在药物研发过程中，后期修饰药物分子功能基团能够迅速加速药物发现过程，特别是通过交换氢键供体和受体，或调节药物的重要理化性质如logP、溶解度或极性表面积。一个行之有效的策略是通过延展配体来置换与受体相互作用的水分子，从而提高配体的效力。受这一应用的启发，研究团队开发了一种新策略，能够高选择性地将吡啶中的氮原子转变为带有酯基的碳，这种酯基提供了灵活的功能基团操作平台。吡啶是FDA批准药物中常见的结构，因此其后期修饰对于加速药物发现具有重要意义。先前已有的方法包括吡啶环的开环和重环化，或通过钛烷基化合物将吡啶转化为烷基苯，但这些方法受限于取代基的种类和功能基团的兼容性。本研究团队提出了一种[4+2]环加成策略，通过两步法实现吡啶到苯的转化：首先是1,2-加成产生二氢吡啶，然后进行与炔烃的[4+2]环加成和逆[4+2]环加成级联反应。（图1D）这种方法不仅克服了先前方法的局限性，而且在实际操作中更加简便，适用范围更广。
图片来源：JACS
作者首先通过1,2-加成反应将吡啶去芳构化生成二氢吡啶，然后利用与炔烃的[4+2]环加成和逆[4+2]环加成级联反应将其转化为带有酯基的苯。实验中，研究团队选择了几种吡啶衍生物作为起始材料，通过钠硼氢化物和氯甲酸烷基酯进行去芳构化处理，得到二氢吡啶中间体。然后，这些中间体在不同条件下与甲基丙炔酸酯或二甲基乙炔二羧酸酯进行[4+2]环加成反应，最终得到目标产物。（图2）
图片来源：JACS
本研究开发的基于水置换的吡啶高选择性转苯方法，为药物研发提供了一个强有力的工具，不仅提高了药物发现的效率，还拓宽了药物分子的设计空间，对未来的药物化学研究具有重要的指导意义和应用价值。首先，它为药物分子的后期修饰提供了一种高效简便的工具，使得研究人员可以在不需要独立合成新分子的情况下，通过单原子变化来迅速研究药物与靶标之间的相互作用。这不仅大大缩短了药物发现的周期，还提高了新药开发的效率。其次，这种方法在反应条件上的宽容性和操作的简便性，使其能够应用于多种吡啶衍生物的转化，展示了广泛的适用范围。通过对不同药物分子进行后期修饰，可以快速生成一系列新的药物类似物，从而提高药物筛选的速度和成功率。此外，研究中通过炔烃引入的酯基功能性团，不仅可以直接用于药物设计，还可以进一步转化为其他重要的药物功能基团如羧酸、酰胺和腈等。这种灵活性进一步增强了该方法在药物化学中的应用潜力。
标题：Regioselective Pyridine to Benzene Edit Inspired by Water- Displacement
作者：Benjamin R. Boswell,* Zhensheng Zhao, Ryan L. Gonciarz, and Keyur M. Pandya
链接：https://doi.org/10.1021/jacs.4c05999
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