The Effect of Counterion and Tertiary Amine on the Efficiency of N‐Triazinylammonium Sulfonates in Solution and Solid‐Phase Peptide Synthesis

Abstract

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.

4‐(4,6‐Dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium Toluene‐4‐sulfonate (DMT/NMM/TsO−) Universal Coupling Reagent for Synthesis in Solution

“…Substitution of the nucleophilic chloride anion with the less nucleophilic sulphonate produced a collection of stable coupling reagents with diverse reactivities ( Scheme , pathway I). Screening their synthetic potential revealed p ‐toluenesulphonate 7 to be the most expedient for SPPS . Because acylating components are used in large excess in SPPS, attempts were made to investigate the use of 7 under standard conditions in representative syntheses in solution.…”

Novel tool in rheumatoid arthritis diagnosis—The usage of urease flap region peptidomimetics

“…The synthesis was performed according to standard SPPS procedure of peptide immobilized on the cellulose support . As a coupling reagent was used 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium 4‐toluenesulfonate (DMT/NMM/TsO − ) . The first step of the synthesis includes the functionalization of the cellulose matrix by using DCMT.…”

“…23 As a coupling reagent was used 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholinium 4-toluenesulfonate (DMT/NMM/TsO − ). 24 The first step of the synthesis includes the functionalization of the cellulose matrix by using DCMT. In the next step functionalized cellulose matrix 2 was treated with N-methylmorpholine yielded the triazine based coupling reagent 3 immobilized on the solid support.…”

Study on the Materials Formed by Self‐Assembling Hydrophobic, Aromatic Peptides Dedicated to Be Used for Regenerative Medicine

“…Peptides 1-6 were synthesized according to SPPS protocols using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO À ) as a coupling reagent. [35] The purity of the peptides ranged from 97.01 to 98.95 %. In the preliminary stage of the studies, a morphology of structures formed during the aggregation occurring under physiological conditions (37°C, pH 7.2) was checked.…”