Synthesis of tubuphenylalanine

Abstract

In this work, we have developed an efficient synthetic route for gram-scale synthesis of N-Boc-tubuphenylalanine benzyl ester (N-Boc-Tup-OBn) and N-Boc-epi-tubuphenylalanine benzyl ester (N-Boc-epi-Tup-OBn). These -aminoacid intermediates are key components for synthesis of anticancer tetrapeptides, tubulysins and can be used to derive novel tubulysin architectures with better therapeutic indices. A regio- and stereoselective hydroboration of (R)-4-methyl-N-(4-methyl-1-phenylpent-4-en-2yl)benzenesulfonamide and subsequent in situ oxidation in alkaline medium was used as the key step to provide corresponding N-tosyl 1,4-amino alcohols, which were effectively transformed into the desired y-aminoacid intermediates in overall excellent yields.