| Autor: |
Hofman GJ; School of Chemistry , University of Southampton , Highfield, Southampton SO17 1BJ , United Kingdom.; Department of Organic and Macromolecular Chemistry , Ghent University , Campus Sterre, S4, Krijgslaan 281 , Ghent B-9000 , Belgium., Ottoy E; Department of Organic and Macromolecular Chemistry , Ghent University , Campus Sterre, S4, Krijgslaan 281 , Ghent B-9000 , Belgium., Light ME; School of Chemistry , University of Southampton , Highfield, Southampton SO17 1BJ , United Kingdom., Kieffer B; Biomolecular NMR , University of Strasbourg , IGBMC, CNRS UMR 7104, INSERM U1258, 1 rue Laurent Fries/BP 10142 , Illkirch Cedex 67404 , France., Martins JC; Department of Organic and Macromolecular Chemistry , Ghent University , Campus Sterre, S4, Krijgslaan 281 , Ghent B-9000 , Belgium., Kuprov I; School of Chemistry , University of Southampton , Highfield, Southampton SO17 1BJ , United Kingdom., Sinnaeve D; Department of Organic and Macromolecular Chemistry , Ghent University , Campus Sterre, S4, Krijgslaan 281 , Ghent B-9000 , Belgium., Linclau B; School of Chemistry , University of Southampton , Highfield, Southampton SO17 1BJ , United Kingdom. |
| Abstrakt: |
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. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry. 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 (3 S,4 S)- and (3 R,4 R)-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 for the interrogation of its role in, for instance, protein stability or folding. |
