Synthesis of stereochemically diverse cyclic analogs of tubulysins

Abstract

The synthesis of tubulysin analogs containing stereochemically diverse cyclic Tuv moieties is described. A tetrahydropyranyl moiety was incorporated into the Tuv unit by enantioselective hetero Diels-Alder reactions of Danishefsky's diene and thiazole aldehyde. Four different stereoisomers of cyclic Tuv units were used as surrogates for the Tuv moiety. The synthesized stereochemically diverse simplified cyclic analogs were evaluated for the inhibition of tubulin polymerization.

Keywords: Antitumor agents; Asymmetric catalysis; Hetero Diels–Alder reaction; Peptides; Tubulysin.