Transition Metal‐Catalyzed Desymmetrizations Based on CH Activation Processes

Abstract

The relevance of chiral pharmaceuticals and fine chemicals has encouraged the development of synthetic methods that allow the preparation of these products in enantioselective form. Of the different strategies, those relying on the metal‐catalyzed enantioselective activation of CH bonds are especially appealing, owing to their step and atom economy. This is particularly the case in desymmetrization approaches, because of the simplicity of the reactants, and their intrinsic complexity increase characteristics. This article reviews the current state of the art on transition metal‐catalyzed desymmetrizing functionalizations involving enantiodetermining CH activation steps.

Axially Chiral 2-Hydroxybiaryls by Palladium-Catalyzed Enantioselective C–H Activation

“…Even more appealing is the possibility of performing these reactions in an asymmetric fashion and, hence, obtaining valuable chiral products from nonfunctionalized racemic or achiral starting materials . In this context, there has been a growing interest in the use of enantioselective C–H bond functionalizations for producing axially chiral biaryls because these structures represent privileged scaffolds for catalysis and synthesis . Despite recent progress in this area, most of the examples so far described require the preinstallation of auxiliary directing groups for the C–H activation, such as pyridines, sulfoxides, thioethers, phosphine oxides, pyridine oxides, amides or aldehydes, most of which are not needed for the subsequent exploitation of the chiral products .…”

“… 2 In this context, there has been a growing interest in the use of enantioselective C–H bond functionalizations for producing axially chiral biaryls because these structures represent privileged scaffolds for catalysis and synthesis. 3 Despite recent progress in this area, most of the examples so far described require the preinstallation of auxiliary directing groups for the C–H activation, such as pyridines, sulfoxides, thioethers, phosphine oxides, pyridine oxides, amides or aldehydes, most of which are not needed for the subsequent exploitation of the chiral products. 4 Indeed, the presence of these groups restricts the utility of the resulting atropoisomers for the synthesis of biorelevant products or for the preparation of chiral ligands and catalysts.…”

A palladium catalyzed asymmetric desymmetrization approach to enantioenriched 1,3-disubstituted isoindolines

“… 4 Despite the significant advancement in this area, there is still room to develop new and potential asymmetric C–H functionalization strategies for constructing new chiral scaffolds. 5 In 2008, the Yu group reported the first palladium catalyzed enantioselective C–H activation by utilizing a mono-N-protected amino acid as a chiral ligand. 6 Thereafter various Pd-catalysed asymmetric C–H functionalization reactions using a mono-N-protected amino acid as a chiral ligand have been reported.…”

Chiral Ligands Based on Binaphthyl Scaffolds for Pd-Catalyzed Enantioselective C–H Activation/Cycloaddition Reactions

“…A major ongoing challenge in the area is the development of enantioselective versions, especially for reactions in which the asymmetry is created in the C–H activation step . Despite significant progress, the number of such asymmetric reactions is still small, and in many cases the resulting enantioselectivities are far from optimal . A major breakthrough in the field was the discovery by Yu and co-workers of mono-N-protected amino acids (MPAAs) as efficient chiral ligands to promote a broad variety of Pd-catalyzed enantioselective C–H functionalizations .…”

“…2 Despite significant progress, the number of such asymmetric reactions is still small, and in many cases the resulting enantioselectivities are far from optimal. 3 A major breakthrough in the field was the discovery by Yu and co-workers of mono-N-protected amino acids (MPAAs) as efficient chiral ligands to promote a broad variety of Pdcatalyzed enantioselective C−H functionalizations. 4 Mechanistic studies have established that these ligands bind the metal in a bidentate manner, with the N-acyl moiety acting as an internal base to drive the C−H activation step (concerted metalation−deprotonation (CMD) mechanism).…”