NEW METHODS FOR ALKALOID SYNTHESIS - FACILE TOTAL SYNTHESES OF (+/-)-O-METHYLJOUBERTIAMINE AND (+/-)-MESEMBRINE

A general strategy for the construction of quaternary carbon atoms via geminal alkylation operations has been successfully employed in the facile total syntheses of the Sceletium alkaloids (±)-0-methyljoubertiamine (2) and (±)-mesembrine (3). The key step in these syntheses features the direct homologation of the monoprotected 1, 4-diones 14 and 23 into the enamine 15 and the metallo enamine 26, respectively, using variants of the Wittig reaction. The subsequent reactionof the enamine 15 with allyl bromide resulted in the generation of a fully substituted carbon atomthat was suitably functionalized for transformation to (±)-0-methyljoubertiamine (2). On the other hand, alkylation of the metallo enamine 26 with N-(2-bromoethyl)-N-methylcarbamate (27) allowed theeventual construction of the 4, 4-disubstituted cyclohexenone 29 which was readily elaborated into(±)-mesembrine (3). The efficiency of this new entry to the cis-3a-aryloctahydroindole alkaloids is underscored by thesynthesis of (±)-mesembrine (3) from veratraldehyde in 40% overall yield. An alternative synthesis of the cyclohexenone29is also described which exploits an improved procedure for the spiroannelation of a cyclohexenone at a carbonyl center. This useful synthetic method features the alkylation of the metallo enamines that are generated by homologation operations with 2-(2-bromoethyl)-2-methyl-1, 3-dioxolane, 31 —?32 —33—- 29. © 1979, American Chemical Society. All rights reserved.