Hybrid Organometallic and Enzymatic Tandem Catalysis for Oxyfunctionalisation Reactions
Introduction
In recent years, enzyme-mediated oxyfunctionalisation reactions, such as hydroxylations, epoxidations, and sulfoxidations, have gained significant attention for their high selectivity in organic chemistry. Unspecific peroxygenases (UPOs), especially the evolved recombinant variant from Agrocybe aegerita (rAaeUPO PaDa-I), have shown great potential in these transformations. However, one major limitation of UPOs is their sensitivity to high concentrations of hydrogen peroxide (H₂O₂), which can lead to enzyme deactivation.
To overcome this challenge, a hybrid approach combining organometallic catalysis with enzymatic processes has emerged. In this study, the organometallic complex [Cp*Ir(pica)NO₃] (pica = picolinamidate) is used to regenerate FMNH₂ from FMN, producing a steady supply of H₂O₂ in situ. This system is combined with rAaeUPO to catalyze a wide range of oxyfunctionalisation reactions.
Hybrid Catalysis Approach
Organometallic Catalyst
The organometallic complex [Cp*Ir(pica)NO₃] efficiently regenerates FMNH₂ from FMN, using formate as a hydride source. This FMNH₂ spontaneously reacts with molecular oxygen, generating H₂O₂, which serves as the oxygen donor for the rAaeUPO-catalyzed reactions. This tandem catalytic system allows for controlled and sustained H₂O₂ production, preventing UPO deactivation and enabling continuous oxyfunctionalisation reactions.
Enzymatic Oxyfunctionalisation
The evolved rAaeUPO PaDa-I is capable of inserting oxygen into non-activated aliphatic and aromatic C-H bonds, enabling the conversion of substrates like ethylbenzene, cis-methyl styrene, and cyclohexane into valuable products. When paired with the organometallic catalyst, this system demonstrated high selectivity and turnover numbers (TONs) for the target reactions.
Key Results
- High Efficiency: The hybrid system achieved TONs up to 18,933 for the selective transformation of ethylbenzene into (R)-1-phenylethanol, with an enantiomeric excess (ee) of over 99%. Similarly, cis-methyl styrene was oxidized to (1R,2S)-cis-methyl styrene oxide with ee > 99% and a TON of 13,488.
- Wide Substrate Scope: The system was also tested on various other substrates, including cyclohexane and thioanisole. Although the conversion rates were lower for these substrates, the results still demonstrated the versatility of the hybrid catalytic system.
- Optimization of Conditions: The study found that the optimal molar ratio of the organometallic catalyst to rAaeUPO was 50:1. At higher ratios, mutual inhibition between the two catalysts became significant, reducing the overall efficiency of the system.
- Methanol as a Cosolvent: To improve reaction conditions, methanol was used as a cosolvent instead of acetonitrile, resulting in higher product yields without significant enzyme inhibition.
Conclusion
This study demonstrates the effectiveness of combining organometallic and enzymatic catalysis for oxyfunctionalisation reactions. The hybrid system offers a promising alternative to traditional methods, with the ability to generate H₂O₂ in situ and perform highly selective transformations. While further optimization is required for preparative-scale applications, the results suggest that this tandem catalytic approach has significant potential for industrial applications.
Future Directions
Further research will focus on improving the stability and scalability of the system. This includes exploring immobilization strategies for the catalysts and developing biphasic reaction systems to avoid enzyme inhibition by water-miscible cosolvents. Additionally, optimizing the integration of the organometallic and enzymatic components will be critical to enhancing the overall efficiency of the process.