Chiral Phosphoric Acid–Palladium(II) Complex Catalyzed Asymmetric Desymmetrization of Biaryl Compounds by C(sp³)–H Activation

Abstract

Desymmetrization is an essential method for the synthesis of chiral compounds, particularly chiral biaryls. We have developed an enantioselective synthesis of axially chiral biaryls by desymmetrization using C­(sp3)–H activation catalyzed by chiral palladium phosphate. Mechanistic studies show that C–H activation is the rate- and enantiomer-determining step. To the best of our knowledge, this is the first report of asymmetric desymmetrization of axially chiral compounds by C­(sp3)–H activation.

Recent advances in catalytic asymmetric synthesis

“…In 2023, Akiyama and coworkers reported the first example of axially chiral biaryl desymmetrization by directing group-assisted atroposelective C (sp³)-H activation using a CPA-Pd(II) catalyst ( Figure 2B ) ( Uchikura et al, 2023 ). The reaction of biaryls bearing a picolinamido moiety at the 2′-position as the directing group with aryl iodides catalyzed by Pd(OAc) 2 - B 2 with Ag 3 PO 4 as an additive, afforded chiral biaryl products 2B in 45–85% yield and 84–97% e.e.…”

Enantioselective synthesis of 3-(N-indolyl)quinolines containing axial and central chiralities

“…As part of our continued interest in developing atroposelective reactions using chiral phosphoric acid (CPA) catalysis 14 and for addressing the above-mentioned issues, we envisaged that the Minisci-type radical functionalization by photoredox-chiral acid hybrid catalysis would provide the desired quinolines in high yields and with excellent enantioselectivities. 15 The stereoselective Minisci reaction under photoredox catalysis is a powerful method for the transformation of heteroarenes under mild conditions.…”

Axially Chiral 2-Hydroxybiaryls by Palladium-Catalyzed Enantioselective C–H Activation

“…In this context, there has been a growing interest in the use of enantioselective C–H bond functionalizations for producing axially chiral biaryls because these structures represent privileged scaffolds for catalysis and synthesis . Despite recent progress in this area, most of the examples so far described require the preinstallation of auxiliary directing groups for the C–H activation, such as pyridines, sulfoxides, thioethers, phosphine oxides, pyridine oxides, amides or aldehydes, most of which are not needed for the subsequent exploitation of the chiral products . Indeed, the presence of these groups restricts the utility of the resulting atropoisomers for the synthesis of biorelevant products or for the preparation of chiral ligands and catalysts.…”