Research Collection Doctoral Thesis Synthesis and evaluation as glycosidase inhibitors of aminocarbasugars, spiro-diaziridines, spiro-aziridines, and 7-azanorbornanes. Neighbouring group participation in the bromination of N-acylated cyclohex-3-en-1-amines Author(s): Kapferer, Peter Publication Date: 2005 Permanent Link: https://doi.org/10.3929/ethz-a-004959408 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Doctoral Thesis ETH No. 16026 Synthesis and Evaluation as Glycosidase Inhibitors of Aminocarbasugars, spiro-Diaziridines, spiro-Aziridines, and 7-Azanorbornanes. Neighbouring Group Participation in the Bromination of N-Acylated Cyclohex-3-en-1-amines A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZURICH for the degree of Doctor of Natural Sciences presented by PETER KAPFERER Diplom-Chemiker, University of Freiburg, Germany Master of Science, University of Connecticut at Storrs, USA born 21.02.1972 citizen of the Federal Republic of Germany accepted on the recommendation of Professor Andrea Vasella, examiner Professor Erick M. Carreira, co-examiner 2005 Acknowledgements I am indebted to Prof. Andrea Vasella for welcoming me in his group, entrusting me with challenging projects, and for generous financial support. He drew my attention to unexpected discoveries, and encouraged me to conquer prejudice with experimentation. I am grateful to Prof. E. Carreira for generously co-examining this thesis. I would like to thank Dr. B. Bernet for his attentive correction of parts of this thesis and my papers, for his kind support with all computer issues, and for his help in the interpretation of NMR spectra. I thank Mr. T. Mäder for technical assistance and Mrs. C. Dörfler and Mrs. N.-M. Haydon for help in all administrative issues. I thank Prof. F. Merckt and Dr. C. Thilgen for their good cooperation in the organisation of the exam sessions. I thank my friends Prof. Francisco Sarabia and Dr. Yoshiaki Isshiki for their help and for the numerous fruitful chemical discussions that we had in E 32. I would also like to thank all those colleagues in the Vasella group and in the Laboratory of Organic Chemistry who have contributed to a scientific and friendly atmosphere. I thank my diploma student Nathalie Leclerc for her contributions to this work. Parts of this work have been published: “Carbasaccharides via Ring-Closing Alkene Metathesis. A Synthesis of (+)-Valienamine from D-Glucose”, P. Kapferer, F. Sarabia, A. Vasella, Helv. Chim. Acta 1999, 82, 645-656. “Synthesis and Evaluation as Glycosidase Inhibitors of Carbasugar-Derived Spirodiaziridines, Spirodiazirines, and Spiroaziridines”, P. Kapferer, V. Birault, J.-F. Poisson, A. Vasella, Helv. Chim. Acta 2003, 86, 2210-2227. “Electrophilic Bromination of N-Acylated Cyclohex-3-en-1-amines: Synthesis of 7- Azanorbornanes”, P. Kapferer, A. Vasella, Helv. Chim. Acta 2004, 87, 2764-2789. “We are all agreed that your theory is crazy. The question, which divides us, is whether it is crazy enough to have a chance of being correct. My own feeling is that it is not crazy enough.” Niels Bohr For my parents For Petra Contents Summary 1 Zusammenfassung 5 Prologue 9 1. Introduction 11 1.1. Glycosides and Glycosidases 11 1.2. Medical Implications of Glycosidases 13 1.3. Reaction Mechanism of Glycosidases) 16 1.4. Oxycarbenium Ions 19 1.5. Geometrical Considerations 20 1.6. High-Energy Reactive Substrate Conformations in Enzymatic Glycoside Hydrolysis – Crystal Structure Analysis of Glycosidases in Complex with Ligands 25 1.7. Glycosidase Inhibitors 32 1.8. Aims and Questions 47 2. Part 1: Carbasugars from Sugars via Ring-Closing Alkene Metathesis 60 2.1. Carbasugars and Valienamine 60 2.1.1. De Novo Syntheses of Carbasugars 62 2.1.1.1. By Cycloadditions and Cyclisations 62 2.1.1.2. From Arenes and Cycloalkanes 68 2.1.2. Carbasugars From Naturally Occurring Carbasugars 70 2.1.3. Carbasugars From Sugars 71 2.1.3.1. By Intramolecular Nucleophilic Addition and Substitution 71 2.1.3.2. By Intramolecular Cycloadditions 77 2.1.3.3. By Radical Cyclisations 79 2.1.3.4. By Other Types of Cyclisations 83 2.1.4. Syntheses of (+)-Valienamine 87 2.2. Alkene Metathesis 98 2.2.1. Ring-Closing Alkene Metathesis 100 2.2.2. Mechanism of the Ring-Closing Alkene Metathesis with Grubbs's Catalysts 103 2.2.3. Influence of Functional Groups and Catalyst Complexation 107 2.2.4. Application of RCM in Organic Synthesis 114 2.2.5. Ring-Closing Alkene Metathesis in Carbohydrate Chemistry – Overview 118 2.2.6. Carbasugars via Ring-Closing Alkene Metathesis 120 2.3. Results and Discussion 128 2.3.1. Synthesis of (+)-Valienamine from D-Glucose via RCM 129 2.3.2. Synthesis of the MOM-Protected Glucose-Derived Carbasugar 468 136 2.3.3. Synthesis of Derivatives of the manno-Isomer of (+)-Valienamine from D- Mannose via RCM 138 2.3.4. Synthesis of an Orthogonally Protected D-Mannose-Derived Carbasugar 143 2.3.5. Synthesis of Carbocyclic Analogues of D-Arabinose via RCM 146 2.4. Conclusions 148 3. Part 2: Synthesis of Carbasugar-Derived spiro-Diaziridines and spiro-Aziridines, of 1-epi- Validamine, and of 5a-Amino-5a-carba-pyranoses 150 3.1. Introduction 150 3.1.1. Synthesis of Diaziridines 151 3.1.2. Properties of Diaziridines 158 3.1.3. Carbohydrate-Derived Diaziridines and Diazirines 159 3.1.4. Previous Work Directed at the Synthesis of Carbasugar-Derived spiro-Diaziridines 162 3.1.5. Synthesis of Aziridines 164 3.2. Results and Discussion 171 3.2.1. Diaziridines 171 3.2.2. Aziridines 183 3.2.3. 1-epi-Validamine 192 3.2.4. Inhibition of the β-Glucosidase from Caldocellum saccharolyticum, the β- Glucosidases from Sweet Almonds, and the α-Glucosidase from Brewer’s Yeast by the Diaziridines 45 and 615, the Aziridines 46 and 47, and 1-Epi-Validamine (48) 193 3.3. Synthesis and Evaluation as Glycosidase Inhibitors of 5a-Amino-5a- Carbaglucopyranoses 199 3.3.1. Introduction 199 3.3.2. Results and Discussion 199 3.4. Conclusions and Outlook 204 4. Part 3: Bridged Bicyclic Amines as Glycosidase Inhibitors Mimicking Distorted Reactive Substrate Conformers. The Synthesis of 7-Azabicyclo[2.2.1]heptanes and Approaches to the Synthesis of 6-Azabicyclo[3.1.1]heptanes 205 4.1. Introduction 205 4.1.1. Synthesis of 6-Azabicyclo[3.1.1]heptanes 206 4.1.2. Synthesis of 7-Azabicyclo[2.2.1]heptanes 209 4.2. Results and Discussion 215 4.2.1. Electrophilic Bromination of N-Acyl-4-Aminocyclohexenes 215 4.2.2. Cyclisation of 3,4-Dibromocyclohexylamines 229 4.2.3. Glycosidase Inhibition by the 7-Azanorbornanes 58.HCl and 59.HCl 256 4.3. Attempts Towards the Synthesis of 6-Azabicyclo[3.1.1]heptanes 258 4.3.1. By Pd-Catalysed Intramolecular Allylic Amination 258 4.3.1.1. Introduction 258 4.3.1.2. Results and Discussion 263 4.3.2. Attempted Synthesis of Azetidines by [3.3]Sigmatropic Rearrangements 270 4.4. Conclusions and Outlook 277 5. Part 4: Varia 278 5.1. 1-C-(Benzyloxymethyl)cyclohex-3-enylamine 278 5.2. Concerning The Ideal Transition State Analogue 279 6. Experimental Part 281 References 387 Abbreviations DMAP 4-dimethylaminopyridine DME 1,2-dimethoxy ethane DMF dimethylformamide DMSO dimethylsulfoxide eq. equivalents FC flash chromatography FPT freeze-pump-thaw τ1/2 half the width of an NMR signal at 50% of its height. IC50 inhibitor concentration at 50% inhibition mCPBA 3-chloroperbenzoic acid MS molecular sieves NBS N-bromosuccinimide NMO N-methyl morpholine N oxide TLC thin layer chromatography For analytical methods, substituents, and protecting groups I use the common abbreviations (see text books of general and organic chemistry and of protecting groups). 1 Summary (+)-Valienamine (22) was prepared in seven steps and in an overall yield of 27% from 2,3,4,6-tetra-O-benzyl-D-glucopyranose (39). Key steps of the synthesis were a ring-closing metathesis of the diene 441 to the cyclohexenol 40 in the presence of Grubbs’s ruthenium complexes 312 (58% yield of 40) or 315 (91% yield of 40), and a [3.3]-sigmatropic rearrangement of the cyanate 457 derived from 40 to the isocyanate 458. Similarly, the cyclohexenol 42 was prepared in four steps and 64% yield from 2,3,4,6-tetra-O-benzyl-D- mannopyranose and transformed into the derivatives 43 (88%) and 479 (84%) of the manno- isomer of (+)-valienamine. The cyclopentenol 424 was prepared in four steps and 47% yield from 2,3,5-tri-O-benzyl-D-arabinofuranose. OH OBn OBn BnO OH O OBn OH BnO BnO BnO OBnOBn HO BnO HO NH2 BnO OH HO OBn 39 441 40 22 The carbasugar-derived spiro-diaziridines 45 and 615, potential inhibitors of α- and β - glucosidases, were prepared from the validoxylamine A-derived cyclohexanone 606 using the Schmitz method. The trimethylsilyl protecting groups of 606 are crucial for the formation of 45 in good yields. Oxidation of 45 gave the spiro-diazirine 613. The diaziridine 45 (pKHA = 2.6) and the diazirine 613 did not inhibit the β-glucosidases from sweet almonds, the β- glucosidase from Caldocellum saccharolyticum, and the α-glucosidase from yeast. The N- benzyl diaziridine 615 proved a very weak inhibitor of the α-glucosidase, but did not inhibit the β-glucosidases. To determine if the weak inhibition by the diaziridines is due to the low basicity or to geometric factors, I prepared the spiro-aziridines 46 and 47 and 1-epi-validamine (48) and evaluated their inhibitory activity. I also included the known inhibition data for validamine (12) in the comparison.