Deconstructing & Remodelling Alkenes

Catalytic Remodeling of Complex Alkenes to Oxonitriles Through C=C Double Bond Deconstruction

Z. Cheng,^† K. Huang,^† C. Wang,^† L. Chen,^† X. Li, Z. Hu, X. Shan, P.-F. Cao, H. Sun, W. Chen, C. Li, Z. Zhang, H. Tan, X. Jiang, G. Zhang, Z. Zhang, M. Lin, L. Wang, A. Zheng, C. Xia,* T. Wang, S. Song, X. Shu & N. Jiao*

Science 2025, 387, 1083–1090 (DOI: 10.1126/science.adq8918)

The authors report a heterogeneous copper-catalyzed C=C double-bond cleavage, which enables the remodeling of complex molecules by converting the carbons on either side of the C=C double bond to carbonyl and cyano groups, respectively. This method provides an efficient protocol to conveniently transform terpenoids, glycals, steroids, and bioactive molecules to privileged scaffolds with underexplored chemical space.

Oxidative Amination by Nitrogen Atom Insertion into Carbon-Carbon Double Bonds

Y. Brägger,^† A.-S. K. Paschke,^† N. Nasiri, B. B. Botlik, F. Felician & B. Morandi*

Science 2025, 387, 1108–1114 (DOI: 10.1126/science.adq4980)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-6r5wn) 🔓

The authors report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates, which can be converted into nitriles or amidine products, depending on the initial alkene substitution pattern. PIFA, a commercially available and inexpensive hypervalent iodine reagent, is key to this operationally simple process, which works on a range of unactivated alkenes. The method can also be used as a general strategy for synthesizing amides and amines, as well as ¹⁵N-labeled molecules.

Sulfonyl Hydrazides as a General Redox-Neutral Platform for Radical Cross-Coupling

J. Sun,^† Á. Péter,^† J. He,^‡ J. Tsien,^‡ H. Zhang,^‡ D. A. Cagan, B. P. Vokits, D. S. Peters, M. S. Oderinde, M. D. Mandler, P. Richardson, D. Chen, M. D. Palkowitz, N. Raheja, Y. Kawamata & P. S. Baran*

Science, First Release (DOI: 10.1126/science.adu6406)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-40szn) 🔓

The authors disclose sulfonyl hydrazides as versatile radical precursors, exemplified with seven C–C bond forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox active esters, aryl halides, alkenyl halides, alkynyl halides and a trifluoromethylating reagent to forge C(sp³)-C(sp³), C(sp³)-C(sp²) and C(sp³)-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary as these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water compatible reaction conditions are operationally simple and contribute to streamlining synthesis and late-stage functionalization.

Preparation, Separation and Storage of N-Monofluoromethyl Amides and Carbamates

M. Tao, J. Qian, L. Deng, D. M. Wilson, X. Zhang* & J. Liu*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01767-2)

N-Monofluoromethyl (N-CH₂F) amides represent a practical modification of the amide bond that can mimic N-CH₃ amides. Despite the potential value in transforming peptides and peptidomimetics with N-CH₂F, the very existence of this structure has been controversial. Here, the authors report the preparation of N-CH₂F amides and carbamates, and their use in the modification of drugs, peptides and heteroaryl amides without racemization or epimerization. The stability of nine structurally diverse N-CH₂F amides was tested in eight different media, showing that most compounds remained 60–100% intact for 24 h.

Biomimetic 1,2-Amino Migration via Photoredox Catalysis

W. Fan,^† Y. Cui,^† B. Zhan,^† Y. Chen, L. Bao, Y. Liang & X. Zhang*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01775-2) 🔓

The authors present a biomimetic 1,2-amino migration through the synergistic combination of a biocatalytic mechanism and photoredox catalysis, enabling the modular synthesis of γ-substituted β-amino acids from abundant α-amino-acid derivatives. This mild method features excellent substrate and functional group compatibility, affording a range of γ-substituted β-amino acids (>80 examples) without the need for laborious multistep synthesis.

Non-Enzymatic Methylcyclization of Alkenes

I. Plangger,^† E. Schmidhammer,^† S. Schaar, K. Wurst, M. Podewitz* & T. Magauer*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01774-3) 🔓

Methyltransferases catalyse the transfer of methyl groups onto a wide variety of substrates, while bifunctional methyltransferase–cyclases transfer a methyl group onto alkenes and induce cyclization (methylcyclization). Although recent years have seen advances in the methylation of alkenes, the reactivity of methyltransferase–cyclases has yet to be developed into a synthetically viable method. Here, the authors report a silver(I)-mediated electrophilic methylcyclization that rivals selectivities found in enzymes while not being limited by their inherent substrate specificity. The method uses commercial reagents, is applicable to a wide range of substrates and affords unique structures that are difficult to access via conventional synthetic methods.

A Three-Step Strategy for the Conversion of Pyridines into Benzonitriles

R. Güdük, N. Kehl,^‡ C. Stavagna,^‡ M. J. Tilby, O. Turner, A. Ruffoni,* H. P. Caldora* & D. Leonori*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00759-x)

The bioisosteric replacement of benzenes with pyridines is often pursued because the nitrogen atom in pyridine can enhance biological potency and metabolic stability. Conversely, replacing pyridines with benzenes, particularly benzonitriles, can also be of value as they are similarly polarized and can effectively mimic their hydrogen-bond acceptor properties. Here, the authors introduce a strategy for converting pyridines into benzonitriles using a three-step protocol beginning with pyridine N-oxidation, followed by photochemical deconstruction in the presence of an amine. This sequence produces a nitrile-containing butadiene, which undergoes a formal Diels–Alder cycloaddition with alkynes and alkenes to construct the benzonitrile ring.

Cross-Electrophile Coupling to Form Sterically Hindered C(sp²)–C(sp³) Bonds: Ni and Co Afford Complementary Reactivity

T. Wu,^† A. J. Castro,^† K. Ganguli, M. E. Rotella,* N. Ye, F. Gallou, B. Wu* & D. J. Weix*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16912)

The authors report two methods that couple secondary alkyl bromides with aryl halides containing sterically hindered C–X bonds: 1) ortho-substituted aryl bromides with nickel catalysts and 2) di-ortho-substituted aryl iodides with cobalt catalysts. Stoichiometric experiments and deuterium labeling studies show that 1) [Co] is better than [Ni] for oxidative addition of di-ortho-substituted Ar–I and 2) [Co] is better than [Ni] for radical capture/reductive elimination steps with di-ortho-substituted arenes.

Photoredox-Catalyzed Nucleophilic Aromatic Substitution of Halophenols with Azoles via Oligomeric Phenylene Oxide Radicals

J. Seliger, L. R. Fries,^‡ J. M. Meinhardt^‡ & R. R. Knowles*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01012)

The authors report a photocatalytic protocol for formal S_NAr of electron-rich 4-halophenols with azole nucleophiles under mild, redox-neutral conditions. The transformation proceeds via a two-stage mechanism consisting of initial halophenol oligomerization to produce a key oligo(phenylene oxide) intermediate and its subsequent breakdown through S_NAr with the azole enabled by photoredox-catalyzed arene umpolung. The synthetic utility of this method is demonstrated across 17 (pseudo)halophenols bearing a variety of leaving groups (F, Cl, Br, OMs, and OTs) and 22 azole examples.

Asymmetric Counteranion-Directed Halogen Bonding Catalysis

D. L. Reinhard, A. Iniutina, S. Reese, T. Shaw, C. Merten, B. List* & S. M. Huber*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18378) 🔓

Halogen bonding has been established as a promising tool in organocatalysis. Asymmetric processes are nevertheless scarce, and their applications are limited to a few studies applying chiral halogen bond donors. Here, the authors combine halogen bonding with asymmetric counteranion-directed catalysis, providing the first highly enantioselective example of such an approach. A strong bidentate iodine(III)-based catalyst with chiral disulfonimides as counteranions is applied in the first asymmetric organocatalysis of the Diels–Alder reaction between cyclopentadiene and trans-β-nitrostyrene, the key step in the synthesis of the drug fencamfamine, which was prepared with high enantioselectivity.

C–C Cleavage/Cross-Coupling Approach for the Modular Synthesis of Medium-to-Large Sized Rings: Total Synthesis of Resorcylic Acid Lactone Natural Products

L. T. Göttemann, C. Amber,^‡ K. Mahmood,^‡ P. Mader, I. Kokculer, T. Andris, B. P. Zavesky* & R. Sarpong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00801)

The synthesis of medium (8–11 membered) and large sized (≥12 membered) cyclic systems is often challenging due to the introduction of transannular strain and loss of degrees of freedom in forming macrocycles. To address these challenges, the authors report a strategy for the synthesis of medium-to-large sized rings, which leverages strain-release and metal templating through a palladium-mediated C–C cleavage/cross-coupling. The transformation enabled the short total synthesis of resorcylic acid lactone (RAL) natural products and unnatural analogues of late-stage intermediates.

Catalysis in the Excited State: Bringing Innate Transition Metal Photochemistry into Play

F. Juliá*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.4c07962) 🔓

This Perspective examines advances in the application of transition metal complexes as standalone photocatalysts, exploiting the innate reactivity of their excited states beyond their common use as photoredox catalysts. An account of relevant examples is dissected to provide a discussion on the electronic reorganization, the orbitals involved, and the associated reactivity of different types of excited states. This analysis aims to provide practitioners with fundamental principles and guiding strategies to understand, design, and apply light-activation strategies to homogeneous transition metal catalysis for organic synthesis.

Enabling Aryl Chloride-Mediated Palladium/Norbornene Cooperative Catalysis

R. Ye, X. Liu & G. Dong*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202500897)

While palladium/norbornene (Pd/NBE) cooperative catalysis has become increasingly useful for arene functionalization, its substrate scope has been mainly restricted to reactive aryl iodides and bromides. Here, the authors report the first general Pd/NBE-catalyzed vicinal difunctionalization of aryl chlorides, which can now undergo successful ortho alkylation, amination, and acylation with different ipso terminations, including olefination, hydrogenation, and alkynylation. The late-stage derivatizations of complex bioactive compounds and sequential functionalizations of polyhaloarenes have been achieved.

Skeletal Modification via Activation of Relatively Unstrained C–C Bonds

R. Zhang & G. Dong*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.5c00014)

In this Account, the authors summarize their recent progress in skeletal modifications through the catalytic activation of relatively unstrained C–C bonds. The major topics covered include the following: (1) skeletal rearrangement and “cut-and-sew” transformations of cyclic ketones, (2) chain homologation of linear amides and downsizing of lactams, and (3) “cut-and-sew” transformations of biphenols.

Diversity-Generating Skeletal Editing Transformations

F.-P. Wu,^† J. L. Tyler^† & F. Glorius*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.4c00820)

In this Account, the authors describe their efforts to develop novel skeletal editing transformations in which a modification to the central motif of a molecule is performed simultaneously with the incorporation of additional functionality that can be easily varied through a judicious choice of the reagents.

Behold, The Woolly Mouse

🐁 Behold, the woolly mouse. Colossal Biosciences, as their name might suggest, have huge ambitions. Their CEO describes them as the “world's first de-extinction and species preservation company” aiming to bring back the woolly mammoth, the dodo and the lesser known thylacine (Tasmanian tiger). That’s about as Jurassic Park as it gets for now but they’ve just released some interesting proof of principle results on their mammoth quest, the aptly named “woolly mouse”, created by identifying gene variants linked to mammoth woolliness and modifying seven genes in the mice to give them hair similar to that of the extinct behemoth.

With half of all species alive today projected to go extinct within the next 50–100 years, research like this is clearly important but it raises ethical and ecological concerns such as the introduction of these species back into an ecosystem that has adapted to their absence. Ethically, those opposed ask if we should be playing God, while others ask “where are the tiny tusks?” - I guess it’s up to you where you lie on that issue. In the meantime, the team has given themselves a deadline of 2028 to complete the full process but has more immediate plans to test whether or not the woolly mouse’s fuzzy pelt will make them more tolerant to the cold.