Total synthesis of spirocyclic PKS-NRPS-based natural products

Abstract

1. We describe the total synthesis of (±)-berkeleyamide D using a biosynthetically inspired strategy. The spirocyclic core of berkeleyamide D was constructed via sequential epoxidations and a late-stage base-mediated cyclization of a biosynthetically relevant precursor. Our synthetic solution might be applicable to access other fungal natural products of this family. 2. The total synthesis of (±)-azaspirene was achieved in a total of six steps from commercially available materials. Keys to the conciseness of our synthetic approach were the effective γ-lactam formation from linear precursor and successful tandem epoxidations of γ-lactam to afford α,β-epoxy-γ-hydroxy-γ-lactam intermediate. While our streamlined synthesis of azaspirene sought inspiration from its biogenetic hypothesis, experimentally observed chemical reactivity of biosynthetically relevant precursors conversely provides insights to the biological origin of this natural product. 3. We completed a nine-step total synthesis of (–)-FD-838 and (–)-cephalimysin A. Keys to the success were biogenetically guided assembly of the highly oxidized spirocyclic core by Snider-type tandem epoxidations and efficient chirality transfer from a chiral pool material. Our synthetic approach provides a general and versatile solution to access spirocyclic PKS-NRPS-based secondary fungal metabolites.