Enrico

Nature Synthesis, Published online: 13 June 2025; doi:10.1038/s44160-025-00824-5

The isolation of a crystalline radical cation carbon(I) species, generated via single-electron transfer between a carbodicarbene and a nitroaromatic compound, is reported. The resulting radical ion pair can mediate various C–O and C–C cross-coupling reactions with electron-deficient arenes bearing a leaving group.

Theodor Förster's name is forever linked to FRET (Förster resonance energy transfer) and while his development of FRET theory is well known and recognized, only few is documented about his scientific career and life from 1933 to 1951. By reviewing documents from different archives, this Viewpoint Article discusses Förster's life and career before, during, and after National Socialism in Germany.

Abstract

FRET stands for Förster resonance energy transfer. While much is known about resonance energy transfer, much less is known about Förster–apart from the fact that he was the one who translated FRET from a theoretical phenomenon into a broadly usable method for investigating and understanding biomolecular interactions on the nanoscale. Arguably, a major reason for the limited recognition of Theodor Förster is his scientific career during the Nazi time in Germany about which little is documented. By reviewing documents from different archives, this Viewpoint Article–on the occasion of the 50^th anniversary of his death–sheds some light on Förster's life from 1933 to 1951 and describes how a young scientist struggled during dark times in history.

Nature, Published online: 10 June 2025; doi:10.1038/d41586-025-01225-6

Doing a PhD is really hard. Here’s how I’ve learnt to enjoy the process.

This study reports the first cobalt-catalysed C–H functionalization of furfural derivatives, demonstrating distinct reactivities based on the substrate. Furfurylimines enable selective C5–H alkenylation with alkynes, whereas free aldehydes undergo decarbonylative C2-alkenylation. These results establish a novel strategy using formyl groups as traceless handles for cobalt- catalysed C–C bond formation.

Nature Synthesis, Published online: 04 June 2025; doi:10.1038/s44160-025-00821-8

The lack of stable and versatile bicyclo[1.1.1]pentyl reagents hinders their broader adoption as aryl bioisosteres in drug discovery. Now, a stable, bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT+) reagent is developed for modular bicyclo[1.1.1]pentane bioisostere production.

Herein we focus on spin-center shift (SCS) as a radical-mediated ring opening process and exploit it to a photochemi-cal or electrochemical carbonylative ring expansion of cyclic carboxylic acids. The reaction involves single electron reduc-tion of a carbonyl group derived cyclic carboxylic acids to form a ketyl radical, which undergoes SCS to generate an α-carbonyl radical and a heteroatom anion or a carbanion along with ring opening. Then, the radical undergoes hydrogen atom transfer (HAT) with a reductant or radical coupling, while the anion undergoes intramolecular acyl substitution with the recovered carbonyl group. This protocol allows to convert readily available cyclic carboxylic acids to lactams, lactones and ketones through taking the exocyclic carbonyl group of carboxylic acid into the cyclic framework. The process com-bined with α-amino C–H carboxylation of cyclic aliphatic amines becomes a molecular editing technology for carbonyla-tive ring expansion of ticlopidine and streamlined synthesis of ivabradine fragment.

A sequential process combining hydrogenation and a subsequent stereomutation is presented for trans selective hydrogenation of quinolines using water as the hydrogen atom source. Mechanistic studies reveal that the hydrogenation proceeds through a cascade process comprising an initial cis selective photocatalytic hydrogenation of the heteroarene core of the quinoline followed by a trans selective photoisomerization.

Abstract

The design of a sequential process combining hydrogenation and a subsequent stereomutation is an attractive strategy for the stereoselective reduction of cyclic disubstituted π–systems to access the thermodynamically more stable trans isomer, which would be the minor compound considering a kinetically controlled cis hydrogenation process. Herein, we demonstrate stereoselective photocatalytic phosphine-mediated quinoline reductions with water as the hydrogen atom source under mild conditions to afford the corresponding 1,2,3,4-tetrahydroquinolines with complete selectivity towards reduction of the heteroaromatic part. The method shows broad functional group tolerance and provides access to trans-2,3-disubstituted tetrahydroquinolines with moderate to excellent diastereoselectivity. These trans isomers are not readily obtained using established methods, as transition-metal-catalyzed regioselective quinoline hydrogenations provide the corresponding cis-2,3-disubstituted isomers with high selectivity. Mechanistic studies reveal that the hydrogenation of the 2,3-disubstituted quinolines proceeds through a cascade process comprising an initial cis selective photocatalytic hydrogenation of the heteroarene core of the quinoline, followed by a trans selective photoisomerization.

The formation of polyynes with an odd number of conjugated triple bonds is synthetically demanding. To address this problem, we have developed and optimized the synthesis of triynes via alkyne metathesis of diynes using molybdenum catalysts. We demonstrate the potential of this method through the synthesis of more challenging and complex products, including macrocycles containing triynes, a pentayne, and triyne precursors to [7]cumulenes. The key to the success of the proposed methodology is achieving a balance between the selectivity and reactivity of the molybdenum and diyne precursors, which requires optimization of both steric hindrance and electronic factors.

Alcohols are highly common organic compounds but remain scarce as alkyl donors in synthetic procedures. Here, we describe an electrochemical procedure for their deoxygenative cross-electrophile coupling with hydrosilanes, furnishing organosilane products in good to excellent yields. Mechanistic studies provide insights into the operating pathways of this semi-paired electrolytic transformation, suggesting that silyl ethers are likely reaction intermediates. Furthermore, a unified mechanistic proposal is presented that accounts for observed reactivity differences compared to analogous deoxygenative electrocarboxylation.

3-Oxabicyclo[3.1.1]heptanes were designed as saturated isosteres of meta-benzene. Crystallographic analysis revealed that these structures and meta-benzene have identical geometric properties. Replacement of the central benzene ring in the anticancer drug Sonidegib with 3-oxabicyclo[3.1.1]heptane provided a patent-free analogue with a nanomolar potency, reduced lipophilicity, and improved water solubility (>500%).

Abstract

3-Oxabicyclo[3.1.1]heptanes were designed as saturated isosteres of meta-benzene. Crystallographic analysis revealed that these structures and meta-benzene have identical geometric properties. Replacement of the central benzene ring in the anticancer drug Sonidegib with 3-oxabicyclo[3.1.1]heptane provided a patent-free analogue with a nanomolar potency, reduced lipophilicity, and improved water solubility (>500%).

Disclosed herein is the invention of a method for facile C–H alkylation of a range of (hetero)arenes under Ni-catalysis. This reaction takes place at 50 °C, is scalable, tolerates heterocyclic substrates, and can be applied to both primary and complex secondary alkyl donors. Success hinges on the use of sulfonylhydrazide-based alkyl donors that mildly generate alkyl radicals thereby obviating the need for alkyl halide precursors that require more harsh conditions to activate. The demonstrated substrate scope is broad (>70 examples), and the reaction was also applied to natural product synthesis. Mechanistic studies (both computational and experimental) suggest that an asynchronous, amine-assisted C–H activation pathway is operative which may have larger implications for the field.

We report a novel electrochemical oxidation of benzyl alcohols. We found that trifluoroethanol plays a role as a hydrogen atom transfer (HAT) mediator, enabling the oxidation of electron-deficient substrates that are difficult to directly oxidize on electrode surfaces. Density-functional theory calculations, cyclic voltammetry measurements and constant potential electrolysis studies supported the proposed HAT mechanism. Moreover, the obtained carbonyl compounds could be functionalized in an electro-chemically one-pot manner, further highlighting their synthetic utility.

Metathesis and reversible catalytic reactions are fundamentally intriguing and powerful tools in modern synthetic chemistry. While most reversible catalytic reactions are predicated on breaking and forming reactive functional groups, the ability to leverage the C–H bond as a functional group into metathesis reactions has proved to be exceptionally challenging. Here, we develop a C–H/C–X metathesis reaction through a radical swapping protocol where a hydrogen and halogen are traded between molecules via reversible hydrogen atom transfer (HAT) and halogen atom transfer (XAT) that allows for mild C–H halogenation. The reversibility of this process allows for selective dehalogenation of polyhalogenated products to form monohalogenated products. Leveraging the reversibility of this process, halogenated organic pollutants can also serve as a halogen source for C–H halogenation. In the broader context, this work establishes that incorporating reversible metathesis logic in C–H bond functionalization can provide complementary advantages in synthetic strategies.

We report a metallaphotocatalytic strategy for the selective methylation of (hetero)aryl bromides via nickel-catalyzed cross-coupling with bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃), as a commercially available, air-stable, and non-pyrophoric aluminum-based reagent. The method enables a fast, robust, and scalable methylation protocol that broadly accommodates various functional groups while preventing protodehalogenation. Mechanistic studies confirm the unprecedented generation of methyl radicals from an organo-aluminum precursor under photoredox conditions, bypassing the limitations of conventional two-electron pathways. This work expands the toolbox of practical radical precursors and provides a streamlined approach for selective C(sp²)–CH3 bond formation.

A stereoselective total synthesis of nimbolide has been achieved in a convergent, 11-step sequence from α-methyl-(R)-carvone. The strategy relied on a stereoselective palladium-catalyzed borylative Heck cyclization where the A-ring of the nimbolide core was constructed while simultaneously installing oxidation at C28. Selective manipulations delivered a fully decorated decalin moiety on large scale. Then, a stereoretentive etherification reaction brought together two fragments and forged the critical C–O bond with high selectivity. Finally, a regioselective radical cyclization and late-stage lactonization completed the total synthesis of nimbolide.

Free radicals were first discovered over 120 years ago by Gomberg and the first radical cross-couplings demonstrated by Kochi in the 1970's. Fueled by the need for general methods to couple C(sp3)-fragments, this area has seen an explosion of renewed interest. In contrast to widely employed polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (Suzuki, Negishi, Kumada, etc.), radical cross-coupling is advantageous when applied to the coupling of saturated systems due to the mild conditions employed and enhanced chemoselectivity associated with single electron chemistry. Indeed, the ability to employ ubiquitous carbon-based fragments (carboxylic acids, alcohols, amines, olefins, etc.) in cross-coupling has dramatically simplified access to a variety of complex molecules. Despite these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be impossible due to their near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of radical cross-coupling can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to solve this vexing challenge for the first time thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.