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Approaches Towards the Synthesis of 1,1 -Bis-Hydroxymethyl-1 ,5-Dideoxy- 1 ,5-Imino-L-Fucitol

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Approaches Towards the Synthesis of 1,1 -Bis-Hydroxymethyl-1 ,5-Dideoxy- 1 ,5-Imino-L-Fucitol Approaches towards the synthesis of 1,1 -Bis-hydroxymethyl-1 ,5-dideoxy- 1 ,5-imino-L-fucitol David Tristram Brown A thesis submitted for the degree of Doctor of Philosophy University of Edinburgh September 2001 C: This thesis is submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy at the University of Edinburgh. Unless otherwise stated, the work described is original and has not been previously submitted in whole or in part for any degree at this or any other university. David Tristram Brown University of Edinburgh September 2001 11 to my parents 111 Acknowledgements Acknowledgements Firstly, I would like to thank Prof. Nicholas Turner for giving me the opportunity to work with him on this project, and for his advice, support and encouragement over the last four years. I would also like to thank EPSRC for financial support. I am grateful to all those providing technical support and services within the department, especially John Millar and Wesley Kerr for their help with NMR, Simon Parsons and co-workers for determining crystal structures, and Sally Shirran for running the open access mass spectrometry service. Finally, I would like to thank all those who have worked with me in Lab. 34, and everyone within the Turner and Flitsch groups for their support, companionship and tearoom chats over the last four years. lv Contents Contents Acknowledgements . iv Contents ...................................................................................................................... V Abbreviations ........................................................................................................... vli Abstract ....................................................................................................................... X Chapter1: Introduction ............................................................................................ 1 Part I: The biological significance of L-fucose ................................................ 1 The role of carbohydrates in biology ........................................................... 1 The biological response to foreign bodies ................................................... 1 Inhibition of the cell-protein interaction......................................................3 Glycosidase and glycosyltransferase inhibition...........................................3 Inhibitordesign ............................................................................................8 Part II: Piperidine synthesis ........................................................................... 10 SN2 displacement reactions........................................................................ 10 Nucleophilic epoxide opening.................................................................... 13 Reduction of ö-lactams .............................................................................. 14 Metathesis.................................................................................................. 18 Intramolecular hydroamination.................................................................. 22 Rearrangements.......................................................................................... 23 Aza-Diels-Alder reactions.......................................................................... 24 1,3-Dipolar cycloaddition .......................................................................... 25 Claisen rearrangement................................................................................ 26 Enzymaticprocedures................................................................................ 27 Summary.................................................................................................... 28 Part III: Retrosynthetic analysis of the target molecule 14 ............................ 29 Chapter2: Results and Discussion Part I.............................................................. 34 Nucleophilic cyclisation approach................................................................. 34 Electrophilic cyclisation approach................................................................. 47 Chapter 3: Results and Discussion Part II ............................................................. 56 Aza-Diels-Alder reactions with imino dienophiles........................................ 57 Aza-Diels-Alder reactions of oxazinone dienes............................................. 59 V Contents Chapter 4: Results and Discussion Part III ........................................................... 68 Oxidative cleavage/ring closure methodology...............................................68 Conclusions....................................................................................................90 FutureWork................................................................................................... 93 Chapter5: Experimental ......................................................................................... 95 Experimental techniques................................................................................ 95 Nucleophilic cyclisation approach................................................................. 97 Electrophilic cyclisation approach............................................................... 109 Diels-Alder approach: oxazinone as diene I ................................................ 116 Diels-Alder approach: oxazinone as diene II ............................................... 120 Oxidative cleavage/ring closure route.......................................................... 125 References ............................................................................................................... 140 Appendix ................................................................................................................. 146 vi Abbreviations Abbreviations Ac acetyl A.P.C.I. Atmospheric Pressure Chemical lonisation Ar aryl Boc tert-butoxycarbonyl Bn benzyl BTAC benzyltrimethylammonium chloride BTMSA bis-trimethisilylacetylene BuLi n-butyl lithium 'Bu tert-butyl Bz benzoyl CAN ceric ammonium nitrate Cbz carbobenzyloxy CEVE chloroethyl vinyl ether Cp* C5Me5 CSA camphor sulfonic acid DBU 1 ,8-diazabicyclo[5,4,O]undec-7-ene DCM dichioromethane d.e. diastereomeric excess DEAD diethyl azodicarboxylate DEKM diethylketomalonate DHAP dihydroxyacetone phosphate DIBAL di-iso-butylaluminium hydride DMAP 4-(dimethylamino)pyridine DMF dimethylformamide 2,2-DMP 2,2-dimethoxypropane DPPA diphenylphosphoryl azide DS dodecyl sulfate E.I. electron impact ES(MS) electrospray (mass spectrometry) vii Abbreviations Et ethyl EVE ethyl vinyl ether FAB fast atom bombardment FucT fucosyltransferase GDP guanosine diphosphate IEDDA inverse electron demand Diels-Alder J coupling constant LDA lithium diisopropylamide MeLi methyl lithium mp melting point m/z mass/charge ratio NMO N-methyl-morpholine-N-oxide NMR nuclear magnetic resonance Nuc nucleophile P generic protecting group Ph phenyl R generic substituent RF retention factor sat. aq. saturated aqueous sLe' sialyl Lewis-X TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBVE tert-butyl vinyl ether TEMPO 2,2 ,6,6-tetramethyl- 1 -piperidinyloxy Tf trifluoromethylsulfonyl (triflyl) TFA trifluoroacetic acid THF tetrahydrofuran TIPS tri-iso-propylsilyl tic thin layer chromatography TMS trimethylsilyl Ts para-toluenesulfonyl (tosyl) U uracil viii Abbreviations x non-specific leaving group z benzyloxycarbonyl Ix Abstract Abstract This thesis describes the design and testing of various strategies for the synthesis of the polyhydroxylated bis-hydroxymethyl piperidine i, a component of a potential transition state inhibitor of an a-( 1 ,3)-fucosyltransferase. HO OH OH HN "OH OH The first chapter reviews the current methods by which complex piperidines are synthesised and outlines the aims of this project. The second chapter describes the attempted construction of an appropriate linear precursor for a nucleophilic cyclisation of an amine onto an epoxide. This chapter also describes an approach which attempted the electrophilic cyclisation of an alkene onto an imine, however an aza-Cope [3,3]-sigmatropic shift took precedence. The third chapter describes attempts to construct the target via a catalytic aza-Diels-Alder reaction of an oxazinone. The fourth chapter describes an approach in which an inverse electron demand Diels-Alder reaction was used to establish the core stereochemistry. The piperidine ring was set up via a ring cleavage/reclosure method incorporating a Hofmann rearrangement and oxidative cleavage of an alkene. This method was used to synthesise the piperidine ii, however time constraints did not allow the extension of the approach beyond this test-case to the target i. ZH2Ae . AcO'' 6H 6R 6H ii iii It is proposed that a simple, efficient and adaptable methodology for the synthesis of this motif has been established. x Introduction Chapter 1: Introduction Part I: The biological significance of L-fucose The role of carbohydrates in biology The biological importance of carbohydrates in the storage and transport of energy for living cells has long been known. Recently, carbohydrates have also been identified as essential mediators of cell-cell and cell-protein interactions, and hence they play a key role in signalling and recognition processes within the body. Research into this new area has already provided some promising results, leading to the development and testing of carbohydrate-based therapeutics.' Most carbohydrates of biological
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