Synthesis of linear and cyclic opioid‐based peptide analogs containing multiple N‐methylated amino acid residues

A series of six novel opioid peptide analogs containing one to three N ‐methylamino acid residues, and six cyclic counterparts of these peptides were prepared by the solid‐phase method. Introduction of two consecutive N ‐methylated amino acids, as well as cyclization of such conformationally constrained sequences, turned out to be challenging. The use of a recently reported triazine‐based coupling reagent, 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium toluene‐4‐sulfonate, enabled the synthesis and cyclization of the designed analogs in acceptable yields and with a lesser amount of by‐products than observed with the standard coupling reagents such as TBTU or HATU.Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.