Ironing Out Carbene Stability

Harnessing Carbene Polarity: Unified Catalytic Access to Donor, Neutral, and Acceptor Carbenes

K. N. M. Nguyen,^† X. Mo,^† B. M. DeMuynck,^† M. Elsayed,^‡ J. J. A. Garwood,^‡ D. T. Ngo,^‡ I. K. Rana^‡ & D. A. Nagib*

Science 2025, 389, 183–189 (DOI: 10.1126/science.adw4177)

The authors report a unified strategy to access a full range of carbenes, including those with donor substituents (EDG: OMe, NR₂, alkyl), acceptor substituents (EWG: CN, CO₂R), and electronically neutral or non-polar substituents (H, BR₂, SiR₃, halide, aryl, heteroaryl). This Fe-catalyzed method harnesses α-Cl radicals and couples an exceptionally wide array of carbenes in [2+1] cyclopropanations and σ-bond insertions. This mild, robust, and electronically tunable synthetic method facilitated the development of a better classification system for catalytic metal carbenes, as well as a carbene “click-like” reaction and aqueous adaptation for chemical biology applications.

Stereodivergent Synthesis of Perhydrobenz[e]indene Terpenoids

C. Yang, C. J. Huck, Y. D. Boyko, S. Ning, U. Vezonik, A. S. Shved, S. E. Denmark, B. K. Mai* & D. Sarlah*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07068)

The authors describe a stereodivergent Rautenstrauch rearrangement in which a choice of Au- or Pd-based catalyst provided uniform entry toward all four possible stereoisomers of the 6/6/5 tricyclic core of perhydrobenz[e]indene terpenoids, ultimately leading to the total syntheses of several distinctive perhydrobenz[e]indene natural products, including N-acetyl-polyveoline, dasyscyphin B, and rhabdastin B.

Monofluoromethyl Radical Mediated Halogen-Atom Transfer

N. Ramkumar,^† A. P. Raiskuma,^† L. Baumane, S. Belyakov, K. Traskovskis & J. Veliks*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c08589) 🔓

The authors present a novel halogen-atom transfer (XAT) method that eliminates the need for photocatalysts by utilizing the direct excitation of a monofluoroacetoxy ligand-containing hypervalent iodine(III) reagent. This approach allows nucleophilic monofluoromethyl radicals to efficiently form carbon radicals from activated alkyl halides. These radicals can subsequently functionalize unactivated alkenes through atom transfer radical addition (ATRA).

Ni-Catalyzed Reductive Ring Contraction via Desulfurative Cross-Coupling

J. Zhou & R. Y. Liu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07642)

The construction of C–C bonds by contractive “deletion” of the sulfur atom from a C–S–C motif is a useful transformation for the synthesis of complex heterocycles. A few homogeneous metal systems have been reported to mediate such desulfurizations, but under harsh conditions and without catalytic turnover. Here, the authors report a catalytic solution using an accessible Ni precatalyst, inexpensive additives, and mild conditions to provide access to a broad scope of fused heterocycles.

Data Science-Guided Development of Deoxyfluorination Reagents with Enhanced Reactivity, Practicality, and Safety

M. E. Ruos, N. P. Romer,^‡ J. A. Deichert,^‡ L. M. Alabanza, S. S. Gandhi, G. Z. Brown, R. C. Walroth, K. Cruz, F. Gosselin, A. Y. Hong,* M. S. Sigman* & A. G. Doyle*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07548)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-l4zvs) 🔓

The authors report the discovery and development of several new (hetero)aryl sulfonyl fluoride reagents that have enhanced deoxyfluorination reactivity, improved physical properties, and excellent safety profiles compared to those of PyFluor and other fluorination reagents. The top-performing reagents demonstrated broad applicability across diverse alcohol substrate classes, including complex natural products and active pharmaceutical ingredients.

Enantioconvergent Chan–Lam Coupling: Synthesis of Chiral Benzylic Amides via Cu-Catalyzed Deborylative Amidation

J. Vu, G. C. Haug, T. J. Schubert, J. F. Head, R. S. Paton* & Y. Dong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05884)

The authors demonstrate the first enantioconvergent Chan–Lam C(sp³)–N coupling using synthetically modular alkylboronic pinacol esters. The transformation imparts a high degree of enantioselectivity and tolerates a wide range of functional groups, heterocycles, and pharmaceutically relevant frameworks.

[1,3]-Hydride Shift in α-Boryl Cations: Strategic Design of Fluorine-Triggered Cyclopropanation

S. Han, Y. Lee, J. Seo, J. Lee & S. H. Cho*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c08276)

The authors report direct observation and synthetic demonstration of the [1,3]-hydride shift using α-fluoro-diborylalkanes. Initial [1,2]-fluoride migration generates an α-boryl cation that selectively undergoes a [1,3]-hydride shift via a three-center two-electron interaction, enabling efficient synthesis of cyclopropyl boronic esters.

Pericyclic Umpolung in a Catalytic Asymmetric Diels–Alder Reaction of Tropone with Enol Ethers

T. Zheng,^† Z. Wang,^† B. Mitschke, N. Nöthling, M. Leutzsch, F. Neese & B. List*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05709) 🔓

The authors report a chiral confined acid-catalyzed, asymmetric Umpolung of the Diels–Alder reaction whereby tropone reacts with enol ethers to deliver “contra-FMO” products with high yield, stereoselectivity, and regioselectivity. Mechanistic and computational studies indicate that a network of attractive noncovalent interactions, including π–π-interactions, nonclassical hydrogen bonding, and dispersion, governs the inverted regioselectivity.

Concise Synthesis of Fostriecin and Analogs through Late-Stage Chemoenzymatic Installation of Their Key Pharmacophores

Y. Jiang,^† X. Yu^† & H. Renata*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05269)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-c4zc6) 🔓

The authors report a modular chemoenzymatic approach to fostriecin and its analogs in a collective manner in 9 steps (longest linear sequence) from readily available (R)-1,2,4-butanetriol. The synthesis features a convergent assembly of three key fragments and a late-stage chemoenzymatic derivatization of an advanced intermediate that (i) installs two of the key pharmacophores and (ii) allows ready diversification of the hydrophobic tail.

Enantioconvergent Radical-Radical Cross-Coupling via Magnesium-Mediated Charge-Transfer Photocatalysis

L. Yan, H.-Q. Yang, W.-L. Yu, X.-G. Zhang & P.-F. Xu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03154)

This study introduces an asymmetric photochemical bifunctional catalytic process that utilizes a combination of magnesium salts and chiral PyBOX-type C₂-symmetric ligands under visible light irradiation to enable the selective α-amidation of β-keto esters via an N-centered radical mechanism, facilitating the synthesis of substituted β-keto amino acid derivatives with a fully substituted stereocenter. The reaction proceeds in good yields (up to 79%) and excellent enantioselectivity (up to 94%).

Bidirectional Modification of a Galbulimima Alkaloid Identifies Selective Opioid Ligands

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

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00573) 🔓

The authors report a bidirectional diversification and optimization campaign of the mu- and kappa-opioid receptor antagonist GB18, a naturally occurring Galbulimima alkaloid. First, piperidine to pyridine replacement altered the pharmacology from antagonism to partial agonism, with reduced potency but higher selectivity for kappa- over mu-. Second, this was optimized via a mutually chemoselective cross-coupling of an alkyl iodide/vinyl triflate pair that led to a series of KOR-selective full agonists, some of which demonstrated bias for G protein activation over β-arrestin2 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 displayed an increase in exploratory, anxiolytic-like behaviors with no signs of sedation.

Visible Light Promotes P^III/P^V-Catalyzed Reductive N-Arylation of Nitroarenes at Room Temperature

B. Kang, M. N. Lavagnino, J. B. Gordon, K. G. Reynolds, D. G. Nocera & A. T. Radosevich*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c04341)

Visible-light irradiation is found to accelerate the reductive coupling of nitroarenes and arylboronic acids under the conditions of P^III/P^V catalysis. Specifically, blue-light (λ_exc = 427 nm) illumination of a catalytic mixture composed of a redox active main group catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide) and terminal reductant (1,3-diphenyldisiloxane) enables formation of diarylamines from nitroarenes and arylboronic acids at ambient temperature.

Overcoming Limitations in Chan-Lam Amination with Alkylboronic Esters via Aminyl Radical Substitution

H. Xiao, P. Cao, W. Xiong & T. Yang*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-8kq46) 🔓

The authors report an N-alkylation protocol that overcomes the limitations of boron-to-copper transmetalation in Chan-Lam couplings by using alkylboronic pinacol esters as radical precursors via aminyl radical-mediated boron abstraction. This approach enables the N-alkylation of a wide range of N-nucleophiles with boronic esters containing diverse functional groups. The utility of this protocol was demonstrated through the sequential N-alkylation of a substrate with multiple reactive sites, and the late-stage modification of complex bioactive molecules.

👉️ For recent, complementary methodology on the use of aminyl radical-mediated boron abstraction to overcome sluggish boron-to-copper transmetalation in C(sp³)–N couplings, see here, for a paper from Sang and Gestwicki.

Thianthrenium Salt Mediated Homologative 1,3-Dielectrophilic Activation Strategy for Alkene Difunctionalization

S. Paul,^† A. Richardson,^† L. Buck, G. Centonze, R. Coccia, F. Sardelli & M. Silvi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-xvts1) 🔓

The authors disclose a thianthrenium salt mediated homologative dielectrophilic activation method for unactivated alkenes, which provides access to 1,3-diazides, diamines, diols, dihalides, dithiols as well as their heterodifunctionalized products with complete regiocontrol. At the core of this strategy is a novel sulfonium atom-transfer reagent, which undergoes selective bond cleavage to reveal a methyl thianthrenium radical, a versatile electrophilic homologative synthon.

A Flexible and Affordable Self-Driving Laboratory for Automated Reaction Optimization

S. Pilon,^† E. Savino,^† O. M. Bayley,^† M. Vanzella, M. Claros, P. Siasiaridis, J. Liu, F. Lukas, M. Damian, V. Tseliou, N. Intini, A. Slattery, J. S. J. Orduna, T. den Hartog, R. A. H. Peters, A. F. G. Gargano, F. G. Mutti & T. Noël*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-73xqf) 🔓

The authors introduce RoboChem-Flex, a low-cost, modular self-driving laboratory platform designed to democratize autonomous chemical experimentation. The system combines customizable, in-house-built hardware with a flexible Python-based software framework that integrates real-time device control and advanced Bayesian optimization strategies, including multi-objective and transfer learning workflows. The platform was validated across six diverse case studies, including photocatalysis, biocatalysis, thermal cross-couplings, and enantioselective catalysis, spanning both single and multi-objective optimizations.

Skeletal Editing: Where Are We Now?

✂️ Skeletal editing: where are we now? A decade ago, photoredox catalysis was taking the organic chemistry world by storm—it still is to some extent. However, I think most people would agree that the focus has shifted towards skeletal editing, not that the two can’t overlap (they frequently do).

Both fields have a rich history. Photochemistry, for example, dates back centuries and I’m sure everyone has seen the iconic image of photochemistry pioneer Giacomo Ciamician, standing on the terrace of his lab at the University of Bologna, surrounded by flasks basking in the Italian sun. That photo was captured around 1912, over 30 years after Ciamician discovered the Ciamician–Dennstedt rearrangement, arguably the first example of a skeletal editing reaction.

Today, photochemistry, electrochemistry, and even enzymes have opened up new avenues for what we would consider “modern” skeletal editing (e.g. single-atom edits) using milder, more selective conditions. Reactions that were once considered “moonshots” in 2018 have been brought to life only 4 years later by pioneers such as Mark Levin and Richmond Sarpong.

Interest in skeletal editing is growing fast. A 2023 Nature article noted that in the two years prior to its publication, over 100 research papers had already mentioned the field—a number that has surely grown since. If you’re interested in the history of skeletal editing, its major players, and its potential to shape drug discovery, C&EN have recently published an excellent feature: “Skeletal editing: How close are we to true cut-and-paste chemistry?”—well worth a read, and to consider which centuries-old techniques might be modernised into the next big thing.