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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Triazine Condensing Agents for Synthesis of Peptide Bond inAqueous MediaKrzysztof J. Zajac, Ireneusz Kaminski, Justyna Fraczyk, andZbigniew J. KaminskiInstitute of Organic Chemistry, Technical University of Lodz, 90-924, Lodz, PolandIntroductionSuccessful synthesis of the peptides bond in aqueous media still remains a challengealthough several attempts have been made to resolve the problems [1]. To perform peptidesynthesis in water, the coupling reagent must be water-soluble, maintain solubility andreactivity of intermediate products, preserve enantiomeric homogeneity of products instrongly polar environment and form conveniently removable waste (if any) in order tofacilitate isolation of the main product. The pursuit for aqueous-compatible couplingreagent is promoted both by environmental problem of the safe disposal of large amountsof organic solvents required for SPPS, as well as by demand for efficient method useful formodification of complex molecules, incompatible with organic solvents, such as proteinsand carbohydrates.Results and DiscussionCoupling reagents were prepared in two subsequent stages by treatment 2,4-dichloro-6-methoxy-1,3,5-triazine (1) with aromatic and aliphatic aminosulphonic acids [2] in thepresence of base, followed by quaternization of reactive intermediate in reaction withNMM and formation of zwitterionic final products 2a-f. Activation of N-protectedcarboxylic components with 2a-f proceeded in aqueous solution or in water miscibleorganic solvent affording water soluble intermediates 3a-f due to the presence of sulphonicgroup (Figure 1).ORCl1) H 2 N X SO 3 H / NaHCO 3N +HNOHN N2) O NN NPG OMeO N Cl1THF/waterMeO NXN SO3-H2a-fX = alkyl, arylOHNPG ORN NMeO NX -N SOH33a-fsubstrates with standard protecting groups(PG) become soluble in aqueous mediaFig. 1. Synthesis of water-soluble coupling reagents 2a-f and activation of N-protectedcarboxylic component.It has been observed that the structure of aminosulphonic acids have an effect on theefficiency of 2a-f (see Figure 2). The most versatile as coupling reagent has been found 2a,which was obtained from 4-aminobenzenesulphonic acid. Its structure was confirmed byX-ray analysis.MeOMeONNNNN + MeO2aNN HNN + MeO2dN Hyield: 88%yield: 88%OSO OOOSOMeOMeONNNNN + MeO2bNN HNN + MeO2eN Hyield: 62%yield: 69%OOSOOSOOMeOMeONNNNN + MeO2cNNMeN +ON HO S Oyield: 72%N HOOSOyield: 68%O2fFig. 2. Coupling reagents 2a-f for peptide synthesis in aqueous media.126