Fluorinated Prolines as Conformational Tools and Reporters for Peptide and Protein Chemistry

Amide bonds at the proline nitrogen are particularly susceptible to rotation, affording cis and trans isomers. Installation of a stereochemically defined electron-withdrawing fluorine atom or fluorinated groups has the power to influence the cis-trans conformational preferences of the amide bond in X-(F)Pro (where X = any other amino acid). Advantageously, this also provides a sensitive reporter for ¹⁹F nuclear magnetic resonance (NMR) studies of protein conformation, interactions, and dynamics. We deliberately use the term "fluorinated prolines" as an all-encompassing term to describe proline analogues containing one or more fluorine atoms and to avoid confusion with the more well-known 4-fluoroprolines. This review presents a critical discussion of the growing repertoire of fluorinated prolines that have been described and, importantly, provides a comparison of their uses and relative influence on amide-bond conformation and discusses the significant potential of using ¹⁹F NMR as a tool to probe conformational changes in polypeptides.