Amines: From Endpoint to Entry Point

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Boryl Radical β-Scission Enables Divergent Deaminative Cross-Coupling of Amines

Z. Zhang,^† G. Lonardi,^† T. Sephton,^† Y. C. Guersoy, C. Stavagna, M. Bietti & D. Leonori*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-ch3wj) 🔓

The authors report a strategy that repositions primary, secondary, and tertiary amines as versatile handles for divergent cross-coupling. The platform relies on in situ activation via borane coordination and exploits a copper catalytic redox system that generates amine-ligated boryl radicals, which undergo β-scission across the C(sp³)–N bond to release alkyl radicals. These intermediates engage in copper-catalyzed cross-couplings with a broad array of C-, N-, O-, and S-based nucleophiles. The method tolerates diverse amine classes, enables modular functionalization, and supports late-stage editing of complex drug scaffolds.

Modular Arene Functionalization by Differential 1,2-Diborylation

J. Huo, Y. Fu,* M. J. Tang, Y. Su, S. Hu, P. Liu* & G. Dong*

Nature 2025 (DOI: 10.1038/s41586-025-09284-5)

The authors report a nickel-catalyzed vicinal diborylation method that can directly install two chemically differentiated boryl groups in a regio- and site-selective manner using readily available aryl triflates or chlorides as substrates. The reaction is simple and scalable, operating under mild conditions with a broad substrate scope and excellent functional group tolerance. Given that each boryl group can be independently transformed into various functional groups, the method offers a modular, regioselective, and divergent approach to access diverse vicinal difunctionalized arenes, showing promise for constructing analogue libraries.

Enantioconvergent Carbenoid Insertion into Carbon–Boron Bonds

Q. Xie, T. H. Tugwell, M. C. Madhusudhanan, J. Li, P. Liu* & G. Dong*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00836-1)

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

The authors report an enantioconvergent approach for direct insertion of various carbon-, oxygen-, nitrogen-, sulfur- and silicon-substituted carbenoids into carbon–boron bonds of readily available boronic acid derivatives. Excellent stereoselectivity was achieved and enabled by a class of chiral oxazaborolidines derived from inexpensive α-amino esters. The method is scalable, each chiral centre can be independently controlled without being influenced by nearby stereocentres, and iterative operations of this process simplify the syntheses of complex molecules with multiple stereocentres.

Radical Strategy to the Boron-to-Copper Transmetalation Problem: N-Alkylation with Alkylboronic Esters

R. Sang* & J. E. Gestwicki*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07856) 🔓

While the integration of alkylboron reagents with copper catalysis offers a promising approach to forge C(sp³)–N bonds, the inherently sluggish nature of boron-to-copper transmetalation presents a significant challenge. Here, the authors develop a radical strategy to circumvent the two-electron transmetalation problem via an alkyl radical-capture mechanism, wherein the alkyl radical is generated through an aminyl radical-mediated boron abstraction. Leveraging a reductively activated boron-group transfer reagent, this mechanistically distinct approach enables a general N-alkylation using a diverse array of readily available N-nucleophiles and alkylboronic esters with excellent regioselectivity, operational simplicity, broad functionality compatibility and scalability.

Asymmetric Total Synthesis of (−)-Crotonine G and (−)-Crotonolide D

H. Yu, Y. Hatano, P.-J. Chen, S. C. Virgil & B. M. Stoltz*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07585)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-zh07z) 🔓

The authors report the first enantioselective total syntheses of crotonine G and crotonolide D using a SmI₂ mediated ketyl radical cyclization to form the highly congested quaternary carbon and an oxidative olefin cleavage to install the unusual C-19 and C-20 oxidation pattern. Finally, palladium-catalyzed carbonylation, furan oxidation and acid mediated condensation/epimerization complete the synthesis.

Toward Iridium-Catalyzed Asymmetric Branched-Selective α-Alkylation of Aldehydes with Unactivated Alkenes Enabled by a Pyrazole Mediator

K. Chen, B. Lopez, J. Bilenker & G. Dong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c08385)

Here, as an initial model study, the authors report a stepwise asymmetric α-alkylation of aldehydes with simple alkenes as the coupling partner. The reaction is enabled by a distinct pyrazole mediator and catalyzed by a chiral cationic Ir complex. The C–H alkylation of the N-alkenyl pyrazole intermediates proceeded with excellent enantioselectivity and high branched selectivity.

Enantioselective Synthesis of 2,3-Disubstituted Azetidines via Copper-Catalyzed Boryl Allylation of Azetines

M. Zhu & J. Sun*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07821) 🔓

The authors disclose a highly enantioselective difunctionalization of azetines to access chiral 2,3-disubstituted azetidines. Using Cu/bisphosphine as the catalyst, two versatile functionalities (boryl and allyl) were installed on azetine with concomitant construction of two new stereogenic centers. In almost all cases, single isomers were obtained with complete regio-, enantio-, and diastereoselectivies on the azetidine motif as well as excellent control on the double bond configuration.

👉️ For recent, unrelated but nonetheless interesting methodology on the synthesis of 3-azetidinones from α-amino esters, see here, for a pre-print from the group of K. A. Scheidt.

General Modular and Convergent Approach to Diversely Functionalized Allylic Systems

S. Giri, N. Kvasovs & V. Gevorgyan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02866)

Synthesis of allylic functionalized motifs forging C–O, C–C, and C–S bonds has been achieved via visible-light-induced palladium catalysis. Simple alkenes, readily available 1,1-dielectrophiles, and commercially available nucleophiles are directly coupled in a sequential manner to construct a diverse array of medicinally relevant complex molecules. Unlike the classical Tsuji-Trost reaction, this protocol eliminates the need for pre-functionalized starting materials.

Gram-Scale Total Synthesis of Illisimonin A

L. Zhu,^† J. Li^† & Z. Lu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07921)

Illisimonin A, a structurally complex sesquiterpenoid isolated from the Illicium genus, possesses a 5/5/5/5/5 pentacyclic scaffold featuring seven contiguous, fully substituted chiral quaternary carbon centers. Here, the authors report a gram-scale total synthesis of (±)-Illisimonin A achieved in 14 steps, featuring: (i) a pentafulvene-involved intramolecular [6+2] cycloaddition, (ii) a pentafulvene-involved intramolecular alkylation, (iii) a nitroso-Diels–Alder reaction, and (iv) a late-stage Ru-catalyzed oxidative lactonization.

A Concise Total Synthesis of Glycinoeclepin A

K. Shen, Q. Wang, T. Zhu, Y. Qiao & P. Hu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07696)

The authors report a concise and modular synthesis of the complex triterpenoid glycinoeclepin A, a picomolar hatching stimulus for the notorious pest soybean cyst nematode. The synthesis features the strategic use of a polyfunctional intermediate bearing an aldehyde, a vinyl triflate, and an exo-cyclic alkene. A Cr-mediated diastereoselective homoallenylation of the aldehyde, followed by a Pd-catalyzed intramolecular oxygenative cyclization forged the densely functionalized 5,6-fused core system and the oxa-bicyclic appendage was installed via an allyl phosphonate enabled coupling.

Iodonitrene-Mediated Nitrogen Transfer to Alkenes for the Direct Synthesis of NH-Aziridines

Y. Gelato,^† L. Marraffa,^† F. Pasca, P. Natho, G. Romanazzi, A. Tota, M. Colella & R. Luisi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-9w93z) 🔓

The authors presents a novel method for the direct synthesis of NH-aziridines from a broad range of alkenes under mild conditions. Traditional approaches often rely on specialized nitrogen-transfer reagents, harsh or environmentally hazardous conditions, or require multiple steps for N-deprotection. In contrast, this method uses aqueous ammonia and (diacetoxyiodo)benzene (PIDA) at 0 °C, offering a straightforward and environmentally friendly alternative.

Aliphatic Aldehydes as CO Surrogates via Photocatalyzed Hydrogen Atom Transfer

L. Raineri,^† V. Morlacci,^† A. M. Constantin,^† A. Voronov, G. Maestri, N. Della Ca’* & L. Capaldo*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-1mzqs) 🔓

The authors report the use of aliphatic aldehydes as a convenient class of CO photo-surrogates under photocatalyzed decarbonylative hydrogen atom transfer conditions. Compared to previously reported surrogates, these carbonyl compounds are inexpensive, commercially available, and don’t require expensive noble metals or prohibitive conditions to enable CO release.

👉️ For recent, complementary methodology on the use of aldehydes as CO releasing agents, see here, for a pre-print from the group of M. Fagnoni.

Decarboxylative Oxygenation Enabled by O–H Bond Selective Proton-Coupled Electron Transfer Ability of Photoexcited Nitroarenes

A. D. Duke, S. Banerjee, A. P. Thupili, D. R. Pradhan, M. J. Vetticatt* & M. Parasram*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-s55n1) 🔓

The authors report that tuning the aromatic substituents of photoexcited nitroarenes enables selective decarboxylative oxygenation of carboxylic acids via proton-coupled electron transfer (PCET). Following PCET and CO₂ extrusion from carboxylic acids, oxygen atom transfer (OAT) from the photoexcited nitroarene to the resulting alkyl radicals yields carbonyl products, and can also enable the dehomologation of arylacetaldehydes and arylacetic acids.

Decagram-Scale Synthesis of GB13, a Galbulimima Alkaloid Precursor

S. M. Freeman,^† E. M. Landwehr,^† J. J. Rojas, R. Tanaka, J. B. Bailey, M. Gembicky & R. A. Shenvi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-490r9) 🔓

The Galbulimima alkaloids affect nervous system function in mammals but have proven challenging to study and optimize due to their low and variable abundance in plant matter. Here, the authors synthesized 12.97 g of the alkaloid GB13 to investigate its conversion to diverse congeners. These divergent transformations required understanding and control of aza-Michael ring-chain tautomerism, which influenced scaffold reactivity profoundly. A series of chemoselective oxidations, including an unusual iodoamine rearrangement, and a C–H amination catalyzed by OsO₄, identified a single general solution to the class II, III and IV Galbulimima alkaloids.

Visible Light-Induced Pd-Catalyzed Cross-Electrophile Coupling of 2-(pseudo)Haloazines

D. Raja,^† P. Ghosh,^† S. Maiti & D. Maiti*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-j9d4b) 🔓

The authors report a visible light-induced, Pd-catalyzed cross-electrophile coupling of unsymmetrical 2,2′-bis-azaarenes and 2-heteroarylazines using the corresponding bromides and triflates as coupling partners. The interplay of light-induced and ground state Pd-catalytic cycles is enhanced through the design of new phosphine-based ligands. The mild coupling protocol exhibits wide functional group tolerance and versatility to access a broad spectrum of unsymmetrical 2,2′-bis-azaarenes.

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From Polymer to Painkiller

🦠 From polymer to painkiller. I’m sure when Wilhelm Lossen discovered his eponymous rearrangement in 1872, he couldn’t have imagined that over 150 years later, bacteria would be harnessing it to transform plastic waste into paracetamol—but here we are.

A team of researchers at the University of Edinburgh have successfully engineered a strain of E. coli capable of converting plastic waste into paracetamol, as detailed in a recent Nature Chemistry publication. By taking polyethylene terephthalate (PET), a common plastic used in food and drinks packaging, and degrading it to one of its constituent monomers (terephthalic acid) then activating it as an acyl hydroxamate, the new-to-nature enzymatic Lossen rearrangement could be carried out to deliver the painkiller in 92% yield with near-zero carbon emissions.

Since traditional paracetamol production relies on petrochemical feedstocks, this work represents a significant step towards sustainable pharmaceutical synthesis while simultaneously dealing with the problem of plastic pollution—PET alone accounts for roughly 350 million tonnes of waste globally each year. The team is now focused on further developing and scaling-up the process.

NB: Neither plastics nor paracetamol had been invented when Lossen discovered his rearrangement; the former would take another 35 years while the latter missed out by just 6 years. In the meantime, Lossen kept himself busy by studying the effects of cocaine on mucous membranes.