Enantioselective Dearomatization–Rearomatization Strategy to Access Tertiary Alkyl Fluorides

Fluorinated quaternary stereocenters have emerged as
indispensable
structural motifs in the development of pharmaceuticals. However,
strategies for accessing enantioenriched fluorinated gem-diarylmethanes remain largely underdeveloped, with efficient catalytic
enantioselective approaches for gem-diheteroaryl
tertiary alkyl fluorides being particularly scarce. Herein, we report
a general copper–biphosphine catalytic system for the enantioselective
heteroarylation of 2-alkyl azaarenes with 2-nitroheteroarenes via
a dearomatization–rearomatization process, enabling the modular
synthesis of enantioenriched gem-diheteroarylalkanes
featuring a fluorinated quaternary stereocenter. Mechanistic experimental
studies and density functional theory (DFT) calculations suggest that
the reaction proceeds through asymmetric dearomatized addition of
chiral copper-ligated α-fluoro aza-heteroarenyl enolates to
2-nitroheteroarenes, followed by HNO2 elimination-driven
rearomatization. This protocol features a wide substrate scope and
high ee values (>60 examples, up to >99% ee), and its synthetic
application
is further demonstrated by downstream transformations and successful
late-stage functionalization of complex bioactive molecules.