Total Synthesis, Stereochemical Assignment, and Structural Revision of HA 23.

The absolute configurations of the polyketide fragment in the 12-membered macrolide HA 23 were initially proposed based on the "Biochemistry-based Rule" and subsequently confirmed through its first successful total synthesis. This synthesis, accomplished in 18 linear steps with an overall yield of 6.9%, featured key transformations including the Julia-Kocienski olefination, the Paterson anti-aldol reaction, and cross-metathesis. Importantly, the synthetic effort also corrected a prior misassignment of the tyrosine residue's stereochemistry. These results provide strong validation of the biochemistry-based rule as a reliable approach for predicting the absolute configurations of reduced polyketides derived from fungal sources and prompted a structural revision of natural HA 23.