Asymmetric Amination of Alkyl Radicals

Asymmetric Amination of Alkyl Radicals with Two Minimally Different Alkyl Substituents

Y.-F. Zhang,^† B. Wang,^† Z. Chen,^† J.-R. Liu,^† N.-Y. Yang, J.-M. Xiang, J. Liu, Q.-S. Gu, X. Hong* & X.-Y. Liu*

Science 2025, 388, 283–291 (DOI: 10.1126/science.adu3996)

Differentiating between similar alkyl groups is a major challenge in asymmetric catalysis and achieving enantiocontrol over unactivated prochiral alkyl radicals is even more difficult, owing to their high reactivity and limited interactions with chiral catalysts. In this study, the authors report a copper-catalyzed asymmetric amination of unactivated prochiral secondary alkyl radicals to produce highly enantioenriched α-chiral alkyl amines. Mechanistic studies reveal that bulky peripheral modifications on the ligands help create a truncated cone-shaped chiral pocket, enabling precise enantiodiscrimination through steric hindrance and noncovalent interactions.

Iron-Catalysed Radical Markovnikov Hydroamidation of Complex Alkenes

M. Huang, C. G. Daniliuc & A. Studer*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00792-w) 🔓

The authors present a method for the iron-catalysed radical hydroamidation of alkenes using a readily prepared radical amidation reagent that facilitates the efficient transfer of a synthetically valuable cyanamide functionality across activated and unactivated alkenes. The scope of the reaction is broad, the synthesis of ¹⁵N-labelled amines is possible and subsequent chemistry to convert the cyanamide functionality into other useful groups further validates the value of the methodology.

Stereoconvergent Reduction of Alkenes using a Repurposed Iron-based Dioxygenase

Z. Wan,^† X. Zhang,^† H. Zhuang, Z. Xie, L. Yu, Z. Fu, Y. Sun, W. Wang, R. Wu* & P. Ji*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00788-6)

The authors report the repurposing of non-haem iron-based dioxygenases to catalyse the stereoconvergent reduction of alkenes through an iron hydride intermediate, by introducing silanes to the biocatalytic system. Directed evolution of gentisate 1,2-dioxygenase led to iron-based ene-reductases with high efficiency (up to 99% yield), excellent enantioselectivity (23 examples with >99% e.e.) and compatibility with a structurally diverse range of substrates.

Photocatalytic Synthesis of Substituted 2-Aryl Morpholines via Diastereoselective Annulation

T. A. Brisco, S. De Kreijger, V. N. Nair, L. Troian-Gautier* & U. K. Tambar*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01832)

The authors present a photocatalytic, diastereoselective annulation strategy for the synthesis of morpholines from readily available starting materials, employing a visible-light-activated photocatalyst, Lewis acid, and Brønsted acid to achieve high yields and stereoselectivity. The method provides access to diverse substitution patterns, including challenging tri- and tetra-substituted morpholines, and is applicable to piperidines, pyrrolidines, and other privileged nitrogen heterocycles.

Synergistic LMCT and Ni Catalysis for Methylative Cross-Coupling Using tert-Butanol: Modulating Radical Pathways via Selective Bond Homolysis

L. Duan, Y. Lin, Q. An & Z. Zuo*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03711) 🔓

The authors present a photocatalytic methylative cross-coupling reaction that capitalizes on the synergistic interplay between ligand-to-metal charge transfer (LMCT) and Ni catalysis, enabling the use of tert-butanol as an efficient and benign methylating reagent. Under mild reaction conditions, this strategy affords efficient methylation of sp³ carbons adjacent to carbonyls and sp² centers, demonstrating broad functional group tolerance and applicability in late-stage functionalization of bioactive molecules. Additionally, trideuteromethylative coupling can be facilely achieved using commercial tert-butanol-d₁₀.

Hydrodealkenylative C(sp³)–C(sp²) Bond Fragmentation Using Isayama–Mukaiyama Peroxidation

J. H. Dworkin, Z. M. Chen, K. C. Cheasty, A. V. Rubio & O. Kwon*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00540)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-vz1c5) 🔓

Advancements in radical capture strategies have expanded the range of products accessible from alkenes through dealkenylative synthesis. However, these methods rely on ozonolysis to generate key peroxide intermediates, which has several limitations: (i) alkenes containing electron-rich aromatics, (ii) sterically hindered alkenes, (iii) internal nucleophiles and electrophiles, and (iv) allylic alcohols. In this paper, the authors use Isayama–Mukaiyama peroxidation to overcome these limitations and rescue previously inaccessible alkene substrates, broadening the applicability of dealkenylative functionalization.

Broadly Applicable Copper(I)-Catalyzed Alkyne Semihydrogenation and Hydrogenation of α,β-Unsaturated Amides Enabled by Bifunctional Iminopyridine Ligands

M. Gorai, J. H. Franzen, P. Rotering, T. Rüffer, F. Dielmann & J. F. Teichert*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01339) 🔓

A highly active bifunctional catalyst consisting of a copper(I)/N-heterocyclic carbene complex and a basic 2-iminopyridine subunit allows for copper hydride chemistry under low H₂ pressure (1 bar; balloon pressure). The bifunctional catalyst tolerates a variety of functional groups in catalytic alkyne semihydrogenations and for the first time, allows for the catalytic hydrogenation of α,β-unsaturated amides (a substrate class hitherto unreactive in copper hydride catalysis) at low H₂ pressure.

Synergistic Photoenzymatic Anti-Markovnikov Hydroarylation of Olefins via Heteroaryl Radical Intermediates

P. Mukherjee, Z. Alassad & T. K. Hyster*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01066)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-xp59w) 🔓

The authors report a synergistic photoenzymatic hydroarylation of olefins using flavin-dependent “ene”-reductases with ruthenium photoredox catalysts. Enzyme homologues were identified, which provide access to both product enantiomers in >80% yield with up to 99:1 enantiomeric ratio using a method that is effective for both styrenyl- and unactivated alkenes.

Harnessing O-Vinylhydroxylamines for Ring-Annulation: A Scalable Approach to Azaindolines and Azaindole

Z. Grimm,^† C. Randolph,^† O. Buravov, P. Mykhailiuk* & L. Kürti*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-4p67k) 🔓

The authors report a convenient strategy for the synthesis of 7-azaindolines and 7-azaindoles using O-vinylhydroxylamines as ring-annulation reagents. In this approach, O-vinylhydroxylamines undergo N-arylation with aza-arene N-oxides, triggering a rapid [3,3]-sigmatropic rearrangement, which is followed by re-aromatization and cyclization to deliver 7-azaindolines that can be readily dehydrated to afford the corresponding 7-azaindoles. The method offers a broad substrate scope, enables access to an array of highly functionalized derivatives and the mild reaction conditions facilitate late-stage functionalization of complex molecules.

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

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

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

This account chronicles the authors chemoenzymatic strategy toward various limonoids from two feedstock terpenes, sclareol and sclareolide. An initial route starting from sclareol successfully delivered the limonoid tetracyclic skeleton but lacked the versatility required to access more oxidized family members. However, a second-generation strategy from sclareolide enabled 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.

C–H Amination of Unactivated Arenes and Heteroarenes Through a Dearomative (3+2) Cycloaddition

S. Pradhan, F. Mohammadi, R. Tanase, K. Amaike, K. Itami* & J. Bouffard*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2024-mj889-v2) 🔓

The authors report that azidium ions enabled the telescoped C–H amination of unactivated arenes and heteroarenes through a cycloaddition/bond cleavage sequence. The versatility of this approach was showcased in the late-stage amination of natural products, pharmaceuticals and agrochemicals. Comparison with electrophilic halogenation/Buchwald-Hartwig amination or Ir-catalyzed borylation/Chan-Lam amination sequences revealed that the C–H amination can provide a regio- or site-selectivity that complements these most widely used approaches.

Translation of Nickel-Catalyzed C(sp²)–C(sp³) Cross-Electrophile Coupling to Non-Amide Solvents

B. D. Akana-Schneider,^† J. M. Mouat,^† S. Zhang, M. E. Akana, B. Wu* & D. J. Weix*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c01011)

The authors report that the combination of a strongly donating, bidentate nitrogen ligand, LiI, and 4-picoline enables the cross-electrophile coupling of organobromides in a variety of alcohol, ester, and ethereal solvents at up to 50 g scale, avoiding commonly used yet undesirable amide solvents, such as DMF, DMA and NMP.

Enantioselective Conjugate Addition of Aldehydes to Oxetane- and Azetidine-Containing Nitroolefins: An Entry to Spirocyclic Pyrrolidines

A. Budinská, Q. Lefebvre & H. Wennemers*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c00844)

Enantioselective amine-catalyzed conjugate additions of aldehydes to oxetane- and azetidine-containing nitroolefins afford γ-nitroaldehydes as key building blocks en route to spirocyclic oxetane/azetidine-pyrrolidines. The study provided insights into the stability and reactivity of these β,β-disubstituted nitroolefins and enabled the enantioselective synthesis of chiral oxetanes and azetidines in moderate-to-high yields and enantioselectivities.

Synthesis through C(sp³)–C(sp²) Bond Scission in Alkenes and Ketones

M. Šimek, J. H. Dworkin & O. Kwon*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.5c00156)

In this Account, the authors summarize their research into dealkenylative and deacylative synthesis, the former of which has allowed for the development of: (i) hydrodealkenylation, (ii) dealkenylative thiylation, (iii) dealkenylative alkenylation, (iv) oxodealkenylation, (v) dealkenylative alkynylation, (vi) halodealkenylation, and (vii) aminodealkenylation. Beyond alkenes, straightforward methodology for the homolytic deacylative cleavage of ketones has also been developed.

Not Quite Earth 2.0

🔭 Not quite Earth 2.0. Super Earth exoplanet K2-18 b has been making headlines recently after a team of astronomers led by the University of Cambridge detected the “chemical fingerprints” of dimethyl sulfide (DMS) and/or dimethyl disulfide (DMDS) in the atmosphere, leading to the claim that the planet held the “strongest hints yet of biological activity outside the Solar System”.

K2-18 b, a sub-Neptunian planet at about 2.6 times the size of Earth, orbits the red dwarf star K2-18 within its habitable zone—the distance from a star at which liquid water could exist on orbiting planets’ surfaces. However, K2-18 b is unlikely to be Earth 2.0, it might actually be a “hycean planet” - a planet with a hydrogen-rich atmosphere and a water ocean-covered surface.

Analysis of the planet’s atmosphere using data gathered from the James Webb Space Telescope’s (JWST) Mid-Infrared Instrument (MIRI) suggested the presence of DMS and/or DMDS, both of which are known as “biosignature” gases, and they are more-or-less produced exclusively by microbial life such as marine phytoplankton. Interestingly, this research comes just two years after the same team’s discovery of an abundance of methane and carbon dioxide in the planet’s atmosphere.

Whether these signals are proof of life or not is heavily debated, the presence of DMS was also found on a lifeless comet last year and we don’t know much about these hycean planets or their atmospheric chemical processes. Other astronomers are also sceptical of the data presented, suggesting that the observations could simply be statistical fluctuations. Meanwhile, the team hope to get more time on the JWST to fully validate their observation but it’s unlikely we’ll be exploring K2-18 b any time soon, the planet is 124 light-years (730 trillion miles) away and anyone who’s ever performed a Swern oxidation will not be keen to visit. Although, maybe Jeff Bezos and Katy Perry can put something together…