Evaluation of green and efficient deep eutectic solvents as media for extracting alkaloids from lotus leaf

Deep eutectic solvents (DESs) were applied as eco-friendly solvents in this study for the extraction of alkaloids from lotus leaf, including O-nornuciferine, N-nornuciferine, nuciferine and roemerine. A series of hydrophilic and hydrophobic DESs with different hydrogen bond donors and a acceptors were synthesized and screened for a suitable DESs for extraction of alkaloids from lotus leaf. The study results showed that the hydrophilic DES with choline chloride and propanediol had the highest extraction yield. The main factors affecting the extraction efficiency—choline chloride–propanediol ratio, water content in deep eutectic solvents, solid–liquid ratio and extraction time—were investigated via a single-factor experiment. The optimized extraction conditions were 30% of water in choline chloride–propanediol (1:4) for heated extraction for 30 min and solid–liquid ratio 1:100 g/ml. Under optimum conditions, the extraction yields of O-nornuciferine, N-nornuciferine, nuciferine and roemerine were 0.069, 0.152, 0.334 and 0.041 g/100 g respectively, which were higher than those of methanol in acidified aqueous solution. This study suggests considerable potential for DESs as promising materials for the green and efficient extraction solvents for bioactive alkaloids from natural sources.     

Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure through the addition of a carbon-centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS-induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine-type alkaloids as well as providing useful intermediates for their syntheses.     

The 1H and 13C NMR chemical shifts of Strychnos alkaloids revisited at the DFT level

The density functional theory calculation of ¹H and ¹³C NMR chemical shifts in a series of ten 10 classically known Strychnos alkaloids with a strychnine skeleton was performed at the PBE0/pcSseg-2//pcseg-2 level. It was found that calculated ¹H and ¹³C NMR chemical shifts provided a markedly good correlation with experiment characterized by a mean absolute error of 0.08 ppm in the range of 7 ppm for protons and 1.67 ppm in the range of 150 ppm for carbons, so that a mean absolute percentage error was as small as ~1% in both cases.     

Nucleoside alkaloids with anti-platelet aggregation activity from the rhizomes of Ligusticum striatum

Two new (1–2) and six known (3–8) nucleoside alkaloids were isolated from the rhizomes of Ligusticum striatum DC. Compounds 1 and 2 (liguadenosines A and B) were unusual N-10 substituted adenosine derivatives. Their structures were elucidated by extensive spectroscopic analyses and ECD calculation. Most of them significantly inhibited the abnormal increase in platelet aggregation induced by ADP at concentrations of 50 and 100 μM. Particularly, the inhibitory effect of 3 was equivalent to aspirin.     

Fused N-Heterocycles with Contiguous Stereogenic Centers Accessed by an Asymmetric Catalytic Cascade Reaction of Tertiary Enamides

We report in this article a cascade reaction strategy for the synthesis of complex N-heterocyclic compounds with contiguous and tetrasubstituted stereogenic carbons. Under the sequential catalysis of a chiral binol–Ti complex and BF₃, cyclopentanone-derived tertiary enamides undergo an enantioselective enamine addition to ketone carbonyls followed by diastereoselective trapping of the resulting acyliminiums by electron-rich aryl moieties to furnish four- and five-membered ring-fused N-heterocyclic products as the sole diastereomers in high yields with up to 99 % ee.     

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp³)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.     

Simultaneous analysis of tropane alkaloids in teas and herbal teas by liquid chromatography coupled to high‐resolution mass spectrometry (Orbitrap)

A new method has been developed for the simultaneous determination of 13 tropane alkaloids in tea and herbal teas using high‐performance liquid chromatography coupled to an Exactive‐Orbitrap analyzer. A mixture of methanol, water, and formic acid was used for the extraction of the target compounds followed by a solid‐phase extraction step. The validated method provided recoveries from 75 to 128% with intra‐ and interday precision lower than or equal to 24% (except for apoatropine). Limits of quantification ranged from 5 to 20 μg/kg. Eleven tea and herbal tea samples and two contaminated samples with Datura stramonium seeds were analyzed. Tropane alkaloids were detected in six samples with concentrations from 5 (apoatropine) to 4340 μg/kg (sum of physoperuvine, pseudotropine, and tropine), whereas concentrations from 5 (apoatropine) to 1725 μg/kg (sum of physoperuvine, pseudotropine, and tropine) were found in the contaminated samples.     

A new erythrinan N-oxide alkaloid from Erythrina stricta

This phytochemical study of stems and leaves of Erythrina stricta led to the isolation of twenty-three alkaloids, one of them previously unreported, 11β-hydroxyerythratidine N-oxide. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analyses including HSQC, HMBC, ¹H–¹H COSY, NOESY, as well as HRESIMS data in addition to comparison with reports in the literature.     

Pharmacokinetics of monoester‐diterpenoid alkaloids in myocardial infarction and normal rats after oral administration of Sini decoction by microdialysis combined with liquid chromatography–tandem mass spectrometry

Monoester‐diterpenoid alkaloids are the main bioactive components of Sini decoction, which is a well‐known traditional Chinese medicine formula for the treatment of myocardial infarction (MI) and heart failure in China. In this work, an ultra‐high‐performance liquid chromatography–mass spectrometry combined with microdialysis method was successfully established and applied for investigating for the first time comparative plasma pharmacokinetics of three monoester‐diterpenoid alkaloids (benzoylmesaconitine, benzoylaconitine and benzoylhypacoitine) in normal and MI rats after oral administration of Sini decoction. The statistical results of pharmacokinetic parameters demonstrated that benzoylmesaconitine, benzoylaconitine and benzoylhypacoitine showed lower peak concentration, longer half‐life, smaller area under the concentration–time curve, slower clearance, time to peak concentration and mean residence time in MI rats than in normal rats (p < 0.05), which indicated that monoester‐diterpenoid alkaloids exhibited lower systemic exposure and slower elimination in the MI rats. The results provided the experimental basis for understanding the metabolic fate and therapeutic effects of Sini decoction.     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.