Traditional monooxygenase cytochrome P450s, although extraordinary in substrate versatility and oxidation capacity, have been hampered by their reliance on expensive nicotinamide cofactors such as NAD(P)H and the inefficient electron transfer mediated via redox partner proteins. These limitations not only inflate the cost but also complicate the operational stability and scalability of such enzymatic systems for industrial applications. Contrastingly, CYP152 family enzymes, designated as P450 peroxygenases, circumvent these barriers by utilizing hydrogen peroxide (H₂O₂) directly as an oxidant. This unique catalytic mechanism renders them exceptionally attractive for green chemistry since H₂O₂ is cheap, readily available, and its reduction byproduct is merely water, thereby aligning the enzymatic process with sustainable and atom-economical principles.

Prof. Li’s research group has meticulously dissected and expanded the catalytic potential of microbial CYP152 peroxygenases through intensive molecular engineering. Their approach includes exploring the enzymatic mechanisms, discovering novel enzyme variants, and strategically modifying the protein architecture to enhance substrate specificity and catalytic efficiency. Previous contributions from this group, published across several respected journals, have laid the groundwork for the latest achievement in asymmetric biotransformations, showcasing the robust nature of these biocatalysts and their adaptability toward structurally diverse substrates.

The centerpiece of this breakthrough is the engineering of the P450_BSβ peroxygenase variants, notably the F46A and F292A mutants. These engineered enzymes demonstrate remarkable proficiency in converting phenylacetic acid derivatives — inexpensive and readily accessible starting materials — into (R)-mandelic acid derivatives with unprecedented enantioselectivity and catalytic turnover. The reported total turnover numbers (TTNs) reach an impressive 11,722, indicative of both high enzymatic stability and efficient substrate conversion, while consistently achieving enantiomeric excess (ee) values above 99% across multiple substrate examples. This level of enantio-purity is critical for the application of these hydroxy acids as chiral building blocks in pharmaceutical synthesis.

The ramifications of this enzymatic platform extend far beyond mere synthetic achievement. (R)-mandelic acid and its derivatives occupy a central position in organic synthesis as chiral resolving agents, precursors to medicinal compounds, and key intermediates in various pharmaceutical manufacturing processes. Historically, the synthetic routes toward these molecules have been fraught with difficulties — limited yields, poor stereocontrol, harsh chemical conditions, and environmental burdens from hazardous reagents. The enzymatic route developed by Li et al. offers a sustainable and atom-economic alternative, circumventing the need for metal catalysts or complex cofactor recycling systems, and operating effectively under ambient conditions.

One of the most compelling demonstrations of this technology’s practicality is its scalability. The researchers successfully executed semi-preparative syntheses of (R)-mandelic acid and (R)-p-fluoromandelic acid with isolated yields exceeding 92%, affirming the method’s potential transition from laboratory curiosity to industrial utility. These results exemplify how biocatalysis can marry green chemistry principles with industrially relevant production metrics, potentially revolutionizing the manufacture of high-value chiral hydroxy acids.

Underpinning the enzymatic performance, the structural insights into the CYP152 active site modifications reveal how subtle amino acid substitutions, such as those at phenylalanine residues 46 and 292, modulate the enzyme’s substrate binding pocket and catalytic geometry. These alterations enhance substrate positioning and reactivity, facilitating efficient hydrogen peroxide activation and selective α-hydroxylation. This precision engineering underscores the power of protein design and directed evolution methodologies in tailoring enzyme functionality toward bespoke synthetic goals.

The environmental implications of deploying CYP152 peroxygenase-based processes are significant. By replacing conventional chemical oxidations, which often rely on expensive and toxic metal catalysts or stoichiometric oxidants generating harmful waste, this biocatalytic system adheres to the principles of green chemistry. It reduces hazardous waste generation, lowers energy consumption due to mild operating conditions, and utilizes a benign oxidant whose decomposition product is innocuous water. Such advantages align with global efforts to minimize the chemical industry’s environmental footprint while enhancing process efficiency.

Looking forward, the success of this enzymatic platform paves the way for expanding the substrate repertoire of CYP152 peroxygenases to other structurally challenging molecules, thereby broadening the scope of sustainable biomanufacturing in pharmaceuticals and fine chemicals. The modular nature of enzyme engineering suggests that further customization could unlock access to a wider array of chiral hydroxylated products, offering unprecedented flexibility in synthetic routes.

This research not only marks a pivotal advance in enzyme catalysis but also exemplifies the broader convergence of biotechnology, synthetic chemistry, and sustainable industrial practices. Prof. Li’s statement emphasizes that this strategy not only enriches the toolbox available for chiral molecule preparation but also contributes significantly to the green production of high-value compounds crucial for medicinal and synthetic chemistry.

The study benefits from substantial support provided by the National Natural Science Foundation of China and the Natural Science Foundation of Shandong Province, reflecting the strategic importance and potential impact of this work on both scientific and industrial sectors.

As the chemical industry seeks to transition toward greener methodologies, innovations like this CYP152 peroxygenase system stand at the forefront, demonstrating that sustainable biocatalysis can meet, and even exceed, the efficacy of traditional synthetic approaches. The integration of such enzymatic tools promises to redefine chiral synthesis paradigms, unlocking new avenues for efficient and environmentally friendly drug development.

Subject of Research: Biocatalytic asymmetric α-hydroxylation of aromatic carboxylic acids using engineered CYP152 peroxygenases.

Article Title: CYP152 Peroxygenases Open a Green Pathway to Chiral Molecules.

News Publication Date: Information not explicitly provided; article DOI indicates 2025.

Web References:
http://dx.doi.org/10.1016/j.scib.2025.10.031

References:
Angew. Chem. Int. Ed. 2025, 2021; Sci. Bull. 2024; Biotechnol. Biofuels 2020, 2019, 2017, 2015, 2014; ChemCatChem 2019; Sci. Rep. 2017

Image Credits: ©Science China Press

Keywords

Life sciences, Health and medicine, Chemistry, Pharmaceuticals

Photocyclization reactions — where light energy induces the formation of cyclic molecular structures — have long fascinated chemists for their ability to create architecturally complex frameworks. Yet, achieving enantioselectivity, the preferential formation of one chiral isomer over another, remains an enduring challenge. Traditional photo-induced reactions often lack the directional control necessary to favor one enantiomer, limiting their utility in medicinal chemistry where the three-dimensional arrangement of atoms dictates biological activity.

The innovation by Soika, Onneken, Wiegmann, and colleagues leverages a unique Al–salen complex that acts as a ‘privileged catalyst’—a term reserved for catalysts exhibiting broad efficiency and selectivity across a wide array of substrates. By ingeniously integrating energy transfer mechanisms into this catalytic platform, the researchers orchestrate a photocyclization process that not only proceeds under mild conditions but does so with remarkable enantioselective precision.

Central to this breakthrough is the coupling of photophysical phenomena with chiral catalysis. The Al–salen catalyst absorbs visible light, entering an excited state capable of transferring energy selectively to the substrate. This interaction prompts cyclization while the chiral environment imparted by the ligand framework biases the reaction pathway towards one enantiomer. Unlike classical photocatalysis which often relies on electron transfer mechanisms, this energy transfer approach sidesteps competing redox processes, minimizing side reactions and improving overall yield and selectivity.

The mechanistic insight garnered from spectroscopic and computational studies sheds light on the delicate interplay between catalyst excitation, energy migration, and substrate activation. The team employed transient absorption spectroscopy to capture short-lived excited states, confirming the efficient energy relay between catalyst and reactant. Complementary quantum chemical calculations detailed the potential energy surfaces, rationalizing the observed stereochemical outcomes by illustrating the steric and electronic effects within the catalyst-substrate complex.

Notably, the approach is versatile, accommodating a variety of substrates with different functional groups and electronic properties. This adaptability underscores the concept of the Al–salen catalyst as a privileged scaffold, capable of inducing stereocontrol across disparate molecular architectures. The methodology’s compatibility with visible light also bodes well for sustainable chemistry, offering a low-energy alternative to traditional thermal cyclization reactions which often require harsh reagents and conditions.

The implications for synthetic organic chemistry are profound. By demonstrating the controlled use of energy transfer within enantioselective photochemical transformations, this work paves the way for novel reaction design strategies. The ability to harness light in a stereoselective fashion opens new avenues for assembling chiral molecules, which are otherwise difficult or cumbersome to synthesize via classical methods.

Beyond synthetic utility, this development resonates with broader trends in green chemistry. Utilizing photons as traceless reagents reduces chemical waste and energy consumption, aligning with principles of atom economy and environmental stewardship. The catalytic system’s operational simplicity—ambient temperatures, visible light irradiation, and catalytic rather than stoichiometric amounts—improves its appeal for large-scale applications, including pharmaceutical manufacturing where enantiopurity is strictly mandated.

This accomplishment also invites inquiry into the design principles of photocatalysts. The success of the Al–salen framework suggests that integrating robust chiral ligands with photoactive metal centers can yield catalysts that elegantly combine photophysical and stereochemical functions. It encourages chemists to explore other metal-ligand combinations capable of mediating energy transfer with chiral induction, hinting at a new class of multifunctional catalytic systems.

Furthermore, this catalyst’s dual role as both chromophore and chiral director reflects a sophisticated level of molecular engineering. It highlights the power of ligand design to modulate not only the electronic properties of metal centers but also the spatial environment during excited-state reactions. Consequently, the interface between inorganic coordination chemistry and photophysics stands out as a fertile ground for innovation in asymmetric catalysis.

The research also underscores the importance of interdisciplinary collaboration. Advancing such complex photocatalytic systems required seamless integration of synthetic chemistry, spectroscopy, computational modeling, and mechanistic analysis. This collective effort exemplifies how modern chemical discoveries arise at the intersection of multiple specialties, advancing the frontiers of molecular science.

Looking forward, the potential to adapt this energy transfer-enabled, enantioselective photocyclization to more intricate natural product syntheses or the creation of functional materials is alluring. The modularity of the catalyst system could permit fine-tuning for particular substrates or reaction conditions, facilitating access to a wider array of chiral molecules previously inaccessible or economically unfeasible to produce.

Importantly, this approach may inspire novel photochemical strategies beyond cyclization reactions. The fundamental concept of using chiral catalysts to mediate enantioselective energy transfer could be generalized to other transformations involving radicals or excited intermediates, broadening the toolbox available to synthetic chemists.

In conclusion, the work by Soika et al. marks a milestone in asymmetric photocatalysis. By harnessing the unique properties of Al–salen catalysts to mediate enantioselective photocyclization through energy transfer, the study presents a sophisticated yet practical method to create chiral cyclic molecules with high precision. This strategy not only expands the horizons of photocatalytic reaction design but also aligns with sustainable and efficient synthesis paradigms, poised to catalyze further advances in both academic research and industrial applications.

As synthetic methodologies continue to evolve, the fusion of light-driven processes with chiral catalysis stands to revolutionize how chemists construct molecular complexity. The promise of this energy transfer-enabled photocyclization system is a beacon for future exploration, inviting the scientific community to envision new ways in which the subtle dance of photons and catalysts can be choreographed to build life-changing molecules.

Subject of Research: Enantioselective photocyclization enabled by energy transfer catalysis using an aluminum-salen complex.

Article Title: Energy transfer-enabled enantioselective photocyclization using a privileged Al–salen catalyst.

Article References:
Soika, J., Onneken, C., Wiegmann, T. et al. Energy transfer-enabled enantioselective photocyclization using a privileged Al–salen catalyst. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01857-1

Image Credits: AI Generated