Taras Shevchenko National University of Kyiv , Chemistry Department, Volodymyrska 64, 01601 Kyiv, Ukraine.
Enamine Limited, Chervonotkatska 78, 01103 Kyiv, Ukraine.
J Org Chem. 2017 Sep 1;82(17):8831-8841. doi: 10.1021/acs.joc.7b00803. Epub 2017 Jun 21.
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 pK 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.
胶原蛋白的三螺旋结构是动物体内最丰富的蛋白质，其稳定性归功于脯氨酸残基 4 位上的翻译后羟基基团。为了阐明这一现象的本质，我们研究了 4-取代基对肽基脯氨酸类似物中酰胺异构的影响。2,4-甲烷脯氨酸的刚性双环骨架使我们能够在不影响立体电子效应的情况下，跟踪取代基（电子效应）对键的影响。这些脯氨酸类似物是通过（2-烯丙氨基）丙烯酸衍生物的[2+2]光环加成制备的。随后的 pK 研究表明，4-氟取代具有显著的电子效应，而 4-甲基取代的影响可以忽略不计。在低温条件下，在模型化合物中测量了反式/顺式酰胺的比例。观察到的反式酰胺的优势是非常特殊的，在这方面，2,4-甲烷脯氨酸比脯氨酸更接近一级α-氨基酸。同时，与 N-乙酰脯氨酸相比，酰胺的旋转速度要高 3-4 个数量级。最后，我们的结果表明，4-取代基的电子效应对酰胺异构化的动力学有影响，但对反式构象的热力学优势没有影响。
