Published on Web 05/23/2002
Total Synthesis of (-)-Bafilomycin A1
Karl A. Scheidt,1 Thomas D. Bannister,2 Akihiro Tasaka,2 Michael D. Wendt,2
Brad M. Savall,1 Glenn J. Fegley,2 and William R. Roush*,1
Contribution from the Department of Chemistry, UniVersity of Michigan,
Ann Arbor, Michigan 48109, and Department of Chemistry, Indiana UniVersity,
Bloomington, Indiana 47405
Received December 27, 2001
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 â-alkoxy aldehyde 14, while the vinylboronic acid component 39 was
synthesized by a nine-step sequence from â-hydroxy-R-methyl butyrate 44 via a sequence involving the
R-methoxypropargylation of chiral aldehyde 49 with the R-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
A1.
Introduction
that is necessary for biological activity. The structurally distinc-
tive C(2)-C(5) dienyl methyl ether system is also found in other
members of this family.
Bafilomycin A1 (1)3 is a member of the plecomacrolide family
(formerly known as the hygolide family)4 of macrolide antibiot-
ics that includes the hygrolidins,5,6 the concanamycins (e.g.,
concanomycin A, 2),7 and formamicin, 3.8,9 Bafilomycin A1 is
a potent vacuolar H+-ATPase inhibitor that displays broad
antibacterial and antifungal activity.10 The stereochemistry of
bafilomycin A1, initially assigned by Corey on the basis of a
molecular modeling analysis of published NMR data,4 was
subsequently verified by X-ray crystallography.11,12 Bafilomycin
A1 contains an acid- and base-sensitive six-membered hemiketal
that participates in a hydrogen-bond network with the C(17)
hydroxyl group and the carbonyl of the 16-membered lactone
In view of the interesting chemical structures and potent
biological properties, considerable effort has been devoted to
the development of efficient syntheses of members of this
family. Total syntheses of bafilomycin A1 have been recorded
by Evans13,14 and Toshima,15-17 and very recently total syntheses
of bafilomycin A1 and V1 have been accomplished by Hanessian
and Marshall, respectively.18,19 A total synthesis of hygrolidin
has been accomplished by Yonemitsu,20,21 and total syntheses
of concanamycin F (the aglycone of concanamycin A) have been
recorded by both the Toshima and Paterson groups.22-24 Several
25-28
studies on the synthesis of bafilomycin A1
and of bafilo-
(1) University of Michigan.
(2) Indiana University.
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Matsumura, S. J. Org. Chem. 2001, 66, 1708.
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Chem., Int. Ed. 2000, 39, 1308.
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10.1021/ja017885e CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 6981-6990
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