Chemoenzymatic Synthesis of the Cyclopiane Family of Diterpenoid Natural Products

A three‐stage chemoenzymatic synthesis of the cyclopiane family and related diterpenes is reported. Deoxyconidiogenol with a 6/5/5/5‐fused tetracyclic cyclopiane skeleton was first produced by an engineered E. coli host harboring the corresponding terpene cyclase PchDS. Ten cyclopiane diterpenes were synthesized by late‐stage functionalization of rings A, B and D of the cyclopiane skeleton through direct redox operations, directed C‐H activation, and enzymatic hydroxylation, respectively. Skeletal diversification was achieved by taking advantage of the selective 1,2‐alkyl migration of a cyclopiane cation generated chemically or enzymatically. Three cyclopiane‐related skeletons, including the spiro 5/5/5/5‐tetracyclic skeleton of spiroviolene, the angular 5/6/5/5‐fused ring system of phomopsene, and the new linear 5/6/5/5‐fused tetracyclic ring system of amycolatene, were produced either by chemical skeletal transformation from the cyclopiane skeleton, or by terpene cyclases discovered by genome mining.