Total Synthesis of the Nominal Structure of (+)-Talaromyolide D

We describe a convergent and stereoselective total synthesis of the nominal structure of (+)-talaromyolide D (<b>4</b>), a recently isolated secondary metabolite. This meroterpenoid features a unique pentacyclic skeleton distinguished by a fused 6/6/6 dihydroisocoumarin core and an unusual pendant dimethylcyclobutanol embedded within a sequence of four contiguous stereocenters. Our synthetic strategy was enabled by a stereoretentive, nickel-catalyzed electrochemical sp²-sp³ decarboxylative cross-coupling, a two-fold bidirectional stitching sequence comprised of an oxime-directed β-C(sp³)-H arylation and S_NAr to establish the central ring system of the target as well as a series of two late-stage carboxylic-acid-directed C(sp²)-H oxidation reactions to ultimately access the isocoumarin lactone substructure. This asymmetric synthesis provides the first access to the reported structure of talaromyolide D (<b>4</b>). Comparison of the spectral data showed that the structure of this natural product had been misassigned, and our strategy may present an opportunity for further structural elucidation of the talaromyolide family isolates.