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Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals 1 , 2 . The introduction of amines onto functionalized aromatics at specific and pre-determined positions ( ortho versus meta versus para ) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates 3 – 6 . The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C–H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists 7 , enables a predetermined and site-selective carbon–nitrogen (C–N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C–N coupling protocol by preparing commercial medicines and by the late-stage amination–aromatization of natural products, steroids and terpene feedstocks. A dual cobalt and photocatalysis system provides a way to assemble anilines from cyclohexanones and amines by progressively dehydrating the intermediate imine.

In the chemical industry, it is often necessary to activate carbon–carbon bonds in order to synthesize complex organic molecules, but this is challenging when starting with simple five- or six-membered carbon rings; a new method uses a rhodium pre-catalyst and an amino-pyridine co-catalyst, enabling an overall energetically favourable reaction that involves activation of carbon–carbon bonds plus activation of carbon–hydrogen bonds. Access to tetralones Most molecules of interest to organic chemists are primarily made up of carbon skeletons, so carbon–carbon bond activation is of prime importance in making and modifying such molecules. Transition-metal-mediated carbon–carbon bond activation of cyclic carbon species is a versatile approach, but challenging for five- and six-membered rings because the lack of ring strain provides an insufficient driving force for the reaction. Now, Guangbin Dong and co-workers demonstrate a rhodium-catalysed activation of phenyl-functionalized unstrained cyclopentanones, giving rapid access to tetralones. In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon–carbon single bonds (C–C bonds) in simple substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . The challenge in achieving such activation is the kinetic inertness of C–C bonds and the relative weakness of newly formed carbon–metal bonds 6 , 14 . The most common tactic starts with a three- or four-membered carbon-ring system 9 , 10 , 11 , 12 , 13 , in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C–C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C–C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N -heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C–C bond can be activated; this is followed by activation of a carbon–hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones—a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.

Aromatic molecules are key constituents of many pharmaceuticals, electronic materials, and commodity plastics. The utility of these molecules directly reflects the identity and pattern of substituents on the aromatic ring. Here, we report a palladium(II) catalyst system, incorporating an unconventional ortho-dimethylaminopyridine ligand, for the conversion of substituted cyclohexanones to the corresponding phenols. The reaction proceeds via successive dehydrogenation of two saturated carbon-carbon bonds of the six-membered ring and uses molecular oxygen as the hydrogen acceptor. This reactivity demonstrates a versatile and efficient strategy for the synthesis of substituted aromatic molecules with fundamentally different selectivity constraints from the numerous known synthetic methods that rely on substitution of a preexisting aromatic ring.

Biological production of chemicals often requires the use of cellular cofactors, such as nicotinamide adenine dinucleotide phosphate (NADP + ). These cofactors are expensive to use in vitro and difficult to control in vivo. We demonstrate the development of a noncanonical redox cofactor system based on nicotinamide mononucleotide (NMN + ). The key enzyme in the system is a computationally designed glucose dehydrogenase with a 10 7 -fold cofactor specificity switch toward NMN + over NADP + based on apparent enzymatic activity. We demonstrate that this system can be used to support diverse redox chemistries in vitro with high total turnover number (~39,000), to channel reducing power in Escherichia coli whole cells specifically from glucose to a pharmaceutical intermediate, levodione, and to sustain the high metabolic flux required for the central carbon metabolism to support growth. Overall, this work demonstrates efficient use of a noncanonical cofactor in biocatalysis and metabolic pathway design. Redesign of a glucose dehydrogenase to use nicotinamide mononucleotide (NMN + ) instead of NAD(P) + enables the development of a noncanonical cofactor system that can be used to support redox chemistries both in vitro and in Escherichia coli .

Curcumin, a pharmacological agent found in turmeric’s rhizome, has been studied for its various therapeutic properties. However, its clinical development is hindered by its instability and low solubility in water, resulting in inadequate oral bioavailability. Two potential curcumin analogs, 2,5-bis(4’-hydroxy-3’,5’-dimethoxybenylidene)cyclopentanone (PGV-5) and 2,6-bis(4’-hydroxy-3’,5’-dimethoxybenylidene)cyclohexanone (HGV-5), are being developed to address this issue and enhance their therapeutic efficacy. The study aims to screen novel curcumin analog compounds by integrating in silico assessment of ADME properties, acute toxicity studies, and computational analysis. PGV-5 and HGV-5 are classified as Global Harmonized System of Classification and Labeling of Chemicals (GHS) class 4 and class 5, respectively, in acute toxicity assessment, as they cause histopathological changes in the heart and lungs. Their ADME profile indicates they serve as effective P-glycoprotein (P-gp) inhibitors, making them potential candidates for development as anti-multidrug resistance agents, particularly in cancer cells. Molecular docking on P-gp revealed significant inhibitory capability relative to curcumin, exhibiting comparable binding characteristics to the native ligand, as evidenced by superior docking scores. Subsequent molecular dynamics simulations confirmed the stable interaction of both compounds with P-gp, with HGV-5 showing the most favorable binding free energy. Target gene mapping revealed several pivotal targets including AKT1, STAT3, EGFR, and NF-κB1. These findings suggest that PGV-5 and HGV-5 merit further research as agents against multidrug-resistant in cancer, regardless of their toxicity profiles. Further confirmation of their effects requires more laboratory studies and clinical trials.

Cremeomycin is a diazo-containing natural product. Assignment of the functions of individual enzymes in the gene cluster for cremeomycin biosynthesis reveals a pathway by which Streptomyces cremeus converts L -aspartic acid into the nitrous acid needed for diazotization chemistry. Although some diazo compounds have bioactivities of medicinal interest, little is known about diazo group formation in nature. Here we describe an unprecedented nitrous acid biosynthetic pathway responsible for the formation of a diazo group in the biosynthesis of the ortho -diazoquinone secondary metabolite cremeomycin in Streptomyces cremeus. This finding provides important insights into the biosynthetic pathways not only for diazo compounds but also for other naturally occurring compounds containing nitrogen-nitrogen bonds.

The C-C σ-bond activation of unstrained cycloketones represents an ingenious and advanced technique in synthetic chemistry, but it remains a challenging area which has been largely underexplored. Herein we report an efficient strategy for the direct C-C cleavage of cyclohexanones and cyclopentanones. The cyclic C-C σ-bond is readily cleaved under mild conditions with the aid of an in situ formed side-chain aryl radical. Density functional theory calculations are carried out to shed light on the unusual regioselectivity of C-C bond cleavage. The reaction affords a variety of structurally diverse 3-coumaranones and indanones that widely exist in natural products and bioactive molecules, illustrating the synthetic value of this method. C-C bond scission of unstrained cycloketones with high regioselectivity is a challenging synthetic task. Here, the authors show a facile C-C cleavage of cyclohexanones and cyclopentanones with unusual selectivity under mild conditions with the aid of an in situ formed side-chain aryl radical.

Certain photosynthetic marine organisms have evolved mechanisms to counteract UV-radiation by synthesizing UV-absorbing compounds, such as mycosporine-like amino acids (MAAs). In this study, MAAs were separated from the extracts of marine green alga Chlamydomonas hedleyi using HPLC and were identified as porphyra-334, shinorine, and mycosporine-glycine (mycosporine-Gly), based on their retention times and maximum absorption wavelengths. Furthermore, their structures were confirmed by triple quadrupole MS/MS. Their roles as UV-absorbing compounds were investigated in the human fibroblast cell line HaCaT by analyzing the expression levels of genes associated with antioxidant activity, inflammation, and skin aging in response to UV irradiation. The mycosporine-Gly extract, but not the other MAAs, had strong antioxidant activity in the 2,2-diphenyl-1-picryhydrazyl (DPPH) assay. Furthermore, treatment with mycosporine-Gly resulted in a significant decrease in COX-2 mRNA levels, which are typically increased in response to inflammation in the skin, in a concentration-dependent manner. Additionally, in the presence of MAAs, the UV-suppressed genes, procollagen C proteinase enhancer (PCOLCE) and elastin, which are related to skin aging, had increased expression levels equal to those in UV-mock treated cells. Interestingly, the increased expression of involucrin after UV exposure was suppressed by treatment with the MAAs mycosporine-Gly and shinorine, but not porphyra-334. This is the first report investigating the biological activities of microalgae-derived MAAs in human cells.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27; HPPD) is one of the important target enzymes in the development of herbicides. To discover novel HPPD inhibitors with unique molecular, 39 cyclohexanedione derivations containing pyrazole and pyridine groups were designed and synthesized. The preliminary herbicidal activity test results showed that some compounds had obvious inhibitory effects on monocotyledon and dicotyledonous weeds. The herbicidal spectrums of the highly active compounds were further determined, and the compound G31 exhibited the best inhibitory rate over 90% against Plantago depressa Willd and Capsella bursa-pastoris at the dosages of 75.0 and 37.5 g ai/ha, which is comparable to the control herbicide mesotrione. Moreover, compound G31 showed excellent crop safety, with less than or equal to 10% injury rates to corn, sorghum, soybean and cotton at a dosage of 225 g ai/ha. Molecular docking and molecular dynamics simulation analysis revealed that the compound G31 could stably bind to Arabidopsis thaliana HPPD (A t HPPD). This study indicated that the compound G31 could be used as a lead molecular structure for the development of novel HPPD inhibitors, which provided an idea for the design of new herbicides with unique molecular scaffold. Graphical abstract

Targeting drug-resistant Acinetobacter baumannii , two fungal strains, Epicoccum sp. 1-042 and Penicillium sp. 19-115, were identified from 35 fungi isolated from Tibet. Bioassay-guided isolation from Epicoccum sp. 1-042 yielded a novel cyclohexenone, epiconone ( 1 ), and parasitenone ( 2 ), while patulin ( 3 ) was isolated from Penicillium sp. 19-115. Structural elucidation was accomplished through comprehensive spectroscopic analysis and quantum chemistry calculations. The biosynthetic pathways of compounds 1 and 2 were proposed based on bioinformatics analysis. Compounds 1  −  3 exhibited antibacterial activity against carbapenem-resistant Acinetobacter baumannii (CRAB) with MIC values ranging from 4 to 128  μ g mL -1 .