Bioinspired Asymmetric Total Synthesis of Emeriones A–C

Abstract

We report an asymmetric bioinspired total synthesis of the fungal metabolites emeriones A–C via stereoselective late-stage epoxidation or endoperoxidation of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffold is synthesized in an 8pi/6pi electrocyclization cascade of a stereodefined (E,E,Z,Z,E)-pentaene, which contains the fully assembled and unprotected side chains of the natural products. The pentaene is constructed convergently through Stille cross-coupling of two similarly complex polyenes. The anti-aldol side chain of the emeriones is made using a Paterson-aldol approach, and the epoxide of the dioxobicyclo[3.1.0] side chain is synthesized via ring-closure onto an oxidized para-methoxyphenyl acetal. Our total synthesis has enabled the revision of the structure of emerione C and the synthesis of a “missing” family member, which we hereby call emerione D. DFT calculations indicate the two methyl groups that reside on the cyclobutene ring are critical for the stereochemical outcome of 8pi/6pi electrocyclization.