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

• Published in: Angewandte Chemie International Edition 2024-06, Vol.63 (23), p.e202402038-n/a
• Main Authors: Su, Zheng, Tan, Binhong, He, Hui, Chen, Kaifeng, Chen, Shixin, Lei, Hongtao, Chen, Tie‐Gen, Ni, Shao‐Fei, Li, Zhaodong
• Format: Article
• Language: English
• Subjects: Aldehydes; amino acid esters; Amino acids; asymmetric synthesis; Catalysis; Chemical reactions; Cross coupling; Cyclopropane; Enantiomers; Esters; fluorine; Imines; Intermediates; Nickel; Optical activity; Organic compounds; Palladium
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202402038

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. A robust palladium/nickel/chiral aldehyde synergistic relay system was developed for the enantioselective ring‐opening functionalization of gem‐difluorinated cyclopropanes with N‐unprotected amino acid esters, enabling the efficient assembly of α‐quaternary α‐amino acid esters bearing a linear 2‐fluoroallylic motif in a highly enantioselective manner.