Gram-scale Synthesis Research Articles

Expression of Concern: "Gram-scale synthesis of ZnS/NiO core-shell hierarchical nanostructures and their enhanced H2 production in crude glycerol and sulphide wastewater" [Environ. Res., 199 (2021) 111323

Expression of Concern: "Gram-scale synthesis of ZnS/NiO core-shell hierarchical nanostructures and their enhanced H2 production in crude glycerol and sulphide wastewater" [Environ. Res., 199 (2021) 111323

Lignin-Based Mucus-Mimicking Antiviral Hydrogels with Enzyme Stability and Tunable Porosity.

Mucus is a complex hydrogel that acts as a defensive and protective barrier in various parts of the human body. The rise in the level of viral infections has underscored the importance of advancing research into mucus-mimicking hydrogels for the efficient design of antiviral agents. Herein, we demonstrate the gram-scale synthesis of biocompatible, lignin-based virus-binding inhibitors that reduce waste and ensure long-term availability. The lignin-based inhibitors are equipped with sulfate moieties, which are known binding partners for many viruses, including SARS-CoV-2 and herpes viruses. In addition, cross-linking the synthesized inhibitors yielded hydrogels that mimicked native mucus concerning surface functionality and rheology. The degree of sulfation exhibits a very strong impact on the mesh size distribution of the hydrogels, which provides a new means to fine-tune the steric and electrostatic contributions of the virus-hydrogel interaction. This feature strongly impacts the sequestration capability of the lignin-based hydrogels, which is demonstrated by infection inhibition assays involving human herpes simplex virus 1, influenza A viruses, and the bacterium Escherichia coli (E. coli). These measurements showed a reduction in plaque-forming units (HSV-1) and colony-forming units (E. coli) by more than 4 orders of magnitude, indicating the potent inhibition by the lignin-based hydrogels.

Defect-Induced Electron Localization Promotes D2O Dissociation and Nitrile Adsorption for Deuterated Amines.

Electrochemical reductive deuteration of nitriles is a promising strategy for synthesizing deuterated amines with D2O as the deuterated source. However, this reaction suffers from high overpotentials owing to the sluggish D2O dissociation kinetics and high thermodynamic stability of the C≡N triple bond. Here, low-coordinated copper (LC-Cu) is designed to decrease the overpotential for the electrosynthesis of the precursor of Melatonin-d4, 5-methoxytryptamine-d4, by 100 mV with a 68% yield (Faraday efficiency), which is 4 times greater than that of high-coordinated copper (HC-Cu). The low coordinated sites induced an enrichment of electrons to concentrate K+ ions hydrated deuterium water (K·D2O) and decrease the energy of the Volmer step via the polarization effect, leading to a continuous supplementation of *D for the reductive deuteration of nitriles. Moreover, the enhanced local electric field changes the adsorption configuration of nitriles from a semibridge model to a flat model, leading to faster reduction kinetics of nitriles with a high reaction rate at lower potentials. High deuterium incorporation, a wide substrate scope, and easy gram-scale synthesis over LC-Cu at 300 mA rationalize the design concept. Furthermore, the enhanced antitumor and antioxidation effects of Melatonin-d4 highlight the great promise of deuterated drugs.

Microwave-Assisted Cobalt-Catalyzed Synthesis of Quinazolinones via Acceptorless Dehydrogenative Coupling under Neat Condition.

Herein, we present a sustainable and atom-economical approach for the synthesis of quinazolinones via acceptorless dehydrogenative coupling (ADC) using earth-abundant Co-salt, (CoCl2) as the catalyst under neat condition. This method is distinguished by its green credentials, like, solvent-free, microwave-assisted heating, cost-effective, use of renewable alcohols, and generating only H2 and water as byproducts. Remarkably, this protocol achieves quinazolinone synthesis without the need for external ligands, oxidants, or additional additives. Two synthetic pathways were developed: one involving the coupling of alcohols with 2-aminobenzamide, and the other with N-phenyl-substituted 2-aminobenzamides and its derivative. The scalability of this method, demonstrated through gram-scale synthesis, highlights its potential for industrial applications. Mechanistic insights were explored through control experiments, intermediate detection by HRMS, and Hammett analysis, shedding light on the plausible reaction pathway.

Oxo-Sulfonylation of 1,7-Enynes via a Multicomponent Oxidative Radical Polar Crossover Approach.

Diastereoselective synthesis of trans-3,4-difunctionalized tetrahydroquinoline and chromane derivatives via the oxo-sulfonylation of 1,7-enynes is demonstrated. The reaction involves a three-component oxidative radical polar crossover (ORPC) approach wherein a vinyl carbocation intermediate undergoes nucleophilic substitution to afford the corresponding keto functional group. Deprotection of the N-Ts group, gram-scale synthesis, and other synthetic applications were illustrated. Control experiments and mechanistic studies show that water acts as the nucleophile in this reaction.

Microwave-Assisted Synthesis of Heterocycles via Rhodium(III)-Catalyzed C-H Activation: Norbornadiene as an Acetylene Equivalent.

General procedures for the rhodium-catalyzed annulation of aryl/heteroaryl O-pivaloyl hydroxamic acids and norbornadiene have been developed. Employing norbornadiene as an acetylene equivalent enables utilization of diverse heterocyclic substrates for this transformation which fail to react or undergo competitive Lossen rearrangement under previously reported conditions. Microwave heating significantly reduces reaction times compared to conventional protocols and allows a one-step process to be realized. The conditions described herein have been adapted for gram-scale synthesis and applied to the formal synthesis of Pfizer clinical candidates.

Photoredox-Catalyzed Alkene Acylesterification with Acyloxime Esters via C-C and Tertiary C-O Bond Formation.

We describe an efficient acyl esterification method for alkenes utilizing acyloxime esters as bifunctional reagents featuring radical acylation and congested C-O bond formation. This approach is characterized by mild photoredox conditions, high step and atom economy, a broad substrate scope, and excellent regioselectivity. A variety of valuable α-acyl hindered alcohol esters, including those obtained via gram-scale synthesis and late-stage functionalization of pharmaceutical molecules, were presented, demonstrating its synthetic potential and practicability.

Photoredox/Sulfide Dual Catalysis for Modular Synthesis of Multi-substituted Furan Rings via Catalytic Indirect Reductive Quenching.

The catalytic indirect reductive quenching method is facilitated by a combination of Ir(III) photoredox and sulfide dual-catalysis system. This study demonstrated a method for synthesizing multi-substituted furans by using a photoredox/sulfide dual-catalysis system. This method enables the synthesis of various furan derivatives, including spirofurans and phthalans. The utility of this system was demonstrated through gram-scale synthesis of the pharmaceutical molecule talopram. Mechanistic studies and density functional theory calculations suggested the formation of sulfonium species via sulfide radical cations, followed by intramolecular cyclization to produce the desired furan derivatives.

Electrochemically Driven Site-Selective N-Hydroxymethylation of Indoles and Derivatives.

Described herein is a facile electrochemical strategy for the generation of formaldehyde from N,N-dimethylacetamide (DMA) and water (H2O) toward a direct and site-selective N-hydroxymethylation of indoles and derivatives. Mechanistic studies suggested that N-(hydroxymethyl)-N-methylacetamide generated in situ from DMA/H2O under electrochemical conditions serves as a formaldehyde surrogate. The developed methodology features mild, base- and metal catalyst-free conditions. The reaction can accommodate a broad range of substrate scopes and offers an alternative route to access a series of N-hydroxymethylated indole, bis-indole, carbazole, and indazole derivatives. A gram-scale synthesis was demonstrated to show the scaled-up applicability of this transformation.

General access to furan-substituted gem-difluoroalkenes enabled by PFTB-promoted cross-coupling of ene-yne-ketones and difluorocarbene.

Replacement of a carbonyl group with fluorinated bioisostere (e.g., CF2[double bond, length as m-dash]C) has been adopted as a key tactical strategy in drug design and development, which typically improves potency and modulates lipophilicity while maintaining biological activity. Consequently, new gem-difluoroalkenation reactions have undoubtedly accelerated this shift, and conceptually innovative practices would be of great benefit to medicinal chemists. Here we describe an expeditous protocol for the direct assembly of furan-substituted gem-difluoroalkenes via PFTB-promoted cross-coupling of ene-yne-ketones and difluorocarbene. In this multi-step tandem reaction process, the furan ring and the gem-difluorovinyl group are constructed simultaneously in an efficient manner. These products can serve as bioisosteres of the α-carbonyl furan core, which is an important scaffold present in natural products and drug candidates. The broad generality and practicality of this method for late-stage modification of bioactive molecules, gram-scale synthesis and versatile derivatisation of products has been described. Biological activity evaluation showed that the gem-difluoroalkene skeleton exhibited dramatic antitumor activity.

Photo-induced transformation of α-diazocarbonyl compounds into mono-substituted alpha-halogen derivatives.

Herein, the hydrogen halogenation reaction of diazo compounds with three new halogenating agents under photoinduced conditions is reported. This method realized hydrofluorination, hydrochlorination, and hydrobromination (56 cases in total, with the highest preparative yield of 94%) without requiring heating, transition metal catalysts or photocatalysts and exhibits a broad substrate scope. Notably, gram-scale synthesis using a continuous flow reactor was performed.

Gram-scale green synthesis of a highly stable cationic covalent organic framework for efficient and selective removal of ReO4 -/99TcO4.

Covalent organic frameworks (COFs) have developed as efficient and selective adsorbents to mitigate 99TcO4 - contamination. However, the eco-friendly and scalable production of COF-based adsorbents for the removal of 99TcO4 - has not yet been reported. This study explores the potential of a cationic COF (TpDB-COF) synthesized via a green hydrothermal method, achieving gram-scale yields per batch, thereby addressing a significant limitation of existing COF production methods. The TpDB-COF demonstrates an exceptional stability in strongly acidic conditions (2 weeks in 3 M HNO3), as well as in various organic solvents, making it suitable for harsh nuclear waste environments. Adsorption experiments using ReO4 - as a surrogate for 99TcO4 - show rapid adsorption kinetics, reaching nearly 100% removal efficiency within 1 min (with initial concentration of 28 ppm at a solid-to-liquid ratio of 1 g L-1), a maximum adsorption capacity of 570 mg g-1 and excellent stability. Moreover, the COF maintains high selectivity for ReO4 - even in the presence of competing anions such as SO4 2- and NO3 -. These findings highlight that the hydrothermal synthesis is an effective method to synthesize COF adsorbents for efficient removal of 99TcO4 - and offers a sustainable approach for practical applications.

High-yielding total synthesis of embelin, rapanone, and irisoquin A, D, F.

Simple and sustainable three- and four-step sequences of di-OH-protection/mono-OMe-deprotection/OrgRC and di-OH-protection/mono-OMe-deprotection/OrgRC/OMe-deprotection protocols were developed to construct biologically active natural products of irisoquin, irisoquin A, irisoquin D, irisoquin F, sorgoleone-364, embelin, rapanone, 5-O-methylembelin, 5-O-methylrapanone and their analogues from the commercially available 2,5-dihydroxy-1,4-benzoquinone, aliphatic aldehydes and Hantzsch ester (1,4-DHP) in very good to excellent yields by using organocatalytic reductive coupling (OrgRC) as key reaction. Many of these natural compounds exhibited a broad spectrum of biological activities including antioxidant, anti-inflammatory, anticonvulsant, anxiolytic, analgesic, anthelmintic, antitumor, antibacterial, and antifertility properties. At the same time, simple and readily available 2,5-dihydroxy-1,4-benzoquinone was transformed into a functionally rich library of 2,5-dihydroxy-3,6-dialkyl-1,4-benzoquinones in very good yields by using sequential OrgRC followed by deprotection reactions and resulting natural/unnatural products would be excellent targets for investigation to show their biological activities compared to known natural products. Further, we tried to synthesize another mero-sesquiterpenoid of (+)-cyclospongiaquinone-1 from a chiral bicyclic aldehyde and hydroxy-1,4-benzoquinone by using OrgRC followed by etherification reactions, but we ended up with the synthesis of their ring-open analogues in good yields. The high-yielding gram-scale chemoselective synthesis of natural products irisoquin and demethylated-irisoquin demonstrated the potential to conduct these processes on larger scales.

Structure-guided engineering an (R)-transaminase from Mycobacterium neoaurum for efficient synthesis of chiral N-heterocyclic amines.

(R)-selective amine transaminases (R-ATAs) show considerable potential for the asymmetric synthesis of chiral drug intermediates. However, the low catalytic efficiency of natural R-ATAs toward bulky ketone substrates, such as N-heterocyclic compounds, severely limits its industrial application. In this study, five putative (R)-ATAs were mined from NCBI database, among which MnTA showed the highest activity for N-Boc-3-pyrrolidinone (1a) and N-Boc-3-piperidone (2a), and its crystal structure was performed. Furthermore, a structure-guided engineering strategy combined with directed evolution and in silico design was executed. Four key sites for substrate binding were identified based on alanine scanning. Then, a saturated mutation library was constructed, and residues G66 and F127 were found to be the key sites affecting substrate binding. By further combining mutation and iterative saturation mutation, variants with markedly improved activity were obtained. The optimal mutant MnTA-M1 (F127M) and MnTA-M5 (G66L/H67N/F127M/L160I) also displayed significantly enhanced activity toward various cyclic ketones or bulky N-heterocyclic ketone analogs. Finally, the gram-scale synthesis of (R)-3-amino-N-Boc-pyrrolidin (1b) and (R)-3-amino-N-Boc-piperidine (2b) was performed by the best mutants, achieving the space-time yields (STY) of 108 and 214g/L·d, respectively. This research provides efficient biocatalysts for the synthesis of various chiral N-heterocyclic amines, along with a structural insight into the molecular mechanism for enhanced catalytic performance.

Facile access to chiral anti-1,2-diol derivatives via Ir-catalyzed asymmetric hydrogenation of α-alkoxy-β-ketoesters.

The iridium-catalyzed asymmetric hydrogenation of α-alkoxy-β-ketoesters via dynamic kinetic resolution has been achieved with high efficiency and enantioselectivity. This strategy allows for the synthesis of differentiated anti-1,2-diol derivatives in high yields, exhibiting excellent enantio- and diastereoselectivity (up to 99% yield, 99% ee, and 99 : 1 dr). Additionally, high turnover number (TON) experiments (up to 1000 TON) and gram-scale synthesis of a key fragment of the potential drug Tesaglitazar were successfully performed, highlighting the protocol's potential for broader applications.

Continuous-flow chemo-enzymatic gram-scale synthesis of indole-3-acetic acid

In this work, a chemo-enzymatic reaction was developed to synthesize indole-3-acetic acid (IAA) in a continuous flow mode.

Late-stage C-H trifluoroacetylation of quinoxaline-2(1H)-ones using masked trifluoroacyl reagents.

A strategy for trifluoroacetylation of quinoxaline-2(1H)-ones has been investigated. This strategy employs masked trifluoroacyl reagents to obtain trifluoroacetylated quinoxaline-2(1H)-ones under metal-, catalyst-, and light-free conditions. This approach is distinguished by its functional group compatibility and tolerance, as well as the simplicity of the experimental process, making it suitable for gram-scale synthesis.

HFIP mediated oxime ether synthesis: a metal, base and additive free approach.

Oxime ethers are extensively present as key components in numerous active pharmaceutical ingredients and many other synthetically viable organic compounds. Herein, we present a metal, base and additive free mild C-O bond formation strategy for the synthesis of oxime ethers from various oxime derivatives and tertiary and secondary aryl alcohols. The reaction is carried out in the presence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the green solvent at 30 °C. The reaction tolerates both aldoximes and ketoximes including ketoximes bearing heteroatoms, furnishing high yields (up to 99%). The formation of a triphenylmethyl carbocation as an intermediate is supported via UV-Vis spectroscopy. Successful gram-scale synthesis of the oxime ether, low energy input and simple reaction conditions further highlight the potential of this reaction to effectively transition from the laboratory scale to industrial production. A broad substrate scope compatibility was also observed.

Scalable synthesis of (±)-gregatin A via a 1,3-dipolar cycloaddition strategy.

A 6-step gram-scale synthesis of the fungal polyketide (±)-gregatin A is described. The synthetic route features an intermolecular 1,3-dipolar cycloaddition, a Mo-mediated disconnection of the isoxazole skeleton, and an acid-mediated deprotection/enamine hydrolysis and hemiketalization cascade.

Base-Free Synthesis of S-Alkyl Isothioureas Through Ring-Opening Reaction of Sulfonium Salts with Isothiocyanates and Amines.

A convenient and base-free three-component reaction has been developed for the synthesis of S-alkyl substituted isothioureas from cyclic sulfonium salts, isothiocyanates, and amines. This protocol provides an alternative avenue to access a series of S-alkyl substituted isothioureas in moderate to good yields through ring-opening reaction of aryl, alkenyl and alkynyl sulfonium salts. The present strategy features operational simplicity, good functional group tolerance, gram-scale synthesis and high reaction efficiency.