Formal Chemoenzymatic Skeletal Editing of Fusicoccane Core to Access 6-Aza-Fusicoccanes

Abstract

Fusicoccane (FC)-type diterpenoids constitute a family of cyclic diterpenoids featuring a 5/8/5-fused tricyclic carbon skeleton. These natural products have attracted considerable attention owing to their unique biological functions, including plant hormone-like properties and antiproliferative activities against cancer cells. Herein, we report the stereoselective synthesis of 6-aza-FC-type analogs via a chemoenzymatic skeletal editing approach using CotB2, a diterpene synthase responsible for constructing the FC skeleton. Based on the biosynthetic reaction mechanism, we designed an unnatural substrate bearing an amide moiety at the C6–C7 position of geranylgeranyl pyrophosphate. CotB2 promoted the cyclization of this substrate to afford an optically active 5/11-fused lactam in a stereoselective manner. Subsequent intramolecular cyclization of the resulting lactam through an epoxide intermediate furnished 6-aza-FC derivatives, in which the C6 carbon of FC skeleton is replaced with a nitrogen atom. Notably, one of the 6-aza-FC analogs exhibited selective cytotoxicity toward cancer cells, while displaying reduced activity toward HUVEC cells.