Epothilone analogs improved

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

Fortunately, the medicinal chemical efforts applied to understand and improve the biological activity of epothilones have been enormous. Epothilones, unlike PTX with its baccatin core, can be produced through several synthetic approaches discussed in this volume. Accordingly, the structural variety of analogs tested has been vast. Three excellent reviews have highlighted developments over the past decade [40-421. Many hundreds of analogs have been produced and tested, but very few have significantly better potency than the natural products. 

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