetone with α-Keto Esters Catalyzed by Primary-Tertiary Diamine Organocatalyst 139

4.1 Introduction 139

4.2 Primary-Tertiary Amine Catalysts Derived from Natural Amino Acids 140

4.2.1 Catalyst Design 140

4.2.2 Synthesis of Catalysts 141

4.3 Results and Discussion 143

4.3.1 Catalyst Screening 143

4.3.2 Additives 144

4.3.3 Effects of Solvents 145

4.3.4 Scope of Substrates 146

4.3.5 Preparation of Chiral Lactones with Adjacent Quaternary Centers 149

4.4 Conclusion 150

4.5 Experimental Section 151

4.5.1 Experimental Materials and General Methods 151

4.5.2 Catalyst Synthesis and Characterization 151

4.5.3 Synthesis and Characterization of Reaction Substrates 171

4.5.4 Experimental Procedure for the Aldol Reaction 180

4.5.5 Characterization of Aldol Products 180

4.5.6 Synthesis and Characterization of Chiral Lactones 190

PART II: EXPLORING DNA-CLEAVING ACTIVITIES OF VARACIN B AND VARACIN C 192

Chapter 5 Synthesis, Characterization and DNA-Cleaving Activities of Varacin B and Varacin C 192

5.1 Introduction 192

5.1.1 Varacin Family 192

5.1.2 Varacin B and Varacin C 193

5.1.3 Project Objectives 194

5.2 Results and Discussion 195

5.2.1 Preparation of Varacin B and Varacin C 195

5.2.1.1 Synthetic Route of Varacin B and Varacin C 195

5.2.1.2 UV-Induced Isomerization 197

5.2.1.3 Optimization of UV Irradiated Isomerization 198

5.2.1.3.1 Effects of UV Wavelengths 199

5.2.1.3.2 Effects of Various Solvents 200

5.2.2 DNA-Cleaving Activities of Varacin B and Varacin C 201

5.2.2.1 Acid-Promoted DNA-Cleaving Activities of Varacin B 202

5.2.2.2 Photo-Induced DNA-Cleaving Activities of Varacin B and Varacin C 205 5.3 Conclusion 206 5.4 Experimental Section 207 5.4.1 Experimental Materials and General Methods 207 5.4.2 Synthesis and Characterization of Intermediates, Varacin B and Varacin C 209

Chapter 6 References 216

Appendix: 1 H NMR, 13 C NMR, HPLC Data of Some Selected Examples I

Summary

This thesis comprises two independent projects: the first one is the development

of direct asymmetric organocatalytic aldol reactions that are mediated by primary amino acid-based catalysts The second project focuses on the use of synthetic natural

products varacin B and varacin C salts as potential anti-cancer agents Chapters 1, 2, 3

and 4 are concerned with the first topic, and chapter 5 is related to the second topic Chapter 1 provides a brief historic overview of the development of asymmetric organic catalysts, and some important organocatalysts are illustrated The development of direct asymmetric aldol reactions in the last ten years has also been described in detail

Chapter 2 describes a natural primary amino acid L-tryptophan as an efficient organocatalyst for the direct asymmetric aldol reactions of cyclic ketones and aromatic aldehydes in the presence of water Meanwhile, the DFT calculation of reaction mechanism and the reaction pathway in aqueous media was also investigated Chapter 3 depicts the design and synthesis of some natural primary amino acid analogues derived from L-serine and L-threonine as novel organocatalysts and the investigation of their direct asymmetric aldol reactions in aqueous media The

asymmetric organocatalytic aldol reactions employing tert-butylsiloxyacetone as a

donor offer an easy access to synthetically versatile 1,2-diols compounds Our findings represent a novel application of primary amino acids and their derivatives as organocatalysts organic reactions carried out in aqueous media

Chapter 4 presents novel primary-tertiary diamine organocatalysts derived from

L-serine The asymmetric aldol reactions between acetone and various α-keto esters catalyzed by diamine catalysts were investigated Chiral lactones with adjacent quaternary chiral centers from aldol products were obtained in high yields, and with high diastereoselectivities

In chapter 5, natural products varacin B and varacin C salts were prepared and characterized, and their DNA-cleaving activities under acid-promoted or UV-induced conditions were studied It was found that both varacin B and varacin C displayed good DNA cleavage activities, and such compounds represent promising structural

scaffolds for the future development of anti-cancer therapeutics.

List of Tables

Table 2-1 The aldol reactions catalyzed by primary amino acids and their derivatives

3 3

Table 2-2 The aldol reactions catalyzed by L-tryptophan in different solvents 36

Table 2-3 The aldol reactions catalyzed by L-tryptophan in different equivalents of

water 37

Table 2-4 The influences of the substrates ratio and catalyst loading for the aldol

reactions 38

Table 2-5 Tryptophan-catalysed aldol reactions of various ketones in water 40

Table 2-6 Tryptophan-catalysed aldol reactions in organic solvent 41

Table 2-7 Tryptophan-catalysed aldol reactions of various aldehydes in water 43

Table 2-8 Distribution of tryptophan in mixtures of cyclohexanone/water and

Table 2-11 The mass and ee distribution of tryptophan in different phases 57

Table 2-12 The surfactant influence of tryptophan-catalysed aldol reactions in the

mixture of SDS and water 60

Table 3-1 Catalyst screening for the aldol reactions in the presence of water 88

Table 3-2 Optimization studies on the aldol reactions in the presence of water 89

Table 3-3 Catalyst 3-1a-catalysed the aldol reactions with various aldehydes in the

presence of water 90

Table 3-4 The investigation of the recovery and reused of catalyst 3-1a 92

Table 3-5 The catalyst screening for the aldol reactions of

tert-butyldimethylsiloxyacetone 94

Table 3-6 The influences of the aldol reactions catalyzed by different loadings of

catalyst 3-1b 95 Table 3-7 The water influences of catalyst 3-1b-catalysed aldol reactions 96 Table 3-8 The catalyst 3-1b-catalysed the aldol reactions of various ketones 99 Table 3-9 The catalyst 3-1b-catalysed the aldol reactions of various aldehydes 99 Table 3-10 The desilylation methods of aldol product 3-19a 101

Table 3-11 The aldol reactions catalyzed by catalyst 3-1a with various ee values in the

presence of water 102

Table 3-12 The aldol reactions catalyzed by catalyst 3-1b with various ee values in

the presence of water 104

Table 4-1 Aldol-type reactions catalyzed by various catalysts 143 Table 4-2 The influences of various additives for the aldol-type reactions 145

Table 4-3 The influences of catalyst 4-7c-catalysed the aldol-type reactions in

different organic solvents 146

Table 4-4 Catalyst 4-7c-catalysed the aldol-type reactions of various ketone

List of Schemes

Scheme 1-1 Several representative organocatalysts 3

Scheme 1-2 Enamine catalysis of nucleophilic addition (left) and substitution

(right) reaction 5

Scheme 1-3 The iminium catalytic cycle 6

Scheme 1-4 Indirect aldol reaction and direct aldol reaction 8

Scheme 1-5 Models of action in proline-catalysis 9

Scheme 1-6 Hajos-Parrish-Eder-Sauer-Wiechert-reactions 10

Scheme 1-7 L-Proline-catalysed aldol reactions of acyclic ketones and various aldehydes 10

Scheme 1-8 L-Proline-catalysed aldol reactions of α-functionalized ketones 11

Scheme 1-9 L-Proline-catalysed aldol reactions of cyclohexanone 12

Scheme 1-10 Selected L-proline derivatives as organocatalysts 13

Scheme 1-11 L-Proline amide-catalysed aldol reactions 13

Scheme 1-12 L-Proline and primary amino acid-mediated enamine catalytic cycles 16 Scheme 1-13 Primary amino acids as organocatalysts for Robinson-type annulation 1 7 Scheme 1-14 Primary amino acid-promoted Robinson-type annulations 18

Scheme 1-15 Selected organocatalysts for aldol reactions 19

Scheme 1-16 L-Alanine-catalysed intermolecular aldol reactions 20

Scheme 2-1 Organocatalysts examined in this study 31

Scheme 2-2 Synthetic route to prepare L-tryptophan derivatives 32

Scheme 2-3 The main aldol products obtained in Table 2-5 and Table 2-6 45

Scheme 2-4 Balance of imine and enamine 58

Scheme 3-1 Catalysts used in our study 85

Scheme 3-2 Synthesis of L-threonine derivatives and L-serine derivatives 86

Scheme 3-3 Synthesis of catalyst 3-3a-d 86

Scheme 3-4 Synthesis of catalysts 3-4a and 3-4b 87

Scheme 3-5 Synthesis of syn-1,2-diols 2-25 101

Scheme 4-1 Several diamine organocatalysts for aldol reaction 140

Scheme 4-2 Organocatalysts designed in this chapter 141

Scheme 4-3 Synthetic route for catalysts 4-7a-d, 4-8a-b and 4-9a-c 142

Scheme 4-4 Synthesis of 2-hydroxy-γ-butyrolactones 150

Scheme 5-1 Structures of varacin, varacin A, varacin B and varacin C 193

Scheme 5-2 Proposed mechanism of DNA cleavage by varacin C 194

Scheme 5-3 Synthesis of varacin B and varacin C 196

Scheme 5-4 Oxidation of the trithioles 197

Scheme 5-5 Plausible mechanism for the rearrangement from 5-13 to 5-14 198

Scheme 5-6 The conversion of circular supercoiled DNA 201

Figure 2-3 Schematic diagram of the structures and energies of species involved in

the formation of the (S,R) enantiomeric product 52

Figure 2-4 Plot of tryptophan ee versus product ee for the aldol reactions in water 55

Figure 2-5 Plot of tryptophan ee versus product ee for the aldol reactions in DMSO

5 6

Figure 2-6 ESI-MS spectrum from the aqueous phase 58

Figure 3-1 Plot of catalyst 3-1a ee versus product ee for the aldol reactions in water

103

Figure 3-2 The linear effect in the L-threonine derivative catalyzed aldol reaction of

tert-butyldimethylsiloxyacetone with p-nitrobenzaldehyde in water 105

Figure 3-3 Proposed transition state model 106

Figure 5-1 Acid-promoted DNA cleavage by varacin B in sodium phosphate buffer

solutions at various pH values 203

Figure 5-2 Acid-promoted DNA cleavage by various concentrations of varacin B 204

Figure 5-3 Activation of varacin B-promoted DNA cleavage by various nucleophiles

205

Figure 5-4 Photo-induced DNA cleavage by varacin B or varacin C 206

Cbz benzyloxycarbonyl

EA ethyl acetate

IPA isopropanol

q quartet

List of Publications

Journal Articles:

1．Zhaoqin Jiang, Zhian Liang, Xiaoyu Wu, and Yixin Lu* “Asymmetric Aldol

Reactions Catalyzed by Tryptophan in Water” Chem Commun 2006, 2801-2803

2．Xiaoyu Wu, Zhaoqin Jiang (co-first author), Han-Ming Shen, and Yixin Lu*

“Highly Efficient Threonine-Derived Organocatalysts for Direct Asymmetric

Aldol Reactions in Water” Adv Synth Catal 2007, 349, 812-816

3．Zhaoqin Jiang, Hui Yang, Xiao Han, Jie Luo, Ming Wah Wong*, and Yixin Lu*

“Direct Asymmetric Aldol Reactions between Aldehydes and Ketones Catalyzed

by L-Tryptophan in the Presence of Water” Org Biomol Chem 2010, DOI:

10.1039/B921460G

4．Zhaoqin Jiang and Yixin Lu, “Direct asymmetric aldol reaction of acetone with α-ketoesters catalyzed by primary–tertiary diamine organocatalysts” (submitted to

Tetrahedron Letters)

5．Zhaoqin Jiang, Jie Luo, and Yixin Lu* “Asymmetric Aldol Reactions Catalyzed

by Tryptophan in Aqueous Phase: How Do Reactions Take Place?” (manuscript in preparation)

6．Zhaoqin Jiang, Yifan Wang, Tianhu Li*, and Yixin Lu* “Acid-promoted DNA Cleavage Activities of Varacin B” (manuscript in preparation)

7．Zhaoqin Jiang, Xiaoyu Wu and Yixin Lu* “Direct Asymmetric Aldol Reactions Promoted by Threonine and its Derivatives in Aqueous Media” (manuscript in preparation)

Conferences and Posters:

1 Lili Cheng, Zhaoqin Jiang, Xiaoyu Wu and Yixin Lu* “Highly Enantioselective Organic Reactions Promoted by Primary Amino Acid-derivatived

Organocatalysts” invited lecture, Japan-Singapore Bilateral Symposium on

Catalysis, National University of Singapore (NUS), Singapore, January 07 - 08,

(ISCOC-6), Grand Copthorne Waterfront Hotel, Singapore, December 18 - 21,

2006

3 Zhaoqin Jiang, Zhian Liang, Xiaoyu Wu and Yixin Lu* “The Direct Asymmetric

Aldol Reactions Catalyzed by Tryptophan in Water” invited lecture, 9 th International Symposium by Chinese Organic Chemists (ISCOC-9) & 6 th International Symposium by Chinese Inorganic Chemists (ISCOC-6), Grand

Copthorne Waterfront Hotel, Singapore, December 18 - 21, 2006

4 Lili Cheng, Zhaoqin Jiang, Xiaoyu Wu and Yixin Lu* “Environmentally benign

organocatalysis in water”, invited lecture, The third International Conference on Energy and Environment Materials, ICEEM-2006, Guangzhou, P R China,

December 8 - 10, 2006.

PART I: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL REACTIONS MEDIATED BY PRIMARY AMINO ACID-DERIVED ORGANOCATALYSTS

Chapter 1 Introduction and Literature Surevy

1.1 Asymmetric Synthesis

The enantioselective production of chiral molecules is of fundamental importance for a sustainable modern society The wide applications of synthetic chiral chemicals as single-enantiomer pharmaceuticals, in electronic and optical devices, as components in polymers or semiconductors with novel properties and as probes of biological and physical functions, have made asymmetric catalysis a predominant area

of current scientific research.1 Chiral molecules represent close to one third of all drugs sold worldwide, and production of chiral pharmaceuticals has become an intensively investigated research area.2 The FDA has more rigorous regulatory controls of enantiomeric composition of drug candidates, and it is well established that optically pure drugs can provide better therapeutic effects over the racemic mixture of drug candidates.3,4

Molecular chirality is a principal element in nature that plays a crucial role in science and technology.5 Discovery of truly efficient methods for obtaining chiral substances is a great challenge for synthetic chemists Asymmetric catalysis is an

ideal method for synthesizing optically active compounds.6-8 Various chemical approaches, which typically make use of a catalytic amount of transition metal complexes, enzymes, or small chiral organic molecules as efficient asymmetric catalysts, can produce naturally and non-naturally occurring chiral materials in large quantities Enantioselective synthesis9 is defined as the transformation of achiral substances into optically enriched molecules, mainly through the use of chiral catalysts, solvents, and reagents.10 Recent developments in this area are turning chemists’ dreams, which is the discovery of truly efficient methods of obtaining chiral substances, into reality at both academic and industrial levels

1.2 Asymmetric Organocatalysis

1.2.1 Introduction

The man-made catalysts that play an important role in catalyzed reactions mainly comprise organometallic catalysts and organocatalysts Just as its name implies, an organometallic catalyst is a transition metal complex, which often requires a chiral ligand to render high stereochemical control The transition metals are usually toxic, expensive, and the transition metal-based catalysts are typically unstable to moisture and air and the chiral products produced suffer from possible contamination by the toxic metals On the other hand, an organocatalyst is an organic compound which exhibits catalytic activities The use of organocatalysts would not induce contamination, a disadvantage inherent in the transition metal-based catalysis

Organocatalytic reactions could be traced to a venerable history because there is evidence that such catalysis played a crucial role in the formation of prebiotic key building blocks, such as sugars, thus allowing the introduction and spread of homochirality in living organism.11

The past few years have witnessed a spectacular advancement in new catalytic methods based on organic molecules A huge number of chemical reactions, such as aldol reactions1,3,4,12, Mannich reactions13-15, Baylis-Hillman reactions16, Michael addition reactions17,18, Stetter reactions19,20, Diels-Alder reactions8,21 and epoxidation22,23 among others, can be performed asymmetrically in the presence of a catalytic amount of small organic molecules.1,3,4,16c,21e Moreover, the scope of organocatalysts has expanded considerably, including the C2-symmetric cinchona alkaloid derivatives24-27, DMAP derivatives28,29, imidazole derivatives30,31, proline derivatives32, thiourea derivatives33-35 and phase-transfer catalysis36 Some selective organic catalysts are illustrated in Scheme 1-1

N

N

NH2H OMe

N

N OH H

OMe

N

N NH H OMe

S N H

quinine (1-1) epi-Q-NH2 (1-2) quinidine derivatives (1-3)

N

H H

Ph Ph

Me2N

chiral DMAP derivative (1-6)

Ar

Ar OTMS N

The advantages of organocatalysts are notable: they are usually robust, inexpensive, readily available, and non-toxic Because of their inertness to moisture and oxygen, demanding reaction conditions are usually not required in many cases Furthermore, these organocatalysts can be anchored to a solid support and reused more conveniently than organometallic/bioorganic analogues, showing promising adaptability to high-throughput screening and process chemistry

Organocatalysts can catalyze chemical reactions through four main mechanisms:3,4 (a) Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst The chiral catalyst is not consumed in the reaction and does not require parallel regeneration; (b) Organic molecules that form reactive intermediates The chiral catalyst is consumed in the reaction and requires regeneration in a parallel catalytic cycle; (c) Phase-transfer reactions The chiral catalyst forms a host-guest complex with the substrate and shuttles between the standard organic solvent and a second phase; (d) Molecular-cavity accelerated asymmetric transformations, in which the catalyst may select between the competing substrates, depending on size and structure criteria

1.2.2 Enamine Catalysis and Iminium Catalysis

The vast majority of organocatalytic reactions are amine-based reactions.37 In asymmetric amino catalysis, amino acids, peptides, alkaloids, and synthetic nitrogen-containing molecules are used as chiral catalysts Most of these reactions

proceed by the generalized enamine cycle or as charge-accelerated reactions through the formation of iminium intermediates

The catalytic mechanism of enamine catalysis38-40 is shown in Scheme 1-2

Accordingly, the enamine, which is generated from a carbonyl compound via iminium

ion formation, as an activated nucleophile, can react with an electrophile X=Y (or

X-Y) via nucleophilic addition (or substitution) to form α-modified iminium ion

intermediate The desired product (and HY) is finally obtained after hydrolysis

R

O

R'

R N

R'

R N

R' R

R'

R R'

- H 2 O

- H + H

R N

R' N

R N

R'

Y

R R'

+ H 2 O + H Y

enamine intermediate

enamine intermediate

α-modified iminium ion α-modified iminium ion

Y

X

Scheme 1-2 Enamine catalysis of nucleophilic addition (left) and substitution (right) reaction

Enamine catalysis using proline or related catalysts has been applied to both intermolecular and intramolecular addition reactions with various electrophiles These electrophiles include carbonyl compounds (C=O) in aldol reactions,41 imines (C=N)

in Mannich reactions,42 diazocarboxylates (N=N) in α-aminations,43,44 nitrosobenzene (O=N) in α-aminooxylation45 and Michael acceptors (C=C) in conjugated additions, among others.46

The iminium catalytic cycle for nucleophilic addition39,47 is presented in Scheme 1-3 Initially, the α,β-unsaturated aldehyde reacts with the related catalyst to form the

iminium ion Conjugated addition of a nucleophile with the new electrophile HX then gives an enamine intermediate, which yields the final product after hydrolysis

H

O

H N

H

N N

R Nu HX

H N

R Nu

X H

O

Nu R

X

enamine intermediate iminium ion

*

Scheme 1-3 The iminium catalytic cycle

Since the first example of iminium catalysis was reported by MacMillan et al in

2000,48 the same group has quickly established that chiral amino acids derived imidazolidinones could effectively catalyze Diels-Alder reactions,49,50 1,3-diploar cycloadditions,51 and conjugated additions52 (1-8 and 1-9 in Scheme 1-1) In addition,

highly enantioselective epoxidations,53 cyclopropanations,54 and conjugate reductions were also developed recently.55,56 Like enamine catalysis, the field of iminium catalysis has become a flourishing research area

Enamine and iminium catalysis are two distinct reaction modes in organocatalysis In iminium catalysis, carbonyl compounds are activated by lowering the LUMO energy of the system, making them more susceptible to nucleophilic attack

In enamine catalysis, on the other hand, carbonyl compounds are converted into the more nucleophilic enamines, a transformation that increases the HOMO of

nucleophiles The enamine and iminium catalysis are closely related Enamine

catalysis proceeds via iminium ion formation and always results in iminium ion

formation, while iminium catalysis proceeds in an opposite but complementary fashion and typically results in the formation of an enamine intermediate Such complementarity of both activation modes has found wide applications in organocatalytic tandem reactions

1.3 Direct Asymmetric Aldol Reactions Catalyzed by Proline and its Derivatives

Although Kane previously described the known aldol condensation,57 the aldol reaction was firstly discovered by Wurtz in 1872.58 The aldol reaction could be catalyzed either under basic or acidic conditions.59 One or more stereogenic centers can be created in addition to new C-C bond formation For this reason, this asymmetric transformation has been chosen historically as a proof of the efficiency of new methodology.60

Asymmetric aldol reactions can be performed indirectly and directly, depending

on which nucleophilic form is used.4 The indirect aldol reaction requires a modified ketone such as an activated enolate, whereas the direct aldol reaction involves a ketone in a non-activated form as nucleophile (Scheme 1-4) Denmark et al have successfully applied phosphoramides as catalyst to the indirect asymmetric aldol reaction.60a Later, the Cinchona alkaloid-based ammonium salt and carbocation were

also proven to be excellent catalysts.61,62

R2

R1OSi(R4)3

R2

H R3O

R1O

R2

R3

OH Catalyst

R2

R3

OH

* *+

unmodified ketone

Scheme 1-4 Indirect aldol reaction and direct aldol reaction

A milestone in the area of asymmetric organocatalysis came in the 1970s The ability of proline to catalyze the direct aldol reaction was discovered in two industrial groups.63,64 Surprisingly, the catalytic potential of proline in asymmetric aldol reaction was not explored further In 2000, List, Barbas and Lerner demonstrated that asymmetric aldol reaction can be catalyzed by L-proline and its structural analogues for branched aliphatic aldehydes with moderate-to-excellent enantioselectivities.41 In the past few years, a huge number of enantioselective organocatalytic aldol reactions appeared.12e,38-40,65-72 In this literature survey, we will mainly focus on the direct asymmetric aldol reaction catalyzed by secondary or primary amino acids and their

analogues via the enamine mechanism Some other organocatalysts, such as cinchona

alkaloid derivatives and phase-transfer catalysis are not covered

1.3.1 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline

1.3.1.1 Introduction

There are several reasons why L-proline has become the best and most versatile

organocatalyst to date First, proline is an abundant chiral molecule that is inexpensive and available in both enantiomeric forms It is believed that the remarkable catalytic efficiency of proline is due to its unique molecular structure – five-membered pyrrolidine ring and its bifunctionality (Scheme 1-5) The two functional groups, the carboxylic acid and the amine portion in each molecule, can both act as an acid or base and facilitate chemical transformations in a cooperative manner, similar to enzymatic catalysis Proline’s unique nucleophilic reactivity is primarily a consequence of the pyrrolidine portion, which forms iminium ions and enamines with carbonyl compounds more readily than most other amines, including cyclic ones such

as piperidine.73 The carboxylate further contributes to proline’s amino catalysis by acting as a general Brønsted cocatalyst

N H

COOH

N

COO

N COOH

Bifunctional Acid/Base Catalysis

Iminium Catalysis

R Enamine Catalysis

Scheme 1-5 Models of action in proline-catalysis

1.3.1.2 Intramolecular Aldol Reactions

The first example of using proline in the enantioselective intramolecular aldol reaction (Robinson-type annulation) was a crucial event in the history of organocatalysis.74,75L-Proline 1-10 efficiently promoted an direct intramolecular aldol reaction, such as 1-12 and 1-15 to give aldols 1-14 and Wieland-Miescher ketone 1-17

(WMK) in good yields and with excellent ee values (Scheme 1-6).64,75 Enantiopure Wieland-Miescher ketone has proven to be a particularly useful synthon for the construction of various biologically active compounds including steroids, terpenes, and taxol.76-79 Several similar asymmetric intramolecular aldol reactions of diketones80-83 or triketones84-89 were reported following the initial report

1.3.1.3 Intermolecular Aldol Reactions

In 2000, List, Barbas and Lerner reported the pioneering study on the L-proline- catalysed intermolecular aldol reaction.41,90,91 The reaction of acetone 1-11a (R1, R2 =

H) and different aromatic aldehydes afforded the desired aldol products 1-19 in good

yields and with good ee values in DMSO (Scheme 1-7) In the following years, synthetic applications of the proline-catalysed aldol reactions of acyclic alkyl ketones and aldehydes were heavily investigated.92-120

The use of α-functionalized ketones as nucleophiles has permitted access to chiral compounds of high interest List and co-workers elegantly demonstrated that

α-hydroxyacetone 1-20a effectively served as a donor to afford anti-1,2-diols 1-21

with excellent enantioselectivity (Scheme 1-8),121 which represented the first catalytic

asymmetric synthesis of anti-1,2-diols and complements the asymmetric

dihydroxylation developed by Sharpless et al.122 Using the same conditions,

tert-butyl(dimethyl)silyloxyacetone 1-20b (X = OTBS) reacted with aromatic aldehydes affording as main product anti-1-21 with good enantioselectivities.123Similar enantioselectivities of the main products iso-1-22 were obtained when

α-substituted-α,β-unsaturated aldehydes were used A mixture of two isomers 1-21 were obtained when α-fluoroacetone 1-20d and α-chloroacetone 1-20e were used as a

O

R OH X

O

R

X

O OH +

+

Scheme 1-8 L -Proline-catalysed the aldol reactions of α-functionalized ketones

The aldol reactions between cyclohexanone and aldehydes were also examined Low yields and high enantioselectivities were obtained for the reaction of aqueous

formaldehyde with cyclohexanone catalyzed by 1-10 (Scheme 1-9).125 The use of a ball-milling technique facilitated this reaction, reducing the reaction time from days to hours and increasing the enantioselectivity in some cases.104,106 Moreover, the

addition of a small amount of water was found to have a beneficial effect.126

O

R

1-10 (10-30 mol%)

O OH R

O OH R + +

O H

1-23

Solvent, rt

Scheme 1-9 L -Proline-catalysed the aldol reactions of cyclohexanone

1.3.2 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline Derivatives

Although proline is effective, it is not perfect Thus a large number of proline derivatives have been investigated as new organocatalysts These proline analogues aimed mainly to overcome problems associated with proline catalysis, such as limited solvent compatibility, high catalyst loading, longer reaction time and low stereoselectivities in certain cases They can be classified as the following: (1) prolinamide derivatives; (2) prolinamine derivatives; (3) proline sulfonimide derivatives; (4) proline peptide derivatives; (5) 4-hydroxyproline derivatives; (6) pyrrolidine derivatives Several selected organocatalysts are shown in Scheme 1-10 The application of the above six types of catalysts in organocatalytic asymmetric aldol reactions will be selectively described

COOEt OH

COOEt O

NH

N H HN

O NH

O

H N

1-34

N

H

Ph HN

1-30

F3C O

N H

1-36

N H

HN SO2CF3

1-32

N H

TBDPSO

O

N H

O OH O

HO

1-35 Scheme 1-10 Selected L -proline derivatives as organocatalysts

The catalytic activity of the proline amide-type catalysts may be improved by

introducing another chiral moiety into the catalyst For example, catalyst 1-27 was

introduced by Gong et al, for the aldol reaction between p-nitrobenzaldehyde and

ketones.127-130 The presence of only 2 mol% of 1-27 allowed the formation of the

corresponding β-hydroxyketones with very high enantioselectivity Moreover, similar catalysts could be employed in ionic liquids, yielding aldol products with up to 99%

96-99% ee

R1 = Me or H

Scheme 1-11 L -Proline amide-catalysed aldol reactions

The bisprolinamide derived from 1,1’-binaphthyl-2,2’-dimine (BINAM) 1-28 was a very efficient catalyst for the aldol reaction of α-(alkoxy) acetones 1-20 or

cyclohexanone 1-23 and aldehydes, affording the corresponding major anti- aldol

products with good stereoselectivity.132-136 Moreover, the catalytic system could be recycled and reused three times without much decrease in chemical yield and enantioselectivity.133

Proline sulfonimide derivative 1-33137,138 and silyloxyproline derivative 1-34139

have been shown to be very efficient for the aldol reaction between cyclic ketones and

aldehydes In addition, the pyrrolidine-2-yl-1H-tetrazole catalyst 1-36, widely

employed in the literature, has been found to be significantly more reactive and more stereoselective in some cases than proline in various aldol reactions.32g,140,141

The reaction of acyclic ketones (1-11 and 1-20) and cyclic ketones catalyzed by

the C2-symmetric (2S,5S)-pyrrolidine-2,5-dicarboxylic acid 1-35 and triethylamine,

gave the corresponding products with moderate results.142 Surprisingly, the use of

cyclohexanone as the source of nucleophile yielded syn- product as the main product,

albeit the diastereoselectivity was low

1.4 Direct Asymmetric Aldol Reactions Catalyzed by Primary Amino Acids and their Derivatives as Organocatalysts

1.4.1 Primary versus Secondary Amino Acids in Intermolecular Aldol

Reactions: Mechanistic Considerations

In modern organocatalysis, the use of chiral secondary amines has proven to be

an extremely powerful approach, and dominated the realm of amino catalysis early on There have been many organocatalysts containing the pyrrolidine core that were widely used in either enamine catalysis or iminium activation However, the use of primary amino acid-mediated enamine catalysis is rather infrequent It was found that primary amino acids, such as valine and phenylalanine, were poor catalysts for aldol reactions under the reaction conditions investigated, according to the initial report by List and Barbas41,91 on proline-catalysed direct intermolecular asymmetric aldol reactions This seems to be reasonable as it is well accepted that a secondary enamine

is better stabilized than its primary counterpart by hyperconjugation However, in fact, primary amines were good catalysts in the intramolecular aldol reactions It was implied that effective formation of the enamine from a primary amine is feasible The proline and primary amino acid-mediated enamine catalytic cycles are compared in Scheme 1-12 It was recognized that a secondary enamine is better stable because of hyperconjugation, whereas a primary amine gives the predominant imine form Since primary amino acids serve as efficient catalysts in enamine catalysis,

effective tautomerization of their imine form a’ to the enamine form b’ is absolutely

essential A few recent reports143-147 demonstrated that primary amine-based enamines could be effectively generated, suggesting the potential use of primary amines in

enamine catalysis In addition, the presence of an extra N–H in the enamine b’

intermediate derived from the primary amino group may facilitate the control of the enamine structure, and direct the reaction to occur with specific reactivity and

selectivity, which may not be attainable via proline catalysis Moreover, the ready

availability of a number of natural amino acids offers great flexibility in structural modified for the design of chiral organocatalysts All these factors combined make primary amino acids interesting and promising catalysts in organocatalysis

-H2O

H N

R1+

a'

H N

R1RCHO

H

N COOH

R1 R2R HO

H2O

COOH R'

NH2 H

+

-H +

R2COOH R'

R2COOH R'

H + +

+

R' -H +

Primary amino acid-catalyzed aldol reaction Proline-catalyzed aldol reaction

Scheme 1-12 L -Proline and primary amino acid-mediated enamine catalytic cycles Despite the great success with pyrrolidine-containing chiral catalyst, other catalysts have also been investigated in the aldol reaction, achieving better results in some It was not until 2004/2005 when primary amino acids were reinvestigated and established as effective organocatalysts in asymmetric catalysis Recently, many exciting discoveries have been made in chiral primary amine-catalysed asymmetric

1.4.2 Intramolecular Aldol Reactions

Shortly after the enantioselective synthesis of bicyclic diketones 1-14 and 1-17

was reported by two industrial research groups in 1970s,74,75 it was reported that

ent-1-14 could be obtained with 83% ee by employing β-amino acid 1-38 as

catalyst.150 Following these findings, other β-amino acids, (1R,2S)-cis-pentacin 1-37,

β3-homophenylalanine 1-38 and β-homoleucine 1-39 were found to be good catalysts

for this annulation process (Scheme 1-6).151,152

H 2 N OH

O OH

O

NH2

H2N

OH O

Ph

H2N OH

O Ph

Scheme 1-13 Primary amino acids as Organocatalysts for Robinson-type annulation

The synthesis of Wieland-Miescher ketone (WMK) analogues 1-42a, 1-42b and 1-42c were investigated by employing either α- or β-primary amino acids as the

catalysts (Scheme 1-14) From a set of 15 different α-amino acids, (S)-phenylalanine

1-40 emerged as the best catalyst to promote the cyclization of triketone 1-41a,

affording the bicyclic compound ent-1-42a in moderate yield and with good enantiomeric excess, and the seven-membered ring ent-1-42b in good yield and with

modest enantioselectivity.153 Ketone ent-1-42a has been also prepared in good yield

and with good enantioselectivity by using amino acids 1-38154 and ent-1-40155 The other Wieland-Miescher ketone analogues bearing an angular protected hydroxymethyl group have been successfully synthesized by using either catalyst

ent-1-40 or 1-38.156-158

O R O

O n

R O

n O

Solvent, HClO4 or CSA

up to 91% ee

Scheme 1-14 Primary amino acid-promoted Robinson-type annulations

1.4.3 Intermolecular Aldol Reactions

Although it was shown in List’s initial report41,91 that primary and acyclic secondary aliphatic α-amino acids failed to catalyze the intermolecular aldol reaction, this concept was recently challenged by Pizzarello and Weber.11 They showed that alanine and isovaline could catalyze aldol condensations of glycoaldehyde in water to produce tetroses The results of this study indicate that it has prebiotic plausibility,

albeit the enantioselectivity was very low (ca 10% ee for threose, 5.4% ee for

erythrose) Subsequently, a number of primary amino acids and their derivatives have been investigated as catalysts for the asymmetric aldol reactions Some selective

primary amino acids or peptides with primary amino groups at the N-terminal as

organocatalysts are listed in Scheme 1-15