Chen Hua-Hong, Jiang Jia-Tian, Yang Ye-Nan, Ye Long-Wu, Zhou Bo
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
State Key Laboratory of Organometallic Chemistry, Shanghai, Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
Angew Chem Int Ed Engl. 2025 May 26;64(22):e202505167. doi: 10.1002/anie.202505167. Epub 2025 Mar 27.
Carboxylic acids are readily available chemicals with broad applications in chemistry-related areas, and their coupling with amines and alcohols is a fundamental transformation in organic synthesis. However, the catalytic enantioselective coupling of carboxylic acids remains elusive, especially for the atroposelective reaction. Here we report a chiral Brønsted acid (CBA)-catalyzed atroposelective coupling of carboxylic acids with amines and alcohols using ynamides as coupling reagents. The novel enantiocontrol involving CBA-catalyzed ester addition enables the straightforward construction of axially chiral amides and planar-chiral esters with high enantioselectivities through atroposelective intermolecular amidation and intramolecular macrolactonization. Diverse medicinally relevant carboxylic acids can undergo direct late-stage modification by this method. Importantly, this reaction represents the first atroposelective coupling of carboxylic acids with amines, as well as the first chemocatalytic atroposelective coupling of carboxylic acids with alcohols. The resulting atropisomeric skeletons can be readily derivatized to chiral ligands and catalysts for asymmetric catalysis.
羧酸是易于获得的化学品，在化学相关领域有广泛应用，它们与胺和醇的偶联是有机合成中的一种基本转化反应。然而，羧酸的催化对映选择性偶联仍然难以实现，尤其是对于阻转选择性反应。在此，我们报道了一种手性布朗斯特酸（CBA）催化的羧酸与胺和醇的阻转选择性偶联反应，该反应使用炔酰胺作为偶联试剂。涉及CBA催化酯加成的新型对映体控制，能够通过阻转选择性分子间酰胺化和分子内大环内酯化，以高对映选择性直接构建轴向手性酰胺和平面手性酯。多种具有药用价值的羧酸可通过该方法进行直接的后期修饰。重要的是，该反应代表了首例羧酸与胺的阻转选择性偶联，以及首例羧酸与醇的化学催化阻转选择性偶联。所得到的阻转异构骨架可容易地衍生化为用于不对称催化的手性配体和催化剂。
