Guanidine catalyzed enantioselective desymmetrization of meso aziridines 1

Table of Contents Summary List of Schemes List of Tables List of Figures List of Abbreviations Chapter 1 Catalytic Asymmetric Ring Opening of meso-Aziridines 1.1 Metal catalyzed

Table of Contents Summary

List of Schemes

List of Tables

List of Figures

List of Abbreviations

Chapter 1

Catalytic Asymmetric Ring Opening of meso-Aziridines

1.1 Metal catalyzed asymmetric ring opening of meso-aziridines - 3 1.2 Organocatalytic asymmetric ring opening of meso-aziridines - 11

1.3 Conclusion - 19

Chapter 2

Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with

Thiols

2.1 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso N-tosyl

aziridines with thiols - 24 2.2 Synthesis of novel chiral guanidines - 36

2.3 Guanidine catalyzed enantioselective desymmetrization of meso N-acyl

aziridines with thiols - 40

2.4 Guanidine catalyzed enantioselective desymmetrization of cis-aziridine-2,3-

dicarboxylates with thiols - 48 2.5 Conclusion - 53

Chapter 3

Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with

Carbamodithioic Acids

3.1 Introduction - 60

3.2 Guanidine catalyzed enantioselective desymmetrization of meso-aziridines with

in situ generated carbamodithioic acids - 64

3.3 Synthesis of chiral β-amino sulfonic acid - 69

3.4 Conclusion - 71

Chapter 4 Experimental 4.1 General Procedures - 76

4.2 Preparation of the aminoindanol derived guanidines - 77

4.3 Desymmetrization of meso N-acyl aziridines with thiols - 80

4.4 Preparation of chiral allylic amide - 90

4.5 Preparation and desymmetrization of cis-aziridine-2,3-dicaboxylates - 92

4.6 Desymmetrization of meso N-acyl aziridines with carbamodithioic acids - 99

4.7 Preparation of chiral β-amino sulfonic acid - 107

4.8 X-ray crystallographic analysis - 109

Appendix Ⅰ Chapter 5 Enantioselective Catalytic Intramolecular Michael Additions: Asymmetric Synthesis of Chiral γ-Lactones 5.1 Introduction - 116

5.2 Synthesis of substrates - 118

5.3 TBD catalyzed intramolecular Michael Additions - 118

5.4 Cinchona alkaloids catalyzed intramolecular Michael Additions - 120

5.5 Conclusion - 123

5.6 Experimental - 124

Appendix Ⅱ Copies of NMR Spectrum - 141

Publications - 179

Summary

The aim of this study is to develop highly enantioselective desymmetrization of

meso-aziridines using chiral guanidines as catalysts

Chiral guanidine 79b was easily synthesized in two steps from commercially

available (1R,2R)-1-amino-2-indanol It was found to be an efficient Brønsted base catalyst for the enantioselective desymmetrization of meso N-acyl aziridines with

benzenethiols High yields (90-94%) and enantioselectivities (88-95% ee) were achieved The enantiopure 1,2-difunctionalized products obtained can be used to generate chiral allylic amides via simple transformations Desymmetrization of

cis-N-tosyl-aziridine-2,3-dicarboxylates with arenethiols was also developed as a

direct synthetic approach towards β-substituted aspartates, with ees up to 90%

The nucleophile scope of the chiral guanidine catalyzed desymmetrization of

meso-aziridines was expanded to include carbamodithioic acid, which was generated

in situ from an amine and CS2 Moderate to high yields (up to 98%) and good enantioselectivities (up to 90% ee) were also achieved The optical purity of the ring-opened products could be enhanced to excellent ee values (up to 99%) after a single recrystallization This is the first time on the use of carbamodithioic acid as a nucleophile in the asymmetric ring opening of aziridines The methodology also provided a novel and practical protocol for the synthesis of enantiomerically enriched β-amino sulfonic acids

List of Schemes

Scheme 1.1 Catalytic asymmetric ring opening of aziridines

Scheme 1.2 Et2Zn-dialkyl tartrate complex promoted asymmetric ring opening

of meso-aziridines with thiols developed by Oguni and co-workers

Scheme 1.3 Copper-catalyzed desymmetrization of meso N-Ts aziridine 4a with

MeMgBr developed by Müller and co-workers

Scheme 1.4 Chromium-catalyzed desymmetrization of meso-aziridines with

Scheme 1.5 Proposed mechanism of gadolinium-catalyzed desymmetrization of

meso-aziridines with TMSCN

Scheme 1.6 Gadolinium-catalyzed desymmetrization of meso-aziridines with

TMSCN developed by Shibasaki and co-workers

Scheme 1.7 Yttrium-catalyzed desymmetrization of meso-aziridines with

Scheme 1.8 Desymmetrization of meso-aziridines with TMSCN catalyzed by

Gd complexes derived from ligand 14 and 15 developed by

Shibasaki and co-workers

Scheme 1.9 Niobium-catalyzed desymmetrization of meso-aziridines with

aniline developed by Kobayashi and co-workers

Scheme 1.10 Yttrium-catalyzed desymmetrization of meso-aziridines with

Scheme 1.11 Chiral phosphoric acid-catalyzed desymmetrization of meso-

Scheme 1.12 Chiral phosphoric acid-catalyzed desymmetrization of meso-

aziridines with TMS-SPh developed by Della Sala and co-workers

Scheme 1.13 Chiral phosphoric acid-catalyzed desymmetrization of meso-

aziridines with thiols developed by Antilla and co-workers

Scheme 1.14 Desymmetrization of meso-aziridines with thiols under phase-

Scheme 1.15 Asymmetric ring opening of unsubstituted aziridine with 1,3-

dicarbonyl compounds under phase-transfer conditions developed

by Dixon and co-workers

Scheme 1.16 Quinine-catalyzed desymmetrization of meso-aziridines with thiols

developed by Wu and co-workers

Scheme 1.17 Prolinol-catalyzed desymmetrization of meso-aziridines with thiols

developed by Della and co-workers

Scheme 2.1 Synthesis of symmetrical chiral bicyclic guanidine 39

Scheme 2.2 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl

maleimide with 1,3-diketones, β-ketoesters, dithiomalonates

Scheme 2.3 Chiral bicyclic guanidine catalyzed Michael reactions of cyclic

enones and furanone with dithiomalonate 41f

Scheme 2.4 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl

trans-4-oxo-4-arylbut-2-enoates

Scheme 2.5 Chiral bicyclic guanidine catalyzed Michael reactions of 2-cyclo-

penten-1-one with various 1,3-dicarbonyl compounds

Scheme 2.6 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl

maleimide with benzoylacetate using triethylamine as solvent

Scheme 2.7 Chiral bicyclic guanidine catalyzed phospha-Michael additions of

various diaryl phosphine oxides to conjugated aryl nitroalkenes

Scheme 2.8 Chiral bicyclic guanidine catalyzed protonation of 1-phthalimido-

acrylate with thiophenols

Scheme 2.9 Chiral bicyclic guanidine catalyzed protonation of itaconimides

with diaryl phosphine oxides

Scheme 2.10 Chiral bicyclic guanidine catalyzed protonation of axially chiral

N-(2-tert-butylphenyl)itaconimide

Scheme 2.11 Chiral bicyclic guanidine catalyzed Michael reactions of dithranol

57

Scheme 2.12 Chiral bicyclic guanidine catalyzed Diels-Alder reactions of

anthrones

Scheme 2.13 Synthesis of guanidine from DMC 69 and amine

Scheme 2.14 Synthesis of bis-guanidinium salt 73·2HBF4

Scheme 2.15 Synthesis of guanidinium salt from aminoindanol

Scheme 2.16 Synthesis of O-Bn aminoindanol

Scheme 2.17 Synthesis of guanidinium salts from O-protected aminoindanols

Scheme 2.18 Preparation of chiral allylic amide 83

Scheme 2.19 Proposed catalytic cycle of chiral guanidine catalyzed

desymmetrization of meso-aziridines

Scheme 2.20 Synthesis of cis-aziridine-2,3-dicarboxylates

Scheme 3.1 Synthesis of dithiocarbamates

Scheme 3.2 Reaction of 2-aminomethyloxiranes with carbon disulfide

Scheme 3.3 One-pot reaction of epoxides with amine/CS2

Scheme 3.4 Synthesis of carbodithioic acid esters of fluoxetine

Scheme 3.5 Ring opening reaction of meso N-tosyl aziridine 4a with amines and

CS2

Scheme 3.6 Preparation of chiral β-amino sulfonic acid 99.

Scheme 5.1 Synthesis of γ-lactones via tandem radical addition-cyclization

reaction

Scheme 5.2 Synthesis of γ-lactones via intramolecular Michael addition

Scheme 5.3 Synthesis of γ-lactones via 1,5-electrocyclic ring closure reaction

Scheme 5.4 Synthesis of donor–acceptor functionalized substrates 102

List of Tables

Table 2.1 Various chiral guanidines catalyzed desymmetrization of meso N-tosyl

aziridine 4c with benzenethiol 63a

Table 2.2 Solvent effect on the chiral guanidine 39 catalyzed desymmetrization of

meso N-tosyl aziridine 4a with benzenethiol 63a

Table 2.3 Temperature and concentration effects on the chiral guanidine 39

catalyzed desymmetrization of meso N-tosyl aziridines 4a, 4d with

benzenethiol 63a

Table 2.4 Chiral guanidines catalyzed desymmetrization of meso-aziridines 4a, 1a

with bethiol 63a

Table 2.5 Desymmetrization of meso N-acyl aziridines 21a, 12a with benzenethiol

63a catalyzed by chiral guanidine 79b

Table 2.6 Desymmetrization of meso N-acyl aziridine 12a with various thiols

catalyzed by chiral guanidine 79b

Table 2.7 Effect of catalyst loading on the desymmetrization of meso N-acyl

aziridine 12a with benzenethiol 63d

Table 2.8 Desymmetrization of various meso N-3,5-dinitrobenzoyl aziridines 12

with benzenethiol 63d catalyzed by guanidine 79b

Table 2.9 Chiral guanidine 79a catalyzed desymmetrization of various cis-

aziridine-2,3-dicarboxylates 91a-d with benzenethiol 63a

Table 2.10 Solvent and concentration effects on the desymmetrization of cis-

aziridine-2,3-dicarboxylate 91d with benzenethiol 63c catalyzed by guanidine 79b

Table 2.11 Desymmetrization of cis-aziridine-2,3-dicarboxylate 91d with various

thiols catalyzed by guanidine 79b

Table 3.1 Chiral guanidine 79b catalyzed desymmetrization of meso N-tosyl

Table 3.2 Chiral guanidine 79b catalyzed desymmetrization of meso N-acyl

Table 3.3 Chiral guanidine 79b catalyzed desymmetrization of various meso

N-acyl aziridines 12 with amine and CS2

Table 5.1 TBD catalyzed intramolecular Michael addition reactions

Table 5.2 Optimization of the reaction conditions for intramolecular Michael

addition reactions of α,β-unsaturated carbonyl compound 102b

Table 5.3 Preparation of various chiral γ-lactones by enantioselective intra-

molecular Michael addition reactions of α,β-unsaturated carbonyl

compounds 102

List of Figures

Figure 2.1 General sturcture of guanidine

Figure 2.2 Structural diversity of the aminoindanol isomers

Figure 2.3 O-protected aminoindanols

Figure 2.4 X-ray structure of 81c

Figure 2.5 Structure of aziridine-2,3-dicarboxylate and aspartic acid

Figure 3.1 General structure of dithiocarbamate

Figure 3.2 Structure of fluoxetine

Figure 5.1 Structure of γ-lactone

List of Abbreviations

t

o

dr diastereomeric ratio

min minute(s)

i