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

(2019) JOURNAL OF ORGANIC CHEMISTRY. 84(6). p.3100-3120
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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. 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 (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 for the interrogation of its role in, for instance, protein stability or folding.
Keywords
CIS-TRANS ISOMERIZATION, COLLAGEN TRIPLE-HELIX, ENANTIOSELECTIVE, SYNTHESES, SCALE SYNTHESIS, AMINO-ACIDS, PROTEIN, PROLINE, FLUORINE, STABILITY, PEPTIDE

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Chicago
Hofman, Gert-Jan, Emile Ottoy, Mark E Light, Bruno Kieffer, José Martins, Ilya Kuprov, Davy Sinnaeve, and Bruno Linclau. 2019. “Synthesis and Conformational Properties of 3,4-difluoro-L-prolines.” Journal of Organic Chemistry 84 (6): 3100–3120.
APA
Hofman, G.-J., Ottoy, E., Light, M. E., Kieffer, B., Martins, J., Kuprov, I., Sinnaeve, D., et al. (2019). Synthesis and conformational properties of 3,4-difluoro-L-prolines. JOURNAL OF ORGANIC CHEMISTRY, 84(6), 3100–3120.
Vancouver
1.
Hofman G-J, Ottoy E, Light ME, Kieffer B, Martins J, Kuprov I, et al. Synthesis and conformational properties of 3,4-difluoro-L-prolines. JOURNAL OF ORGANIC CHEMISTRY. 2019;84(6):3100–20.
MLA
Hofman, Gert-Jan et al. “Synthesis and Conformational Properties of 3,4-difluoro-L-prolines.” JOURNAL OF ORGANIC CHEMISTRY 84.6 (2019): 3100–3120. Print.
@article{8616612,
  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. 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 (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 for the interrogation of its role in, for instance, protein stability or folding.},
  author       = {Hofman, Gert-Jan and Ottoy, Emile and Light, Mark E and Kieffer, Bruno and Martins, José and Kuprov, Ilya and Sinnaeve, Davy and Linclau, Bruno},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  keywords     = {CIS-TRANS ISOMERIZATION,COLLAGEN TRIPLE-HELIX,ENANTIOSELECTIVE,SYNTHESES,SCALE SYNTHESIS,AMINO-ACIDS,PROTEIN,PROLINE,FLUORINE,STABILITY,PEPTIDE},
  language     = {eng},
  number       = {6},
  pages        = {3100--3120},
  title        = {Synthesis and conformational properties of 3,4-difluoro-L-prolines},
  url          = {http://dx.doi.org/10.1021/acs.joc.8b02920},
  volume       = {84},
  year         = {2019},
}

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