Evolution of a Short Route to Strychnine by Using the Samarium-Diiodide-Induced Cascade Cyclization as a Key Step

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI2 allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14% overall yield in ten steps, or 10% overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI2-induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.