Catalytic Asymmetric Construction of Axially and Centrally Chiral Heterobiaryls by Minisci Reaction

Abstract

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.

Accessing chiral sulfones bearing quaternary carbon stereocenters via photoinduced radical sulfur dioxide insertion and Truce–Smiles rearrangement

“…In this respect, Lin and Liu have independently described copper-catalyzed enantioselective sulfonyl radical-initiated difunctionalization of alkenes to obtain a series of chiral sulfone derivatives 17 , 18 . This approach benefits further from the emergence of visible light photoredox catalysis, which has enabled generation of radicals under mild conditions via single-electron transfer from precursors 19 – 21 or through radical insertion of sulfur dioxide 22 – 36 . Using a photocatalytic system comprised of chiral bis-cyclometalated rhodium(III) complex, Meggers and Wu accomplished enantioselective conjugate addition of sulfonyl radicals to activated alkenes for the efficient synthesis of chiral sulfones 19 , 20 .…”

Enantioselective Friedel–Crafts Reaction of 2-Alkynyphenols with Aromatic Ethers by Chiral Brønsted Acid Catalysis

“…The axially chiral styrene 3d was also tested as a ligand for the enantioselective addition of diethylzinc to naphthalene formaldehyde, giving product 8 in a 68% yield and with 23% ee (Scheme ). Next, the olefins 3d could also be easily converted into the corresponding triflate, and then the one-pot Pd­(OAc) 2 -catalyzed reaction between diphenyl phosphine oxide and the triflate at 120 °C furnished 5 in a 57% yield and 92% ee (Scheme B). In addition, NaH could also promote the reaction of 4e and Tf 2 O in DCM, affording the corresponding triflate 6 in an 87% yield and with 93% ee.…”

N–O Bond Activation by Energy Transfer Photocatalysis

“…Over the decades, N–O activation has been efficiently achieved through visible-light-driven reductive SET of an electrophore, wherein the disparity between the electron densities at the N and O heteroatoms due to the presence of unique functional groups is exploited to selectively generate either (i) an O-centered radical (O • ) and N – from N electrophores or (ii) a N-centered radical (N • ) and O – from O electrophores (Figure a). N -Alkoxypyridinium salts, − N -(acyloxy)­phthalimides, and thiohydroxamic esters act as N electrophores, whereas O electrophores consist of oxime derivatives, − N -(acyloxy)­phthalimides, , N , O -disulfonyl- N -alkylhydroxylamines, , N -oxyamines, N -oxyamides, − N -oxycarbamates, − and dioxazolones . The weakening of the N–O bond after SET reduction eventually results thermodynamically favored defragmentation.…”