Ji Pengwei, Liu Xiaopei, Xu Jiwei, Zhang Xu, Guo Jianhua, Chen Wen-Wen, Zhao Baoguo
The Education Ministry Key Lab of Resource Chemistry, Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, 200234, China.
Angew Chem Int Ed Engl. 2022 Nov 25;61(48):e202206111. doi: 10.1002/anie.202206111. Epub 2022 Oct 26.
Direct asymmetric functionalization of the inert α C-H bonds of N-unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pK ≈42.6) of the α C-H bonds and interruption of the nucleophilic NH group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric α-C-H addition of N-unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl β-aminoalcohols in 54-84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The α C-H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 10 times (from pK 42.6 to pK 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C-H bonds enabled by an organocatalyst.
N-未保护的炔丙基胺的惰性α C-H键的直接不对称官能团化是有机化学中的一大挑战，这是由于α C-H键的低酸度（pK≈42.6）以及亲核NH基团的干扰。通过使用手性吡哆醛作为羰基催化剂，我们成功实现了N-未保护的炔丙基胺与三氟甲基酮的直接不对称α-C-H加成，以54-84％的产率和优异的立体选择性（高达20:1的非对映体比例和99％的对映体过量）生成了多种手性炔基β-氨基醇。炔丙基胺的α C-H键通过形成亚胺中间体而被吡哆醛催化剂大大活化，导致酸度增加高达10倍（从pK 42.6增加到pK 20.1），这使其酸性足以在温和条件下被去质子化以进行不对称加成。这项工作为有机催化剂实现惰性C-H键的不对称官能团化提供了一个令人印象深刻的例子。
