美国俄亥俄州立大学Sevov, Christo S.研究团队报道了可独立镍-烷基配合物的还原烷基-烷基偶联。相关研究成果于2024年8月29日发表在《自然》。

两个烷基亲电试剂选择性交叉偶联以构建复杂分子仍然是有机合成中的一个挑战。已知的反应针对特定的亲电试剂进行了优化，并且不适用于来源于常见烷基构建块的可互换变化的亲电底物，如胺、羧酸和卤化物。这些限制限制了可以修饰的烷基底物的类型，并最终限制了可以探索的化学空间。

该文中，研究人员报告了这些限制的通用解决方案，使烷基-烷基交叉偶联反应的组合方法成为可能。这种方法依赖于发现异常持久的镍（烷基）络合物，这些络合物可以通过烷基卤化物、氧化还原活性酯或吡啶鎓盐的氧化加成直接形成。

所得烷基络合物可以分离或直接伸缩，并与第二个烷基亲电试剂偶联，这代表了以前未知的交叉选择性反应。通过脱卤、脱羧或脱氨基偶联的各种组合，氨基酸、天然产物、药物和类药物构建块的快速多样化展示了这种合成能力的实用性。除了强大的范围外，该项工作还通过晶体学分析、立体化学探针和光谱研究提供了对合成相关镍（烷基）配合物的有机金属化学的见解。

附：英文原文

Title: Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes

Author: Zubaydi, Samir Al, Waske, Shivam, Akyildiz, Volkan, Starbuck, Hunter F., Majumder, Mayukh, Moore, Curtis E., Kalyani, Dipannita, Sevov, Christo S.

Issue&Volume: 2024-08-29

Abstract: The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis.1,2 Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids, and halides.3–5 These limitations restrict the types of alkyl substrates that can be modified and, ultimately, the chemical space that can be explored.6 Here we report a general solution to these limitations that enables a combinatorial approach to alkyl-alkyl cross-coupling reactions. This methodology relies on the discovery of unusually persistent Ni(alkyl) complexes that can be formed directly by oxidative addition of alkyl halides, redox-active esters, or pyridinium salts. The resulting alkyl complexes can be isolated or directly telescoped to couple with a second alkyl electrophile, which represent cross-selective reactions that were previously unknown. The utility of this synthetic capability is showcased in the rapid diversification of amino acids, natural products, pharmaceuticals, and drug-like building blocks by various combinations of dehalogenative, decarboxylative, or deaminative coupling. In addition to a robust scope, this work provides insights into the organometallic chemistry of synthetically relevant Ni(alkyl) complexes through crystallographic analysis, stereochemical probes, and spectroscopic studies.

DOI: 10.1038/s41586-024-07987-9

Source: https://www.nature.com/articles/s41586-024-07987-9