Lu Heng, Xiao Ruo-Xuan, Shi Chang-Yun, Song Zi-Lan, Lin Hou-Wen, Zhang Ao
Pharm-X Center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Commun Chem. 2022 Jul 4;5(1):78. doi: 10.1038/s42004-022-00694-4.
As a unique organofluorine fragment, gem-difluoromethylated motifs have received widespread attention. Here, a convenient and efficient synthesis of aryldifluoromethyl aryl ethers (ArCFOAr') was established via Nickel-catalyzed aryloxydifluoromethylation with arylboronic acids. This approach features easily accessible starting materials, good tolerance of functionalities, and mild reaction conditions. Diverse late-stage difluoromethylation of many pharmaceuticals and natural products were readily realized. Notably, a new difluoromethylated PD-1/PD-L1 immune checkpoint inhibitor was conveniently synthesized and showed both improved metabolic stability and enhanced antitumor efficacy. Preliminary mechanistic studies suggested the involvement of a Ni(I/III) catalytic cycle.
作为一种独特的有机氟片段，偕二氟甲基化基序受到了广泛关注。在此，通过镍催化芳基硼酸的芳氧基二氟甲基化反应，建立了一种便捷高效的芳基二氟甲基芳基醚（ArCFOAr'）的合成方法。该方法具有起始原料易于获得、官能团耐受性好以及反应条件温和等特点。许多药物和天然产物的多样化后期二氟甲基化反应很容易实现。值得注意的是，一种新型的二氟甲基化PD-1/PD-L1免疫检查点抑制剂被方便地合成出来，并表现出改善的代谢稳定性和增强的抗肿瘤功效。初步机理研究表明涉及镍（I/III）催化循环。
