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A peptidyl-prolyl model study: How does the electronic effect influence the amide bond conformation?
Citation key 163.2017 Mykhailiuk
Author Mykhailiuk, P., and Kubyshkin, V., and Bach, T., and Budisa, N.
Pages 8831 - 8841
Year 2017
DOI doi: 10.1021/acs.joc.7b00803
Journal J. Org. Chem. [highlighted by cover page]
Volume 82
Abstract The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)acrylic acid derivatives. Subsequent pKa studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The trans/cis amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a trans-amide is extraordinary, and in this regard, 2,4-methanoproline is closer to primary α-amino acids than to proline. At the same time the amide rotation velocities were 3−4 orders of magnitude higher when compared to N-acetylprolyl. Finally, our results indicate that the electronic effect of the 4-substituent only affects the kinetics of the amide isomerization but not the thermodynamic prevalence for the trans-rotamer
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