Equilibrium-Controlled Stereoselective Sequential Cyclizations Enabled Concise Total Synthesis of Complex Indole Alkaloid, Tronocarpine

Abstract

Tronocarpine is a pentacyclic monoterpenoid indole alkaloid, isolated from Tabernaemontana corymbosa in 2000 by Kam and coworkers. Although several synthetic studies of this molecule have been reported, no total synthesis has been reported until the end of 2019. The first asymmetric total synthesis of tronocarpine was reported by Han and coworkers in twenty steps from tryptamine, utilizing a catalytic asymmetric Michael/aldol cascade reaction. At about the same time, we, too, succeeded in carrying out the racemic total synthesis of tronocarpine and reported our achievement in the beginning of 2021. Our investigations set the equilibrium-controlled stereoselective tandem cyclization as a key reaction. The designed tandem cyclization, with a chain-like substrate including an indole ring, all-carbon units, and functional groups, was realized to construct the pentacyclic skeleton of tronocarpine in a one-pot operation. Thereby, we reduced the number of synthetic steps significantly, achieving the concise total synthesis of tronocarpine in nine steps from commercially available reagents. This synthetic strategy resulted in the construction of an azabicyclo[3.3.1]nonane core—a key skeleton of tronocarpine—which could then be applied to the total synthesis of other chippiine–dippinine-type alkaloids. We also succeeded in achieving the enzymatic optical resolution, to obtain chiral products of the thus-developed synthetic routes.