Acid-promoted rearrangement of arylmethyl azides: applications toward the synthesis of N-arylmethyl arenes and polycyclic heteroaromatic compounds

An acid-promoted Aubé–Schmidt's rearrangement of arylmethyl azides provides a useful in situ iminium ion intermediate, which can be efficiently trapped by various nucleophiles. We report here the reaction of this iminium ion with aromatic nucleophiles to give N-arylmethyl arenes and the reaction with heteroaromatic compounds to give fused polycyclic heteroaromatic products in a formal [4+2] cycloaddition. The short synthesis of isocrytolepine, an antimalarial agent, further demonstrated the utility of this process.     

A novel approach for the synthesis of lophocladines A, B and C1 analogues

A novel approach for the syntheses of lophocladines A and B has been developed. These compounds were prepared in 4-6 steps with moderate to excellent overall yields. The key step involved the nucleophilic substitution of 4-chloronicotinic acid with the carbanion generated from phenylacetonitrile. Subsequent reduction of the cyano group, lactamization and oxidation furnished lophocladine A in 50% yield over 4 steps. Further amination with various amines led to lophocladine B and its C1 analogues in good yields. In addition, the synthesized compounds were evaluated for their cytotoxicity against leukaemia cells.     

Cu(I)-mediated lactone formation in subcritical water: a benign synthesis of benzopyranones and urolithins A–C

Benzopyranones were successfully synthesized using Cu(I)-mediated C–O bond formation in subcritical water. A number of benzopyranone derivatives including polymethoxy benzopyranones, benzopyranopyridones, chromenoindolones, and furochromenones were synthesized in satisfactory yield. This methodology was further applied to synthesize the intestinal microbial metabolites, urolithins A, B, and C, which were found to exhibit potent antioxidant activity.     

Synthesis and antibacterial activity of methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride

The methylated chitosan containing different aromatic moieties were synthesized by two steps, the reductive amination and the methylation. The chemical structures of all methylated derivatives, methylated N-(4-N,N-dimethylaminocinnamyl) chitosan chloride (MDMCMCh), methylated N-(4-pyridylmethyl) chitosan chloride (MPyMeCh), and N,N,N-trimethyl chitosan chloride (TMChC) were characterized by ATR-FTIR and ¹H NMR spectroscopy. The molecular weights of the methylated chitosan derivatives were determined by gel permeation chromatography. The results revealed that the molecular weights of chitosan and N-aryl chitosan derivatives could be reduced by the methylation process. The degree of N-substitution (DS) and the degree of quaternization (DQ) were calculated by ¹H NMR ranged from 50% to 76%, and 28% to 82%, respectively. The water solubility of the methylated chitosan derivatives decreased with increasing concentration and pH. The antibacterial studies of these methylated chitosan derivatives were carried out by using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods against Escherichia coli ATCC 25922 (Gram-negative) and Staphylococcus aureus ATCC 6538 (Gram-positive) bacteria. It was found that the MDMCMCh showed higher antibacterial activity than TMChC while MPyMeCh exhibited reduced antibacterial activity against both bacteria at the same DQ level. In comparison to each of the chemical structure, it was found that the antibacterial activity was not only dependent on the DQ but it was also dependent on the positively charged location and the molecular weight.     

Acetophenone diglycosides from Erythroxylum cambodianum

Two new acetophenone diglycosides, erythroxylosides A and B, were isolated from the aerial portion of Erythroxylum cambodianum together with (+)-catechin, (-)-epicatechin, quercetin 3-O-rutinoside, (3S,5R,6R,7E,9S-megastigman-7-ene-3,5,6,9-tetrol 3-O-beta-D-glucopyranoside and citroside A. The structural elucidations were based on analyses of chemical and spectroscopic data.     

Utility of polymer-supported reagents in the total synthesis of lamellarins

Four solid-supported reagents have been utilized in the multistep synthesis of lamellarins. The use of Amberlyst A-26 Br(3)(-) and polymer bound pyridine hydrobromide perbromide (PVPHP) for keto alpha-bromination of the less studied ortho-substituted acetophenone derivatives selectively furnished the corresponding monobromination products (phenacyl bromide derivatives), which were used directly in condensation reactions with benzyldihydroisoquinoline mediated by Amberlyst A-26 NaCO(3)(-). The 2H-pyrrole carbonates subsequently underwent intramolecular Friedel-Crafts transacylation followed by lactonization to provide the lamellarin skeleton. Alternatively, Amberlyst A-26 NaCO(3)(-) effectively served as base in condensation reaction of benzyldihydroisoquinoline with alpha-nitrocinnamate derivatives to provide the corresponding 2-ethoxycarbonyl pyrroles, which smoothly underwent O-debenzylation reaction followed by lactonization to furnish the lamellarin skeleton. The novel Amberlyst-15 mediated lactonization reactions effectively combined the otherwise two separate steps into a single transformation.     

Megastigmane glucosides from Equisetum debile and E. diffusum

A new megastigmane diglucoside, (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3,9-O-beta-D-diglucopyranoside (3), was isolated from the aerial portion of Equisetum debile along with macarangioside D (debiloside A), sammangaoside A, (6R,9S)-3-oxo-alpha-ionol 9-O-beta-D-glucopyranoside, debiloside B, kaempferol 3-O-sophoroside, kaempferol 3,7-O-beta-D-diglucopyranoside, kaempferol 3-O-sophoroside-7-O-beta-D-glucopyranoside, phenylethyl O-beta-D-glucopyranoside, (Z)-3-hexenyl O-beta-D-glucopyranoside, (7S,8R)-dehydrodiconiferyl 4-O-beta-D-glucopyranoside, and L-tryptophan. The absolute configuration at C-6 of the original structure of debilo-side A was revised to 6R-configuration, and was identical with macarangioside D (1). From the aerial portion of E. diffusum, four compounds, sammangaoside A, kaempferol 3-O-sophoroside and L-tryptophan and (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3-O-beta-D-glucopyranoside were identified. The spectroscopic data of (3S,5R,6S,7E,9S)-megastigman-7-ene-5,6-epoxy-3,9-diol 3-O-beta-D-glucopyranoside (13) were found to be identical with corchoionoside A (9R-isomeric compound). The structure of corchoionoside A was also discussed. Structure determinations were based on physical data and spectroscopic evidence.     

Solid-supported acids as mild and versatile reagents for the deprotection of aromatic ethers

p-Toluene sulfonic acid (p-TsOH) immobilized either on polystyrene (PS) or silica (Si) was found to be effective in cleaving aromatic ethers containing isopropyl, tert-butyl, allyl, and benzyl groups, as well as mono-, di-, and trimethoxylated benzyl groups, in moderate to excellent yields (54-95%). These protecting groups could be selectively deprotected when they were simultaneously present on the same or different aromatic rings in a substrate.     

Rapid analysis of clenbuterol, salbutamol, procaterol, and fenoterol in pharmaceuticals and human urine by capillary electrophoresis

Capillary electrophoresis (CE) with UV detection for the simultaneous and short-time analysis of clenbuterol, salbutamol, procaterol, fenoterol is described and validated. Optimized conditions were found to be a 10 mmoll(-1) borate buffer (pH 10.0), an separation voltage of 19 kV, and a separation temperature of 32 degrees C. Detection was set at 205 nm. Under the optimized conditions, analyses of the four analytes in pharmaceutical and human urine samples were carried out in approximately 1 min. The interference of the sample matrix was not observed. The LOD (limits of detection) defined at S/N of 3:1 was found between 0.5 and 2.0 mgl(-1) for the analytes. The linearity of the detector response was within the range from 2.0 to 30 mgl(-1) with correlation coefficient >0.996.     

Facile and Divergent Synthesis of Lamellarins and Lactam‐Containing Derivatives with Improved Drug Likeness and Biological Activities

With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone‐to‐lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK‐3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine‐derived natural products and justify their further development, especially into anticancer agents.