Synthesis and conformational properties of 3,4-difluoro-L-prolines

Abstract

Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/trans isomerization) are introduced. Simultaneous fluorination at the 3- and 4-positions is expected to either reinforce or oppose these effects. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-L-proline diastereoisomers. The yet unreported conformational properties are described for (3S,4S)- and (3R,4R)-difluoro-L-proline, which are shown to bias ring pucker and cis-trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis-trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline’s distinct conformational and dynamical properties, allowing to interrogate its role in, for instance, protein stability or folding.

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Identifiers

ORCID for Mark Light: orcid.org/0000-0002-0585-0843

ORCID for Ilya Kuprov: orcid.org/0000-0003-0430-2682

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

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