HETEROCYCLES IN ASYMMETRIC-SYNTHESIS .2. EFFICIENT ASYMMETRIC APPROACHES TO HETEROYOHIMBINE, YOHIMBINE AND RELATED ALKALOIDS

Asymmetric syntheses of heteroyohimbine, yohimbine, and related alkaloids are reported. The piperidine derivative ethyl (-)-(3-acetyl-1-benzylpiperidin-4-yl)acetate (-)-2, which was obtained by an asymmetric intramolecular Michael reaction of the acyclic compound ethyl 5-[benzyl-(3-oxobutyl)-amino]pent-2-enoate 1, was stereoselectively converted into the (-)-lactone methyl (1S,4aR,8aR)-3,4,4a,5,6,7,8,8a-octahydro-1-methyl-3-oxo-1H-pyrano[3,4-c]pyridine-7-carboxylate (-)-7 and (+)-olefin methyl [(R)-3-(Z)-ethylidene-1-methoxycarbonylpiperidin-4-yl]acetate 15. The (-)-lactone (-)-7 was transformed into (-)-ajmalicine 3 in 5 steps. The (+)-olefin (+)-15 is the precursor in a published route to (-)-tetrahydroalstonine. The (-)-piperdine (-)-2 was also converted into the alpha,beta-unsaturated ketone t-butyl (4aR,8aR)-(-)-1,2,3,4,4a,5,6,8a-octahydro-6-oxoisoquinoline-2-carboxylate (-)-30 in 6 steps. Stereoselective introduction of the methoxycarbonyl group into this last compound, followed by stereoselective reduction of the ketone moiety with L-Selectride, afforded the D/E-ring system of (+)-yohimbine. This can be converted into yohimbine by following the established sequence. The conversion of the (-)-piperidine derivative (-)-2 ethyl [(4R,5R)-5-ethyl-2-oxopiperidin-4-yl]acetate (+)-21 for the synthesis of (-)-emetine 23 was also accomplished.