Martí-Centelles Vicente, Burguete M Isabel, Cativiela Carlos, Luis Santiago V
Departamento de Química Inorgánica y Orgánica, ESTCE, Universitat Jaume I , E-12071 Castellón, Spain.
J Org Chem. 2014 Jan 17;79(2):559-70. doi: 10.1021/jo4022309. Epub 2013 Dec 23.
A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br(-) has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds.
已经合成了一族含有非天然氨基酸的拟肽大环化合物。对大环化反应进行了实验和计算研究，证明了氨基酸侧链和催化溴离子的关键作用。溴离子作为外部模板，协助开链前体折叠成合适的构象。计算表明，在阴离子存在下，侧链对大环化能垒的影响非常小。然而，对开链前体构象平衡的影响非常重要。总体而言，开链中间体的两个反应端以正确取向彼此靠近的那些构象的稳定化是决定大环化成功的关键参数。对于含有环己基丙氨酸的化合物，发现其产率最高，在Br(-)存在下，计算预测的最稳定构象异构体具有适合环化的预组织。实验与理论之间的显著一致性表明，这里所考虑的计算方法对于预测其他相关体系的行为以及设计合成新大环化合物的合适路线可能非常有用。
