CYCLIZATION OF ALL-L-PENTAPEPTIDES BY MEANS OF 1-HYDROXY-7-AZABENZOTRIAZOLE-DERIVED URONIUM AND PHOSPHONIUM REAGENTS

Due to their restricted conformational flexibility, cyclic peptides ar e of great interest in connection with structure-activity relationship s, especially the elucidation of bioactive conformations. For linear p eptides that do not contain turn structure-inducing amino acid residue s, the cyclization reaction may be an inherently improbable or slow pr ocess, and side reactions, such as cyclodimerization and epimerization at the C-terminal residue, may dominate. A number of 1-hydroxy-7-azab enzotriazole-based onium salts were examined for cyclization of thymop entin-derived pentapeptides and the results compared with data from mo re conventional coupling reagents. The azabenzotriazol-derived couplin g reagents stood out as being the most effective by far. The cyclizati ons proceed extremely rapidly, and in contrast to other coupling reage nts, C-terminal epimerization was generally less than 10%. C-terminal D-amino acid residues favor the formation of monocyclic pentapeptide r ings. A similar effect was observed for cyclization of linear N-methyl amino acid-containing peptides, suggesting that reversible amide bond alkylation such as Hmb-modification should be useful in promoting the cyclization of pepitdes devoid of turn-inducing amino acid residues.