Asymmetric Synthesis of Sultones and Sulfonic Acid Derivatives

187 Pages·2004·1.2 MB·English

Asymmetric Synthesis of
Sultones and Sulfonic Acid Derivatives

Von der Fakultät für Mathematik, Informatik und Naturwissenschaften
der Rheinisch-Westfälischen Technischen Hochschule Aachen
zur Erlangung des akademischen Grades eines
Doktors der Naturwissenschaften
genehmigte Dissertation

Vorgelegt von

Wacharee Harnying

aus Surin, Thailand

Berichter: Universitätsprofessor Dr. D. Enders
Universitätsprofessor Dr. H.-J. Gais

Tag der mündlichen Prüfung: 3. September 2004

Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.

This work has been carried out at the Institute of Organic Chemistry, RWTH Aachen under
the supervision of Prof. Dr. Dieter Enders between September 2001 and April 2004.

Parts of this work have been published:

1. “A Practical Approach towards the Asymmetric Synthesis of α,γ-Substituted γ-Sultones”
D. Enders, W. Harnying, N. Vignola, Synlett 2002, 1727-1729.

2. “Asymmetric Michael Addition of Chiral Lithiated Sulfonates: Diastereo- and
Enantioselective Synthesis of α,β-Disubstituted γ-Nitro and β-Alkoxycarbonyl Methyl
Sulfonates” D. Enders, O. M. Berner, N. Vignola, W. Harnying, Synthesis 2002, 1945-
1952.

3. “Asymmetric Synthesis of α,γ-Substituted γ-Sultones via Allylation of Chiral Lithiated
Sulfonates” D. Enders, W. Harnying, N. Vignola, Eur. J. Org. Chem. 2003, 3939-3947.

4. “Asymmetric Synthesis of α,γ-Substituted γ-Alkoxy Methyl Sulfonates via
Diastereospecific Ring-Opening of Sultones” D. Enders, W. Harnying, Arkivoc 2004, 2,
181-188.

5. “Diastereoselective Hydrolysis of α,γ-Substituted γ-Sultones in the Asymmetric
Synthesis of γ-Hydroxy Sulfonates” D. Enders, W. Harnying, G. Raabe, Synthesis 2004,
590-594.

6. “A Highly Efficient Asymmetric Synthesis of Homotaurine Derivatives via
Diastereoselective Ring-Opening of γ-Sultones” D. Enders, W. Harnying, Synthesis
2004, in press.

7. “Efficient Asymmetric Synthesis of α-Alkylated Methyl Sulfonates” D. Enders, N.
Vignola, O. M. Berner, W. Harnying, Tetrahedron 2004, in press.

ACKNOWLEDGEMENTS

Firstly, I would like to express my appreciation to Prof. Dr. D. Enders for giving me the great
opportunity to do my PhD in his group and for his encouragement throughout the course of
this work.

I am grateful to Prof. Dr. G. Raabe for the Röntgen-structure determinations and Dr. J.
Runsink for the NOE-measurements, Kamila Hennig, Sabine Drehsen and Desiree Gilliam for
measurement of gaschromatography, analytic and preparative HPLC.

I would like to thank my labmates Dr. Bert Nolte and Jörg Gries, Christiaan Rijksen, Tim
Balensiefer, Achim Lenzen and especially Dr. Nicola Vignola, Dr. Otto Mathias Berner and
Dr. Jean-Claude Adelbrecht who worked with me on the same subject, for their kind
cooperation, suggestions, and invaluable help in the lab.
I also would like to thank all members of AK-Enders for their kindness and generous
assistance throughout this work which made my time in Germany a great experience.

Special thanks go to Dr. Jean-Claude Adelbrecht and particularly Achim Lenzen for their
patience and generous help for the correction of my publications and this manuscript.

I gratefully acknowledge to Dr. Wolfgang Bettray and Karin Risse for their administrative
assistance of my life in Germany.

I am especially grateful to the Deutche Forschungsgemeinschaft (Graduiertenkolleg 440, SFB
380) for financial support which enabled me to undertake this study and Khon Kaen
University, Thailand for supporting my study in Germany.

Finally, I thank my parents and elder brother for their loving care and unquestioning support.

Wacharee Harnying

CONTENTS
1 INTRODUCTION 1
1.1 Biological activity of sulfonic acids 1
1.2 Asymmetric synthesis of sulfonic acids 5
1.2.1 Asymmetric induction by using a chiral auxiliary 5
1.2.2 Asymmetric induction by using chiral catalysts 9
1.2.3 Synthesis starting from chiral substrates 11
1.3 Sultones in organic chemistry 15
1.3.1 Novel syntheses and reactions of α,β-unsaturated γ-sultones 17
1.3.2 Diastereoselective syntheses of saturated aliphatic sultones 21
1.3.3 Synthetic application of sultones 23
1.4 Biological activity of sultones 29
1.5 Objectives 31
2 RESULTS AND DISCUSSION 33
2.1 Asymmetic synthesis of α,γ-substituted γ-sultones 33
2.1.1 Synthesis of allylated cyclohexyl sulfonates as starting materials for the
preparation of racemic α,γ-substituted γ-sultones 34
2.1.2 Preparation of the chiral auxiliary 35
2.1.3 Preparation of chiral sulfonates 35
2.1.4 Allylation of the chiral sulfonates 36
2.1.5 Cleavage of the chiral auxiliary 38
2.1.6 Removal of the chiral auxiliary and cyclization to form γ-sultones 40
2.2 Synthetic application of chiral γ-sultones: The asymmetric synthesis of sulfonic
acid derivatives via ring-opening reactions of sultones 45
2.2.1 Mechanistic study of the ring-opening reactions and asymmetric synthesis of
γ-alkoxy sulfonates 45
2.2.2 Asymmetric synthesis of α,γ-substituted γ-hydroxy sulfonates 50
2.2.3 Asymmetric synthesis of α,γ-substituted γ-amino sulfonates 54
2.3 Asymmetric synthesis of α,β-substituted γ-hydroxy and γ-amino sulfonates 63
2.3.1 Asymmetric synthesis of α,β-substituted γ-hydroxy sulfonates 66
2.3.2 Asymmetric synthesis of α,β-substituted γ-amino sulfonates 67
3 CONCLUSION 71
4 OUTLOOK 75
5 EXPERIMENTAL SECTION 79
5.1 General remarks 79
5.2 General procedures (GP) 80
5.3 Allylation of cyclohexyl sulfonates 83
5.4 Preparation of chiral sulfonates 89
5.5 Allylation of chiral sulfonates 93
5.6 Removal of the chiral auxiliary to give the α-allylated methyl sulfonates 103
5.7 Removal of the chiral auxiliary and subsequent cyclization to form α,γ-
substituted γ-sultones 108
5.8 Synthesis of α,γ-substituted γ-alkoxy methyl sulfonates 119
5.9 Synthesis of α,γ-substituted γ-hydroxy methyl sulfonates 126
5.10 Synthesis of α,γ-substituted γ-azido isopropyl sulfonates 133
5.11 Synthesis of α,γ-substituted N-Boc-protected γ-amino isopropyl sulfonates 142
5.12 Synthesis of α,β-substituted β-alkoxycarbonyl and γ-hydroxy methyl sulfonates
155
5.13 Synthesis of α,β-substituted γ-nitro and γ-amino isopropyl sulfonates 160
5.14 X-ray data 169
6 REFERENCES 171
1 INTRODUCTION

1.1 Biological activity of sulfonic acids

Sulfonic acid derivatives are important components in mammals and are involved in various
and important physiological processes.1 The best known are 2-aminoethanesulfonic acid
(taurine, TA) and related compounds such as 3-aminopropane-sulfonic acid (homotaurine,
HTA), 2-hydroxyethanesulfonic acid (isethionic acid, ISA), cysteic acid (CA),
guanidoethanesulfonic acid (guanidotaurine, GES), for example which are intensively studied
on their involvement in biological functions (Figure 1).

NH
2
HO S
3
Taurine, TA
OH
HO3S NH2 HO3S
Homotaurine, HTA Isethionic acid, ISA
NH H
HO3S 2 HO S N NH2
3
COOH
NH
Cysteic acid, CA guanidotaurine, GES

Figure 1. Taurine and related compounds.

Taurine has been found in relatively high concentrations in the central nervous system (CNS)
and brain, and also found in high concentration in muscles, and particularly in heart. The
possible role of TA is that of an inhibitory transmitter or a CNS modulator. Homotaurine is a
structural analogue of γ-aminobutyric acid (GABA), which is of great importance as a specific
inhibitor of impulse transmission in the CNS,2 and it has been reported that homotaurine has
more potent inhibitory effects than taurine.3
However, in many cases the physiological roles of these sulfonic acid derivatives remained
unclear. To get further insight into their mode of action a stereoselective access to these
derivatives is desirable and compulsory for physiological tests.
1
Introduction
Some sulfonic acids have been extracted from natural and show biological properties. For
example, 6-gingesulfonic acid (1), which was isolated from ginger (Zingiberis rhizoma) and is
used for the treatment of headache and stomachache (Figure 2).4

O SO H
3
H CO
3
* CH3
HO
6-Gingesulfonicacid (1)

Figure 2. 6-Gingesulfonic acid (1).

Capon et al. have isolated echinosulfonic acid A, B and C (2-4), novel bromoindole sulfonic
acids from the southern Australian marine sponge, Echinodictyum (Figure 3). 5 They show
antibacterial activity.

RO SO H
3
Echinosulfonic acid A (2), R = Et
Br Br Echinosulfonic acid B (3), R = Me
N N Echinosulfonic acid C (4), R = H
H
CO Me
2

Figure 3. Echinosulfonic acids A, B and C (2-4).

Interestingly, some sulfonic acids have been synthesized and have been shown to posses
pharmacological activities. Prager and co-workers have synthesized saclofen (5) and
hydroxysaclofen (6) (Figure 4). Their racemates exhibited activity as specific antagonists for
GABA receptors.6 Moreover, they have reported the synthesis of both enantiomers of
B
hydroxysaclofen.7 Their biological tests of both enantiomers as antagonists of GABA at the
GABA receptor showed that (R)-(−)-hydroxysaclofen was completely inactive, while (S)-
B
(+)-hydroxysaclofen was a potent and specific antagonist with an activity 2 to 3 times that of
the racemate. In the case of saclofen, the racemate has been resolved by the use of chiral
analytical HPLC and only (R)-(−)-saclofen was shown to be active.8

2