Enantioselective ring opening of tropinone. A new entry into tropane alkaloids

Abstract

The lithium enolate of tropinone reacts with alkyl chloroformates to give 6-N-carboalkoxy-N-methyl-2-cycloheptenones (4). These compounds can be produced enantioselectively, in up to 95% ee, if chiral lithium amides (derived from optically pure amines 5–7) are used for deprotonation of tropinone in the presence of additives. The effect of additives such as LiCl, LiBr, LiF, LiClO 4 , CeCl 3 , ZnCl 2 , LiOH, TMEDA, HMPA, and DMPU on enantioselectivity of this deprotonation–ring opening sequence varies from slight to very large depending on the chiral amide – additive combination. Especially large increases in enantioselectivity are observed when the chiral, C2 symmetrical, lithium bis-α,α′-methylbenzylamide (Li-5a) is used with one equivalent of LiCl. This reagent is best generated in situ from the corresponding amine hydrochloride and n-BuLi (2 equiv.). The ring-opening reaction combined with transposition of the carbonyl group (via Wharton reaction or allylic oxidation) provides a new method of stereoselective synthesis of tropane alkaloids having a protected hydroxyl at C-6 or C-7 (6β- and 7β-acetoxytropanes 14a, b) and physoperuvine (19). Keywords: enantioselective deprotonation, tropane alkaloids.