青蒿乙素的化学转化

本文报道青蒿乙素(2)的若干化学转化,如:青蒿乙素的催化氢化得到三个化合物5,6,7.6与三氟化硼-乙醚配合物反应生成8和9.6用硷水解以及2,6,7分别与五羰基铁进行脱氧反应,得到相应的化合物18,3和4。     

Affordable and rapid HPTLC method for the simultaneous analysis of artemisinin and its metabolite artemisinic acid in Artemisia annua L.

Artemisinin (AN) and artemisinic acid (AA), valuable phyto‐pharmaceutical molecules, are well known anti‐malarials, but their activities against diseases like cancer, schistosomiasis, HIV, hepatitis‐B and leishmaniasis are also being reported. For the simultaneous estimation of AN and AA in the callus and leaf extracts of A. annua L. plants, we embarked upon a simple, rapid, selective, reliable and fairly economical high performance thin layer chromatography (HPTLC) method. Experimental conditions such as band size, chamber saturation time, migration of solvent front and slit width were critically studied and the optimum conditions were selected. The separations were achieved using toluene–ethyl acetate, 9:1 (v/v) as mobile phase on pre‐coated silica gel plates, G 60F₂₅₄. Good resolution was achieved with R_f values of 0.35 ± 0.02 and 0.26 ± 0.02 at 536 nm for AN and 626 nm for AA, respectively, in absorption–reflectance mode. The method displayed a linear relationship with r² value 0.992 and 0.994 for AN and AA, respectively, in the concentration range of 300–1500 ng for AN and 200–1000 ng for AA. The method was validated for specificity by obtaining in‐situ UV overlay spectra and sensitivity by estimating limit of detection (30 ng for AN and 15 ng for AA) and limit of quantitation (80 ng for AN and 45 ng for AA) values. The accuracy was checked by the recovery studies conducted at three different levels with the known concentrations and the average percentage recovery was 101.99% for AN and 103.84% for AA. The precision was analyzed by interday and intraday precision and was 1.09 and 1.00% RSD for AN and 1.22 and 6.05% RSD for AA. The analysis of statistical data substantiates that this HPTLC method can be used for the simultaneous estimation of AN and AA in biological samples. Copyright © 2015 John Wiley & Sons, Ltd.     

Simultaneous isolation of artemisinin and its precursors from Artemisia annua L. by preparative RP-HPLC

It is still a major challenge to simultaneously isolate artemisinin and its precursors, especially dihydroartemisinic acid and artemisinic acid, from herbal Artemisia annua. A rapid, economical and automatical chromatographic separation process to isolate and purify artemisinin, dihydroartemisinic acid and artemisinic acid at the same time on a preparative scale was developed. The procedure included solvent extraction of ground Artemisia annua leaves by refluxing and purification of crude extract by preparative reverse-phase high-performance liquid chromatography (RP-HPLC). Fractions containing artemisinin and its precursors were collected and identified by gas chromatography and mass spectrometry. High purity of artemisinin, dihydroartemisinic acid and artemisinic acid was obtained by preparative HPLC with a C(18) column and 60% acetonitrile in water as the mobile phase. The techniques described here are useful tools for the preparative-scale isolation of artemisinin and its precursors in a fast, cost-effective and environmental friendly manner.     

A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross‐resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4‐trioxolane activity based protein‐profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi‐quantitatively, suggesting a common mechanism of action that raises concerns about potential cross‐resistance liabilities.     

Development and validation of a simple thin layer chromatographic method for the analysis of artemisinin in Artemisia annua L. plant extracts

Owing to the development of parasite resistance to standard antimalarial treatments like chloroquine and sulfadoxine-pyrimethamine, the demand for Artemisia annua, a key ingredient for new and highly effective antimalarial drugs, is huge. Therefore selective and precise methods to determine the content of artemisinin in dry plant material and in raw impure extracts are needed. In this work a method is described for the clear separation and extraction of artemisinin from other plant components in the Artemisia annua L. plant by thin-layer chromatography (TLC). To obtain optimal extraction and recovery efficiency, several parameters were evaluated, including choice of extraction solvent, TLC plate type and sensitivity between UV and visible light. Method validation was performed on both the dry plant material and non-purified plant extracts. Toluene presented the highest extraction efficiency compared with petroleum ether, hexane and methanol. Reversed-phase plates showed more concentrated spots than normal-phase plates, while the sensitivity of the analysis in UV was comparable to that in visible light but less precise. The impure plant extracts were analyzed by both TLC and HPLC-UV at 215 nm and both methods met the requirements for linearity, selectivity, precision and accuracy. Hence, the proposed TLC method can easily be used for both qualitative and quantitative control of the raw plant extract in areas where advanced methods are scarce.     

Applications of inorganic‐organic hybrid architectures based on polyoxometalates in catalyzed and photocatalyzed chemical transformations

The scope of this article is to reveal the fruitful combination of POM species with metal coordination complexes, leading to the construction of several efficient multifunctional catalysts. In this review, we try to underscore various catalytic and photocatalytic reactions catalyzed by POM‐based inorganic‐organic hybrid. Notably, it has been well established that depending on the type of the reaction, the activity and selectivity of these hybrid catalyst can be drastically improved by the rational and correct choice of the organic metal complex and POM anion providing a marriage of convenience.     

Simultaneous determination of artemisinin and its analogs and flavonoids in Artemisia annua crude extracts with the use of NMR spectroscopy

Artemisia annua is a promising and potent antimalarial herbal drug. This activity has been ascribed to its component artemisinin, a sesquiterpene lactone. The ability to determine artemisinin and its known analogs in plant extracts is an especially difficult task because the compounds are present in low concentrations, are thermolabile, and lack ultraviolet or fluorescent chromophores. We report herein a facile and rapid 1-D ¹H, 1-D total correlation spectroscopy, 2-D ¹H–¹³C heteronuclear single quantum coherence, and ¹H–¹³C heteronuclear multiple bond correlation nuclear magnetic resonance techniques for the simultaneous identification and quantification of artemisinin and five of its analogs along with five flavonoids, an aromatic ketone, and camphor (in total, 13 compounds) in crude diethyl ether A. annua extract without the need of laborious isolation of the individual analytes. The above method was validated in terms of precision, linearity, and limit of detection. The analytical results were found to be in excellent agreement with those obtained with the use of the time consuming high-performance liquid chromatography with diode-array detection and liquid chromatography with tandem mass spectrometry for the compounds that standards were available.     

青蒿素生物合成的研究III: 青蒿素和青蒿素B生物合成中的关键性中间体-青蒿素

以[15-^3H]青蒿酸为前体用青蒿匀聚浆体进行青蒿素和青蒿素B的生物合成.实验结果表明, 在青蒿植物由MVA生物合成青蒿素和青蒿素B的途径中, 青蒿酸是关键性中间体.     

酪氨酸酶催化下以吡啰红为指示剂荧光测定青蒿素

Fluorescence decrease ratio （F0/F） was applied to determination of artemisinin （qinghaosu, QHS） based on the catalytic effect of tyrosinase using tetraethyldiaminoxanthenyl chloride （pyronine B, PB） as monitor. A catalyst used commonly in the decomposition of QHS, tyrosinase, exhibited higher binding activity than hemin, which was expressed as Michaelis-Menten parameters, km, Vmax, and kcat respectively. Interaction of QHS with tyrosinase was inhibited in the presence of deactivating agents at high temperature whereas enhanced by ethanol. Under optimal conditions, a concentration of 1.4×10^-7-8.4×10^-7 mol·L^-1of QHS could be determined on the basis of fluorescence decrease ratio of PB, with a detection limit 3tr of 2.6×10^-9 mol·L^-1. The proposed method was applied to detection of the concentration of QHS in the media of plasma and urine.     

Simultaneous densitometric determination of artemisinin, artemisinic acid and arteannuin-B in Artemisia annua using reversed-phase thin layer chromatography

A rapid and simple RP-TLC method for simultaneous quantification of pharmacologically important sesquiterpene artemisinin (AM) together with its precursors arteannuin-B (AB) and artemisinic acid (AA) in the inflorescence part of Artemisia annua plant has been developed. The RP-TLC of sesquiterpenes was performed on RP-18 F254 S thin-layer chromatographic plates by developing in mobile phase, containing 0.2% TFA in water/ACN (35:65, v/v). The densitometric determination of AM, AB and AA was carried out after derivatization with anisaldehyde reagent at 426 nm in absorption-reflectance mode.     

Stereoselective synthesis of simplactone B via Prins cyclisation

The synthesis of simplactone B has been achieved through a series of nine steps in 85% overall yield using Prins cyclisation as the key step with high stereochemical control.     

吡啰红B为指示剂细胞色素C催化荧光测定青蒿素

在细胞色素C催化下,吡啰红B与青蒿素反应导致荧光降低,细胞色素C与青蒿素的反应为酶-底物模型。动力学研究表明,稳态催化速率依赖于酶和底物浓度,催化常数Km、Vm ax及Kcat分别为3.3×10-5mol/L,5.4×10-6mol.L-1.s-1和13.5 s-1,催化活性受去活化剂和乙醇抑制。在pH 5.3、25℃及7.6×10-7mol/L的细胞色素C催化条件下,荧光降低值ΔF(F0-F)与青蒿素浓度在7.1×10-8~1.1×10-6mol/L范围内呈线性关系;检出限为7.2×10-9mol/L;加标回收率为96.3%~106.8%。方法已用于测定血浆和尿液介质中的微量青蒿素。     

Stereoselective synthesis and transformations of pinane-based 1,3-diaminoalcohols

A library of pinane-based 1,3-diaminoalcohols and 5-aminomethyloxazolidin-2-ones was developed from commercially available (1R)-(?)-myrtenol which was transformed to N-trichloroacetyl protected allyl amine via Overmann rearrangement followed by stereoselective epoxidation with mCPBA resulting in key intermedier epoxy-amine. In order to obtain the diaminoalcohol moiety, aminolysis and azidolysis of the oxirane ring was performed. The cleavage of the oxirane ring proceeded regioselectively, affording N-trichloroacetyl protected 1,3-diaminoalcohols and oxazolidin-2-ones, which were obtained also via a thermal cyclisation. Since N deprotection of diaminoalcohols was unsuccessful under varied conditions, the protecting group was changed and Boc-protected analogues were synthesised. In this case, removal of the Boc protecting group was successful resulting in the planned diamino alcohols. An unexpected extreme δ Me_α-9 value (0.11 ppm) was measured for the dibenzylaminomethyl-substituted oxazolidine-2-one, and the stereostructure was refined by means of DFT geometry optimization. The obtained potential catalysts were applied in the test reaction of benzaldehyde and diethylzinc with low to moderate enantioselectivities (up to 74% ee).     

Structure of vinylacetylene tetrabromide and some of its chemical transformations

Conclusions Vinylacetylene tetrabromide is a mixture of the geometric isomers of 1,2,3,4-tetrabromo-1-butene, the dehydrobromination of which isomers gives the trans-and cis-isomers of 1,2,3-tribromo-1,3-butadiene.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1759–1763, August, 1972.     

Stereoselective total synthesis of sporiolide B and attempted synthesis of sporiolide A

A simple and efficient stereoselective total synthesis of sporiolide B and attempted synthesis of sporiolide A, from epichlorohydrin, using asymmetric synthetic approach is reported. The key reactions involved are Sharpless epoxidation, Jacobsen reaction, syn-allylation, Yamaguchi esterification, and Grubbs ring-closing metatheses reaction to result in the macrocyclic ring system.     

Stereoselective synthesis of pachastrissamine (jaspine B)

A stereoselective synthesis in enantiopure form of the natural anhydrophytosphingosine pachastrissamine (jaspine B), a metabolite isolated from sponges, is described. The chiral epoxide (R)-glycidol was the starting material. Key steps of this synthesis are a Sharpless asymmetric epoxidation, an intramolecular stereospecific epoxide opening mediated by a trichloroacetimidate group, and the formation of a tetrahydrofuran ring via intramolecular nucleophilic displacement.     

Convenient syntheses and transformations of 2-C-malonyl carbohydrates

2-C-malonyl carbohydrates were synthesized in only few steps and high yields by radical additions of malonates to glycals. For the first time, the undesired formation of nitrates was completely suppressed with anhydrous cerium ammonium nitrate (CAN) as oxidizing agent. A coherent explanation for the high stereoselectivities of the additions to gluco-configured glycals was provided by variation of the substituents in the 3-position. We established steric effects for the face selectivity, and electronic effects strongly influence the reactivity of the double bonds. The scope and limitation of transition-metal-mediated radical reactions in the synthesis of 2-C-branched carbohydrates was thoroughly investigated. Thus, unsaturated disaccharides and benzyl-protected glycals were used as substrates for the first time. Finally, the 2-C-malonyl carbohydrates were transformed into various products by decarboxylation, saponification and reduction, which afforded interesting precursors for C-disaccharides. In this paper we describe the syntheses of more than 40 new 2-C-analogues of carbohydrates, which were isolated in high yields in analytically pure form. Therefore, the transition-metal-mediated radical addition of malonates to glycals offers a simple and convenient entry to such important carbohydrate derivatives.