Total Syntheses of Epothilones A and B

• Published in: Journal of the American Chemical Society Vol. 119; no. 42; pp. 10073 - 10092
• Main Authors: Meng, Dongfang, Bertinato, Peter, Balog, Aaron, Su, Dai-Shi, Kamenecka, Ted, Sorensen, Erik J, Danishefsky, Samuel J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.10.1997; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; SECONDARY ALCOHOLS; DESS-MARTIN PERIODINANE; ORGANIC-SYNTHESIS; CROSS-COUPLING REACTIONS; RING-CLOSING METATHESIS; UNSATURATED SUGARS; RIFAMYCIN-S; CYCLOCONDENSATION REACTIONS; OLEFIN METATHESIS; ETHYL DIAZOACETATE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja971946k

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 ). 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.