Enantioselective Double Carbonylation Enabled by High-Valent Palladium Catalysis.

Palladium-catalyzed carbonylation reactions are efficient methods for synthesizing valuable molecules. However, realizing a carbonylation with excellent yield and chemo-, regio-, and enantioselectivities by classical low-valent palladium catalysis is highly challenging. Herein, we describe an enantioselective carbonylation reaction using a high-valent palladium catalysis strategy and employing a chiral sulfoxide phosphine (SOP) ligand. This double aminocarbonylation reaction begins with the formation of a carbamoylpalladium(II) species, which undergoes enantioselective oxidative addition with a cyclic diaryliodonium salt to generate a palladium(IV) intermediate, followed by a second CO insertion and reductive elimination. The mechanism has been illustrated with experimental and computational studies.

Synthesis of Tribenzo[b,d,f]azepines via Palladium-Catalyzed Annulation Reaction of 2-Iodobiphenyls with 2-Halogenoanilines.

A palladium-catalyzed annulation reaction of 2-iodobiphenyls with 2-halogenoanilines has been developed. A variety of 2-iodobiphenyls and 2-halogenoanilines can undergo this transformation. Diversified tribenzo[b,d,f]azepine derivatives can be synthesized in moderate to excellent yields according to this method.

[Chemical Constituents from Przewalskia tangutica].

Objective: To study the Chemical constituents from Przewalskia tangutica. Methods: The compounds were isolated and identified from n-butanol extract of Przewalskia tangutica by various chromatographic and spectral techniques. Results: Twelve polar compounds were isolated and identified as scopolin( 1),fabiatrin( 2),rutin( 3),queroetin-3-O-rutinoside-7-O-ß-D-glucopyranoside( 4),protocatechuate( 5),vanillic acid( 6),thymine( 7),uracil( 8),cytosine( 9),adenine( 10),uridine( 11) and adenosine( 12). Conclusion: Compounds 3 ~ 5,8 ~ 12 are obtained from Przewalskia tangutica for the first time.

Untargeted analysis of sesquiterpene pyridine alkaloids from the dried roots of Tripterygium wilfordii using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

RATIONALE: Sesquiterpene pyridine alkaloids are a large group of highly oxygenated sesquiterpenoids that have attracted attention in the fields of medicine because of their significant biological activities. METHODS: Reference compounds including 14 sesquiterpene pyridine alkaloids and one dihydroagarofuran ester were analyzed by collision-induced dissociation tandem mass spectrometry (CID-MS/MS). A high-performance liquid chromatography/electrospray ionization (HPLC/ESI)-MS/MS method at two collision energies was adopted to investigate the botanical extracts of Tripterygium wilfordii. RESULTS: For 15 reference compounds, in the high mass range, the product ions were formed by the loss of side chains or H2 O. In the low mass range, the high-abundance product ions at m/z 206, 204, or 194 were the characteristic ions of the pyridine moiety. The characteristic product ion at m/z 310 was formed through an ion-neutral complex intermediate. Fifty-four sesquiterpenoid derivatives, including 50 sesquiterpene pyridine alkaloids, were identified or tentatively characterized in botanical extracts of T. wilfordii based on their elemental constituents, characteristic fragmentation patterns, and the major product ion profiles of the reference compounds ascertained with HPLC/ESI-MS/MS at two collision energies. It seems that isocratic energy was appropriate for the untargeted analysis of compounds with molecular weights exceeding 800 Da, whereas a linear gradient energy vs molecular weight was suitable for those compounds with molecular weights below 800 Da. CONCLUSIONS: The HPLC/ESI-MS/MS method, combining characteristic fragmentation patterns and the profiles of the product ions generated at different collision energies, is an effective technique for characterizing untargeted compounds.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Analysis of mexicanolide- and phragmalin-type limonoids from Heynea trijuga using high-performance liquid chromatography/electrospray tandem mass spectrometry.

RATIONALE: Limonoids, a class of tetranortriterpenoids, exhibit various biological effects, including acting as potent antifeedants and insect growth-regulators against various pests. The analysis of phragmalin- and mexicanolide-type limonoids by collision-induced dissociation tandem mass spectrometry (CID-MS/MS) has not been reported. METHODS: A high-performance liquid chromatography/electrospray ionization (HPLC/ESI)-MS/MS method was developed to investigate the fragmentation patterns of [M+NH4 ](+) ions for nine reference phragmalin- and mexicanolide-type limonoids. The method was also used in the identification of limonoid compounds in botanic extracts of Heynea trijuga. RESULTS: The losses of side chains and the furan part were the major fragmentation patterns. However, there was variation in the relative abundances of product ions resulting from the same fragmentation pathways. A total of 89 phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga were detected and 50 of these compounds were identified or tentatively characterized based on elemental constituents, fragmentation pathways, and the profile of the major product ions of reference compounds. In addition, the isomers could be tentatively distinguished. CONCLUSIONS: An HPLC/ESI-MS/MS method was developed and could be used to simultaneously identify and screen phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga.

Evaluation of relative isotopic abundance measurements in a quadrupole time-of-flight mass spectrometer for elemental composition determination of natural products in traditional Chinese medicine.

The relative isotopic abundance (RIA) measurement errors of a quadrupole time-of-flight (Q-ToF) instrument incorporating analog-to-digital converter detectors were systemically evaluated by stochastically collecting about 200 data in positive ion mass spectrometry (MS) mode. Errors varied with peak intensities at definite spectral acquisition rates but were very close, even if peak intensities changed sharply at different spectral acquisition rates with the same concentration. Intensity thresholds were systematically defined at 1 Hz of spectral acquisition rates. RIA measurement errors were also evaluated using peak area. It seemed that peak area was better adapted for the high-intensity ions while peak intensity was suited for very low-intensity ions. Several known compounds were selected for RIA measurements for product ions in tandem mass spectropmetry (MS/MS) mode. An extract of a representative traditional Chinese medicinal, Paederia scandens was analyzed with high-performance liquid chromatography-electrospray ionization-QToF-MS/MS. The unique elemental compositions of some compounds could not be identified even with exact masses and MS/MS spectra of measured and reference compounds. RIA errors, especially of (M+2)M(-1), provided vital information for determining the elemental composition.

Analyses of the iridoid glucoside dimers in Paederia scandens using HPLC-ESI-MS/MS.

INTRODUCTION: Many dimers consisting of structurally similar monomers are difficult to be identified even using NMR. Rapid structural identification of iridoid glycoside dimers, especially isomeric dimers in a complicated matrix, remains desirable. OBJECTIVE: To develop a rapid, sensitive analytical method for structural elucidation of trace iridoid glycoside isomers in a complicated extract. METHODS: Three isomeric iridoid glucoside dimers, paederoscandoside, saprosmoside E and saprosmoside D, were isolated and further analysed by electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) in positive-ion mode. Energy-resolved mass spectrometry (ERMS) was used to provide information on the relative intensity of ions versus collision energy. The crude extract of Paederia scandens was analysed by HPLC-ESI-MS/MS. RESULTS: The relative abundance of product ions in the MS/MS spectra from ammonium adduct ions varied greatly for the three isomers. The energy-resolved experiments enhanced differences among the three isomers. A total of 13 iridoid glucoside dimers (three groups of isomers) in the extract of P. scandens were identified or tentatively characterised by using HPLC-ESI-QTOF based on the tandem mass spectra of references. CONCLUSION: Linkage sites between different hydroxyl groups on the sugar and carboxyl groups for the three groups of isomers are confirmed. The reason for fragmentation differences might be that cleavage of the glycosidic bond accompanies the active H in vicinal hydroxyl rearrangement. The MS method is a useful tool for the analysis of isomers, especially trace isomers in a complicated extract.

Synthesis of Sulfilimines via Selective S-C Bond Formation in Water.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

Analysis of cipadesin limonoids from Cipadessa cinerascens using electrospray ionization quadrupole time-of-flight tandem mass spectrometry and quantum chemical calculations.

RATIONALE: Limonoids, a class of tetranortriterpenoids, exhibit various biological effects, such as insect antifeedant and growth regulating activities, antimicrobial activity, potent cell adhesion inhibitory effects, antimalarial activity, anticancer activities, and antioxidant activity. The potential application brings the need for reliable, fast and low-cost analysis of this class of compounds. METHODS: Six cipadesin limonoids (1-6), including a pairs of isomers, from leaves and barks of Cipadessa cinerascens were investigated by electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) in positive-ion mode. Characteristic processes were further studied by theoretical calculations. RESULTS: 1,3-Hydrogen rearrangement might play a significant role in the cleavage of -O- bridge bond in ring B and further produces some characteristic ions. For [M + Na](+) precursor ions, the product ion at m/z 133 might indicate the structure of ring A and the losses of CO(2) and AcOH occur readily. Interestingly, the radical product ion at m/z 460 from [M + Na](+) ions seems to be the characteristic ion for compound 1. A deuterium-labeling experiment supported the processes forming the radical ion. For [M + NH(4)](+) ions, high-abundance product ions resulting from sequential loss of AcOH can be observed. In addition, a pairs of isomers was unambiguously differentiated based on MS or MS/MS spectra. CONCLUSIONS: In summary, sufficient information obtained from fragmentation experiments of [M + Na](+), [M + NH(4)](+) or [M + H](+) precursor ions is especially valuable for rapid identification of these limonoids or their metabolites in complex mixtures. The high-abundance radical product ion is of scientific interest.

Electrospray ionization tandem mass spectrometry of chaetoglobosins.

RATIONALE: Chaetoglobosins are a family of macrocyclic polyketide alkaloids. They possess many similar isomers and exhibit a wide range of biological activities. Thus, there is a need for reliable, fast, and low-cost analysis of this class of compounds. METHODS: A series of seven chaetoglobosins from Chaetomium globosum, including two types of isomers, were investigated using electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) in both positive- and negative-ion mode. The identity of major product ions was supported by deuterium-labeling experiments. RESULTS: In positive-ion mode, the product ion at m/z 130 is the characteristic ion of the indolyl group. A McLafferty rearrangement might play a significant role in the fragmentation of the macrocycle moiety for most chaetoglobosins and produces two series of characteristic product ions, accompanied by neutral losses. The characteristic product ion at m/z 309 in the MS/MS spectrum of chaetoglobosins E indicates the structure of the cyclic olefinic bond in ring B and can be used to distinguish it from the isomers, chaetoglobosins F(ex) , which has an exocyclic double bond on ring B. In negative-ion mode, the McLafferty rearrangement has an important role in the fragmentation pattern of the macrocycle. Some high-abundance radical ions were detected. The radical product ion at m/z 138 might differentiate chaetoglobosins F and penochalasin F, isomers which have very similar structures. CONCLUSIONS: In summary, complementary information obtained from fragmentation experiments of [M+H](+) and [M-H](-) precursor ions is especially valuable for rapid identification of chaetoglobosins. The high-abundance radical ions in negative-ion mode are also of scientific interest.

Analysis of sesterterpenoids from Aspergillus terreus using ESI-QTOF and ESI-IT.

INTRODUCTION: Biosynthesis of terretonin was studied due to the interesting skeleton of this series of sesterterpenoids. Very recently, López-Gresa reported two new sesterterpenoids (terretonins E and F) which are inhibitors of the mammalian mitochondrial respiratory chain. Mass spectrometry (MS), especially tandem mass spectrometry, has been one of the most important physicochemical methods for the identification of trace natural products due to it rapidity, sensitivity and low levels of sample consumption. The potential application prospect and unique skeleton prompted us to study structural characterisation using MS. OBJECTIVE: To obtain sufficient information for rapid structural elucidation of this class of compounds using MS. METHODOLOGY: The elemental composition of the product ions was confirmed by low-energy ESI-CID-QTOF-MS/MS analyses. The fragmentation pathways were postulated on the basis of ESI-QTOF-MS/MS/MS and ESI-IT-MS(n) spectra. Common features and major differences between ESI-QTOF-MS/MS and IT-MS(n) spectra were compared. For ESI-QTOF-MS/MS/MS experiments, capillary exit voltage was raised to induce in-source dissociation. Ammonium acetate or acetic acid were added into solutions to improve the intensity of [M + H]+. The collision energy was optimised to achieve sufficient fragmentation. Some fragmentation pathways were unambiguously proposed by the variety of abundance of fragment ions at different collision energies even without MS(n) spectra. RESULTS: Fragmentation pathways of five representative sesterterpenoids were elucidated using ESI-QTOF-MS/MS/MS and ESI-IT-MS(n) in both positive- and negative-ion mode. The key group of characterising fragmentation profiles was ring B, and these fragmentation patterns are helpful to identify different types of sestertepenoids. CONCLUSION: Complementary information obtained from fragmentation experiments of [M + H]+ (or [M + NH4]+ and [M-H](-) precursor ions is especially valuable for rapid identification of this kind of sesterterpenoid.

Palladium-Catalyzed Synthesis and Anticancer Activity of Paclitaxel-Dehydroepiandrosterone Hybrids.

According to the activity-structure relationship of the C-13 side chain in paclitaxel or docetaxel, eighteen novel paclitaxel-dehydroepiandrosterone (DHEA) hybrids were designed and synthesized by Pd(II)-catalyzed Suzuki-Miyaura cross-coupling of 17-trifluoromethanesulfonic enolate-DHEA with different aryl boronic acids. The in vitro anticancer activity of the hybrids against a human liver cancer cell line (HepG-2) was evaluated by MTT assay, showing that most of these hybrids possessed moderate antiproliferative activity against the HepG-2 cancer cell line. Among these hybrids, three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues exhibited moderate anticancer activity. The optimal compound 7i showed superior anticancer activity against the HepG-2 cell line with an IC50 value of 26.39 µM.

Synthesis and Evaluation of a Series of New Bulleyaconitine A Derivatives as Analgesics.

As a nonaddictive analgesic widely used in clinics, the LD50 of bulleyaconitine A is just only 0.92 mg/kg, which exhibits obvious toxicity. Therefore, 31 new non-natural C19-diterpenoid alkaloids (2a-w, 2'a-e, 3, 4a, and 4b) were designed and synthesized from bulleyaconitine A to develop nonaddictive analgesics with low toxicity. The chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) spectra. The analgesic activities were evaluated by a hot plate test in mice. At the dosage of 10 mg/kg, six compounds (2d, 2j, 2k, 2m, 2t, 2w) exhibited good analgesic activities (increased pain threshold >100%) with a long duration. Among them, 2w showed the best analgesic activity and the longest duration. Its pain threshold reached 166.35% in 15 min, peaked at 30 min (182.35%), and remained 82.59% even at 60 min.

Analysis of caffeic acid derivatives from Osmanthus yunnanensis using electrospray ionization quadrupole time-of-flight mass spectrometry.

A series of six caffeic acid derivatives (1-6) in Osmanthus yunnanensis were investigated by electrospray quadrupole time-of-flight tandem mass spectrometry (ESI-QToF-MS/MS) in both negative- and positive-ion modes. High-quality MS/MS spectra of [M + H](+) are generated from high-abundance protonated parent ions obtained by addition of ammonium chloride to the solutions. Fragmentation mechanisms of [M - H](-) and [M + H](+) precursor ions were proposed and elemental compositions of most of the product ions were confirmed on the basis of the high-resolution ESI-collision-induced dissociation (CID)- MS/MS spectra. It was found that the fragment ions at m/z 179, m/z 161, m/z 135 and m/z 134 in negative-ion mode and at m/z 163, m/z 145 and m/z 135 in positive mode should be the characteristic ions of caffeic acid. In addition, the radical fragment ions with high abundance were observed for many caffeic acid derivatives especially for 4. The structural elements of unknown compounds 7 and 8 were tentatively identified on based on tandem mass spectra of known ones.

Natural products as important tyrosine kinase inhibitors.

As an important source of drugs, natural products play an important role in the discovery and development of new drugs. More than 60% of anti-tumor drugs are closely related to natural products. At the same time, as the main cause of tumors, the abnormal activity of tyrosine kinase has become an important target for clinical treatment. Although, small molecule targeted drugs dominate the cancer treatment. Natural active products are driving the development of new tyrosine kinase inhibitors with their unique mode of action and molecular structure diversity. Obtaining new chemical entities with tyrosine kinase inhibitory activity from natural active products will bring new breakthroughs in the research of anticancer drugs. In this paper, different tyrosine kinases are mainly classified as targets, and natural products and derivatives which have been found to inhibit tyrosine kinase activity have been described. It is hoped that by analyzing the different aspects of the source, structural characteristics, mechanism of action and biological activity of these natural products, we will find new members that can be developed into drugs and promote the development of anti-tumor drugs.

Electrospray mass spectrometry and tandem mass spectrometry of bimetallic oxovanadium complexes.

A series of six bimetallic oxovanadium complexes (1-6; only one was purified) were investigated by electrospray quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) in negative-ion mode. Radical molecular anions [M]*(-) were observed in MS mode. Fragmentation patterns of [M]*(-) were proposed, and elemental compositions of most of the product ions were confirmed on the basis of the high-resolution ESI-CID-MS/MS spectra. A complicated series of low-abundance product ions similar to electron impact (EI) ionization spectra indicated the radical character of the precursor ions. Fragment ions at m/z 214, 200, and 182 seem to be the characteristic ions of bimetallic oxovanadium complexes. These ions implied the presence of a V-O-V bridge bond, which might contribute to stabilization of the radical. To obtain more information for structural elucidation, three representative bimetallic oxovanadium complexes (1-3) were analyzed further by MS in positive-ion mode. Positive-ion ESI-MS produced adduct ions of [M + H](+), [M + Na](+), and [M + K](+). The fragmentation patterns of [M + Na](+) were different than those of radical molecular anions [M]*(-). Relatively simple fragmentation occurred for [M + Na](+), possibly due to even-electron ion character. Negative-ion MS and MS/MS spectra of the hydrolysis product of Complex 1 supported these finding, in particular, the existence of a V-O-V bridge bond.

Hydroxycinnamoylmalated flavone C-glycosides from Lemna japonica.

Three previously undescribed flavone C-glycosides (1-3), along with seven known ones (4-10), were isolated and characterized from the smallest flowering aquatic plant, Lemna japonica. On the basis of spectroscopic analysis and alkaline hydrolysis, compounds 1-3 were identified to be luteolin 6-C-(2″-O-trans-caffeoyl-d-malate)-ß-glucoside (1), apigenin 6-C-(2″-O-trans-caffeoyl-d-malate)-ß-glucoside (2), and luteolin 6-C-(2″-O-trans-coumaroyl-d-malate)-ß-glucoside (3). Compounds 1-3 are characteristic of a trans-coumaroyl-d-malate or trans-caffeoyl-d-malate linked to C-2″ of the glucose, which was reported for the first time. Compounds 1-3 exhibited weak cytotoxicity against HepG-2, SW-620, and A-549 cell lines, with IC50 values between 42.5 and 19.2µg/ml, and moderate antioxidant activity. Meanwhile compound 3 displayed moderate nematocidal activity with an EC50 value of 1.56mg/ml.