Total syntheses of epothilones A and B

Dongfang Meng, Peter Bertinato, Aaron Balog, Dai Shi Su, Ted Kamenecka, Erik J. Sorensen, Samuel J. Danishefsky

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Abstract

Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme 1). Of these four, three were reduced to practice. In one approach, the action of a base on a substance possessing an acetate ester and a nonenolizable aldehyde brought about a remarkably effective macroaldolization see (89 → 90 + 91; 99 → 100 + 101), simultaneously creating the C2-C3 bond and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16-membered macrolide of the epothilones could be fashioned through a C12-C13 ring-closing olefin metathesis (e.g. see 111 → 90 + 117; 122 → 105 + 123) and through macrolactonization of the appropriate hydroxy acid (e.g. see 88 → 93). The application of a stereospecific B-alkyl Suzuki coupling strategy permitted the establishment of a cis C12-C13 olefin, thus setting the stage for an eventual site- and diastereoselective epoxidation reaction (see 96 → 2; 106 → 3). The development of a novel cyclopropane solvolysis strategy for incorporating the geminal methyl groups of the epothilones (see 39 → 40 → 41), and the use of Lewis acid catalyzed diene-aldehyde cyclocondensation (LACDAC) (see 35 + 36 → 37) and asymmetric allylation (see 10 → 76) methodology are also noteworthy.

Original languageEnglish (US)
Pages (from-to)10073-10092
Number of pages20
JournalJournal of the American Chemical Society
Volume119
Issue number42
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Meng, D., Bertinato, P., Balog, A., Su, D. S., Kamenecka, T., Sorensen, E. J., & Danishefsky, S. J. (1997). Total syntheses of epothilones A and B. Journal of the American Chemical Society, 119(42), 10073-10092. https://doi.org/10.1021/ja971946k