Short Synthesis of Alkaloid (-)-205B

The alkaloid (-)-205B has in the past served as a testing ground for novel approaches in nitrogen heterocycle synthesis. We herein report a highly straightforward synthesis of (-)-205B in just six synthetic steps, making it the shortest route currently known. The central steps of our approach are a vinylogous Mukaiyama-Mannich reaction to establish the first two stereogenic centers with excellent diastereo- and enantiocontrol followed by zinc-mediated Barbier allylation to set the third chiral center with high substrate control. Upon cyclization of the Barbier product to lactam and enolate methylation, the third ring is annulated by a one-pot sequence of lactam reduction and aza-Prins cyclization to directly set the final stereogenic center with complete cis-stereoselectivity. As the iminium ion undergoing the aza-Prins cyclization rapidly isomerized to a planar enamine intermediate, the alkaloid was eventually obtained as a 1:1 mixture of C6 diastereomers, which were readily separated by chromatography. Yet, the target natural product was obtained isomerically pure in an overall yield of 12%, which compares favorably with all previous syntheses.