Synthesis of 2-(4,6-Dimethoxy-1,3,5-triazin-2-yloxyimino) Derivatives: Application in Solution Peptide Synthesis

Abstract

A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for reactivity in solution peptide synthesis. The new triazinyloxyimino derivatives failed to activate the carboxyl group during formation of peptide bonds, but gave the corresponding N-triazinyl amino acid derivatives as a major product. The oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) uronium salt was superior to other uronium salts in terms of racemization, while 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) gave the best results.

Development of Triazinone-Based Condensing Reagents for Amide Formation

“…Racemization at α-position of phenylalanine moiety of 17fd was not observed (Supporting Information, Figure S1). These results indicate that 1-O i Pr is superior to a triazine-type condensing reagent, DMT-MM­(TsO) (77, 98% de), and comparable with other recently reported Oxyma-type condensing reagents, such as HOTU (100, >99% de), o -NosylOXY (91, >99% de), and TsOXY (93, 97% de) …”

“…Racemization at α-position of phenylalanine moiety of 17fd was not observed (Supporting Information, Figure S1). These results indicate that 1-OiPr is superior to a triazine-type condensing reagent, DMT-MM-(TsO) (77, 98% de), 12 (100, >99% de), 13 o-NosylOXY (91, >99% de), 14 and TsOXY (93, 97% de). 15 Based on the comparison of the reaction times for synthesizing aromatic amide 17ca using 1-OiPr (10 min, entry 11 in Table 2), 1-NMe 2 (7 h, entry 13 in Table 2), and DMT-MM (2 h), 1c the order of reactivity of these condensing reagents was 1-OiPr > DMT-MM > 1-NMe 2 .…”

“…General Methods. Nuclear magnetic resonance ( 1 H NMR (400 MHz), 13 C NMR (100 MHz)) spectra or nuclear magnetic resonance ( 1 H NMR (600 MHz), 13 C NMR (150 MHz)) spectra were determined on a JEOL JNM-ECS400 spectrometer or a JEOL JNM-ECA600 spectrometer. Chemical shifts for 1 H NMR are reported as δ values relative to tetramethylsilane as the internal standard and coupling constants are in hertz (Hz).…”

“…The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet, and br = broad. Chemical shifts for 13 C NMR were reported in ppm relative to the center line of a triplet at 77.16 ppm for deuteriochloroform and 49.00 ppm for CD 3 OD. Mass spectra were measured on JMS-T100TD, JMS−SX102A.…”

OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis

“…In 2010, our group reported the synthesis and characterization of 1,3,5-triazinyloxyimino derivatives. 89 These compounds failed to activate the carboxyl group during the formation of peptide bonds but gave the corresponding Ntriazinyl amino acid derivatives as the major products (Scheme 28).…”