A Faster Way to Antivirals

A Unified Platform for Nucleoside Analog Synthesis

M. J. Anketell, E. Fung, W. Liu, M. Shinde, C. Q. He, K. W. C. Ng, S. M. Silverman, L.-C. Campeau, R. Pantophlet & R. Britton*

Science 2026, First Release (DOI: 10.1126/science.aed6880)

Nucleoside analogs (NAs) are essential antiviral and anticancer therapies. Despite decades of focused efforts, their chemical space remains underexplored due to lengthy, single-molecule-oriented syntheses that lack the flexibility required to generate NA libraries. Here, the authors report a flexible, robust, and efficient platform for the high-throughput synthesis of NAs using a photoredox coupling strategy. This approach produces both C- and N-linked NAs and unifies the synthesis of several disparate NA classes, including 4′-thio, 4′-imino, and ProTides, all from a simple, scalable intermediate. Using this platform, a diverse NA library was generated and several hit compounds with anti-HIV-1 activity were identified.

Collective Synthesis of 1,2,4-Trisubstituted, meta- and ortho-Substituted Arene Bioisosteres from Bicyclobutanes

F. Wu,^† J.-J. Wang,^† Y. Xiao,^† Q. Peng, Y.-J. Li, K. Peng, Q. Han, M. Wei, Yu Qian,* W. Zhang,* G. Wang* & J.-J. Feng*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02097-7)

The authors describe a practical route to enantiomerically pure 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) via cycloadditions of bicyclo[1.1.0]butanes with 1,4-dithiane-2,5-diol. This method produces cycloadducts with two or three exit vectors, which serve as bioisosteres of ortho-substituted and 1,2,4-trisubstituted benzenes, respectively. The products can be further elaborated into diverse scaffolds, including 1,5-disubstituted thiabicyclo[3.1.1]heptenes. Crystallographic, pharmacokinetic, and biological evaluations of thia-BCHep analogues of diflunisal, salicylanilide, and the anticancer drug sonidegib demonstrate thia-BCHeps as viable surrogates for meta-, ortho-, and 1,2,4-trisubstituted benzene rings in drug discovery.

Peripheral Aryl Group Transposition on Pyridines using Photoredox Catalysis

E. Y. K. Tan, T.-Y. Peng, T. Wakabayashi & S. Chiba*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01023-6) 🔓

The authors report a method to enable regioselective migration of a peripheral aryl group on pyridines via 1,2-aryl migration of azacylohexadienyl radical intermediates generated by temporary dearomatization of the pyridine rings under photoredox catalysis. This process transfers aryl substituents from the para- or ortho-position of pyridines to the meta-position by three different permutations: C4-to-C5, C4-to-C3 and C2-to-C3 aryl group transpositions. The protocol exhibits broad functional group compatibility, offering streamlined access to a library of diverse meta-arylpyridines without the need for de novo synthesis.

Switchable and Selective Synthesis of Unsymmetrical N-Aryl Pyrazoles from 1,2,3-Thiadiazine S-Oxides

A. Fanourakis, Y. Liu,^‡ P. Mukherjee,^‡ A. Garipov, C. A. Reiher,* C. B. Kelly,* S. E. Reynolds, P. J. Saucedo, O. Gutierrez* & M. D. Levin*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c22914)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-0w2xk) 🔓

The authors report a new, highly selective copper-catalyzed synthesis of unsymmetrical N-aryl pyrazoles from 1,2,3-thiadiazine S-oxides (TDSOs) and diaryl iodonium electrophiles. The regiochemical outcome is determined by the choice of the copper catalyst and base, in contrast with typical substrate-controlled approaches. This “switchable” approach enables access to either pyrazole isomer from a given starting material, with high selectivity observed in each case. The scope of both protocols is broad and amenable to automation, thus facilitating the rapid generation of a medicinally relevant, diverse pyrazole library.

Photodriven Sm-Catalyzed Asymmetric Ketyl-Olefin Coupling

L.-M. Chen,^† D. E. Tarnopol,^† S. E. Reisman* & J. C. Peters*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c20884) 🔓

SmI₂ is a privileged, single-electron reductant employed in the synthesis of diverse products. Though traditionally used in (super)stoichiometric amounts, SmI₂ has recently been employed catalytically with viable turnover strategies. Enantioselective reductive cross-coupling reactions mediated by SmI₂ are scarce and asymmetric methods that use catalytic quantities of SmI₂ are unknown. Here, the authors report an enantioselective ketyl-olefin coupling, employing a SmI₂-derived catalyst with a widely available chiral pyridine-bis(oxazoline) (PyBOX) ligand and a commercially available Ir photocatalyst.

Electrolysis-Assisted Reduction of Dimethylformamide for Unactivated Alkene Functionalizations

Y. Xi,^† S. Sharma,^† C. O. Kappe & G. Laudadio*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c17824) 🔓

N,N-Dimethylformamide (DMF) is a widely used solvent that can serve as a reagent under certain conditions. However, its direct single-electron reduction remains challenging due to its low reduction potential. Here, the authors report the electrolysis-assisted generation of the DMF distonic radical anion and demonstrate its synthetic utility through the functionalization of mono- and disubstituted olefins, affording hydroformylated and hydroaminomethylated products.

Enantioselective Synthesis of Spirolactones and Spirolactams Under Low Catalyst Loadings

T. Saito, A. Navarro & H. M. L. Davies*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c01407) 🔓

The authors report a Rh₂(S-p-PhTPCP)₄-catalyzed [2+1] cyclopropanation between 3-diazo δ-lactones and lactams, and a wide range of alkene substrates, enabling the facile synthesis of 5-oxa and 5-azaspiro[2.5]octanones in yields up to 98%, reasonable levels of diastereoselectivity (up to 11:1 d.r.), and high levels of enantioselectivity (up to 98% e.e.). The reaction can be run with 0.00005 mol% of catalyst, resulting in 1,740,000 TON, while maintaining stereocontrol.

Photocatalytic Cross-Coupling of Phenols and Heteroaryl Halides With Machine Learning-Guided Reaction Prediction

M. C. Carson, A. Wu, K. B. Duggal, M. E. Rotella & M. C. Kozlowski*

Angew. Chem. Int. Ed. 2026, Early View (DOI: 10.1002/anie.8222003) 🔓

A redox-neutral photochemical method enables direct C(sp² )–C(sp² ) bond formation between phenols and heteroaryl halides using an organic dye and base. Complementary radical generation allows efficient cross-coupling in up to 91% yield. Mechanistic studies, DFT, HTE, and machine learning rationalize and predict reactivity, offering a sustainable approach to this challenging transformation.

Highly Chemoselective Access to Alkyl-Sulfur Compounds via N₂ Extrusion of Alkyl Hydrazines

S. Wang, D. A. Cagan, J. Tsien, J. Zhang, T. Gogula, A. V. R. Murthy, S. K. Nangunoori, G. Boga, M. S. Oderinde, A. M. Turner, H. C. Hang, Y. Kawamata* & P. S. Baran*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000647/v1) 🔓

The authors report a unified platform for the divergent synthesis of alkyl sulfur(VI) derivatives from abundant, unactivated feedstocks including ketones, alcohols, amines, and structurally complex molecules. Central to this method is the use of alkyl hydrazines (or their sulfonylated derivatives) as practical radical precursors, readily prepared from these feedstocks by conventional transformations. Upon simple thermal activation, these hydrazines undergo homolysis to generate alkyl radicals under mild, operationally simple conditions without the need for photocatalysts, expensive metals, or elaborate setups. The chemoselectivity of this approach is demonstrated through the synthesis of over 70 sulfur-containing molecules, including direct functionalization of complex natural products without protecting groups.

Enantioselective Synthesis of 1,3-Bicyclo[2.1.1]hexanes as meta-Benzene Bioisosteres

C. Pérez-Sánchez, P. Garrido-García, D. Fernández, S. Ortega-Gutiérrez, M. Martín-Fontecha, D. González-Pinardo, I. Fernández, T. Rigotti* & M. Tortosa*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000646/v1) 🔓

The authors report an enantioselective copper-catalyzed protoborylation that desymmetrizes bicyclo[2.1.1]hex-2-enes to access 1,3-disubstituted bicyclo[2.1.1]hexanes—mimics of meta-substituted benzenes. The resulting versatile enantioenriched building blocks were incorporated into a range of drug analogues, leading to improved solubility, metabolic stability, and permeability relative to the parent compounds. The analogues retained biological activity by targeting the same molecular receptors, validating these scaffolds as suitable meta-benzene bioisosteres.

Late-Stage Aryl NCF₃ and SCF₃ Installation Enabled by Coupling Flow-Generated Anions with Aryl Thianthrenium Salts

D. Nagornîi, Á. Valdés-Maqueda, S. Stocchetti, N. Kaplaneris, Z. He & T. Noël*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000577/v2) 🔓

The authors report a flow-enabled platform that allows for the late-stage installation of NCF₃ and SCF₃ groups onto aryl frameworks through the coupling of flow-generated nucleophilic heteroatom-CF₃ anions with aryl thianthrenium salts. Readily available organic precursors are converted on demand into NCF₃ and SCF₃ anions using a CsF-packed bed reactor, allowing safe handling of highly reactive fluorinated intermediates while minimizing fluorinated waste. The resulting anions are subsequently engaged in a copper-mediated, photocatalytic cross-coupling, enabling efficient formation of aryl-NCF₃ and aryl-SCF₃ bonds under mild conditions.

👉️ For further recent work by the same authors on “Direct δ-Lactone Synthesis from Free Alcohols via Photoinduced δ-C(sp³ )-H Carbonylation in Flow”, see here.

Cobalt-Catalyzed Asymmetric Cyclopropanation of Heteroaryl Alkenes with Homogeneous Zinc Carbenoids

M. C. Deem, D. Lehnherr, T. Wang, X. Wang, Y.-h. Lam, S. M. Silverman, J. A. Newman, Q. Lin, E. M. Phillips, M. Christensen, C. K. Chung, Z. Zhou* & H. Yang*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000548/v1) 🔓

The authors report a homogeneous catalytic asymmetric cyclopropanation by merging chiral pyridine bis-oxazoline (PyBox)-cobalt catalysts with readily accessible zinc carbenoids. This method enables facile access to chiral cyclopropanes bearing pyridyl, pyrimidyl, and other nitrogen-containing heterocyclic substituents with high enantioselectivities. The high enantioselectivity, homogeneity, and compatibility with various green solvents render this method amenable to scale up and application across diverse heteroaryl substrates.

Thianthrenium Salts in Photochemistry

Z. Bai & T. Ritter*

Acc. Chem. Res. 2026, ASAP (DOI: 10.1021/acs.accounts.5c00863) 🔓

In this Account, the authors retrace the conceptual evolution of thianthrenium chemistry in their laboratory, from its origins in aromatic C–H functionalization to its diverse applications in photochemistry. Advances enabled by thianthrenium salts in photocatalysis are highlighted and classified into two categories: photocatalytic single-electron transfer (photoredox catalysis) and photocatalytic energy transfer. Within photoredox catalysis, three mechanistic modes are distinguished: (i) conventional photoredox catalysis, (ii) dual photoredox/transition-metal catalysis, and (iii) photoinduced transition-metal catalysis. The direct homolytic cleavage of thianthrenium and selenium salts under visible-light irradiation is also discussed.

Visible-Light-Mediated aza Paternò–Büchi Reactions and Related Cycloadditions for the Formation of Azetidines and Azetines

C. H. Ng & C. S. Schindler*

Acc. Chem. Res. 2026, ASAP (DOI: 10.1021/acs.accounts.5c00914)

In this Account, the authors present their work on visible-light-mediated imine-based [2+2] cycloadditions, which rely on a key design principle of energy transfer photocatalysis: careful matching of the triplet energies of the photosensitizer and substrate for selective substrate sensitization. The use of visible-light limits sensitization to activated (i.e., conjugated) alkenes and certain imines, rendering unactivated (i.e., unconjugated) alkenes and alkynes inaccessible. On the basis of this principle, six distinct strategies (Types I–VI) were developed to access azetidines and azetines. These strategies differentiate intra- and intermolecular transformations and the reactivity of three substrate classes: activated alkenes, unactivated alkenes, and alkynes.

Ancient Psychedelics

💊 Ancient Psychedelics. For nearly two millennia, pilgrims traveled to Eleusis, near Athens, to participate in one of the ancient world’s most secretive rites: the Eleusinian Mysteries. Among the initiates were figures such as the Roman orator Cicero and the philosopher-emperor Marcus Aurelius.

Participants described the experience as life-changing, transforming their understanding of death and existence. At the centre of the ritual was a drink called kykeon, said to contain barley, water and mint. However, barley can also be infected by the fungus Ergot, which produces lysergic acid derivatives—molecules related to LSD—and may offer an explanation for the transcendent experiences.

Recently, researchers tested whether ancient Greeks could realistically isolate these psychoactive compounds using only technologies available at the time. Their experiments showed that boiling ergot in strongly alkaline ash water could remove many toxic alkaloids while leaving the psychedelic components intact, suggesting that a psychoactive kykeon was plausible.

Other ancient cultures also exploited microbes in surprisingly sophisticated ways, with the Ancient Nubians providing an interesting example. Chemical analysis of skeletons from Nubia (present-day Sudan), dating from around 250–550 AD, shows that people regularly consumed the antibiotic Tetracycline. Researchers believe it was produced during the fermentation of beer made from grain contaminated with Streptomyces bacteria. While they would not have understood the microbiology, the health benefits were likely obvious enough for the practice to persist.

Whether kykeon contained psychedelic compounds or not remains uncertain, but if it did, it does raise the question of whether Marcus Aurelius penned parts of Meditations shortly after the experience.

NB: The Eleusinian rituals revolved around the myth of the harvest goddess Demeter, whose daughter Persephone was abducted by Hades. Demeter searched desperately for her daughter and, in her grief, the earth became barren. Eventually, Zeus intervened and ordered Persephone’s return. However, before she could leave, Hades tricked her into consuming pomegranate seeds grown in the underworld. Because she had tasted the food of the dead, she was bound to return for a portion of every year. Her descent and return became a mythological explanation for the seasons: when Persephone is with Hades, Demeter mourns and the earth grows cold and barren (autumn and winter), when she returns, spring and summer bring new life and growth.