Upgrading Pyridine

Transformation of Pyridines into 2D and 3D Fused Bicyclic Heterocycles

X. Tao, H. Han,^‡ J. Jeong,^‡ D. Kim & S. Hong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06469)

The authors report a metal-free approach for converting pyridines into planar (2D) and three-dimensional (3D) fused bicyclic heterocycles through an orchestrated sequence of nucleophilic addition, 6π-electrocyclic ring opening/ring closure, and fused ring formation. The methodology exploits the unique reactivity of N-pyridinium salts with hydrazine nucleophiles, accommodating diverse functional groups in a sequential one-pot protocol. Notably, the newly synthesized pyrazolopyridazine scaffolds exhibit low-micromolar inhibitory activity over JNK1.

A Selenoxide for Single-Atom Protein Modification of Tyrosine Residues Enabled by Water-Resistant Chalcogen and Hydrogen Bonding

S. Lin,^† M. Hirao,^† P. Hartmann, M. Leutzsch, M. S. Sterling, A. Vetere, S. Klimmek, H. Hinrichs, J. M. Mengeler, J. Lehmann, J. Samsonowicz-Gόrski, F. Berger & T. Ritter*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01842-8) 🔓

The authors report a C–H functionalization reaction of tyrosine residues to access peptides and proteins modified by small structural changes including single-atom substitutions. A rationally designed selenoxide introduces a versatile selenonium linchpin featuring a C_tyr–Se bond that can be used for further transformations at specific tyrosine residues. Key to the advance is the interplay of water-resistant, intramolecular chalcogen and hydrogen bonding of the selenoxide reagent, which allows chemo- and site-selective electrophilic aromatic substitution of tyrosine residues in aqueous solutions.

Thianthrenium-Enabled Modular Synthesis of Bicyclo[1.1.1]pentanes

Z. Bai, Z. Wang, T. H.-F. Wong & T. Ritter*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00821-8) 🔓

The authors describe a stable, bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT⁺) reagent for modular BCP bioisostere production. The cationic thianthrenium group at the neopentyl site of IBM-TT⁺ facilitates chemoselective substitutions through electrostatic interactions, overcoming the high energy barriers of bimolecular nucleophilic substitution (S_N2) at neopentyl sites. The retained BCP iodide functionality serves as a second versatile handle for metal–halogen exchange, photoredox chemistry or transition-metal catalysis.

Cooperative Organosulfur/Photoredox Catalysis Enables Radical-Polar Crossover C(sp³)–N Coupling via Inner-Sphere Electron Shuttling

Y. Hong, C. Park, J. Jang, M. Oh, D. Kim, S. Lee* & S. Y. Hong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00352)

The authors present a cooperative catalytic platform that diverts the radical-polar crossover mechanism from outer-sphere to inner-sphere manifolds, enabling C(sp³)–N coupling of redox active esters with otherwise oxidizable (hetero)arylamines. The key to success was the identification of an organosulfur catalyst capable of selectively shuttling electrons between the photocatalyst and the incipient radical in preference to competing arylamine oxidation.

Divergent Total Syntheses of Rearranged Steroids Swinhoeisterols A–C

G. Huang, X. Zhang, Y.-C. Gu & J. Gui*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07053)

Swinhoeisterols A–C are 13(14→8),14(8→7)-di-abeo steroids possessing a 6/6/5/7 tetracyclic core framework and potent inhibitory activity against histone acetyltransferase p300. Here, the authors report their divergent total syntheses from (S)-Wieland–Miescher ketone utilizing a tandem Negishi/Heck cross-coupling of a chloroenol triflate to install a methylenecyclopentene motif, which undergoes a Baran reductive olefin coupling to enable the simultaneous construction of the seven-membered ring and two contiguous stereocenters, including a quaternary carbon center.

Alkyl Fluoride Synthesis via Cu-Mediated Deacetylative Fluorination

Z. Zhang, K. Chen, P. Liu & G. Dong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c08175)

The authors report a Cu-mediated deacylative fluorination approach that can convert a wide range of methyl ketones to the corresponding alkyl fluorides using a ketone activation reagent and a nucleophilic fluoride source. The reaction features broad functional group tolerance and the capability for: (i) late-stage fluorination, (ii) fluoro-annulation, (iii) synthesis of α,α-di-deuterated fluorides, and (iv) degree-controlled synthesis of mono-, di-, and trifluoro alkanes from a single ketone starting material.

Iridium-Catalyzed Nitrene-Mediated Enantioselective 1,2-Hydride Shift Enabled by Attractive Noncovalent Interactions for Chiral δ-Lactam Synthesis

Q.-K. Fan, Z.-Q. Bai, G. He, G. Chen & H. Wang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03919)

The authors introduce a nitrene-mediated strategy that generates carbocation intermediates through intramolecular metal-nitrenoid transfer to alkenes, followed by a ligand-enabled, stereocontrolled, and accelerated 1,2-hydride shift facilitated by attractive noncovalent interactions. The methodology yields δ-lactams bearing contiguous γ,δ-stereocenters with excellent yields, enantio- and diastereoselectivities (>95% e.e., >20:1 d.r. in most cases).

Palladium-Catalyzed Methylene β-C–H Fluorination of Native Amides

Y.-H. Li & J.-Q. Yu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06237)

The authors report a ligand-accelerated Pd-catalyzed methylene β-C–H fluorination of native amides using a bidentate neutral amide-pyridone ligand. This ligand design features the enhancement of catalyst-substrate interactions via stabilization of the cationic palladium center and acceleration of methylene C–H activation, enabling the stereo- and site-selective fluorination of native amides under relatively mild conditions.

Development of Sclareol- and Sclareolide-Based Chemoenzymatic Approaches to Ring Intact and Seco Limonoids

F. Chen, J. Li & H. Renata*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06404)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-ftj6v) 🔓

The authors report a chemoenzymatic strategy toward various limonoids from two feedstock terpenes, sclareol and sclareolide. An initial route starting from sclareol delivered the limonoid tetracyclic skeleton but lacked the versatility to access more oxidized family members. A second-generation strategy from sclareolide was conceived to allow convergent access to gedunin, Corey’s protolimonoid, nimbocinol and azadiradione. Finally, the strategy was further extended to the synthesis of two ring-seco limonoids, methyl angolensate and mexicanolide.

Asymmetric Total Synthesis of 4,9,10-Trihydroxyguaia-11(13)en-12,6-olide and Discovery of Its Anticancer Activity against Atypical Teratoid Rhabdoid Tumor

H. Lee, H. Jang, H. Myung, A. Rivera, A. F. Averette, J. Heitman, J. Park, D. Kim, H. Kim & J. Hong*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00332) 🔓

4,9,10-Trihydroxyguaia-11(13)en-12,6-olide (1) is a newly identified 6,12-guaianolide with an underdetermined absolute stereochemistry isolated from the genus Anvillea garcinii. Here, the authors report the asymmetric total synthesis and initial assignment of 1 in 20 steps from (R)-limonene with an overall yield of 4%. Preliminary biological testing of 1 uncovers new anticancer activity against rare and aggressive childhood atypical teratoid rhabdoid tumor (ATRT) and other cancer cell lines.

Harnessing Bifunctional N-Benzoyloxyamides for Photoredox Amidative Dual Functionalizations of Alkenes

H. Ryoo,^† H. Keum,^† D. Kim & S. Chang*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506290)

The authors present a photocatalytic strategy for the intermolecular dual functionalizations of alkenes using N–O bifunctional reagents. By leveraging N-benzoyloxyamides as bifunctional precursors for generating both amidyl radical and internal O-nucleophiles, this approach achieves chemoselective olefin amidation with simultaneous incorporation of additional functional groups. The current method readily accesses a range of doubly functionalized amino products through 1,2-amidooxygenation, amidoazidation, and formal anti-Markovnikov hydroamidation.

Ni-Catalyzed Reductive Coupling of Acetals with Anhydrides and Vinyl Triflates via Single-Electron C–O Activation: A Polarity-Convergent Approach to Native and Umpolung Aldehyde Reactivity

E. Kim,^† M. A. Borden,^† J. Hwang, A. G. Doyle* & S. Dongbang*

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

The authors report a Ni-catalyzed reductive cross-coupling of benzaldehyde-derived acetals with acyl anhydrides or vinyl triflates that provides modular access to α-substituted ethers. A Lewis acid and a zinc reductant convert the acetal substrates to α-oxy alkyl radicals, which undergo selective C(sp³)-C(sp²) bond formation mediated by a Ni catalyst.

Modular Access to N–SF₅ Azetidines

R. Li,^† C. Hu,^† C. Liu,^† T. Lyness, W. Li, C.-Y. Cai, E. Crossley, Y. Kanda, R. R. Merchant, B. S. Matsuura, N. S. Williams & T. Qin*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-q0c07) 🔓

The authors have developed a modular coupling approach using bench-stable, scalable SF₅-transfer reagents to enable efficient access to N–SF₅ azetidines. The method provides a user-friendly protocol with mild reaction conditions and broad functional group tolerance, and the resulting scaffolds demonstrate high aqueous stability and lipophilicity.

👉️ For recent, complementary methodology towards N–SF₅ azetidines, see here and here, for two papers from the groups of C. R. Pitts and A. Tlili, respectively.

Bidirectional Modification of a Galbulimima Alkaloid Identifies Selective Opioid Ligands

F. M. Zielke,^† S. Woo,^† S. Kasmali,^† A. Volf, V. Dang, J. B. Bailey, M. Gembicky, L. M. Bohn* & R. A. Shenvi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-642tw) 🔓

The authors report a bidirectional diversification and optimization campaign of the newly identified mu- and kappa-opioid receptor antagonist GB18, a naturally occurring Galbulimima alkaloid. First, replacement of the piperidine with pyridine was found to alter the pharmacology from antagonism to partial agonism, with reduced potency but higher receptor selectivity for kappa- over mu-. Second, this hit was optimised via development of a mutually chemoselective cross-coupling of an alkyl iodide/vinyl triflate pair that lead to a series of low- and sub-nanomolar KOR-selective full agonists, some of which demonstrate bias for G protein activation over βarrestin2 recruitment. Third, three leads were advanced to in vivo (mouse) analysis and demonstrated brain penetrance and behavioral effects. In an open-field activity assay, it was demonstrated that by increasing G protein signaling preference, agonists display an increase in exploratory, anxiolytic-like behaviors with no signs of sedation.

Catalytic Acyloin-Type Heterocoupling of Thioesters via a Putative Cobalt Siloxycarbene

L. Kong,^† K. Zong,^† J. Guo & R. Shenvi*

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

The authors report a method to access α-siloxycarbenes from thioesters via reductive silylation of cobalt acyls. The reaction effects carbonyl dimerization with unprecedented hetero- and stereoselectivity to yield unsymmetrical tetrasubstituted disiloxyalkenes, while avoiding competitive decarbonylation. These products could be further elaborated to new functionalized fragments, heterocycles, and challenging enolsilanes.

Radio Silence

📻️ Radio silence. Nature have just released their selection of the best science images in May, featuring a strong solar flare, captured by NASA’s Solar Dynamics Observatory (SDO) on the 14^th May. The “X-class” flare, which ranks it amongst the most intense solar flares, triggered several radio blackouts across Europe, Asia and the Middle East—the side of the Earth that was sunlit at the time—due to ionization of Earth’s upper atmosphere from the flare’s intense outburst of electromagnetic radiation. Under normal conditions, high frequency radio waves travel long distances by refraction in the upper atmosphere; however, during these powerful solar flares, they lose energy through absorption or scattering, causing the signal to degrade or be lost entirely.

💻️ Let there be light. Be sure to catch the German Chemical Society’s next Medicinal Chemistry webinar on Tuesday 24^th June from Dr. Maria Mendez of Sanofi on the “Discovery and Optimization of a New Class of RIPK1 Inhibitors Enabled by Late-Stage Photoredox Catalysis”.