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首页> 外文期刊>Chemistry: A European journal >Template effects in S _N2 displacements for the preparation of pseudopeptidic macrocycles
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Template effects in S _N2 displacements for the preparation of pseudopeptidic macrocycles

机译：S_N2置换中的模板效应，用于制备拟肽大环化合物

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摘要

Macrocyclisation reactions of C _2-symmetric pseudopeptides containing central pyridine-derived spacers are affected by the presence of different anions. The selection of the proper anion gives excellent results for the preparation of the corresponding macrocyclic structures. Kinetic studies show that the presence of those anions enhances both the yield and the rate of the reaction. Computational studies at the B3LYP/6-31G* level have allowed us to rationalise the experimental results. The obtained transition states (TSs) show that the interaction between the anion and the open-chain pseudopeptidic chain has a stabilising effect. The anion stabilises the two TSs involved: the first one, which involves the formation of the initial bond between the two subunits and leads to an open-chain intermediate, and the second one, which precedes the formation of the cyclic structure. The optimum anion (Br - when the central spacer is derived from 2,6-bis(aminomethyl) pyridine, is able to act as a template, in that it forces the two ends of the open-chain intermediate to approach each other by forming hydrogen bonds with the two amino acid subunits present in the intermediate. This stabilises the second TS to a greater extent than the first one, and thus, favours macrocyclisation over the competing oligomerisation reactions. The computational calculations also allowed us to predict the outcome of new experiments. Accordingly, the synthesis of the pseudopeptidic macrocycle derived from 2,6-diaminopyridine was not successful under the optimised conditions previously used. Nevertheless, calculations predicted that in this case Cl - should be more efficient than Br -, and this was subsequently experimentally confirmed. Interestingly, the presence of different substituents on the constituent amino acids seems to play a minor role in the overall process.
机译：包含中心吡啶衍生的间隔基的C _2对称假肽的大环化反应受不同阴离子的存在的影响。选择合适的阴离子可为制备相应的大环结构提供出色的结果。动力学研究表明，这些阴离子的存在可提高产率和反应速度。 B3LYP / 6-31G *水平的计算研究使我们能够合理化实验结果。所获得的过渡态（TSs）表明，阴离子与开链假肽链之间的相互作用具有稳定作用。阴离子使涉及的两个TS稳定化：第一个涉及两个亚基之间的初始键的形成并导致开链中间体，第二个涉及环状结构的形成。最佳阴离子（Br-当中心间隔基衍生自2,6-双（氨基甲基）吡啶时，能够充当模板，因为它通过形成开环中间体的两端迫使彼此接近与中间体中存在的两个氨基酸亚基形成氢键，这使第二种TS稳定程度高于第一个TS，从而有利于大环化而不是竞争性的低聚反应，计算结果也使我们可以预测新的TS因此，由2，6-二氨基吡啶衍生的假肽大环化合物在先前使用的最优化条件下未能成功合成，尽管如此，计算预测在这种情况下，Cl-的效率应高于Br-，随后通过实验有趣的是，组成氨基酸上不同取代基的存在似乎在整个过程中起着很小的作用。

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