A [2,3]-Wittig rearrangement approach towards the stereoselective synthesis of the C(10)–C(20) backbone of the fumonisins by CARA SLABBERT Submitted in partial fulfillment of the requirement for the degree MAGISTER SCIENTIAE in the Faculty of Natural & Agricultural Sciences UNIVERSITY OF PRETORIA PRETORIA Supervisor: Prof. R. Vleggaar March 2011 © University of Pretoria DECLARATION I, Cara Slabbert, declare that the dissertation, which I hereby submit for the degree Magister Scientiae at the University of Pretoria, is my own work and has not previously been submitted by me for the degree at this or any other tertiary institution. Signature: ………………….. Date: ……………… C. Slabbert ii ACKNOWLEDGEMENTS I would like to express my gratefulness to the following people: To my supervisor: Professor Robert Vleggaar, for guidance, both academically and personally, throughout this period of time. I would also like to acknowledge my parents, Leon and Maretha, without the sacrifices you so willingly made; I would definitely not have been able to even attempt this. Thank you. Johann, my husband, I want to thank you for your friendship, love and continuous encouragement. I would also like to thank Eric Palmer, not only for the running of NMR samples and NMR training, but also for being a great and reliable friend. To the lifelong friends I made: Samson, Gianna, Cathryn, Karl, Elise, Chantal, Stephen and Marion, thank you. Finally, I would like to thank the University of Pretoria and the NRF for the financial assistance which enabled me to support myself during this period. iii SUMMARY Fusarium verticillioides (= Fusarium moniliforme) a common fungal contaminant of maize throughout the world has been associated with diseases in both man and animals. The structure of the fumonisins, a family of structurally related mycotoxins isolated from cultures associated with the high incidence of human oesophageal cancer in the Transkei region in South Africa and with equine leucoencephalomalacia, a neurological disorder in horses and donkeys, has been established. The main mycotoxin, fumonisin B1 consists of the diester formed by the C(14) and C(15) hydroxyl groups of (2S,3S,5R,10R,12S,14S,15R,16R)-2- amino-12,16-dimethyleicosane-3,10,14,15-pentaol with the Si carboxy group of propane- 1,2,3-tricarboxylic acid. A comparison of the structures of the 28 known fumonisins reveals that they share a common structural motif for the C(11)C(20) unit, and probably also the same stereochemistry for the 4 stereogenic centres present in this unit. Disconnection of the C(9)–C(10) bond in a retrosynthetic analysis of the fumonisins C20 backbone (C19 in the fumonisin C series) identifies (3S,5S,6R,7R)-3,7-dimethylundecane-1,5,6-triol as a common building block for the synthesis of any of the fumonisins. In the dissertation the retrosynthetic analysis of this 3,7-dimethylundecane-1,5,6-triol building block identifies (3S,4R,5R)-5-methylnonane-1,3,4-triol as a viable target which in turn could be derived from a simple starting material trans-4-hexen-3-one. Key reactions identified to realise the required transformations leading to the identified target included kinetic enzymatic resolution of the racemic alcohol obtained from trans-4-hexen-3-one, and a pivotal role for both the [2,3]-Wittig rearrangement and the use of Sharpless asymmetric epoxidation methodology as these reactions generated the requisite stereogenic centres present in (3S,4R,5R)-5-methylnonane-3,4-diol. In this manner a synthetic route from trans-4-hexen-3- one to (2R,3R,4R,5R,6E)-4-(benzyloxy)-2,3-epoxy-5-methylnon-6-en-1-ol using appropriate functional group transformations and protective group strategies, with complete stereochemical control, were developed in this work. Alternative strategies to overcome problems encountered during the synthesis are presented for future work. The conversion of the 4-(benzyloxy)-2,3-epoxy-5-methylnon-6-en-1-ol intermediate to the protected 5- methylnonane-1,3,4-triol target could not be carried out due to time constraints and material shortages. iv ABBREVIATIONS AIBN 2,2′-Azobisisobutyronitrile aq aquous Ar Aryl 9-BBN 9-Borabicyclo[3.3.1]nonane BINAL-H 2,2′-Dihydroxy-1,1′-binaphthyl lithium aluminium hydride BINOL 1,1′-Bi-2,2′-naphthol Bn Benzyl Boc tert-Butyloxycarbonyl Bu n-Butyl Cbz Benzyloxycarbonyl CSA Camphorsulfonic acid d Days DCM Dichloromethane de Diastereomeric excess DET Diethyl tartrate DEAD Diethyl azodicarboxylate DIBALH Diisobutylaluminium hydride DIPT Diisopropyl tartrate DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMT Dimethyl tartrate dr Diastereomeric ratio EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ee Enantiomeric excess Et Ethyl IBX 2-Iodoxybenzoic acid Ipc Isopinocamphenyl LAH Lithium aluminium hydride LDA Lithium diisopropylamide LHMDS Lithium bis(trimethylsilyl)amide MCPBA m-Chloroperbenzoic acid Me Methyl Ms Mesyl (methanesulfonyl) MS Mass spectrometry MTPA -Methoxy--trifluoromethylphenylacetyl NBS N-Bromosuccinimide v NMO N-Methylmorpholine-N-oxide Ph Phenyl PPL Porcine pancreatic lipase PPTS Pyridinium p-toluenesulfonate Pr Propyl Py Pyridine Red-Al bis-(2-Methoxyethoxy)aluminum hydride TBDPS t-Butyldiphenylsilyl TBDPS t-Butyldiphenylsilyl TBHP t-Butyl hydroperoxide TBS t-Butyldimethylsilyl Tf Trifluoromethanesulfonyl THF Tetrahydrofuran THP 2-Tetrahydropyranyl Ts p-Toluenesulfonyl vi TABLE OF CONTENTS Chapter 1 INTRODUCTION 1.1 BACKGROUND...................................................................................................1 1.1.1 Environmental Health Criteria Monographs................................................1 1.1.2 The Fumonisins............................................................................................2 1.2 THE FUMONISINS.............................................................................................3 1.2.2 Absolute Configuration................................................................................6 1.3 RELATED COMPOUNDS.................................................................................7 1.3.1 AAL-Toxins.................................................................................................7 1.3.2 Biosynthesis of the Fumonisins...................................................................8 1.4 FUMONISIN B1..................................................................................................10 1.5 PREVIOUS SYNTHETIC APPROACHES....................................................10 1.6 PRESENT APPROACH TOWARDS THE C(10)-C(20) SEGMENT OF FB1............................................................................................25 Chapter 2 RETROSYNTHETIC ANALYSIS 2.1 RETROSYNTHETIC ANALYSIS OF THE FUMONISIN B1 BACKBONE.......................................................................................................26 2.2 C10 - C20 FRAGMENT........................................................................................27 2.3 C12 - C20 FRAGMENT........................................................................................28 Chapter 3 SYNTHETIC STUDIES 3.1 PROPOSED SYNTHETIC SEQUENCE.........................................................30 3.2 SELECTIVE REDUCTION..............................................................................32 3.2.1 Theoretical Aspects....................................................................................32 3.2.2 Experimental Discussion............................................................................34 3.3 KINETIC ENZYMATIC RESOLUTION........................................................35 3.3.1 Theoretical Aspects.....................................................................................35 vii 3.3.2 Experimental Discussion............................................................................38 3.3.3 Alternative Approaches..............................................................................40 3.4 ETHER SYNTHESIS: PHASE TRANSFER CATALYSIS.....................45 3.4.1 Theoretical Aspects.....................................................................................45 3.4.2 Experimental Discussion............................................................................46 3.5 [2,3]-WITTIG REARRANGEMENT..........................................................48 3.5.1 Theoretical Aspects.....................................................................................48 3.5.2 Experimental Discussion............................................................................49 3.6 ROUTE 1........................................................................................................50 3.6.1 Protection of the Secondary Hydroxy Group..............................................51 3.7 HYDROXYMETHYLATION......................................................................57 3.7.1 Theoretical Aspects.....................................................................................57 3.7.2 Experimental Discussion............................................................................57 3.8 ROUTE 2........................................................................................................58 3.8.1 Protection of Primary Alcohol using t-Butyldimethylsilyl Ether..............59 3.8.2 Experimental Discussion............................................................................59 3.8.3 Protection of Primary Alcohol as t-Butyldiphenylsilyl Ether.....................60 3.8.4 Experimental Discussion............................................................................61