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.

尽管芳香环是药物活性化合物中的常见元素，但这些基序的存在给药物的可开发性带来了一些不利因素¹ 。通过用非芳香族等排基序取代芳香环，可以改善药物化合物中的非最佳效力、代谢稳定性、溶解度和亲脂性² 。此外，虽然芳香环是平面的并且缺乏三维性，但大多数药物靶标的结合口袋是手性的。因此，等排取代的立体化学构型可能提供额外的机会来提高衍生配体对靶受体的亲和力。这种方法的一个显着障碍是缺乏简单且可扩展的从容易获得的前体中催化对映选择性合成候选等排体的方法。在这里，我们提出了一种以前未知的钯催化反应，该反应将烃衍生的前体转化为手性含硼去甲三环烷，并且我们表明这些去甲三环烷的形状使它们成为间位二取代芳环的合理等排物。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广泛结构的途径。我们还表明，将去甲三环烷纳入药物基序中可以改善生物物理特性以及立体化学依赖性活性。我们预计这些特征，再加上功能化去甲三环烷支架的简单、廉价的合成，将使该平台成为组装新生物活性剂的有用基础。