Finn Moeller

Strain-release-driven reactions represent a powerful strategy to access a diverse array of chemical scaffolds. The direct activation of alkyl non-biased cyclopropanes and cyclobutanes through electrochemical oxidation facilitates the formation of a wide range of oxazoline and oxazine derivatives, offering crucial insights into the oxidation of small cycloalkane rings.

Abstract

Capitalizing the inherent strain energy within molecules, strain-release-driven reactions have been widely employed in organic synthesis. Small cycloalkanes like cyclopropanes and cyclobutanes, with their moderate ring strain, typically require dense functionalization to induce bias or distal activation of (hetero) aromatic rings via single-electron oxidation for relieving the tension. In this study, we present a pioneering direct activation of alkyl cyclopropanes/butanes through electrochemical oxidation. This approach not only showcases the potential for ring-opening of cyclopropane/butane under electrochemical conditions but also streamlines the synthesis of diverse oxazolines and oxazines. The applicability of our method is exemplified by its broad substrate scopes. Notably, the products derived from cyclobutanes undergo a formal ring contraction to cyclopropanes, introducing an intriguing aspect to our discoveries. These discoveries mark a significant advancement in strain-release-driven skeletal rearrangement reactions of moderately strained rings, offering sustainable and efficient synthetic pathways for future endeavours.

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper-catalyzed γ-C(sp3)−H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-Lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ-lactam products enables the synthesis of a range of biologically important motifs, including γ-amino acids, δ-amino alcohols, and pyrrolidines.

The reaction between N,C,N-pincer bismuthinidenes and organic azides leads to isolation of elusive monomeric iminobismuthanes, which can be spectroscopically and crystallographically characterized. This novel reactivity led to the development of a protocol for the catalytic reduction of organic azides using pinacolborane (HBpin) under mild conditions.

Abstract

We report the stoichiometric and catalytic reactivity of organobismuth(I) complexes with organic azides. Treatment of N,C,N-pincer bismuthinidenes with organic azides (acyl, sulfonyl, and bulky aryl) results in monomeric iminobismuthanes which can be structurally characterized —including the formal Bi=N double bond— by multinuclear NMR spectroscopy and single-crystal X-ray diffraction. Building upon the stoichiometric reactivity of the monomeric iminobismuthanes, catalytic reduction of a broad range of organic azides is developed. DFT calculations of the catalytic reaction pathway support the redox nature of the overall process.

We present a chaperone-derived Cu⁺-binding peptide featuring the conserved MTCGGC Cu⁺ binding motif, which self-assembles into nanofibers within cancer cells. These nanofibers have multiple MTCGGC Cu⁺-binding motifs on their surfaces, allowing for efficient capture of intracellular Cu⁺ ions. This process disrupts the Cu⁺ homeostasis network of cancer cells. Our study offers a novel therapeutic intervention targeting metal ion homeostasis in cancer.

Abstract

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu⁺ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu⁺ homeostasis in cancer cells are rarely explored because small molecule Cu⁺ chelators have poor binding affinity in comparison to the intracellular Cu⁺ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu⁺ chaperone-inspired supramolecular approach to disrupt Cu⁺ homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu⁺ due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu⁺ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu⁺ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu⁺ binding must work in synergy to successfully disrupt Cu⁺ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.

By systematically reviewing the ligand modification strategy from both the mechanistic and applicable scenarios towards heterogeneous electrocatalysis, this work aims to propose methodological guidance from the preparation of ligand-modified catalysts and the regulation of interfacial properties, thus providing a potential protocol for promoting in-depth research and further applications of ligand-modified catalytic systems.

Abstract

The development of efficient catalytic materials in the energy field could promote the structural transformation from traditional fossil fuels to sustainable energy. In heterogeneous catalytic reactions, ligand modification is an effective way to regulate both electronic and steric structures of catalytic sites, thus paving a prospective avenue to design the interfacial structures of heterogeneous catalysts for energy conversion. Although great achievements have been obtained for the study and applications of heterogeneous ligand-modified catalysts, the systematical refinements of ligand modification strategies are still lacking. Here, we reviewed the ligand modification strategy from both the mechanistic and applicable scenarios by focusing on heterogeneous electrocatalysis. We elucidated the ligand-modified catalysts in detail from the perspectives of basic concepts, preparation, regulation of physicochemical properties of catalytic sites, and applications in different electrocatalysis. Notably, we bridged the electrocatalytic performance with the electronic/steric effects induced by ligand modification to gain intrinsic structure-performance relations. We also discussed the challenges and future perspectives of ligand modification strategies in heterogeneous catalysis.

Synthetic organic electrochemistry is a highly useful redox method, enabling diverse transformations. This study explores pyrolytic carbon electrodes in powerful rAP processes and C−C as well as C−N bond-forming reactions. Pyrolytic carbon offers a cost-effective alternative to traditional amorphous carbon materials (glassy carbon, GC, or reticulated vitreous carbon, RVC), which are often expensive or unsuitable for large-scale flow reactions.

Abstract

Synthetic organic electrochemistry is recognized as one of the most sustainable forms of redox chemistry that can enable a wide variety of useful transformations. In this study, readily prepared pyrolytic carbon electrodes are explored in several powerful rAP transformations as well as C−C and C−N bond forming reactions. Pyrolytic carbon provides an alternative to classic amorphous carbon-based materials that are either expensive or ill-suited to large-scale flow reactions.

A general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) starting from azabicyclo[1.1.0]butanes (ABB) and styrenes under photochemical conditions is reported. The reaction follows a polar-radical-polar relay strategy in which the key step is a photocatalytic atom-transfer-radical-addition (ATRA) reaction.

Abstract

C(sp³)-rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen-containing heterocycles are in high demand. Herein, we report a general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar-radical-polar relay strategy that leverages a fast acid-mediated ring-opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB-ketones and we demonstrate the 1-aza-BCH products can be further functionalized to access larger saturated, conformationally rigid heterocycles.

Nature Chemistry, Published online: 23 October 2024; doi:10.1038/s41557-024-01657-z

About two thirds of western society are extroverts, but the contemplative nature of science means that this is not true of the academic population. Bruce Gibb discusses extraversion and introversion in science and asks whether the movement towards larger projects involving teams of scientists is making it harder for introverts and for disruptive discoveries.

Synopsis: The influence of the model base and acid on the stability of renewable furan derivatives in various solvents has been studied during heating. The results obtained allowed us to classify reaction systems according to their ability to stabilize furans under acidic or basic conditions, which is crucial for conducting a wide range of reactions in organic synthesis.

Abstract

The transition toward renewable resources is pivotal for the sustainability of the chemical industry, making the exploration of biobased furanic platform chemicals derived from plant biomass of paramount importance. These compounds, promising alternatives to petroleum-derived aromatics, face challenges in terms of stability under synthetic conditions, limiting their practical application in the fuel, chemical, and pharmaceutical sectors. Our study presents a comprehensive evaluation of the stability of furan derivatives in various solvents and under different conditions, addressing the significant challenge of their instability. Through systematic experiments involving GC–MS, NMR, FT–IR and SEM analyses, we identified key degradation pathways and conditions that either promote stability or lead to undesirable degradation products. These findings demonstrate the strong stabilizing effect of polar aprotic solvents, especially DMF, and reveal the dependence of furan stability on solvent and additive type. This research opens new avenues in the utilization of renewable furans by providing critical insights into their behavior under synthetic conditions, significantly impacting the development of sustainable materials and processes. The broad appeal of this study lies in its potential to guide the selection of conditions for the efficient and sustainable synthesis of furan-based chemicals, marking a significant advance in green chemistry and materials science.

Polyethylene degraded through an unreported reaction pathway, with water activation involved, resulting in shorter-chain alkanes, alkenes, alcohols and ketones (C_n, n≲50). The reaction was driven by ball milling, avoiding high temperature and pressurization. No noble-metal or complex catalysts were used. Only earth-abundant Al₂O₃ was milled with reactants.

Abstract

Polyethylene (PE) is the most prevalent type of plastic waste and also the most challenging to depolymerize because of its inert carbon-carbon (C−C) bonds.^[1] High temperature and noble metals are usually required for depolymerization.^[2] To avoid using noble metals, costly reagents and harsh reaction conditions, it is worthwhile but challenging to explore new reaction pathways.^[3] We report an unprecedented mechanochemical reaction of PE and water to result in shorter-chain alkanes, alkenes, alcohols, and ketones (C_n, where n≲50), with above 80 % of starting carbon converted into these products, which could be a valuable feedstock for re-entering chemical value chains. This reaction is driven solely by ball milling, without heating and pressurizing. No costly catalysts are used. Instead, only earth-abundant Al₂O₃ was milled with reactants.

The catalytic formation of C–C bonds from aryl halides is a highly attractive but unexplored area in the emerging field of bismuth redox catalysis. We report a chemoselective bismuth-photocatalyzed activation and coupling of (hetero)aryl iodides with pyrrole derivatives to forge C(sp²)–C(sp²) bonds via C–H functionalization. The bismuth complex features two different light-driven processes: an MLCT transition that promotes oxidative addition into Bi(I) and an LLCT-enabled homolytic cleavage of aryl–Bi(III) bonds.

Abstract

Within the emerging field of bismuth redox catalysis, the catalytic formation of C−C bonds using aryl halides would be highly desirable; yet such a process remains a synthetic challenge. Herein, we present a chemoselective bismuth-photocatalyzed activation and subsequent coupling of (hetero)aryl iodides with pyrrole derivatives to access C(sp²)−C(sp²) linkages through C−H functionalization. This unique reactivity is the result of the bismuth complex featuring two redox state-dependent interactions with light, which 1) activates the Bi(I) complex for oxidative addition via MLCT, and 2) promotes the homolytic cleavage of aryl Bi(III) intermediates through a LLCT process.

The synthesis and isolation of a bismuth-based analogue of the venerable triphenylphosphine oxide (Ph3PO) has remained a chimera to synthetic chemists for many years, due to its predicted high reactivity and instability. Through the hydrolysis of a cationic fluorotriarylbismuthonium(V) salt, we report here the isolation of unique hydroxytriarylbismuth(V) complexes, which served as precursor for the formation of the elusive monomeric triarylbismuthine oxide Dipp3Bi═O. Combined spectroscopic, crystallographic and computational studies provided insight into the bonding situation of the first monomeric triorganobismuth oxide complex. The Dipp3Bi═O and Mes3BiO·LiBArF complex exhibits O-atom transfer reactivity, an uncommon reactivity feature for Ar3Pn=O.

To bridge the gap between the customizability of in-house machined reactors and the reproducibility of commercially available reactors, we have developed a suite of 3D-printed components that are compatible with the ElectraSyn. These components serve to increase the applicability, range of reactions and contexts that can be used with it. They can be downloaded and inexpensively recreated.

Abstract

Electrosynthetic reactions are performed in either custom-made reactors that are developed and machined in-house or commercially available systems that offer good reproducibility but come at a high cost. To bridge this divide between customizability and reproducibility, we have developed the Open-ESyn, which is a suite of 3D-printed components compatible with the popular ElectraSyn. This collection of parts increases the electrosynthesis that can be performed with the ElectraSyn, expanding, for example, the scale, temperature and the type of electrodes that can be used. The standardized reactor environment can be inexpensively recreated, thereby maintaining the reproducibility of the ElectraSyn ecosystem.

Cathodic reduction of 2-cinnamyl-substituted nitroarenes under constant current electrolysis affords a broad array of substituted quinoline N-oxides through a mechanism involving a 1,5-hydrogen atom abstraction.

Abstract

Electrochemical reduction of 2-allyl-substituted nitroarenes using a simple, undivided electrochemical cell with non-precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5-hydrogen atom transfer reactions to construct quinoline N-oxides bearing aryl-, heteroaryl-, alkenyl-, benzyl-, sulfonyl-, or carboxyl groups.

The targeted photoactivation of periodate provides a novel and operationally straightforward method for accessing oxenoid-type reactivity. Computational studies have revealed a geometric transition in periodate geometry which, when irradiated, allows for the facile extrusion of molecular oxygen. This new reaction pathway allows for the epoxidation of a broad range of olefin substrates using an organic-soluble source of periodate and violet light irradiation.

Abstract

The chemistry of low-valent intermediates continues to inspire new modes of reactivity across synthetic chemistry. But while the generation and reactivity of both carbenes and nitrenes are well-established, difficulties in accessing oxene, their oxygen-based congener, has severely hampered its application in synthesis. Here, we report a conceptually novel approach towards oxenoid reactivity through the violet-light photolysis of tetrabutylammonium periodate. Computational studies reveal an unexpected geometric change upon periodate photoexcitation that facilitates intersystem crossing and near-barrierless dissociation of triplet periodate into oxene. Under these operationally simple conditions, we have demonstrated the epoxidation of a wide range of substituted olefins, revealing unprecedented functional group compatibility. By overcoming the historic challenges associated with employing oxene as an intermediate in organic chemistry, we believe that this platform will inspire the development of new reactive oxygen-based methodologies across industry and academia.

“My favorite molecule is tryptophan because it already has two rings and a chiral center… If I won a million dollars in the lottery I would hire ten postdocs…” Find out more about Hugh Nakamura in his Introducing… Profile.

The first total syntheses of β- and γ-naphthocyclinones, the pyranonaphthoquinone dimers sharing unique dibenzobicyclo[3.2.1]octadienone skeleton, have been accomplished. The challenges are 1) stereoselective synthesis of the bicyclic skeleton and 2) enantio- and diasteoselective preparation of the pyranonaphthoquinone monomer. The keys in the total synthesis were 1) the design of the common intermediate convertible to both acceptor and donor units, 2) chiral Rh-catalyzed stereoselective 1,4-addition to couple the monomer units, and 3) thiolate-meditated reductive cyclization to form the bicyclic core.

Abstract

After half a century from their isolation in 1974, we report the first total syntheses of β- and γ-naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]-octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh-catalyzed enantioselective 1,4-addition followed by thiolate-mediated reductive cyclization, and 2) judicious design of a common chiral, non-racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

Hexafluoro-isopropanol (HFIP) is a popular solvent strongly enhancing reaction rates. Its unique properties are thought to be connected to its hydrogen-bond structure. Here we investigate the hydrogen-bond dynamics of HFIP and its non-fluorinated counterpart, isopropanol, by means of infrared and dielectric spectroscopy. We show that the smaller size and faster dynamics of hydrogen-bonded clusters in HFIP play an important role in its superior solvent properties.

Abstract

Using fluorinated mono-alcohols, in particular hexafluoro-isopropanol (HFIP), as a solvent can enhance chemical reaction rates in a spectacular manner. Previous work has shown evidence that this enhancement is related to the hydrogen-bond structure of these liquids. Here, we investigate the hydrogen-bond dynamics of HFIP and compare it to that of its non-fluorinated analog, isopropanol. Ultrafast infrared spectroscopy experiments show that the dynamics of individual hydrogen-bonds is about twice as slow in HFIP as in isopropanol. Surprisingly, from dielectric spectroscopy we find the opposite behavior for the dynamics of hydrogen-bonded clusters: collective rearrangements are 3 times faster in HFIP than in isopropanol. This difference indicates that the hydrogen-bonded clusters in HFIP are smaller than in isopropanol. The differences in cluster size can be traced to changes in the hydrogen-bond donor and acceptor strengths upon fluorination. The smaller cluster size can boost reaction rates in HFIP by increasing the concentration of reactive, terminal OH-groups of the clusters, whereas the fast collective dynamics can increase the rate of formation of hydrogen-bonds with the reactants. The longer lifetime of the individual hydrogen-bonds in HFIP can enhance the stability of the hydrogen-bonded clusters, and so increase the probability of reactant-solvent hydrogen-bonding.

This novel platform for automated electrochemical synthesis of compound libraries in flow enabled the C−X arylation of>30 aryl halide scaffolds in the presence of diverse amines (including sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid electrode passivation.

Abstract

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure–activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C−X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across>30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C−X arylation compound libraries using flow electrochemistry.

(Z)-Enamides are important motifs, due to their prevalence in bio-active molecules. However, few strategies are known to obtain them stereoselectively. Herein we report a nickel catalyst which, combined with simultaneous photoredox and energy transfer catalysis, enables the selective formation of (Z)-enamides. Di- and tri- functionalized functionalized olefin products can be obtained in high yields and stereoselectivity, respectively, from a redox-modulated nickel intermediate. Selective and challenging nickel-catalyzed β-H abstraction is attainable through kinetic control facilitated by an external additive.

The phlegmacin biosynthesis in the mushroom Cortinarius odorifer reveals that CoUPO1, an unspecific peroxygenase, catalyzes the dimerization step by regio- and stereoselective oxidative phenol coupling. This study demonstrates that mushrooms evolved aryl coupling independently of any other group of organisms.

Abstract

Bioactive dimeric (pre-)anthraquinones are ubiquitous in nature and are found in bacteria, fungi, insects, and plants. Their biosynthesis via oxidative phenol coupling (OPC) is catalyzed by cytochrome P450 enzymes, peroxidases, or laccases. While the biocatalysis of OPC in molds (Ascomycota) is well-known, the respective enzymes in mushroom-forming fungi (Basidiomycota) are unknown. Here, we report on the biosynthesis of the atropisomers phlegmacin A₁ and B₁ of the mushroom Cortinarius odorifer. The biosynthesis of these unsymmetrically 7,10’-homo-coupled dihydroanthracenones was heterologously reconstituted in the mold Aspergillus niger. Methylation of the parental monomer atrochrysone to its 6-O-methyl ether torosachrysone by the O-methyltransferase CoOMT1 precedes the regioselective homocoupling to phlegmacin, catalyzed by the enzyme CoUPO1 annotated as an “unspecific peroxygenase” (UPO). Our results reveal an unprecedented UPO reaction, thereby expanding the biocatalytic portfolio of oxidative phenol coupling beyond the commonly reported enzymes. The results show that Basidiomycota use peroxygenases to selectively couple aryls independently of and convergently to any other group of organisms, emphasizing the central role of OPC in natural processes.