Synthesis of a new class of homochiral amines and novel bio-active tropanes

Abstract

This thesis describes two main programmes: the synthesis of a new class of homochiral amines and the synthesis of ketone analogues of 3a-esterified tropane alkaloids. In chapter one, a scaled-up synthesis of (5)-a-(diphenylmethyl)pyrrolidine 1 is described. The key hydrogenation step of the oxazolidinone intermediate 2 was extended to the synthesis of the other chiral amines 70, 73, 76, 79 and 82. Hydrogenation of the oxazolidinones proceeded in good yields (71 - 87 %) and was not susceptible to racemisation. Thus, a convenient route from amino acid ester hydrochlorides (S)-valine 65, (S)-phenylalanine 66, (S)-alanine 67, (S)-isoleucine 68 and (S)-leucine 69 allowed a range of novel chiral amines to be prepared. In chapters two and three, a new route to ketone analogues of tropane esters is described. In chapter two, results of an attempt to prepare ketone 110 are outlined. Ketone 110 is an analogue of the tropane alkaloid littorine 101, where the bridging ester O atom is replaced by a CH2 group. The first approach to ketone 110 involved the Wittig reaction of acetylmethylenephosphorane 118 and the Homer-Wadsworth- Emmons reaction of diethylbenzoylmethanephosphonate 122 with tropinone 116. Tropinone 116 was found to be particularly unreactive in both cases. The second approach to ketone 110 involved the coupling reactions of both N-troc-3a- tosyloxymethyltropane 170 and N-troc-3 a-iodomethyltropane 185 with 2-phenylacetyl- 1,3-dithiane 147 and 1,3-ditihiane 142. These were also unreactive and as a result the synthesis of ketone 110 remains unresolved. In chapter three, the synthesis of other ketone analogues of naturally occurring 3 a- esterified tropane alkaloids is described. A six-step route to the ketones was devised and in this route the Grignard reactions of tropan-3 -ylacetaldehyde 227 emerged as the key to the success of the strategy. Three ketone analogues 218, 219 and 220 of tropate esters were successfully prepared. Ketone 220, the analogue of apoatropine 201, was found to be a muscarinic acetylcholine receptor antagonist (EC(_50) 1.9x10(^-7) M) in guinea-pigileum, showing a 500-fold less activity than atropine 202. However the activity is still within the clinical range.