Alkenes, Made to Order

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Boron-Mediated Modular Assembly of Tetrasubstituted Alkenes

L. Wei, M. V. Popescu, A. Noble, R. S. Paton* & V. K. Aggarwal*

Nature 2025 (DOI: 10.1038/s41586-025-09209-2) 🔓

The authors report the boron-mediated assembly of tetrasubstituted alkenes with complete control of the double-bond geometry. The migrating group and electrophile add syn across the alkyne. Mild oxidation leads to intermediate borinic esters, which can be isolated or reacted directly in a range of transformations, including cross-couplings and homologation reactions. In particular, subjecting the intermediate borinic esters to Zweifel olefination conditions can give either retention or inversion of the double-bond geometry, depending on whether base is present or not. Different positional and stereoisomers of the tetrasubstituted alkenes can be easily accessed, and the method was showcased through the rapid synthesis of drug molecules and natural products with high yield and stereocontrol.

Total Synthesis of Chartelline C

N. M. Bartfield,^† B. W. Alexander^† & S. B. Herzon*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07148)

Chartellines are cytotoxic marine alkaloids with heavily oxidized structures, comprising a spirocyclic β-lactam, a halogenated indolenine, a chloroenamide, and a 2-haloimidazole, which have motivated extensive efforts toward their synthesis. However, only a single synthesis of any chartelline has been reported in the nearly 40 years since their isolation. Here, the authors describe a route to chartelline C from a macrolactam that was previously employed en route to the related securine and securamine alkaloids, and show that chartelline C reacts with sulfur-based nucleophiles, suggesting that further studies of their biological activity may be warranted.

Regiodivergent α- and β-Functionalization of Saturated N-Heterocycles by Photocatalytic Oxidation

J. W. Rackl,^† A. F. Müller,^† A. Profyllidou & H. Wennemers*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06177) 🔓

The authors present a photocatalytic, regiodivergent method for the functionalization of saturated N-heterocycles at either the α- or the β-position. A tert-butyl carbamate (Boc)-stabilized iminium ion serves as the key intermediate en route to either α-hydroxylation or β-elimination, depending on the choice of base. The operationally simple procedures use a readily available flavin-based catalyst, aqueous media and do not require metals, giving rapid access to a large set of functionalized piperidines.

Synthesis of Borylated Orphaned Cyclopropanes through a Boron-Enabled Cycloisomerization Reaction

J. M. Posz, A. V. Nair, R. Van Hoveln* & M. K. Brown*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05763)

The authors disclose a strategy to prepare borylated cyclopropanes through the use of a boron-enabled cycloisomerization reaction. The method relies on the generation of a triplet biradical through an energy transfer process. Subsequent 1,2-boron shift leads to the formation of a triplet 1,3-biradical, which is poised to undergo radical recombination in concert with intersystem crossing. The generated borylated cyclopropanes are useful intermediates, as a variety of highly substituted cyclopropanes can be easily prepared.

Direct Generation of Carboxyl Radicals from Carboxylic Acids Catalyzed by Photoactivated Ketones

K. Yamashita,* H. Sano, Y. Goto, H. Hayashi* & Y. Hamashima*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04571)

The authors present a photoactivated ketone-catalyzed direct generation of carboxyl radicals via hydrogen atom transfer (HAT) from the O–H bond of carboxylic acids facilitated by hydrogen-bonding interaction between the ketone photocatalyst and the carboxylic acid, leaving weaker C–H bonds intact. The protocol was applied to the direct decarboxylative functionalization of aliphatic carboxylic acids and extended to the preparation of benzoyloxy radicals, which enable site-selective C(sp³)–H alkylation of ortho-alkyl-substituted benzoic acids via a 1,5-HAT process.

Distal C(sp³)-H Amidation via Ind*Rh^III Catalyzed Nitrene Transfer

H. J. Ross, Y. Yu, L. Atkin, M. Ghorbani, K. Mint, N. Warne, K. Kempe & D. L. Priebbenow*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06232)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-m5xps) 🔓

The Ind*Rh^III catalyzed distal amidation of C(sp³)–H sites was explored, harnessing amides as weakly coordinating directing groups. The combined use of an Ind*Rh^III complex and 2-pyridone ligand delivered the enhanced catalytic activity required to functionalize both primary and secondary β-C(sp³)–H sites. The accelerated nitrene transfer catalysis facilitated the late-stage functionalization of pharmaceutical derivatives and the synthesis of drug conjugates bearing peptides, biotin, or E3-ligase binders.

Synthesis of 1,n-Diamines via Selective Catalytic C–H Diamination

T. Bissonnier, E. Brunard, M. Andresini, S. Poyer, T. Saget* & P. Dauban*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05969)

A new strategy for the conversion of alkanes to diamines is reported. It relies on a one-pot dirhodium(II)-catalyzed amination of two C(sp³)–H bonds with sulfamates in the presence of an iodine(III) oxidant. The approach gives access to diamines with various substitution patterns depending on the C–H bonds that are cleaved, producing 1,n-diamines (2<n<7) isolated with high levels of regioselectivity, yields of up to 86%, and enantiomeric ratios of up to 94.5:5.5.

Versatile Butenolide Syntheses via a Structure-Oriented C–H Activation Reaction

Y.-K. Lin, D. Kim, Y. Ouyang & J.-Q. Yu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c09040)

The authors report the development of a palladium catalyst that enables the one-step conversion of aliphatic acids into ubiquitous butenolides involving triple functionalizations of methylene and methine C–H bonds with tert-butyl hydroperoxide (TBHP) as the sole oxidant. The unprecedented triazole–pyridone ligand is essential for realizing this “butenolide-oriented” C–H activation reaction. The availability of diverse aliphatic acids allows rapid access to unexplored but medicinally interesting butenolides and the improved syntheses of bioactive natural products and drug molecules were achieved using this reaction with catalyst loadings as low as 1 mol%.

Predictable C–H Functionalization of Complex beta-Fused Azines: A Mechanistically Bound Site-Specific Oxidation

C. Obradors,* C. A. Reiher, C. Grosanu, M. Muuronen, R. Tessier, E. M. Larin & V. Lehuédé

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00797) 🔓

The authors report the straightforward C–H functionalization of multiple beta-fused azines toward a C–O bond formation with exclusive as well as predictable regiocontrol. Mild conditions enable the presence of a vast variety of motifs with orthogonal reactivity to transition-metals and highly sensitive moieties while also adding a divergent synthetic handle for further derivatizations in >10 distinct heterocyclic scaffolds.

Development, Application, and Mechanistic Interrogation of a Dual Ni Catalysis Approach to Photoredox-Based C(sp³)–C(sp³) Cross-Coupling

E. M. Bucci,^† M. A. Perea,^† R. F. Lalisse, P. Mukherjee, T. J. Raab, L. K. Valloli, D. S. Min, M. J. Bird,* O. Gutierrez* & A. G. Doyle*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-xjl6p) 🔓

The authors report the development, application, and interrogation of a conceptually-novel mechanistic framework for C(sp³)–Me bond formation using two distinct Ni catalysts capable of cross-coupling sterically and electronically diverse alkyl halides with methyl radical generated photocatalytically from benzaldehyde dimethyl acetal. By modifying the alkyl substituents on the acetal coupling partner, cross-couplings beyond methylation were demonstrated to access an array of 1°–1° and 1°–2° alkyl–alkyl bonds.

Late-Stage Diversification of Native Tryptophan-containing Peptides and Peptide Drugs through Nitrogen Atom Insertion

A.-S. K. Paschke,^† E. J. Meeus,^† M. A. Masota, F. Hoffmann, N. M. Grob* & B. Morandi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-4pzg0) 🔓

The authors demonstrate the epimerization-free, site-selective late-stage diversification of tryptophan-containing native peptides through nitrogen atom insertion in solution. The direct application of this rapid and straightforward method to structurally complex peptide drugs underscores the broader potential of atom insertion reactions in drug discovery beyond small molecules.

Reductive Coupling of Acrylamides and Carbonyls via Solvated Electrons from Excited-State Acridyl Radicals

R. K. El Mokadem,^† T. M. Lazarus^† & D. A. Nicewicz*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102647)

The reductive coupling of carbonyls and alkenes is primarily promoted by super stoichiometric quantities of samarium diiodide (SmI₂). This reductant requires fresh preparation under moisture-free anaerobic conditions for successful reactivity. Here, the authors describe a method for reductively coupling acrylamides with unactivated ketones and aldehydes by employing acridine radicals as excited-state reductants.

A Galaxy in Full Colour

🔭 A galaxy in full colour. Nature have just released their selection of the best science images in June, featuring an ultra-detailed image of the Sculptor Galaxy, located 11 million light-years away, using the European Southern Observatory’s Very Large Telescope—technically its four individual (and very large) telescopes, each equipped with a primary mirror measuring 8.2 metres in diameter.

The scale of the galactic snapshot can’t be understated, it spans an area 65,000 light-years wide and first analysis of the data has already revealed around 500 planetary nebulae - regions of gas and dust ejected from dying stars. Unlike earlier images with limited hues, this one features thousands of colors representing stars, gas and dust, all of which emit light at different wavelengths and provide information about the galaxy's age, composition, and motion.