Synthesis of cyclo-Diglycyl- l -lysyl-diglycyl- l -lysyl and Hydrolysis by Trypsin

A protected cyclic hexapeptide (XVI), cyclo-(diglycyl-ε-benzyloxycarbonyl-l-lysyl)2, was synthesized in three different ways; the cyclization reactions of a protected tripeptide azide, a protected tripeptide active ester, and a protected hexapeptide active ester produced the protected cyclic hexapeptide (XVI) in fairly good yields. The product (XVI) was then converted by hydrogenolysis to the cyclic hexapeptide (XVII), cyclo-(digrycyl-l-lysyl)2. It was found that the cyclic hexapeptide was hydrolyzed slowly by trypsin to a tripeptide diglycyl-lysine, whereas a synthetic hexapeptide, diglycyl-lysyl-diglycyl-lysine, was hydrolyzed very rapidly to the tripeptide.