title: Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis.
abstract: Considering the increasing importance of fluorinated peptides, the development of efficient and reliable synthetic methods for the incorporation of unnatural fluorinated amino acids into peptides is a current matter of interest. In this study, we report the convenient Boc/benzyl and Cbz/tert-butyl protection of both enantiomers of the quaternarized amino acid α-trifluoromethylalanine [(R)- and (S)-α-Tfm-Ala]. Because of the deactivation of the nitrogen atom of this synthetic amino acid by the strong electron withdrawing trifluoromethyl group, the peptide coupling on this position is a challenge. In order to provide a robust synthetic methodology for the incorporation of enantiopure (R)- and (S)-α-trifluoromethylalanines into peptides, we report herein the preparation of dipeptides ready to use for solid phase peptide synthesis. The difficult peptide coupling on the nitrogen atom of the α-trifluoromethylalanines was performed in solution phase by means of highly electrophilic amino acid chlorides or mixed anhydrides. The synthetic effectiveness of this fluorinated dipeptide building block strategy is illustrated by the solid phase peptide synthesis (SPPS) of the Ac-Ala-Phe-(R)-α-Tfm-Ala-Ala-NH2 tetrapeptide.
authors.affiliation: Laboratoire de Chimie Biologique (LCB), EA4505, Université de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise, 95000, Cergy-Pontoise cedex, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Devillers
authors.affiliation: Laboratoire de Chimie Biologique (LCB), EA4505, Université de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise, 95000, Cergy-Pontoise cedex, France. julien.pytkowicz@u-cergy.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Pytkowicz
authors.affiliation: Laboratoire de Chimie Biologique (LCB), EA4505, Université de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise, 95000, Cergy-Pontoise cedex, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Chelain
authors.affiliation: Laboratoire de Chimie Biologique (LCB), EA4505, Université de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise, 95000, Cergy-Pontoise cedex, France. thierry.brigaud@u-cergy.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Brigaud
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*
chemical_list: D004151:Dipeptides; C507723:alpha-trifluoromethylalanine; D000409:Alanine
keywords: Dipeptides; Fluorinated amino acids; Fluorinated peptides; Mixed anhydrides activation; Solid phase peptide synthesis; α-Trifluoromethylalanine