Asymmetric Synthesis of Sultones and Sulfonic Acid Derivatives”

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). NH2 HO3S Taurine, TA OH HO3SNH2 HO3S Homotaurine, HTA Isethionic acid, ISA H NH2 HO3S NNH2 HO3S 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 OSO3H H3CO * CH3 HO 6-Gingesulfonic acid (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 SO3H Echinosulfonic acid A (2), R = Et Br Br Echinosulfonic acid B (3), R = Me N N H Echinosulfonic acid C (4), R = H CO2Me 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 6 GABAB receptors. Moreover, they have reported the synthesis of both enantiomers of hydroxysaclofen.7 Their biological tests of both enantiomers as antagonists of GABA at the GABAB receptor showed that (R)-(−)-hydroxysaclofen was completely inactive, while (S)- (+)-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 Introduction Cl Cl HO H2NSO3H H2NSO3H (R)-Saclofen (5) (S)-Hydroxysaclofen (6) Figure 4. Saclofen (5) and hydroxysaclofen (6) as potential GABAB receptor antagonists. Biller et al. have discovered that the α-phosphono sulfonic acids (α-PSAs) 7 and 9,9 and the orally bioavailable prodrug esters 8 and 10 (Figure 5), 10 are potent squalene synthase inhibitors, which have great potential as antihypercholesterolemic agents due to the strategic location of the enzyme at the first committed step in the cholesterol biosynthetic pathway. Furthermore, they have demonstrated the synthesis and biological evaluation of the α-PSA 9 in optically pure form which reinforces the importance for further pharmaceutical developments.11 Enantiomer (S)-9 was 16-fold more potent than (R)-9 as an inhibitor of squalene synthase with IC50 values of 68 and 1120 nM, respectively.

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