Tubulysins (1) are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far.[1, 2] The tubulysins were first described by Höfle, Reichenbach, and co-workers in 2000. [3,4] Several representatives are active with GI 50 values (growth inhibition of 50 %) in the low picomolar range against the NCI-60 cancer cell-line panel, and some are highly antiangiogenic.[5] Semisynthetic tubulysins, derived from isolated material, show promising in vivo anticancer properties and are candidates for antibody conjugates. Thus, tubulysins are attractive leads as novel anticancer agents. [5] However, so far, tubulysins can only be produced by a fermentation process that yields less than 10 mg L À1 by several rather tedious chromatographic purification steps. Thus, and

A highly convergent and stereocontrolled synthesis of epothilone D (4) is reported. Key features are a cheap and Z-selective synthesis of the northern half based on nerol and acetoacetate and chromium(II)-mediated Reformatsky reactions as a powerful tool for chemoselective asymmetric carbon-carbon bond formations, including an unusual stereospecific macroaldolization.

Tubulysins (1) are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far.[1, 2] The tubulysins were first described by Höfle, Reichenbach, and co-workers in 2000. [3,4] Several representatives are active with GI 50 values (growth inhibition of 50 %) in the low picomolar range against the NCI-60 cancer cell-line panel, and some are highly antiangiogenic.[5] Semisynthetic tubulysins, derived from isolated material, show promising in vivo anticancer properties and are candidates for antibody conjugates. Thus, tubulysins are attractive leads as novel anticancer agents. [5] However, so far, tubulysins can only be produced by a fermentation process that yields less than 10 mg L À1 by several rather tedious chromatographic purification steps. Thus, and

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