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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, 2010Biocompatible Triazole Ligations via 1,3-Dipolar Cycloadditionsof Peptidyl Phosphoranes and Azido PeptidesJörg Rademann 1,2* and Ahsanullah 2,31 Medicinal Chemistry, Leipzig University, 04103, Leipzig, Germany; 2 Leibniz-Institut ofMolecular Pharmacology, Robert-Rössle-Str. 10, 13125, Berlin, Germany; 3 Institute ofChemistry and Biochemistry, Free University Berlin, Takustr. 3, 14195, Berlin, GermanyIntroductionRecently, we have found a versatile and practical approach for the integration ofC-acylation steps within classical, Fmoc-based N-acylation, i.e. peptide chemistry [1]. Theresulting C-terminal peptide electrophiles have served as valuable synthetic intermediatesin C-terminal variation and heterocyclic-derivatization of peptides [2].Peptidyl phosphorane, a C-terminal peptide electrophile, can also act as adipolarophile and participate in 1,3-dipolar cycloaddition reactions. Among dipole partners,azido group would be an obvious choice because triazole will be the resultant product inthat case and triazole ligations have found wide range use in all the disciplines ofchemistry. Catalytic versions of Huisgen’s 1,3-dipolar cycloadditon (azide-alkynecycloaddition) result in regioselective triazole formation especially, Cu-catalyzed triazoleligation has become very popular over the recent years. Metal catalysis, however, limitstheir use as biocompatible ligation although strain-promoted triazole ligation has beendiscovered as an alternate to avoid metal catalysis but regioselectivity is lost in that case.Thus, azide-phosphorane triazole ligation, avoiding metal catalysis but retainingregioselectivity, is an exciting extension in peptide ligation methods.Results and DiscussionPolymer-supported triphenylphosphine was alkylated with tert-butyl bromo acetate andresulting phosphoranylidene acetate was acylated with activated amino acid throughracemization-free C acylation and the peptide chain was elongated through Fmoc-basedsolid phase peptide synthesis (SPPS), as shown in Figure 1. After N-acetylation of thePh PhPOOSPPSA.A-OHFmoc.HNPhR 1OPh PhO R 1 PH 2 NONHR n+1 n O OPhPFig. 1. Synthesis of polymersupportedpeptidyl phosphoranes.OOamino terminus of the peptide chain or couplingazido acid at the N-terminus, the tert-butyl esterwas saponified with TFA. Ester cleavage proceedswith instantaneous decarboxylation resulting inpeptidyl phosphorane or azido-peptidyl phosphoranedepending on N-terminus of peptide chain, asshown in Figure 2.In addition to their use in synthesis of variouspeptide electrophiles and peptide-heterocyclechimera, peptidyl phosphoranes can act asdipolarophile and react with azide dipole intriazole ligation.H 2 NOR n+1NHPh PhR 1 Pn OOOi) AC 2 Oii) TFAi) A.A-N 3ii) TFAN 3OHNR n+2OOPh PhR 1 PNHR n+1 n OHNOPh PhR 1 PNHR n+1 n OAzido-pep.NHR 1 N NNR 1'ONHHNn+1 RHN nOn= 0,1,2,3,6Fig. 2. Triazole ligation for peptide turns and cyclopeptides with cis-locked triazole ringincorporated.heatR 1NR n+2NN30