We report herein a stereoselective synthesis of the side chains of mycolactones A (1 A) and B (1 B). These side chains 2 A and 2 B, respectively, are protected as a methoxymethyl (MOM) ether at C12 and tert-butyldimethylsilyl (TBS) derivatives at C13 and C15, and are thus ready to be used as intermediates for the synthesis of 1 A and 1 B (Scheme 1).
Mycolactones A (1 A) and B (1 B) were isolated in 1999 by Small and co-workers [1] from Mycobacterium ulcerans, the causative pathogen of Buruli ulcer. Although their gross structures (atom connectivities) were elucidated through 2D NMR spectroscopic analysis, [1b] the finer stereochemical details were established by comparative NMR spectroscopic analysis of various stereoisomers of the molecular core [2] and the side chains as well as the entire compound, [3] prepared through stereodivergent syntheses. [4, 5] Apart from their biological and medicinal significance, both 1 A and 1 B contain conjugated pentaenes that display a rare and synthetically difficult methyl-substitution pattern, as well as two adjacent oxygenated asymmetric carbon centers; these compounds thus caught our attention as attractive and challenging synthetic targets. Although the head-to-tail (Hto-T; Scheme 2) construction of the pentaene fragment through the combined use of hydrozirconation-Pd-catalyzed cross-coupling [6] and carboalumination-Pd-catalyzed crosscoupling [6a-c, 7] appears eminently feasible, most of the widely employed methods for the asymmetric synthesis of trisubstituted alkenes with an a-chiral substituent at the tail end, including those cited above, [2-5] involve tail-to-head (T-to-H; Scheme 2) construction. The synthesis of at least part of the desired pentaene fragments of 2 A and 2 B thus calls for the use of the same Tto-H construction protocol (Scheme 2).
It then occurred to us that the stereoselective T-to-H construction of trisubstituted alkenes by stepwise double substitution of 1,1-dihalo-1-alkenes [8-10] could be combined with the H-to-T construction of an appropriate head side fragment to produce 2 A and 2 B. Accordingly, the C1-C7 segment of 2 B, that is, 3 B, was synthesized in six steps from propargyl alcohol in 23 % overall yield with > 98 % stereoselectivity (Scheme 3). Throughout its synthesis no other stereoisomer was detected. Although the Pd-catalyzed cross-coupling generally proceeds in higher yields with protected alcohol derivatives, the Zr-catalyzed carboalumination of unprotected allyl and propargyl alcohol derivatives proceeds in higher yields than that of their protected derivatives. Thus, the synthesis of 3 B (Scheme 3) may represent a compromise that favors efficiency, but no further efforts were made to optimize the yield of 3 B. The hydrozirconation reaction in the first step makes use of a recently developed in situ generation of [HZrCp 2 Cl] by the treatment of iBu 2 AlH with [Cp 2 ZrCl 2 ] (Cp = cyclopentadienyl). [11] The use of ethynylzinc reagents in Pd-catalyzed alkynylation [12, 13] permits the direct synthesis of terminal alkynes that would otherwise require two additional steps for protection and deprotection, such as with the Sonogashira alkynylation. [13, 14] The T-to-H synthesis of 4, which can serve as a key intermediate corresponding to the C8-C16 segment of either Scheme 1. Mycolactones A and B and their triprotected side chains.