Methyl groups are ubiquitous in natural products and biologically active compounds, but methods for their selective transformation in such structures are limited. For example, terpenoids contain many ...

Photothermal conversion can promote plastic depolymerization (chemical recycling to a monomer) through light-to-heat conversion. The highly localized temperature gradient near the photothermal agent s...

Continuous-flow photochemistry allows late-stage functionalization of N-heteroaromatics with gaseous alkane.

The increasing structural complexity of heterocycles in pharmaceuticals, agrochemicals, and functional materials continues to challenge synthetic design, particularly when step economy, scalability, a...

The structural prominence of indole-based sulfur-containing compounds in pharmacologically relevant substances stems from their versatile biofunctional capabilities. Despite their significance, the st...

The synthesis of the hindered and polyfluorinated dialkyl ethers poses challenges owing to the bulkiness of tertiary alcohols and the low nucleophilicity of polyfluorinated alcohols. Additionally, associated competitive side reactions always provide poor reactivities. Although certain strategies, such as electrocatalytic decarboxylation and hydroalkoxylation, have been explored, a straightforward method for obtaining ethers with structural diversity remains elusive. In this study, we have exploited the photoinduced approach that involves the in situ formation of singlet carbenes followed by O–H insertions to access the hindered and polyfluorinated ethers with congested or polyfluorinated alcohols. Moreover, other nucleophiles such as phenols, H2O, thiols, silanols, tributyltin hydride, etc., are also tolerable to obtain valuable products. The gram-scale synthesis of marketed drugs and the modification of complex molecules demonstrate the practicality of this approach. The detailed mechanistic studies have elucidated the key intermediates and reaction mechanism, which were distinct from traditional metal-carbenoid O–H insertions.

Lipid membranes are central to cellular life. Complementing experiments, computational modeling has been essential in unraveling complex lipid-biomolecule interactions, crucial in both academia and industry. The Martini model, a coarse-grained force field for efficient molecular dynamics simulations, is widely used to study membrane phenomena but has faced limitations, particularly in capturing realistic lipid phase behavior. Here, we present refined Martini 3 lipid models with a mapping scheme that distinguishes lipid tails that differ by just two carbon atoms, enhancing the structural resolution and thermodynamic accuracy of model membrane systems including ternary mixtures. The expanded Martini lipid library includes thousands of models, enabling simulations of complex and biologically relevant systems. These advancements establish Martini as a robust platform for lipid-based simulations across diverse fields.

This In Focus article illustrates how curiosity-driven fundamental research in nuclear magnetic resonance (NMR) gave rise to transformative technologies, including modern spectroscopy and magnetic resonance imaging. By tracing this pathway from basic discoveries to broad societal and economic impact, the article serves as a resource emphasizing the essential role of sustained investment in fundamental scientific research.

Multicomponent reactions are powerful tools for expanding the chemical space in drug discovery, yet achieving selectivity remains a formidable challenge. Here, we introduce a multicatalytic strategy t...

The convergence of generative artificial intelligence (AI) platforms and automated laboratory systems is ushering in a new era of drug discovery, in which a plain-language prompt can initiate a fully ...

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and protein misfolding, yet the structural dynamics of proteins and their post-translational modifications during disease pro...

Direct manipulation of C–H bonds enclosed in complex scaffolds persists today as an elusive disconnection when aiming for high and predictable site-selectivity. Its development toward the late-stage d...

N-oxyl species are promising hydrogen atom transfer (HAT) catalysts to advance C–H bond activation reactions. However, because of the complex structure–activity relationship within the N-oxyl structure, catalyst optimization is a key challenge, particularly for simultaneous improvement across multiple parameters. This paper describes a data-driven approach to optimize N-oxyl hydrogen atom transfer catalysts. A focused library of 50 N-hydroxy compounds was synthesized and characterized by three parameters─oxidation peak potential, HAT reactivity, and stability─to generate a database. Statistical modeling of these activities described by their intrinsic physical organic parameters was used to build predictive models for catalyst discovery and to understand their structure–activity relationships. Virtual screening of 102 synthesizable candidates allowed for rapid identification of several ideal catalyst candidates. These statistical models clearly suggest that N-oxyl substructures bearing an adjacent heteroatom are more optimal HAT catalysts compared to the historical focus, phthalimide-N-oxyl, by striking the best balance among all three target experimental properties.

Mutanofactins are a family of natural products produced by Streptococcus mutans from the human oral microbiome. We report a unified approach to all mutanofactins by developing a total synthesis amenable to diversification. The key to success for the most complex members, mutanofactins 607 and 697, was an acyl ketene based strategy. Access to the family enabled comprehensive biological profiling, where we demonstrate that all mutanofactins are biofilm promoting in Streptococcus mutans. Experiments were extended to other inhabitants of the oral microbiome for the first time: Streptococcus gordonii and Streptococcus oralis, two early colonizers, were similarly affected with mutanofactins being biofilm promoting. Conversely, Veillonella dispar and Fusobacterium nucleatum showed little to no reaction to mutanofactins. Biophysical investigations based on quartz crystal microbalance with dissipation monitoring and atomic force microscopy reveal a previously unknown mucin–mutanofactin 697 interaction. Incubation of a mucin layer with mutanofactin 697 induces a morphology change within the mucin layer, which promotes bacterial adhesion and biofilm formation. This unique property of mutanofactin 697 might be key to early stages of biofilm formation in the human oral microbiome. Combined, an interdisciplinary approach consisting of total synthesis, microbiology and biophysical characterization provides insight into the roles of mutanofactins in the oral microbiome.

Asymmetric catalysis is the most sustainable means of achieving efficient production of enantioenriched compounds, which are valuable to the pharmaceutical industry and advanced functionalized materials. The field has undergone considerable development since its inception about 60 years ago. The development of new chiral ligands or organocatalysts or the discovery of new reactions all led to spectacular progress in terms of activity and enantioselectivity. In this context, this Outlook article aims to highlight major advances that demonstrate the central role of asymmetric catalysis in sustainability, with the examples discussed representing a selection shaped by the authors’ scientific perspective and sensitivity. This includes recent innovations in catalyst recycling, the use of less precious and less toxic metals in asymmetric organometallic catalysis, as well as the control of the positioning of catalytic sites, to further improve their efficiency. The development of asymmetric electrocatalysis and photocatalysis as well as of mechanochemistry and continuous flow chemistry is also discussed. Finally, the complexity and step-economy issues are raised with the presentation of relevant examples of asymmetric multicatalytic processes and new challenging transformations that include late-stage functionalization reactions, molecular edition or reactions targeting the creation of axial, planar or helicoidal chirality.

The guaianolide family of sesquiterpene lactones is known for its distinctive structural features and diverse biological activities. 4,9,10-Trihydroxyguaia-11(13)en-12,6-olide, with an underdetermined absolute stereochemistry (1 or ent-1), is a newly identified 6,12-guaianolide isolated from the genus Anvillea garcinii. Motivated by the potential biological activity of the natural product, we pursue its stereoselective synthesis. Starting from (R)-limonene, an asymmetric total synthesis of 4α,9α,10α-trihydroxyguaia-11(13)en-12,6α-olide (1) is accomplished in 20 steps with an overall yield of 4%, utilizing key transformations such as stereoselective reductive epoxide opening and additions of methyl lithiopropiolate and allyl cuprate. Most significantly, preliminary biological testing uncovers new anticancer activity of 1 against rare and aggressive childhood atypical teratoid rhabdoid tumor (ATRT) and other cancer cell lines. We anticipate that our synthetic strategy will enable the development of chemical probes and derivatives derived from 1 for mechanism of action studies and anticancer drug discovery.

The formylglycine-generating enzyme (FGE) catalyzes the selective oxidation of a peptidyl-cysteine to form formylglycine, a critical cotranslational modification for type I sulfatase activation and a useful bioconjugation handle. Previous studies have shown that the substrate peptidyl-cysteine binds to the linear bis-thiolate Cu(I) site of FGE to form a trigonal planar tris-thiolate Cu(I) structure that activates O2 for the oxidation of the Cβ–H of the cysteine substrate via an unknown mechanism. Here, we employed a combination of stopped-flow kinetic, spectroscopic (UV–vis absorption, XAS, and EPR), and computational (DFT/TD-DFT calculations) methods to observe and characterize the key intermediates in this reaction for FGE from Streptomyces coelicolor. Our results define the reaction coordinate of FGE, which involves H-atom abstraction from the Cβ–H bond of the cysteine substrate by a reactive Cu(II)–O2•– species to form the now experimentally observed Cu(I)–OOH intermediate bound to a peptidyl-thioaldehyde, which proceeds to oxidize one of the protein-derived cysteine residues to a sulfenate that is end-on O-coordinated to Cu(I). These results provide fundamental insights into how the unusual mononuclear Cu(I) site of FGE activates O2 for cysteine oxidation and stores oxidizing equivalents during catalysis by employing a Cu(I)–sulfenate intermediate with an end-on O-coordination that is unprecedented in biology.

The structural prevalence of chiral N-bridged cyclic scaffolds in pharmacologically relevant substances originates from their multifaceted biofunctional capacities, particularly in privileged natural product architectures. Despite advances in central chirality, the precise and expeditious construction of axially chiral N-bridged cyclic scaffolds with impeccably full enantiocontrol and highly structural diversity remains largely underexploited due to the lack of efficient synthetic methods. Here, we disclose an unprecedented Rh(I)/diene-catalyzed carbene coupling reaction of arylboronic acid with β-hydroxy α-diazocarbonyl compounds through a remotely controlled desymmetrization strategy, furnishing a diverse array of three-dimensional nonatropisomeric axially chiral alkylidene N-bridged [3.2.1] and [3.3.1] ring systems. This straightforward methodology operates without redox requirements, demonstrating extensive applicability across diverse substrates (>50 examples) while maintaining exceptional control of chemo- and enantioselectivity (up to 97% yield, mostly 95–99% ee). The synthetic utility of these compounds was further validated via sequential elaboration processes, allowing for modular assembly of novel N-bridged bicyclic systems with configurationally defined axial chirality.