SIDE REACTIONS IN PEPTIDE SYNTHESIS. VI.

Abstract

The acid catalyzed O → C migration of the benzyl group in the side chain of tyrosine could be reduced by applying HBr in a mixture of phenol and p‐cresol instead of HBr in trifluoroacetic acid for acidolytic deprotection. This side reaction occurs also during the removal of Boc groups. The loss of O‐benzyl protection and the formation of 3‐benzyltyrosine residues could be suppressed by the application of a 7:3 mixture of trifluoroacetic acid and acetic acid. The acid‐ and base‐catalyzed ring closure of β‐benzylaspartyl residues to aminosuccinyl derivatives was also studied. In this case HBr in trifluoroacetic acid was found to be relatively harmless. Deprotection with HBr in a mixture of trifluoroacetic acid and p‐cresol can be applied for peptides that contain both β‐benzylaspartyl and O‐benzyltyrosyl residues. An attempt to reduce the rate of the base‐catalyzed side reaction by application of hindered tertiary amines was abandoned because the tertiary amines which were effective in this respect led to significant reduction of the rate of the desired reaction, the aminolysis of active esters, as well. A satisfactory solution for the problem was found in the selective catalysis of the active ester reaction with 1‐hydroxybenzotriazole o 4‐dimethylaminopyridine. These catalysts do not enhance the rate of ring closure and in their presence essentially pure β‐benzylaspartyl peptides can be produced in good yield.