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 (IC(50) = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide 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 significantly extended the scope of the above-mentioned methodologies.
Department of Chemistry, Stanford University, Stanford, California, 94305-5080, USA.
Barry M
BM
Trost
Brendan M
BM
O'Boyle
Daniel
D
Hund
D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry; D005663:Furans / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism
D001688:Biological Products; D005663:Furans; D018942:Macrolides; D013141:Spiro Compounds; C520774:spiroketal; C504254:ushikulide A