Dynamic Orbital Selection

Generalizing Arene C–H Alkylations by Radical-Radical Cross-Coupling

J. Großkopf, C. Gopatta, R. T. Martin, A. Haseloer & D. W. C. MacMillan*

Nature 2025 (DOI: 10.1038/s41586-025-08887-2)

Traditionally, the direct alkylation of arenes is achieved under Friedel–Crafts reaction conditions using strong Brønsted or Lewis acids, resulting in poor functional group tolerance and low selectivity, limiting their implementation in late-stage functionalization. Here, the authors report a novel strategy for the selective coupling of differently hybridized radical species, termed dynamic orbital selection. This mechanistic paradigm overcomes common limitations of Friedel-Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst based on their respective binding properties. As a result, a general and modular reaction has been developed for the direct alkylation of native arene C–H bonds using alcohols and carboxylic acids as the alkylating agents.

Iron-Catalysed Direct Coupling of Organosodium Compounds

I. Takahashi,^† A. Tortajada,^† D. E. Anderson, L. Ilies,* E. Hevia* & S. Asako*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00771-1) 🔓

Organosodium reagents have traditionally been considered as highly reactive, engaging in uncontrollable reactions, and as a result have been scarcely used in organic synthesis, especially in combination with transition-metal catalysis. Here, the authors report the use of organosodium compounds as C(sp²)–Na nucleophilic partners in iron-catalysed oxidative homocoupling and cross-coupling with alkyl halides.

Photoinduced Nickel-Catalysed Enantioconvergent sp³–sp³ Coupling of Unactivated Olefins and Aziridines

L. Zhang, H. Wang, T. G. Santiago, W.-J. Yue & R. Martin*

Nat. Catal. 2025 (DOI: 10.1038/s41929-025-01319-4)

Although the ready availability of olefins and aziridines makes them ideal precursors to forge enantioenriched sp³–sp³ architectures with added-value amine functions, an enantioconvergent catalytic scenario of these counterparts has not yet been realized. Here, the authors describe a nickel-catalysed blueprint that enables the enantioselective construction of amine-containing sp³–sp³ architectures via photoinduced enantioconvergent coupling of racemic aziridines with alkylzirconium reagents generated in situ from unactivated terminal and even internal olefins.

Photoinduced, Copper-Catalyzed Enantioconvergent Synthesis of β-Aminoalcohol Derivatives

A. Mondal & G. C. Fu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02417)

While the substitution of an alkyl electrophile by a nitrogen nucleophile is a seemingly straightforward approach to generate a C–N bond, classical substitution pathways have limitations in the case of unactivated secondary and tertiary alkyl electrophiles. Therefore, recent reports that transition metals can catalyze substitution reactions of such electrophiles are of considerable significance; however, virtually no methods have been developed where absolute stereochemistry is controlled together with C–N bond formation. Here, the authors address this dual challenge by describing a photoinduced, copper-catalyzed enantioconvergent synthesis of β-aminoalcohol derivatives via the coupling of anilines with racemic, unactivated β-haloethers.

Total Synthesis of Enlicitide Decanoate

H. Li, D. A. Thaisrivongs,* G. Shang,* Y. Chen, Q. Chen, L. Tan, K.-J. Xiao, R. T. Larson, J. T. Kuethe, J. Lee, N. R. Deprez, A. F. Nolting, M. Poirier, P. G. Bulger, E. L. Regalado, M. Biba, F.-R. Tsay, J. DaSilva, C. K. Prier, C. A. Strulson, K. Zawatzky, Z. Liu, J. A. Newman, K. Sokolowsky, W. Tang, K. Hullen, N. Thakur, C. Welch, S. Patel, Y. He, J. Xu, N. Variankaval, A. Klapars, J. Kong, R. Desmond, R. Varsolona, P. E. Maligres, C. A. P. Siepermann, L. Robison, T. Piou, C. Hartmanshenn, A. Chandra, A. Patel, M. R. Becker, G. Liu, J. Duan, B. Wan, C. Xiao, Y. Yuan, X. Cao, L. Chen, R. Yi, Z. Wu, M. Feng, D. Li, Z. Song, Y. Dong, J. Sun B. Li, G. Shao, L.-C. Campeau & J. Yin

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15966)

The authors report the total synthesis of enlicitide decanoate, an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 that is being developed for the treatment of atherosclerotic cardiovascular disease. It is a highly complex macrocyclic peptide with a significant number of nonpeptide structural elements that presents a daunting synthetic chemistry challenge. The development of a convergent, efficient, and robust manufacturing process that enables the large-scale production of enlicitide has been described.

Configuration Retention in P-Trifluoromethyl Phosphine Enabled Rh(I)-Catalyzed Decarbonylative Coupling of Carboxylates and Boroxines

S. Zhang, B. Li & S. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03546)

Decarboxylative cross-coupling has become an important strategy for C–C or C–X bond formation due to its versatility, and the low cost and structural diversity of carboxylic acids. However, memory of chirality, or more general retention of configuration in this transformation has seldom been studied. Here, the authors report a novel π-acceptor-type ligand, P-trifluoromethyl phosphine, for the Rh(I)-catalyzed decarbonylative coupling of carboxylates and boroxines, where the configuration of the α-carbon can be fully retained in this transformation for chiral, cis-, or trans-substrates.

An Atomically Dispersed Mn Photocatalyst for Vicinal Dichlorination of Nonactivated Alkenes

P. K. Sahoo,^† R. Maiti,^† P. Ren, J. J. D. Jaén, X. Dai, G. Barcaro, S. Monti, A. Skorynina, A. Rokicińska, A. Jaworski, L. Simonelli, P. Kuśtrowski, J. Rabeah & S. Das*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16413)

A novel Mn-based single-atom photocatalyst is disclosed for the dichlorination of alkenes to achieve vicinal dichlorinated products using N-chlorosuccinimide as a mild chlorinating agent. In developing this catalyst, the atomic dispersion of Mn on aryl-amino-substituted graphitic carbon nitride (f-C₃N₄) was achieved, marking the first instance of a heterogeneous version and offering an operationally simple, sustainable, and efficient pathway for the dichlorination of alkenes. This material was extensively characterized to understand it at the atomic level, and gram-scale and reusability tests were performed to demonstrate its applicability on an industrial scale.

Ligand-Controlled Regioselective Dearomative Vicinal and Conjugate Hydroboration of Quinolines

C. Hu,^† C.-Y. Cai,^† E. S. Barta, R. R. Merchant, B. S. Matsuura, S.-J. Chen, S. Chen* & T. Qin*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17247)

The authors present an efficient method for selectively introducing boron onto quinolines through dearomative hydroboration using easily accessible and stable phosphine-ligated borane complexes. Vicinal 5,6- and conjugate 5,8-hydroborated products could be obtained regioselectively by modifying the phosphine ligand and these borane building blocks were diversified by a range of downstream functionalizations.

Enantiospecific Synthesis of α-Tertiary Amines: Ruthenium-Catalyzed Allylic Amination with Aqueous Ammonia

S. M. Papidocha,^† H. R. Wilke,^† K. J. Patej,^† M. Isomura, T. J. Stucky, L. Rothenbühler & E. M. Carreira*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01928)

Ammonia stands out as the most available, cost-effective, and atom-economical source of nitrogen for organic synthesis. In the laboratory, it is safely and most conveniently handled in aqueous solution. Despite the advantages, the direct application of aqueous ammonia in the field of transition-metal catalysis remains a significant challenge. Here, the authors report the first ruthenium-catalyzed allylic substitution using ammonia. The catalytic system, consisting of [Cp*Ru(MeCN)₃]PF₆ and a phenoxythiazoline ligand, enables the enantiospecific amination of tertiary allylic carbonates in aqueous media and affords enantioenriched primary amines as single regioisomers in high yields.

Molecular Design Principles for Photoactive Transition Metal Complexes: A Guide for “Photo-Motivated” Chemists

G. Morselli, C. Reber* & O. S. Wenger*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02096) 🔓

Luminescence and photochemistry involve electronically excited states that are inherently unstable and therefore spontaneously decay to electronic ground states, in most cases by nonradiative energy release that generates heat. This energy dissipation can occur on a time scale of 100 fs (∼10^–13 s) and usually needs to be slowed down to at least the nanosecond (∼10^–9 s) time scale for luminescence and intermolecular photochemistry to occur. This is a challenging task with many different factors to consider. An alternative emerging strategy is to target dissociative excited states that lead to metal–ligand bond homolysis on the subnanosecond time scale to access synthetically useful radicals. Based on a thorough review at the most recent advances in the field, this article aims to provide a concise guide to obtaining luminescent and photochemically useful coordination compounds with d-block elements.

3-Oxabicyclo[3.1.1]heptane as an Isostere for meta-Benzene

D. Dibchak & P. K. Mykhailiuk*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202505519)

3‑Oxabicyclo[3.1.1]heptanes were designed as saturated isosteres of meta-benzene. Crystallographic analysis revealed that these structures and meta-benzene have identical geometric properties. Replacement of the central benzene ring in the anticancer drug Sonidegib with 3-oxabicyclo[3.1.1]heptane provided a patent-free analogue with a nanomolar potency, reduced lipophilicity and improved water solubility (>500%).

👉️ For a recent, related publication on 3-oxabicyclo[3.1.1]heptanes by Ryabchuk and co-workers, see: here.

Photocatalytic Generation of a Ground-State Electron Donor through Water Activation

M.-A. Wiethoff, L. Lezius & A. Studer*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202501757) 🔓

This study presents catalytically generated phosphine oxide radical anions, derived from commercial phosphines and water as potent single-electron reductants that show redox potentials as low as –3.3 V (vs. SCE). Cyclic voltammetry studies and DFT calculations offer insights into these P-based ground-state electron donors, broadening the scope of phosphoranyl radical chemistry.

Alkyl Sulfonylhydrazide-Enabled, Chemoselective Ni-Catalyzed Directed C(sp²)–H Alkylation via Low-Temperature, Amine-Assisted Metalation/Deprotonation

S. Wang,^† D. A. Cagan,^† Y. Cao,^† B. P. Vokits, M. D. Palkowitz, Y. Kawamata, P. S. Baran* & K. M. Engle*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-4sf42) 🔓

The authors report the facile C–H alkylation of a range of (hetero)arenes under Ni-catalysis. The reaction takes place at 50 °C, is scalable, tolerates heterocyclic substrates, and can be applied to both primary and complex secondary alkyl donors. Success hinges on the use of sulfonylhydrazide-based alkyl donors that mildly generate alkyl radicals thereby obviating the need for alkyl halide precursors that require more harsh conditions to activate. The demonstrated substrate scope is broad (>70 examples) and the reaction was also applied to natural product synthesis.

Scalable Transannular Bromocyclization Approach to Functionalized bis-Heterobicyclo[3.n.1]anes

D. P. Wood,* N. Hernandez, J. A. Newman & R. E. Johnson*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-76xt9) 🔓

The authors report a scalable, transannular bromocyclization route to prepare functionalized 2-oxa-4-azabicyclo[3.2.1]oct-3-ene and 2-oxa-4-azabicyclo[3.1.1]hept-3-ene scaffolds from readily accessible alkene building blocks. This method demonstrates broad functional group compatibility and introduces a bromide handle for further diversification of the core. X-ray crystal structural analysis of these scaffolds illustrate the improved alignment of the exit vectors with those of meta-benzene and pyridine rings.

Electrochemical Oxidative Dynamic Kinetic Resolution of Phosphines using Chiral Supporting Electrolytes

C. Liu,^† K. Mao,^† Y. Wang, C. Gu, J. M. Putziger, N. I. Cemalovic, C. Muniz, Y. Qi & S. Lin*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-4h2db) 🔓

The authors describe the use of substoichiometric chiral phosphate salts as supporting electrolytes to facilitate the oxidation of racemic trivalent phosphines to afford enantioenriched phosphine oxides. The approach relies on a dynamic kinetic resolution strategy that exploits the rapid pyramidal inversion of an anodically generated phosphoniumyl radical cation, while a high concentration of chiral phosphate at the electrode–electrolyte interface enhances enantioselective control during rate-limiting nucleophilic addition.

Total Synthesis of Brevianamide S

A. R. Lockyer, H. E. Jones, N. J. Green, R. C. Godfrey, V. P. Demertzidou, G. S. Nichol & A. L. Lawrence*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c00860) 🔓

The first total synthesis of the alkaloid brevianamide S has been achieved in eight steps. This natural product, isolated from Aspergillus versicolor, exhibits selective antibacterial activity against Bacille Calmette-Guérin (BCG), a commonly used surrogate for Mycobacterium tuberculosis. Brevianamide S is proposed to act through a novel, yet-to-be-elucidated mechanism, making it a promising lead in the development of next-generation antitubercular agents. The approach employs a bidirectional synthetic strategy, involving a bespoke alkenyl–alkenyl Stille cross-coupling reaction and a double aldol condensation.

AI on Caffeine

🧠 AI on caffeine. Three years ago, C&EN ran a story about Dall-E Mini, the AI image generator, and its ability—or rather lack thereof—to depict chemical structures. Well, three years later, their newly titled article “AI doesn’t know how to depict chemistry” fails to instil much hope that anything has changed.

C&EN tasked three generative AI chatbots (ChatGPT, Google Gemini & Grok) with drawing the chemical structure of caffeine; all of which failed with spectacularly unique results. While Grok (results shown above) depicted caffeine as what appears to be a MOF (metal-organic framework), Google Gemini attempted to label its incorrect structures with hallucinated gibberish, such as “occlisge inhine”. Further prompting led Grok to incorporate five bonds to carbon and finally, ChatGPT refused to generate a structure at all, instead offering inadequate step-by-step drawing instructions.

Part of the problem may be genAI’s use of search engines chock-full of stock images of Erlenmeyer flasks overflowing with colourful liquids and incorrect “Hollywood-style” chemical structures (how many of us have paused a movie or TV show just to furiously point out an incorrect chemical structure). Given the importance of correct structural formula in chemistry and how, regardless of the language we speak, we all understand it, I think our jobs are pretty safe from AI for now!