DFT Study on Retigerane-Type Sesterterpenoid Biosynthesis: Initial Conformation of GFPP Regulates Biosynthetic Pathway, Ring-Construction Order and Stereochemistry.

Retigerane-type sesterterpenoids, which feature a unique 5/6/5/5/5 fused pentacyclic structure with an angular-type triquinane moiety, are biosynthesized via successive carbocation-mediated reactions triggered by terpene cyclases. However, the precise biosynthetic pathways/mechanisms, wherein steric inversion of the carbon skeleton occurs at least once, remain elusive. Two plausible reaction pathways have been proposed, which differ in the order of ring cyclization: A → B/C → D/E-ring(s) (Route 1) and A → E → B → C/D-ring(s) (Route 2). Since the reaction intermediates of these complicated domino-type reaction sequences are experimentally inaccessible, we employed comprehensive density functional theory (DFT) calculations to evaluate these routes. The results indicate that retigeranin biosynthesis proceeds via Route 2 involving a multistep carbocation cascade, in which the order of ring cyclization (A → E → B → C/D) is the key to constructing the angular 5/5/5 triquinane structure with the correct stereochemistry at C3. The result also suggests that slight differences in the initial conformation have a significant effect on the order of cyclization and steric inversion. The computed pathway/mechanism also provides a rational basis for the formation of various related terpenes/terpenoids.