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.

Stereoselective Synthesis of Axially Chiral Allenes and Styrenes via Chiral Phosphoric Acid Catalysis: An Overview

“…In 2021, Lin and co-workers established a chiral phosphoric acid catalyzed a highly regio-, diastereo-, and enantioselective dearomatization reaction of 1-substituted 2-naphthols (53) and β,γ-alkynyl-α-imino esters (48). The highly functionalized naphthalenone derivatives (54) with allene moiety, exhibiting both a quaternary stereocenter and axial chirality, were obtained in good yields (up to 82%) with high diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 96% ee) (Scheme 16). Control experiments showed that high to excellent stereoselectivity is the result of a dual hydrogen bonding interaction between substrates and chiral phosphoric acid, with the substituent at the 1-position of 2-naphthol playing a key role in controlling regioselectivity.…”

“…Motivated by elegant findings regarding the construction of axially chiral derivatives of styrene, Gu et al, − Xu et al and Shi et al , reported palladium catalyzed enantioselective synthesis of axially chiral styrene derivatives. This advancement serves as a model for the atroposelective catalytic synthesis of derivatives of the axially chiral styrene.…”

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

“…More recently, Shi and co-workers reported a Pd-catalyzed enantioselective CÀH olefination for synthesis of axially chiral styrenes through cTDG strategy (Scheme 15). [39] Employing amino amide cTDG7 as transient Scheme 12. Pd-catalyzed atroposelective CÀH functionalization to access enantioenriched pentatomic biaryls using cTDG1 (Shi et al, 2019).…”

“…Pd-catalyzed enantioselective synthesis of axially chiral styrenes via cTDG strategy (Shi et al, 2020). [39] Angewandte Chemie crucial for the reactivity and enantioselectivity. Detailed investigation of the steric effect and pK a value of the acid additives disclosed that the weak and bulky aliphatic carboxylic acids exhibited better enantiocontrol.…”

Copper-Catalyzed Asymmetric Functionalization of Vinyl Radicals for the Access to Vinylarene Atropisomers

“…5 The Shi and Wang groups reported the palladium-catalyzed atroposelective C−H alkenylation and alkynylation, respectively, where a palladacycle species was involved as a key intermediate (Scheme 1b). 6 Despite these impressive advances, the development of new methods involving conceptually innovative synthetic chemistry for their concise and efficient synthesis is highly desirable.…”