Selektive Amidspaltung bei Peptiden mit alpha,alpha-disubstituierten alpha-Aminosäuren

Abstract

A new synthesis of dipeptides with terminal alpha,alpha-disubstituted alpha-amino acids, using 2,2-disubstituted 3-amino-2H-azirines 1 as amino-acid equivalents, is demonstrated. The reaction of 1 with N-protected amino acids leads to the corresponding dipeptide amides in excellent yield. It is shown that the previously described selective hydrolysis (HCl, toluene, 80°, or HCI, MeCN/H2O, 80°) of the terminal amide group results in an extensive epimerization of the second last amino acid. An acid-catalyzed enolization in the intermediate oxazole-5(4H)-ones is responsible for this loss of configurational integrity. In the present paper, a selective hydrolysis of the terminal amide group under very mild conditions is described: In 3N HCI (THF/H2O 1:1), the dipeptide N,N-dimethylamides or N-methylanilides are hydrolized at 25-35° to the optically pure dipeptides in very good yield.