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Ring pucker and cis/trans isomerism of 3,4-difluoroprolines

Emile Ottoy (UGent) , Gert-Jan Hofman (UGent) , Bruno Linclau (UGent) , José Martins (UGent) , Ilya Kuprov and Davy Sinnaeve (UGent)
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Abstract
Fluorination of amino acids has become a powerful tool in protein engineering, mainly because it allows one to manipulate the amino acid’s conformational and dynamical properties while only introducing a minimal steric perturbation [1,2]. In case of proline, the five-membered ring pucker equilibrium can be controlled when introducing a fluorine at the 3- or 4-position. For both positions, fluorination according to the R stereochemistry leads to a bias towards the Cγ exo pucker, while the S stereochemistry leads to a pronounced preference for the Cγ endo pucker [3]. Also the cis/trans isomerism of the Xaa-Pro peptide bond is affected by fluorination. Not only the cis:trans ratio is altered [3], but also the isomerization kinetics is accelerated [4], as the electron withdrawing fluorine group diminishes the double bond character of the peptide bond. Furthermore, the presence of fluorine allows the use of 19F NMR, which can provide site-specific information about structural and dynamical changes due to the sparse spectra and the high chemical shift dispersion of the 19F nucleus [5]. This property is especially useful in low-complexity peptide or protein sequences, such as oligoproline stretches. In our group, we have recently synthesized three of the four possible 3,4-difluoro-L-proline analogues [6,7]. Simultaneous fluorination of both the 3- and 4-position is expected to either reinforce or counteract the bias in the puckering equilibrium compared to their monofluorinated progenitors, while cis/trans isomerization rates will be even more increased. With this novel class of fluoroprolines, we hope to broaden the scope of possible applications for these compounds, ranging from strong conformational modulators to conformationally non-biased 19F NMR probes, in order to unravel the role of proline in the biological processes in which it is involved. This poster will discuss a thorough conformational analysis of these 3,4-difluoroprolines as Ac-FPro-OMe model compounds by means of a combination of NMR and DFT calculations. Both a detailed analysis of the five-membered ring pucker and cis/trans isomerism will be presented. References 1. Buer, B. C., Marsh, E. N. G. Protein Sci. 2012, 21, 453-462. 2. Odar, C., Winkler, M., Wiltschi, B. Biotechnol. J. 2015, 10, 427-446. 3. Kim, W., Hardcastle, K. I., Conticello, V. P. Angew. Chem. Int. Ed. Engl. 2006, 45, 8141-8145. 4. Renner, C., Alefelder, S., Bae, J. H., Budisa, N., Huber, R., Moroder, L. Angew. Chem. Int. Ed. Engl. 2001, 40, 923-925. 5. Chen, H., Viel, S., Ziarelli, F., Peng, L. Chem. Soc. Rev. 2013, 42, 7971-7982. 6. Hofman, G.-J., Ottoy, E., Light, M. E., Kieffer, B., Kuprov, I., Martins, J. C., Sinnaeve, D., Linclau, B. Chem. Commun. (Camb.) 2018, 54, 5118-5121. 7. Hofman, G.-J., Ottoy, E., Light, M. E., Kieffer, B., Martins, J. C., Kuprov, I., Sinnaeve, D., Linclau, B. submitted for publication.

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Chicago
Ottoy, Emile, Gert-Jan Hofman, Bruno Linclau, José Martins, Ilya Kuprov, and Davy Sinnaeve. 2018. “Ring Pucker and Cis/trans Isomerism of 3,4-difluoroprolines.” In Young Belgian Magnetic Resonance Scientist, 17th Symposium, Abstracts.
APA
Ottoy, E., Hofman, G.-J., Linclau, B., Martins, J., Kuprov, I., & Sinnaeve, D. (2018). Ring pucker and cis/trans isomerism of 3,4-difluoroprolines. Young Belgian Magnetic Resonance Scientist, 17th Symposium, Abstracts. Presented at the 17th Young Belgian Magnetic Resonance Scientist symposium  (YBMRS 2018).
Vancouver
1.
Ottoy E, Hofman G-J, Linclau B, Martins J, Kuprov I, Sinnaeve D. Ring pucker and cis/trans isomerism of 3,4-difluoroprolines. Young Belgian Magnetic Resonance Scientist, 17th Symposium, Abstracts. 2018.
MLA
Ottoy, Emile et al. “Ring Pucker and Cis/trans Isomerism of 3,4-difluoroprolines.” Young Belgian Magnetic Resonance Scientist, 17th Symposium, Abstracts. 2018. Print.
@inproceedings{8585129,
  abstract     = {Fluorination of amino acids has become a powerful tool in protein engineering, mainly because it allows one to manipulate the amino acid{\textquoteright}s conformational and dynamical properties while only introducing a minimal steric perturbation [1,2]. In case of proline, the five-membered ring pucker equilibrium can be controlled when introducing a fluorine at the 3- or 4-position. For both positions, fluorination according to the R stereochemistry leads to a bias towards the C\ensuremath{\gamma} exo pucker, while the S stereochemistry leads to a pronounced preference for the C\ensuremath{\gamma} endo pucker [3]. Also the cis/trans isomerism of the Xaa-Pro peptide bond is affected by fluorination. Not only the cis:trans ratio is altered [3], but also the isomerization kinetics is accelerated [4], as the electron withdrawing fluorine group diminishes the double bond character of the peptide bond. Furthermore, the presence of fluorine allows the use of 19F NMR, which can provide site-specific information about structural and dynamical changes due to the sparse spectra and the high chemical shift dispersion of the 19F nucleus [5]. This property is especially useful in low-complexity peptide or protein sequences, such as oligoproline stretches.
In our group, we have recently synthesized three of the four possible 3,4-difluoro-L-proline analogues [6,7]. Simultaneous fluorination of both the 3- and 4-position is expected to either reinforce or counteract the bias in the puckering equilibrium compared to their monofluorinated progenitors, while cis/trans isomerization rates will be even more increased. With this novel class of fluoroprolines, we hope to broaden the scope of possible applications for these compounds, ranging from strong conformational modulators to conformationally non-biased 19F NMR probes, in order to unravel the role of proline in the biological processes in which it is involved.
This poster will discuss a thorough conformational analysis of these 3,4-difluoroprolines as Ac-FPro-OMe model compounds by means of a combination of NMR and DFT calculations. Both a detailed analysis of the five-membered ring pucker and cis/trans isomerism will be presented.
References
1. Buer, B. C., Marsh, E. N. G. Protein Sci. 2012, 21, 453-462.
2. Odar, C., Winkler, M., Wiltschi, B. Biotechnol. J. 2015, 10, 427-446.
3. Kim, W., Hardcastle, K. I., Conticello, V. P. Angew. Chem. Int. Ed. Engl. 2006, 45, 8141-8145.
4. Renner, C., Alefelder, S., Bae, J. H., Budisa, N., Huber, R., Moroder, L. Angew. Chem. Int. Ed. Engl. 2001, 40, 923-925.
5. Chen, H., Viel, S., Ziarelli, F., Peng, L. Chem. Soc. Rev. 2013, 42, 7971-7982.
6. Hofman, G.-J., Ottoy, E., Light, M. E., Kieffer, B., Kuprov, I., Martins, J. C., Sinnaeve, D., Linclau, B. Chem. Commun. (Camb.) 2018, 54, 5118-5121.
7. Hofman, G.-J., Ottoy, E., Light, M. E., Kieffer, B., Martins, J. C., Kuprov, I., Sinnaeve, D., Linclau, B. submitted for publication.},
  author       = {Ottoy, Emile and Hofman, Gert-Jan and Linclau, Bruno and Martins, Jos{\'e} and Kuprov, Ilya and Sinnaeve, Davy},
  booktitle    = {Young Belgian Magnetic Resonance Scientist, 17th Symposium, Abstracts},
  language     = {eng},
  location     = {Spa, Belgium},
  title        = {Ring pucker and cis/trans isomerism of 3,4-difluoroprolines},
  year         = {2018},
}