Total Synthesis of Bafilomycin V1:  A Methanolysis Product of the Macrolide Bafilomycin C2

• Published in: Journal of organic chemistry Vol. 67; no. 3; pp. 733 - 740
• Main Authors: Marshall, James A., Adams, Nicholas D.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08.02.2002
• Subjects: Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Organic chemistry; Preparations and properties; Zinc Organic compounds; Stille coupling; Propargylic compound; Lactonization; Chemical synthesis; Allenic compound; Macrolide; Organic stannane; Total synthesis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo015864x

A synthesis of bafilomycin V1, a methanolysis product of the macrolide natural product bafilomycin C2, is described. The route utilizes chiral nonracemic allenylzinc reagents, prepared in situ from propargylic mesylates, to access key segments of this methyl ester. The acetylenic moieties of the derived homopropargylic alcohol adducts play an important role in further elaboration of these subunits. Final assemblage of the 25-carbon chain, containing 12 stereocenters, an α-methoxy Z,E 1,3-dienic ester, and an additional E,E 1,3-diene, was achieved through Stille coupling of an acetylene-derived vinyl stannane and vinyl iodide of approximate equal complexity. Attempted cyclization of several C15 hydroxy acid derivatives to the 16-membered lactone bafilomycin A1, a potent inhibitor of vacuolar ATPases, could not be achieved.