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

Abstract

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A solvation induced ring puckering effect in fluorinated prolines and its inclusion in classical force-fields

“…Rapid progress in experimental capability and synthesis have led to the testing of a variety of novel substituted prolines such as trifluoromethylated prolines and poly-fluorinated prolines. 41 These have further extended the tunability of cis and trans populations. Such methods of imposing stereo-electronic effects by pre-organizing amino acids have been shown to impart proteins with extraordinary conformational stability without perturbing its native structure.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…Proline is often a critical residue in terms of defining a peptide or protein’s secondary structures and it is ubiquitous within the sequences of cyclic peptides. Given this, there has been significant effort invested into accessing fluorinated proline derivatives [ 84 ], and multiple reports on the stereoselective synthesis of mono-fluoro prolines have been disclosed [ 85 , 86 ]. Several research groups, however, have focused on the synthesis of prolines substituted with multiple fluorines.…”

“…It is known that the introduction of a fluorine atom to either the 3 or 4 position of the proline ring can have a dramatic impact on the conformation adopted by the ring. In particular, their presence will encourage puckering of the ring and a change in cis/trans isomerisation [ 85 , 86 ]. Having a fluorine atom on both the 3 and 4 positions of the ring leads to a question as to what conformation the different stereoisomers will adopt.…”

Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates

“…The emergence of fluorine in drug design highlighted the potential of fluorinated amino acids, peptides and mimetics, and the possibility to tailor their geometry with such a peculiar element . In particular, proline surrogates, which were fluorinated or trifluoromethylated in their lateral chain, were examined as useful conformational tuning tools that allowed fine control of the cis ‐ or trans ‐prolyl amide bond population . Previous studies on model peptides have established the stereoelectronic effects imparted by the CF 3 group on the rotational energy barrier and puckering of the oxazolidine core .…”