Braca

Science, Volume 388, Issue 6747, Page 665-670, May 2025.

Nature, Published online: 09 May 2025; doi:10.1038/d41586-025-01437-w

Chatbot can analyse health-care imagery, such as PDFs of test results, to accurately diagnose a range of medical conditions.

A biocatalytic platform for aniline synthesis, based on the oxidative amination of readily available cyclohexanones, has been reported. Engineered variants exhibit broad substrate compatibility, enabling the synthesis of 40 structurally diverse secondary and tertiary anilines with conversions of up to 91%. Mechanistic studies revealed that directed evolution enhanced enzyme performance in imine desaturation while suppressing phenol formation.

Abstract

Aniline motifs are commonly found in natural products and synthetic molecules. While chemists have developed numerous methods for constructing C(sp²)─N bonds, their biocatalytic counterparts in nature are primarily limited to P450-based protein machineries. To address this limitation, we developed a biocatalytic platform for aniline synthesis based on oxidative amination of cyclohexanones. Through directed evolution of a flavin-dependent enzyme PtOYE, we identified several protein catalysts (e.g., OYE_G3 and OYE_M3) that exhibited activity across a broad array of substrates, enabling the preparation of 40 different secondary and tertiary anilines with various substitution patterns in up to 91% GC conversion. Mechanistic investigations revealed the improved kinetic performance of the evolved variants on the desaturation of imines. Additionally, mutations introduced through protein engineering further reduced the propensity for phenol formation. This enzymatic platform represents a highly promising application of flavin-dependent enzymes, showcasing their great potential in organic synthesis and drug development.

Nature Chemistry, Published online: 06 May 2025; doi:10.1038/s41557-025-01820-0

Recent studies have shown that energy transfer photoenzymes can be engineered to promote stereocontrolled [2 + 2] cycloadditions; however, existing systems rely on ultraviolet light and display limited photochemical efficiencies. A generation of thioxanthone-containing photoenzymes now harnesses visible light to drive challenging photochemical conversions with high efficiencies and selectivities.

Introduction of alkyl substituents onto nucleophilic nitrogen atoms in amines is a central synthetic strategy for increasing molecular complexity and structural diversity in medicinal chemistry, organic synthesis, and materi-als science. Although the direct transfer of a stereogenic alkyl group onto a nitrogen atom by N-alkylation is one of the most efficient approaches to asymmetric C(sp3)–N bond formation, few methods are available for the enan-tioconvergent N-alkylation of amines with racemic alkyl transfer reagents. We report herein, a previously unex-plored enantioconvergent decarboxylative N-alkylation of aromatic amines with racemic carboxylic acids. The reaction is enabled by a merger of acridine photocatalysis with Co(salen)-catalyzed asymmetric radical–polar crossover (RPC). The study provides a simple synthetic segway to medicinally and synthetically valuable α-chiral benzylic amines and elucidates the structural, electronic, and bonding effects that govern the stereocontrol imparted by the privileged Co(salen)-based asymmetric RPC catalytic system.

Visible light-driven photochemistry has advanced significantly, offering diverse methodologies in synthetic organic chemistry. Photocatalysis using red and near-infrared (NIR) light is particularly notable due to its lower energy, reduced phototoxicity, minimized side reactions, and deeper penetration into reaction media. This minireview summarizes recent developments in red- and NIR-mediated photocatalysis, emphasizing radical generation and reactive intermediates for organic synthesis. Applications in small-molecule activation, polymer chemistry, and biologically relevant transformations are discussed, highlighting the growing potential of these photochemical processes in fundamental and applied chemistry.

Abstract

The field of visible light-mediated photochemistry has experienced significant growth, leading to the development of a wide array of methodologies in synthetic organic chemistry. In particular, photocatalysis by using long-wavelength light such as red and near-infrared (NIR) light has garnered substantial attention. These strategies have inherent benefits of low energy, including minimal health hazards, less side reactions, and increased penetration through diverse reaction media. In this minireview, we present an overview of recent advancements in red- and NIR light-induced photocatalysis for the generation of various radicals and key intermediates in organic synthesis. Additionally, this minireview will recount the application of small-molecule activation, polymer science, and bio-related aspects to offer a comprehensive framework and insight of photochemistry mediated by red and NIR light.

The design of artificial enzymes represents a transformative advancement in biocatalysis, enabling the creation of enzyme for nonnatural reactions. Herein, recent progress in the design of enzymes is highlighted featuring unnatural catalytic residues introduced via site-specific chemical modification. This concept emphasizes the methodologies employed, the challenges, and future directions for expanding potential applications of artificial enzyme design in biocatalysis.

The design of artificial enzymes represents a transformative advancement in biocatalysis, enabling the creation of bespoke biocatalysts for nonnatural reactions. A key innovation in this field is the introduction of unnatural catalytic residues through site-specific chemical modification, which significantly expands the chemical repertoire of natural enzymes. This approach combines precision engineering with cutting-edge methodologies, including chemical ligation, noncanonical amino acid incorporation and directed evolution. These strategies facilitate the development of enzymes with novel catalytic activities, modify substrate specificities, and enhance stability under nonphysiological conditions. This concept examines the methodologies, challenges, and future directions in the design of enzymes with unnatural catalytic residues via site-specific chemical modification, with a focus on their functional impact and transformative potential in synthetic chemistry and biocatalysis.

Nature, Published online: 22 April 2025; doi:10.1038/s41586-025-09011-0

Stereoretentive radical cross-coupling

Designing and developing synthetically useful biocatalytic reactions that operate via novel mechanisms represent a central challenge in modern biocatalysis research. By coupling photoredox catalysis and metalloenzyme catalysis, we harness cooperative photometallobiocatalysis to merge enzymatically generated, open-shell iron carbenoids with reactive radical intermediates formed via excited-state chemistry. This strategy enables a new class of intermolecular radical C–C coupling reactions with excellent enantio- and diastereoselectivities. Central to the successful implementation of this design is the directed evolution of a small metalloprotein catalyst, derived from a thermophilic cytochrome c, to achieve challenging stereocontrol in radical C–C coupling via an outersphere mechanism. These photobiocatalytic, formal metal carbenoid-radical coupling reactions advance a new form of stereoselective outer-sphere metal carbenoid chemistry, providing a powerful strategy to design and evolve biocatalytic C–C bond forming reactions through otherwise challenging intermolecular asymmetric radical couplings.

Nature Synthesis, Published online: 17 April 2025; doi:10.1038/s44160-025-00792-w

An iron-catalysed radical Markovnikov hydroamidation of alkenes using a cyanamide reagent is reported. The method achieves C–N bond formation with high yields and selectivity and is applicable to a wide range of alkenes and natural products. The cyanamide functionality can be transformed into various functional groups, highlighting its potential for advanced applications in natural product synthesis.

New systems can identify unknown proteins in samples from diseased tissue, the environment, and archaeological sites

Prolonged operation accumulates damage that is similar to fatigue in an electrode

Nature Synthesis, Published online: 14 April 2025; doi:10.1038/s44160-025-00788-6

A repurposed non-haem, iron-based dioxygenase enables the stereoconvergent reduction of alkenes with excellent selectivity. Mechanistic studies support an iron hydride pathway and reveal the molecular mechanism of stereoconvergence.

A new-to-nature biocatalytic radical alkylation of 2-acyl imidazoles is achieved through the cross-integration of a Lewis-acid (LA)-type artificial metalloenzyme (ArM) and a photobiocatalysis strategy. Directed evolution leads to enantiodivergent synthesis with different mutants. Detailed mechanistic studies illustrate a difference in reactivity and enantiomeric preference between the illuminated and dark conditions.

Abstract

Artificial metalloenzymes (ArMs) and photoenzymatic catalysis represent two cutting-edge approaches to creating new enzyme reactivity. However, the potential of merging these two strategies remains underdeveloped for enantiocontrolled biotransformations. Herein, we develop a synergistic metalloenzymatic and photoredox catalysis platform to enable enantiodivergent radical alkylation of 2-acyl imidazoles. Specifically, cupin proteins are redesigned to function as copper(II)-based Lewis-acid-enzymes (LAses), which, in synergy with tripyridinyl-ruthenium-based photoredox catalysis, precisely control the generation, reactivity, and selectivity of abiological radicals, thereby unlocking non-natural enzyme reactivity. Powered by protein engineering, repurposed photo-LAses facilitate the green and efficient synthesis of diverse enantioenriched α-chiral ketones in high enantioselectivity (both enantiomers accessible, up to 97% yield and 98.5:1.5 enantiomeric ratio [er]). Detailed mechanistic studies suggest a radical addition to the metalloenzymatic enolate pathway and explain the switched selectivity from dark to photoconditions.

A new-to-nature biocatalytic radical alkylation of 2-acyl imidazoles is achieved through the cross-integration of a Lewis-acid (LA)-type artificial metalloenzyme (ArM) and a photobiocatalysis strategy. Directed evolution leads to enantiodivergent synthesis with different mutants. Detailed mechanistic studies illustrate a difference in reactivity and enantiomeric preference between the illuminated and dark conditions.

Abstract

Artificial metalloenzymes (ArMs) and photoenzymatic catalysis represent two cutting-edge approaches to creating new enzyme reactivity. However, the potential of merging these two strategies remains underdeveloped for enantiocontrolled biotransformations. Herein, we develop a synergistic metalloenzymatic and photoredox catalysis platform to enable enantiodivergent radical alkylation of 2-acyl imidazoles. Specifically, cupin proteins are redesigned to function as copper(II)-based Lewis-acid-enzymes (LAses), which, in synergy with tripyridinyl-ruthenium-based photoredox catalysis, precisely control the generation, reactivity, and selectivity of abiological radicals, thereby unlocking non-natural enzyme reactivity. Powered by protein engineering, repurposed photo-LAses facilitate the green and efficient synthesis of diverse enantioenriched α-chiral ketones in high enantioselectivity (both enantiomers accessible, up to 97% yield and 98.5:1.5 enantiomeric ratio [er]). Detailed mechanistic studies suggest a radical addition to the metalloenzymatic enolate pathway and explain the switched selectivity from dark to photoconditions.

De novo protein design has been used to create functional protein assemblies, but its reliance on standard amino acids limits the integration of synthetic supramolecular strategies for precise control of molecular assemblies. Herein, we present an artificial protein assembly that integrates synthetic supramolecular design with de novo protein engineering. Focusing on unit and connection rigidity, we designed and created the Bi-Porphyrin Acquisition Designer protein (BiPAD), which captures two highly designable synthetic porphyrins, via state-of-the-art generative protein design to fuse α/β-folded porphyrin-binding motifs. BiPADs captured rigid porphyrins, each bearing an additional metal coordination site, resulting in a metal-responsive cyclic assembly with the intended structure. Furthermore, high-speed atomic force microscopy revealed dynamic structural changes in the BiPAD assembly. This work expands the designability of artificial protein assemblies, paving the way for the synergistic design of functional systems through the integration of protein engineering and synthetic chemistry.

Engineered P450 enzymes were employed to catalyze the asymmetric oxidation of dihydrosilanes, producing Si-stereogenic chiral silanols with good yields and high enantioselectivies. The evolved variant ASOx-6 exhibits a 54-fold activity increase compared to the wild-type enzyme on the model substrate. A combination of experimental and computational mechanistic studies provided detailed insights into this biocatalytic process.

Abstract

Chiral silanols are important synthetic targets and have garnered increasing attention in the materials and pharmaceutical industries over recent decades. A promising approach for their efficient synthesis is asymmetric silane oxidation. While chemists have developed several transition-metal-catalyzed systems for asymmetric hydrolytic oxidation of silanes, no biocatalytic methods have been available for enantioselective synthesis of Si-stereogenic compounds, including chiral silanols. Here, we present an enzymatic platform for the asymmetric aerobic mono-oxidation of dihydrosilanes using an engineered P450_BM3 enzyme. Through six iterative rounds of directed evolution, we identified the optimal evolved variant, ASOx-6, which exhibits a 54-fold improvement in k _cat/K _M compared with the wild-type enzyme. Moreover, a variety of aryl–alkyl substituted dihydrosilanes are accepted by ASOx-6, including those bearing heteroaromatic rings. Finally, mechanistic insights obtained from kinetic isotope experiments and computational studies further elucidate the nature of this biocatalytic transformation.

Innovation in biocatalysis is rapidly increasingly the diversity of catalytic reactivity that can be mediated by enzymes, addressing a key bottleneck for their widespread adoption in industrial chemical synthesis. A key approach to this is building enzymes with unnatural catalytic components that provide an expanded palette with new possibilities for enzymatic reactivity.

The expanding applications of biocatalysis in the chemical and pharmaceutical sectors herald a greener future for these industries. Yet, the range of chemical reactions known to enzymes only covers a small fraction of what is required for modern synthetic routes. To continue the increases in sustainability afforded by converting chemical processes into enzymatic ones, fundamentally new kinds of biocatalytic reactivity are required. Perhaps the very components from which enzymes are constructed, a palette of canonical amino acids and cofactors, inherently limit their catalytic possibilities, even if all the available natural sequence space can be explored. In recent years, there has been an explosion of strategies to produce new biocatalytic function through the incorporation of noncanonical amino acids and synthetic cofactors, new colors which are added to the enzyme design palette. This has enabled new enzymatic reactions that proceed via organocatalytic, organometallic, and photocatalytic mechanisms. Aside from designing new enzymatic activities from scratch, exogenous photocatalysts have recently also been used in synergy with natural enzyme active sites to diverge their reactivity towards radical pathways. This review will highlight recent developments in enriching enzymatic chemistry with new unnatural components, providing an outlook for future directions and needed developments for practicality and sustainability.