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Enzymatic Catalyzation of Diazo Compounds for the Formation of Lactones: An Intramolecular C–H Functionalization Strategy

Portrait of Ishanka Manatunga, speaker
Ishanka Manatunga
Graduate Student, Department of Chemistry
University of Georgia
iSTEM Building 2, Room 1218
Organic Seminar

Diazo compounds were first discovered by Peter Griess in 1858.1 The diazo group has been widely used due to its diverse reactivity, including alkylation, carbene generation, nucleophilic addition, homologation, and ring expansion. 

These compounds can react with a wide number of transition metal complexes capable of transferring carbenes, including carbene insertion reactions into C–H, Si–H, N–H, O–H, and S–H bonds, sulfur ylide mediated epoxidation and cyclopropanation reactions.2 In a traditional C–H activation manifold, the highly reactive metal complex is inserted into a C–H bond. Regeneration of the active metal complex to form the C–H activation product has proved difficult. In contrast, C–H functionalization via a metal carbene approach typically uses a high-energy diazo compound and loss of nitrogen which provides the driving force for the energetically unfavorable formation of the carbene.The major breakthrough in this field was the discovery of carbenes functionalized with both donor and acceptor groups which were much more chemoselective than the traditional carbenes. 

Intramolecular carbene C−H insertion, catalyzed by transition metals such as rhodium, and copper has received significant attention for the synthesis of lactones.4 Due to the thermodynamic stability of the intermediates and products, however, intramolecular C–H insertion has been mainly limited to the synthesis of five-membered γ-lactones and formation of lactones with different ring sizes often proceed with poor regio- or enantioselectivity.5 

Nature relies on a C–O bond disconnection retrosynthetic strategy, for the synthesis of many lactones. A new-to-nature C–C bond-forming strategy to assemble diverse lactone structures using engineered “carbene transferases” could catalyze intramolecular carbene insertions into benzylic or allylic C–H bonds, which allow the synthesis of lactones with different ring sizes and ring scaffolds. Six-membered δ-lactones and seven-membered ε-lactones were synthesized overcoming the thermodynamically unfavorable ring strain.5


  1. Patai, S. The Chemistry of Diazonium and Diazo Groups, Part 1; 1978
  2. Docherty, Jamie H, et al. Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C-C Bonds in Complex Molecules. Chemical Reviews, 2023, vol. 123 (12), 7692-7760. 
  3. Davies, Huw M. L., and James R. Manning. Catalytic C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion.  Nature, 2008, vol. 451, 7177, 417–424. 
  4. Kar, Vanessa, et al. Highly Selective Intramolecular Carbene Insertion into Primary C–H Bond of α-Diazoacetamides Mediated by a (P-Cymene) Ruthenium (II) Carboxylate Complex. Journal of the American Chemical Society, 2012, vol. 134, no. 18, 7588–7591. 
  5. Wackelin, D. J.; Mao, R.; Sicinski, K. M.; Zhao, Y.; Das, A.; Chen, K.; Arnold, F. H. Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy. Journal of the American Chemical Society, 2024, 146 (2), 1580–1587. 
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