A. Mondal,^† J. J. C. Struijs,^† C. J. N. Doyle,^† Z. Chen, Z. Wang, W. Tangamornchaipattana, C. Allais, P. F. Richardson, J. Piper, R. S. Paton, S. Aldridge* & V. Gouverneur*

Science 2026, 393, 514–521 (DOI: 10.1126/science.aec6298)

The authors introduce bench-stable neopentoxyphosphonium salts that enable Appel-type fluorination of alcohols using potassium fluoride, overcoming the longstanding challenge of fluoride sequestration as a difluorophosphorane under conventional Appel conditions. Hydrogen-bonding phase-transfer catalysis promotes KF solubilization and P–F bond cleavage, enabling stereoinvertive fluorination through an alkoxyphosphonium fluoride ion pair.

👉 C&EN write-up, here.

👉 In the Pipeline write-up, here.

Z. Zhu, P. Zhang, B. Gao, K. S. Ly, H. Tao, Y. Fu, Z. Lin & Y. Quan*

Nature 2026 (DOI: 10.1038/s41586-026-10931-8)

The authors report an unusual dual-site migration in which a borinane ring moves along a carbon chain, enabling the controlled relocation of two distant sites. This “borinane rearrangement” traverses up to eight carbon atoms with high regio- and diastereoselectivity, while the resulting boracycles provide versatile intermediates for divergent synthesis of (hetero)cycles and remote difunctionalization.

C. C. Sorensen,^† S. Wang,^† Y. Ouyang, S. Waheed, C. G. Page, G. Mann, S. Allmendinger & T. K. Hyster*

Nature 2026 (DOI: 10.1038/s41586-026-10930-9)

The authors establish pyridoxal 5′-phosphate (PLP) as a photoenzymatic cofactor, expanding visible-light biocatalysis to PLP-dependent enzymes. By combining non-native benzyl amine substrates with photosensitizer-mediated Förster resonance energy transfer, the strategy accesses an excited-state quinonoid intermediate that functions as a potent single-electron reductant. This redox-neutral approach enables asymmetric radical–radical cross-coupling between benzyl amines and reductive radical precursors.

Y.-Q. Zhang,^† S.-H. Li^† & M. J. Koh*

Nat. Commun. 2026 (DOI: 10.1038/s41467-026-76238-4) 🔓

The authors report a catalyst-free, photoinduced oxygen deletion of oxetanes, enabling highly chemo- and regioselective ring contraction and skeletal remodelling. Using iodoform under visible-light irradiation, the strategy converts oxetanes into cyclopropanes and benzoheterocycles with broad functional-group tolerance. The method also enables late-stage functionalisation and streamlined syntheses of pharmaceutical scaffolds.

K. Das, S. Chakraborty, E. Paenurk & B. König*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c10599) 🔓

The authors report a photocatalytic strategy for the direct C–H alkylation of nitroarenes, overcoming a longstanding limitation of Friedel–Crafts chemistry. Using readily available carboxylic acids as alkyl radical precursors, the method enables selective alkyl radical addition to electron-deficient nitroarenes while preserving the nitro functionality and tolerating a broad range of functional groups. The approach is compatible with diverse nitroarenes and can also utilise alkyltrifluoroborates as alternative radical precursors.

J. Ying,^† J. Yang,^† C. Zheng,^† Y. Tan & Z. Lu*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c08244) 🔓

The authors report a cobalt-catalysed enantioselective borylcyclopropanation of alkenes, providing direct access to chiral cis-cyclopropylboronates with excellent enantio- and diastereoselectivity. The versatile C–B bond enables stereospecific conversion into a broad range of functionalised cis-cyclopropanes, including valuable cyclopropylamines and medicinally relevant scaffolds.

G. Toth-Williams, H. E. Patten-Trujillo, Y. G. Ahmed, W. DeSnoo, Y. Kraemer, A. Höppner, S. Ning, A. R. Leslie, A. C. Gao, J. C. Fettinger, D. J. Tantillo* & J. T. Shaw*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c04114)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv.15000280/v1) 🔓

The authors report a rhodium-catalyzed intramolecular cyclization of sulfonimidamides that forms a new N–heteroatom bond, enabling access to diverse aromatic heterocycles featuring stereogenic sulfur centers. Computational and spectroscopic studies reveal the relationship between stereochemistry, aromaticity, and the unique electronic and geometric properties of these heterocycles. The potential of this scaffold was demonstrated through the synthesis of an enzalutamide analogue, which exhibited good potency against enzalutamide-resistant prostate cancer cells while maintaining favorable physicochemical and pharmacokinetic properties.

👉 C&EN write-up, here.

E. L. Kuker, C. E. Wallace, S. A. Corio, A. E. de Vos, J. S. Hirschi* & V. M. Dong*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c05233)

The authors report a regio- and enantioselective Rh-catalysed hydroacylation of 2-azetines, in which ligand choice controls access to either chiral 2-acylazetidines or achiral 3-acylazetidines. Electron-rich Josiphos ligands promote highly enantioselective formation of 2-acylazetidines, whereas biaryl bisphosphines favour the complementary 3-acylazetidine regioisomer. Mechanistic analysis reveals that biaryl bisphosphines allow regioselectivity to follow the substrate’s intrinsic electronic preference, whereas bulkier Josiphos ligands override it through favourable steric and non-covalent interactions.

M. Lemmerer,^† D. C. Emmet,^† A. S. K. Lahdenperä, D. J. Davies, A. Dahiya, K. Ermanis & R. J. Phipps*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c10166) 🔓

The authors report a chiral hydrogen atom abstraction catalyst that enables stereoselective epimerization of 1,3-diols, allowing stereoisomeric mixtures to be "descrambled" after synthesis rather than controlling stereochemistry during their formation. The method enables highly selective kinetic resolution of symmetric diols and, for suitably substituted unsymmetrical diols, provides access to both syn- and anti-diastereomers in high enantiomeric excess.

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

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c05089) 🔓

The authors report a nickel-catalysed C–N cross-electrophile coupling that directly unites carbon and nitrogen electrophiles. This base-free protocol exhibits broad functional-group tolerance, including base-sensitive substrates and is compatible with late-stage functionalisation. Readily accessible nitrogen electrophiles, prepared from diverse starting materials including C–H bonds and olefins, enable the synthesis of secondary and tertiary amines, unsymmetrical diamines, and the one-pot functionalisation of native amines.

💊 Better Medicines, Same Odds. Drug discovery has become vastly more sophisticated over the past six decades, and few examples illustrate that progress better than cystic fibrosis. In the 1960s, treatment was largely supportive and median survival was only around 15 years. Following the discovery of the CFTR gene in 1989, CFTR modulators such as Ivacaftor (2012) and Trikafta (2019) transformed treatment. Today, people born with cystic fibrosis can expect to live into their 60s, with median predicted survival around 66 years.

Yet despite advances like these, roughly nine out of ten drug candidates entering clinical trials still fail to reach approval. A new analysis spanning six decades of drug development examined clinical attrition data from 32 publications, covering 60 datasets from 1963–2017. Mean clinical failure rates remained remarkably consistent: approximately 90% in the 1960s, falling to ~80% in the 1980s before climbing back to ~91% in the 2010s. Across 36 datasets analysing reasons for clinical failure, ~77% were attributed to biological factors, principally inadequate efficacy, safety/toxicity concerns, and unfavourable PK/PD or bioavailability.

The authors argue that these findings strengthen the case for more human-relevant ‘New Approach Methodologies’ (NAMs), including organoids, organ-on-chip models and physiologically based pharmacokinetic modelling. AI-based models may also contribute by extracting insights from human datasets, although their ability to improve prospective clinical success rates remains to be demonstrated.