Braca

Science, Ahead of Print.

A biocatalytic strategy was developed for the synthesis of enantioenriched halogenated cyclopropanes via enzyme-catalyzed cyclopropanation of chloro- and bromo-substituted olefins in the presence of diazoacetonitrile with engineered myoglobins. This method was applied to the transformation of a range of alpha- and beta-chloro/bromo vinylarenes with good to excellent diastereo- and enantioselectivity (up to 99% de and ee).

Abstract

Halogenated cyclopropanes are highly desirable building blocks for both agrochemical and medicinal chemistry due to their unique structural features and ability to interact with biological targets through halogen bonds. However, methods for the highly diastereo- and enantioselective synthesis of these molecules are underdeveloped. Herein, we report the development of a new biocatalytic strategy to efficiently synthesize enantioenriched halogenated cyclopropanes through the enzymatic cyclopropanation of chloro- and bromo-substituted olefins in the presence of diazoacetonitrile using engineered myoglobin-based catalysts. This method tolerates a wide range of chloro- and bromo-containing olefins at both α- and β-positions with high yields (up to 75%) and excellent diastereo- and enantioselectivity (up to 99% de and ee). These transformations provide access to enantioenriched halogenated cyclopropanes that are challenging to prepare using existing methods, highlighting the value of engineered carbene transfer biocatalysts toward the asymmetric synthesis of enantiopure halogenated cyclopropane building blocks for applications in medicinal chemistry, agrochemicals, and target-directed synthesis.

Privileged chiral catalysts have transformed asymmetric synthesis, conferring generality to processes that are routinely leveraged in the construction of societally important functional small molecules. This mini-review is intended to survey the conception and evolution of privileged chiral photocatalyst scaffolds that enable simultaneous orchestration of reactivity and enantioselectivity in non-ground state regimes.

Abstract

Privileged chiral catalysts have transformed asymmetric synthesis, conferring generality to processes that are routinely leveraged in the construction of societally important functional small molecules. Operating in the ground state, these catalysts are conspicuous in their ability to simultaneously regulate reactivity and translate chiral information, often with broad substrate tolerance: this technology continues to expedite chemical space exploration. In stark contrast to the specificity of many enzymatic transformations, this promiscuity affords remarkable latitude for creative endeavour in synthesis. Given the transformative impact that stereoselective photocatalysis has had over the last decade, identifying privileged chiral catalysts that permit reactivity and enantioselectivity to be regulated in excited-state scenarios has emerged as an attractive but challenging frontier. Providing solutions to address this paradox will require the reactivity/selectivity divide to be reconciled through the validation of chiral scaffolds that effectively operate in non-ground state environments. Inspired by the venerable treatment by Yoon and Jacobsen entitled “Privileged chiral catalysts” (Science 2003, 299, 1691–1693), this mini-review is intended to survey the conception and evolution of privileged chiral photocatalyst scaffolds, and offer a perspective on emerging contenders.

Nature, Published online: 30 July 2025; doi:10.1038/s41586-025-09308-0

Cytochrome P450 enzymes can be repurposed to catalyse asymmetric metal–hydride hydrogen atom transfer, a new-to-nature reaction.

Natural alcohol and sugar dehydrogenases that utilize the redox cofactor pyrroloquinoline quinone (PQQ) can be repurposed for enantioselective photoredox catalysis. Upon blue-light irradiation, redox-neutral radical cyclizations are catalyzed. This work adds a new class of enzymes to the toolbox of photobiocatalysis.

Abstract

Photoenzymatic catalysis facilitates stereoselective new-to-nature chemistry under mild conditions. In addition to the rational design of artificial photoenzymes, naturally occurring redox enzymes can be repurposed to promote photoredox catalysis in the chiral protein environment. Here, we show that enzymes utilizing the pyrroloquinoline quinone (PQQ) cofactor expand the toolbox of photobiocatalysis. PQQ absorbs visible light and is capable of single-electron transfer. It thus exhibits mechanistic similarities to flavin cofactors, which are widely used for photoenzymatic approaches. First, we established the trimethyl ester PQQMe₃ as a stand-alone photoredox catalyst in pure organic solvent. Upon excitation, PQQMe₃ enables the redox-neutral radical cyclization of an N-(bromoalkyl)-substituted indole. We then tested a panel of PQQ-dependent sugar and alcohol dehydrogenases for photoenzymatic catalysis in aqueous buffer, focusing on a redox-neutral radical reaction to form oxindoles. Under optimized reaction conditions, we obtained a 69% yield and an 82:18 enantiomeric ratio. Our work thus demonstrates that PQQ enzymes are capable of stereoselective photoredox catalysis. Future enzyme engineering efforts based on computational modeling and directed evolution will fully unlock their synthetic potential.

Nature Catalysis, Published online: 24 July 2025; doi:10.1038/s41929-025-01353-2

Changing the catalytic metal centre of a non-haem iron dioxygenase to copper results in an enzyme capable of Lewis acid catalysis of new-to-nature enantioselective Conia-ene reactions.

We describe the study and engineering of nonheme Fe enzymes as highly efficient biocatalysts for 1,3-nitrogen migration reactions, enabling the enantioselective synthesis of non-canonical amino acids, which represent valuable building blocks in pharmaceuticals, peptide therapeutics, and asymmetric synthesis. Nonheme Fe enzyme Isopenicillin N synthase from Emericella nidulans (EniIPNS) was repurposed and evolved into a quadruple mutant (V185L I187V S102I R279H, IPNSNim), enabling the conversion of a range of azanyl esters into N-protected L-amino acids with enantiopreference opposite to our previously engineered D-amino acid producing 1-aminocyclopropane-1-carboxylate oxidase (ACCONim). Notably, IPNSNim achieved a total turnover number of 16,700, surpassing state-of-the-art small-molecule Fe catalysts by 340-fold and representing the highest TTN reported for a nonheme Fe enzyme in a new-to-nature reaction. Together with ACCONim, this platform enabled access to either enantiomer of non-canonical amino acids with high efficiency. Mechanistic studies using deuterium-labeled substrates indicated that, in contrast to ACCONim, the hydrogen atom transfer (HAT) step is not the rate-limiting step in IPNS-catalyzed nitrogen migration reaction. Moreover, unlike ACCO, IPNS confers excellent enantiocontrol over the HAT event. Combined computational and experimental studies shed light on the origin of enantiodivergence, unraveling a rare mechanistic and enantioselectivity dichotomy in asymmetric nitrogen migration catalyzed by two phylogenetically related enzymes IPNS and ACCO.

Synlett
DOI: 10.1055/a-2597-0098

Achieving selective functionalization of distal C–H bonds, particularly remote aromatic C(sp 2)–H bonds, is a formidable challenge in organic synthesis. Recently, we have developed an innovative para-selective acylation strategy that targets ultra-remote aryl C(sp 2)–H bonds located eight bonds away from an activation site, utilizing radical N-heterocyclic carbene (NHC) organocatalysis. This method is based on a novel single-electron pathway, enabling site-selective activation of aryl C–H bonds through generated nitrogen-centered radicals in situ. This approach shows immense potential for the functionalization of pharmaceuticals, amino acids, and peptides, underscoring its importance in medicinal chemistry.1 Introduction2 Our Strategy of Ultra-Remote Activation via NHC Organocatalysis3 Features and Applications of the NHC-Catalytic Ultra-Remote Acylation4 Conclusion and Perspectives
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Nature, Published online: 16 July 2025; doi:10.1038/s41586-025-09291-6

A redox reaction network, comprising concurrent oxidation and reduction pathways, is described that can drive autonomous unidirectional motion about a C–C bond in a structurally simple synthetic molecular motor based on an achiral biphenyl.

Thioxanthone is a highly versatile and effective organocatalyst for photochemical applications, with its low-toxicity, metal-free structure driving growing interest in sustainable photocatalysis. Building on our previous 2021 review, this update covers advances from 2021–2025 in thioxanthone-based synthetic organic photochemistry – excluding polymerization and is organized by reaction type to highlight its expanding versatility.

Abstract

Thioxanthone (TX) and its derivatives are standout, heavy-atom-free triplet photosensitizers, due to their high triplet energy, long-lived triplet states, and ability to work synergistically with metal catalysts. These features render them highly useful in photochemical processes. A previous 2021 review covered TX's photophysical properties and photochemical applications. This review constitutes an update and highlights the growing number of studies since then, demonstrating TX's versatility in synthetic organic photochemistry. The content covers the literature during the period 2021–2025 and is organized by reaction type excluding applications in polymerization reactions.

Alkyl halides are ubiquitous motifs in pharmaceuticals, agrochemicals, and materials, yet direct access to regioisomeric variants re-mains limited. Conventional hydrohalogenation of alkenes proceeds via ionic or radical pathways and is generally confined to 1,2-addition. Here, we report a dual cobalt/photoredox catalytic platform that enables remote-Markovnikov-selective 1,3-hydrobromination and hydrochlorination of allyl carboxylates. The transformation proceeds via a metal–hydride hydrogen atom transfer (MHAT) from a Co–H species, 1,2-radical acyloxy migration (1,2-RAM), and halogen atom transfer (XAT) from a Co–X complex. This strategy delivers β-acyloxy alkyl halides under mild conditions, with broad functional group tolerance, compatibility with complex molecules, and scalability. Mechanistic experiments support a radical relay sequence that diverges from classical regi-oselectivity to access formal 1,3-addition products. This work establishes a general approach to regioselective C–X bond formation via programmable radical migration and expands the synthetic toolbox for alkene hydrofunctionalization.

Nature Catalysis, Published online: 14 July 2025; doi:10.1038/s41929-025-01366-x

Enantioselective catalytic C(sp3)–H fluorination has been limited to electrophilic fluorine sources. Now chiral palladium catalysts bearing amino sulfonamide ligands enable enantioselective incorporation of nucleophilic fluoride into unactivated aliphatic C–H bonds with demonstrated applications to 18F-radiolabelling using [18F]KF.

The convergent, stereoselective, and protecting-group-free synthesis of non-canonical amino acids, particularly those bearing a tetrasubstituted α-stereogenic center, remains a challenging task. By leveraging pyridoxal radical biocatalysis, we developed photobiocatalytic oxidative coupling methods for the assembly of α-tetrasubstituted amino acids, including β-branched variants, in a diastereo- and enantioselective fashion. Through repurposing and directed evolution of Thermotoga maritima threonine aldolases, we transformed a traditionally two-electron pyridoxal phosphate (PLP) dependent enzyme into a highly active and stereoselective biocatalyst for single-electron C–C bond formation, enabling enantioconvergent conversion of a broad range of racemic organoboron substrates. Our evolved radical C–C bond forming PLP enzymes achieved a total turnover number (TTN) of 3,100 under dual photobiocatalytic conditions, the highest TTN reported to date for an unnatural photobiocatalytic transformation. Mechanistic studies using radical clock probes and electron paramagnetic resonance (EPR) spectroscopy uncovered an unexpected role of free PLP in oxidative radical generation under photochemical conditions. Molecular dynamics (MD) simulations further elucidated the origin of enantio- and diastereoselectivity in the key radical addition step between the enzymatic quinonoid and the carbon-centered radical. Collectively, these results underscore the power of pyridoxal radical biocatalysis to access a broad spectrum of valuable non-canonical amino acid products via intermolecular, enzyme-controlled asymmetric radical chemistry, a transformation that remains elusive to both state-of-the-art small-molecule catalysis and native enzymology.

N-alkylated heteroarenes are key structural motifs in bioactive compounds, but their regioselective synthesis via coupling of readily available azoles with haloalkanes remains very challenging. Here, we present a mild biocatalytic approach that proceeds on gram-scale, is highly chemo- and regioselective, offering rapid access to valuable N-alkylated building blocks and enabling demanding late-stage alkylations.

Abstract

The alkylation with electrophilic haloalkanes is a key methodology in chemical synthesis to build desired molecules. Although alkylation of compounds bearing a single nucleophilic site is routine, the selective alkylation of polyfunctional molecules with multiple competing nucleophilic positions of comparable reactivity is often very challenging. In this work, we report a generalizable solution for selective alkylation chemistry that combines the selectivity of enzyme catalysis with the reactivity of off-the-shelf alkylation reagents. We employ engineered transferases in a modular cyclic cascade and use functionalized N-heteroarenes as challenging proof-of-concept substrates. This catalytic alkylation approach is mild, highly chemo- and regioselective, proceeds on gram-scale, provides rapid access to important N-alkylated heterocyclic building blocks and enables challenging late-stage alkylations. This study demonstrates a generalizable strategy to streamline synthetic routes to many pharmaceutically important compounds by selective biocatalytic alkylation of polyfunctional molecules and ambident nucleophiles.

A metalloenzyme-catalyzed asymmetric transfer hydrogenation platform has been developed for the stereoselective synthesis of chiral amines. In contrast to natural NAD(P)H-dependent C═N bond reductases, this strategy employs carbonic anhydrase or P450 as a catalyst in combination with a silane-reducing agent, offering a fully orthogonal alternative to conventional NAD(P)H-dependent cellular processes.

Abstract

Chiral amines are prevalent in natural products, pharmaceuticals, and organic catalysts. Their increasing demand has driven the advancement of synthetic methods. In this study, we developed a metalloenzyme-catalyzed asymmetric transfer hydrogenation method for the synthesis of chiral amines. Given the challenges of traditional chemical synthesis, which relies on precious metals and complex synthetic ligands, our approach utilizes base metals derived from natural metalloenzymes for transfer hydrogenation and employs protein scaffolds to achieve stereochemical control. Furthermore, in contrast to natural NAD(P)H-dependent C═N bond reductases, this strategy utilizes silanes as reducing agents and is entirely orthogonal to conventional NAD(P)H-dependent cellular functions. This reactivity highlights the potential to develop new-to-nature enzymatic functions capable of addressing challenges in both organic synthesis and biosynthesis.

Alkyl halides are ubiquitous motifs in pharmaceuticals, agrochemicals, and materials, yet direct access to regioisomeric variants re-mains limited. Conventional hydrohalogenation of alkenes proceeds via ionic or radical pathways and is generally confined to 1,2-addition. Here, we report a dual cobalt/photoredox catalytic platform that enables remote-Markovnikov-selective 1,3-hydrobromination and hydrochlorination of allyl carboxylates. The transformation proceeds via a metal–hydride hydrogen atom transfer (MHAT) from a Co–H species, 1,2-radical acyloxy migration (1,2-RAM), and halogen atom transfer (XAT) from a Co–X complex. This strategy delivers β-acyloxy alkyl halides under mild conditions, with broad functional group tolerance, compatibility with complex molecules, and scalability. Mechanistic experiments support a radical relay sequence that diverges from classical regi-oselectivity to access formal 1,3-addition products. This work establishes a general approach to regioselective C–X bond formation via programmable radical migration and expands the synthetic toolbox for alkene hydrofunctionalization.

Nature Chemical Biology, Published online: 08 July 2025; doi:10.1038/s41589-025-01953-w

Nonheme Fe enzymes with open coordination sites hold the potential for advancing new-to-nature reactions. Here a plant-derived nonheme Fe enzyme, 1-aminocyclopropane-1-carboxylic acid oxidase, is evolved and repurposed to catalyze 1,3-nitrogen migration reactions, enabling the enantioselective synthesis of noncanonical amino acids.

Nature Catalysis, Published online: 04 July 2025; doi:10.1038/s41929-025-01350-5

The scope of Lewis acid catalysis mediated by enzymes is low compared with the range of reactions it drives in organic synthesis. Now the substitution of the iron centre with copper, and the subsequent directed evolution, enabled a non-haem iron hydroxylase to efficiently catalyse asymmetric abiotic Conia-ene cyclizations.

Nature Catalysis, Published online: 04 July 2025; doi:10.1038/s41929-025-01372-z

The intermolecular addition of O-centred radicals to alkenes is a challenging endeavour in synthetic chemistry. Now ene-reductases are used to tame reactive O-radicals for intermolecular and enantioselective radical hydroalkoxylation involving a ground-state single-electron radical mechanism.