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Analysis of the five-membered ring pucker of β- and γ-fluorinated prolines by means of NMR spectroscopy and pseudorotation theory

Emile Ottoy (UGent) , Gert-Jan Hofman (UGent) , José Martins (UGent) , Bruno Linclau (UGent) and Davy Sinnaeve (UGent)
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Abstract
Introducing fluorine in proline enables modulating its conformational properties, which is useful to study the structure-function relation of proline within biomolecules [1]. There are two defining aspects of the proline conformation: the five-membered ring pucker, and the ratio between peptide bond trans and cis rotamers [2]. Fluorine substitutions influence both these aspects by means of stereoelectronic effects, such as the so-called gauche effect. [3] We will present the analysis of the ring puckers of seven (fluoro)proline analogues in both chloroform and water using NMR spectroscopy: Pro, (4R) FPro, (4S) FPro, 4,4 F2Pro, (3R) FPro, (3S) FPro or 3,3 F2Pro. These are studied as Ac X OMe derivatives. The first three analogues are well known in terms of their puckering behaviour [4] and are used to validate our methodology, while the puckering preferences of the latter four are less well known. The ring pucker can be determined separately for the trans and the cis isomers, as these are in slow exchange on the NMR time-scale. The analysis occurs through analysis of the vicinal 1H 1H and 1H 19F couplings. For this, the recently developed PSYCHEDELIC experiment was used, which allows straightforward extraction of 1H 1H and 1H 19F couplings from crowded NMR spectra. [5] Subsequently, the obtained scalar couplings are converted to torsion angles using Karplus relations [6,7] which are then translated into five-membered ring pseudorotation angles (P and vmax) by means of the Altona-Sundaralingam formalism [8]. These two parameters completely describe the ring pucker. The results of the conformational analysis and impact of various fluorine substitution patterns will be presented in detail. 1. B.K. Kay, M.P. Williamson, M. Sudol, FASEB J., 2000, 14, 231 2. K.M. Thomas, D. Naduthambi, G. Tririya, N.J. Zondlo, Org. Lett., 2005, 7, 2397 3. D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308 4. M. Salwiczek, E.K. Nyakatura, U.I. Gerling, S. Ye, B. Koksch, Chem. Soc. Rev., 2012, 41, 2135 5. D. Sinnaeve, M. Foroozandeh, M. Nilsson, G.A. Morris, Angew. Chem. Int. Ed. Engl., 2016, 55, 1090 6. E. Diez, J. San-Fabian, J. Guilleme, Mol. Phys., 1989, 68, 49 7. C. Thibaudeau, J. Plavec, J. Chattopadhyaya, J. Org. Chem., 1998, 63, 4967 8. C. Altona, M. Sundaralingam, J. Am. Chem. Soc., 1972, 94, 8205

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Chicago
Ottoy, Emile, Gert-Jan Hofman, José Martins, Bruno Linclau, and Davy Sinnaeve. 2016. “Analysis of the Five-membered Ring Pucker of Β- and Γ-fluorinated Prolines by Means of NMR Spectroscopy and Pseudorotation Theory.” In Young Belgian Magnetic Resonance Scientist, 15th Symposium, Abstracts.
APA
Ottoy, E., Hofman, G.-J., Martins, J., Linclau, B., & Sinnaeve, D. (2016). Analysis of the five-membered ring pucker of β- and γ-fluorinated prolines by means of NMR spectroscopy and pseudorotation theory. Young Belgian Magnetic Resonance Scientist, 15th Symposium, Abstracts. Presented at the 15th Young Belgian Magnetic Resonance Scientist (YBMRS) symposium.
Vancouver
1.
Ottoy E, Hofman G-J, Martins J, Linclau B, Sinnaeve D. Analysis of the five-membered ring pucker of β- and γ-fluorinated prolines by means of NMR spectroscopy and pseudorotation theory. Young Belgian Magnetic Resonance Scientist, 15th Symposium, Abstracts. 2016.
MLA
Ottoy, Emile, Gert-Jan Hofman, José Martins, et al. “Analysis of the Five-membered Ring Pucker of Β- and Γ-fluorinated Prolines by Means of NMR Spectroscopy and Pseudorotation Theory.” Young Belgian Magnetic Resonance Scientist, 15th Symposium, Abstracts. 2016. Print.
@inproceedings{8553604,
  abstract     = {Introducing fluorine in proline enables modulating its conformational properties, which is useful to study the structure-function relation of proline within biomolecules [1]. There are two defining aspects of the proline conformation: the five-membered ring pucker, and the ratio between peptide bond trans and cis rotamers [2]. Fluorine substitutions influence both these aspects by means of stereoelectronic effects, such as the so-called gauche effect. [3]
We will present the analysis of the ring puckers of seven (fluoro)proline analogues in both chloroform and water using NMR spectroscopy: Pro, (4R) FPro, (4S) FPro, 4,4 F2Pro, (3R) FPro, (3S) FPro or 3,3 F2Pro. These are studied as Ac X OMe derivatives. The first three analogues are well known in terms of their puckering behaviour [4] and are used to validate our methodology, while the puckering preferences of the latter four are less well known. The ring pucker can be determined separately for the trans and the cis isomers, as these are in slow exchange on the NMR time-scale. The analysis occurs through analysis of the vicinal 1H 1H and 1H 19F couplings. For this, the recently developed PSYCHEDELIC experiment was used, which allows straightforward extraction of 1H 1H and 1H 19F couplings from crowded NMR spectra. [5] Subsequently, the obtained scalar couplings are converted to torsion angles using Karplus relations [6,7] which are then translated into five-membered ring pseudorotation angles (P and vmax) by means of the Altona-Sundaralingam formalism [8]. These two parameters completely describe the ring pucker. The results of the conformational analysis and impact of various fluorine substitution patterns will be presented in detail.
1. B.K. Kay, M.P. Williamson, M. Sudol, FASEB J., 2000, 14, 231
2. K.M. Thomas, D. Naduthambi, G. Tririya, N.J. Zondlo, Org. Lett., 2005, 7, 2397
3. D. O{\textquoteright}Hagan, Chem. Soc. Rev., 2008, 37, 308
4. M. Salwiczek, E.K. Nyakatura, U.I. Gerling, S. Ye, B. Koksch, Chem. Soc. Rev., 2012, 41, 2135
5. D. Sinnaeve, M. Foroozandeh, M. Nilsson, G.A. Morris, Angew. Chem. Int. Ed. Engl., 2016, 55, 1090
6. E. Diez, J. San-Fabian, J. Guilleme, Mol. Phys., 1989, 68, 49
7. C. Thibaudeau, J. Plavec, J. Chattopadhyaya, J. Org. Chem., 1998, 63, 4967
8. C. Altona, M. Sundaralingam, J. Am. Chem. Soc., 1972, 94, 8205},
  author       = {Ottoy, Emile and Hofman, Gert-Jan and Martins, Jos{\'e} and Linclau, Bruno and Sinnaeve, Davy},
  booktitle    = {Young Belgian Magnetic Resonance Scientist, 15th Symposium, Abstracts},
  language     = {eng},
  location     = {Spa, Belgium},
  title        = {Analysis of the five-membered ring pucker of \ensuremath{\beta}- and \ensuremath{\gamma}-fluorinated prolines by means of NMR spectroscopy and pseudorotation theory},
  year         = {2016},
}