Epothilones A and B, two compounds that have been recently isolated from myxobacterium Sorangium cellulosum strain 90, have generated intense interest among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with microtubules and anticancer potential of these molecules. Like taxol, they exhibit cytotoxicity against tumour cells by inducing microtubule assembly and stabilization, even in taxol-resistant cell lines. Following the structural elucidation of these molecules by X-ray crystallography in 1996, several syntheses of epothilones A and B have been reported, indicative of the potential importance of these molecules in the cancer field. Here we report the first solid-phase synthesis of epothilone A, the total synthesis of epothilone B, and the generation of a small epothilone library. The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-product synthesis and, together with solution-phase synthesis of other epothilones, paves the way for the generation of large combinatorial libraries of these important molecules for biological screening.
The total syntheses of epothilones A (1) and B
(2) and several analogues thereof are described.
The
reported strategy relies on a macrolactonization approach and features
selective epoxidation of the macrocycle double
bond in precursors 3 and 4 (Scheme ),
respectively, as well as high convergency and flexibility.
Building blocks
9−12 and 15 were constructed by
asymmetric processes and coupled via Wittig, aldol, and
macrolactonization reactions
to afford the basic skeleton of epothilones and that of several of
their analogues by a relatively short route. The
utilization of intermediate 14, obtained via a
stereoselective Wittig reaction and its Enders coupling to SAMP
hydrazone
13 (Scheme ), in combination with a stereoselective aldol
reaction with the modified substrate 69 (Scheme
)
improved the stereoselectivity and efficiency of the total synthesis of
these new and highly potent microtubule binding
antitumor agents.
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