Prediction of High-Yielding Single-Step or Cascade Pericyclic Reactions for the Synthesis of Complex Synthetic Targets
Prediction of High-Yielding Single-Step or Cascade Pericyclic Reactions for the Synthesis of Complex Synthetic Targets
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用于合成复杂合成目标的高产单步或级联周环反应的预测
DOI：
10.1021/jacs.2c09830
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发表时间：
2022
影响因子：
15
通讯作者：
Maeda Satoshi
中科院分区：
文献类型：
--
作者：
Mita Tsuyoshi;Takano Hideaki;Hayashi Hiroki;Kanna Wataru;Harabuchi Yu;Houk K. N.;Maeda Satoshi
周环反应是指没有离子或自由基中间体的环状协同过渡态反应，自20世纪60年代定义以来，得到了广泛的研究，著名的Woodward-Hoffmann规则预测了它们的立体选择性和化学选择性。在这里，我们描述了一种全自动的反应路径搜索方法，即人工诱导反应(AFIR)，通过基于产物的量子化学辅助反合成分析(QCaRA)，通过热允许的周环反应，在不使用任何先验实验知识的情况下，将输入化合物追溯到合理的起始物质。所有类型的周环反应，包括环加成反应、烯反应、基团转移反应、络合反应、电环反应和Sigmato反应，都通过协同反应途径被成功地追溯，并用正确的立体化学计算得到了起始物质。此外，AFIR被用来预测所识别的反应路径是否可以预期以相对于所识别的起始材料的其他可能的反应以良好的产率发生。为了展示其实用价值，这项最先进的技术还被应用于具有相对较高原子数(52个原子：烯二酸C甲酯)的天然产物的逆合成分析，该天然产物由Nicolaou于1982年首次合成，并通过三个周环反应级联反应(一个Diels-Alder反应以及6个π和8个π电环反应)为相应的起始多烯提供了正确的立体专一性。此外，不仅遵守伍德沃德-霍夫曼规则的系统，而且违反这些规则的系统，如胡克最近计算的系统，都可以准确地进行逆向综合。
Pericyclic reactions, which involve cyclic concerted transition states without ionic or radical intermediates, have been extensively studied since their definition in the 1960s, and the famous Woodward–Hoffmann rules predict their stereoselectivity and chemoselectivity. Here, we describe the application of a fully automated reaction-path search method, that is, the artificial force induced reaction (AFIR), to trace an input compound back to reasonable starting materials through thermally allowed pericyclic reactions via product-based quantum-chemistry-aided retrosynthetic analysis (QCaRA) without using any a priori experimental knowledge. All categories of pericyclic reactions, including cycloadditions, ene reactions, group-transfer, cheletropic, electrocyclic, and sigmatropic reactions, were successfully traced back via concerted reaction pathways, and starting materials were computationally obtained with the correct stereochemistry. Furthermore, AFIR was used to predict whether the identified reaction pathway can be expected to occur in good yield relative to other possible reactions of the identified starting material. In order to showcase its practical utility, this state-of-the-art technology was also applied to the retrosynthetic analysis of a natural product with a relatively high number of atoms (52 atoms: endiandric acid C methyl ester), which was first synthesized by Nicolaou in 1982 and provided the corresponding starting polyenes with the correct stereospecificity via three pericyclic reaction cascades (one Diels–Alder reaction as well as 6π and 8π electrocyclic reactions). Moreover, not only systems that obey the Woodward–Hoffmann rules but also systems that violate these rules, such as those recently calculated by Houk, can be retrosynthesized accurately.