Development of Axially Chiral Styrene-Type Carboxylic Acid Ligands via Palladium-Catalyzed Asymmetric C–H Alkynylation

Abstract

A weakly coordinated carboxylate-directed palladiumcatalyzed atroposelective C−H alkynylation method for the development of novel axially chiral styrene-type carboxylic acids is disclosed. This transformation exhibits good yields (up to 85%), excellent enantiocontrol (up to 99% ee), and mild conditions. Notably, the synthetic utility of the resulting alkynyl carboxylic acid derivatives was demonstrated by various derivatizations as well as their potential as chiral ligands in asymmetric C− H activations.

Axially chiral alkenes: Atroposelective synthesis and applications

“…Compared to the biaryl analogues (CCA13-15), this seminal study informed the potential or even the superiority of axially chiral alkenes in selectivity control of certain asymmetric reactions. In related research on Co-catalyzed asymmetric C-H activation and functionalization reported by Shi [58] and Wang [60,61] (Scheme 31b and c), similar results were observed. While there is room for improvement, these preliminary studies showcased the promising use of axially chiral styrene-type CCAs.…”

“…The emergence of chiral carboxylic acids (CCAs) as powerful ligands in asymmetric C-H functionalization has driven the design and synthesis of axially chiral carboxylic acids. Beginning from readily available racemic cinnamic acid derivatives (102), Wang recently reported the Pdcatalyzed atroposelective C-H arylation (104) [60], alkenylation (106) [60] and alkynylation (108) [61] to streamline the access of CCAs based on axially chiral alkene skeletons (Scheme 17). The carboxyl group which functions as key motif of CCA ligands serves the role of directing group.…”

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

“…For instance, Tan, Yan, Shi, and others disclosed an appealing organocatalytic method for the synthesis of axially chiral vinyl arenes with an open-chain alkene, involving an allene intermediate (Scheme a) . 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 b) . Despite these impressive advances, the development of new methods involving conceptually innovative synthetic chemistry for their concise and efficient synthesis is highly desirable.…”

Construction of axial chirality by asymmetric alpha C–H alkenylation of aryl alkenes

“…3 In contrast, axially chiral styrenes are a more challenging target by asymmetric C–H functionalization due to their lower rotation barriers as well as the relatively higher temperature for C–H activation. 4–6 Asymmetric cross-coupling between alkenes and arenes provides an efficient method to form a styrene axis. For example, He and co-workers reported the iridium-catalysed synthesis of axially chiral styrenes by tandem asymmetric C–H allylation and stereospecific 1,3-hydride transfer induced olefin isomerization.…”