Selektive Amidspaltung bei Peptiden mit α,α‐disubstituierten α‐Aminosäuren

Abstract

Selective Amide Cleavage in Peptides Containing α,α‐Disubstituted α‐Amino AcidsA new synthesis of dipeptides with terminal α,α‐disubstituted α‐amino acids, using 2,2‐disubtituted 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 HCl, 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 HCl (THF/H2O 1:1), the dipeptide N,N‐dimethylamides or N‐methytlanilides are hydrolized at 25–35° to the optically pure dipeptides in very good yield.