Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids

• Published in: Angewandte Chemie International Edition Vol. 62; no. 47; pp. e202313838 - n/a
• Main Authors: Luo, Yicong, Ma, Yuqi, Li, Guanlin, Huo, Xiaohong, Zhang, Wanbin
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.11.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Allylic Substitution; Amino Acid; Amino acid substitution; Amino acids; Bimetallic Catalysis; Catalysis; Catalysts; Chemistry; Chemistry, Multidisciplinary; Copper; C−F Bond Activation; Density functional theory; Enantiomers; Fluorination; Fluorine; Imines; Lithium; Palladium; Peptides; Physical Sciences; Science & Technology; Stereodivergent Synthesis; Stereoselectivity; Substrates; Synthesis; Ternary systems; Bimetallic Catalysis; Amino Acid; ACTIVATION; IRIDIUM; PHARMACEUTICALS; C-F Bond Activation; ENANTIOSELECTIVE FLUORINATION; ALKYLATION; COMPLEXES; Allylic Substitution; Stereodivergent Synthesis; CONSTRUCTION; CATALYZED ALLYLIC SUBSTITUTION; ALPHA-ALLYLATION; DUAL CATALYSIS
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202313838

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C−F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non‐natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio‐, diastereo‐, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F−Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity. A desymmetrization of geminal difluoromethylenes using a palladium/copper/lithium ternary system was developed for the stereodivergent synthesis of chiral fluorinated amino acids. This ternary system afforded the allylic and benzylic substituted fluorinated α‐amino acids in good yields with excellent stereoselectivities in a stereodivergent manner (up to >99 % ee and >20 : 1 dr)