美国德克萨斯大学Tian Qin团队开发了一种作为交叉偶联伴侣的烷基亚磺酸盐，用于可编程、立体定向地安装C(sp³)生物等效官能团。相关论文于2023年3月2日发表于国际顶尖学术期刊《自然—化学》杂志上。

在该研究中，团队展示了烷基亚硫酸盐参与硫烷介导的C(sp³)-C (sp²)交叉偶联的能力，从而允许这些烷基生物等效官能团的可编程和立体定向安装。该方法简化逆合成分析的能力被多种药物相关骨架的改进合成所证明。对这一硫化学机理的实验研究和理论计算揭示了通过四氢呋喃溶剂化稳定的硫烷中间体烷基格氏活化的配体偶联趋势。

据了解，近年来，各种含季碳的环烷基，特别是环丙基和环丁基三氟甲基，成为药物类分子中很有前途的生物等效官能团。这种生物等效官能团的模块化安装仍然是合成化学家的挑战。亚磺酸烷基试剂之前被开发作为自由基前驱体用于制备具有所需烷基生物等效异构团的功能化杂环化合物。然而，这种转化的固有（自由基）反应性对任何芳香族或杂环芳香族骨架的功能化提出了反应性和区域选择性挑战。

附：英文原文

Title: Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres

Author: Zhou, Min, Tsien, Jet, Dykstra, Ryan, Hughes, Jonathan M. E., Peters, Byron K., Merchant, Rohan R., Gutierrez, Osvaldo, Qin, Tian

Issue&Volume: 2023-03-02

Abstract: In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)–C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

DOI: 10.1038/s41557-023-01150-z

Source: https://www.nature.com/articles/s41557-023-01150-z