Catalytic C–C Construction

Stereospecific Alkyl–Alkyl Cross-Coupling of Boronic Esters

X. Zhang, K. T. Palka, M. Zhang & J. P. Morken*

Nature 2026 (DOI: 10.1038/s41586-026-10261-9)

Enantiomerically enriched boronic esters have emerged as versatile building blocks for modular synthesis. However, their use in the catalytic construction of C–C bonds, particularly at stereogenic carbon centers, remains a significant challenge. Here, the authors report a stereospecific C–C coupling catalyzed by a copper acetylide complex. The reaction proceeds via four-coordinate boron “ate” complexes while remaining inert to common functional groups, including boronic esters, enabling efficient modular assembly of complex molecules. Applications to the synthesis of (–)-spongidepsin and the carbon skeleton of fluvirucinine A1 are demonstrated.

Formal Diels–Alder Reaction of Saturated Carboxylic Acids via C–H Activation

Q. He,^† Y. Lu,^† T. Sheng, N. Chekshin, J.-L. Yan, T. Zhang & J.-Q. Yu*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02077-x) 🔓

The authors report a catalytic system that enables abundant cyclic carboxylic acids to couple with dienophiles in a formal Diels–Alder manner with excellent regioselectivity, forging bridged bicyclic scaffolds. Dienes are generated in situ and rapidly intercepted with a variety of dienophiles, furnishing the bridged bicyclic motifs with exclusive endo-selectivity. Notably, β-, γ- and δ-methylene C–H bonds are functionalized with exclusive regioselectivity controlled by one catalyst.

Divergent Housane Synthesis via Intramolecular [2+2] Cycloaddition of 1,4-Dienes

F. Zhang, J. Domack, N. Hölter, C. G. Daniliuc & F. Glorius*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-00997-7)

The authors disclose a substrate-dependent, divergent strategy to access a broad family of housanes through an intramolecular energy transfer-mediated [2+2] cycloaddition of 1,4-dienes. This method rapidly builds up strain while suppressing the di-π-methane rearrangement, thereby expanding the toolkit for efficient exploration of housane chemical space. Substituent engineering enables switching between single and double energy transfer pathways to deliver 1,3- and 1,2-disubstituted housanes with excellent stereocontrol and broad functional-group tolerance.

Photocatalytic Direct Deoxytrifluoromethoxylation of Phenols

J. Zhou, J.-Y. Li, C. Su, Y.-X. Luan,* Q. Huang* & P. Tang*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c00511)

The authors developed a photoredox strategy to achieve the deoxytrifluoromethoxylation of phenols. This approach leverages the propensity of the OCF₃ anion to decompose into difluorophosgene, which subsequently reacts in situ with phenol to form an aryl carbonofluoridate, thereby reducing the bond energy of the C–O bond. The use of organic photoredox catalysts enables the operation of this method under mild conditions, with simple procedures and broad applicability to various phenolic substrates, and exhibits excellent selectivity among multiple C–O bonds.

Mechanism-Inspired Ligand Design for Efficient Copper-Catalyzed C–N Coupling of Aryl and Heteroaryl Chlorides

W. Zhao,^† W. M. Amberg,^† G. Rao, Y. Xie, C. N. Pierson, S. M. Fantasia, S. M. Rummelt, K. Püntener, R. D. Britt & J. F. Hartwig*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c20640) 🔓

The authors report a catalytic system designed to destabilize bis-ligated copper(II) oxalamide complexes, the predominant species in aryl bromide couplings mediated by oxalamide-supported catalysts. A sterically hindered oxalamide ligand combined with Cu(I) or Cu(II) enables the coupling of aryl and heteroaryl chlorides with primary amines and aqueous ammonia under mild conditions at low catalyst loadings (0.03–1 mol %), achieving turnover numbers of up to 2300.

Potassium Bisulfite’s Role in Developing a Robust Platform for Enantioenriched N-Alkylpyridinium Salts as Piperidine Precursors

J. D. Selingo, J. R. King, B. Pio, A. J. Neel, Y.-H. Lam, R. S. Paton, M. L. Maddess* & A. McNally*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c20464) 🔓

The authors report a platform for the synthesis of enantioenriched N-(α-chiral)alkylpyridinium salts from commercially available pyridines and enantiopure primary amines. These salts serve as versatile precursors to stereoenriched N-(α-chiral)alkylpiperidines via established reduction protocols. Potassium metabisulfite was identified as a reaction additive that enhances pyridinium formation and high-throughput experimentation demonstrated broad scope across both coupling partners.

Total Synthesis of iso-Gladiolin Methyl Ester (Lagriene Methyl Ester) via Catalytic Asymmetric C–C Coupling of Alcohols

K. L. Verboom,^† Y. Cho,^† J. A. Duncan, Y. Zhang, L. M. Alkhalaf, G. L. Challis* & M. J. Krische*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c22672)

Gladiolin, a specialized metabolite of Burkholderia gladioli, is an antitubercular 22-membered macrolide that inhibits RNA polymerase at a site distinct from rifampicin, rendering it active against drug-resistant strains of Mtb. Lagriene, a 24-membered macrolide isolated from an alternate strain of B. gladioli, is the ring-expanded isomer of gladiolin, termed iso-gladiolin. Gladiolin readily isomerizes to iso-gladiolin, suggesting that its biological activity may arise from the ring-expanded form. Here, the authors report the total synthesis of iso-gladiolin methyl ester via gladiolin methyl ester in 16 steps (LLS) using a quadruply convergent strategy, with each fragment assembled through catalytic asymmetric alcohol-mediated C–C coupling.

Ligand Design Enables Introduction of Nonaromatic Arylating Agents in Palladium-Catalyzed C–H Arylation of Arenes

Y. Bairagi, S. Moni, S. Mukherjee, S. Maji, A. Raul, C. Teja, R. De, B. Mondal* & D. Maiti*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c13471)

Conventional palladium-catalyzed methods for biaryl construction often rely on costly and unstable arylating agents that require prefunctionalized substrates. The authors report an alternative strategy that employs cyclic allyl alcohols and 1,4-epoxy naphthalenes as arylating agents for direct C–H arylation. Rational ligand design enhances catalytic efficiency and regioselectivity, providing a sustainable and atom-economical approach to late-stage functionalization.

9-Bismatriptycene (BisTrip) Enables Single-Aryl Transfer for Regiospecific α-Arylation of Carbonyl Compounds

L. Li,* F. Carpaneto, P.-P. Chen, K. N. Houk & V. H. Rawal*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000175/v1) 🔓

The authors report that 9-bismatriptycene (BisTrip), a rigid shackled form of triphenylbismuth, functions as a universal aryl group transporter, enabling controlled and regiospecific α-arylation across a wide range of ketones. BisTrip can be readily loaded with aryl groups from simple arylboronic acids in a one-pot procedure to give Aryl-BisTrip and is recovered in quantitative yield after aryl transfer to the carbonyl substrate. Significantly, the arylation of basic enolates proceeds at “warp speed”, reaching completion within seconds even at –78 °C, delivering record selectivity in a memory-of-chirality experiment.

Base-Free C–N Cross-Electrophile Coupling via a Nitrogen-First Mechanism

S. Samanta, L. Patel, D. Manna, M. Ojeda & D. C. Powers*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000151/v1) 🔓

The authors report a nickel-catalyzed C–N cross-electrophile coupling (XEC) that combines carbon and nitrogen electrophiles. This mild protocol exhibits broad functional group tolerance including base-sensitive substrates and is compatible with late-stage applications. The necessary nitrogen electrophiles can be accessed from diverse starting materials, including C-H bonds and olefins. Strategic implementation of C–N XEC enables synthesis of designer amines, unsymmetrical diamines, and native amine functionalization through a two-step, one-pot N-phenothiazination, C–N XEC sequence.

Deprotonative Single Electron Oxidation as a General and Controllably Selective Platform for Benzylic C–H Functionalization

N. J. Coradi & J. S. Bandar*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000228/v1) 🔓

The authors report a new strategy for benzylic radical generation via sequential deprotonation and single-electron oxidation. Using HMDS bases, low concentrations of benzylic carbanions are generated, oxidized, and trapped with TEMPO. Transient carbanion formation promotes selective radical coupling over dimerization, enhancing functional group tolerance and site-selectivity. The method is effective for alkylarenes with high oxidation potentials and tolerates weak C–H bonds and oxidatively sensitive functional groups. The method enables TEMPO installation on densely functionalized molecules, including pharmaceutical and N-heteroaryl substrates. Site-selectivity can be tuned by adjusting base strength, allowing selective functionalization of different benzylic positions.

C5-Halogenation of Pyridines via Zincke Iminium Intermediates

K. L. Dowell, K. R. Steenback, J. N. Levy & A. McNally*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000142/v1) 🔓

The authors report a ring-opening, halogenation, and ring-closing sequence that enables C5-selective iodination and bromination of pyridines. The method employs Zincke iminium salts that undergo C5-selective halogenation with N-halosuccinimides, reversing the C3 selectivity observed with NTf-Zincke imines. The reaction proceeds without C3 blocking groups, tolerates diverse functional groups, and is compatible with complex pyridine-containing structures.

Nucleophilic Regioselective meta-Halogenation and -Sulfuration of Pyridine N-Oxides

T. Wang, C. Li, C. Jiang, N. Jiao & S. Song*

Chem 2026, Online Now (DOI: 10.1016/j.chempr.2025.102887)

The authors report a nucleophilic strategy for the regioselective meta-halogenation of pyridine N-oxides with the use of imidoyl halides, which function in both deoxygenation and halogenation processes. This strategy realizes C5-selective chlorination and bromination via steric hindrance effects and can be extended to the meta-sulfuration of pyridines with the use of common thiols.

Timing Alzheimer’s

🧠 Timing Alzheimer’s. A single blood test measuring an abnormal form of the protein tau could function as a molecular “clock” for Alzheimer’s disease, predicting not just who will develop the disease, but when.

In a study published in Nature Medicine, researchers used phosphorylated tau at position 217 (p-tau217)—an abnormal tau species that accumulates years before symptoms appear—as a biomarker of disease progression. By analysing blood samples collected over time from more than 600 cognitively unimpaired older adults, the team could determine the percentage of p-tau217 relative to total tau (%p-tau217). The ratio increased in a broadly consistent manner prior to symptom onset and by modelling the age at which an individual became “p-tau217 positive”, the researchers could estimate the onset of Alzheimer’s symptoms within approximately three to four years.

With anti-amyloid therapies such as lecanemab and donanemab now being evaluated in pre-symptomatic populations, a scalable, minimally invasive blood-based biomarker would enable more precise patient stratification in early-stage trials.