Total Synthesis and Stereochemical Assignment of (-)-Ushikulide A

We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp IUK-102 and exhibits potent immunosuppressant activity (IC50 = 70 nM). To embark upon art ushikulide A synthesis, a tentative assignment was made based on analogy to cytovancin (2), a related macrclide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde With methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and siignificantly extended the scope of the above-mentioned methodologies