The synthesis of diverse terpene architectures from phenols

Nature has evolved exquisite synthetic pathways for terpenes by combining isoprenes into chains, folding them into carbocycles and then oxidizing and/or rearranging them into a vast range of complex molecules (>50,000 examples). Although laboratory syntheses can sometimes emulate elements of this process, additional approaches that can similarly emulate nature’s approach and lead to molecular diversity are desirable. Here we show that the synthesis of polycyclic terpene molecules can be achieved through a predictable and reliable process that starts from phenols. The synthetic route comprises three steps: prenylation, dearomatization and/or prenyl migration, and, finally, epoxidation and/or radical cyclization. Critically, the third step uses a cooperative bimetallic catalyst to mediate the cyclization of epoxy enones under hydrogenative conditions. Overall, this approach leads to the stereocontrolled formation of bicyclic-, linear-, angular-, clovane- and propellane-based terpene structures with functional groups that allow further manipulation. For example, these motifs can be repurposed for ring contractions to access additional terpene-based architectures. Of note, several natural products were prepared through a formal total synthesis using this approach; these routes are as concise as, and often shorter than, previously reported syntheses.