Hémisynthèse stéréosélective d’acides aminés hétérosubstitués sur la chaîne latérale : application au radiofluoromarquage pour l’imagerie de peptides

Abstract : Stereoselective hemisynthesis of lateral chain heterosubstituted aminoacids.Applications on radiofluorolabeling for peptide imaging.This thesis work, which was carried out at the Institute of Molecular Chemistry of the University of Burgundy and in collaboration with the Institute of Cognitive and Integrative Neurosciences of Aquitaine, focuses on the development of new methods for the synthesis of side chain heterosubstituted amino acids including phosphine containing or silyl groups, as well as on their applications. In a first part, the synthesis of side chain silylated amino acids is achieved without racemization using a key Wittig reaction between a phosphonium salt, derived from L-aspartic acid, and an aromatic aldehyde bearing the silyl group. These aminoacids have been used in peptide synthesis to give silylated di- and tripeptides by reaction with alanine and phenylalanine derivatives. It has been shown that the silylated aminoacids and peptides can be fluorinated by reaction with fluorides, and that in the case of di-t-butylsilyl derivatives, the fluorinated compounds obtained are found to be very stable at physiological pH. The study of the fluorination of di-t-butylsilyl peptides by K18F / K222 allowed to obtain radiolabelled derivatives with radiochemical yields and molar activities reaching 39% and 410 GBq.mol-1, respectively. In the second part, the synthesis of aminoacids and peptides heterosubstituted or functionalized on the side chain, was developed. The principle of this synthesis is based on a [3 + 2] cycloaddition between an aminoacid bearing an azido group with disubstituted alkyne. While the reaction catalyzed using a copper salt or a ruthenium complex does not lead to the desired products, the cycloaddition was developed under microwave irradiation using glycerol as a solvent. Under these conditions, 13 new amino acids carrying a triazole ring at the γ position, and bearing silyles, phosphines, amines, amides.. substituents were prepared without racemization and with yields up to 89%. The methodologies developed in this thesis offer new efficient ways for the synthesis of silyl or phosphorus amino acid derivatives, useful for coordination chemistry, asymmetric catalysis and radiolabeling by the fluoride ion18F-.Key words: Phosphoniums, aminoacids, silanes, [18F]-radiofluorination, triazoles
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Baptiste Rugeri. Hémisynthèse stéréosélective d’acides aminés hétérosubstitués sur la chaîne latérale : application au radiofluoromarquage pour l’imagerie de peptides. Chimie organique. Université Bourgogne Franche-Comté, 2017. Français. ⟨NNT : 2017UBFCK060⟩. ⟨tel-02149578⟩

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