Enantioselective Total Synthesis of (-)-Vinigrol: The Evolution of a Transannular Diels-Alder Strategy

J Org Chem. 2024 Feb 2;89(3):1709-1718. doi: 10.1021/acs.joc.3c02407. Epub 2024 Jan 10.

Abstract

Vinigrol is a structurally and stereochemically complex diterpenoid that displays various potent pharmacological activities. Two generations of synthetic routes were designed and pursued based on a transannular Diels-Alder (TADA) cycloaddition strategy. An intramolecular [2 + 2]photocycloaddition in the presence of the chelating Lewis acid (MgBr2·Et2O) was first discovered to enable the reaction of sterically challenging substrates, which was followed by [2 + 2]cycloreversion to provide α-pyrones fused with a 10-membered ring. Eventually, a new and scalable synthetic route toward (-)-vinigrol was developed and provided over 600 mg materials, manifesting the power of macrocyclic stereocontrol and TADA reaction.