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This review presents a fundamental aspect of cobalt-based photocatalysis with reference to its different working mechanisms with and without external photocatalyst, in detail. Recent advances in this field over a span of last six years have been discussed along with the strategies for such reactions and the existing challenges.

Abstract

Over the past few decades, the merger of photocatalysis and transition metal-based catalysis or self-photoexcitation of transition metals has emerged as a useful tool in organic transformations. In this context, cobalt-based systems have attracted significant attention as sustainable alternatives to the widely explored platinum group heavy metals (iridium, rhodium, ruthenium) for photocatalytic chemical transformations. This review encompasses the basic types of cobalt-based homogeneous photocatalytic systems, their working principles, and the recent developments (2018-2024) in C−X (X=C, N, O, H, Si) bond formations. Noteworthy to mention that cobalt-based heterogeneous photocatalysis is beyond the scope of the present review. An elaborate presentation on the mechanistic intricacies of cobalt-based photocatalysis, without any external photocatalyst, and cobalt-based dual organophotoredox catalysis have been provided in this comprehensive review, excluding the dual-metal photoredox catalysis. To the best of our knowledge, this is the only contemporary review encompassing the aforementioned two major types of cobalt-based photocatalysis, in general synthetic chemistry, covering all types of C−X bond formations spanning a range of the last six years.

Nature, Published online: 24 January 2025; doi:10.1038/d41586-025-00177-1

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A new-to-nature enzymatic platform for the enantioselective trifluoromethylazidation of alkenes has been successfully established. Through 11 rounds of directed evolution, an engineered variant of nonheme iron enzyme, BsQueD-CF_3, was developed, enabling the production of a wide range of enantioenriched CF₃-containing molecules. This platform based on metalloenzymes would open a new avenue for biocatalytic trifluoromethylation chemistry.

Abstract

Organofluorines, particularly those containing trifluoromethyl (CF₃) groups, play a critical role in medicinal chemistry. While trifluoromethylation of alkenes provides a powerful synthetic route to construct CF₃-containing compounds with broad structural and functional diversity, achieving enantioselective control in these reactions remains a formidable challenge. In this study, we engineered a nonheme iron enzyme, quercetin 2,3-dioxygenase from Bacillus subtilis (BsQueD), for the enantioselective trifluoromethylazidation of alkenes. Through directed evolution, the final variant BsQueD-CF₃ exhibited excellent enantioselectivity, with an enantiomeric ratio (e.r.) of up to 98 : 2. Preliminary mechanistic studies suggest the involvement of radical intermediates. This work expands biocatalytic organofluorine chemistry by reprogramming metalloenzymes for innovative trifluoromethylation reactions.

Visible light-driven pyridoxal radical biocatalysis has emerged as a new strategy for the stereoselective synthesis of valuable noncanonical amino acids in a protecting-group-free fashion. In our previously developed dehydroxylative C−C coupling using engineered PLPdependent tryptophan synthases, an enzyme-controlled unusual a-stereochemistry reversal and pH-controlled enantiopreference were observed. Herein, through high-throughput photobiocatalysis, we evolved a set of stereochemically complementary PLP radical enzymes, allowing the synthesis of both L- and D-amino acids with enhanced enantiocontrol across a broad pH window. These newly engineered L- and D-amino acid synthases permitted the use of a broad range of organoboron substrates, including boronates, trifluoroborates and boronic acids, with excellent efficiency. Mechanistic studies unveiled unexpected PLP racemase activity with our earlier PLP enzyme variants. This promiscuous racemase activity was abolished in our evolved amino acid synthases, shedding light on the origin of enhanced enantiocontrol. Further mechanistic investigations suggest a switch of proton donor to account for the stereoinvertive formation of D-amino acids, highlighting an unusual stereoinversion mechanism which is rare in conventional two-electron PLP enzymology.

Heteroaromatic alkylations are indispensable reactions for synthesizing biologically active molecules. The anti-Markovnikov hydroarylation of olefins using heteroaryl hal-ides furnishes the product as a single regioisomer, however, catalytic variants are ineffective in controlling the stereochem-ical outcome of these reactions. Here, we report a synergistic photoenzymatic hydroarylation of olefins using flavin-dependent ‘ene’-reductases with ruthenium photoredox cata-lysts. Enzyme homologs were identified, which provide access to both product enantiomers in greater than 80% yield with up to 99:1 er. This method is effective for styrenyl and unactivat-ed alkenes, highlighting the generality of this approach. Bind-ing assay study revealed strong binding of the photocatalyst with the enzyme for superior catalytic activity. Mechanistic studies suggest efficient intermolecular coupling is possible because alkene binding accelerates the consumption of the aryl halide.

Nature, Published online: 20 January 2025; doi:10.1038/d41586-025-00179-z

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Override the intrinsic preference of regioselectivity. An enantioselective nickel-catalyzed syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones is reported to access alkenyl cyclobutanols. A carbonyl-directed hydrometalation step is the key to override the intrinsic electronic effect guided regioselectivity. The products are demonstrated to readily advance to enantioenriched three-dimensional bioisosteres.

Abstract

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni−H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

The pyrrolysyl pair has dominated noncanonical amino acids (ncAAs) incorporation in eukaryotes, but additional engineerable pairs are needed to further expand this toolbox. Although E. coli leucyl-tRNA synthetase (EcLeuRS) is a promising candidate, engineering its substrate specificity has been much less successful. Here, we optimized a yeast-based directed evolution system to rapidly engineer EcLeuRS to charge diverse ncAAs in mammalian cells.

Abstract

Site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in eukaryotes has predominantly relied on the pyrrolysyl-tRNA synthetase/tRNA pair. However, access to additional easily engineered pairs is crucial for expanding the structural diversity of the ncAA toolbox in eukaryotes. The Escherichia coli-derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair presents a particularly promising alternative. This pair has been engineered to charge a small yet structurally diverse group of ncAAs in eukaryotic cells. However, expanding the substrate scope of EcLeuRS has been difficult due to the suboptimal yeast-based directed evolution platform used for its engineering. In this study, we address this limitation by optimizing the yeast-based directed evolution platform for efficient selection of ncAA-selective EcLeuRS mutants. Using the optimized selection system, we demonstrate rapid isolation of many novel EcLeuRS mutants capable of incorporating various ncAAs in mammalian cells, including ornithine and N^ϵ-acetyl-methyllysine, a recently discovered post-translational modification in mammalian cells.

Nature Communications, Published online: 11 January 2025; doi:10.1038/s41467-025-55944-5

The authors design an isothermal compressibility-assisted dynamic squeezing index perturbation (iCASE) methodology to improve enzyme stability and efficacy, which is combined with machine learning predictive models to advance enzyme optimization.

Nature, Published online: 14 January 2025; doi:10.1038/d41586-025-00037-y

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Nature, Published online: 15 January 2025; doi:10.1038/s41586-025-08611-0

Engineered enzymes for enantioselective nucleophilic aromatic substitutions

Nature Chemistry, Published online: 13 January 2025; doi:10.1038/s41557-024-01707-6

The demand for large, position-specific modified RNA molecules is high across diverse fields. Now a DNA polymerase has been engineered to enable the efficient and flexible synthesis of such molecules using a pause–restart strategy. This methodology can be implemented in both liquid and hybrid solid–liquid phases.

Cooperative catalysis with an enzyme and a small-molecule photocatalyst has very recently emerged as a potentially general activation mode to advance novel biocatalytic reactions with synthetic utility. Herein, we report cooperative photobiocatalysis involving an engineered nonheme Fe enzyme and a tailored photoredox catalyst as a unifying strategy for the catalytic enantioconvergent decarboxylative azidation, thiocyanation and isocyanation of redox-active esters via a radical mechanism. Through the survey and directed evolution of nonheme Fe enzymes, we repurposed and further evolved metapyrocatechase (MPC), a nonheme Fe extradiol dioxygenase not previously studied in new-to-nature biocatalysis, for the enantioselective C–N3, C–SCN and C–NCO bond formation through a radical rebound mechanism with an enzymatic Fe–X intermediate (X = N3, NCS, and NCO). A range of primary, secondary and tertiary alkyl radical precursors were effectively converted by our engineered MPC, allowing the syntheses of organic azides, thiocyanates and isocyanates with good to excellent enantiocontrol. Further chemical derivatization of these products furnished valuable compounds including enantioenriched amines, triazoles, ureas and SCF3-containing products. Computational studies via DFT and MD simulations shed light on the mechanism as well as the binding poses of the alkyl radical intermediate in the enzyme active site and the π-facial selectivity in the enantiodetermining radical rebound. Overall, cooperative photometallobiocatalysis with nonheme Fe enzymes provides a new platform for the development of challenging asymmetric radical transformations eluding small-molecule catalysis.

Nature Chemical Biology, Published online: 08 January 2025; doi:10.1038/s41589-024-01819-7

Artificial metalloenzymes (ArMs) often have sensitive metal centers. Here the authors enhance ArM performance by inducing liquid–liquid phase separation in Escherichia coli, creating protective compartments. This strategy boosts ArM loading, stabilizes activity and enables in vivo applications.

Nature Catalysis, Published online: 08 January 2025; doi:10.1038/s41929-024-01276-4

The efficiency of enantioselective sp3 C–H bond oxidation using small synthetic catalysts is usually limited. Now a catalytic system involving a Cu(II)-bound tert-butoxy radical for site-selective C–H bond cleavage achieves allylic and propargylic sp3 C–H oxidation with the C–H substrates as the limiting reagent.

Nature Chemical Biology, Published online: 03 January 2025; doi:10.1038/s41589-024-01783-2

An orthogonal alphaviral RNA replication system with chemically inducible control of RNA mutagenesis enables RNA-based directed evolution in mammalian cells.

Nature Synthesis, Published online: 02 January 2025; doi:10.1038/s44160-024-00698-z

Methods for the anti-Markovnikov-selective hydrochlorination of unsaturated C–C bonds are limited by the need for stoichiometric reagents, highly oxidizing photocatalysts and multiple synthetic steps. Now the combination of ligand-to-metal charge transfer and hydrogen atom transfer reactivity enables the anti-Markovnikov-selective hydro- and deuterochlorination of unsaturated hydrocarbons using iron photocatalysis.

Nature Chemistry, Published online: 03 January 2025; doi:10.1038/s41557-024-01695-7

Amino alcohols are essential in pharmaceuticals, agrochemicals and other applications. Now, using a serine-derived chiral carboxylic acid, an electrocatalytic decarboxylative transformation enables efficient and stereoselective access to diverse amino alcohols. This method is scalable, modular and could offer rapid synthesis of medicinal compounds and key building blocks.

Nature Chemistry, Published online: 07 January 2025; doi:10.1038/s41557-024-01701-y

Paulina Krzyszowska and Ewa Pacholska-Dudziak recap the history of porphyrins, their biological relevance, and discuss examples of their use in modern applications.

Sequential incorporation of an organic photocatalytic cofactor and a metal cofactor into streptavidin leads to artificial metalloenzymes (ArMs) that catalyze tandem abiotic transformations such as enantioselective formal C−H hydroxylation and photooxidation-Michael addition. This work introduces a programmable approach for the construction of ArMs that can catalyze tandem abiotic reactions.

Abstract

Artificial metalloenzymes (ArMs) enable the integration of abiotic cofactors within a native protein scaffold, allowing for non-natural catalytic activities. Previous ArMs, however, have primarily relied on single cofactor systems, limiting them to only one catalytic function. Here we present an approach to construct ArMs embedding two catalytic cofactors based on the biotin-streptavidin technology. By incorporating multiple catalytic cofactors into the four binding sites of streptavidin, we engineered programmable ArMs for tandem abiotic transformations including an enantioselective formal C−H hydroxylation and a photooxidation-Michael addition. This work thus outlines a promising strategy for the development of ArMs embedding multiple cofactors.

Nature Chemistry, Published online: 03 January 2025; doi:10.1038/s41557-024-01692-w

Alkyl amines are found in a wide array of bioactive compounds, making strategies for their synthesis very important. Now, a method has been developed to synthesize tertiary alkyl amines via photoinduced, copper-catalysed nucleophilic substitution of unactivated alkyl halides by secondary alkyl amines, with key copper intermediates elucidated in a detailed mechanistic study.