Stereoselective Access to Tubuphenylalanine and Tubuvaline: Improved Mn-Mediated Radical Additions and Assembly of A Tubulysin Tetrapeptide Analog

Synthesis of tubuphenylalanine and tubuvaline, α-substituted γ-amino acid building blocks for tubulysin family of antimitotic compounds, has been improved using a radical addition reaction in the presence of unprotected hydroxyl functionality. The key carbon–carbon bond construction entails stereoselective Mn-mediated photolytic additions of alkyl iodides to the C=N bond of chiral N-acylhydrazones, and generates the chiral amines in high yield with complete stereocontrol. Reductive N–N bond cleavage and alcohol oxidation converted these amino alcohols into the corresponding γ-amino acids. The route to tubuvaline proceeded via peptide coupling with serine methyl ester, followed by a high-yielding sequence to convert the serine amide to a thiazole. Finally, peptide bond construction established the tubulysin framework in the form of a C-terminal alcohol analog. Attempted oxidation to the C-terminal carboxylate was unsuccessful; control experiments with dipeptide 18 showed a cyclization interfered with the desired oxidation process.