Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes. Under similar conditions, the one-pot reaction of tryptamines, alkyl propiolates and β-nitroalkenes resulted in functionalized tetrahydroindolizino[8,7-b]indoles. The reaction mechanism involved sequential generation of β-enamino ester, Michael addition, Pictet–Spengler reaction and annulation process. The reaction showed high atomic economy and met the goals of sustainable chemistry.

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes.     

Synthesis and molecular modeling studies of cholinesterase inhibitor dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines]

A set of dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] 8a–l was regioselectively synthesized utilizing multi-component azomethine cycloaddition reaction of 3-(arylmethylidene)pyrrolidine-2,5-diones 5a–e, isatins 6a–c and sarcosine 7. Single crystal X-ray studies of 8c add conclusive support for the structure. Compounds 8e and 8g reveal cholinesterase inhibitory properties with promising efficacy against both AChE and BChE and were found to be more selective towards AChE than BChE as indicted by the selectivity index like Donepezil (a clinically used cholinesterase inhibitory drug). Molecular modeling studies assist in understanding the bio-observations and identifying the responsible parameters behind biological properties.

Dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines] were regioselectively synthesized revealing cholinesterase (AChE, BChE) inhibitory properties.     

Elucidating the intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid-solid interface

Star-shaped 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules self-assemble at the solid–liquid interface into a compact hexagonal nanoarchitecture on graphite. High resolution scanning tunneling microscopy (STM) images of the molecules reveal intramolecular features. Comparison of the experimental data with calculated molecular charge density contours shows that the molecular features in the STM images correspond to molecular LUMO+2.

Intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid–solid interface.     

Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

2,2′,2′′,4,4′,4′′,6,6′,6′′-Nonanitro-1,1′:3′,1′′-terphenyl (NONA) is currently recognized as an excellent heat-resistant explosive. To improve the atomistic understanding of the thermal decomposition paths of NONA, we performed a series of reactive force field (ReaxFF) molecular dynamics simulations under extreme conditions of temperature and pressure. The results show that two distinct initial decomposition mechanisms are the homolytic cleavage of the C–NO₂ bond and nitro–nitrite (NO₂ → ONO) isomerization followed by NO fission. Bimolecular and fused ring compounds are found in the subsequent decomposition of NONA. The product identification analysis under finite time steps showed that the gaseous products are CO₂, N₂, and H₂O. The amount of CO₂ is energetically more favorable for the system at high temperature or low density. The carbon-containing clusters are a favorable growth pathway at low temperatures, and this process was further demonstrated by the analysis of diffusion coefficients. The increase of the crystal density accelerates the decomposition of NONA judged by the analysis of reaction kinetic parameters and activation barriers. In the endothermic and exothermic stages, a 20% increase in NONA density increases the activation energies by 3.24 and 0.48 kcal mol⁻¹, respectively. The values of activation energies (49.34–49.82 kcal mol⁻¹) agree with the experimental data in the initial decomposition stage.

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.     

Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4′-alkylsubstituted derivatives hardly available by other means.

One-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and subsequent acid-assisted spirocyclization allowed for diastereoselective preparation of 4′H-spiro[indole-3,5′-isoxazoles].     

Supported l-tryptophan on Fe3O4@SiO2 as an efficient and magnetically separable catalyst for one-pot construction of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives

In this work, l-tryptophan functionalized silica-coated magnetic nanoparticles were readily prepared and evaluated as a recyclable magnetic nanocatalyst for the synthesis of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives through the one-pot four-component reaction of malononitrile, cyclohexanone, aromatic aldehydes, and 1,3-indandione. This novel magnetic nanocatalyst was confirmed to be effective and provide products in moderate to excellent yields under reflux conditions. The structure of obtained nanoparticles was characterized using FT-IR, XRD, VSM, EDX, elemental mapping, FE-SEM, and TGA. This synthetic protocol provides several benefits such as excellent yields in short reaction times (64–91%), saving costs, reusability of the catalyst using an external magnet (seven runs), and low catalyst loading.

l-Tryptophan functionalized silica-coated magnetic nanoparticles were prepared and evaluated as a magnetic nanocatalyst for the synthesis of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives through the one-pot four-component reaction.     

Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4′-pyrano[2,3-c]pyrazol], spiro[indoline-3,5′-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3′-indoline] and spiro[benzo[g]chromene-4,3′-indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.

Synthesis of spirooxindole pyrans by a sequential four-component reaction of nitroketene dithioacetals, alkylamine/benzylamine, isatin, and active methylene compounds.     

Base-promoted lipase-catalyzed kinetic resolution of atropisomeric 1,1′-biaryl-2,2′-diols

Herein we report a dramatic acceleration of the lipase-catalyzed kinetic resolution of atropisomeric 1,1′-biaryl-2,2′-diols by the addition of sodium carbonate. This result likely originates from the increased nucleophilicity of the phenolic hydroxyl group toward the acyl-enzyme intermediate. Under these conditions, various substituted C₂-symmetric and non-C₂-symmetric binaphthols and biphenols were efficiently resolved with ∼50% conversion in only 13–30 h with excellent enantioselectivity.

The addition of a stoichiometric amount of Na₂CO₃ dramatically accelerates the lipase-catalyzed kinetic resolution of a range of atropisomeric 1,1′-biaryl-2,2′-diols.     

Copper-catalyzed intramolecular cross dehydrogenative coupling approach to coumestans from 2′-hydroxyl-3-arylcoumarins

A copper-catalyzed intramolecular cross dehydrogenative C–O coupling reaction of 2′-hydroxyl-3-arylcoumarins was developed. This protocol provided a facile and efficient strategy for the construction of natural coumestans and derivatives in moderate to high yields. This transformation exhibited good functional group compatibility and was amenable to substrates with free phenolic hydroxyl groups.

A copper-catalyzed intramolecular cross dehydrogenative C–O coupling reaction of 2′-hydroxyl-3-arylcoumarins was developed.     

2′-Fluoro-c-di-GMP as an oral vaccine adjuvant

Bis-(3′–5′)-cyclic dimeric 2′-deoxy-2′-fluoroguanosine monophosphate (2′-F-c-di-GMP) was synthesized through the modified H-phosphonate chemistry. Oral immunization of C57BL/6 mice with Helicobacter pylori cell-free sonicate extract adjuvanted with 2′-F-c-di-GMP led to the production of antigen-specific antibodies in feces and sera, and lowered bacterial counts in the stomach upon post-vaccination infections in immunized mice. Similarly, oral vaccination of BALB/c mice with flagillin proteins from Clostridium difficile and Listeria monocytogenes adjuvanted with 2′-F-c-di-GMP led to production of antigen-specific antibodies both systemically and mucosally. The adjuvanticity of 2′-F-c-di-GMP is associated with the enhanced induction of interferon γ. These results demonstrated the excellent oral adjuvanticity of 2′-F-c-di-GMP.

2′-F-c-di-GMP was synthesized through the modified H-phosphonate chemistry. 2′-F-c-di-GMP was found to be an effective mucosal vaccine adjuvant, both intranasally and orally.     

Synthesis,cytotoxicity evaluation and molecular docking studies on 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone derivatives

2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC, 1) was isolated from seeds of Syzygium nervosum A.Cunn. ex DC. exhibiting intriguing biological activities. Herein, thirty three DMC derivatives including 4′-O-monosubstituted-DMC (2), 7-O-acylated-4-hydroxycoumarin derivatives (3), stilbene–coumarin derivatives (4), 2′,4′-disubstituted-DMC (5), and flavanone derivatives (6), were synthesised through acylation, alkylations, and sulfonylation. These semi-synthetic DMC derivatives were evaluated for in vitro cytotoxicity against six carcinoma cell lines. It was found that most derivatives exhibited higher cytotoxicity than DMC. In particular, 4′-O-caproylated-DMC (2b) and 4′-O-methylated-DMC (2g) displayed the strongest cytotoxicity against SH-SY5Y with IC₅₀ values of 5.20 and 7.52 μM, respectively. Additionally, 4′-O-benzylated-DMC (2h) demonstrated the strongest cytotoxicity against A-549 and FaDu with IC₅₀ values of 9.99 and 13.98 μM, respectively. Our structure–activity relationship (SAR) highlights the importance of 2′-OH and the derivatisation pattern of 4′-OH. Furthermore, molecular docking simulation studies shed further light on how these bioactive compounds interact with cyclin-dependent kinase 2 (CDK2).

Semi-synthetic DMC derivatives were synthesised and displayed biological potency against various cancer cell lines.      

Synthesis of pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones and molecular docking study of their affinity against the COVID-19 main protease

A novel series of fused pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones were synthesized and their affinity against the COVID-19 main protease was investigated using molecular docking study and compared to that of some used standard clinical drugs. These compounds were obtained in good to excellent yields from 63 to 91% in the presence of 30 mol% catalyst in ethanol at reflux for 2 h through an efficient one-pot three-component reaction including an intramolecular rearrangement and a cyclization through intramolecular nucleophilic reaction. The results of in silico studies showed that electronegativity, resonance effects, hydrophobic interaction, halogen and hydrogen bonding had significant effects on the performance of these compounds as an inhibitor ligand. Also, these results indicated the proper affinity of these compounds against the COVID-19 main protease with excellent binding energies (especially 4r = −8.77, 4q = −8.73 and 4m = −8.63) in comparison to remdesivir, chloroquine, hydroxychloroquine, molnupiravir and nirmatrelvir drugs.

A novel series of fused pyrazolo[5′,1′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones were synthesized and their affinity against the COVID-19 main protease was investigated using molecular docking study and compared to that of some used clinical drugs.     

Role of imine isomerization in the stereocontrol of the Staudinger reaction between ketenes and imines

Computational–experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp²-hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions.

Experimental and computational studies reveal the importance of isomerization pathways in the Staudinger reaction between ketenes and imines. In the studied cases, the stereochemistry is determined by the pre-cycloaddition isomerization step.     

Anti-inflammatory butenolide derivatives from the coral-derived fungus Aspergillus terreus and structure revisions of aspernolides D and G,butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4). The new structures were characterized on the basis of comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 were a pair of rare C-8′′ epimers with vicinal diol motifs. The absolute configurations of 1–4 were determined via [Mo₂(AcO)₄] induced circular dichroism (ICD) spectra and comparison of their experimental ECD spectra. Importantly, the structures of reported aspernolides D and G, butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI have been correspondingly revised via a combined strategy of experimental validations, ¹³C NMR predictions by ACD/Labs software, and ¹³C NMR calculations. Herein we provide valuable referenced ¹³C NMR data (C-7′′, C-8′′, and C-9′′) for the structure elucidations of butenolide derivatives with 1-(2-hydroxyphenyl)-3-methylbutane-2,3-diol, 2-(2,3-dihydrobenzofuran-2-yl)propan-2-ol, or 2,2-dimethylchroman-3-ol motifs. Additionally, all the isolates (1–10) were assessed for anti-inflammatory activity by measuring the amount of NO production in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages, and compound 10 showed an even stronger inhibitory effect than the postive control indomethacin, presenting it as a promising lead compound for the development of new anti-inflammatory agents.

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4).     

A novel substrate directed multicomponent reaction for the syntheses of tetrahydro-spiro[pyrazolo[4,3-f]quinoline]-8,5′-pyrimidines and tetrahydro-pyrazolo[4,3-f]pyrimido[4,5-b]quinolines via selective multiple C–C bond formation under metal-free conditions

A versatile and substrate oriented multicomponent reaction for the syntheses of novel highly diastereoselective tetrahydro-1′H-spiro[pyrazolo[4,3-f]quinoline-8,5′-pyrimidine]-2′,4′,6′(3′H)-triones (d.r. up to 20 : 1 (syn : anti)) and tetrahydro-8H-pyrazolo[4,3-f]pyrimido[4,5-b]quinoline-8,10(9H)-diones via formation of selective multiple C–C bonds under identical reaction conditions (viz. ethanol as a reaction medium and deep eutectic mixture as a catalyst) is demonstrated. Both approaches involve mild reaction conditions, use of non-hazardous solvents, and facilitate good to excellent reaction yields of the target compounds.

Substrate selectivity in the novel multi-component reaction of 5-aminoindazole, barbituric acid derivatives and aldehyde is explored.     

Exploring an anomaly: the synthesis of 7,7′-diazaindirubin through a 7-azaindoxyl intermediate

Two independent methods generating 7-azaindoxyl as an intermediate verify that 7,7′-diazaindirubin is formed exclusively over 7,7′-diazaindigo. This contrasts with long-standing knowledge related to the reactivity of indoxyl, which proceeds via a radical-initiated homodimerization process, leading to indigo. A series of experiments confirms 7-azaindoxyl as an intermediate with results suggesting a condensation pathway followed by oxidation.

Generation of 7-azaindoxyl under acidic conditions leads exclusively to 7,7′-diazaindirubin over 7,7′-diazaindigo through a condensation pathway.     

Investigation of the electrochemical oxidation of 2,3′-bisindolylmethanes in positive-ion electrospray ionization mass spectrometry

Electrochemical reactions in electrospray may affect the electrospray ionization mass spectrometry (ESI-MS) detection of the analytes. During ESI-MS analysis of 2,3′-bisindolylmethanes in the positive-ion mode, when methanol or acetonitrile was used as the solvent, electrochemical oxidation products as the dehydro and radical cations were observed. Lower sample introduction rates tended to result in a higher oxidation ratio of 2,3′-bisindolylmethanes. The ESI-MS experiments of 2,3′-bisindolylmethanes in different acetonitrile/methanol solvent mixtures indicated that abundant H⁺, Na⁺ or K⁺ would facilitate the adduct formation process, and otherwise electrochemical oxidation dominated the ionization process. Additionally, when dichloromethane was used as the solvent, [M − 3H]⁺, [M − 2H]⁺˙ and [M − 3H + O]⁺ ions are the predominant ions, and the experimental results revealed that the dehydrogenation and oxidative dehydrogenation reactions of 2,3′-bisindolylmethanes in dichloromethane are electrochemical reactions.

The electrochemical oxidation reactions of 2,3′-bisindolylmethanes were affected by the solvent in the positive-ion electrospray ionization mass spectrometry (ESI-MS).     

Direct enantioseparation of axially chiral 1,1′-biaryl-2,2′-diols using amidine-based resolving agents

Amidine-based optically active resolving agents for enantiomer separation of axially chiral 1,1′-biaryl-2,2′-diols have been developed. A strongly basic amidine bearing no substituents on its nitrogen atoms enables the formation of their diastereomeric salts upon being mixed with weakly acidic phenol derivatives. Enantiopure 1,1′-biaryl-2,2′-diols can be obtained in high yields after only one crystallization of their salts with the chiral amidine derived from dehydroabietic acid. X-ray crystallography revealed that the amidine moiety forms a salt with the phenol group and additional intermolecular NH/π interactions contribute to the efficient chiral recognition process.

Enantioseparation of atropisomeric biphenols using a chiral amidine derived from dehydroabietic acid was reported. Only one crystallization of their mixture gave pure diastereomeric salts of biphenols from racemate.     

A compatibility study on the glycosylation of 4,4′-dihydroxyazobenzene

Photoresponsive glycoconjugates based on the azobenzene photoswitch are valuable molecules which can be used as tools for the investigation of carbohydrate–protein interactions or as precursors of shape-switchable molecular architectures, for example. To access such compounds, glycosylation of 4,4′-dihydroxyazobenzene (DHAB) is a critical step, frequently giving heterogeneous results because DHAB is a challenging glycosyl acceptor. Therefore, DHAB glucosylation was studied using nine different glycosyl donors, and reaction conditions were systematically varied in order to find a reliable procedure, especially towards the preparation of azobenzene bis-glucosides. Particular emphasis was put on glucosyl donors which were differentiated at the primary 6-position (N₃, OAc) for further functionalisation. The present study allowed us to identify suitable glycosyl donors and reaction conditions matching with DHAB, affording the bis-glycosylated products in fair yields and good stereocontrol.

The glycosylation of 4,4′-dihydroxyazobenzene was investigated to identify suitable conditions providing access to valuable photoswitchable glycoconjugates.     

P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

3′-N-(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-3′-amino-2′,3′-dideoxy-ribonucleosides (_NOTP-N), that bear a 4,4-unsubstituted, 4,4-dimethyl, or 4,4-pentamethylene substituted oxathiaphospholane ring, were synthesized. Within these three series, _NOTP-N differed by canonical nucleobases (i.e., Ade^Bz, Cyt^Bz, Gua^iBu, or Thy). The monomers were chromatographically separated into P-diastereomers, which were further used to prepare N_NPSN′ dinucleotides (3), as well as short P-stereodefined oligo(deoxyribonucleoside N3′→O5′ phosphoramidothioate)s (NPS-) and chimeric NPS/PO- and NPS/PS-oligomers. The condensation reaction for _NOTP-N monomers was found to be 5–6 times slower than the analogous OTP derivatives. When the 5′-end nucleoside of a growing oligomer adopts a C3′-endo conformation, a conformational ‘clash’ with the incoming _NOTP-N monomer takes place, which is a main factor decreasing the repetitive yield of chain elongation. Although both isomers of N_NPSN′ were digested by the HINT1 phosphoramidase enzyme, the isomers hydrolyzed at a faster rate were tentatively assigned the R_P absolute configuration. This assignment is supported by X-ray analysis of the protected dinucleotide ^DMTdG^iBu_NPSMeT_OAc, which is P-stereoequivalent to the hydrolyzed faster P-diastereomer of dG_NPST.

Separated P-diastereomers of 3′-N-(2-thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-3′-amino-2′,3′-dideoxy-ribonucleosides were used to prepare P-stereodefined N_NPSN′ dinucleotides and short NPS-, NPS/PO- and NPS/PS-oligomers.