In recent years, transition metal–hydrides have emerged as powerful catalysts in the realm of organic synthesis, particularly for hydrofunctionalization reactions involving unsaturated substrates such as carbonyls, alkenes, and alkynes. Their capacity to transfer hydride ions heterolytically has long been leveraged to transform these compounds with precision. However, the complementary process of metal–hydride hydrogen atom transfer (MHAT), characterized by homolytic cleavage, is now garnering increasing attention. MHAT enables radical hydrofunctionalization, an approach that is especially promising for the late-stage functionalization of unactivated alkenes—substrates historically challenging to manipulate due to their relative inertness. This shift towards MHAT underscores a new frontier in complex molecule diversification, with radical intermediates facilitating unique transformations previously inaccessible through conventional methods.
Despite its potential, asymmetric catalysis via MHAT has remained a formidable challenge. Central to this difficulty is the inherently weak interaction between transient prochiral organic radicals and chiral catalysts. Radical species are often fleeting and poorly controlled, complicating efforts to induce enantioselectivity—control over the spatial arrangement of atoms that defines a molecule’s three-dimensional shape and its biological activity. Overcoming these limitations is pivotal, as asymmetric radical processes can unlock pathways to enantioenriched products highly valued in pharmaceuticals and agrochemicals.
Addressing this gap, a recent breakthrough harnesses the versatility of cytochrome P450 enzymes (CYPs)—nature’s own catalysts known for their versatile oxidative transformations. Recognized chiefly for their ability to activate molecular oxygen and perform selective oxidations, certain CYPs have now been repurposed to catalyze MHAT, a reaction that does not naturally occur in biological systems. This pioneering endeavor employed directed evolution, a technique that mimics natural selection in the laboratory to iteratively improve enzyme performance. Starting with a variant of the P450_BM3 enzyme, researchers developed a triple mutant capable of performing radical cyclizations on unactivated alkenes with remarkable stereocontrol.
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The evolved P450_BM3 mutant demonstrated the ability to catalyze MHAT radical cyclization reactions that forge diverse cyclic amines such as pyrrolidines and piperidines—structural motifs frequently encountered in bioactive molecules. These transformations were achieved under aerobic whole-cell conditions, highlighting the practicality and robustness of the biocatalytic system. Strikingly, the reactions produced enantiomeric ratios as high as 98:2, signifying exceptional control over the stereochemical outcome and marking a notable advance in asymmetric radical chemistry.
Beyond substrates with electron-deficient alkenes, the repurposed enzymes expanded their substrate scope to include alternative radical acceptors such as hydrazones, oximes, and nitriles. This breadth underscores the enzyme’s adaptability and the potential for broad application in synthesizing structurally diverse heterocycles. The integration of these unconventional radical acceptors suggests new strategic avenues for assembling complex architectures in synthetic chemistry, combining the power of enzymatic precision with radical reactivity.
Mechanistic investigations into the catalytic cycle revealed that the enzyme operates through an MHAT pathway initiated by homolytic cleavage of a transient iron(III)–hydride intermediate. This fleeting species is central to the reaction, mediating hydrogen atom transfer to initiate radical formation. The homolytic cleavage contrasts with the more common heterolytic mechanisms of metal–hydride species and opens new mechanistic spaces that enzymes can exploit. These mechanistic insights also provide a blueprint for further engineering of enzymes tailored for radical transformations, guided by understanding how metalloenzymes can harness homolytic metal–hydride chemistry.
A testament to the power of directed evolution, starting from a different cytochrome P450 scaffold—CYP119—researchers evolved a stereocomplementary MHATase that delivers the opposite enantiomeric product with equally high selectivity. This stereocomplementarity showcases the tunability of enzymatic systems through iterative mutation and selection, enabling fine control over stereochemical outcomes and expanding practical synthetic capabilities. The availability of two complementary enzymes offers synthetic chemists versatile tools for stereodivergent synthesis, an essential aspect of drug discovery and development.
This groundbreaking work exemplifies how the natural versatility of metalloenzymes can be expanded by engineering novel reactivities, extending beyond their canonical functionalities. By integrating homolytic metal–hydride reactivity into biocatalysts, this study charts a course toward a new class of asymmetric radical biocatalysts. Such catalysts could revolutionize synthetic strategies by marrying the selectivity and sustainability of enzymatic approaches with the expansive reaction space accessible via radical intermediates.
The implications of this discovery extend beyond academic curiosity. Enzymatic MHAT catalysis has the potential to transform synthetic routes to chiral nitrogen heterocycles, privileged motifs in medicinal chemistry. The mild reaction conditions, use of whole-cell catalysts, and high stereoselectivity promise greener, more efficient synthetic processes that could supplant harsher traditional methods relying on metal complexes or radical initiators. Moreover, the ability to perform late-stage functionalizations on complex molecules opens doors to rapid diversification of pharmaceuticals and natural products.
Future avenues of research include expanding substrate scope to even more challenging alkenes and radical acceptors, optimizing enzyme stability and turnover in industrial settings, and combining MHAT biocatalysis with other enzymatic or chemical transformations in cascade sequences. Such integrated approaches could enable streamlined syntheses of molecules with dense stereochemical information, tackling synthetic challenges that have long stymied chemists.
Overall, this landmark study underscores a paradigm shift in asymmetric catalysis, where the power of radical intermediates traditionally constrained by lack of selectivity is now harnessed with exquisite control via engineered enzymes. It demonstrates the promise of melding bioinspiration with chemical innovation to unlock new frontiers in molecular synthesis.
As the toolkit of biocatalysis expands with innovative MHATases, synthetic chemists stand at the cusp of a radical revolution—one where enzymes not only mimic but also transcend natural capabilities to access previously elusive chemical space. In this dynamic interplay of radical chemistry and enzyme engineering, the future of asymmetric synthesis gleams brightly.
Subject of Research: Repurposing cytochrome P450 enzymes to catalyze asymmetric metal-hydride hydrogen atom transfer (MHAT) for radical hydrofunctionalization of unactivated alkenes.
Article Title: Repurposing haemoproteins for asymmetric metal-catalysed H atom transfer.
Article References:
Zhang, X., Chen, D., Álvarez, M. et al. Repurposing haemoproteins for asymmetric metal-catalysed H atom transfer. Nature (2025). https://doi.org/10.1038/s41586-025-09308-0
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Tags: advancements in radical chemistryasymmetric metal hydrogen atom transferchiral catalysts in synthesiscomplex molecule diversification strategiesenantioselective radical processeshydride ion transfer mechanismslate-stage functionalization of alkenesmetal-hydride catalysis in organic chemistrypharmaceuticals and agrochemicals synthesisprochiral organic radicalsradical hydrofunctionalization techniquestransition metal hydrides
