TOTAL SYNTHESIS OF THE MACROLIDE ANTIBIOTIC CYTOVARICIN

A convergent asymmetric synthesis of the antineoplastic macrolide antibiotic cytovaricin has been achieved through the synthesis and coupling of the illustrated spiroketal and polyol glycoside subunits. All absolute stereochemical relationships within the target structure were ultimately controlled by the use of asymmetric aldol, alkylation, or epoxidation methodology. Union of the two subunits was accomplished by Julia-Lythgoe trans olefination, providing direct access to a suitable macrolactonization substrate. A high-yielding ring closure (92%) and subsequent three-step refunctionalization of the macrocyclicproduct afforded cytovaricin. In supporting studies, the solution conformation and chemical reactivity of the natural product were also examined. Three-dimensional overlay of cytovaricin with rutamycin A indicates an unexpected homology between the two structures, in turn suggesting a potential mode of action for cytovaricin. © 1990, American Chemical Society. All rights reserved.