Visible-Light-Mediated Catalytic Asymmetric Synthesis of a-Amino Esters via Free Carbene Insertion into N-H Bond

Authors: Ying Zhou, Yan Zhang, Canghai Yu, Xin Yue, Feng Jiang and Wengang Guo*

Abstract: A method that facilitates the construction of valuable chiral products exploiting simple high energy intermediates in an atom- and sustainable fashion could prove highly enabling for asymmetric synthesis. Free carbenes are one kind of such high energy intermediates and their utilization in catalytic asymmetric reactions is still elusive, due to the existence of severe racemic background reaction. In our pursuit to develop catalytic asymmetric N-H insertion reaction of free carbene, a general chiral Brønsted acid-catalyzed enantioselective protonation of the in situ generated ammonium ylide was discovered under visible-light irradiation of diazo compound in the presence of arylamine, furnishing the desired a-amino esters with moderate to high enantioselectivity and yield. More importantly, it was found there is a remarkable correlation between the enantioselectivity of product and  substituent electronic parameter (s_para) of substrates. This work not only demonstrates chiral phosphoric acid catalysis is compatible with free carbene insertion reactions without disturbing deactivation O-H insertion side reactions, but also indicates the pKa of arylamine is also a significant parameter for turning the enantioselectivity of the reaction.  The method disclosed herein is expected to bring new insights into the use of free carbene in the catalytic asymmetric reactions under metal free conditions

Congratulations to Zhou Ying!

The major results in this work:

(1)

(2)

The related articels about catalytic asymmetric free carbene insertion reactions:

(1) For N-H insertion: During the preparation of this manuscript, an elegant visible light-promoted asymmetric free carbene insertion into N-H Bond enabled by a high-pKa Brønsted acid was reported by the group of Zhou: J.-B. Pan, X.-G. Zhang, Y.-F. Shi, A.-C. Han, Y.-J. Chen, J. Ouyang, M.-L. Li, Q.-L. Zhou, Angew. Chem. Int. Ed. 62 (2023) e202300691.

(2) For N-H insertion: Wengang Guo*, Ying Zhou, Hongling Xie, Xin Yue, Feng Jiang, Hai Huang, Zhengyu Han, and Jianwei Sun*, Chem. Sci., 2023, 14, 843-848.

(3) For N-H insertion: Ying Zhou, Yan Zhang and Wengang Guo* et al., Tetrahedron Lett., 2023, accepted.

(4) For N-H insertion: H. Saito, D. Morita, T. Uchiyama, M. Miyake, S. Miyairi, Tetrahedron Lett. 2012, 53, 6662-6664

(5) For C-C insertion: H. Zhang, Z. Wang, Z. Wang, Y. Chu, S. Wang, X.-P. Hui*, ACS Catal. 2022, 12, 5510-5516.

(6) For C-C insertion: S. Li and X. Liu* et al., ACS Catal. 2023, 13, 4656-4666.