A Nontraditional Cross-Coupling

Aryl Acid-Alcohol Cross-Coupling: C(sp³)–C(sp²) Bond Formation from Nontraditional Precursors

E. Lin, J. Z. Wang, E. Mao, S. Tsang, K. M. Carsch, C. N. P. Kullmer, R. E. McNamee, J. R. Long,* C. “Chip” Le* & D. W. C. MacMillan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15827)

Recently, the MacMillan group have developed robust protocols to harness alcohols as alkyl radical precursors, but the activation of aryl acids remains relatively unexplored. Here, the authors describe the merger of N-heterocyclic carbene (NHC)-mediated deoxygenation and nickel-mediated decarbonylation of aryl acids toward C(sp³)–C(sp²) bond formation. The utility of this method is demonstrated through the synthesis of a diverse range of aryl–alkyl cross-coupled products and the late-stage functionalization of complex molecules, including drugs, natural products, and biomolecules.

Stereoretentive Radical Cross-Coupling

J. Sun,^† J. He,^† L. Massaro,^† D. A. Cagan, J. Tsien, Y. Wang, F. C. Attard, J. E. Smith, J. S. Lee, Y. Kawamata & P. S. Baran*

Nature 2025 (DOI: 10.1038/s41586-025-09011-0)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-h9snj) 🔓

Enantiospecific cross-couplings involving free radicals are unknown and generally believed to be challenging due to near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of these reactions can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here, the authors show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to enable the enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands.

Photochemically Enabled Total Syntheses of Stemoamide Alkaloids

N. R. Akkawi & D. A. Nicewicz*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01788)

The authors disclose the use of photochemical synthetic strategies to construct three stemoamide alkaloids in the shortest sequences to date. The key disconnection involves the use of both the oxidative and reductive capabilities of an acridinium photoredox catalyst to forge the densely functionalized tetrahydrofuran ring. The resultant butyrolactone serves as a handle to construct a unique oxaspirocyclic butenolide, and finally, a late-stage heteroarene transmutation provides a linchpin intermediate used to access three stemoamide alkaloids.

Stereoselective Total Synthesis of Nimbolide

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

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04899)

Previously: ChemRxiv (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 performing oxidation at C(28). 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.

Decarboxylative Cross-Acyl Coupling of Carboxylic Acids with Aldehydes Enabled by Nickel/Photoredox Catalysis

X.-B. Yan,* Y.-Q. Liu, N. Wang, T. Zhang, D. Li, Z. Wang, Y. Lin* & K. Zhang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00372)

The authors present a general method for accessing unsymmetrical alkyl–aryl and alkyl–alkyl ketones via nickel/photoredox-catalyzed decarboxylative cross-acyl coupling reactions between carboxylic acids and aldehydes without the need for an additional pre-activation procedure. By using a peroxide as both the oxidant and hydrogen atom transfer (HAT) reagent, oxidative single electron transfer (SET) of carboxylates and HAT of aldehydes was achieved, and the generated alkyl and acyl radicals were chemoselectively coupled by nickel catalysis with broad substrate scope and good functional group compatibility.

Cobalt-Catalyzed Syntheses of Esters and Carboxylic Acids from Alkenes Promoted by Light

M. S. Faculak,^† M. R. Rodriguez^† & E. J. Alexanian*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03769)

The authors report alkene alkoxycarbonylations and hydroxycarbonylations catalyzed by unmodified, inexpensive cobalt carbonyl [Co₂(CO)₈] under mild conditions promoted by light. The method displays a broad substrate scope with respect to the alkene and alcohol components, and alkoxycarbonylations can even proceed efficiently with just 1 equivalent of both coupling partners.

Photocatalyst-Dependent Enantioselectivity in the Light-Driven Deracemization of Cyclic α-Aryl Ketones

J. Y. Wang, E. Villalona & R. R. Knowles*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00847)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-9qsq1) 🔓

The authors report a photoredox-enabled deracemization of cyclic α-aryl ketones that occurs with high stereoselectivity and yield, and proceeds by mechanistically distinct proton transfer reactions. This reaction is jointly mediated by a visible-light photocatalyst and a chiral phosphate base cocatalyst under blue light irradiation.

Catalyst-Controlled Regiodivergent Synthesis of Bicyclo[2.1.1]hexanes via Photochemical Strain-Release Cycloadditions

Y.-C. Chang, M. Martín, K. Bortey, Q. Lefebvre, T. Fessard, C. Salome,* R. J. Vázquez* & M. K. Brown*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02425)

The authors demonstrate a new design for the photocatalyst-controlled regiodivergent synthesis of bicyclo[2.1.1]hexanes, in which two distinct substitution patterns were achieved under photochemical conditions with catalyst control. This was possible due to the activating group, N-methylimidazole, not only playing an important role in guiding divergent pathways but also enabling transformation to various functional groups.

Proton-Modulated Nickel Hydride Electrocatalysis for the Hydrogenation of Unsaturated Bonds and Olefin Isomerization

X. Song,^† Y.-Q. Huang,^† B. Zhao, H. Wu, X. Qi* & J. Wang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03821)

The electrochemical generation of transition-metal hydrides represents a sustainable approach to expand the scope of electrocatalytic hydrogenation and isomerization. Here, the authors designed a bifunctional ligand with a pendant amine moiety to promote Ni–H formation, which enabled selective (semi)hydrogenation of a diverse range of substrates and also demonstrated tunable positional selectivity for olefin isomerization by employing different proton sources.

Desulfurizative Fluorination of N–CF₃ Thioformamides for the Efficient Synthesis of N(CF₃)(CF₂H) Amines with Enhanced Stability

G. Wycich, J. Ponce-de-León, L. Liu & F. Schoenebeck*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506154) 🔓

N-Substitution has recently emerged as a powerful approach to improve metabolic stability, with N-CF₃ amines demonstrating enhanced lipophilicity and reduced susceptibility to oxidation, albeit with inherent instability to hydrolysis. This report discloses the further evolution of N-CF₃ amines through the introduction of an additional N-difluoromethyl unit, resulting in an extraordinary 2,000-fold increase in stability. The first general synthetic strategy for accessing N(CF₃)(CF₂H) amines is reported using an operationally simple desulfurization–fluorination strategy of N-CF₃ thioformamides, and is characterized by broad functional group tolerance.

Reductive Radical Chain Initiation Through the Thermal Generation of Carbon Dioxide Radical Anion

E. R. X. Lim, B. D. Cooper, M. Shanmugam, J. Da Luz, E. J. L. McInnes, C. Trujillo, J. J. Douglas & M. J. James*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-b3059) 🔓

The authors report a general, thermally driven and scalable solution for the reductive initiation of radical chains, by reacting inexpensive azo initiators and formate salts to form carbon dioxide radical anion. Substoichiometric quantities of this initiator system were used to form C(sp²)–C(sp³), C(sp²)–S, C(sp²)–H, C(sp²)–B and C(sp²)–P bonds from complex (hetero)aryl halides, with high chemoselectivity and under transition-metal-free conditions.

Facile Access to Hindered Ethers via Photoinduced O–H Bond Insertions

Y. Zhang,^† X. Han,^† D. Li,^† D. Wang, J. Wang, X. Luan, S.-F. Ni,* S. Das* & W.-D. Zhang*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00099) 🔓

The synthesis of hindered and polyfluorinated dialkyl ethers poses challenges due to the bulkiness of tertiary alcohols and low nucleophilicity of polyfluorinated alcohols. In this study, the authors utilized a photoinduced approach that involves the in situ formation of singlet carbenes followed by O–H insertions to access hindered and polyfluorinated ethers. Other nucleophiles such as phenols, H₂O and thiols are amenable to the process, and the gram-scale synthesis of marketed drugs and modification of complex molecules is also demonstrated.

Ligand-Enabled Override of the Memory Effect in Rh-Catalyzed Asymmetric Suzuki Reactions

K. Liu,^† D. Egea-Arrebola,^† R. Ardkhean,^† L. Cunningham, K. E. Christensen, R. S. Paton* & S. P. Fletcher*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102550) 🔓

The authors report an asymmetric cross-coupling method between aryl boronic acids and linear allylic phosphates to give branched allylic products. This Suzuki-type reaction overcomes the “memory effect” in Rh catalysis, enabling an overall S_N2′ transformation and forming a new stereogenic center adjacent to a terminal vinyl moiety. The method tolerates preexisting stereogenic centers, allowing drugs and natural products to be elaborated via diastereoselective allylic arylations, and can be used in an iterative strategy to give contiguous aryl-substituted stereogenic centers.

The Brain Drain Begins

🧠 The brain drain begins. Analysis of data from Nature Careers global science jobs platform has revealed that US scientists have submitted 32% more applications for international jobs between January and March of this year than during the same period last year, in what appears to be a response to the Trump administration’s cuts—and general hostility—to scientific research.

Cuts to the US National Institutes of Health (NIH), the termination of more than 200 federal grants for HIV and AIDS research alongside the cancellation of $400 million in federal grants and contracts to Columbia University, and $800 million in grants to Johns Hopkins University—the latter of which led to the loss of 2000 jobs—will all have played a role in the upcoming exodus. However, it won’t just be the US that suffers, NIH-funded research contributed to 354 of 356 drugs that were approved by the US Food and Drug Administration (FDA) between 2010–2019, and in the past decade alone the NIH has also been acknowledged as a funder on over 1.3 million biomedical-research publications.

Nature’s analysis follows on from their recent poll of US researchers, which found that 75% (>1200 respondents) were planning to leave the country following the Trump administration’s disruptions to science, and some institutions are already looking to take advantage of this influx of talent. Aix-Marseille University in France has set aside €15 million for their Safe Place for Science initiative to attract 15 researchers working on climate, the environment, health and the human and social sciences. So far, the scheme has attracted 298 applications with 70% of those coming from the US. In the other direction, applications to US institutions from researchers in Europe have dropped 41% (March 2025 vs. March 2024), which also tracks with the recent freefall in tourism from the continent. Hopefully European institutions will take advantage of this potentially transformative situation and open up access to scientific funding and support, instead of getting caught up in the usual bureaucracy.