Enantioselective Synthesis of Biaryl Atropisomers by Pd‐Catalyzed C−H Olefination using Chiral Spiro Phosphoric Acid Ligands

Abstract

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

“…Very recently, the You group elegantly demonstrated the highly enantioselective synthesis of axially chiral heterobiaryl compounds by Rh I ‐catalyzed atroposelective C−H arylation with 2‐pyridine, 2‐isoquinoline, and their derivatives as DGs (up to 97 % ee ) . Our group reported a Pd II ‐catalyzed atroposelective C−H olefination with quinoline as the DG . The use of phosphine oxide as a DG has been achieved by Yang and co‐workers in Pd II ‐catalyzed asymmetric C−H olefination .…”

Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies

“…This innovative strategy developed by Shi and co-workers 12 is based on the generation of a transient chiral auxiliary by in situ condensation of the substrate with sub-stoichiometric amount of free amino acids, reaching excellent enantioselectivities in their reaction with activated alkenes (Scheme 6C). The same group also used Pd(OAc) 2 in combination with chiral spiro phosphoric acids for the efficient, highly enantioselective catalytic desymmetrization of two different types of substrates via oxidative C-H alkenylation: First, the heterocyclic N atom of 8-arylquinolines 13 was used as the directing group using STRIP as an optimal ligand and AgOAc as the oxidant (Scheme 6D). Second, a similar spirocyclic phosphoric acid (SPA) in combination with Ag 2 CO 3 as the terminal oxidant was applied to the desymmetrization of biaryl amines (Scheme 6E).…”

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

“…(Scheme 66). [ 71a ] ( R )‐ SPA 22 , was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields (up to 98%) with excellent enantioselectivities (up to 98 % ee).…”

“…A broad range of axially chiral biaryl‐2‐amines can be obtained in good yields with high enantioselectivities (up to 97% ee) (Scheme 67). [ 71b ] ( R )‐ SPA 17 was proved to be an efficient ligand and the loading of catalyst could be reduced to 1 mol% without erosion of enantiocontrol in gram‐scale synthesis. Moreover, this strategy offers an expedient way to synthesize axially chiral biaryl‐2‐amines and provides a platform for a set of chiral ligands.…”