Effects of fluorination on the conformation of proline : an NMR study

Introducing fluorine in proline allows modulating its conformational properties, which is useful to study the structure-activity relation of proline within biomolecules [1]. There are two aspects that determine the proline conformation: the five-membered ring puckering equilibrium, and the peptide bond cis/trans equilibrium [2]. Fluorine substitutions influence these equilibria by means of the strong stereoelectronic effects fluorine induces [3], e.g. the gauche effect. We investigated the conformational preferences of eight (fluoro)proline analogues (Ac-XOMe and Ac-X-NMe2 in which X is Pro, (4R)-FPro, (4S)-FPro or 4,4-F2Pro) [4] in both chloroform and water using NMR spectroscopy. Ac-X-NMe2 derivatives are better mimics for oligoproline peptides than Ac-X-OMe [5]. A direct comparison between both sets of compounds will be made. The five-membered ring pucker was determined separately for the trans and the cis isomers through analysis of the vicinal 1H-1H and 1H-19F couplings. For this, the recently developed PSYCHEDELIC experiment [6] for extracting scalar couplings was used, which allows to extract 1H-1H and 1H-19F couplings from crowded NMR spectra. The kinetics of the cis/trans isomerisation of the amide bond was investigated using 2D EXSY spectra or selective inversion recovery experiments [7]. References: 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. C. Siebler, B. Maryasin, M. Kuemin, R.S. Erdmann, C. Rigling, C. Grünenfelder, C. Ochsenfeld, H. Wennemers, Chem. Sci., 2015, 6, 6725 6. D. Sinnaeve, M. Foroozandeh, M. Nilsson, G.A. Morris, Angew. Chem. Int. Ed. Engl., 2016, 55, 1090 7. A.D. Bain, Prog. Nucl. Magn. Reson. Spectrosc., 2003, 43, 6