Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes

Zheng Su; Binhong Tan; Hui He; Kaifeng Chen; Shixin Chen; Hongtao Lei; Tie-Gen Chen; Shao-Fei Ni; Zhaodong Li

doi:10.1002/anie.202402038

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes

Angew Chem Int Ed Engl. 2024 Feb 27:e202402038. doi: 10.1002/anie.202402038. Online ahead of print.

Authors

Zheng Su¹, Binhong Tan¹, Hui He², Kaifeng Chen¹, Shixin Chen¹, Hongtao Lei³, Tie-Gen Chen⁴, Shao-Fei Ni², Zhaodong Li¹

Affiliations

¹ National Key Laboratory of Green Pesticide, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
² Department of Chemistry, Shantou University, Shantou, 515063, Guangdong, China.
³ Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou, 510641, China.
⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, 528400, Guangdong, China.

PMID: 38412055
DOI: 10.1002/anie.202402038

Abstract

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Keywords: amino acid esters; asymmetric synthesis; fluorine; nickel; palladium.

Abstract

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