Tubulysins are natural products isolated from myxobacterial species. As cytoskeleton interacting agents, tubulysins are mitotic poisons and are extremely potent cytotoxins, thus exceeding the cell growth inhibition of any clinically relevant traditional chemotherapeutic. Structurally, tubulysins are closely related linear tetrapeptides comprised of unusual and/or hydrophobic amino acid segments. The isolation of a single natural tubulysin from culture extracts requires multistep chromatography and provides only limited quantities.  Several total syntheses of natural tubulysins and some structurally simplified analogues have been reported, but their application is limited to small lab scale.  Among the multiple challenging synthetic and stereochemical issues, most striking is the generation of the labile N,O-diacyl N,O-acetal.   Herein, we present a streamlined total synthesis of a tubulysin B derivative modified for conjugation with targeting ligands.  This convergent protocol produces gram quantities of the desired derivative utilizing only simple medium pressure reverse phase and normal phase column chromatography.  In addition, isolation of highly toxic tubulysin B as a synthetic intermediate is avoided.

Efficient synthesis of an activated tubulysin B derivative for ligand targeting

244th National Meeting (2012)

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