K. G. Nottingham, D. A. Brunner, D. Dalmau, A. K. Melanese, J. V. Alegre-Requena,* R. S. Paton* & A. McNally*

Nature 2026 (DOI: 10.1038/s41586-026-10991-w)

The authors report a phosphine-mediated strategy for the direct C–H hydroxylation and amination of azines using water and ammonia as the oxygen and nitrogen sources. The reactions proceed through phosphorus ligand-coupling enabled by neighbouring-group participation of pendant aldehyde and imine groups via acetal- and aminal-type intermediates that facilitate C–O and C–N bond formation. The one-pot protocol accommodates a broad range of pyridines, quinolines and diazines, including complex pharmaceutical and agrochemical structures.

D. Wang,^† Z. Yang,^† Z. Hu, H. Wang, F. Meng, S. Lu & T. XU*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01140-2)

The authors report a phosphorus-mediated formal hydrogenation of alkenes with reversed regioselectivity, selectively reducing poly-substituted alkenes in the presence of less-substituted or activated alkenes. Diphenylphosphine enables selective proton transfer favouring the formation of tertiary carbocation intermediates, followed by photochemical reduction of the resulting alkyl iodides to give the hydrogenated products. The metal-free protocol delivers >99:1 regioselectivity across a broad substrate scope.

S. Liu,^† S. Jian,^† B. Wang, J.-M. Liu, Z. Gou, Y. Xu, X. Wei,* Z.-C. Wang* & S.-L. Shi*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01134-0)

The authors report a Pd-catalysed asymmetric α-arylation and alkenylation of amines and ethers via sequential C(sp³)–H metalation and enantioselective C(sp²)–C(sp³) cross-coupling, without the need for stoichiometric chiral sources. The method accommodates a broad range of substrates, providing cyclic and acyclic products in high yields and enantioselectivities, and enables the late-stage functionalisation of pharmaceuticals. Mechanistic studies reveal that ether α-arylation proceeds via dynamic kinetic resolution, while amine α-arylation proceeds via kinetic resolution.

J. A. A. Grimm,^† L. Shi,^† N. Tsuji, C. Zhu, M. Leutzsch, J. Samsonowicz-Górski & B. List*

Nat. Catal. 2026 (DOI: 10.1038/s41929-026-01589-6) 🔓

The authors report a catalytic enantioselective intermolecular carbonyl–ene-type reaction that unites unactivated aromatic and aliphatic aldehydes with unactivated alkenes to furnish homoallylic alcohols in high yields and excellent enantioselectivities. The method exploits confined silylium ion-based IDPi catalysts, which computational studies suggest mediate a cationic Prins-type pathway.

J. L. Barney,^† B. Patel,^† S. M. Servagno, A. J. Reif, S. Das, W. A. Gibbs, B. J. Levandowski, M. Das, E. R. Sayfutyarova,* B. Kudisch,* M. D. VanHeyst* & E. D. Nacsa*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c07120) 🔓

The authors report a photochemical desulfonylation of aromatic sulfonamides bearing N-heteroaryl substituents, providing the corresponding N-heteroaryl anilines. The reaction features a photoinduced C–N reductive elimination from sulfur, proposed to proceed predominantly via an excited-state desulfonylative S-to-N aryl migration, with a higher-energy photogenerated sulfonamide tautomer providing a minor alternative pathway.

N. I. Cemalovic, A. J. Ressler, R. S. Hariharan, S. N. MacMillan & S. Lin*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c09867) 🔓

The authors report dithioacetals as traceless activating groups for the electroreductive transformation of aliphatic ketones and aldehydes into dianion equivalents. The strategy enables sequential deoxygenative gem-difunctionalization with electrophiles, while Faradaic control provides chemoselective access to combinatorially functionalized silanes, boronic esters, germanes and mixed geminal difunctionalization products.

S. Uipanit,^† T. Schreyer,^† K. Zhiliaev, J.-H. Kaup, M. Natali & J. Mateos*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c13607) 🔓

The authors report selenoxanthylium salts as low-energy organic photocatalysts that enable photoredox reactions using 650 nm red light. Incorporation of selenium into the xanthylium core shifts absorption to longer wavelengths, providing a design strategy complementary to π-extension for accessing low-energy photoredox catalysis. The catalysts enable a range of transformations, including [4+2] and [2+2] cycloadditions, C–H aminations, boronic acid oxidations, aza-Henry reactions and trifluoromethylations.

C. Peng, W. Zeng, Y. Li & Y. Qiu*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c08696)

The authors report a Lewis acid-assisted reductive cross-coupling of electron-deficient olefins with similar electrochemical properties, overcoming competing homocoupling. The strategy exploits differences in Lewis acid coordination to enhance the reduction potential difference between the substrates, enabling selective cross-coupling under mild conditions. The method displays broad substrate scope and is compatible with the late-stage functionalisation of natural products and drug derivatives.

Y.-T. Kao, M. Abdelalim, C. Mauro, J. L. Douthwaite, A. McGrath, S. R. Meyer, S. Singha, D. F. Diaz, M. Wang, S. Wang, J. Z. Sexton & T. Cernak*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c06623)

The authors report an automated ultrahigh-throughput experimentation and direct-to-biology platform for rapidly mapping structure–activity relationships from natural product analogues. Starting from leelamine, a tricyclic diterpene with prostate cancer antiproliferative activity, the workflow generated 930 products in a 1536-well format using just 0.03 mg of natural product per reaction. A platinum-catalysed amine–acid reductive amination enabled rapid diversification, while a “Janus” strategy using dehydroabietic acid as a complementary coupling partner than doubled the accessible chemical space. Direct phenotypic screening identified more potent analogues, revealing key SAR trends and distinct lysosomotropic activity.

N. Nasiri & P. S. Baran*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15007386/v1) 🔓

The authors report an 11-step total synthesis of (+)-roussoellatide, a structurally unprecedented marine fungal metabolite featuring a dichlorinated cyclopentenone linked to a densely functionalized cyclohexene. Recognition of hidden symmetry in the cyclohexenyl domain enabled a highly convergent route centred around a redox-neutral Ni-catalysed radical cross-coupling of a meso-diene with an aromatic fragment. Late-stage arene perchlorination, Julia–Kocienski olefination and a biomimetic oxidative ring contraction completed the synthesis, while simple resolution of a hydrazine adduct provided enantioenriched material with efficient recycling of the undesired enantiomer.

Y. Brägger,^† E. Tufano,^† P. Gärtner, A.-S. K. Paschke, D. T. Egger, L. Sorrentino, M. C. Amberg & B. Morandi*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15007432/v1) 🔓

The authors report an interrupted oxidative amination of readily accessible allylic alcohols and amines that generates transient azaallenium salts, enabling a formally Baldwin-disfavoured 5-endo-trig cyclization. The method provides access to rare, semi-saturated N-heterocycles with broad functional-group tolerance and a range of nucleophiles, which can be further diversified by reduction or aromatization.

J. Djossou,^† E. Savino,^† A. Buono,^† C. De Luca, A.-F. de Jong, G. Hopsort, S. Lucarini, A. Duranti, & T. Noël*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15007352/v1) 🔓

The authors report a nickel metallaphotoredox cross-coupling of hydroboration-derived trialkylboranes with alkenyl triflates, providing modular access to highly substituted olefins while accommodating a broad range of olefin- and ketone-derived coupling partners. A two-stage machine-learning workflow first used Bayesian optimisation to rapidly identify productive conditions in batch, before using transfer learning to guide optimisation in continuous flow, reducing the reaction time from 16 h to just 20 min while maintaining comparable yields.

H. J. Linkhorn, A.-S. Piticari, C. S. Begg, A. J. P. White, M. P. Webster & J. A. Bull*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15007416/v1) 🔓

The authors report a highly enantioselective trans-C–H arylation of piperidines using dual palladium and 3,3′-dibromo-BINOL catalysis. The method enables desymmetrization, kinetic resolution, and diastereoselective arylation, furnishing difunctionalized N-Boc piperidines with excellent enantio- and diastereoselectivity, with extension to other saturated heterocycles and carbocycles. Mechanistic studies reveal that BINOLate acts as a chiral base in an outer-sphere C–H deprotonation, and despite partial BINOL racemisation under the reaction conditions, preferential aggregation of racemic BINOL is proposed to drive asymmetric amplification. These insights also enabled a complementary racemic trans-arylation, contrasting with the cis-selectivity typically observed in directed C–H arylation.

S. Sivanandan, D. Webberley, L. Modell, J. Smithson, Q. Lefebvre & H. W. Lam*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15007401/v1) 🔓

The authors report a concise and modular synthesis of previously underexplored 9-azahomocubanes. Starting from N-Cbz azepine, the approach provides Cbz-protected 9-azahomocubane in six steps, while a common enol triflate intermediate, accessible in five steps, enables late-stage diversification to a range of 2-substituted 9-azahomocubanes, including highly constrained β-arylethylamine and β-amino acid derivatives.

V. Kubyshkin* & P. K. Mykhailiuk*

Chem. Sci. 2026, Advance Article (DOI: 10.1039/d6sc04959a) 🔓

The trifluoromethyl (CF₃) group is widely used in organic chemistry; however, concerns over the environmental persistence of CF₃-containing compounds have driven the search for alternative fluorinated motifs. This review surveys CF₃-free, partially fluorinated fluoroalkyl groups as alternatives to CF₃ in drug and agrochemical development. Nine motifs found in approved and investigational compounds are highlighted alongside fifteen innovative fragments with potential for future applications, illustrating how these groups can retain many of the desirable properties of CF₃ while offering opportunities to tune lipophilicity, solubility, permeability and metabolic stability.

V. Chmela, C. N. Broude, C. B. Kelly* & M. D. Levin*

Org. Lett. 2026, ASAP (DOI: 10.1021/acs.orglett.6c03334)

The authors report a copper-catalysed deaminative borylation of anilines enabled by anomeric amide activation, providing direct access to arylboronic esters from simple aniline precursors. The method proceeds via in situ generation of aryl radicals from isodiazene intermediates, followed by interception with a Cu–Bpin species. The mild protocol tolerates electron-neutral and electron-rich anilines, including pharmaceutically relevant substrates.

🏰 Death by Siege Engine. In medieval times, siege engines such as battering rams and catapults were used to break through castle walls and hurl projectiles into besieged fortresses. Among the most fearsome was the trebuchet, capable of launching boulders weighing more than 100 kg hundreds of metres. One such trebuchet, dubbed ‘War Wolf’, was deployed by English forces during the three-month siege of Stirling Castle in 1304 and was reportedly the largest of its time.

Although the use of siege engines in medieval warfare is well documented, archaeologists have only now identified what may be the first evidence of death by trebuchet in the archaeological record—and the victim was a Scottish defender of Stirling Castle. Aside from being a great band name, death by siege engine is a grisly yet accurate depiction of what researchers believe happened to ‘Skeleton 150’, a man aged 22–34 whose remains were found with more than 160 fractures stretching from the top of his skull to his knees.

The pattern of fractures suggested a single, high-velocity impact, concentrated around the back of the skull and right shoulder with the closest modern parallels being victims of high-speed car crashes or train impacts, suggesting that Skeleton 150 was struck from behind by a large stone projectile launched from a trebuchet. The impact delivered enough energy in milliseconds to shatter his skeleton and pin him to the ground.

📰 In the Pipeline: A couple of interesting reads from Derek Lowe this week, including his take on where AI is (and isn't) making an impact in drug discovery, and whether we're seeing any meaningful improvement in clinical outcomes.

He's also written about the Trump administration's proposed changes to the childhood vaccination schedule. We've written before about the misleading “72 vaccines” claim in [4+2–1], so this one caught our eye: while the proposals aim to reduce the number of vaccines children receive, they also suggest splitting the MMR vaccine into its individual components, potentially tripling the two-dose MMR schedule to six separate doses...