Synthesis of Axially Chiral Styrenes through Pd‐Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

Abstract

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through PdII‐catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII‐catalyzed enantioselective C(sp3)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity‐determining step.

Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018–2020

“…Atroposelective C(sp 2 )-H functionalisation. Several new reports of atroposelective allylation, 34 naphthylation, 35 alkynylation 36 allylation and alkenylation [37][38][39] for the synthesis of axially chiral products have been disclosed (Scheme 10). All methods used either L-tert-leucine, L-valine or derivatives as a transient directing group, in which chiral information is effectively transferred to give high enantioselectivities under relatively mild reaction conditions.…”

“…The use of styrenes, less conformationally stable substrates, was achieved using an amide derivative of L-tert-leucine (Scheme 10f ). 39 A silver-free system was developed, using cobalt acetate, benzoquinone under an oxygen atmosphere, presumably to promote reoxidation of palladium, though mechanistic discussion of the specific roles of these reagents was not elaborated. When using substituted styrene aldehydes with a high enough barrier to interconversion, high yields and ees could be obtained.…”

Transition Metal‐Catalyzed Enantioselective C−H Functionalization via Chiral Transient Directing Group Strategies

“…More recently, Shi and co‐workers reported a Pd‐catalyzed enantioselective C−H olefination for synthesis of axially chiral styrenes through c TDG strategy (Scheme 15). [39] Employing amino amide c TDG7 as transient chiral auxiliary, a broad scope of enantioenriched axially chiral styrenes were synthesized in good yields with excellent enantioselectivities (up to 99 % ee ). Notably, experiments and DFT calculation results revealed that bulky substituents ortho to the axis were crucial for the enantioselectivity ( 58 b , 96 % ee , Δ G ≠ =31.4 kcal mol −1 ; 58 c , 73 % ee , Δ G ≠ =29.6 kcal mol −1 ; 58 d , 0 % ee , Δ G ≠ =22.4 kcal mol −1 ).…”

Chiral Transient Directing Group Strategies in Asymmetric Synthesis

“…The applicability of the synthesized axially chiral styrenes as chiral ligands in asymmetric synthesis was also demonstrated. [31]…”

“…Alongside acrylaldehydes, the scope of olefins were also explored and divergent acrylates, alkenylphosphate, phenylsulphate, and styrenes were found to be tolerable. The applicability of the synthesized axially chiral styrenes as chiral ligands in asymmetric synthesis was also demonstrated …”