The Effect of Counter-ion and Tertiary Amine on the Efficiency of N-Triazinylammonium Sulfonates in Solution and Solid-Phase Peptide Synthesis.

A collection of N-triazinylammonium sulfonates, designed according to the concept of “superactive esters”, was obtained by treatment of ammonium sulfonates with 2-chloro-4,6-dimethoxy-1,3,5-triazine. The structure of the tertiary amine as well as sulfonate anion influenced their reactivity and stability in N,N-dimethylformamide (DMF) solution. The reagents were successfully used in solution- and solid-phase synthesis of Z-, Boc-, and Fmoc-protected peptides containing natural and unnatural sterically hindered amino acids as well as in [2+1] fragment condensation approaches, yielding the final products in 80–100 % yield and high optical purity. In manual SPPS of the [Aib]2[Aib]4-enkephalin analogue and the ACP(65–74) peptide fragment VQAAIDYINEG, several sulfonates yielded peptides significantly faster than TBTU or HATU. Comparative analyses demonstrated that 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium 4-toluenesulfonate was the most versatile reagent in a wide range of coupling procedures.