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C-oligosaccharides are found in natural products and drug molecules, but their synthesis is challenging. Here, the authors report a strategy for the stereoselective and efficient synthesis of Coligosaccharides via palladium-catalyzed nondirected C1–H glycosylation/C2-alkenylation, cyanation, and alkynylation of 2-iodoglycals with glycosyl chloride donors.

Unlike the more common C–H functionalization, methods for the functionalization of C–C bonds are scarce. Here, Ackermann and co-workers show that an inexpensive manganese catalyst is capable of selectively activating C–C bonds for alkylations, alkenylations, and allylations in water.

The high fraction of sp³-hybridized carbon atoms (Fsp³) in cyclobutanes makes them promising bioisosteres for arenes. Now by combining bicyclo[1.1.0]butane C–C activation with remote meta-C–H functionalization, via a ruthenacycle-mediated halogen-atom transfer process, densely decorated Fsp³-rich cyclobutanes can be formed in a single step with high chemo- and position selectivity.

Traditional methylamine synthesis from methanol and ammonia relies on high-temperature and high-pressure reaction conditions, resulting in byproducts and challenging purification. Now, electrochemical nitromethane reduction under mild conditions has been realized with a copper catalyst, enabling selective and sustainable methylamine synthesis.

The design of efficient and selective catalysts is a formidable challenge in chemical science. Here the authors design a data-driven workflow to achieve the digitalized knowledge transfer between the synthetically relevant transformations, which was demonstrated in the prediction of chiral carboxylic acid co-catalyst for the cobalt-catalyzed asymmetric C–H alkylation of indoles.

Electrochemistry has emerged as an increasingly viable tool in molecular synthesis. Here the authors realize electrocatalyzed C−H activations, with the aid of data science and artificial intelligence, towards selective alkenylations for late-stage drug diversifications.

A multitask graph neural network is developed with mechanism-informed reaction graphs for site-selectivity prediction of ruthenium-catalysed C‒H functionalization of arenes. The extrapolative prediction ability of the model is verified by experimental tests. Interpretation of the model deepens our understanding of the origins of the site selectivity.

Bioorthogonal diversification of peptides is generally dependent on impractical prefunctionalization methods. Here, the authors develop a manganese(I)-catalyzed C–H fluorescent labeling with BODIPY probes, which enables the development of activatable fluorophores to image cell function.

Whileortho-selective C-H activation is well explored, general meta-selective methods are rare and often require directing groups that are retained in the final products. Here the authors show that transient imine groups can be used to direct the meta-functionalization of a range of arenes.

The preparation of disulfides mainly relies on oxidative couplings of two sulfur-containing compounds, a strategy which has side reactions and other shortcomings. In this work, the authors present a reductive nickel-catalyzed cross-electrophile coupling of unactivated alkyl bromides with symmetrical tetrasulfides to form unsymmetrical disulfides, proceeding via trisulfide intermediates.

Controlling the selectivity of electrocatalysed C–H activation with earth-abundant base metals can increase its synthetic impact. Now chemodivergence of an electrocatalysed enantioselective C–H activation is achieved by using either ligand-bound Ni or Co in the catalytic system.

The chromone scaffold is present in drugs and bioactive natural products, but conventional approaches to access chromones require stoichiometric amounts of oxidants. Here, the authors report rhodaelectro-catalyzed assembly of chromones by electrochemical formyl C–H activations, providing the basis for late-stage peptide diversification.

Chalcogen-containing compounds find broad application in chemical industry. Here, the authors report a nickel-catalyzed reductive chalcogenation of unactivated alkyl bromides with thiosulfonates and selenosulfonates to access a range of unsymmetrical sulfides and selenides under mild conditions.

Palladium-catalyzed late-stage diversification of structurally complex peptides has major shortcomings. Here, the authors developed a ruthenium-catalyzed C–H alkylations of peptides allowing for fluorescence labeling, late-stage diversifications and peptide ligations by solid phase peptide synthesis.

Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta-C–H alkylation method facilitating the biological properties modulation of therapeutic agents.

PROTACs are uniquely powerful therapeutic agents, but their synthetic tractability significantly limit drug discovery programs. Here, the authors developed a single step synthesis of PROTAC conjugates via late stage ruthenium-catalysed C–H amidation.

A highly efficient stereoselective C−H alkylation of indoles with aryl alkenes is achieved by sustainable iron catalysis, leading to atropoenriched and enantioenriched substituted indoles with high structural diversity. Detailed mechanistic studies by experiment, Mössbauer spectroscopy and computation reveal the origin of the catalytic efficacy and stereoselectivity.

C–H activation in organic chemistry usually relies on precious and toxic transition metals. Now it is reported that a sustainable photo-promoted iron-catalysed aromatic imine C–H alkenylation reaction with alkynes circumvents previous limitations of related iron-catalysed reactions that required additives or high reaction temperatures.

Controlling the site-selectivity of C–H activation reactions is a major obstacle for the development of synthetically useful methodology. Now, meta-C–H functionalizations of arenes have been achieved by exploiting weak secondary interactions of a metal-coordinating ligand with the substrate.

Enantioselectivity prediction in asymmetric catalysis is a long-standing challenge in synthetic chemistry. Now, a data-driven workflow is designed to implement transition state knowledge in machine learning, enabling accurate enantioselectivity prediction of asymmetric pallada-electrocatalysed C–H activation reactions. Model interpretation provides insight into the effect of olefins on the enantioselectivity determination.

Despite the importance of C–H methylation in medicinal chemistry, the application to densely functionalized complex molecules remains a challenge. Now, a novel cobalt-catalysed method takes advantage of inherently present functional groups to guide the C–H activation and a boron-based methyl source enables the late stage C–H methylation of pharmaceutically relevant substrates.

Enantioselective electrocatalysis is emerging as an increasingly versatile tool in organic synthesis. Now, by applying asymmetric Lewis acid catalysis with an elaborated ligand design, radical electrochemical amination is accomplished with full selectivity control.

A method of selectively activating both allylic carbon–hydrogen bonds and carbon–carbon bonds can furnish sophisticated molecular scaffolds with all-carbon quaternary stereogenic centres that can themselves be derivatized.

This Resource combines amplicon sequencing, shotgun metagenomic sequencing and untargeted metabolomics to provide a global view of microbial–metabolite associations across Earth’s environments.

This Primer provides an overview of the best practices for C–H activation as well as key advances in asymmetric, photoinduced and electrocatalytic-mediated catalysis for this synthetic platform. An overview of how C–H activation facilitates the synthesis of molecules such as structurally complex (bio)polymers and drugs is provided along with the current challenges and priorities for the next decade.

Electrocatalysis is now being used for many oxidation reactions in organic synthesis. This protocol describes how to set up an electrolytic cell for use in cobalt-catalyzed C–H/N–H alkyne annulations and C–H oxygenations.

Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

Indolizine-2-carbaldehydes are important precursors for indolizine synthesis, however, their efficient construction remains challenging. Here, a recyclable stereoauxiliary aminocatalyzed strategy for one-pot synthesis of 1,2,3-trisubstituted indolizine-2-carbaldehydes is reported, via [3+2] annulations of acyl pyridines and α,β-unsaturated aldehydes.