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

Selective Amide Cleavage in Peptides Containing α,α‐Disubstituted α‐Amino Acids A new synthesis of dipeptides with terminal α,α‐disubstituted α‐amino acids, using 2,2‐disubtituted 3‐amino‐2 H ‐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/H 2 O, 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(4 H )‐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 3 N HCl (THF/H 2 O 1:1), the dipeptide N , N ‐dimethylamides or N ‐methytlanilides are hydrolized at 25–35° to the optically pure dipeptides in very good yield.