One-Carbon Alkene Homologation

One-Carbon Homologation of Alkenes

M. C. Grocott & M. J. Gaunt*

Nature 2025 (DOI: 10.1038/s41586-025-09159-9)

The authors report a catalytic one-carbon homologation process by leveraging a novel multifaceted allyl-sulfone reagent to enable a streamlined one-pot process, involving cross-metathesis and a fragmentation/retro-ene cascade to formally insert a single methylene unit to the alkene chain. Amongst applications of this process to structurally and functionally complex molecules, the transformation can also generate previously unexplored homologues of Cyclosporine-A, which show modulated pharmacological and biological properties that could provide promising leads to cyclophilin inhibitors.

C-to-N Atom Swapping and Skeletal Editing in Indoles and Benzofurans

Z. Wang, P. Xu,^‡ S.-M. Guo,^‡ C. G. Daniliuc & A. Studer*

Nature 2025 (DOI: 10.1038/s41586-025-09019-6) 🔓

The authors present a C-to-N atom swap in indoles at the C2 position to give indazoles through oxidative cleavage of the heteroarene core and subsequent ring closure with reactions proceeding through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C-to-N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles.

Synthesis of Chiral Difluoromethyl Cyclopropanes Through Desymmetric Difluoromethylation of Cyclopropenes Enabled by Enantioselective Copper Catalysis

D. Ding, S. Chen, L. Yin, W.-T. Ou, J. A. Krause, M.-J. Cheng & W. Liu*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00809-4)

The authors report the use of difluoromethyl–copper complexes for the development of a desymmetric difluoromethylation reaction using enantioselective copper catalysis. Through desymmetric difluoromethylation of cyclopropenes and subsequent electrophilic functionalization, this method achieves high efficiency and enantioselectivity, enabling the modular construction of chiral difluoromethyl cyclopropane moieties.

Cobalt-Catalysed Alkene Hydronitration Enabled by Anomeric Nitroamide

Y. Wang, M. M. Bogner, J. B. Bailey, L. N. Grant, M. Gembicky, P. F. Richardson & P. S. Baran*

Nat. Catal. 2025 (DOI: 10.1038/s41929-025-01336-3)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-s1mhh) 🔓

The authors report the development of an anomeric nitroamide-based reagent that enables selective metal-hydride hydrogen atom transfer-based Co-catalysed alkene hydronitration for the preparation of tertiary nitro compounds. This mild, scalable reaction shows broad functional group tolerance and its synthetic application was demonstrated via late-stage nitration of complex alkenes derived from drugs and natural products. The anomeric nitroamide reagent was deemed safe by energetic measurements and its reactivity rationalized based on X-ray crystallographic analysis.

Kharasch-Type Haloalkylation of Alkenes by Photoinduced Copper Catalysis

Y. Cai, M. Dawor, G. Gaurav & T. Ritter*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05699) 🔓

Traditional Kharasch addition requires simple polyhalogenated compounds or those with electron-withdrawing groups at the α-carbon. Here, the authors present a Kharasch-type reaction utilizing a broad range of carboxylic acid-derived redox-active esters as the alkyl source, which enables the efficient introduction of highly functionalized alkyl groups. The method produces α-halo carbonyls that enable versatile nucleophilic substitutions for synthesizing valuable compounds, such as unnatural α-amino acids.

3-Selective Pyridine Fluorination via Zincke Imine Intermediates

M. A. Hart, B. J. H. Uhlenbruck, J. N. Levy & A. McNally*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03091)

The authors developed a C3-selective pyridine fluorination process using ring-opened Zincke imines that undergo regioselective C–F bond formation with electrophilic fluorination reagents, resulting in C3-fluoropyridines after ring closure. The process can accommodate a wide range of pyridine substitution patterns, tolerate various appended functional groups and is viable for the late-stage fluorination of pyridine-containing drugs.

Concise Total Synthesis of Ambiguine P

Y. Fei,^† B. Fan,^† Z. Liu,^† M. Ba, Z. Cui, P. Yang* & A. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00395)

Ambiguine P is a synthetically challenging representative of the hapalindole-type natural products. Inspired by the biosynthesis of this indole terpenoid family, the authors developed a Cope/Prins/Friedel–Crafts cascade, achieving a six-step synthesis of ambiguine P from 2,2-dimethylcycloheptanone. Altered from the biosynthetic pathway, this cascade strategically commenced with a tricyclic indolenine derivative bearing a seven-membered ring, enabling efficient construction of the pentacyclic scaffold. The oxidation state was elevated through chlorination and hydroxylation in the final stage.

Unlocking Epoxide Radical Anion Reactivity for Asymmetric Cross-Coupling by Copper Metallaphotoredox

F. Teng, Z.-Q. Li, Z.-C. Mao, Z. Zhang, M. Jiang, W.-J. Xiao & J.-R. Chen*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05957)

The authors describe a copper metallaphotoredox platform to unlock epoxide radical anion reactivity, allowing the controlled generation of epoxide radical anions and their enantioconvergent cross-coupling with diverse, readily available partners via distonic radical anion intermediates. These discoveries permit highly regio-, chemo-, and enantioselective hydrocyanation and hydroalkynylation.

Copper-Photoredox-Catalysed C(sp³)–C(sp³) Reductive Cross-Coupling of Alkyl Bromides with BCP-Thianthrenium Reagents

S. Pandit & T. Ritter*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506785) 🔓

The authors report a reductive cross-coupling reaction of bicyclo[1.1.1]pentyl (BCP)-thianthrenium reagents and alkyl bromides, catalysed by a copper/photoredox catalyst system. The approach is the first example of a cross-coupling between BCP-based reagents with alkyl electrophiles.

Enantioselective Total Synthesis of (–)-Psiguadial A

L. P. O’Grady, M. Achtenhagen, M. F. Wisthoff, R. S. Lewis, K. Pfeifer, W. Zheng, M. I. Martin, G. P. A. Yap & W. J. Chain*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506537)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-ghb91-v2) 🔓

The first enantioselective total synthesis of the antiproliferative natural product (–)-psiguadial A is reported, featuring the synthesis and union of a complex tricyclic terpenoid precursor with a polyketide component by an enolate-ortho-quinone methide coupling reaction to form a highly congested carbon–carbon bond, and an acid mediated intramolecular hydration ring-closure to generate the unique oxepane core structure of the natural product.

Enantioselective and Diastereoselective Synthesis of Spiroazabicyclo[2.n]alkanes by Rhodium-Catalyzed Cyclopropanations

J. K. Sailer,^† D. Ly,^† A. Wang, D. Musaev* & H. M. L. Davies*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-5j4tn) 🔓

The authors describe the synthesis of spiroazabicyclo[2.n]alkanes by means of a dirhodium tetracarboxylate catalyzed cyclopropanation of exocyclic olefins using do-nor/acceptor carbenes. The optimum chiral dirhodium tetracarboxylate catalyst, Rh₂(p-PhTPCP)₄ results in highly enantioselective cyclopropanation of symmetrical azacyclomethylidenes, highly enantioselective and diastereoselective cyclopropanation of non-symmetrical azacyclomethylidenes, and can achieve up to 83,000 turnovers.

Cobalt-Salen Catalyzed Hydration of Alkenes with Water: A Complementary Ionic Approach to the Mukaiyama Hydration

D. G. Groves,^† R. H. Hoogesteger,^† B. Emayavaramban & C. P. Johnston*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-3w794) 🔓

The hydration of alkenes is a convenient method for the introduction of an alcohol functional group, ideally via the direct addition of water across an alkene; however, current transition metal-catalyzed protocols (Mukaiyama-type hydration) are dominated by radical addition to molecular oxygen. Here, the authors report a cobalt-salen catalyzed hydration of alkenes proceeding via a radical-polar crossover mechanism and subsequent nucleophilic attack of water.

Modular Synthetic Platform for Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery

A. R. Gomez-Angel,^† H. F. Klein,^† S. Y. Yao,^† J. R. Donald, J. D. Firth, R. Appiani, C. J. Palmer, J. Lincoln, S. C. C. Lucas, L. Fusani, R. I. Storer & P. O’Brien*

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

The authors present a modular platform for the systematic elaboration of 2D fragment hits into lead-like 3D compounds, utilising nine commercially available bifunctional building blocks that explore a range of vectors in 3D. The building blocks comprise: (i) rigid sp³-rich bicyclic cyclopropane-based structures to fix the vectors, and (ii) two synthetic handles - a protected cyclic amine and a cyclopropyl MIDA boronate. To provide proof-of-concept, starting from the drug Ritlecitinib, the development of inhibitors of Janus kinase 3 (JAK3) around a putative pyrrolopyrimidine 2D fragment hit was explored, streamlining the discovery of a novel and selective 69 nM inhibitor.

Suzuki–Miyaura (Hetero-)aryl Cross-Coupling: Recent Findings and Recommendations

J. W. Meringdal & D. Menche*

Chem. Soc. Rev. 2025, Advance Article (DOI: 10.1039/D4CS01108B)

This tutorial review provides an overview on recent developments in Suzuki–Miyaura reactions, focusing on optimizing the most common application: palladium and nickel phosphine catalyzed (hetero-)aryl bond formation. Key mechanistic insights into ligand selection, base and boron reagent choice as well as potential additives, and their effects on the reaction outcome are discussed in detail. Based on a systematic analysis, these parameters are grouped together and recommended conditions for each group are provided to accelerate the optimization process.

What Lies (3000 km) Beneath

🌋 What lies (3000 km) beneath. Analysis of volcanic rocks from Hawaii has uncovered evidence that plumes of hot magma may be transporting material from the Earth’s core to its surface, through nearly 3000 km of mantle.

By focusing their search on the Hawaiian islands, which were formed by “hot spot volcanism” where magma rises from deep within the Earth’s mantle, the team were able to identify rocks enriched in one particular isotope of the precious metal ruthenium, ¹⁰⁰Ru, which is known to be in higher abundance within the Earth’s core.