Copper-Catalyzed Asymmetric Reactions in Organic Synthesis

Copper catalysts have emerged as versatile and cost-effective tools for inducing enantioselectivity in a wide array of organic transformations. By employing chiral ligands, copper complexes can orchestrate the formation of stereocentres under mild conditions, often via radical pathways or dual photoredox strategies. Key reaction classes include asymmetric C(sp3)–H functionalisation, enantioselective cyanation and carboesterification, decarboxylative couplings and allylic oxidations. Mechanistic control is achieved through careful ligand design, which governs single-electron transfer events, radical capture and inner-sphere coupling. The breadth of substrate scope ranges from simple hydrocarbons to complex peptides and unsaturated carboxylic acids, enabling late-stage functionalisation of bioactive molecules. Numerous protocols proceed at ambient temperature and under visible light, minimising energy input and waste. Such reactions find broad applications in the synthesis of pharmaceutically relevant chiral building blocks, agrochemicals and molecular probes. Recent advances in computational studies have further clarified the role of ligand electronics and sterics, paving the way for rational catalyst optimisation. The integration of copper-catalysed asymmetric methodologies complements existing metal-based systems, offering unique reactivity profiles and expanding the toolkit for enantioselective synthesis on both laboratory and industrial scales.

Research from Nature Portfolio

Recent studies have demonstrated a copper-catalysed asymmetric cyanoalkylation of C(sp3)–H bonds in glycine derivatives and peptides, delivering high enantioselectivities and enabling late-stage modification of peptide frameworks. The process relies on an in situ formed chiral phosphine–copper complex that mediates single-electron reduction of cycloalkanone oxime esters and controls stereochemical induction. Another milestone involves enantioselective allylic C–H oxidation of cyclic and acyclic olefins using copper(I)–biphenyl bisoxazoline complexes with perester oxidants. This protocol achieves excellent yields and optical purities, and density functional theory studies elucidate the active catalyst geometry, electronic interactions and factors governing enantioselectivity. Together, these contributions underscore copper’s capacity to unite radical generation and precise stereoinduction across diverse substrates.

Copper-Catalyzed Asymmetric Reactions in Organic Synthesis publication trend

The graph below shows the total number of articles in copper-catalyzed asymmetric reactions in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Enantioselectivity: Preference for formation of one enantiomer over its mirror image in a chiral reaction.

C(sp3)–H bond: A single bond between an sp3-hybridised carbon atom and a hydrogen atom, often less reactive than C(sp2)–H bonds.

Photoredox catalysis: Catalysis that utilises light to drive redox processes, generating radical intermediates under mild conditions.

Chiral ligand: An asymmetric organic molecule bound to a metal centre that induces stereochemical bias in catalytic reactions.

Late-stage functionalisation: Modification of complex molecules at a late point in a synthetic sequence to introduce new functionality without de novo synthesis.

Decarboxylative transformation: A reaction that removes carbon dioxide from a carboxylic acid to generate reactive species, often radicals, for subsequent coupling.

References

1. Copper-catalyzed asymmetric C(sp3)-H cyanoalkylation of glycine derivatives and peptides. Nature Communications (2023).
2. Preparation and DFT studies of chiral Cu (I)-complexes of biphenyl bisoxazolines and their application in enantioselective Kharasch–Sosnovsky reaction. Scientific Reports (2022).
3. Enantioselective cyanation of propargylic C–H bonds via cooperative photoredox and copper catalysis. Chemical Communications (2023).
4. Copper-catalyzed enantioselective decarboxylative cyanation of β,γ-unsaturated carboxylic acids to access chiral allyl nitriles. Cell Reports Physical Science (2022).