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.

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1,970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM͞VBL 100 cells, IC 50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 M, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25-40 mg͞kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7͞ Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i.v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

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