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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, 2010Convenient Synthesis of Tfm-Dipeptides from UnprotectedEnantiopure α-Tfm-Proline and α-Tfm-AlanineGrégory Chaume, Nathalie Lensen, Caroline Caupène, andThierry BrigaudLaboratoire SOSCO, Université de Cergy-Pontoise, 5, mail Gay Lussac,Cergy-Pontoise, F-95000, FranceIntroductionThe major disadvantages of peptides as therapeutic agents are their rapid degradation bypeptidase and their low lipophilicity. In this context, α-trifluoromethyl-α-amino acids(α-Tfm-AAs) are very attractive compounds for the design of biologically active molecules[1]. Their incorporation into peptides increases chemical and thermal stability, resistance toprotease degradation and enhances hydrophobicity giving a better affinity for lipidmembranes [2]. Moreover, their incorporation into peptides induces particularconformational stabilisations and better auto-assembly [3]. In addition, labeled 19 F peptidesare of a big interest for structure elucidation and biochemical process investigations [4]. Inthe course of our studies, we have recently reported efficient and scalable methodologiesfor the synthesis of enantiopure α-Tfm-AAs [5-9]. Here, we report the synthesis of highlylipophilic dipeptide building blocks from enantiopure α-Tfm-AAs [10].Results and DiscussionThanks to a convenient gram-scale strategy for the synthesis of (S)- and (R)-α-Tfm-prolines[12], we were able to undertake a methodological study in order to incorporate thispromising unnatural amino acid in a peptide chain. We anticipated that α-Tfm-AAs shouldbe deployable in peptide coupling reactions without protection of their nitrogen atoms dueto the strong deactivation of the amino group by the CF 3 group. The peptide couplingmethodological study allowed us to establish the best coupling conditions to avoid theformation of the diketopiperazine side product and to optimize the coupling yield. Thus,one equivalent of α-Tfm-proline is added to two equivalent amount of the non-fluorinatedamino acid in the presence of the coupling reagents HOBt/EDCI. These optimizedconditions were then successfully applied to the coupling of various amino acids withunprotected α-Tfm-proline (Figure 1). The enantiopure dipeptides derived fromunprotected (S)-α-Tfm-proline and alanine, valine, phenylalanine and leucine wereconveniently obtained in good yields (76-95%) without any traces of diketopiperazine. Thecoupling reaction starting from unprotected (R)-α-Tfm-proline was also very efficient.In order to extend the methodology to acyclic α-Tfm-AAs, the coupling of α-Tfmalanine[8] was investigated. Coupling reactions between unprotected (R)-α-Tfm-alanineand non-fluorinated α-amino acids were achieved following the same procedure designedfor α-Tfm-proline. The corresponding dipeptides were conveniently obtained in 77-82%isolated yields without formation of diketopiperazine (Figure 2).As a proof-of-concept of the incorporation of enantiopure α-Tfm-AAs into peptidechains, coupling reaction of the (R)-α-Tfm-Ala-L-Leu-OBn dipeptide at its N-terminus wasFig. 1. α-Tfm-Proline containing dipeptides.72