美国波士顿学院Morken, James P.团队报道了间苯等排体的催化不对称合成。相关研究成果发表在2024年8月21日出版的《自然》。

尽管芳香环是药物活性化合物中的常见基序，但这些基序的存在对药物的可开发性带来了一些不利影响。通过将芳香环替换为非芳香族等排体化合物，可以提高药物化合物中的非最佳效力、代谢稳定性、溶解度和亲脂性。

此外，尽管芳香环是平面的，缺乏三维性，但大多数药物靶标的结合口袋都是手性的。因此，等量替代物的立体化学构型可能为提高衍生配体对靶受体的亲和力提供了额外的机会。这种方法的一个显著障碍是缺乏从现成的前体中简单和可扩展的催化对映选择性合成候选异构体。

该文中，研究人员提出了一种以前未知的将烃衍生的前体转化为手性含硼的去甲三环的钯催化反应，表明这些去甲三环的形状使它们成为间二取代芳香环的合理等排体。使用手性催化剂，Pd催化的反应可以以对映选择性的方式完成，随后硼基团的转化提供了获得各种结构的途径。研究还表明，将去甲三环芳烃掺入药物基序可以改善生物物理性质以及立体化学依赖性活性。

研究认为，这些特征，再加上功能化去甲三环霉素支架的简单、廉价合成，将使该平台成为组装新生物活性剂的有用基础。

附：英文原文

Title: Catalytic asymmetric synthesis of meta benzene isosteres

Author: Zhang, Mingkai, Chapman, Matthew, Sarode, Bhagyesh R., Xiong, Bingcong, Liang, Hao, Chen, James K., Weerapana, Eranthie, Morken, James P.

Issue&Volume: 2024-08-21

Abstract: Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents.

DOI: 10.1038/s41586-024-07865-4

Source: https://www.nature.com/articles/s41586-024-07865-4