The first stereospecific total-synthesis of the C-19 methyl substituted macroline- sarpagine indole alkaloids macrocarpine A-G has been completed. The key steps included an effective method for the enolate driven copper mediated cross-coupling of a vinyl iodide (2) with a ketone effected in high yield (86-89%) to replace an expensive Pd-mediated cross-coupling process (68-72%). An unusual cyclization product (3b) which presumably formed via a radical mechanism was observed and inhibited with TEMPO as the radical scavenger. The investigation into the mechanism revealed more than one competing pathways towards the cross-coupled products. This new cross-coupling condition provides a better route to the pentacyclic ketone (3a) which is a key intermediate common to many C-19 methyl substituted sarpagine-macroline indole alkaloids. Studies towards the optimization of the reaction conditions and elucidation of the cross-coupling reaction mechanism will be presented.

First total-synthesis of macroline indole alkaloids macrocarpine A-G via an efficient, enolate-driven, copper-mediated cross-coupling process

251st National Meeting (2016)

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