The 2′-phosphodiesterase inhibitor A-74528, which combines an intriguing biosynthesis with unusual biological activity, is one of the most complex type II polyketides. As a synthetic target, it represents a significant challenge due to its size but also due to a unique carbon skeleton that features a hexacarbocyclic core with an appended pyrone. Here we report our efforts toward the synthesis of A-74528, which culminated in the construction of the full carbon skeleton and the correct installation of all but one stereocenter. Our strategy employs a molybdenum-catalyzed branched allylation to establish the central quaternary carbon and relies on establishing the remaining stereocenters in a substrate-controlled manner. Carbocycles were established using a spiro epoxide annulation, a 1,3-dipolar cycloaddition, followed by an aldol condensation, and a gold-catalyzed hydroarylation. The pyrone was appended to an aldehyde branching off the quaternary stereocenter by a one-carbon homologation and Mukaiyama aldol addition.
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