Asymmetric C–H Functionalization with Chiral Ligands

Asymmetric C–H functionalization with chiral ligands has emerged as a transformative strategy in synthetic chemistry, enabling direct conversion of ubiquitous C–H bonds into carbon–carbon or carbon–heteroatom bonds with high enantioselectivity. The approach leverages transition‐metal catalysis in conjunction with bespoke chiral ligands to create a stereodefined environment, thereby guiding bond formation with precision under mild conditions. Recent advances have broadened the substrate scope to include complex heterocycles and biaryl frameworks, while innovations in ligand architecture and mechanistic understanding have enhanced both reactivity and selectivity. This methodology offers a streamlined route to enantiomerically enriched molecules important for pharmaceutical, agrochemical and material science applications, reducing the number of synthetic steps and minimising waste.

Research from Nature Portfolio

A cobalt‐catalysed atroposelective C–H activation/annulation protocol has been developed for the synthesis of N–N axially chiral frameworks. Using a chiral salicyl-oxazoline ligand and molecular oxygen as the oxidant, a range of N–N atropisomers was accessed in high yield and enantioselectivity under mild conditions, with electrocatalytic variants further extending the method’s sustainability. In parallel, an asymmetric ring-opening of 7-oxabenzonorbornadienes via cobalt-catalysed indole C–H functionalization has been demonstrated. Here, a binaphthyl-derived chiral cyclopentadienyl ligand delivered up to 99 % ee and exploited complementary diastereoselectivities by judicious choice of catalyst, unveiling β-oxygen elimination as the selectivity-determining step. Together, these studies underscore the versatility of cobalt catalysts and the pivotal role of ligand design in achieving both central and axial chirality through direct C–H bond activation.

Asymmetric C–H Functionalization with Chiral Ligands publication trend

The graph below shows the total number of articles in asymmetric c–h functionalization with chiral ligands across all publications each year (not limited to Nature Index journals).

Technical terms

Asymmetric C–H functionalization: Direct transformation of a carbon–hydrogen bond into a new bond in a manner that favours one enantiomer over the other.

Chiral ligand: A molecule that binds to a metal centre and induces a three-dimensional environment, enabling enantioselective catalysis.

Enantioselectivity: The preference for the formation of one enantiomer over its mirror image in a chemical reaction.

Atropisomerism: A type of stereoisomerism arising from restricted rotation about a bond, leading to stable chiral conformations.

C–H activation: The process by which a typically inert C–H bond is cleaved and functionalised, often catalysed by transition metals.

References

1. Cobalt-catalyzed atroposelective C−H activation/annulation to access N−N axially chiral frameworks. Nature Communications (2023).
2. Cobalt(III)-catalyzed asymmetric ring-opening of 7-oxabenzonorbornadienes via indole C–H functionalization. Nature Communications (2023).
3. Recent advances in Rh( i )-catalyzed enantioselective C–H functionalization. Chemical Society Reviews (2024).
4. Enantioselective Cobaltaphotoredox-Catalyzed C–H Activation. Journal of the American Chemical Society (2024).
5. Electrochemical Enantioselective C–H Annulation by Achiral Rhodium(III)/Chiral Brønsted Base Domino Catalysis. ACS Catalysis (2024).