Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade

Abstract

Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Herein we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy efficiently forges challenging 5/8/5-fused ring systems found in numerous complex natural product classes and enabled a nine-step total synthesis of (−)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small-molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficiently accessing historically challenging terpenoid ring systems of interest in medicinal research.

A Radical Cascade Enabling Collective Syntheses of Natural Products

“…[15][16][17][18][19] However, their application in constructing complex naturally predefined architectures, and especially in resolving the major problems-namely collective syntheses of bioactive natural products 20 -is still underexploited. [21][22][23] This is largely because of the high reactivity of radicals, which is difficult to control with multiple functionalities in the substrate, thus resulting in poor stereoselectivity and chemoselectivity. In addition, tedious preparation of an initiating group for the classic radical reaction further impedes its application.…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…397 There have been three total syntheses of members of the ophiobolin family, including the seminal synthesis of ophiobolin C by Kishi in 1989, 398 a synthesis of ophiobolin A by Nakada in 2011, 399,400 and a recent synthesis of 6- epi -ophiobolin N by Maimone in 2016 (Scheme 30). 401 …”

Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases

“…Bifunctional enzymes comprising of fused prenyl transferase and terpene cyclase domains have been discovered from fungi, such as the fusicoccadiene synthase from Phomopsis amygdali (Toyomasu et al, 2007) and ophiobolin sesterterpene synthases from various fungi (Chiba et al, 2013;Brill et al, 2016). However, to the best of our knowledge GTs have not yet been reported as part of multifunctional proteins.…”