Enantioselective Total Syntheses of (+)-Aconicarmichinium C and (+)-Pendulumine I: Strategic Use of a Bridgehead Enone via a Kinetic-Resolution-Enabled Intermolecular Diels–Alder Reaction

Here, we report the asymmetric total syntheses of two C11-oxygenated napelline-type alkaloids, including (+)-Pendulumine I and (+)-Aconicarmichinium C, which hinge on the strategic design of a regioselective and enantiospecific trapping of a highly reactive [3.2.1]-bridgehead enone intermediate via a kinetic-resolution-enabled intermolecular Diels–Alder reaction. Combined experimental and computational studies revealed that the developed bridgehead-enone-mediated [4 + 2]-cycloaddition could proceed in a concerted and enantioselective process, wherein the observed excellent kinetic-resolution outcome was jointly governed by the distinct steric repulsion and the favorable secondary orbital interaction ( endo -type) both between a tailored chiral diene featuring a stereospecific oxygenated substituent at C1 and in situ generated racemic bridgehead enones. Coupled with a transannular intramolecular Mannich reaction to rapidly assemble the cage-like hexacyclic framework and a sequence of organized oxidation-state manipulations to precisely install oxygenated substitutions in the core skeleton, our strategy would streamline the synthetic design of ent -kaurenoid alkaloids and pave the way for their modular syntheses, as well as highlight the powerful utility of bridgehead-enone intermediates in the stereoselective construction of bridged polycyclic systems.