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New Sulfone–Assisted Strategies for Alkaloid NEW SULFONE–ASSISTED STRATEGIES FOR ALKALOID SYNTHESIS Niels T. H. Tholen In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Imperial College London July 2010 Julia Laboratory, Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, United Kingdom Abstract Abstract This thesis is divided into three chapters. Chapter 1 provides brief reviews on the subjects of previous total syntheses of suaveoline, alstonerine and cytisine. In addition, a review concerning the Pictet–Spengler reaction mechanism and its application to the total syntheses of isoquinoline containing natural products has been included as well. Chapter 2 focuses on the research findings in the past three years. Two routes were investigated towards the total synthesis of (±)-suaveoline involving the decarboxylative Claisen rearrangement (dCr), N-sulfonylaziridine chemistry and subsequent nucleophilic ring- opening of the latter by various sulfone-anions. Route A focused on the use of oxo-lithio chelation during aziridine ring-opening while route B employed selective weakening of the * aziridine C–N bond proximal to the olefin by πC–C → σ C–N overlap (Scheme 0.1). R2 Route A Ts R1 2 TsN R = CH2OLi R2 1 Route B 1 Ts R = H R NHTs N R2 = CHCH = CO2CH3 N 2 Scheme 0.1 Attempts towards total synthesis of (±)-alstonerine involved the preparation and subsequent screening of various sulfone-anions against the indolic hydroxy aziridine, followed by an interesting E1cB / Michael addition, cis -Pictet–Spengler cyclization and an ambitious global reduction step. Furthermore progress towards total synthesis of (–)-cytisine involved investigation towards the application of regioselective sulfone-anion hydroxy-aziridine opening mediated by oxo- lithio-chelation. Chapter 3 provides the experimental details and characterization data. 2 Contents Contents Abstract 2 Contents 3 Acknowledgements 6 Abbreviations 8 Stereochemical Notation 12 1. Introduction 13 1.1. Suaveoline 14 1.1.1. Background 14 1.1.2. Previous Total Syntheses of Suaveoline 15 1.1.2.1. Cook’s Total Synthesis 15 1.1.2.2. Bailey’s Approach 20 1.1.2.3. Ohba’s Approach 22 1.2. Alstonerine 24 1.2.1. Background 24 1.2.2. Previous Total Syntheses of Alstonerine 25 1.2.2.1. Cook’s Total Synthesis 25 1.2.2.2. Cook’s Second Approach 27 1.2.2.3. Martin’s Approach 31 1.3. Cytisine 34 1.3.1. Background 34 1.3.2. Previous Total Syntheses of Cytisine 35 1.3.2.1. Van Tamelen’s First Total Synthesis 35 1.3.2.2. O’Neill’s Approach 36 1.3.2.3. Lesma’s Approach 38 1.4. The Pictet–Spengler Cyclization 40 1.5. Recent Progress in Pictet–Spengler Mediated Total Syntheses of Isoquinoline Alkaloids. 46 1.5.1. Small THIQ-derived Natural-occuring Alkaloids 47 1.5.1.1. (±)-Calycotomine 47 1.5.1.2. (±)-Aporphine 48 1.5.1.3. General Strategy Towards THIQ Synthesis 49 1.5.1.4. Summary 50 1.5.2. Asclepiadaceae Alkaloids 51 1.5.2.1. Iron (III)-mediated Phenanthrene Synthesis 51 1.5.2.2. Phenanthrene Synthesis by Cycloisomerization 53 1.5.2.3. Summary 55 1.5.3. Amarylidaceae Alkaloids 56 1.5.3.1. (±)-Crinine and (±)-Crinamine by Diels–Alder 56 3 Contents 1.5.3.2. (+)-Vittatine and (+)-Haemanthamine by Claisen Rearrangement 60 1.5.3.3. (–)-Manthine 63 1.5.3.4. (+)-Nangustine 65 1.5.3.5. Summary 66 1.5.4. Schulzeine A, B and C 67 1.5.4.1. Corey–Link in Schulzeine A, B, C 67 1.5.4.2. Pictet–Spengler Issues Towards Schulzeine A, B, C 69 1.5.4.3. Summary 71 1.5.5. Quinocarcin Family 72 1.5.5.1. Mannich Reaction in (–)-Quinocarcin 72 1.5.5.2. Summary 74 1.5.6. Ecteinascidin Alkaloids 75 1.5.6.1. Pictet–Spengler Cyclization Towards Et-743 75 1.5.6.2. Zhu’s Approach Towards Et-743 78 1.5.6.3. Stereoselective Aldol Applied to Et-583 and Et-597 81 1.5.6.4. Summary 84 1.5.7. Renieramycin Family 85 1.5.7.1. Total Syntheses of (–)-Jorumycin and (–)-Renieramycin G 85 1.5.7.2. (–)-Renieramycin G by Liao 88 1.5.7.3. Aziridine-Mediated Total Syntheses of (–)-Renieramycin M, G and (–)-Jorumycin 90 1.5.7.4. (–)-Cribostatin 4 93 1.5.7.5. Summary 95 1.5.8. Cyanocycline A and Bioxalomycin-β2 96 1.5.8.1. Summary 98 1.6. References 99 4 Contents 2. Results and Discussion 102 2.1. Suaveoline 103 2.1.1. Prior Work within the Craig Group 103 2.1.2. Current Progress Towards (±)-Suaveoline 110 2.1.2.1. Preparation of Hydroxy Aziridine 388 113 2.1.2.2. Decarboxylative Claisen Rearrangement 117 2.1.2.3. Regioselective Ring-Opening of Aziridines 121 2.1.2.4. Towards Vinylogous Aziridine 419 125 2.1.2.5. Tryptophan-Based Approach Towards 419 130 2.1.2.6. Ring-Opening of Aziridine 419 140 2.1.3. Second Generation Approach 143 2.1.3.1. γ-Lactam Formation 144 2.2. Alstonerine 146 2.2.1. Prior Work within the Craig Group 146 2.2.1.1. The Diels–Alder Approach 148 2.2.1.2. The Conjugated Iminium Approach 157 2.2.2. Current Progress Towards (±)-Alstonerine 160 2.2.2.1. Dianion-Mediated Aziridine Ring-Opening 161 2.2.2.2. Alternative Tosyl-Nucleophiles 162 2.2.2.2.1. Sulfonyl-olefin 514 165 2.2.2.2.2. Sulfonic enol-ether 515 168 2.2.2.2.3. Tosyl-Alkyne 519 169 2.2.2.2.4. Tosyl Acetal Hydrolysis 172 2.2.2.2.5. Orthoester 526 173 2.2.2.3. Towards (±)-Alstonerine 177 2.3. Cytisine 180 2.3.1. Current Progress Towards (–)-Cytisine 180 2.3.2.1. Tosyl Acetal 406 182 2.3.2.2. Enantiomerically Pure Aziridinol 545 182 2.3.2.3. Racemic Aziridinol 545 183 2.3.2.4. Aziridine Ring-Opening 184 2.4. Conclusion and Future Work 185 2.4.1. (±)-Suaveoline 185 2.4.2. (±)-Alstonerine 186 2.4.3. (–)-Cytisine 187 2.5. References 188 3. Experimental 191 3.1. (±)-Suaveoline 193 3.2. (±)-Alstonerine 223 3.3. (–)-Cytisine 241 3.4. References 255 5 Acknowledgement Acknowledgement First and foremost I would like to thank Professor Donald Craig for his support and guidance throughout all these years. It has been very rewarding conducting chemistry in such a passionate and motivating research team like the Craig group. I would like to thank the members of the Craig group past and present for their intellectual support and friendship. Special thanks to the Julia lab: Dr. Jason Camp, Dr. Federica Paina, Jamie Highton, Shan Shan Liu, Dr. Pengfei Lu, Simon Partridge, Dr. Sophie Gore, Phin Kok, Marc Montesinos, Claire Doyle, Rik Cleophas and Jasprit Chahal for the great times in and outside of the lab. A big thanks to Jasprit Chahal, Shuhui Yow, Claire Doyle, James Frost and Richard Pett for proofreading my thesis and turning it from a rough draft into a decent report. A special thanks to the Holland Club, my home away from home, the London public parks for providing me with a place to sleep when I couldn’t figure out where I was, Starbucks coffee and the “Store-guys” for sharing the latest gossip. Finally, I would like to thank my family and friends in The Netherlands, UK and around the world for their support and friendship in both good and bad times. Niels 6 This thesis is dedicated to my parents Jean and Truus Tholen–Aarts for their unconditional love, support and dedication over all these years. Without you I would not be what and where I am today. Thank you. 7 Abbreviations List of Abbreviations Å angstrom Ac acetyl AcOH acetic acid AIBN azobisisobutyronitrile Anh. anhydrous Ar aromatic aq. aqueous 9-BBN 9-borabicyclo [3.3.1] nonane Bn benzyl Boc tert -butoxycarbonyl BOP benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium bp boiling point Bu butyl Bz benzoyl ˚C degree Celsius cat. catalytic CAN ceric(IV)ammonium nitrate Cbz carbobenzyloxy CDI N,N '-carbonyldiimidazole CI chemical ionisation Cp cyclopentadienyl CSA 10-camphorsulfonic acid d doublet DBN 1,5-Diazabicyclo[4.3.0]non-5-ene DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene dCr decarboxylative Claisen rearrangement dd doublet of doublet DDC N,N’-dicyclohexylcarbodiimide ddd doublet of doublet of doublet DDQ 2,3-dicyano-5,6-dichloro-para -benzoquinone ddt doublet of doublet of triplet 8 Abbreviations d.e. diastereoisomeric excess DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL diisobutylammonium hydride DIC diisopropylcarbodiimide DIPEA N,N -diisopropylethylamine DMAP 4-dimethylaminopyridine DMDO dimethyldioxirane DME dimethyl ether DMF N,N-dimethylformamide DMP Dess–Martin periodinane DMS dimethyl sulfide DMSO dimethyl sulfoxide dppa diphenylphosphoryl azide dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1'bis(diphenylphosphino)ferrocene d.r diastereomeric ratio dt doublet of triplet dq doublet of quartet E1cB elimination conjugate base Ed. edition EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv. equivalents ESI electrospray ionisation Et ethyl Fmoc 9-fluorenylmethyloxycarbonyl h hours HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HMDS bis(trimethylsilyl)amide HMPA N,N,N' ,N' ,N'' ,N'' -hexamethylphosphoric triamide HOAt 1-hydroxy-7-azabenzotriazole Hz Hertz IBX O-iodoxybenzoic acid 9 Abbreviations iPr iso -propyl IR infra red La lanthanide LA Lewis acid LDA lithium diisopropylamide Ln ligand LTA lead tetraacetate lut. lutidine m multiplet M molar mCPBA meta -chloroperoxybenxoic acid Me methyl m- meta min minutes mmHg millimeter of mercury mL milliliter mol% mole percentage MOM methoxymethyl ether mp melting point Ms methanesulfonyl MS molecular sieves m/z mass/charge ratio n normal Napht.
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