Total Synthesis of Bafilomycin A1

• Published in: Chemistry : a European journal Vol. 18; no. 12; pp. 3598 - 3610
• Main Authors: Kleinbeck, Florian, Fettes, Gabriela J., Fader, Lee D., Carreira, Erick M.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 19-03-2012; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: bafilomycin A1; Catalysis; Chemistry; enyne; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Macrolides - chemical synthesis; Macrolides - chemistry; Models, Molecular; natural products; Oxidation-Reduction; polyketide; Stereoisomerism; total synthesis; Vacuolar Proton-Translocating ATPases - antagonists & inhibitors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201102797

A convergent synthesis of bafilomycin A1, a potent inhibitor of V‐type ATPases, is presented. The synthesis relies on the zinc triflate mediated diastereoselective addition of a complex enyne to a sensitive aldehyde as the key fragment coupling. A ruthenium‐catalyzed trans‐reduction of the resulting propargylic enyne efficiently installs the required C10–C13 trans,trans‐diene subunit, implementing an alternative strategy to traditional palladium‐catalyzed cross‐coupling strategies. A highly selective oxidation of a secondary hydroxyl group in a triol sets the stage for the completion of the synthesis.
Tying the knot: A convergent synthesis of bafilomycin A1 is presented. The synthesis relies on the zinc triflate mediated diastereoselective addition of a complex enyne to a sensitive aldehyde as the key fragment coupling. A ruthenium‐catalyzed trans‐reduction of the resulting propargylic enyne efficiently installs the required C10–C13 trans,trans‐diene subunit.