Total Synthesis of Ferrugine and Synthetic Studies Towards Ferruginine and Stemofoline
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Total Synthesis of Ferrugine and Synthetic Studies Towards Ferruginine and Stemofoline by Shamim Ahmed A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Chemistry ( University of Birmingham August 2009 1 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Acknowledgements Firstly, I would like to acknowledge my supervisor Dr. Richard Grainger for his continued support and endless guidance throughout my PhD. In particular, I am grateful to him for making me believe in myself during the good, the bad and the ugly times. I am forever grateful to my special wife Nilupa for her everlasting enthusiasm, encouragement, guidance and the level of support received throughout this tough process. I would also like to express my gratitude to the past and present group members such as Luke, Katia, Emma, Bhaven, Tyrone and Benedicte for their support and entertainment over the last few years. I am also grateful to the analytical facility for their assistance, in particular Dr Neil Spencer for NMR, Pete Ashton, and Nick May for mass spectrometry and Dr Benson Kariuki for X-Ray crystallography. Finally, I would like to thank my friends and family including the entire Hassan family for their patience, in particular my parents and sister Sabina, Morzina and Anjuna for humouring me at all times. 2 Abstract Tropane alkaloids, containing the 8-azabicyclo[3.2.1]octane ring system, are widespread in Nature. This thesis describes the total synthesis of the tropane alkaloid ferrugine, isolated from the arboreal species Darlingiana ferruginea and attempted synthesis of ferruginine, isolated from the arboreal species D. darlingiana. Formation of a bridged 6-azabicyclic-[3.2.2]-ring system was achieved using a transannular photomediated cyclisation of a carbamoyl radical, generated from a carbamoyl diethyldithiocarbamate, onto an unactivated pendant alkene, followed by group transfer of the dithiocarbamate moiety. The carbamoyl radical cyclisation precursor was synthesised from a known seven-membered ring carboxylic acid. The diastereomeric dithiocarbamates converged to a single alkene upon thermal elimination. Addition of phenyllithium to the amide followed by base-mediated skeletal rearrangement resulted in the total synthesis of the natural product ferrugine, and using a similar strategy the core structure of ferruginine was secured. The stemona alkaloid stemofoline is characterised by a complex azatricyclic ring system unique to this class of natural products. Synthetic efforts have been made toward the synthesis of a cyclisation precursor required for the assembly of this azatricyclic framework, via a proposed tandem 7-endo-trig/5-exo-trig carbamoyl radical cyclisation. The synthesis commenced with the commercially available dimethyl 3,3-thiodipropanoate which was further elaborated and coupled with 5-hepten-2-one to provide an advanced intermediate enone. Addition of ammonia gave a pyrroline which was condensed with triphosgene followed by sodium diethyldithiocarbamate to produce a carbamoyl radical precursor. Unfortunately, efforts towards oxidation and elimination of the sulfide to obtain an α,β-unsaturated ketone proved ineffective. Attempted carbamoyl radical cyclisation-dithiocarbamate group transfer onto enones and nitriles are also presented. 3 ABBREVIATIONS Ac acetyl Bn benzyl Boc t-butoxycarbonyl Bu butyl CI chemical ionisation °C degrees centigrade cat. catalytic cm3 cubic centimetres DBU 1,8-diazabicyclo[5.4.0] undecene DIBAH diisobutylaluminium hydride DIPEA diisopropylethylamine DPPA diphenylphosphorylazide DMAP 4-dimethylamino pyridine DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)- pyrimidinone DMSO dimethylsulfoxide DMF N,N-dimethylformamide de diastereomeric excess ee enantiomeric excess EI electron impact ESI electron spray ionisation Et ethyl g grams GC gas chromatography h hours Hz hertz HMPA hexamethylphosphoramide i- iso- IBX 2-Iodoxybenzoic acid IR infrared spectrometry J coupling constant (Hz) 4 LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide M molar Me methyl min. minutes mL millilitres mp melting point Ms methanesulfonyl MS mass spectrometry MPO 4-methoxypyridine-N-oxide n- normal- NMO 4-methylmorpholine N-oxide NMR nuclear magnetic resonance p- para- PCC pyridinium chlorochromate Ph phenyl ppm parts per million Pr propyl Rf retention factor rt room temperature s- secondary- sat. saturated t- tertiary- TBAF tetra-n-butylammonium fluoride TBDMS t-butyldimethylsilyl TIPS tri-isopropylsilyl Tf trifluoromethanesulfonyl TLC thin layer chromatography TMS trimethylsilyl Ts para-toluenesulfonyl 5 CONTENTS 1. Ferruginine: background and significance 1 Tropane alkaloids 2 Ferrugine: isolation and biological activity 3 Davies’ synthesis of ferruginine 4 Rigby’s synthesis of (+)-ferruginine 6 Rapoport’s synthesis of (+)-ferruginine & (-)-ferruginine 9 Ham’s formal synthesis of ferruginine 13 Husson’s synthesis of (+)-ferruginine 14 Bäckvall’s synthesis of ferruginine 16 Node’s synthesis of (+)-ferruginine & (-)-ferruginine 19 Aggarwal’s synthesis of (+)-ferruginine 22 Bick’s synthesis of (-)-ferrugine 24 2. Aims and Objectives 26 Carbamoyl radical chemistry 27 Proposed syntheses of ferrugine and ferruginine 32 Radical cyclisations 33 Proposed synthesis of stemofoline 35 3. Total synthesis of ferrugine and attempted synthesis of ferruginine 38 Synthesis of cyclisation precursor via carbamoyl chloride 39 Route to cyclisation precursor via imidazolide 42 Synthesis of an eight-membered ring cyclisation precursor 44 6 Carbamoyl radical cyclisation 46 Thermal elimination of dithiocarbamates 50 Tandem carbamoyl radical cyclisation-thermal elimination 52 Completion of the synthesis of ferrugine 53 Attempted synthesis of ferruginine 57 Conclusion and future work 68 4. Stemofoline: Background and significance 70 Stemona alkaloids 71 Stemofoline: isolation and biological activity 73 Overman’s synthesis of asparagamine A 74 Kende’s total synthesis of isostemofoline 79 Thomas’s efforts towards stemofoline 84 Gin’s approach towards stemofoline 91 Olivio’s synthesis of bicyclic γylidenetetronates 99 Smith’s approach to the synthesis of 2 substituted pyrrolidines 102 Livingstone’s stereocontrolled synthesis of bridged pyrrolizidines 106 5. Synthetic efforts towards stemofoline 109 Proposed synthesis of stemofoline 110 Route to cyclisation precursor via carbamoyl chloride 110 Route to cyclisation precursor via imidozolide 119 Proposed route to cyclisation precursor via Wittig olefination 121 Conclusion and future work 125 6. Study of carbamoyl radical cyclisations onto nitriles and enone s 126 Attempted carbamoyl radical cyclisation onto nitriles 127 7 Attempted carbamoyl radical cyclisation onto enones 128 7. Experimental section 131 8. References 179 Appendix: X-ray data for 168, 174 and ferrugine 197 8 1. FERRUGININE: BACKGROUND AND SIGNIFICANCE 1 Tropane alkaloids Tropane alkaloids are nitrogenous bicyclic organic compounds which have the 8- azabicyclo[3.2.1]octane skeleton. The nitrogen bridge is between C1 and C5, two asymmetric carbons but tropane is optically inactive due to symmetry (fig 1). 8 1 2 2 7 1 NMe Me N 8 3 4 5 6 3 7 5 4 6 Fig 1 Currently there are over two hundred tropane alkaloids known to occur in natural sources.1 They are naturally found in many members of the plant families including Solanaceae, Erythroxylaceae, Con-VolVulaceae, Proteaceae, Rhizophoraceae, Brassicaceae, and Euphorbiaceae. They are known for their toxic and important medicinal properties.2-5 Atropine, the racemic form of (-)-hyoscyamine, was first isolated from atropa belladonna in 1833, while (- )-hyoscyamine was also isolated in the same year from hyoscyamus niger.1 These tropane alkaloids are muscarinic receptor agonist that are involved in constriction of the pupil and vasodilation. They are also responsible for moderating the heartbeat and stimulating secretions. While the notorious cocaine, isolated from the dried leaves of erythroxylum coca, can be used for its anaesthetic properties and can also be prepared from its precursor and metabolite, ecogonine (fig 2).2,3 2 Me Me Me Me N N N O N O OMe OH O Ph OH OH OH O O O C H C6H5 6 5 H O H O atropine (-)-hyoscyamine (-)-cocaine (-)-ecogonine Fig 2 Ferrugine: isolation and biological activity The tropane alkaloid (+)-ferruginine (1) was isolated from the arboreal species Darlingiana ferruginea6 and D. darlingiana,7 and its unnatural isomer (-)-ferruginine (2) has been prepared from cocaine.6 Ferruginine is found to be a good agonist for the nicotine acetylcholine receptor (nAchR). Due to its biological activity coupled with an interesting molecular architecture, it has generated considerable synthetic interest culminating in several racemic and enantiospecific syntheses.7-15 Me Me O N N Me Me O (+)-ferruginine (-)-ferruginine From hereon, a comprehensive review of the syntheses of ferruginine will be presented outlining the key chemical transformations involved. 3 Davies synthesis of ferruginine.8 Davies