Total synthesis of (-)-bafilomycin A1

Karl A. Scheidt, Thomas D. Bannister, Akihiro Tasaka, Michael D. Wendt, Brad M. Savall, Glenn J. Fegley, William R. Roush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

A highly stereoselective total synthesis of (-)-bafilomycin A1, the naturally occurring enantiomer of this potent vacuolar ATPase inhibitor, is described. The synthesis features the highly stereoselective aldol reaction of methyl ketone 8b and aldehyde 60c and a Suzuki cross-coupling reaction of the highly functionalized advanced intermediates 12 and 39. Vinyl iodide 12 was synthesized by a 14-step sequence starting from the readily available β-alkoxy aldehyde 14, while the vinylboronic acid component 39 was synthesized by a nine-step sequence from β-hydroxy-α-methyl butyrate 44 via a sequence involving the α-methoxypropargylation of chiral aldehyde 49 with the α-methoxypropargylstannane reagent 54. Syntheses of fragments 12 and 39 also feature diastereoselective double asymmetric crotylboration reactions to set several of the critical stereocenters. The Suzuki cross-coupling of 12 and 39 provided seco ester 40, which following conversion to the seco acid underwent smooth macrolactonization to give 41. The success of the macrocyclization required that C(7)-OH be unprotected. The Mukaiyama aldol reaction between aldehyde 60c and the TMS enol ether generated from 8b provided aldol 65 with high diastereoselectivity. Finally, all silicon protecting groups were removed by treatment of the penultimate intermediate 65 with TAS-F (tris-(dimethylamino)suifonium difluorotrimethyisilicate), thereby completing the total synthesis of (-)-bafilomycin A1.

Original languageEnglish (US)
Pages (from-to)6981-6990
Number of pages10
JournalJournal of the American Chemical Society
Volume124
Issue number24
DOIs
StatePublished - Jun 19 2002

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'Total synthesis of (-)-bafilomycin A<sub>1</sub>'. Together they form a unique fingerprint.

Cite this