Proceedings book download - 5Z.com

Peptidyl phosphoranes were first reacted with electron deficient azides such as triflic azide,tosyl azide, 4-nitro benzoyl azide and 4-carboxyl phenyl azide. The cycloaddition reactionproceeded smoothly in unpolar solvents at room temperature with complete regioselectivityin favor of 1,5-disubstituted triazole. The reaction, however, needed polar solvents andgentle heating in case of relatively electron rich azides such as benzyl azide, methyl 2-azidoacetate and 2-azido-acetamide but still with good yield and complete regioselectivity. Thisreactivity trend and effect of solvent polarity reflects polar transition state involved andLUMO controlled 1,3-dipolar cycloaddition. Finally, this reaction was used for shortpeptides ligation by heating peptidyl phosphoranes with azido peptides in polar solventslike THF and DMF. The potential of ligation products, with 1,5-triazole incorporated, toform stable conformations in solution was investigated using 2D-ROESY spectroscopy andmolecular dynamic simulations. All the structures consistently indicated a turn-like bend inshort peptides [3]. Thus, the triazole ligation method established has potential to introduceβ-turn in short peptide chains. Moreover, the reaction is devoid of any metal catalysis andhas potential to be developed as biocompatible ligation. In this context soluble peptidylphosphoranes were synthesized and used in azido-phosphorane triazole ligation in aqueousmedium at room temperature.Azido-peptidyl phosphoranes in principle can undergo either intra-molecular orintermolecular reactions, the first resulting in triazolyl-cyclopeptide through cyclativecleavage as shown in Figure 2. When, however, azido-dipeptidyl phosphoranes were heatedin DMF, they delivered exclusively dimeric products. In contrast to this, the azidotripeptidylphosphoranes yielded a mixture of monomeric and dimeric triazolylcyclopeptidesthrough competition between intra-versus inter-site reactions. It might bepossible to minimize inter-site reactions by using a more rigid resin with higher percentageof cross linker. To test the assumption, macroporous polystyrene resin (20% divinylbenzene) was used instead of microporous polystyrene (2% polystyrene) and a major shifttowards monomeric product (intra-site reaction) in case of azido-tripeptidyl phosphoranewas observed. Azido-dipeptidyl phopsphoranes, however, still resulted in the formation ofdimeric products (inter-site reaction) despite of using the macroporous resin. Thisobservation indicates that azido dipeptides are too short to be cyclized through cyclativecleavage and inter-site cyclization is strongly favoured in this case. As expected, azidotetrapeptidylphosphoranes resulted in monomeric triazolyl-cyclopeptide either exclusivelyor with minor dimeric product formation. To test the potential of cyclative cleavage forrelatively longer peptide chains, azido-penta- and octa-peptidyl phosphoranes werecyclized in relatively good yield [4]. The cyclization method completely avoids formationof soluble, non cyclized and oligomeric by-products and is superior to solution phasecyclizations. The method provides an easy access to cyclopeptides with locked cis-peptidemimetic.AcknowledgmentsThis work was supported by the Deutsche Forschungsgemeinschaft (Ra895/2, FOR 806, SFB 765),Boehringer Ingelheim Pharma, the Fonds der Chemischen Industrie, the Deutscher AkademischerAustauschdienst and the Higher Education Commission of Pakistan (by a stipend to A.).References1. a) Weik, S., Rademann, J. Angew. Chem. 115, 2595-2598 (2003); Angew. Chem. Int. Ed. 42, 2491-2494 (2003); b) El-Dahshan, A., Weik, S., Rademann, J. Org. Lett. 129, 12670-12671 (2007).2. a) El-Dahshan, A., Ahsanullah, Rademann, J. Biopolymers:Peptide Science 94, 220-228 (2010); b)El-Dahshan, A., Nazir, S., Ahsanullah, Ansari, F.L., Rademann, J. Eur. J. Org. Chem. In press(2010).3.Ahsanullah, Schmieder, P., Kühne, R., Rademann, J. Angew. Chem. Int. Ed. Engl. 48, 5042-5045,(2009).4. Ahsanullah, Rademann, J. Angew. Chem. Int. Ed. Engl. 49, 5378-5382, (2010).31