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

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



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
(M.Sc., Soochow Univ.)



A THESIS SUBMITTED FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY OF SCIENCE

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

2009

PhD Thesis Jiang Zhaoqin
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
my life.
I am deeply grateful to our collaborators, Prof. Li Tianhu and his group members
from our Department of Chemistry, NTU, for their assistance in the biological tests
of our synthetic compounds. I also wish to thank Prof. Wong Ming Wah and his

group members from Department of Chemistry, NUS, for their computational
calculations of our experimental findings.
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.
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PhD Thesis Jiang Zhaoqin
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
REACTIONS MEDIATED BY PRIMARY AMINO
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
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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
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

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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
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.
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PhD Thesis Jiang Zhaoqin
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.
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PhD Thesis Jiang Zhaoqin
List of Tables

Table 2-1 The aldol reactions catalyzed by primary amino acids and their derivatives
33

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
cyclohexanone/brine 53

Table 2-9 The aldol reactions catalyzed by tryptophan with various ee values in the
presence of water 54

Table 2-10 The aldol reactions catalyzed by tryptophan with various ee values in
DMSO 55

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

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PhD Thesis Jiang Zhaoqin
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
acceptors 147

Tabl e 5-1 The influences of different UV wavelengths for this isomerization in
CD
3
CN 199

Table 5-2 The influences of different solvents for this isomerization under 300 nm
irradiation 200
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PhD Thesis Jiang Zhaoqin
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
17
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

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PhD Thesis Jiang Zhaoqin
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
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PhD Thesis Jiang Zhaoqin
List of Figures

Figure 2-1 Optimized geometries of the two lowest-energy conformations of enamine
48

Figure 2-2 Optimized geometries of the four transition states leading to the formation
of (S,R), (S,S), (R,S), (R,R) enantiomeric products 51

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
56

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
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PhD Thesis Jiang Zhaoqin
List of Abbreviations

BINAM 1,1’-binaphthyl-2,2’-dimine
Boc tert-butoxycarbonyl
Bn benzyl
br broad
CAM ceric ammonium molybdate
CAN ceric ammonium nitrate
Cbz benzyloxycarbonyl
C-C bond carbon-carbon bond

CMC critical micelle concentration
D-A reaction Diels-Alder reaction
DCC Dicyclohexyl carbodiimide
DCM dichloromethane
DFT density functional theory
DMAP dimethylaminopyridine
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
d doublet
DNA deoxyribonucleic acid
dr diastereomeric ratio
- xvi -
PhD Thesis Jiang Zhaoqin
EA ethyl acetate
ee enantiomeric excesses
FDA Food and Drug Administration
HOMO highest occupied molecular orbital
HPLC high performance liquid chromatography
HRMS high resolution mass spectra
IPA isopropanol
IRC intrinsic reaction coordinate
LRMS low resolution mass spectra
LUMO lowest unoccupied molecular orbital
m multiplet
MP melting point
mL milliliter
NBO natural bond orbital
NMP N-methylpyrrolidone
NMR nuclear magnetic resonance

PCM polarizable continuum model
PMA phosphomolybdic acid
ppm part per million
PTC phase-transfer catalysis
q quartet
SDS sodium dodecyl sulfate
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PhD Thesis Jiang Zhaoqin
s singlet
TBAF tetra-butyl ammonium fluoride
TBDMS(TBS) tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
TLC thin-layer chromatography
TMS tetramethylsilane
t triplet
Ts toluenesulfonyl
ts transition state
WMK Wieland-Miescher ketone
ZPE zero-point energies
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PhD Thesis Jiang Zhaoqin
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,
2008.

2.
Zhaoqin Jiang, Lili Cheng, Xiaoyu Wu and Yixin Lu*. “Highly enantioselective
organic transformations promoted by hydrophobic organocatalysts in water”,
invited lecture, 9
th
International Symposium byr Chinese Organic Chemists
(ISCOC-9) & 6
th
International Symposium by Chinese Inorganic Chemists
- xix -
PhD Thesis Jiang Zhaoqin
(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.
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PhD Thesis Jiang Zhaoqin
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
- 1 -
PhD Thesis Jiang Zhaoqin
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 synthesis
9
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.
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PhD Thesis Jiang Zhaoqin
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 reactions
1,3,4,12
, Mannich reactions
13-15
, Baylis-Hillman reactions
16
,

Michael
addition reactions
17,18
, Stetter reactions
19,20
, Diels-Alder reactions
8,21
and
epoxidation
22,23
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 C
2
-symmetric cinchona
alkaloid derivatives
24-27
, DMAP derivatives
28,29
, imidazole derivatives
30,31
, proline
derivatives
32
, thiourea derivatives
33-35
and phase-transfer catalysis
36
. Some selective
organic catalysts are illustrated in Scheme 1-1.
N
N
NH
2
H
OMe
N
N
OH

H
OMe
N
N
NH
H
OMe
S N
H
quinine (1-1)
epi-Q-NH
2
(1-2)
quinidine derivatives (1-3)
N
H
H
N
H
O
Br
cinchonidine-derived phase-
transfer catalyst (1-5)
N
Fe
Ph
Ph
Ph
PhPh
Me

2
N
chiral DMAP derivative (1-6)
Ar
Ar
OTMS
N
H
prolinal derivative (1-4)
N
N
imidazole derivative (1-7)
N
N
H
O Me
oxazolidinone (1-8)
oxazolidinone (1-9)
Ph
N
N
H
O Me
Ph
CF
3
CF
3

Scheme 1-1 Several representative organocatalysts

- 3 -