Epimerising All-Carbon Stereocentres

Photocatalyzed Epimerization of Quaternary Stereocenters

L. Wu, B. N. McIntyre, S. Wu, Z. Jiao, C. B. Fox, N. D. Schley & A. W. Schuppe*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16769) 🔓

The authors report a protocol for the precise manipulation of quaternary stereocenters through epimerization. The critical design element of this ketone α-epimerization process was developing a photoactive imine that circumvents the numerous deleterious pathways of carbonyl photochemistry. Excitation of this imine with visible light in the presence of a photocatalyst enabled reversible C–C bond cleavage and reformation to vary the stereochemistry of the quaternary center. The broad utility of this protocol was demonstrated by the topological alteration of various classes of carbocyclic scaffolds bearing diverse functional groups.

Stereospecific Molecular Rearrangement via Nucleophilic Substitution at Quaternary Stereocentres in Acyclic Systems

K. Patel & I. Marek*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01783-2)

The authors present a strategy for preparing complex molecular scaffolds via stereospecific S_N1 at a quaternary stereocentre in acyclic systems. By leveraging neighbouring group participation, unique cyclopropylcarbinyl cation intermediates undergo selective nucleophilic substitution with high diastereoselectivity and complete inversion of configuration at a distal position to the original carbocation via molecular rearrangement. The methodology has been applied to generate homoallylic tertiary fluorides, bromides, chlorides, ethers, thiocyanates and azides.

Enantioselective Hydrodifluoroalkylation of Alkenes with Conformationally Tuned Peptidyl Hydrogen Atom Transfer Catalysts

M. V. P. Pereira Jr., E. P. Geunes, H. Shao, Y. Zhang, J. Cheng, S. V. Magpantay, B. Q. Mercado, J. M. Mayer,* K. N. Houk,* R. R. Knowles* & S. J. Miller*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01166)

The authors report the enantioselective hydrodifluoroalkylation of alkenes proceeding via an asymmetric hydrogen atom transfer catalyzed by thiol-containing tetrapeptides. Photocatalytic generation of a difluoroacetyl radical followed by carbon–carbon bond formation results in a prochiral carbon-centered radical that engages with the chiral catalyst. Notably, incorporating an (S)-β-methyl-substituted cysteine as the N-terminal residue improved selectivity relative to that of the native N-terminal cysteine residue. A range of enantioenriched γ-substituted amides were synthesized in up to a 96:4 enantiomeric ratio.

Diversity Synthesis Using Glutarimides as Rhodium Carbene Precursors in Enantioselective C–H Functionalization and Cyclopropanation

W. F. Tracy, J. C. Sharland, D. Ly, G. H. M. Davies, D. G. Musaev, H. Fang, J. Moreno,* E. C. Cherney* & H. M. L. Davies*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00568) 🔓

The authors report that classical cereblon-binding glutarimide cores can be successfully derivatized to aryl diazoacetates, which in the presence of a dirhodium catalyst, undergo high-yielding and highly enantioselective C–H functionalization of hydrocarbons and cyclopropanation of styrene. These products can be used to create molecular glue degrader-like compounds and intermediates that can be elaborated into effective bifunctional ligand-directed degraders.

Late-Stage Photoredox-Catalyzed Aryl C–H Bond Diazomethylation with Atomic Carbon Reagents

A. Puggioli, L. Jiang, A. G. Herraiz, L. J. Nannini, K. de la Vega-Hernández, A. Rey-Blanco, A. Diéguez-Vázquez, S. Cañellas & M. G. Suero*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00045) 🔓

The authors present a novel class of diazo compounds as atomic carbon reagents substituted with two orthogonal redox-active leaving groups that were exploited in the late-stage construction of chiral centers with aryl C–H bonds from aromatic feedstocks and drug molecules. The applicability of this novel atomic carbon reagent was tested in the automated parallel synthesis of a library of Fenofibrate derivatives.

Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus(V): A Three-Phase Strategy for Modular Preparation of Phosphoramidates

X.-K. Nie, S.-Q. Zhang, X.-Y. Wang, W.-T. Yang, X. Zhang, S.-J. Chen, X. Cui, Z. Tang* & G.-X. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15587)

Despite the availability of methodologies for the selective construction of diverse chiral organophosphorus species, achieving P-stereocenters solely substituted by heteroatoms often relies on diastereomeric synthesis. Here, the authors present a catalytic enantioselective desymmetrization strategy using an electrophilic phosphorus reagent with three leaving groups as a substrate, enabling a three-phase nucleophilic attack with various alcohols and amines.

Capturing Unstable Carbanionic Intermediates via Halogen Transfer: Base-Promoted Oxidative Coupling Reactions of α,α-Difluoromethylarenes

L. V. Hooker & J. S. Bandar*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202502894)

The authors describe the first oxidative coupling protocol of α,α-difluorobenzylic C–H bonds with heteronucleophiles. Here, transiently generated α,α-difluorobenzylic carbanionic intermediates undergo halogen transfer from 2-bromothiophenes to form electrophilic ArCF₂Br compounds for in situ nucleophilic substitution, avoiding α-fluoride elimination pathways that typically plague α-fluorocarbanions, and streamlining the modular synthesis of α,α-difluorobenzyl(thio)ethers.

Benzamide-Directed Hydroarylative Cross-Couplings Using Minimally Activated Alkenes: Enantioselective Synthesis of Tertiary and Quaternary Stereocenters

T. P. Aldhous, R. Chung, A. Hassan, A. G. Dalling, P. Cooper, S. Grélaud, R. J. Mudd, L. J. Feron, P. D. Kemmitt & J. Bower*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202502569) 🔓

Ir-systems modified with ferrocene-based homochiral diphosphonite ligands promote benzamide-directed hydroarylative cross-couplings involving minimally activated alkenes. The processes are highly branched selective and enantioselective, generating benzylic stereocenters under byproduct free conditions.

10-Step, Gram-Scale Total Synthesis of (–)-Bipinnatin J

A. J. Rodriguez,^† M. S. Pokle,^† G. L. Barnes & P. S. Baran*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-6d1f5) 🔓

A concise, scalable total synthesis of (–)-Bipinnatin J is disclosed. Commencing from inexpensive starting materials, this marine diterpenoid was fashioned through a highly convergent synthesis enabled by Ni-electrocatalytic decarboxylative cross–coupling (DCC) taking advantage of succinate as an ethylene 2-carbon bridge, a unique halogen dance-Zweifel sequence to rapidly access a trisubstituted furan, a Ni-mediated 1,6-conjugate addition, and an asymmetric proton transfer.

Stereoselective Total Synthesis of Nimbolide

D. B. Ryffel,^† P. C. Ryffel,^† M. Martinelli, V. R. Pillai & D. Sarlah*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-517d2) 🔓

A stereoselective total synthesis of nimbolide has been achieved in a convergent, 11-step sequence from α-methyl-(R)-carvone. The strategy relied on a stereoselective palladium-catalyzed borylative Heck cyclization where the A-ring of the nimbolide core was constructed while simultaneously installing oxidation at C28. Selective manipulations delivered a fully decorated decalin moiety on large scale. Then, a stereoretentive etherification reaction brought together two fragments and forged the critical C–O bond with high selectivity. Finally, a regioselective radical cyclization and late-stage lactonization completed the total synthesis of nimbolide.

A Catalytic Asymmetric Intramolecular [4+1]-Cycloaddition for the Total Synthesis of Terpene Alkaloid Natural Products

W. Xiu, C. D. Huffman, W. A. Swann, C. W. Li & C. Uyeda*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-mh3h8) 🔓

The authors report a nickel-catalyzed asymmetric intramolecular [4+1]-cycloaddition of a vinylidene and a 1,3-diene to form a [4.3.0]-azabicycle, which features sterically differentiated tri- and tetra-substituted alkenes that can be selectively functionalized to achieve divergent syntheses of 7-epi-incarvilline, hydroxyincarvilline, isoincarvilline, incarvilline, tecomanine, 5-hydroxyskytanthine, and tecostanin.

C–H Functionalization via Single Atom Metathesis of C–H and C–X Bonds

T. C. Jankins, B. Berger, F. A. Aouane, S. Barbeira-Arán, C. Didier, B. Hürlimann, C. Zimmer & B. Morandi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-fgc4s) 🔓

The authors report a C–H/C–X metathesis reaction through a radical swapping protocol where a hydrogen and halogen are traded between molecules via reversible hydrogen atom transfer (HAT) and halogen atom transfer (XAT) that allows for mild C–H halogenation. The reversibility of this process allows for selective dehalogenation of polyhalogenated products to form monohalogenated products. Leveraging the reversibility of this process, halogenated organic pollutants can also serve as a halogen source for C–H halogenation.

Rapid Methylation of Aryl Bromides Using Air-Stable DABCO-bis(Trimethylaluminum) via Nickel Metallaphotoredox Catalysis

J. Djossou, A. Aloia, L. Capaldo, D. D. Snabilié, M. Regnier, A. Monopoli, B. de Bruin & T. Noël*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-fv54r) 🔓

The authors report a metallaphotocatalytic strategy for the selective methylation of (hetero)aryl bromides via nickel-catalyzed cross-coupling with bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃), as a commercially available, air-stable, and non-pyrophoric aluminum-based reagent. The method enables a fast, robust, and scalable methylation protocol that broadly accommodates various functional groups while preventing protodehalogenation.

Synthesis of 1,3-bis-Trifluoromethylated-(hetero)cyclohexane-2-carboxylates from Alkylidenemalononitriles

M. Mando, D. J. Smith, J.-N. Boyn* & A. J. Grenning*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-bzjl4) 🔓

The authors report a method for syn-selective 1,3-bis-trifluoromethylation of (hetero)cycloalkylidene-malononitriles. The malononitrile-containing intermediate can be readily converted into carboxylates (and derivatives thereof) by oxidative decyanation.

The Unwelcome Return of Measles

🦠 The unwelcome return of measles. Measles has been around for over a thousand years and was described as early as the 9^th century by the Persian physician Rhazes, however, it wasn’t until the 18^th century that Scottish doctor Francis Home discovered it was caused by a virus. Fast forward 200 years and by the early 1960s, measles was endemic around the world, infecting approximately 30 million people and causing 2.6 million deaths each year.

Nowadays, thanks to the introduction of the measles vaccine, that number has dropped over 95% to 107,500 deaths in 2023—sadly most of those were from unvaccinated children under the age of 5. Unfortunately, in that same year, only 83% of children received their first dose of measles vaccine, in part caused by post-COVID vaccine hesitancy (despite the fact that COVID vaccines saved an estimated 14 million lives and that since 1974, 154 million lives have been saved through global vaccination efforts - that’s 6 lives every minute of every year).

Measles is now making an unwelcome return to the US, primarily surging in Texas and neighbouring states with 378 cases reported nationwide as of 21^st March and at least 1 confirmed death. Of those cases, 95% were in unvaccinated individuals with 17% requiring hospitalisation. It’s challenging to stop a measles outbreak when vaccination rates in a community drop below 97%, that’s because the basic reproduction number (R₀)—how many people, on average, one person with an illness is expected to infect—is 12–16 for measles (compare that with COVID, which was estimated to be around 1.4–2.5 and took little time to go global).

Most deaths from measles are from disease-related complications, as shown in the figure above, with about 10–30 cases in every 10,000 proving fatal. A 2019 outbreak of measles in Samoa, stoked by anti-vaccine rhetoric, turned out to be more fatal with 83 deaths and 5700 cases (146 deaths per 10,000). Vaccine hesitancy isn’t a new phenomenon and US Secretary of Health and Human Services, Robert F. Kennedy Jr., is yet to give much support for the measles vaccine, promoting unproven treatments such as cod liver oil instead. This outbreak will be particularly concerning for higher risk individuals, such as those who are immunocompromised or parents of children too young to be vaccinated.