The synthesis of fluorinated proline analogues

Abstract

Proline is an exceptional amino acid. The presence of a pyrrolidine ring makes it the only natural amino acid with a secondary amine. This results in the cis-peptide bond (Xaa-Pro) being significantly populated. Additionally, the pyrrolidine ring introduces a unique conformational aspect; the five-membered ring pucker. Both these aspects can determine the stability and structure of proline-containing peptides or proteins, or their interactions with other proteins. Control over proline’s conformational aspects thus provides interesting opportunities for peptide design, as well as for interrogating a proline residue about its function in the peptide.

Introduction of fluorine substituents with well-defined stereochemistry offers an elegant possibility for achieving such control. In addition, 19 F is an extremely sensitive nucleus for NMR spectroscopy, and as such fluoroprolines could be used for studying model peptides in a residue-specific way. For this purpose, access to a wide array of fluoroprolines with different substitutions patterns and well-defined characteristics (ring pucker, cis/trans isomerisation, spectral characteristics) is desired. Ideally, this set would contain fluoroprolines with contrasting properties, as well as analogues with similar conformational properties, but well-separated ¹⁹F NMR chemical shifts as these are of interest for multi-residue labelling strategies.
This thesis describes the syntheses of known and novel prolines analogues with fluorine substitutions at the 3- and/or 4-positions, as well as initial results of their conformational analysis.

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Identifiers

ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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