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

Abstract

A synthesis of bafilomycin V(1), a methanolysis product of the macrolide natural product bafilomycin C(2), 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 alpha-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 A(1), a potent inhibitor of vacuolar ATPases, could not be achieved.

4,5‐Disubstituted N,N′‐Di‐tert‐alkyl Imidazolium Salts: New Synthesis and Structural Features

“…Gratifyingly, this new approach culminated in the development of the general and efficient synthesis of the unprecedented subfamily of 1,3-di-tert-alkyl-4,5-dimethylimidazolium salts 1 a-d starting from rac-but-3-yn-2-yl methanesulfonate [19] (Scheme 1 and Table 1). …”

Organotin Reagents in Cross‐Coupling Reactions

“…Final assembly of the 25-carbon chain (containing 12 stereocenters) of bafilomycin V1 by Marshall and Adams [110] involved an acetylenederived vinyltin and a vinyl iodide of similar complexity. Paquette et al [111] reported a highly convergent three-component 64-step total synthesis of the potent immunosuppressive agent (−)-sanglifehrin A, the penultimate step involving a vinyl-vinyl coupling.…”

Structures and Total Syntheses of the Plecomacrolides

“…In 2002, Marshall and Adams [90] reported a total synthesis of bafilomycin V 1 (112) [8], a seco-ester product obtained from methanolysis of bafilomycin C 2 (111) (Fig. 5), demonstrating stereoselective additions of non-racemic chiral allenylzinc reagents [91] with aldehydes for installation of various stereotriads.…”

“…Attempts were also made to effect macrolactonization of the seco-acid obtained from the methyl ester 135 (KOTMS, THF, rt) [103] in quantitative yield. However, macrolactonization failed with both the Yamaguchi method [51] and the "double activation" method based on 2,2'-dipyridyl disulfide and Ph 3 P [104], presumably due to decomposition of the activated intermediate [90]. At this point, it is interesting to examine the structural difference in the seco-acid 45 (Scheme 6) [41], the seco-acid 75b (Scheme 11) [55], and the seco-acid of 135 [90].…”

“…However, macrolactonization failed with both the Yamaguchi method [51] and the "double activation" method based on 2,2'-dipyridyl disulfide and Ph 3 P [104], presumably due to decomposition of the activated intermediate [90]. At this point, it is interesting to examine the structural difference in the seco-acid 45 (Scheme 6) [41], the seco-acid 75b (Scheme 11) [55], and the seco-acid of 135 [90]. Under the Yamaguchi macrolactonization conditions, the seco-acids 45 and 75b with a shorter side chain gave the desired macrolides in ca.…”