Reductive Cleavage Research Articles

Selective C-N Bond Cleavage in Unstrained Pyrrolidines Enabled by Lewis Acid and Photoredox Catalysis.

Cleavage of inert C-N bonds in unstrained azacycles such as pyrrolidine remains a formidable challenge in synthetic chemistry. To address this, we introduce an effective strategy for the reductive cleavage of the C-N bond in N-benzoyl pyrrolidine, leveraging a combination of Lewis acid and photoredox catalysis. This method involves single-electron transfer to the amide, followed by site-selective cleavage at the C2-N bond. Cyclic voltammetry and NMR studies demonstrated that the Lewis acid is crucial for promoting the single-electron transfer from the photoredox catalyst to the amide carbonyl group. This protocol is widely applicable to various pyrrolidine-containing molecules and enables inert C-N bond cleavage including C-C bond formation via intermolecular radical addition. Furthermore, the current protocol successfully converts pyrrolidines to aziridines, γ-lactones, and tetrahydrofurans, showcasing its potential of the inert C-N bond cleavage for expanding synthetic strategies.

Recent Progress on Organic Electron Donors (OEDs) Enabled Radical Reactions

Over the past few decades, organic transformations facilitated by small organic molecules have witnessed considerable advancements. Small organic molecules have been widely applied to the construction of various skeletons. However, reduction as one of the fundamental reactions is generally initiated by metal‐containing reducing agents, although the initial progress of organic electron donors (OEDs) enabled reductive cleavage of some chemical bonds had been achieved in 1990s. Due to their structural diversity and tunability, OEDs can overcome the limitations of metal‐based reducing agents, such as low selectivity and poor functional group tolerance as well as the environmental problems caused by substantial inorganic waste after reactions. Building on a brief historical overview of OED research, this review focuses on the rencent advancements of the OEDs promoted radical reactions. It covers the reduction of C‐X (X =C, O, N etc.) single bonds, radical cyclization, intermolecular radical addition to unsaturated bonds, radical coupling, functionalization of aromatics, and C‐H bond activation. Additionally, the mechanistic insights of the typical reactions are highlighted for well understanding of the reaction mode involving OEDs.

Enantioselective S-Alkylation of Sulfenamides by Phase-Transfer Catalysis.

A general phase-transfer catalyst (PTC) mediated enantioselective alkylation of N-acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at -40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S-(hetero)aryl and branched and unbranched S-alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever-increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free-NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)-sulfoximine stereoisomer.

Umpolung Approach to Aldol Products via Isoxazoline N-Oxides as Intermediates.

A two-step umpolung approach to the diastereoselective synthesis of aldols was developed, in which a conjugated nitroalkene is used as the synthetic equivalent of the enolonium cation, while a sulfur ylide acts as the equivalent of the α-carbinol anion. The resulting isoxazoline N-oxides undergo catalytic reductive cleavage to aldols under mild conditions at room temperature and under 1 atm hydrogen pressure. The efficiency of the method was demonstrated by the synthesis of a series of polysubstituted β-hydroxyketones that are difficult to synthesize using the classical aldol reaction. The developed approach allows for the regiodivergent assembly of aldols by selecting a nitroalkene isomer with the appropriate position of the C,C double bond.

An Approach for Highly Enantioselective Synthesis of meta-Disubstituted [n]Paracyclophanes.

Atroposelective synthesis of meta-disubstituted [n]paracyclophanes is a difficult task in organic chemistry. We describe a facile approach for the synthesis of meta-disubstituted [n]paracyclophanes using Pd-catalyzed enantioselective C-H olefination and sequential reductive cleavage. A wide range of [n]paracyclophanes was obtained with excellent enantioselectivity. Thermodynamic analysis revealed that the rotational barrier of meta-disubstituted [n]paracyclophanes was lower than that of para-disubstituted [n]paracyclophanes. The synthesized planar-chiral [14]paracyclophane showed a bright fluorescence emission and impressive circularly polarized luminescence activity.

Enantioselective S‐Alkylation of Sulfenamides by Phase‐Transfer Catalysis

AbstractA general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer.

Mechanistic Insights from the Crystal Structure and Computational Analysis of the Radical SAM Deaminase DesII.

Radical S-adenosyl-L-methionine (SAM) enzymes couple the reductive cleavage of SAM to radical-mediated transformations that have proven to be quite broad in scope. DesII is one such enzyme from the biosynthetic pathway of TDP-desosamine where it catalyzes a radical-mediated deamination. Previous studies have suggested that this reaction proceeds via direct elimination of ammonia from an α-hydroxyalkyl radical or its conjugate base (i.e., a ketyl radical) rather than 1,2-migration of the amino group to form a carbinolamine radical intermediate. However, without a crystal structure, the active site features responsible for this chemistry have remained largely unknown. The crystallographic studies described herein help to fill this gap by providing a structural description of the DesII active site. Computational analyses based on the solved crystal structure are consistent with direct elimination and indicate that an active site glutamate residue likely serves as a general base to promote deprotonation of the α-hydroxyalkyl radical intermediate and elimination of the ammonia group.

The methods of synthesis of 2-aminobenzophenones — key precursors of 1,4-benzodiazepines

The review article briefly presents the pharmacological profile and mechanism of action of 1,4-dibenzodiazepines, and the structures of the most important drugs from this class of compounds. The strongest emphasis is placed on presentation of various methods for the synthesis of 2-aminobenzophenones — the most often used precursors in the synthesis of 1,4-benzodiazepines and numerous classes of azaarenes. The reactions or their sequences were grouped according to retrosynthetic strategies based on structural similarities and differences of the reagents used. There were presented not only the most classical methods like Friedel-Crafts acylation or Grignard reaction, but also more advanced transformations utilizing various catalysts and more sophisticated approaches involving the synthesis of heterocyclic systems followed by their reductive or oxidative cleavage. Selected nuances of the presented reactions were discussed, including fragments of mechanisms, limitations of the applicability of a given method, and the advantages of modern solutions over the oldest and more classical methods.

Aryl Silyl Ethers Enable Preferential Ar-O bond Cleavage in Reductive Generation of Aryllithium Species.

Two-electron transfer to haloarenes constitutes one of the most reliable synthetic methodologies for the generation of aryllithiums. In addition to the conventional halides, readily available aryl ethers can function as potent substrates. However, it is known that the reductive cleavage of alkoxides is plagued by insufficient selectivity concerning the cleaving bond adjacent to the ether oxygen, resulting in decreased reliability of these alkoxyarene substrates. In the present study, we discovered that naphthalenes bearing readily installable tert-butyldimethylsilyl ethers undergo two-electron reduction with lithium metal, resulting in lithiation at the position of the original siloxy group. DFT calculations elucidated the rationale for the change in selectivity upon incorporation of the siloxy group. Our results underscore the practical utility of a siloxy group as a leaving group for reductive transformations involving electron transfer.

Molecular Understanding of Li Metal Anode

Developing new liquid electrolyte is a promising approach to enable the next-generation high-energy Li metal battery for wide-ranging application such as electric vehicles (EV). However, the high reactivity of Li metal interface renders it crucial to form favorable solid-electrolyte interphase (SEI), via active electrolyte decomposition, for highly reversible operation of Li-metal anode (LMA). Therefore, deeply understanding how the molecular structures of electrolyte species precisely control both the interfacial reactivity and the operational reversibility of LMA, can further guide and inspire new electrolyte systems with progressively improved battery performance.Herein, we systematically investigated the impact of Li salts with different imide anions dissolved in ether-based solvent, on the resulting Coulombic efficiencies (CE) of LMA, whereas beneficial and detrimental molecular motifs were first identified. By leveraging the non-washing XPS protocol newly developed at Stanford, we managed to uncover the distinct molecular reactivity leading to reductive bond cleavage as well as new bond formation at Li-metal potential. Such nanoscale reactivity of SEI-forming reactions was discovered to profoundly govern the macroscopic performance of LMA, which simultaneously emphasized the significance of electric double layer (EDL). Importantly, aided by gas-titration experiments to quantify the by-products in SEI, we revealed the critical molecular origins of irreversible capacity loss of LMA during continuous Li-metal plating and stripping. These new insights allow us to formulate rational strategies of molecular engineering to design LMA interface with high reversibility and minimal side reactivity.

Harnessing Chlorella vulgaris for the phycoremediation of azo dye: A comprehensive analysis of metabolic responses and antioxidant system

This study investigates the phycoremediation potential of microalgae Chlorella vulgaris in the degradation of Direct green 6 (DG6), a synthetic azo dye commonly used in the textile industry, which poses significant environmental and health risks due to its toxic and carcinogenic properties. Over 50 days of treatment, we analyzed the effects of varying concentrations of DG6 on the biodegradation capabilities of C. vulgaris with the characterization of growth and antioxidant parameters. The findings demonstrate that C. vulgaris reduced DG6 levels significantly (p < 0.05) at higher temperatures (40 °C) compared to other environmental ambient temperatures. Within the acidic range pH < 7 progressive removal efficiency was observed within 25 days in consistency with the enhanced growth indices of biomass concentration (Xm), productivity (Px), specific growth rate (μm), and doubling time (td) at the higher concentration of 60 mg L−1. Induction of both enzymatic and non-enzymatic antioxidant activities were quantified for superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), ascorbate peroxidase (APX), azoreductase, and laccase, as well as changes in the total ascorbate pool (AsA + DHA) and ferric reducing antioxidant power (FRAP). Furthermore, the underlying biodegradation mechanisms were elucidated by identifying the reductive cleavage of azo bonds by azoreductase and breakdown by peroxidases and laccase. These molecular by-products were identified using gas chromatography–mass spectrometry (GC–MS), which shed light on the metabolic pathways involved in DG6 biodegradation. This study underscores the effectiveness of C. vulgaris as a sustainable, low-cost solution for the bioremediation of azo-dye-polluted water. This study lays the groundwork for further exploration into the genetic and metabolic adaptations of algae under complex organic pollutant stress, with potential implications for ecophysiology, biotic interactions, and evolutionary biology.

Diastereoselective 1,3-dipolar intramolecular nitrone olefin cycloaddition (INOC) reaction of a sugar-derived allyl alcohol: Synthesis of functionalized aminocyclopentitols

The DIBAL-H reduction of the Baylis-Hillman sugar adduct, obtained from 3-O-benzyl-1,2-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose yielded trisubstituted alkenes by eliminating the β-hydroxyl group. Subsequently, the hydrolysis of the isopropylidene acetal to the corresponding hemiacetal was reacted with N-benzyl hydroxylamine hydrochloride to generate the nitrone, which underwent diastereoselective intramolecular 1,3-dipolar nitrone olefin cycloaddition (INOC) to give an isoxazolidine skeleton. The concomitant reductive cleavage of the N-O bond and benzyl group of the fused isoxazolidines afforded new functionalized aminocyclopentitols in good yields.

Lignin, extractives and structural carbohydrate characteristics of Thinopyrum intermedium biomass reveal additional valorization opportunities for dual-crop utilization.

Thinopyrum intermedium (Host) Barkworth & D.R. Dewey, or intermediate wheat grass (IWG), is being developed as the first widely-available perennial grain candidate. However, because the crop is still in development, grain yields are lower than those of traditional cereals. Utilization of its non-grain biomass (e.g. for biofuel production and as a source of fine chemicals) would increase the economic value of its cultivation. The present study provides a structural characterization of the lignin and cell wall carbohydrates in IWG biomass and qualitative profiling of biomass extractives and compares them to those of annual wheat (Triticum aestivum) biomass grown in the same location and growing season. The monosaccharide composition and ester-linked phenolic acid contents of vegetative biomass material from annual wheat and IWG were similar. IWG vegetative biomass is rich in feruloylated arabinoxylans (AX) with a very low substitution rate, whereas the AX from IWG bran have a slightly higher substitution rate. The structure of IWG lignin was investigated using both the quantitative derivatization followed by reductive cleavage method and 2D-NMR analysis, revealing an H:G:S lignin that incorporates tricin and is acylated with coumaric acid and smaller amounts of ferulates. IWG and wheat extractives contained fatty acids, various free phenolic compounds (tricin, monolignols and phenolic acids), phenolic conjugates and phytosterols. The present study provides firm support for the further exploration of T. intermedium biomass as a carbohydrate feedstock (e.g, abundant in lightly substituted AX and cellulose polymers) for biofuel production and source of high-value fine chemicals, such as tricin. © 2024 Society of Chemical Industry.

Bulky Alkyl Substituents Enhance the Photocatalytic Activity of Pyridine-Based Donor-Acceptor Molecules in the Direct Reductive Cleavage of the C-Br Bond of Aliphatic Bromides.

We report new pyridine-based donor-acceptor (D-A) molecules that enable the direct reductive transformation of a variety of secondary and tertiary aliphatic bromides. A series of experimental and theoretical results suggested that the D-A molecules promote direct C-Br bond cleavage triggered by the excitation of the complex between the catalyst and the aliphatic bromide and that the alkyl groups significantly contribute to the stabilization of the complex, which improves the efficiency of its excitation.

Development of a Divergent Synthesis of Pleurotinoid Natural Products.

Herein, we describe the evolution of our syntheses of the pleurotinoid natural products pleurotin (1), pleurogrisein (3), and 4-hydroxypleurogrisein (4). An approach based on a proximity-induced intramolecular Diels-Alder cycloaddition of a transient ortho-quinone dimethide (e.g., 6, Scheme 1) was inferior to an alternative construction featuring Gao's titanium(IV)-mediated photoenolization Diels-Alder coupling of ortho-tolualdehyde 20 with functionalized hydrindenone 22. While this pairing exhibited the desired stereoface selectivity and produced cis-fused hydrindanone 23, the successful realization of our syntheses of 1, 3, and 4 required a post-Diels-Alder epimerization of the unactivated stereocenter at C-5 in compound 23. Ultimately, it was possible to generate a reactive oxygen-centered radical via a reductive homolytic cleavage of the N-O bond in 23 and capitalize on its ability to break the C5-H bond in an intramolecular 1,5-hydrogen atom transfer (HAT). The carbon radical arising from this pivotal 1,5-HAT was subsequently trapped in situ by an exogenous thiol in a kinetically controlled HAT reaction to establish the natural configuration at C-5. The successful flipping of the cis-hydrindane in 23 to the challenging trans configuration in 24 provided a firm foundation for a formal synthesis of pleurotin (1), as well as syntheses of pleurogrisein (3) and 4-hydroxypleurogrisein (4).

Selective adsorption and removal of Congo red dye from waste water using catechol-stabilized reusable palladium nanoparticles

Several industries including textile, dye manufacturing industries, paper and pulp industries discharge colored wastewater. The majority of synthetic dyes is composed of toxic azo compounds. Eradication of toxic azo dyes, organic pollutants, radioactive materials from the global ecosystem has received remarkable attention due to their detrimental effects on human health and ecosystem. Nanotechnology-based applications on catalytic degradation of contaminants from aqueous ecosystem have evolved as a major topic of research in the scientific community, to develop a cost-effective and energy-effective strategy. In this context, nanomaterials have gained much attention because of its unique physico-chemical properties. Herein, catechol-generated palladium nanoparticles (PdNPs) have been utilized for the selective removal of congo red dye from wastewater. In this study, Palladium nanocatalyst (4 μg/ml) developed earlier by our group, was screened for degradation of dyes of different nature. The newly developed nanocatalyst was found to be effective against anionic dyes. Among the anaionic dyes, congo red was selected for degdradation study in detail. Complete degradation of congo red dye (CR) (150 μM) is found to happen within 10 min. Besides catalytic degradation, the efficiency of the recycled catalyst was evaluated, which exhibits 60 % efficiency even after the 3rd cycle. Gas chromatography-mass spectrometry (GC–MS) characterization of the degraded products reveals the formation of benzidine, indicating the reductive cleavage of azo linkage of the dye.In summary, the results highlight the potential development of a nanocatalyst for the selective and efficient removal of congo red, suggesting a simple,cost-effective, and reusable approach to prevent industrial pollutant in aqueous ecosystem.

Cleavable azobenzene linkers for the design of stimuli-responsive materials.

The azo linkage (NN) is one of the very few functional groups in organic chemistry that exhibits sensitivity towards thermal, chemical, photochemical, and biological stimuli. Consequently, this property has given rise to a distinct class of responsive materials. For example, thermal sensitivity has led to generation of free radical initiators useful in curing and polymerization applications. Chemically-induced cleavage has aided the development of self-immolative polymers and reactive scaffolds for proteomics applications. Photo-isomerization capability has given rise to photo-responsive systems. Azobenzene cleavage in biologically reducing environments, such as that of the colon, and under tumor hypoxia conditions has led to diagnostic, therapeutic, and delivery materials. Such conditions have also allowed for control over formation (assembly) and disruption (disassembly) of micellar nanoparticles. The aim of this review article is to look beyond the prevalent photosensitivity aspect of the aromatic azo compounds and draw attention to the azo scission reaction as a trigger of the change in the structure and properties of organic materials. Thus, the main discussion begins with the mechanism of the reductive cleavage. Then, its application in the design of molecules that can be activated as drugs and fluorescent sensors, (nano)materials with potential to release active substances, and polymers with side-chain and main-chain self-immolative capacity is discussed. Finally, the status and future challenges in this field are discussed.

Degradation of methyl orange using hydrodynamic cavitation coupled with plasma oxidation and ultraviolet C

Combining multiple advanced oxidation processes (AOPs) is essential for the efficient treatment of dye wastewater. In this study, the degradation efficiencies of various oxidation methods, including hydrodynamic cavitation (HC), dielectric barrier discharge (DBD) plasma oxidation, ultraviolet C (UVC), and their combination HC + DBD + UVC, were investigated for Methyl Orange (MO). The photolysis of ozone (O3) and the degradation mechanism associated with HC + DBD + UVC were analyzed to elucidate the pathway of MO degradation. The results demonstrated that the combination of HC + DBD + UVC exhibited a significantly enhanced degradation efficiency compared to other process combinations, achieving a removal efficiency exceeding 91% within a 5-min timeframe. Optimal parameters for achieving a 99.5% degradation rate of 10 mg/L MO were determined as follows: pH 4, inlet pressure of 1.5 MPa, utilization of eight UV lamps with a power input of 46.11 W. During the degradation process, hydroxyl radicals (·OH) and ozone (O3) played crucial roles, while the incorporation of UV lamps effectively mitigated ozone (O3) emissions and enhanced the oxidation of ozone (O3). In conjunction with the analysis of degradation products using liquid chromatography-mass spectrometry, it is highly probable that the MO degradation pathway involves reductive cleavage of the azo bond through ·OH attack. Compared to other experimental methods in literature, HC + DBD + UVC exhibits significant advantages such as enhanced efficiency and absence of additives. This innovative approach offers a rapid and practical on-site solution for efficient MO dye wastewater treatment.

Elucidating the Degradation Pathways of Human Insulin in the Solid State

While there have been significant advances in the development of peptide oral dosage forms in recent years, highlighted by the clinical and commercial success of approved peptides such as Rybelsus®, there remain several barriers in the way of broad range applicability of this approach to peptide delivery. One such barrier includes the poor physical and chemical stability inherent to their structures, which persists in the solid state although degradation typically occurs at different rates and via different pathways in comparison to the solution state. Using insulin as a model peptide, this work sought to contribute to the development of analytical techniques for investigating common insulin degradation pathways. Chemically denatured, deamidated and aggregated samples were prepared and used to benchmark circular dichroism spectroscopy, reverse phase HPLC and size exclusion chromatography methods for the investigation of unfolding, chemical modifications and covalent aggregation of the insulin molecule respectively. Solid state degraded samples were prepared by heating insulin powder at 60 °C and 75% relative humidity for 1, 3, 5 and 7 d, and the degradation profiles of the samples were evaluated and compared with those observed in solution. While no unfolding was observed to occur, significant deamidation and covalent aggregation were detected. Reductive disulfide bond cleavage using dithiothreitol allowed for separation of the insulin A- and B-chains, offering a facile yet novel means of assessing the mechanisms of deamidation and covalent aggregation occurring in the solid state.

Solid‐Phase Synthesis of Peptidols via Reductive Cleavage Through a Benzotriazole Linker

AbstractPeptidols were prepared through the reductive cleavage of benzotriazole intermediates obtained from the on‐bead activation of 3,4‐diaminobenzoyl linkers. Remarkably, this method used commercially available amino acid residues and resins without further modification. Pure peptidols were collected with only filtration in 49%–87% yield. Only the derivatives with aspartic acid as the first C‐terminal residue required sophisticated chromatography purification. Esters and carboxylic acids were identified as side products and were suppressed by additional reduction or reduction in DMF. Remarkably, the reduction of peptides with the first aspartic acid residue at the C‐terminal afforded a C‐terminal lactone, which could be reduced by deprotection at 0 °C. For the synthesis of branched peptidols, the bulky wedge structures of the branched peptides resulted in low total yields, which were improved to 23%–28% by using peripheral Boc groups and SPPS on the Tental gel resin. In addition, this method gave two peptaibols, SPF‐5506‐A4 and Ac‐Gramicidin A, in 11% and 46% yields, respectively.