JACS Au. 2026 Jul 30;6(9):5207-5213. doi: 10.1021/jacsau.6c00833. eCollection 2026 Sep 28.

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.

PMID:42819916 | PMC:PMC13625530 | DOI:10.1021/jacsau.6c00833