How to perform small peptide cyclizations

Small cyclopeptides of four to six residues are very interesting for their biological properties. Unfortunately, the synthesis of the linear precursor is generally fastidious and the cyclization often occurs in low yields. Molecular modeling used through the genmol program is a powerful tool for predicting the best precursor, as was shown in a previous paper about five tetrapeptides. However, sometimes all the linear precursors of a cyclopeptide can be unfavorable for cyclization when no structural feature (N-Me amino acid. Pro, D-amino acid) is present in the peptide. This led us to develop a method using a reversible chemical modification of the peptide main chain in order to favor the cisoid conformation able to cyclize easily. Tetraphenylalanine was used as a model, with the tert-butyloxycarbonyl (Boc) group as substituent on the main-chain nitrogen atoms. The cyclization yield increases from less than 1 % to 27% after this chemical modification and cleavage of the Boc groups. Molecular modeling on such molecules shows that this yield increase is due to a preferred conformation having the terminal functions close together induced by the Boc substituents.