title: 4-(4,6-di[2,2,2-trifluoroethoxy]-1,3,5-triazin-2-yl)-4-methylomorpholinium tetrafluoroborate. Triazine-based coupling reagents designed for coupling sterically hindered substrates.
abstract: 4-(4,6-Di[2,2,2-trifluoroethoxy]-1,3,5-triazin-2-yl)-4-methylomorpholinium tetrafluoroborate (DFET/NMM/BF(4)) was prepared and used as a reagent for coupling sterically hindered substrates. The formation of the appropriate triazine "superactive" ester in a reaction of DFET/NMM/BF(4) with carboxylic acids was confirmed. The efficiency of the reagent has been studied in the synthesis of Leu-enkephaline pentapeptide carried out on a Fmoc-RinkAmide-AM-PS resin, by systematically modifying the -Gly-Gly- fragment for N-methyl or α,α-disubstituted residues and compared with the efficiency of classic aminium salt 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) under a variety of reaction conditions. In syntheses of Aib-Aib (Aib: α-aminoisobutyric acid), MeVal-MeVal, and MeLeu-MeLeu, the considerably superior performance of enkephaline analogues was obtained for DFET/NMM/BF(4) relative to TBTU, regardless of reaction conditions. Analysis of the couplings involving triazine reagent suggests that factors controlling efficiency of coupling sterically hindered substrates are the structure of the leaving group permitting formation of the cyclic intermediate or cyclic transition state and the absence of strongly solvating solvents. It has to be considered as highly probable that the absence of strongly solvating milieu favors cyclic intermediates or the cyclic transition state. Arrangement of both components into the cyclic intermediate or cyclic transition state by accumulation of the geminal (vicinal) substituents effect (known as the Thorpe-Ingold effect) would compensate retardation of the coupling process caused by steric hindrance.
authors.affiliation: Institute of Organic Chemistry, Technical University of Lodz, Lodz, Poland.
authors.forename: Konrad G
authors.initials: KG
authors.lastname: Jastrzabek
authors.forename: Ramon
authors.initials: R
authors.lastname: Subiros-Funosas
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
authors.forename: Beata
authors.initials: B
authors.lastname: Kolesinska
authors.forename: Zbigniew J
authors.initials: ZJ
authors.lastname: Kaminski
mesh_terms: D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry; D001881:Borates / Q000737:chemistry*; D007202:Indicators and Reagents / Q000737:chemistry; D009025:Morpholines / Q000737:chemistry*; D009584:Nitrogen / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D014227:Triazines / Q000737:chemistry*
chemical_list: C561030:4-(4,6-di(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-4-methylomorpholinium tetrafluoroborate; D000596:Amino Acids; D001881:Borates; D007202:Indicators and Reagents; D009025:Morpholines; D009842:Oligopeptides; D014227:Triazines; D009584:Nitrogen