Enantioselective Total Synthesis of (+)-Bisabosqual A and Studies on Late-Stage C(sp3)–H Functionalization Approaches to Bisabosquals

Abstract

The bisabosquals are a family of natural products from Stachybotrys fungi with mixed polyketide terpene biosynthetic origin. These meroterpenoids feature complex and unique substructures, displaying a benzofuran-fused benzopyran, with 5-contiguous stereocenters, and all-cis ring fusion about the bisabolane-cyclohexyl ring. Additionally, the pentasubstituted aromatic ring features diverse substitution patterns that influence the bioactivity of the specific bisabosqual, which include antifungal, antiproliferative and mammalian squalene synthase inhibition. Interest in their chemical synthesis has largely focused on the tetracyclic core structure with the diverse arene substitutions unaddressed. Herein, we report studies investigating the viability of late-stage aromatic ring functionalization strategies designed to provide divergent access to bisabosqual natural products bearing differential functionality in the aromatic ring. While these studies ultimately proved unsuccessful, insights from these investigations informed our recently reported enantioselective total synthesis of (−)-bisabosqual F. Full details of these studies and extension of this work to the first enantioselective total synthesis of (+)-bisabosqual A are communicated herein.