Total synthesis of (-)-bafilomycin A(1).
A highly stereoselective total synthesis of (-)-bafilomycin A(1), 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 beta-alkoxy aldehyde 14, while the vinylboronic acid component 39 was synthesized by a nine-step sequence from beta-hydroxy-alpha-methyl butyrate 44 via a sequence involving the alpha-methoxypropargylation of chiral aldehyde 49 with the alpha-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)sulfonium difluorotrimethylsilicate), thereby completing the total synthesis of (-)-bafilomycin A(1).
Scheidt
Karl A
KA
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bannister
Thomas D
TD
Tasaka
Akihiro
A
Wendt
Michael D
MD
Savall
Brad M
BM
Fegley
Glenn J
GJ
Roush
William R
WR
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D000935:Antifungal Agents / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D018942:Macrolides; D013237:Stereoisomerism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases