Total Synthesis of Dinorsesquiterpenoid Oxyphyllin A/Belchinoid A.

Here, we report the first synthesis of oxyphyllin A/belchinoid A, a 7,9-seco-8,12-dinor-guaiane sesquiterpene whose isolation was reported independently by two groups in 2023. This synthesis utilizes a key sequential sulfone-mediated intermolecular alkylation/5-endo-tet cyclization reaction to establish the C1, C4, C5 stereocenters. Subsequent transformations, including regio- and stereoselective hydride addition-based desulfonylation via a π-allyl palladium complex and the Wittig reaction with a stable phosphonium ylide, facilitated the synthesis of oxyphyllin A/belchinoid A.

Synthesis of 6H-Chromeno[4,3-b]quinolin-7-ylphosphonates through Three Component Phosphonylation of Coumarin Carbaldehyde and Their Antimicrobial and Photophysical Properties.

Organophosphorylated coumarin derivatives were synthesized by a three-component reaction of 4-chloro-3-formylcoumarin, aromatic amines, and dialkyl phosphite in the presence of ZnCl2. This process includes the formation of C(sp3)-P and C(sp2)-N bonds in one pot. The modular scope of the reaction allowed rapid access to a variety of 6H-chromeno[4,3-b]quinolin-7-ylphosphonate derivatives in good yields. Furthermore, photophysical studies of the products revealed their stimulating fluorescence properties.

Phosphite-imidazole catalyzed N-formylation and N-acylation of amines.

A novel and convenient method for the N-formylation reaction of amines with DMF as a formylating agent has been developed, utilizing a catalytic amount of diethyl phosphite/imidazole. Diethyl phosphite, as a nucleophilic catalyst, plays a significant role in this conversion. The presented method has a broad substrate scope, and various N-formyl products were obtained in good to excellent yields. Moreover, by using DMA instead of DMF, the N-acetylation reaction was also successful. The reaction of o-phenylenediamines with DMF afforded the corresponding benzimidazoles. Furthermore, N-sulfonyl amidines were obtained in good to excellent yields by the reaction of sulfonamides with DMF under similar conditions.

Stereoselective synthesis of vinylphosphonates through aromatic aza-Claisen rearrangement of α-aminophosphonates.

A novel and convenient approach for the synthesis of vinyl phosphonates has been developed, utilizing an aromatic aza-Claisen rearrangement of ß,γ-unsaturated α-aminophosphonates. The synthetic utility of this method was further examined in a gram-scale synthesis. The DFT calculations have provided insights into the basis of the reaction mechanism.

Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate.

PURPOSE: Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e., threo and erythro forms). This study presents the analytical characterization of 4-fluoroethylphenidate (4-FEP) and its differentiation between threo- and erythro-4-FEP. METHODS: Analysis of the samples included high-performance liquid chromatography (HPLC), gas chromatography-electron ionization-mass spectrometry (GC-EI-MS), high-resolution mass spectrometry (HRMS) analyses, nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal structure analysis. RESULTS: NMR spectroscopic investigations confirmed the differences between threo- and erythro-4-FEP, and demonstrated that both isomers could be separated using HPLC and GC methods. Two samples obtained from one vendor in 2019 consisted of threo-4-FEP, whereas the other two samples obtained from a different vendor in 2020 consisted of a mixture of threo- and erythro-4-FEP. CONCLUSIONS: Several analytical approaches including HPLC, GC-EI-MS, HRMS analyses, NMR spectroscopy and X-ray crystal structure analysis enabled the unambiguous identification of threo- and erythro-4-FEP. The analytical data presented in this article will be useful for identifying threo- and erythro-4-FEP included in illicit products.

Synthesis of 1-O-acyl- and 1-oxo-kamebanin analogues and their cytotoxic activity.

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.

Lanceolanone A, a new biflavanone, and a chalcone glucoside from the flower heads of Coreopsis lanceolata and their aldose reductase inhibitory activity and AMPK activation.

The MeOH extract of the flower heads of Coreopsis lanceolata L. (Asteraceae) exhibited aldose reductase (AR) inhibitory activity (IC50 8.36 µg/mL). Bioassay-guided fractionation of the extract resulted in the isolation of a new biflavanone-named Lanceolanone A (1) and a chalcone glucoside (6), along with 12 known compounds (2-5 and 7-14), of which 4, 7, 9, 10, and 12 were isolated from C. lanceolata for the first time. The structures of the new compounds (1 and 6) were determined by extensive spectroscopic analysis, including two-dimensional (2D) NMR, and ECD calculation method. Compounds 2, 4, 11, 13, and 14 exhibited AR inhibitory activities with IC50 values between 2.40 and 9.99 µM. Furthermore, 8-13 at 1.0 mM activated AMPK expression in HepG2 human hepatoma cells compared to the control.

Retusone A, a Guaiane-Type Sesquiterpene Dimer from Wikstroemia retusa and Its Inhibitory Effects on Histone Acetyltransferase HBO1 Expression.

Retusone A (1), a new sesquiterpene dimer consisting of two guaiane-type sesquiterpenoids, and oleodaphnal (2) were isolated from heartwood of Wikstroemia retusa (Thymelaeaceae). The planar structure of 1 was elucidated on the basis of HRESIMS and NMR spectroscopic data, and the relative stereochemistry was established by X-ray diffraction analysis. The absolute configuration of 1 was determined by electronic circular dichroism. Compound 1 suppressed luciferase reporter gene expression driven by the HBO1 (histone acetyltransferase binding to ORC1) gene promoter in human breast cancer MCF7 cells. Compound 1 also decreased the expression of endogenous HBO1 mRNA and protein, and inhibited proliferation of the cells. These results suggest that retusone A (1), which has a unique dimeric sesquiterpenoid structure with inhibitory activity against HBO1 expression, may contribute to the development of a novel therapeutic candidate for the treatment of breast cancer.

Cytotoxic triterpene and steroidal glycosides from the seeds of Digitalis purpurea and the synergistic cytotoxicity of steroidal glycosides and etoposide in SBC-3 cells.

The phytochemical investigations of the seeds of Digitalis purpurea have revealed their richness in cardenolide and pregnane glycosides exhibiting potent cytotoxicity; further chemical examinations of the D. purpurea seeds have achieved the isolation of six triterpene glycosides (1-6), six spirostanol glycosides (7-12), and three furostanol glycosides (13-15), including seven previously unidentified compounds (1-3, 10-12, and 14). Here, the structures of 1-3, 10-12, and 14 were determined via extensive spectroscopic analyses, including two-dimensional (2D) NMR; hydrolysis, followed by chromatographic and spectroscopic analyses; and X-ray crystallographic analysis. The cytotoxic activities of the isolated compounds (1-15) against SBC-3 small cell lung carcinoma and TIG-3 normal human diploid fibroblast cells were evaluated. Triterpene glycoside 3 and spirostanol glycoside 9 exhibited considerable cytotoxicity with IC50 values of 1.0 and 1.7 µM, respectively; they induced apoptotic cell death, which was accompanied by the activation of caspase-3 in SBC-3 cells. Spirostanol glycoside 7 exhibited cytotoxicity toward the SBC-3 cells (IC50 1.3 µM). Additionally, 7 at 0.1 and 1.0 µM synergistically enhanced the cytotoxicity of etoposide against SBC-3 cells; compound 7 induced the release of DAMPs; the release of HMGB1, the secretion of ATP, and the exposure of CALR in the SBC-3 cells. Furthermore, the combination of 7 and etoposide resulted in increasing the extracellular release of DAMPs. These data indicated that 7, as well as its combination with etoposide, might potentially cause immunogenic cell death.

Benzofuran and coumarin derivatives from the root of Angelica dahurica and their PPAR-γ ligand-binding activity.

A phytochemical investigation of the root of Angelica dahurica led to the isolation of benzofuran and coumarin derivatives. This is the first report of the isolation and identification of three furanocoumarin sulfates from A. dahurica root. The structures of a total of twelve undescribed compounds were determined by extensive spectroscopic analysis, including 2D NMR data, hydrolysis, and solvolysis, followed by either physicochemical and spectroscopic data or X-ray crystallographic analysis. The isolated compounds were evaluated for their PPAR-γ ligand-binding activity, and six compounds showed significant PPAR-γ ligand-binding activity. In particular, the undescribed benzofuran derivative, 3-[6,7-furano-9-hydroxy-4-(2″,3″-dihydroxy-3″-methylbutyloxy)]-phenyl propionic acid, exhibited the most potent PPAR-γ ligand-binding activity and accumulated intracellular lipid in 3T3-L1 cells.

Reactions of Bifunctional Perfluoroarylsilanes with Activated C-F Bonds in Perfluorinated Arenes.

Reactions of bifunctional perfluoroarylsilanes, p- and m-C6F4(SiMe3)2 as well as o-BrC6F4SiMe3, with substituted perfluoroarenes having electron-withdrawing groups were investigated using NMR and density functional theory calculation techniques. The C-F bond in perfluoroarenes was activated by the para-position of an electron-withdrawing group, such as CF3, C6F5, CN, and NO2. The reaction of C6F4(SiMe3)2 mainly occurred at the para-position of the perfluoroarenes and also occurred at the ortho-position of C6F5CN and C6F5NO2. Two equivalent reactions of perfluoroarenes with bifunctional p- and m-C6F4(SiMe3)2 provided disubstituted perfluoroarenes, along with a small amount of protonated monosubstituted perfluoroarenes. The reaction of o-BrC6F4SiMe3 with the CF3- and CN-substituted pentafluorobenzenes provided unexpected coupling products between C-Br and C-F bonds, in addition to the coupling products between C-SiMe3 and C-F bonds.

[LC/Tribrid Orbitrap Analysis of Phosphodiesterase-5 Inhibitors and Their Analogs as Adulterants in Dietary Supplements].

LC/Tribrid Orbitrap was developed to determine phosphodiesterase-5 (PDE-5) inhibitors and their analogs as adulterants in dietary supplements. High-resolution MS/MS and MS3 spectra of PDE-5 inhibitors and their analogs were obtained by LC/Tribrid Orbitrap using both higher-energy collisional dissociation and collision-induced dissociation. We investigated dietary supplements that claim to enhance men's sexual performance, and detected PDE-5 inhibitors and their analogs. We also estimated the structures of the PDE-5 inhibitor analogs and the impurities of PDE-5 inhibitors and their analogs in the dietary supplements.

Chemical Bonding in Polarised Push-Pull Ethylenes.

1,1-Diamino-2,2-bis(triflyl)ethylenes with both twisted and planar structures around the partial "C=C" bond were synthesised. Bonding properties in these compounds were analysed by an experimental approach using high-resolution X-ray diffraction data treated with X-ray wavefunction refinement (XWR). In the twisted compound, a dominant contribution of the charge-separated resonance structure was revealed. On the contrary, the nearly planar compound still showed π-bonding character, however, with a considerable contribution of the charge-separated resonance structure.

RA-XXV and RA-XXVI, Bicyclic Hexapeptides from Rubia cordifolia L.: Structure, Synthesis, and Conformation.

Two RA-series bicyclic hexapeptides, RA-XXV (4) and RA-XXVI (5), which have no N-methyl group at Tyr-5, were isolated from the roots of Rubia cordifolia L. Their amino acid compositions and sequences were determined by interpretation of MS, and 1D and 2D NMR data and their relative structures were elucidated by XRD analysis of 4 and RA-XXVI acetate (6). The absolute stereochemistry of 4 was established by the total synthesis of 4, and that of 5, by the chemical correlation with 4. Peptides 4 and 5 exhibited cytotoxicity toward human promyelocytic leukemia HL-60 (IC50 =0.062 and 0.066 µm, respectively) and human colonic carcinoma HCT-116 (IC50 =0.028 and 0.051 µm, respectively) cell lines. Analysis of the conformational structures of 4 and 6 in the crystalline state and those of 4 and 5 in solution revealed that the N-methyl group at Tyr-5 functions to make this series of peptides preferentially adopt the active conformation.

Cycloartane and Oleanane Glycosides from the Tubers of Eranthis cilicica.

Phytochemical analysis of the tubers of Eranthis cilicica was performed as part of our continuous study on the plants of the family Ranunculaceae, which resulted in the isolation of eleven new cycloartane glycosides (1⁻11) and one new oleanane glycoside (13), together with one known oleanane glycoside (12). The structures of the new compounds were determined by extensive spectroscopic analysis, including two-dimensional (2D) NMR, and enzymatic hydrolysis followed by either X-ray crystallographic or chromatographic analysis. The aglycone (1a) of 2 and its C-23 epimer (8a), and the oleanane glycosides (12 and 13) showed cytotoxic activity against HL-60 leukemia cells with IC50 values ranging from 10.6 µM to 101.6 µM. HL-60 cells were much more sensitive to 8a (IC50 14.8 µM) than 1a (IC50 101.1 µM), indicating that the C-23 configuration is associated with the cytotoxicity of these cycloartane derivatives. Compound 12 was revealed so as to partially induce apoptotic cell death in HL-60 cells, as was evident from morphology of HL-60 cells treated with 12.

Structural characterization of dimethyldithiodenafil and dimethylthiocarbodenafil, analogs of sildenafil.

Two analogs of sildenafil (compounds 1 and 2) were detected in three powder products acquired from online drug markets during an LC-UV-MS analysis of psychotropic drugs. Their structures were established by high-resolution mass spectrometry and NMR spectroscopy. Compound 1 was identified as 5-(5-(3,5-dimethylpiperazine-1-carbonothioyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7(6H)-thione and named dimethyldithiodenafil. Compound 2 was identified as 5-(5-(3,5-dimethylpiperazine-1-carbonothioyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and named dimethylthiocarbodenafil. Compound 1 was subjected to the phosphodiesterase assay (IC50=0.20nM). The three powder products were found to contain 12-19mg of dimethyldithiodenafil and 1.4-3.9mg of dimethylthiocarbodenafil per tube.

RA-dimer†B, a New Dimeric RA-series Cyclopeptide Incorporating Two Different Types of Cycloisodityrosine Units, from Rubia cordifolia†L.

RA-dimer B, a new cytotoxic RA-series peptide, was isolated from the roots of Rubia cordifolia L. Its structure was elucidated on the basis of spectroscopic analysis to be a dimeric cyclopeptide composed of deoxybouvardin and allo-RA-V. Those two cyclopeptide units are connected by an ether linkage between the phenolic oxygen atom of deoxybouvardin and the ϵa carbon atom of Tyr-6 of allo-RA-V. RA-dimer B was synthesized by the coupling reaction of deoxybouvardin with the boronic acid derivative of allo-RA-V, and subsequent deprotection, confirming the relative stereochemistry and establishing the absolute configuration of this peptide. RA-dimer B showed cytotoxic activity against human promyelocytic leukaemia HL-60, human colonic carcinoma HCT-116, and human renal cell carcinoma ACHN cells with IC50 values of 0.59, 0.54, and 0.74 µm, respectively.

Alkynyl Cinchona Catalysts affect Enantioselective Trifluoromethylation for Efavirenz under Metal-Free Conditions.

Efavirenz is manufactured worldwide, and its asymmetric synthesis requires a complex organometallic approach, while an organocatalytic approach is far less efficient. The first highly enantioselective approach is disclosed for the synthesis of Efavirenz under nonmetal organocatalysis with up to 93% ee for the Merck intermediate and 91% ee for the Lonsa intermediate using novel alkynyl cinchona catalysts.

Vetiverianines A, B, and C: Sesquiterpenoids from Vetiveria zizanioides Roots.

Three new sesquiterpenoids-vetiverianines A (1), B (2), and C (3)-and a known eudesmane sesquiterpenoid (4) were isolated from the roots of Vetiveria zizanioides. Vetiverianine A (1) has a unique carbon framework comprising a rigid tricyclic ring system. Vetiverianines B (2) and C (3) are new eremophilane sesquiterpenoids. The structures of sesquiterpenoids 1-3, including the absolute configurations, were determined by NMR spectroscopic, X-ray crystallography, and vibrational circular dichroism data analysis. Vetiverianine C (3) exhibited weak cytotoxic activity against HL-60 cells.

A New Neolignan Glycoside from Vetiveria zizanioides Roots.

A new neolignan glycoside (1) and four known aromatic compounds (2-5) were isolated. from the roots of Vetiveria zizanioides. The structure of compound 1 was determined based on spectroscopic analysis and hydrolysis. The structure of known flavonoid glycoside 3 was confirmed by X-ray crystallography. Compound 5 showed weak cytotoxic activity against HL-60 cells with an IC50 value of 13.1 ± 0.04 µM.