TOTAL SYNTHESES OF EPOTHILONE-A AND EPOTHILONE-B

Convergent, stereocontrolled total syntheses of the microtubule-stabil izing 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 (8 9 --> 90 + 91; 99 --> 100 + 101), simultaneously creating the C2-C3 bo nd and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16 -membered macrolide of the epothilones could be fashioned through a C1 2-C13 ring-closing olefin metathesis (e.g. see 111 --> 90 + 117; 122 - -> 105 + 123) and through macrolactonization of the appropriate hydrox y acid (e.g. see 88 --> 93). The application of a stereospecific B-alk yl Suzuki coupling strategy permitted the establishment of a cis C12-C 13 olefin, thus setting the stage for an eventual site-and diastereose lective epoxidation reaction (see 96 --> 2; 106 --> 3). The developmen t of a novel cyclopropane solvolysis strategy for incorporating the ge minal 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) method ology are also noteworthy.