Braca

Nature, Published online: 22 June 2026; doi:10.1038/s41586-026-10807-x

C-glycoside synthesis via radical cross-coupling of glycohydrazides

Metal-hydride hydrogen atom transfer (MHAT) enables Markovnikov-selective generation of carbon-centered radicals from alkenes. This Review highlights how strategic control of these intermediates has expanded alkene hydrofunctionalization through radical addition, radical–polar crossover, radical–radical coupling, and metal-mediated cross-coupling pathways.

ABSTRACT

Metal-hydride hydrogen atom transfer (MHAT) catalysis has emerged as a powerful platform for the selective functionalization of alkenes via carbon-centered radical intermediates. By facilitating outer-sphere hydrogen atom transfer, MHAT circumvents the limitations of classical coordination–insertion pathways and affords direct access to reactive radical species from simple alkene feedstocks. Over the past decade, this chemistry has expanded from reductive hydrogenation to a broad range of hydrofunctionalization protocols, including C─O, C─N, and C─C bond-forming reactions. Central to these advances is the increasing ability to control the subsequent reactivity of alkene-derived radicals, enabling transformations through radical addition, radical–polar crossover, radical–radical coupling, and metal-mediated cross-coupling pathways. Furthermore, merging MHAT with photoredox, electrochemical, and dual catalytic systems has expanded its scope and versatility. Despite these advances, significant challenges persist in achieving precise stereocontrol and broadly applicable enantioselective transformations. This Review summarizes developments in MHAT catalysis from 2014 to 2025, with particular emphasis on mechanistic principles and emerging strategies for selective alkene functionalization.

Luciferases are widely used bioluminescent reporters, yet access to these enzymes has historically relied on recombinant expression. Here, we show that automated fast-flow peptide synthesis (AFPS) enables the rapid production of functional luciferases ...

Science Advances, Volume 12, Issue 25, June 2026.

Metal centers in enzymes are typically considered to operate within well-defined coordination geometries; however, emerging evidence suggests that dynamic metal behavior could also play a functional role. Herein, we report a structure-informed density ...

Metal–hydride hydrogen atom transfer (MHAT) reactivity is well established in homogeneous catalysis, but analogous reactivity in enzyme active sites remains rare and mechanistically underexplored. A recently discovered non-heme Fe/2-oxoglutarate (Fe/2OG) ...

Arginine side chains play important roles in the catalytic sites of many natural and engineered enzymes. This versatility is further exemplified by the recent development of artificial enzymes for SNAr processes, which rely on a key catalytic arginine ...

Angewandte Chemie International Edition, EarlyView.

Nature Chemistry, Published online: 17 June 2026; doi:10.1038/s41557-026-02184-9

There is limited understanding of nickel-catalysed chemistry in nature. Now a bioinformatic pipeline reveals a structurally distinct family of nickel pincer nucleotide-dependent enzymes. Nickel pincer hydride transferase (NphT) was found to catalyse intermolecular hydride transfer by characterizing its crystal structure, conducting structure-guided mutagenesis and measuring its capacity to disproportionate sugars.

Nature Catalysis, Published online: 09 June 2026; doi:10.1038/s41929-026-01539-2

Direct hydrogen atom transfer (d-HAT) for C(sp3)–H functionalization classically relies on O-centred photocatalysts. Now, neutral N-centred acridine photocatalysts have been added to the toolbox, enabling mild, scalable d-HAT that is compatible with a broad substrate scope and transition metal catalysis.

Publication date: November 2026

Source: Tetrahedron, Volume 199

Author(s): Ivan S. Smirnov, Igor O. Nasibullin, Almira R. Kurbangalieva, Tsung-Che Chang, Katsunori Tanaka

Nature Chemical Biology, Published online: 15 June 2026; doi:10.1038/s41589-026-02250-w

The TIM barrel is nature’s most versatile enzyme fold, yet de novo variants lack functional active sites. Minimal de novo TIM barrels have now been converted into enzymes by designing structural lids that generate tailored active sites. These catalysts achieve high efficiencies in Kemp elimination, enabling a generalizable platform to design enzymes on demand from minimal scaffolds.

A native ene-reductase, XenA, was repurposed to catalyze the reverse-enantioselective desaturation of cyclohexanones. The final variant was obtained through extensive protein engineering, combining PROSS-guided computational design with mutagenesis and screening. Mechanistic experiments and computational modelling further revealed the unique mechanistic features underlying this enzymatic desaturation process.

ABSTRACT

Chiral enones are valuable motifs in synthetic intermediates and bioactive molecules, driving significant interest in biocatalysis. Although recent enzymatic desaturation strategies for substituted cyclohexenones provide efficient and highly enantioselective synthetic routes, none offer complementary stereoselectivity. To address this gap, we introduce a stereocomplementary biocatalytic system based on an old yellow enzyme (OYE), XenA from Pseudomonas putida. Although XenA natively catalyzes the reduction of electron-deficient alkenes and exhibits negligible desaturation activity, protein engineering redirected its catalytic function toward desaturation, ultimately yielding a variant that accommodates a range of cyclohexanones with 85%–99% ee and 32%–98% yield. Remarkably, the optimal variant (XenA_4) possesses 46 mutations and exhibits an 11°C increase in melting temperature over the wild type. Mechanistic studies revealed that the unique dimeric structure of the enzyme is pivotal in controlling stereoselectivity by modulating the substrate-binding orientation.

Nature Synthesis, Published online: 12 June 2026; doi:10.1038/s44160-026-01105-5

In this issue, we focus on the use of biocatalysis combined with photo- and electrocatalysis in synthesis.

Unlike typical radical enzymes that yield saturated alkanes via hydrogen atom transfer, the vitamin B_{1 2}-dependent photoreceptor, CarH, intrinsically favors cobalt-mediated β-hydride elimination. Leveraging this reactivity, an engineered photoenzymatic platform enables the non-native intermolecular radical alkylation of activated alkenes under visible light. This strategy selectively delivers functionalized olefins, expanding the synthetic repertoire of radical biocatalysis.

Intermolecular CC bond formation via radical intermediates poses a formidable challenge in biocatalysis, primarily due to the difficulty in suppressing thermodynamically favored reductive quenching pathways such as hydrogen atom transfer (HAT). Here, we report a photoenzymatic platform that leverages an engineered vitamin B₁₂-dependent photoreceptor, CarH, to catalyze the non-native intermolecular radical alkylation of activated alkenes. Through rational protein engineering, specifically the removal of the axial histidine ligand (H132A), we disrupted the inhibitory bis-histidine coordination and expanded the active-site cavity, thereby enhancing catalytic efficiency (up to 67.9% yield) relative to the wild-type enzyme. This strategy enables the highly selective synthesis of functionalized alkenes from a diverse array of N-substituted α-haloamides and a broad scope of activated alkenes—smoothly accommodating electron-rich, electron-deficient, sterically hindered styrenes, and heteroaryl olefins—under mild visible-light irradiation. This study illustrates how modulation of metallocofactor coordination within a protein scaffold can unlock non-natural radical reactivity.

Synthesis
DOI: 10.1055/a-2881-8736

DNA-encoded library (DEL) technology serves as a cornerstone of modern drug discovery, providing a cost-effective platform for the rapid interrogation of therapeutic candidates. However, the prerequisite for DNA-compatible synthetic reactions under aqueous conditions has historically constrained DEL chemical diversity to planar, C(sp2)-rich architectures, resulting from a reliance on traditional two-electron polar transformations. This short review evaluates recent advances in radical-mediated transformations as a powerful means to increase the chemical space of DELs. By facilitating access to three-dimensional sp3-rich scaffolds, these radical methodologies have the potential to significantly broaden the structural diversity of modern DELs.
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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 Chemistry, Published online: 10 June 2026; doi:10.1038/s41557-026-02177-8

Selective radical capture remains a central challenge in transition metal-catalysed transformations involving multiple radical intermediates. Now a ligand-modulated metal–radical polarity-match mechanism exploiting electronic bias for selective radical capture has been identified. This principle enables general photoredox/copper-catalysed 1,2-dicarbofunctionalization of ethylene, providing modular access to structurally diverse 1,2-dicarbofunctionalized ethanes.

Aniline adenine dinucleotide (AnAD), a synthetic cofactor in which the nicotinamide unit of NAD⁺ is replaced by a catalytically active aniline moiety, was designed to reprogram NAD(P)⁺-binding proteins into iminium biocatalysis capable of catalyzing tandem Friedel-Crafts alkylation-enantioselective protonation reactions.

ABSTRACT

Efficient integration of non-natural catalytic motifs into protein scaffolds remains a central challenge in artificial enzyme design. Here we report aniline adenine dinucleotide (AnAD), a NAD⁺-type synthetic cofactor in which the native nicotinamide is replaced by a catalytically active aniline unit. When incorporated into diverse NAD(P)⁺-binding proteins, AnAD introduces an iminium catalysis mechanism that enables tandem Friedel-Crafts alkylation-enantioselective protonation reactions. Screening a panel of natural protein scaffolds revealed broad intrinsic compatibility, while protein engineering further enhanced activity and stereoselectivity, affording artificial enzymes with good substrate generality and tunable enantioselectivity. Mechanistic studies showed that cooperation between AnAD and protein microenvironments, particularly dynamic active-site loop motions, governs both reactivity and enantioselectivity. These results demonstrate the generality and robustness of reprogramming ubiquitous NAD(P)⁺-binding proteins for new-to-nature biotransformations using NAD⁺-type synthetic cofactors.

Designing redox proteins with predictable and tuneable electron transfer properties is a major goal in de novo bioenergetics. Here we show that replacing heme B with a series of structurally conservative non-natural metalloporphyrins enables broad modulation of redox potentials over 400 mV in the de novo designed monoheme m4D2 and diheme 4D2 T19D. The non-natural porphyrins bind with high affinity and do not compromise either the heme binding site or global protein structure, as evidenced by X-ray crystallography and NMR spectroscopy. We also report the native-like NMR structure of m4D2 loaded with the non-natural and symmetric iron 2,4-dimethyldeuteroporphyrin IX, confirming our modular approach to tetrahelical redox protein design. This work establishes a versatile platform for constructing tuneable electron carriers for engineered bioenergetic pathways and bioelectronic applications.

Flavin catalysis represents a powerful tool for constructing complex molecules both in enzymes and in the organic laboratory. Particularly intriguing reactivity is achieved by photochemical excitation of flavin cofactors, which results in strong oxidants ...

Science, Volume 392, Issue 6802, Page 1075-1081, June 2026.

X-ray visualization of copper-binding modes revealed nonspecific surface metal sites that compromise stereoselectivity. Structure-guided mutations suppressed background reactivity and enabled precise enantioselective control in the Michael addition, delivering up to 99% ee. This visualization-driven strategy offers a general approach to optimizing artificial metalloenzymes.

ABSTRACT

A nonheme copper protein based on a TM1459 cupin fold was engineered to catalyze the stereoselective Michael addition of 2-nitropropane to 2-azachalcone. Metal-center screening combined with secondary coordination-sphere engineering enabled the initial control of enantioselectivity. X-ray crystallographic analysis further identified nonspecific metal-binding sites on the protein surface, and targeted surface-residue mutations effectively suppressed undesired background reactions. This structure-guided approach significantly enhanced catalytic performance, affording up to 98% enantiomeric excess (ee) (S) and 99% ee (R). These results demonstrate that the visualization-driven selection of mutation sites provides a powerful and generalizable strategy for optimizing artificial metalloenzymes.