Zhang Ruixin, Xu Jiwei, Liu Siqi, Si Shibo, Chen Jiayao, Wang Lingxiao, Chen Wen-Wen, Zhao Baoguo
The Education Ministry Key Lab of Resource Chemistry, Shanghai Frontiers Science Center of Biomimetic Catalysis, and College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.
J Am Chem Soc. 2024 Sep 25;146(38):25927-25933. doi: 10.1021/jacs.4c09840. Epub 2024 Sep 11.
Direct asymmetric α-C-H conjugate addition of propargylamines to α,β-unsaturated ketones remains a great challenge due to the low α-amino C-H acidity of propargylamines and the nucleophilic interference of the NH group. Utilizing a new type of pyridoxals featuring a benzene-pyridine biaryl skeleton and a bulky amide side chain as carbonyl catalyst, we have accomplished direct asymmetric α-C-H conjugate addition of NH-unprotected propargylamines to α,β-unsaturated ketones. The adducts undergo subsequent intramolecular cyclization, delivering a wide range of chiral polysubstituted 1-pyrrolines in high yields (up to 92%) with excellent diastereo- and enatioelectivities (up to >20:1 dr and 99% ee). This work has demonstrated a straightforward approach to access pharmaceutically important chiral 1-pyrrolines, and it has also provided an impressive instance of direct asymmetric functionalization of inert C-H bonds enabled by biomimetic organocatalysts.
由于炔丙胺的α-氨基C-H酸性较低以及NH基团的亲核干扰，炔丙胺与α,β-不饱和酮的直接不对称α-C-H共轭加成仍然是一个巨大的挑战。利用一种新型的具有苯-吡啶联芳基骨架和庞大酰胺侧链的吡哆醛作为羰基催化剂，我们实现了未保护NH的炔丙胺与α,β-不饱和酮的直接不对称α-C-H共轭加成。加合物随后进行分子内环化，以高产率（高达92%）提供了多种手性多取代1-吡咯啉，具有优异的非对映和对映选择性（高达>20:1的非对映体比例和99%的对映体过量）。这项工作展示了一种直接获得药学上重要的手性1-吡咯啉的方法，并且还提供了一个由仿生有机催化剂实现惰性C-H键直接不对称官能化的令人印象深刻的实例。
