Through a series of keystone studies, synthetic entry into 3,5-dimethylorsellinic acid (DMOA) meroterpenoids has been established. A 13-step synthesis of the caspase-1 inhibitor berkeleyone A was achieved using the first examples of two critical bond-forming reactions: an epoxide-initiated, β-ketoester-terminated polyene cyclization, and a Claisen-isomerization-cyclization cascade to furnish the majority of the natural product carbon skeleton in just six synthetic steps. Oxidative elaboration to protoaustinoid A and berkeleyone A was enabled by the allylic oxidation of an enol triflate, and the synthetic sequence has been leveraged to access natural product analogs for evaluation of cytotoxicity. Intermediates en route to these natural products enabled detailed studies on the biosynthesis of DMOA meroterpenoids, including insights into the bifurcating pathway that distinguishes between the berkeleyone, andrastin, and terretonin families. Computational techniques were used to identify potential mechanisms for enzymatic control of these biosynthetic pathways, and the total synthesis of a number of andrastins and terretonins was achieved.

Synthetic entry into 3,5-dimethylorsellinic acid meroterpenoids

256th National Meeting (2018)

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