Racemization during aminolysis of activated esters of N-alkoxycarbonylamino acids by amino acid anions in partially aqueous solvents and a tactic to minimize it.

Racemization during the aminolysis of activated esters of N-alkoxycarbonylamino acids by amino acid anions in aqueous dimethylformamide was examined by determining the epimeric products by high-performance liquid chromatography. Partial racemization occurred for a variety of esters, particularly when sodium hydrogen carbonate was used to generate the anion of D-valine. The racemization results from prolonged contact of unconsumed ester with the alkaline medium. Variation of the stoichiometry of reagents for reactions with N-benzyloxycarbonylphenylalanine (Z-Phe) 4-nitrophenyl ester revealed that racemization could be minimized by using Na2CO3 as base and a 50% excess of amino acid anion. An efficient synthesis of optically pure Z-L-Phe-D-Val-OH was achieved with a reaction time of 15 min.