Axially chiral biaryls and heterobiaryls constitute the most represented subclass of atropisomers with prevalence in natural products, bioactive compounds, privileged chiral ligand/ catalysts, and optically pure materials. Despite many ionic protocols for their construction, radical-based variants represent another highly desirable and intriguing strategy but are far less developed. Moreover, efficient synthesis of axially chiral heterobiaryl molecules, especially ones having multiple heteroatoms and other types of chiral elements, through radical routes remains extremely limited. We herein disclose the first catalytic asymmetric, metal-free construction of axially and centrally chiral heterobiaryls by Minisci reaction of 5-arylpyrimidines and α-amino acid-derived redox-active esters. This is enabled by the use of 4CzIPN as an organic photoredox catalyst in conjunction with a chiral phosphoric acid catalyst. The reaction achieved a variety of interesting 5arylpyrimidines featuring the union of an axially chiral heterobiaryl and a centrally chiral α-branched amine with generally excellent regio-, diastereo-, and enantioselectivity (up to 82% yield; >19:1 dr; >99% ee). This finding also builds up a new platform for the development of desymmetrization methods via radical-involved atroposelective functionalization at heteroarene of prochiral heterobiaryls.

Atom transfer radical addition (ATRA) reaction of alkenes has had a significant impact on the field of radical difunctionalization of alkenes. Particularly, in the three-component photo-ATRA-type processes, a rich chemical space and structural diversity could be achieved by smart combination of redox-active radical precursors and the third coupling components (e.g., halides, C-, N-, and O-nucleophiles) under mild conditions. However, the inherent complicated mechanisms involving radical chain or outer-sphere SET of the incipient radical intermediates have led to a dearth of general catalytic methods for highly enantioselective variants, especially those regarding asymmetric intermolecular C−O bond formation. Here, we report a visible-light-induced copper-catalyzed asymmetric three-component photo-ATRA-type reaction of alkenes with oxime esters and carboxylic acids. In this process, a highly enantioselective intermolecular C−O cross-coupling between incipient sp 3 -hybridized carbon radicals and carboxylic acids was enabled by the formation of an aryl π-bond-engaged [σ + π]-copper complex. This working hypothesis renders naphthyl or extended conjugation of alkenes to be suitable substrates and allows good stereocontrol. This three-component photo-ATRA-type reaction exhibits broad substrate scope and high functional group tolerance with respect to each component, giving the desired cross-coupling products with generally good yields and enantioselectivity (>70 examples; up to 97% ee). Preliminary experimental and computational studies are also performed to gain insight into the mechanism and stereoregulatory elements. This finding provides a promising platform for the development of other enantioselective benzylic-type radical-based cross-coupling reactions.

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