Citation: Xiang Huang, Dongzhen Xu, Yang Liu, Xia Huang, Yangfan Wu, Dongmei Fang, Bing Xia, Wei Jiao, Jian Liao, Min Wang. Asymmetric synthesis of difluorinated α-quaternary amino acids (DFAAs) via Cu-catalyzed difluorobenzylation of aldimine esters[J]. Chinese Chemical Letters, ;2024, 35(12): 109665. doi: 10.1016/j.cclet.2024.109665 shu

Asymmetric synthesis of difluorinated α-quaternary amino acids (DFAAs) via Cu-catalyzed difluorobenzylation of aldimine esters

Xiang Huang ^{a, c} ,
Dongzhen Xu ^{a, c} ,
Yang Liu ^b ,
Xia Huang ^{b, c} ,
Yangfan Wu ^{a, c} ,
Dongmei Fang ^b ,
Bing Xia ^b ,
Wei Jiao ^b ,
Jian Liao ^{a, b, c, *,} ,
Min Wang ^{b, *,}

a.
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b.
Natural Product Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
c.
University of Chinese Academy of Sciences, Beijing 100049, China

jliao@cib.ac.cn

wangmin@cib.ac.cn

Received Date: 17 November 2023
Revised Date: 1 February 2024
Accepted Date: 17 February 2024
Available Online: 23 February 2024

Figures(6)

Increasing interests of difluorinated amino acids (DFAAs) have been raised in recent years due to their widespread bio-organic and medical applications. However, to date, only few investigations focused on their asymmetric synthesis. Exploring difluoromethyl reagent to tailor a novel pathway and developing efficient catalytic system are highly desirable for constructing structurally diverse chiral DFAAs. Herein, a copper-catalyzed asymmetric difluorobenzylation of aldimine esters is described. By using α,α-difluorinated benzyltriflones as difluoromethyl reagents, this protocol allows the asymmetric synthesis of α-quaternary DFAAs with wide scope, good yields and excellent enantioselectivities (90%-98% ee). Control experiments and DESI-MS analysis demonstrate the reaction probably proceeds via a key difluorocarbocation intermediate. Moreover, polyfluoroarenes are found efficient candidates to polyfluoroaryl amino acids via C-F activation. Gram-scale experiment, late-stage functionalization, synthesis of difluorinated dipeptides and bioactive molecular analogues revealed the utility of the protocol, thereby largely enriching the structural diversity of FAAs and providing more potential opportunities in drug discovery.
- Cu-catalyzed,
- Asymmetric difluorobenzylation,
- Difluorobenzylated α-quaternary amino acids,
- Polyfluoroaryl amino acids,
- Difluorocarbocation
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