Carbene Transfer Reactions in Organic Synthesis

Carbene transfer reactions harness the reactivity of organometallic or enzymatic catalysts to generate highly electrophilic carbenes from diazo or related precursors. These intermediates can undergo cyclopropanation of alkenes, insertion into C–H, N–H, O–H and S–H bonds, enabling rapid assembly of complex molecular architectures under mild conditions. Advances in transition-metal catalysis, particularly with iron, cobalt and rhodium, have delivered catalysts with high turnover frequencies, broad functional-group tolerance and improved selectivity. In parallel, protein-engineering approaches have repurposed and evolved hemoproteins into bespoke carbene transferases, affording enantioselective transformations previously inaccessible to small-molecule systems. Control over the primary and secondary coordination spheres has further refined catalyst performance, allowing chemo-, regio- and stereocontrol in cyclopropanation, C–H functionalisation and heteroatom insertions. These developments impact agrochemicals, pharmaceuticals and materials science, while integration into cascade processes highlights their potential in sustainable synthesis.

Research from Nature Portfolio

Recent studies have elucidated the mechanistic manifold of a haemoprotein-catalysed cyclopropanation using diazoketones. Through a combination of spectroscopic, structural and computational analyses, researchers have characterised key intermediates including an early haem-bound diazo complex and identified carbene formation as the rate-determining step. The discovery of an off-cycle N-bound carbene adduct revealed a competing non-productive pathway that nonetheless regenerates the active catalyst. This mechanistic insight provides a blueprint for the rational design of improved biocatalysts with enhanced turnover and selectivity in new-to-nature carbene transfer reactions.

Carbene Transfer Reactions in Organic Synthesis publication trend

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

Technical terms

Carbene: A neutral divalent carbon species with two nonbonded electrons that can insert into bonds or add to unsaturated systems.

Diazo compound: An organic reagent containing a diazo group (–N₂), which serves as a carbene precursor upon loss of nitrogen.

Cyclopropanation: The formation of three-membered carbocycles through addition of a carbene to an alkene.

Enantioselectivity: Preference of a catalytic reaction to produce one enantiomer over its mirror image.

Insertion reaction: A process in which a carbene species is inserted into a C–H or heteroatom–H bond to form a new bond.

References

1. Mechanistic manifold in a hemoprotein-catalyzed cyclopropanation reaction with diazoketone. Nature Communications (2023).
2. Enantioselective Synthesis of α‑Trifluoromethyl Amines via Biocatalytic N–H Bond Insertion with Acceptor-Acceptor Carbene Donors. Journal of the American Chemical Society (2022).
3. Enantioselective Single and Dual α‑C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer. Journal of the American Chemical Society (2022).
4. New-to-nature chemistry from old protein machinery: carbene and nitrene transferases. Current Opinion in Biotechnology (2020).
5. Transition Metal Catalysis Controlled by Hydrogen Bonding in the Second Coordination Sphere. Chemical Reviews (2022).