Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C–H Olefination

Abstract

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd­(II)-catalyzed thioether-directed alkenyl C–H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

Enantioselective Synthesis of Axially Chiral Styrene‐Carboxylic Esters by Rhodium‐Catalyzed Chelation‐Controlled [2+2+2] Cycloaddition

“…In the last five years, many catalytic asymmetric syntheses have been achieved. The precedented catalytic enantioselective synthesis of the axially chiral styrenes are classified into five types by the bond formation reactions: aryl-vinyl bond forming coupling reactions (type I), [11] arene CÀ H bond functionalization (type II), [12] cis-difunctionalization of alkynes (type III), [13] trans-difunctionalization of alkynes (type IV), [14] and vinyl CÀ H bond functionalization (type V) [6] (Figure 1a). However, the systematic introduction of the alkene and arene substituents (R 1 -R 5 ) of the axially chiral styrenes is hard to achieve with these methods.…”

Transition-metal-catalyzed remote C–H functionalization of thioethers

“… 28 Very recently, Shi and co-workers developed a palladium-catalyzed and thioether-directed atroposelective C–H olefination by employing a novel chiral spiro phosphoric acid ligand SPA ( Scheme 19a ). 29 More than 69 examples of axially chiral styrenes with a conjugated 1,3-diene scaffolds were obtained in good yields (up to 99% yields) with excellent enantioselectivities (up to 99% ee) and complete Z -selectivity control. Subsequently, they also used the same chiral spiro phosphoric acid ligand SPA to prepare axially chiral biaryls through thioether-directed Pd-catalyzed atroposelective C–H olefination ( Scheme 19b ).…”

Pd(II)-Catalyzed C(alkenyl)–H Activation Facilitated by a Transient Directing Group

“…38 Recently Shi reported the synthesis of enantioenriched 1,3dienes containing a chiral C(aryl)-C(dienyl) axis via thioetherdirected Pd(II)-catalyzed C(alkenyl)-H activation to form an endo-palladacycle intermediate with a spirocyclic phosphoric acid as the chiral ligand. 39 Given that our approach proceeds via an exo-palladacycle, we imagined that it could offer access to a complementary collection of axially chiral 1,3-diene products. Thus, we optimized reactions conditions with respect to yield and ee for 3-substituted-2-alkenyl benzaldehyde substrates.…”