A Programmable Synthesis of Diverse Terpene Architectures from Phenols

Over millennia, Nature has evolved exquisite synthetic pathways that combine isoprenes into chains, folds them into carbocycles, and then oxidizes/rearranges them into vast complexity (>50,000 members). While laboratory chemical synthesis can sometimes emulate this process, room exists for additional approaches that can also programmably lead to molecular diversity. Here we show that from simple phenols using 1) prenylation, 2) dearomatization/prenyl migration, and 3) epoxidation/radical cyclization, we can predictably, reliably, and expeditiously make polycyclic terpene frameworks; critically, step three uses the first cooperative bimetallic catalyst to effect cyclization of epoxy enones under H2. Indeed, our approach has led to the stereocontrolled formation of bicyclic, linear, angular, clovane, and propellane-based architectures with functional groups that allow further manipulation; for example, these motifs can be repurposed for ring contractions. Of note, several formal total syntheses have been achieved in routes that are as concise as, and often shorter than, previous efforts.