Braca

A dynamic kinetic resolution approach is developed for the atroposelective synthesis of heterobiaryl primary amines. Using transaminases and leveraging Lewis acid-base interactions to induce racemization, a variety of axially chiral primary amines are produced in high yields and enantioselectivities. This mild, metal-free method expands the scope of biocatalytic asymmetric synthesis.

Atropisomeric heterobiaryl primary amines are of significant interest in both organic and pharmaceutical chemistry. A series of transaminases have been employed to synthesize these valuable compounds with high yields (up to 98% conversion) and excellent enantioselectivities (up to ≥99% ee) via dynamic kinetic resolution of the corresponding heterobiaryl aldehydes. This process features a Lewis acid–base interaction strategy to facilitate labilization of the stereogenic axis.

Atropisomeric scaffolds are important building blocks in natural products, organocatalysts, metal ligands, and functional materials. This review introduces current developments for synthesizing atropisomers employing biocatalytic kinetic resolution, dynamic kinetic resolution, and desymmetrization strategies.

ABSTRACT

The asymmetric synthesis of atropisomers has garnered extensive attention in recent years. Atropisomers constitute a key structural motif in natural products, chiral ligands, organocatalysts, and functional materials. Despite progress driven by transition-metal and organocatalysis, inherent limitations in enantioselectivity and sustainability have hampered further development in this field. Alternatively, biocatalysis offers a promising solution employing strategies including (dynamic) kinetic resolution, desymmetrization, and other strategies. These biocatalytic processes operate under mild, environmentally friendly conditions, achieving high stereoselectivity that is often difficult to attain with traditional methods. This review highlights recent advances in the biocatalytic synthesis of atropisomers and offer insights in the development of the relevant field.

Nature Synthesis, Published online: 20 November 2025; doi:10.1038/s44160-025-00940-2

A dual-cofactor artificial metalloenzyme is developed, incorporating a biotinylated nickel complex and a Strep-tagged peptide catalyst in adjacent streptavidin-binding sites. This synergistic artificial metalloenzyme achieves enantiodivergent Michael addition reactions with tunable stereochemistry and high turnover numbers across diverse ketone and enal substrates.

A desymmetrization strategy for an enantioselective Miyaura-type C(sp²)–B cross-coupling to access highly enantioenriched, axially chiral biaryl boronic esters is disclosed. The enantiomeric excess of the chiral monoborylated product after reductive elimination is further improved by a downstream kinetic resolution, thereby converting the minor enantiomer into the corresponding achiral bisborylated biaryl byproduct.

Abstract

An efficient protocol for a desymmetrizing C(sp²)–B cross-coupling of achiral 1,1′-biaryl-2,6-diyl bis(nonaflates) and B–B reagents is disclosed. An in situ-formed palladium(0)–(S,S)-f-Binaphane complex discriminates between the enantiotopic nonaflate groups, and the subsequent transmetalation of the B–B reagent is enhanced by a copper co-catalyst. The enantiomeric excess of the chiral monoborylated product after reductive elimination is further improved by a downstream kinetic resolution, thereby converting the minor enantiomer into the corresponding achiral bisborylated biaryl byproduct. This enantioselective Miyaura reaction enables the synthesis of highly valuable, axially chiral boron compounds with superb enantiomeric ratios (up to e.r. = 99:1) and exhibits broad substrate scope and good functional-group tolerance.

An effective copper-photoredox catalytic platform enables enantioselective generation of metal-bound P-centered radicals and their stereoretentive transformations within a precisely defined chiral environment. This strategy not only enables efficient synthesis of pharmaceutically relevant P-chiral molecules but also provides mechanistic insights into heteroatom-centered asymmetric radical chemistry.

Abstract

Phosphorus-centered radicals hold transformative potential for organophosphorus synthesis, yet their configurational lability and distinctive reactivity profiles have historically restricted their application in asymmetric catalysis. Herein, we report a copper-photoredox catalytic system that enables the stereoselective generation of copper-bound P-centered radicals and their subequent stereoretentive transformations within a well-defined chiral environment. The synergistic approach achieves unprecedented kinetic resolutions of racemic H-phosphinates with α-trifluoromethyl styrenes or gem-difluorostyrenes, delivering 85 fluorine-containing P-chiral phosphinates with up to 98% ee. The method thereby bridges a synthetic gap for these previously inaccessible, pharmacologically significant compounds. Mechanistic and computational studies reveal a stereochemical relay: enantiodiscriminatory binding of racemic substrates, photoinduced ligand-to-metal charge transfer (LMCT) for radical generation, and stereoretentive bond formation. By reconciling radical reactivity with stereochemical fidelity, our strategy establishes metallaphotoredox catalysis as a versatile paradigm for heteroatom-centered stereochemistry.

The semipinacol rearrangement comprises a valuable class of synthetic organic transformations that provides access to useful molecular scaffolds via C–C bond cleavage and formation. Biocatalytic semipinacol rearrangements are rare, however, and the only naturally occurring semipinacolase catalyzes a reaction that proceeds via chirality transfer on a complex natural product substrate. Herein, we report that flavin-dependent halogenases (FDHs) can catalyze enantioselective halogenative semipinacol rearrangement of pro-chiral allylic alcohols. This biocatalytic platform exhibits a broad substrate scope, affording chiral ketones bearing all-carbon quaternary stereocenters with high enantioselectivity. The reaction system displays a kcat value of 16.86 ± 0.97 min-1, representing the highest reported to date for FDH catalysis, and the T52G mutation was found to play a key role in reshaping the enzyme active site to enable this non-native transformation. This first example of asymmetric C−C bond construction using an FDH highlights the catalytic flexibility of these enzymes and provides access to a diverse range of enantioenriched carbocycles and heterocycles.

Genetic code expansion with a unique hyper-fluorinated phosphotyrosine analog. In this work, we successfully incorporated the unnatural amino acid pentafluorophosphato-difluoromethyl-phenylalanine, carrying seven fluorine atoms and a permanent negative charge into three different proteins via the use of mutated orthogonal aminoacyl-tRNA synthetases. Biological testing revealed the great potential of this approach for furnishing functional phosphoprotein mimetics.

Abstract

Protein phosphorylation is one of the most important posttranslational modifications altering the structure, stability, and activity of more than 13 000 human proteins. In this work, the phosphotyrosine mimetic pentafluorophosphato-difluoromethyl-phenylalanine (PF₅CF₂Phe) was genetically encoded and incorporated into three different proteins. Screening two libraries of orthogonal aminoacyl-tRNA synthetases identified enzymes enabling the efficient and specific incorporation of PF₅CF₂Phe into red fluorescent protein (RFP) via amber stop codon suppression. Two model proteins, human ubiquitin (Ubq) and the B1 immunoglobulin-binding domain of streptococcal protein G (GB1), were prepared with PF₅CF₂Phe mutations and investigated for potential interaction partners. While native GB1 showed no binding to protein tyrosine phosphatases (PTP), PF₅-GB1, with PF₅CF₂Phe at position 17, was a strong inhibitor of the phosphatases PTP1B and SHP2. PF₅-Ubq was produced and converted into the first example of a protein carrying the most prominent phosphotyrosine mimetic, phosphono-difluoromethyl phenylalanine (PO₃CF₂Phe). With increasing need in the biosciences to delineate the functions of complex phosphorylation patterns, genetic encoding of PF₅CF₂Phe yielding phosphoprotein mimetics opens unique opportunities for precise functional studies where site-specific and homogeneous protein modifications are required.

Nature, Published online: 12 November 2025; doi:10.1038/s41586-025-09738-w

A new method for deracemization of atropisomers is described which leverages a P450 enzyme-mediated process involving bond rotation for enantioenrichment.

The formation of C(sp2)–heteroatom bonds is a cornerstone of modern organic synthesis and key for the preparation of pharmaceuticals, agrochemicals, and functional materials. Traditionally, such bond formations have relied on palladium-catalyzed cross-couplings operating through canonical Pd0/PdII cycles, which require complex ligand architectures to control the orthogonal steric and electronic ligand demands for the initial electrophile activation and final bond forming event.Cross-coupling catalysis via paramagnetic Niᴵ and Niᴵᴵᴵ species is an appealing alternative because the bond-forming step is energetically favorable. However, this approach is confined to activated starting materials and requires high catalyst loadings, due to the insufficient catalytic activity and stability of state-of-the-art NiI catalysts. Here, we show that mechanistically guided ligand design overcomes these intrinsic bottlenecks by achieving a well-balanced equilibrium between a highly reactive NiI species and a stabilized ligand-centered radical. Use of a non-nucleophilic base additive promotes visible-light generation of Niᴵ from a bench-stable precatalyst and facilitates reactions with a broad range of nucleophiles. Our results show that this platform provides a highly general set of conditions for coupling challenging aryl halides with N-, O-, S-, and P-based nucleophiles at nickel loadings as low as 100 ppm. Further, this is the first NiI/NiIII catalysis method that couples sterically encumbered nucleophiles. Gram-scale synthesis of pharmaceuticals and late-stage couplings of complex molecules underscore the potential of this approach for medicinal chemistry applications.

Nature Chemical Biology, Published online: 11 November 2025; doi:10.1038/s41589-025-02061-5

Clostridium autoethanogenum produces ethanol from waste gases, but the biosynthetic pathway has been debated. Now, a combination of structural and biochemical data confirms that a key step in the ethanol biosynthesis pathway is acetate reduction by a tungsten-dependent aldehyde:ferredoxin oxido-reductase. This thermodynamically unfavorable reaction is counterbalanced by the coupling of ethanol synthesis with CO oxidation.

A nonheme iron enzyme, leucoanthocyanidin dioxygenase from Arabidopsis thaliana (AtLDOX), was repurposed to catalyze the enantioselective synthesis of a series of chiral α-amino acid derivatives via a 1,3-migratory nitrene C─H insertion process involving hydrogen atom transfer and radical rebound steps.

Abstract

Nonheme iron enzymes are among nature's most versatile catalysts for molecular functionalization. Engineering nonheme enzymes for abiological reactions unlocks new catalytic possibilities beyond the limits of natural evolution. In this work, we engineered a nonheme enzyme, leucoanthocyanidin dioxygenase from Arabidopsis thaliana (AtLDOX), to catalyze an asymmetric 1,3-migratory nitrene C(sp³)─H insertion reaction. Through directed evolution, the final optimized AtLDOX_LS variant efficiently delivers a range of chiral α-amino acids derivatives with exceptional activity and enantioselectivity (up to 81% yield, 850 total turnover number, and 98:2 enantiomeric ratio). Preliminary mechanistic studies suggest the involvement of radical intermediates for this transformation. This work advances the biocatalytic toolbox for radical involved transformations and broadens the scope of enzymatic migration chemistry.

We report a photochemical method for oxidative γ-C─H lactonization of simple carboxylic acid substrates upon LMCT photoactivation. Intriguingly, these conditions suppress the rapid decarboxylation characteristic of oxidized carboxylates, suggesting the intermediacy of metal-stabilized acyloxy radical instead of the dissociative process typically invoked in LMCT photoactivations.

Abstract

Photoinduced ligand-to-metal charge-transfer (LMCT) activation of carboxylic acids has increasingly become recognized as a versatile platform for the development of synthetically useful new reactions. When the metal species is also capable of mediating an oxidative radical coupling process, this approach has been shown to be a powerful strategy for decarboxylative coupling of carboxylate feedstocks with diverse nucleophilic reaction partners. LMCT photoreactions that could engage the acyloxy radical intermediate in other canonical reactions of heteroatom-centered radicals such as 1,5-hydrogen atom transfer (HAT) would broaden the scope of possible reactions. The rapid intrinsic rate of decarboxylation, however, presents a formidable challenge. Herein, we report the LMCT-promoted C─H lactonization of benzoic and aliphatic carboxylic acids. Mechanistic investigations suggest that under the optimized reaction conditions, the key acyloxy radical intermediate can be stabilized by the metal center, enabling 1,5-zHAT to outcompete decarboxylation.

Science historian Nathaniel Comfort reflects on the “most famous scientist of the 20th century, and the most infamous of the 21st”

A cysteine-selective bioconjugation using aromatic cyclopropenium cations is reported. The reaction proceeds rapidly under aqueous conditions, enabling site-selective installation of tetrasubstituted cyclopropene rings on peptides and proteins. The method shows preference for internal cysteines and provides conjugates that serve as efficient radical traps in thiol–ene chemistry, forming stable cyclopropane-linked products.

Abstract

In the realm of organic chemistry, carbocations play a pivotal role as highly reactive intermediates in the synthesis of complex molecules. While cyclase enzymes construct terpenoid natural products through carbocation intermediates, the use of these electrophilic reactive species for peptide and protein bioconjugation in aqueous media remains unexplored. Herein, we disclose the discovery and development of a new chemical modification of peptides and proteins with aromatic cyclopropenium cations, selective at cysteine residues. The bioconjugation is fast, operationally simple, and occurs at low concentration in aqueous media, allowing for the installation of a tetrasubstituted cyclopropene ring with excellent site selectivity. Moreover, the cyclopropenylation is preferential to internal cysteines, thus complementing current methodologies for selective terminal cysteine bioconjugation. These studies further showcased the bioconjugates' utility as radical traps in a thiol–ene process, enabling the formation of cyclopropane-linked conjugates.

Genetically encoded miniature photoenzyme miniSOG (12 kDa) enables spatiotemporally controlled bioorthogonal deboronative hydroxylation of 27 diverse organoboronates in live cells via localized superoxide radical anion O₂ ^•− generation.

Abstract

Artificial photoenzymes hold transformative potential for in vitro biocatalysis, but their translation to live-cell environments demands minimal cellular perturbation and aerobic compatibility. Here, we present miniSOG, a 12 kDa miniature photoenzyme that enables bioorthogonal deboronative hydroxylation via superoxide radical anion (O₂ ^•−) generation under blue light irradiation. Leveraging the inherent photochemistry of flavins, miniSOG facilitates the photoactivation of 27 structurally diverse organoboronates—including aryl/alkyl boronates, fluorophores, anticancer agents, and epigenetic modulators—through a unified O₂ ^•−-mediated mechanism. This system achieves spatiotemporally precise photocatalysis in live cells, where miniSOG's compact size and subcellular targeting enable organelle-specific localization and confined reactivity due to short-range O₂ ^•− diffusion (∼0.2 µm). We demonstrate its utility in light-gated cellular modulation: i) mitochondrial depolarization via localized release of 2,4-dinitrophenol (DNP) to disrupt energy metabolism, and ii) nuclear m⁶A methylation enhancement to epigenetically upregulate autophagy. By repurposing miniSOG's photochemistry for bioorthogonal deboronative hydroxylation, this work establishes a versatile, genetically encoded platform for manipulating fundamental cellular pathways with minimal off-target effects.

Nature Catalysis, Published online: 03 November 2025; doi:10.1038/s41929-025-01436-0

The creation of artificial metalloenzymes compatible with complex biological settings could enable broad applications. Now a de novo-designed artificial metalloenzyme containing an abiological ruthenium cofactor is reported and optimized for ring-closing metathesis in the cytoplasm of whole cells.

Nature Catalysis, Published online: 03 November 2025; doi:10.1038/s41929-025-01435-1

Radical repositioning to activate remote bonds is underdeveloped in synthetic biocatalysis. Now a photobiocatalytic system couples light-driven single-electron transfer and the relocation of unpaired electrons to activate remote C–C and C–H bonds for enzymatically controlled enantioselective acylation.