加州大学Neil K. Garg研究小组宣布他们提出了两种张力双根碱的键插入反应。该研究于2025年2月12日发表于国际一流学术期刊《自然》杂志上。

研究小组报道了一种新的合成方法，提供了一个特别令人垂涎的基序，双环[2.1.1]己烷支架，主题温和的反应条件和操作简单的方案。该方法通过两种罕见的应变片段的耦合进行：瞬态生成的环烯和双环[1.1.0]丁烷，它们分别具有可观的应变能~30 kcal/mol和~60 kcal/mol。该反应被认为是通过双自由基途径通过σ键插入进行的。

然而，不需要外部刺激来产生自由基，反应性被认为是由于每种反应物存在固有的双自由基特性而产生的。这种双根碱特性，8是反应设计中未充分利用的参数，是由每种反应物的严重几何畸变引起的。他们的研究为获得对药物发现有价值的功能化双环[2.1.1]己烷提供了一种方法，强调了如何以化学反应的几何扭曲为主题来实现不寻常的反应模式，并且应该为化学合成中二根类化合物的进一步探索和战略主题提供指导。

据悉，新的合成方法的发展有助于发现新的药物。那些为芳香化合物（即饱和芳烃生物异构体）提供结构替代品的有效途径的方法已成为高度令人垂涎的。这些生物同位体的结合通常会导致有利的药物样特性，并且代表了一个新兴的研究领域。

附：英文原文

Title: σ-Bond insertion reactions of two strained diradicaloids

Author: Tena Meza, Arismel, Rivera, Christina A., Shao, Huiling, Kelleghan, Andrew V., Houk, K. N., Garg, Neil K.

Issue&Volume: 2025-02-12

Abstract: The development of new synthetic methodologies are instrumental for enabling the discovery of new medicines. Those methods that provide efficient access to structural alternatives for aromatic compounds (i.e., saturated arene bioisosteres), have become highly coveted.1,2,3,4 The incorporation of such bioisosteres typically leads to favorable drug-like properties and represents an emerging field of research. Here, we report a new synthetic method that furnishes one especially coveted motif, the bicyclo[2.1.1]hexane scaffold,5,6 using mild reaction conditions and an operationally-simple protocol. The methodology proceeds via the uncommon coupling of two strained fragments: transiently-generated cyclic allenes and bicyclo[1.1.0]butanes, which possess considerable strain energies of ~30 kcal/mol7 and ~60 kcal/mol,6 respectively. The reaction is thought to proceed via a σ-bond insertion through a diradical pathway. However, rather than requiring an external stimulus to generate radical species, reactivity is thought to arise as a result of innate diradical character present in each reactant. This diradicaloid character,8 an underutilized parameter in reaction design, arises from the severe geometric distortions of each reactant. Our studies provide a means to access functionalized bicyclo[2.1.1]hexanes of value for drug discovery, underscore how geometric distortion of reactants can be used to enable uncommon modes of reactivity, and should encourage the further exploration and strategic use of diradicaloids in chemical synthesis.

DOI: 10.1038/s41586-025-08745-1

Source: https://www.nature.com/articles/s41586-025-08745-1