Tong Zixuan, Smith Philip J, Pickford Helena D, Christensen Kirsten E, Anderson Edward A
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Chemistry. 2023 Dec 14;29(70):e202302821. doi: 10.1002/chem.202302821. Epub 2023 Oct 25.
Gold catalysis is an important method for alkyne functionalization. Here we report the gold-catalyzed formal [3+2] aminative cyclization of yndiamides and isoxazoles in a direct synthesis of polysubstituted diaminopyrroles, which are important motifs in drug discovery. Key to this process is the formation, and subsequent cyclization, of an α-imino gold Fischer carbene, which represents a new type of gold carbene intermediate. The reaction proceeds rapidly under mild conditions, with high regioselectivity being achieved by introducing a subtle steric bias between the nitrogen substituents on the yndiamide. DFT calculations revealed that the key to this regioselectivity was the interconversion of isomeric gold keteniminiun ions via a low-barrier π-complex transition state, which establishes a Curtin-Hammett scenario for isoxazole addition. By using benzisoxazoles as substrates, the reaction outcome could be switched to a formal [5+2] cyclization, leading to 1,4-oxazepines.
金催化是炔烃官能化的一种重要方法。在此，我们报道了金催化的二酰胺和异恶唑的形式上的[3+2]胺化环化反应，用于直接合成多取代二氨基吡咯，这是药物发现中的重要结构单元。该过程的关键是α-亚氨基金费歇尔卡宾的形成及其随后的环化，这代表了一种新型的金卡宾中间体。反应在温和条件下快速进行，通过在二酰胺上的氮取代基之间引入细微的空间偏向实现了高区域选择性。密度泛函理论计算表明，这种区域选择性的关键是异构金酮亚胺离子通过低势垒π-络合物过渡态的相互转化，这为异恶唑加成建立了柯廷-哈米特情况。通过使用苯并异恶唑作为底物，反应结果可以转变为形式上的[5+2]环化反应，生成1,4-恶唑并庚因。
