Copper‐Catalyzed Highly Stereoselective Hydrodifluoroallylation of Cyclopropenes and Alkenyl Boronates with 3,3‐Difluoroallyl Sulfonium Salts^†

Abstract

Comprehensive SummaryDespite the paramount applications of organofluorine compounds in life and materials sciences, efficient strategies for stereoselectively constructing the C(sp3)‐CF2R bond at the stereogenic center remain limited. Here, we report a copper‐catalyzed hydrodifluoroallylation of cyclopropenes and alkenyl boronates with 3,3‐difluoroallyl sulfonium salts (DFASs). The use of DFASs overcomes the previous challenge of suppressing the reduction of fluoroalkylating reagents with M‐H species. The reaction provides an array of gem‐difluoroallyl cyclopropanes and borylalkanes with high efficiency and stereoselectivity under mild reaction conditions. Using chiral phosphine ligand could provide gem‐difluoroallyl borylalkanes with high enantioselectivities, paving a new way for the catalytic asymmetric fluoroalkylation with ubiquitous alkenes. The advantages of this protocol are synthetic convenience, high functional group tolerance, and the synthetic versatility of the resulting gem‐difluoroallyl cyclopropanes and borylalkanes. The synthetic utility of this approach has also been demonstrated by the diversified transformations of the gem‐difluoroallylated products and the rapid synthesis of bioactive molecule analogs.

Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts

“…1c, DFASs could be easily prepared from inexpensive and bulk chemical feedstock 3,3,3-trifluoropropene (TFP) or 2-bromo-3,3,3-trifluoroprene through a two or three-step procedure (for details, see ESI†). 20,21 A total conversion of 1a was observed when the reaction was carried out with 1a (1.0 equiv.) and 2a (1.0 equiv.)…”

“…To bridge the gap, we envisioned that the bench-stable 3,3-difluoroallyl sulfonium salts (DFASs) (Fig. 1c) 20,21 could be beneficial for site-selective fluoroalkylation of peptides, because such a type of fluoroalkylating reagent features a flexible molecular scaffold to be readily edited, satisfying varieties of demands for peptide research: (1) the electrophilicity of DFAS could be tuned by the substituents on the sulfur atom, allowing for highly chemical selectivity toward cysteine without affecting other nucleophilic residues or enabling potential proximity-driven reactivity; (2) the β-C of DFASs could be readily modified with bioorthogonal functional groups, such as alkynyl, azide, or useful probes ( e.g. , dyes, biomarkers); (3) upon reacting with a peptide, the newly added gem -difluoroallyl group is a good handle for successive “doubly orthogonal” modifications (Fig.…”