Synthesis of the ABC Ring of Calyciphylline A-Type Alkaloids by a Stereocontrolled Aldol Cyclization: Formal Synthesis of (±)-Himalensine A

Abstract

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention. The synthesis of azatricyclic compound I constitutes a formal synthesis of himalensine A.

Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5–6–7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks

“…At this point, we decided to test the ring expansion method with a more demanding substrate, namely azatricyclo 9 , which has a 6,6,5 ring system (Scheme ) and was previously synthesized by our group in a formal synthesis of rac -himalensine A . The enlargement of the cyclohexanone subunit using the same reaction conditions as in the morphan series was not regioselective, and a 2:1 mixture of ketones 10a and 10b was isolated in 46% overall yield.…”

“…At this point, we decided to test the ring expansion method with a more demanding substrate, namely azatricyclo 9 , which has a 6,6,5 ring system ( Scheme 5 ) and was previously synthesized by our group in a formal synthesis of rac -himalensine A. 20 The enlargement of the cyclohexanone subunit using the same reaction conditions as in the morphan series was not regioselective, and a 2:1 mixture of ketones 10a and 10b was isolated in 46% overall yield. This result was not sufficiently satisfactory to justify continuing with this approach toward the target compound, especially considering the laborious preparation of azatricyclo 9 [type II scaffold ( Scheme 1 )].…”