Chemical modification of ansamitocins. II. Synthesis of 3-epimaytansionoids via 3-maytansinones.

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Abstract
As part of a recent search for new semisynthetic analogs of maytransinoids having a better therapeutic ratio than maytansine [an antitumor agent], 3-epimaytansinoids (VIIa-c [3-epimaytansinol 3-isobutyrate, 3-epimaytansinol 3-n-octanoate and 3-epimaytansinol 3-phenylacetate]) were synthesized starting from ansamitocin P-3, a fermentation product of Nocardia sp., via maytansinol (I). A key intermediate, 3-epimaytansinol (VI), was synthesized by oxidation of I with pyridinium chlorochromate to 3-maytansinone (IV), followed by stereoselective reduction with NaBH4. Esterification of VI with appropriate carboxylic acids gave the corresponding 3-epimaytansinoids (VIIIa-c) in high yields. These compounds did not show the biological activity characteristic of natural maytansinoids to any appreciable degree.