Integrating electrocatalysis with biocatalysis for asymmetric synthesis

Abstract

The integration of electrocatalysis with biocatalysis has recently been developed for the stereoselective synthesis of valuable compounds. This integration leverages the high efficiency and exquisite selectivity of enzymes along with the tunability of electrochemical reactions, providing a versatile approach for asymmetric synthesis with broad prospects. In this highlight, recent advances and future development directions in asymmetric synthesis that integrate electrocatalysis with biocatalysis are presented and discussed. We foresee that more valuable stereoselective transformations using this integrated strategy will be developed in the future.

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Enzyme-based biocatalysis has become a powerful tool for generating enantiomerically pure chemicals in organic synthesis due to high enantioselectivity, gentle reaction conditions, and minimal by-product formation.¹ Enantioselective oxidoreductases, which account for the majority of known enzymes, play an essential role in redox reactions.² They have been extensively exploited to facilitate the efficient production of a variety of chiral compounds in asymmetric synthesis.³ However, the inability to efficiently regenerate expensive reduced cofactors has restricted their application.⁴ Electrochemistry offers an attractive and promising alternative for cofactor regeneration with the advantages of harnessing electricity as a clean energy source, getting rid of by-product generation, and simplifying the product separation process.⁵ Integrating biocatalysis with electrocatalysis brings broader benefits, such as improved reaction efficiency, enhanced selectivity, and the environmentally benign and sustainable production of enantiopure chemicals.

Electrochemistry, a green and sustainable synthetic tool for organic transformations, has attracted considerable interest in synthetic chemistry.⁶ For instance, electrochemical approaches have recently emerged as mild and efficient alternatives for the synthesis of organofluorines.⁷ The application of electrons as cheap and renewable reagents avoids stoichiometric external oxidants or reductants and eliminates undesired by-product generation.⁸ Furthermore, the reactivity and selectivity of electrochemical reactions can be regulated by precisely controlling the applied potential and electric current.⁹ However, asymmetric electrosynthesis remains a challenging field of development and typically requires costly transition metals and chiral catalysts.¹⁰ Additionally, the high reactivity of oxidatively or reductively generated radicals or reactive intermediates poses a challenge for asymmetric electrosynthesis.¹¹ Integrating electrocatalysis with biocatalysis provides a versatile approach for achieving stereo-control in electrochemistry.

The integration of biocatalysis and electrocatalysis is intriguing due to the combined merits of the high efficiency and exquisite selectivity of enzymes along with the tunability of electrochemical reactions.¹² This emerging strategy provides a powerful way to tune substrate and product selectivity, further enriching catalytic strategies to explore more valuable stereoselective transformations for asymmetric synthesis. There are two main modes involved in this integration (Scheme 1). In the first mode, (modified) electrodes are used to regenerate cofactors for the cofactor-dependent oxidoreductases to achieve their natural redox activity. The second mode involves the electroenzymatic cascade reaction, where the electrocatalytic redox reaction initially converts the substrate or co-substrate into an intermediate, which is subsequently catalyzed by the enzymes to generate the chiral product. Although the application of this combined strategy in asymmetric organic synthesis is still in its infancy, recent breakthroughs indicate that it holds great promise for the exploration of novel asymmetric reactions. Herein, we highlight recent advances in asymmetric synthesis that integrate electrocatalysis with biocatalysis and discuss future directions in this field.

Scheme 1 Modes in the integration of electrocatalysis and biocatalysis.

The Minteer group constructed an enhanced bioelectrocatalytic platform for N₂ fixation that combines nitrogenase, diaphorase (DI), L-alanine dehydrogenase (AlaDH), and ω-transaminase (ω-TA) with electrodes to convert N₂ into chiral amine intermediates in one-pot under mild conditions (Scheme 2).¹³ This bioelectrocatalytic system used an H-shaped dual-chamber reactor with oxidized methyl viologen (MV²⁺) as an electron mediator. The cathode directly provides electrons for reduced MV⁺, realizing the efficient regeneration of MV⁺. The reduced MV⁺ then donates electrons to nitrogenase to facilitate the reduction of N₂ to NH₃. DI consumes reduced MV⁺ to regenerate NADH, while MV⁺ is recycled by the cathode. AlaDH, using NADH as a coenzyme, captures NH₃ and transfers it to the acceptor pyruvate to generate alanine. Then the amino group of alanine is transferred by ω-TA to various ketone substrates, ultimately generating enantiomerically pure chiral amine intermediates. Notably, AlaDH consumes the by-product pyruvate to reproduce alanine, shifting the reaction equilibrium towards the amine product side. Employing this system, different prochiral ketones could be aminated to produce the corresponding chiral amines with perfect stereoselectivity (>99% ee).

Scheme 2 A bioelectrocatalytic platform converts N₂ into chiral amine intermediates (mode I).

To overcome the low efficiency of cofactor regeneration and substrate solubility problems in oxidoreductase-based asymmetric synthesis, Minteer and colleagues developed a novel two-phase bioelectrocatalytic system. This system enables the efficient synthesis of chiral β-hydroxy nitriles by integrating alcohol dehydrogenase (AdhS), halohydrin dehalogenase (HHDH) with diaphorase (DH)-modified electrodes (Scheme 3).¹⁴ Diaphorase (DH) was immobilized on the electrode surface with a cobaltocene-modified poly(allylamine) redox polymer to form DH/Cc-PAA bioelectrode. In this bioelectrode, Cc-PAA polymer mediates the transfer of electrons from the electrode to DH, which further utilizes the electrons to catalyze the reduction of NAD⁺ to efficiently regenerate the reduced cofactor NADH. NADH-dependent AdhS then catalyzes the reduction of the model substrate COBE to (S)-CHBE by consuming NADH. HHDH catalyzes the dehalogenation and cyanation of (S)-CHBE to (R)-CHCN. Notably, the use of methyl tert-butyl ether (MTBE) as the second organic phase enhances substrate loading, prevents spontaneous substrate hydrolysis, alleviates substrate inhibition of HHDH activity, improves product yields, and prolongs the lifetime of DH/Cc-PAA bioelectrode. By applying this two-phase bioelectrocatalytic system, different chiral β-hydroxy nitriles could be produced with high enantioselectivity (up to 96% ee).

Scheme 3 Two-phase bioelectrocatalytic system for the efficient synthesis of chiral β-hydroxy nitriles (mode I).

In recent years, the integration of electrochemistry and biocatalysis for the conversion of CO₂ into value-added chemicals has garnered significant attention.¹⁵ The Plumere group presented a bioelectrocatalytic approach that combines electricity-driven cofactor NADPH regeneration with enzymatic CO₂ fixation for the stereoselective C–C bond formation (Scheme 4).¹⁶ They employed 2,2′-viologen modified polyvinyl alcohol (V²⁺-PVA) hydrogel as the redox polymer to co-immobilize ferredoxin NADP⁺ reductase (FNR) with NADPH-dependent crotonyl-CoA carboxylase/reductase (Ccr) on electrode. The V²⁺-PVA/FNR films showed excellent electrocatalytic activity and stability, providing efficient electron transfer from the electrode to FNR for reducing NADP⁺ to NADPH. Sufficient supply of NADPH enabled the Ccr-catalyzed incorporation of CO₂ into crotonyl-CoA for the stereoselective generation of (2S)-ethylmalonyl-CoA. After optimization of conditions, the system was successfully scaled up to achieve a maximum yield of 57% and a faradaic efficiency of 91%.

Scheme 4 A bioelectrocatalytic approach for CO₂ fixation and the stereoselective C–C bond formation (mode I).

The free diffusion of Ccr in solution generally leads to a significant decrease in reaction yields. Therefore, by co-immobilizing the enzymes within a smaller volume, the proximity of the biocatalysts facilitates rapid diffusive transport of intermediates and cofactors among the active sites of the enzymes, resulting in increased reaction rates and enhanced electrocatalytic performance.

Armstrong and co-workers reported a unique approach for driving and controlling enantioselective conversions by coupling nanoconfined enzyme cascades with bidirectional electrocatalysis.¹⁷ They co-confined ferredoxin NADP⁺ reductase (FNR) and alcohol dehydrogenase (ADH) variants within the nanopores of an indium tin oxide (ITO) layer to form (FNR + ADH)@ITO electrode. FNR catalyzed the rapid and reversible NADP⁺/NADPH interconversion in a bidirectional manner controlled by the applied electrode potential. At the same time, ADH immediately recycled NADP⁺ or NADPH to catalyze redox interconversions between ketone and secondary alcohol enantiomers. The deracemization of alcohols could be efficiently achieved through a two-stage process in one pot with two (FNR + ADH)@ITO electrodes in sequence. In the first stage, an electrode containing an enantioselective ADH variant selectively oxidized the undesired alcohol enantiomer to ketone. After a quick switch to the electrode containing another ADH variant with opposing enantioselectivity and a pH adjustment, the ketone was irreversibly reduced to the desired alcohol enantiomer with >90% ee in the second stage.

The majority of the established strategies that integrate biocatalysis and electrocatalysis were limited to oxidoreductases, while electrochemistry is used for cofactors regeneration.¹⁸ In 2022, Guan and co-workers reported an innovative approach that combined enzymes other than oxidoreductases with electrosynthesis, going beyond cofactor regeneration and expanding the scope and synthetic potential of the integrated strategy.¹⁹ They take advantage of the catalytic promiscuity of hydrolase with electrosynthesis for the asymmetric synthesis of complex chiral compounds (Scheme 5). Specifically, they carried out the enantioselective oxidative cross-coupling of 2-substituted indoles and simple ketones in an undivided electrochemical cell with wheat germ lipase (WGL) as the biocatalyst, platinum sheets as electrodes, 4-acetamido 2,2,6,6-tetramethyl-1-piperideoxy (ACT) as the redox mediator, n-Bu₄NPF₆ as electrolyte, and DMF/H₂O as the solvent. A wide range of 2,2-disubstituted 3-carbonyl indoles featuring a stereogenic quaternary carbon center could be successfully obtained with good yields (up to 78%), excellent enantioselectivity (up to 96 : 4 e.r.) and diastereoselectivity (>20 : 1 d.r.).

Scheme 5 Integration of the catalytic promiscuity of lipase (WGL) with electrosynthesis for asymmetric oxidative cross-coupling reaction (mode II).

With regard to the mechanism, ACT is initially oxidized at the anode to generate ACT⁺, which subsequently oxidizes substrate 1 to the N-centered radical cation 3via single electron transfer. Then N-centered radical cation 3 undergoes deprotonation to generate N-centered radical 4. Its resonance structure, the C-centered radical 5, reacts with O₂ to produce radical 6, which further undergoes hydrogen transfer to afford radical 7. Subsequently, radical 7 cleaves a hydroxyl radical to produce intermediate 8. In the active site of WGL, intermediate 8 is protonated to form the electrophilic cationic intermediate 9, while ketone loses a proton to generate enolate 10, which then nucleophilically attacks intermediate 9 to yield the final product 2.

Xu's group reported a deracemization strategy for achieving chiral sulfoxides through the combination of electrocatalysis and biocatalysis (Scheme 6).²⁰ The deracemization process was conducted in an undivided cell with platinum electrodes, methionine sulfoxide reductase A (MsrA) as the biocatalyst, dithiothreitol (DTT) as terminal reductants, and the phosphate buffered saline (PBS) as the electrolyte solution under 4 mA constant current in the atmosphere. Chiral sulfoxides can be achieved up to 95% yield with 99% ee by integrating MsrA-catalyzed reduction for kinetic resolution of racemic sulfoxides with the non-stereoselective anodic oxidation of thioethers. This strategy can be successfully applied to a wide range of substituted sulfoxides, showing good functional group tolerance. Remarkably, the reaction can be easily scaled up. Mechanistic experiments revealed that the anodic oxidation of thioethers proceeded via a radical pathway, and H₂O served as the oxygen atom source during the anodic oxidation process.

Scheme 6 Combination of electrocatalysis and biocatalysis for chiral sulfoxides (mode II).

Recently, Chen and co-workers developed a one-pot electroenzymatic cascade platform that integrated the advantages of enzymatic catalysis and electrocatalysis for efficient asymmetric epoxidation of styrene derivatives (Scheme 7).²¹ Chloroperoxidase (CPO), a heme-containing peroxidase, was functionalized using 1-ethyl-3-methylimidazolium bromide (IL_EMB) and immobilized on cobalt nitrogen-doped carbon nanotubes (CoN@CNT) to form CPO-IL_EMB/CoN@CNT biohybrid. This biohybrid was then dropped on electrode surfaces. The electrochemical measurements showed that CoN@CNT has excellent electrocatalytic properties for oxygen reduction, producing H₂O₂ with high Faradaic efficiency and rate. In situ electrogenerated H₂O₂ was directly utilized by CPO to catalyze the asymmetric epoxidation of styrene, with the merit of maintaining the high catalytic activity of CPO. In a sealed H-type electrolytic cell, CPO-IL_EMB/CoN@CNT achieved 27% styrene conversion within 30 min and yielded 46% ee of chiral styrene oxide with a cascade catalytic efficiency 17 times higher than that of free CPO-IL_EMB in solution. The universality of this electroenzymatic cascade platform was further validated by the successful epoxidation of various chloro-substituted styrene derivatives with high enantioselectivity (49–86% ee).

Scheme 7 A one-pot electroenzymatic cascade platform for asymmetric epoxidation of styrenes (mode II).

In this highlight, the latest advances in asymmetric synthesis that integrate electrocatalysis and biocatalysis have been demonstrated. This versatile approach has gained prominence as it combines the advantages of both electrocatalysis and biocatalysis. By utilizing electricity as a clean energy source and employing enzymes with high stereoselectivity and even with catalytic promiscuity as biocatalysts, the green and efficient production of chiral chemicals can be achieved without the need for stochiometric redox reagents while minimizing the production of by-products. Based on these inspiring breakthroughs, future development direction should focus on the following aspects.

(1) Exploring new types of enzymes for integration with electrocatalysis, which will greatly diversify the reaction types and broaden the application range.

(2) Further design and construction of novel and efficient electroenzymatic cascade reaction systems with good compatibility between enzymes and electrodes, which is crucial for realizing more enantioselective transformations.

(3) Applications of protein engineering such as directed evolution to enhance the activity and stability of enzymes under electrochemical and non-aqueous conditions to achieve new and interesting reactivity.

(4) Design and application of aqueous–organic biphasic media and improved enzyme immobilization techniques as pertinent strategies to improve reaction productivity.

(5) Exploring the non-natural activities of enzymes driven by electricity to achieve novel-to-nature reactivity,²² which will enhance the versatility of enzymes and open up exciting possibilities for new synthetic pathways and the discovery of novel reactions.

We envisage that the integration of biocatalysis and electrocatalysis will be a versatile approach for asymmetric synthesis, leading to more valuable stereoselective transformations and promising for a multitude of synthetic applications.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the Educational Research Project for Young and Middle-aged Teachers in Fujian Province (JAT231005), Fuzhou University (511311), and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2024Z08) is gratefully acknowledged.

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