A bio-inspired cascade and a late-stage directed sp3 C[sbnd]H lithiation enables a concise total synthesis of (−)-virosaine A

Abstract

The asymmetric total synthesis of (−)-virosaine A was achieved in 9% overall yield from commercially/readily available starting materials. Inspired by an intriguing biosynthetic proposal, a novel cascade reaction sequence was developed to efficiently construct the caged polycyclic core of virosaine A. The pivotal cascade precursor was readily available in enantiopure form via a robust route that featured an enantioselective one-pot Diels-Alder cycloaddition/organolithium addition. Several contemporary methods of CH functionalization were applied to the cascade product and yielded a diverse set of novel complex polycycles. Ultimately, a combination of NMR and computational analyses laid the groundwork for a successful directed lithiation strategy to selectively functionalize the caged core and complete the total synthesis of virosaine A.