i SYNTHESIS AND REACTIONS OF SULFINIMINES Leonid Kotei Sasraku-Neequaye This thesis is submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at the University of East Anglia June, 2010 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotation from this thesis or any information derived thereof may be published without the author’s prior written consent ii DECLARATIONS I declare that the work contained within this thesis, submitted by myself for the degree of Doctor of Philosophy is my own original work, except where due reference is made and has not previously been submitted by me for a degree at this or any other university. Leonid Kotei Sasraku-Neequaye iii ABSTRACT A large majority of drugs and drug candidates incorporate amine functionality and these include important compounds such as morphine, quinine and nicotine. N-Sulfinyl-imines (sulfinimines) are a versatile class of intermediates in organic synthesis particularly for the preparation of amines and amine derivatives. We herein report an efficient and cost effective one-pot synthesis of sulfinimines in enantiopure form (>99.8% ee) and in relatively high yields. In our investigations, we developed the scheme that involves the use of 1,2,3- oxathiazolidine-2-oxide derived from (1R, 2S)-(-)-norephedrine as a chiral auxiliary. Opening of the 1,2,3-oxathiazolidine-2-oxide with a mesityl Grignard reagent followed by treatment of the crude mixture with lithium hexamethyldisilasane afforded the mestyl sulfinamide in 72% yield and 76% recovery of the chiral auxiliary. As an extension to this scheme, when the crude reaction mixture obtained after addition of the lithium hexamethyldisilasane was treated with 1.1 equivalents of an aldehyde and three (3) equivalents of Ti(OEt)4 afforded the corresponding mesityl sulfinimines in high yields (>30 – 60%) and excellent enantiomeric excess (>99.8%). This to our knowledge is the first ever 3-step, one-pot syntheses of enantiopure sulfinimines using chiral aminoalcohol derived 1,2,3-oxathiazolidine-2-oxide as a chiral auxiliary. The mesitylsulfinamide thus produced was utilised in a novel free radical cyclisation reaction to yield mesitylsulfinyl protected enantiopure aminoindane in 68% yield. iv ACKNOWLEDGEMENTS I would first of all give thanks to the almighty God for giving me life, wisdom and strength to come this far with my Education. I would also like to express my sincere gratitude to my supervisor, Dr. Robert Stockman, for giving me this opportunity to work under him and for all his support and ideas that he brought to bear on this research. I would also like to thank The University of East Anglia (UEA) and GlaxoSmithKline (GSK) for funding my CASE studentship and Dr. David McPherson for his excellent co-supervision and all the equipments and assistance with my research. My special thanks to all present and previous members of the RAS group: Kordi, Steve, Bella, Max, Alicia, Martin, Induka, Dan, Paul, Louise and Alex for their wonderful support and input towards this research. I am also grateful to all staff and postgraduates of the School of Chemical Sciences for their help in various ways. My heartfelt thanks to Henrietta, my wife, for her love and always being there for me. I would also like to thank my dad Samuel Neequaye Sasraku, my mum Veronica Halan-Crabbe, my siblings Boris, Coretta and Loretta as well as the extended family in Ghana for their support and prayers. I will finally like to thank all my friends, both in the UK and Ghana, for all their support and all workers and staff of The School of Chemical Sciences and Pharmacy, UEA. v ABBREVIATIONS Å angstrom Ac acetyl AIBN 2,2'-azobiisobutyronitrile aq. aqueous Ar aryl atm. atmospheres β beta BBN borabicyclo[3.3.1]nonane Bn benzyl BOC butoxycarbonyl b.p boiling point br broad Bu butyl conc. concentrated cm centimetre Cyc cyclohexyl d doublet DCM dichloromethane δ chemical shift in parts per million dd doublet of doublets de diastereomeric excess DIBAL-H diisobutylaluminium hydride DMAP dimethylamino pyridine DMF dimethylformamide DMSO dimethyl sulfoxide ee enantiomeric excess El electron impact Et ethyl equiv. equivalent h hour(s) HMDS hexamethyldisilazide vi HPLC high performance liquid chromatography HRMS high resolution mass spectroscopy Hz hertz iPr isopropyl IR infra red J coupling constant in NMR spectroscopy LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazane m multiplet M molarity of solution mCPBA meta-chloroperoxybenzoic acid m.p. melting point m/z mass to charge ratio Me methyl min minutes Ms methanesulfonyl MS molecular sieves n normal NaHCO3 Sodium bicarbonate NaHMDS sodium hexamethyldisilazane Na2SO4 sodium sulfate NCS N-chlorosuccinimide NMR nuclear magnetic resonance n.O.e nuclear Overhauser enhancement p para Ph phenyl PMP para-methoxyphenol ppm parts per million PPTS pyridinium para-toluenesulfonate py pyridine q quartet Red-Al Sodium bis(2-methoxyethoxy)aluminum dihydride ref. reference r.t room temperature vii s singlet sat. saturated t triplet TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TLC thin layer chromatography TMEDA N, N, N’, N’-tetramethylethylenediamine TMS trimethylsilyl Ts toluenesulfonyl THF tetrahydrofuran viii TABLE OF CONTENTS 1.0 Introduction . 1 1.1 Syntheses of Sulfinimines . 5 1.1.1 Oxidation . 9 1.1.2 Iminolysis . 10 1.1.3 Condensation . 11 1.2 Reactions of Sulfinimines 1.2.1 Syntheses of amines . 14 1.2.1.1 Hydride reduction . 14 1.2.1.2 Reactions with organometallic compounds . 17 1.2.2 Syntheses of aziridines . 23 1.2.3 Syntheses of amino acids . 32 1.3 Nakadomarin A . 40 1.4 References . 53 2.0 Results and Discussion . 61 2.1 Towards the syntheses of sulfinimines . 62 2.1.1 Synthesis from Sulfinyl Chlorides . 64 2.1.2 Synthesis from amino alcohols . 70 2.2 Attempted Aziridinations . 81 2.3 Model studies towards the BCD ring of Nakadomarin A 90 2.4 References . 112 3.0 Experimental . 116 3.1 Attempted synthesis and resolution of sulfinimines via sulfinyl chlorides . 118 3.2 Synthesis of enantiopure sulfinimines using N-tosyl norephedrine 124 3.3 Synthesis of aziridines . 135 3.4 Syntheses and free radical reactions of sulfinimine derivatives . 140 3.5 References . 155 4.0 Appendices . 156 4.1 Appendix I- Crystal structure analysis of sulfininimine 255 . 166 ix 4.2 Appendix II- Crystal structure analysis of aminoindanyl sulfinamide 280 . 162 4.3 Chiral HPLC Data of the Sulfinimines . 172 Introductions 1 1.0 Introduction Introductions 2 A large majority of drugs and drug candidates incorporate amine functionality; greater than 75% according to some reports.1 Amines include important compounds such as morphine, quinine, nicotine and pseudoephedrine hydrochloride, (Figure 1). Despite their widespread abundance, efficient methods for the asymmetric syntheses of amines are often difficult and not widely available for the many structural classes of amines. N Me N HO HO CH3 H O O NH + - N 2 Cl H H C Me 3 N HO N Nicotine Morphine Quinine Pseudoephedrine Hydrochloride Figure 1 – Some biologically active compounds with amine functionality One of the most versatile procedures used to generate amines is the 1,2-addition of nucleophiles to imines. Imines are readily accessible by the condensation reaction of aldehydes and ketones with primary amines and amine derivatives. However, imines are poor electrophiles (compared to aldehydes and other carbonyl compounds) and when reacted with basic carbanion nucleophiles, are susceptible to competition between 1,2 addition, abstraction of acidic α-protons forming an aza-enolate or the formation of reductive coupling products (Scheme 1). Nitrogen substitution is required to prevent oligomerisation of imines2 and many imines are also hydrolytically unstable. Therefore, there are many challenges in the use and handling of imines as precursors to amines. Chemists have therefore exploited N-substituted imines and used this N-substitution to control reactivity. Introductions 3 R3 R3 R2 1 1 R 2 R N R N Nu 1,2-addition -deprotonation R3 + 1 Nu R 2 N R R1 reduction R3 2 3 R N R trimerisation 1 2 R 2 R3 R N R N N R1 R1 R2 R3 Scheme 1 – Possible reactions of imines A good N-substituent must offer an easy route to stable imines and also activate the imine for the addition of a wide range of nucleophiles. Such a substituent should ideally also be a chiral directing group, be inexpensive to synthesize or purchase and easy to cleave under mild conditions to afford the amine compound.3 Some of the N-substituents that have been used include the toluenesulfonyl (-Ts) the diphenylphosphine (-Dpp) and the para- methoxyphenyl (–PMP) groups. Though these have been used widely as protecting groups, they have however provided several challenges to the synthetic chemist. The –Ts3b,c and – PMP3d groups, for instance, have proved quite difficult to remove without the use of strongly acidic or reductive reagents and whilst it is relatively more easy to remove the – Dpp group, this renders N-Dpp protected substrates less stable and prone to hydrolysis.3e A group of N-substituents that satisfy all of these criteria and provide a very general approach for the synthesis of a broad range of amine-containing compounds3 are the sulfinyl protecting groups. N-Sulfinyl imines (sulfinimines) are a versatile class of intermediates in organic synthesis particularly for the preparation of amines and amine derivatives (Scheme 2).3a,4 Introductions 4 4 OR OMe O 3 O R - + Br - + CO Me R1 R2 O O M O M S 2 R N S 4 R N OR H 1 1 R2 R3 O R R ß-amino acids S aziridine 2-carboxylic acids 2 R N R N-Sulfinyl imines O O CN S Et2AlCN H2C S(O)nMe2 S 2 N R N R R H R1= H n =1, 2 2 -aminonitriles R1 R aziridines Scheme 2 – Some synthetic uses of sulfinimines Sulfinyl imines are stable and isolable compounds.