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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, 2010CF 3 -Pseudoprolines: Synthesis and Conformational Study ofHydrolytically Stable Proline Surrogate Containing DipeptidesOlivier Barbeau 1 , Caroline Caupène 1 , Debby Feytens 2 ,Grégory Chaume, 1 Philippe Lesot 3 , Emeric Miclet 2 , andThierry Brigaud 11 Laboratoire SOSCO, Université de Cergy-Pontoise, 5, mail Gay Lussac, Cergy-Pontoise,F-95000, France; 2 Laboratoire des biomolécules, Université Pierre et Marie Curie, UMR7203, 75005, Paris, France; 3 RMN en Milieu Orienté, ICMMO, UMR CNRS 8182, Bat.410, Université Paris Sud 11, Orsay, 91405, FranceIntroductionThe incorporation of proline derivatives is known to restrict the peptide bond cis/transisomerization, to control the protein folding and consequently to modulate the biologicalactivity of peptides. Pseudoproline residues ( Pro) proved to be versatile tools forovercoming the aggregation encountered during solid phase peptide synthesis.[1,2] Theyalso turned out to be inducers of -turns containing predominantly cis-amide bond anduseful tools in peptide cyclization. Our group is interested in the development of efficientroutes for the preparation of enantiopure -trifluoromethylated amino acids ( -Tfm AAs),[3,4] particularly pyrrolidine-type -Tfm AAs [4-6] and their incorporation into a peptidechain [7]. Here, we will report the preparation of various CF 3 - Pro as well as themethodological study developed to optimize the synthesis of various C-terminal andN-terminal CF 3 - Pro containing dipeptides. Their conformation and their stability towardhydrolysis have been also studied and will be detailed.Results and DiscussionThree CF 3 - Pro esters were conveniently prepared through the condensation reaction oftrifluoroacetaldehyde ethyl hemiacetal or trifluoroacetone with serine or cysteine esterderivatives (Figure 1) [8]. The isolated diastereomerically pure CF 3 - Pro esters areextremely stable thanks to the strong electron-withdrawing effect of CF 3 group. Therefore,there is no epimerization at the C-2 center of the oxazolidine ring through ring-opening andring-closing equilibrium.Fig. 1. Preparation of the CF 3 -pseudoprolines.Then, we turned our attention to the incorporation of CF 3 - Pro units into a peptide chain.First, we studied the coupling reaction at their C-terminus position. After saponification,the reaction of both diastereomers of H-Ser(CF3,H pro)-OMe with L-alanine using standardpeptide coupling reagents gave the corresponding dipeptides in moderate to good yield,depending to the absolute CF 3 configuration (Figure 2). It should be noticed that theprotection of the CF 3 - Pro amino group is not required due to the deactivation imparted bythe CF 3 group.Fig. 2. Preparation of N-terminal CF 3 -Pro containing dipeptides.76