Stereoselective Synthesis of a Tubulysin Core for Antibody–Drug Conjugate Studies

An expeditious synthesis of an advanced tripeptide intermediate en route to a tubulysin antibody–drug conjugate payload is described. The efficient formation of an N-propyl tertiary amide required tailoring the amine component to reduce steric demand. Additionally, double activation of the carboxylate was required via an aluminum–Lewis acid coupled activated ester strategy to enable the formation of the highly congested amide bond with superior retention of stereochemical integrity. Other permutations of reactant structure and reagents met with failure. The realization of this key direct bond construction enabled a convergent solution-phase synthesis of the unnatural tubulysin tripeptide in a highly convergent manner from three simple building blocks in eight steps and 22.4% overall yield utilizing only a single silica gel chromatographic purification.