Switchable Skeletal Editing

Switchable Skeletal Editing of Quinolines Enabled by Cyclizative Sequential Rearrangements

D. Tian, Y.-P. He, L.-S. Yang, Z.-C. Li & H. Wu*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01793-0)

The authors report the tunable skeletal editing of quinolines through Brønsted acid-catalysed reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates and water to generate nitrogen-containing heteroaromatic compounds. Specifically, quinoline N-oxides are first converted into 2-substituted indolines, which can then undergo acid-promoted fragmentation to give indoles, base-facilitated ring-opening to afford 2-alkenylanilines and oxidative cyclization to yield isoquinolinones. Catalytic asymmetric skeletal editing to provide enantioenriched benzazepines and the late-stage skeletal modification of quinoline cores in several drugs is also demonstrated.

Sulfenylcarbene-Mediated Carbon Atom Insertion for the Late-Stage Functionalization of N-Heterocycles

P. Kafle, D. Herndon & I. Sharma*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02012)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-6dncp) 🔓

The authors harness sulfenylcarbenes, which selectively react with alkenes in the presence of more reactive functional groups such as alcohols, carboxylic acids, and amines, to insert a single carbon atom bearing diverse functional groups into pyrroles, indoles, and imidazoles to create synthetically challenging pyridines, quinolines, and pyrimidines, respectively.

Electrochemical Benzylic C–H Carboxylation

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

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00259)

The authors report a direct benzylic C–H carboxylation via halide-promoted linear paired electrolysis to construct a wide range of primary, secondary, and tertiary benzylic carboxylic acids under mild reaction conditions using a transition-metal- and base-free protocol. The direct synthesis of drug molecules, including: Flurbiprofen, Ibuprofen and Naproxen, was demonstrated alongside the late-stage modification of complex compounds.

Cyclic Bifunctional Reagents Enabling a Strain-Release-Driven Formal [3+2] Cycloaddition of 2H-Azirines by Cascade Energy Transfer

A. Petti,^† M. J. Karrasch,^† P. Chahar,^† F. H. Wessels, N. Hölter, F. Boser, C. G. Daniliuc & F. Glorius*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18080) 🔓

The energy transfer-catalyzed ring opening and further decarboxylation of isoxazole-5(4H)-ones enables the in situ generation of strained 2H-azirines. Subsequent selective C(sp²)–C(sp³) bond cleavage of the azirine intermediate allows a formal [3+2] cycloaddition with a range of electrophiles, unlocking access to valuable pyrroline-type moieties. This mild and straightforward method rapidly constructs highly substituted cyclic imines, which can be converted into pyrrolidines, fused oxaziridines, and biologically relevant β-amino acid precursors.

Rh-Catalyzed Enantioselective Aryl C–H Bond Cyclopropylation

E. Palomo, A. Krech,^‡ Y. J. Hsueh,^‡ Z. Li & M. G. Suero*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02331) 🔓

The authors disclose the discovery and development of a site-, regio-, diastereo-, and enantioselective aryl C–H bond cyclopropylation using diazomethyl hypervalent iodine reagents, styrenes, and paddlewheel dirhodium carboxylate catalysts. The strategy enables the construction of cyclopropane rings using aryl C–H bonds from aromatic feedstocks and drug molecules, reaching unexplored “cyclopropanated” chemical space difficult to reach by current strategies.

Regiodivergent Hydroamidation of Alkenes via Cobalt–Hydride Catalysis

B. Liu,^† Q. Lu,^† X. Hu,^† D. Li, Z. Xu, X. Lu,* Y. Fu* & Q. Liu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03484)

The authors report a cobalt-catalyzed regiodivergent hydroamidation of alkenes, enabling enantioselective ipso- and migratory hydroamidation of heterocyclic alkenes with selectivity governed by the choice of cobalt catalyst anions. This protocol exhibits a broad substrate scope, high functional group tolerance and provides an efficient pathway for synthesising structurally diverse amides.

Stereogenic P(V) Synthesis via Catalytic Continuous Substitutions

G.-L. Zheng, Y. Zhang, J.-M. Zhang, L. Chen, X.-S. Xue* & Z.-T. He*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00591)

The authors report a modular strategy to access a variety of stereogenic-at-phosphorus skeletons through designed enantioselective continuous substitutions of simple P(V) precursors. The nucleophilic substitution sequence readily determined the stereoconfiguration of the products and the concise synthesis of ProTide analogs and drug molecules demonstrated the value of the protocol.

Late-Stage Cross-Electrophile Coupling of Arylthianthrenium Salts with (hetero)Aryl (pseudo)Halides via Palladium Catalysis

Y. Xie, L. Zhang & T. Ritter*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202502441) 🔓

The authors present the late-stage cross-coupling of arylthianthrenium salts with diverse (hetero)aryl (pseudo)halides under reductive conditions, in which a palladium(0) catalyst differentiates between two aryl electrophiles based on their respective rates of oxidative addition. The robustness of this method was demonstrated by coupling of two complex fragments that would otherwise be difficult to access in a single step.

Site-Selective Carbonylation of Azetidines via Copper-Catalyzed Difluorocarbene Insertion

F. Zhou,^† T.-D. Tan^† & M. J. Koh*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202505033) 🔓

The authors report a new method to synthesize functionalized γ-lactams through formal carbonylation of azetidines under non-precious metal catalysis. The method leverages a copper-stabilized difluorocarbene to promote site-selective insertion followed by in situ hydrolysis to unmask the lactam group. The utility of this approach was demonstrated through the synthesis of various drug-like lactams and a therapeutic agent for diabetes.

A Rh(II)-Catalyzed Atropisomer Selective Ring Expansion of 3-Aryl Indoles to 4-Aryl Quinolines

R. J. Zanolini,^† M. Basilaia,^† N. K. Dogan, G. J. Rustin, T. Regganie, N. J. Susskind, Y. Mao, & J. L. Gustafson*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-bv1kn) 🔓

The authors report the Rh(II)-catalyzed atropisomer selective ring expansion of 3-aryl indoles with α-halodiazoacetates to furnish 4-aryl quinolines in good yields and enantioselectivity, with strong correlations between enantioselectivity and steric bulk observed at different positions of the substrate. The isolated products were readily further functionalized to allow for a wide array of enantioenriched quinolines.

Construction of Sulfur Stereocenters by Asymmetric Geminate Recasting

A. Porey, R. Trevino, S. Nand, S. O. Fremin, S. K. Dhakal, B. R. Dhungana, A. Das, V. T. B. Nguyen, W. T. Thompson, D. P. Moran, C. K. Giri, H. D. Arman, D. J. Wherritt & O. V. Larionov*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-tmrg8) 🔓

The authors report how “asymmetric geminate recasting”, which involves the homolysis and recombination of a radical pair in a solvent cage promoted by a chiral photocatalyst, can construct chiral sulfur stereocenters through the deracemization of sulfinamides using a bespoke chiral indium photocatalyst.

💡 Short highlight: Here’s an interesting ChemRxiv paper entitled “Contrary to Popular Belief, B₂pin₂ is Not Air Stable”.

Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor

G. McKenna,^† C. Cruz,^† B. Simmons,* J. T. Brewster II,* A. M. Benz-Weeden, T. A. Brandt, Q. A. Bumpers, A. Cook, M. S. A. Elsayed, D. Golec, N. Lewandowski, P. Nguyen, R. W. Pipal, P. Savechenkov, C. E. Wong, E. Tarlton, J. J. Gaudino, R. J. Hinklin* & T. P. Tang

Org. Process Res. Dev. 2025, ASAP (DOI: 10.1021/acs.oprd.4c00441)

The authors report the kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063, using synthetic planning rooted in the “12 Principles of Green Chemistry”, which led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity, increased the yield of the final API, and allowed for the purification of key intermediates through crystallization, among other improvements.

Rapid Access to 3-Substituted Bicyclo[1.1.1]pentanes

K. I. Burton & D. W. C. MacMillan*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102537)

The authors disclose a mild, unified method for the preparation of both alkyl- and aryl-substituted bicyclo[1.1.1]pentanes (BCPs) from bench-stable precursors. This method, which proceeds via dual copper-photoredox catalysis, is capable of installing BCP functionalities onto a range of saturated motifs, aryl-containing residues, and medicinally relevant heterocycles.

Advancing Total Synthesis Through Skeletal Editing

R. Al-Ahmad & M. Dai*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.5c00030) 🔓

The authors detail their work using skeletal editing-based retrosynthetic logic to facilitate natural product synthesis, highlighting: (i) two one-carbon insertion strategies to streamline the total syntheses of complanadine and phleghenrine, (ii) the synthesis of crinipellin and gibberellin diterpenes by leveraging the intrinsic strain of cyclobutanes as precursors to cyclopentanes via cut-and-insert editing or C–C bond migratory ring expansion, and (iii) early efforts in orchestrating structural rearrangement and functional group pairing reactions to access seven monoterpene indole alkaloids and highlight the divergent potential of skeletal editing.

154 Million Lives

💉 154 million lives. I’ve written about this statistic before but now Nature have just released a powerfully illustrated article on the 154 million lives that have been saved through global vaccination efforts since 1974—as I mentioned previously, that’s 6 lives for every minute of every year. So, why are Nature reporting on this figure now? Well, a second confirmed death from the ongoing measles outbreak surging throughout the US has sparked fears that the situation may be worse than originally thought.

Since last writing about this only three weeks ago, the number of confirmed cases has nearly doubled from 378 to 712 with 97% of those occurring in unvaccinated individuals and 11% requiring hospitalisation. In the developed world, people have the luxury of forgetting about diseases like measles or polio, as though they are a relic of the past or worse, believing that they are equivalent to the cold or flu. This makes it easy for anti-vaccine campaigners to prey on the vulnerable and misinformed, and having Robert F. Kennedy Jr. as the US Secretary of Health and Human Services certainly doesn’t help.

Sadly, the two confirmed measles deaths mentioned above were both children, who typically suffer the most from anti-vaccine rhetoric. Only 50 years ago, 10% of newborn babies died in their first year of life, that numbers is now less than 3%, in large part due to vaccinations. Another success story is the eradication of smallpox, an acute contagious disease that was fatal in 30% of cases before it was eradicated globally in 1980. Imagine that, a disease that caused millions of deaths and existed for over 3000 years, wiped out by a concerted, global vaccination effort…

Eliminating cervical cancer may also be on the horizon within the next century. Most cases are linked to infection with the human papillomavirus (HPV) and almost all these cases can be prevented with the HPV vaccine. In fact, last year in Scotland, a study found that no cervical cancer cases had been detected in fully vaccinated women following HPV immunisation at age 12–13 since the programme started in Scotland in 2008.

💡 For those who haven’t seen this yet, Kennedy is now pledging to “find the cause” of autism by September, seemingly ignoring all the research that has already been done in this area (spoiler: it’s not vaccines). For a thorough, scientific debunking of the anti-vaccine movement, I’d recommend reading “Vaccines Did Not Cause Rachel's Autism” by Dr. Peter J. Hotez.