EPC synthesis of tropane alkaloids via enantioselective deprotonation

Abstract

This dissertation deals with the application of enantiotopic group selective reactions to the synthesis of enantiomerically pure compounds (EPC). Deprotonation of tropinone with optically pure, chiral lithium amides was studied. The effects of additives such as lithium chlorids and other lithium salts (LiBr, Lil, LiClO4) on enantioselectivity of deprotonation of tropinone with chiral lithium amides were investigated. Increased selectivity was observed upon addition of lithium chloride in all tested deprotonation reactions. During these studies enantioselectivity as high as 97% ee was achieved in reactions of tropinone with chiral lithium amides prepared from $(S,S)$-$(-)$-$N,N$-bis(1-phenylethyl)amine hydrochloride and $(R)$-1-((2,2-dimethylpropyl)amino-2-phenylethyl) piperidine. Two different protocols for the highly enantioselective deprotonation of tropinone were employed in EPC syntheses of tropane alkaloids: chalcostrobamine, darlingine, isobellendine, knightinol, alkaloid KD-B, physoperuvine, 7β-acetoxy-3α-tigloyloxytropane, and 3$\alpha,7\beta$-diacetoxytropane. The products were obtained in good overall yields and in high optical purity (91-97%). The presented work shows that the enantioselective deprotonation of cyclic Cs symmetrical ketones is an attractive approach to the synthesis of enantiomerically pure natural products.