Total synthesis of mycolactones A and B

Abstract

First and second generation total syntheses of mycolactones A and B are reported. The first generation total synthesis unambiguously confirmed our earlier assignment of the relative and absolute stereochemistry of mycolactones A and B. Knowledge of the chemical properties of the mycolactones accumulated through the first generation total synthesis allowed us to implement several major improvements to the original synthesis, including: (1) optimizing the choice of protecting groups, (2) eliminating the unnecessary adjustment of protecting groups, and (3) improving the overall stereoselectivity and synthetic efficiency. The second generation total synthesis consists of 21 longest linear steps, with 8.8% overall yield.

A Ring‐Closing Metathesis (RCM)‐Based Approach to Mycolactones A/B

“…Briefly, commercially available (R)-3-hydroxybutanoic acid methyl ester (28) was elaborated into aldehyde 30 by a sequence involving tert-butyldimethylsilyl (TBS) protection, DIBAL-H reduction (to give 29), asymmetric crotylboration of 29, TBS protection of the newly formed hydroxyl group, and ozonolysis of the double bond. The yield obtained in the crotylboration step (39 %) was significantly lower than that reported by Kishi (78 %) [19] and, more recently, by Negishi (88 % for a 95:5 mixture of diastereomers) [24b] for the same transformation, but no efforts were made to optimize the reaction. Aldehyde 30 was then converted into dibromoolefin 31 by means of Corey-Fuchs chemistry [36] in 82 % yield; compound 31 was converted to the corresponding terminal acetylene, which was then methylated to give 32.…”

“…The coupling product, after selective deprotection of the C5 hydroxyl group, would then be esterified with I-2 to provide fully protected 1 a/b. Vinyl iodide I-4 and acid I-2 have been described previously by Kishi and co-workers [19] and we planned to follow the published syntheses of these intermediates with some modifications; for I-2, this would involve Horner-Wadsworth-Emmons (HWE) coupling of a phosphonate I-5 and aldehyde I-6 (Scheme 2), which display similar levels of complexity. Alkyl iodide I-3, comprising the core macrolactone of mycolactones with an appended C2 fragment at C11, was to be obtained through ring-closing olefin metathesis (RCM) [2a, 27] between C8 and C9.…”

“…The synthesis of 27 has been described previously by Kishi and co-workers [19] and we have followed the lead provided by this work with only minor modifications (Scheme 6). Briefly, commercially available (R)-3-hydroxybutanoic acid methyl ester (28) was elaborated into aldehyde 30 by a sequence involving tert-butyldimethylsilyl (TBS) protection, DIBAL-H reduction (to give 29), asymmetric crotylboration of 29, TBS protection of the newly formed hydroxyl group, and ozonolysis of the double bond.…”

“…Aldehyde 33 in Kishis synthesis was derived from the shorter aldehyde 39, which in turn could be obtained in seven steps from (S)-3-hydroxybutanoic acid methyl ester, albeit as a 3.8:1 mixture of diastereoisomers. [19] We have thus explored an alternative approach to aldehyde 39 that utilizes d-glucose as an inexpensive chiral starting material and that provides this intermediate as a single isomer. This approach was inspired by previous work by Feringa, Minnaard, and van Summeren, [38] who described the elaboration of methyl-a-d-glucopyranoside (35) into dithiane 36 (Scheme 7), building, in turn, on extensive prior work by Jennings and Jones [39] on the preparation of chlorodeoxy sugars.…”

“…[18] The Kishi group has elaborated first-, [12] second-, [19] and third-generation [20] approaches to the synthesis of mycolactones A/B (1 a/b) and it has also developed syntheses for mycolactones C, [21] E, [22] and F. [23] Beyond the intrinsic synthetic challenges posed by the complex molecular architecture of mycolactones, the synthetic work has been driven by the desire to provide sufficient amounts of pure material for systematic biological studies. The most recent rendition of Kishis mycolactone synthesis featured the construction of the core macrocycle (with C12-C13 already appended) by Yamaguchi macrolactonization, establishment of the complete C12-C20 side chain through formation of the C13-C14 bond by Negishi coupling, and attachment of the C1'-C16' acyl side chain by means of Yamaguchi esterification.…”