Total synthesis of (−)-kopsinine and ent-(+)-kopsinine

Abstract

The total synthesis of (−)-kopsinine and its unnatural enantiomer is detailed, enlisting a late-stage SmI2-mediated transannular free radical conjugate addition reaction for construction of the core bicyclo[2.2.2]octane ring system with strategic C21–C2 bond formation. Key to the approach is assemblage of the underlying skeleton by an intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the precursor C21 functionalized pentacyclic ring system 1 in a single step in which the C3 methyl ester found in the natural product served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole.