手性有机小分子催化烯胺不对称还原

手性胺是合成天然产物和手性药物的重要中间体，亚胺和烯胺的不对称催化还原是制备手性胺最直接有效的方式之一。手性有机小分子催化的亚胺不对称还原已取得了可喜的进展，但到目前为止，有机小分子催化的烯胺不对称还原，尤其是环状烯胺的不对称还原还少有报道。 本研究从手性叔丁基亚磺酰胺出发，设计并合成了一系列含有叔丁基亚磺酰基的新型脲类及硫脲类催化剂，并将其用于催化三氯硅烷对烯胺的不对称还原，尤其是1, 4-二氢吡啶酯类环状烯胺的不对称还原。通过对催化反应条件的优化，发现当添加1eq H2O时，反应收率和对映选择性明显提高，获得高达99% 的收率和88% ee，同时也取得了很好的非对映选择性（dr = 8:92）。首次实现了三氯硅烷对1, 4-二氢吡啶酯类环状烯胺的高立体选择性还原。 通过机理方面的研究，我们推测反应过程中可能是：首先，底物1, 4-二氢吡啶酯与催化剂形成氢键而被活化，当加入添加剂后，添加剂与三氯硅烷反应释放出一个质子，然后受活化的1, 4-二氢吡啶酯捕获该质子转变成更活泼的亚胺正离子的中间体。随后，在催化剂上的手性硫氧的活化下，三氯硅烷的负氢加成到受活化的亚胺正离子的中间体上，最后生成比较有利的反式产物1, 4, 5, 6-四氢吡啶乙酯。 Calalytic enantioselective reduction of imines and enamines represents one of the most straightforward and efficient methods for the preparation of chiral amines, which is an important class of intermediates for the synthesis of natural products and chiral drugs. Significant progresses have been made in organocatalytic enantioselective reduction of imines. However, asymmetric reduction of enamines, especially of cyclic enamines catalyzed by small organocatalysts has scarcely been reported. In this study, starting from chiral tert-butanesulfinamide, a series of structurally simple tert-butanesulfinyl urea and thiourea organocatalysts were developed and employed in asymmetric reduction of enamines by triclorosilane, particularly in the reduction of cyclic enamines such as Hantzsch 1, 4-dihydropyridines. During the optimization of reaction condictions, we found that the addition of one equivalent of H2O could significantly improve the yields and enatioselectivities. Under optimal condictions, 99% yield, up to 88% ee, and 8:92 diastereomeric ratio were obtained. Thus, we have for the first time realized the highly stereoselective reduction of Hantzsch 1, 4-dihydropyridines catalyzed by triclorosilane. As for the mechanism, we speculate that the Hantzsch 1, 4-dihydropyridine was firstly engaged with the catalyst through hydrogen bond. The proton released from the reaction of the additive and triclorosilane next added to one of the C=C bond to make an active iminium intermediate, which was then attacked by the nucleophlic hydrogen of HSiCl3 activated by the Lewis basic sulfinyl function of the catalyst to provide superior trans-1, 4, 5, 6-tetrahydropyridine products.

有机质谱裂解规律及智能解析方法研究

本学位论文分为四个部分，第一部分报道了用串联质谱快速分析合成药物中的微量杂质成分以及分析中药材中的化学成分。第二部分报道了通过质谱和串联质谱发现并合成新型的PdPincer 催化剂，同时对其活性进行测试。第三部分为串联质谱自动解析软件的设计及应用。第四部分概述了应用在质谱中的各种碎裂方式。 第一部分首先总结了5-溴粉防己碱及其类似物的裂解规律，并以此为根据推测出2 个微量杂质的结构。随后针对无患子（Sapindus mukurossi Gatren.）中的皂苷成分，由ESI-QTOF 得到各个皂苷成份的高分辨质量数据进而得到其分子式，然后利用ESI-IT 电喷雾串联质谱对无患子总皂苷中各皂苷成分的结构进行进一步的鉴定。进而以同样的方式，先通过ESI-QTOF 得到黄山药（Dioscoreapanthaica）总皂苷中各个组分化合物的分子式，然后对已有的薯蓣皂苷标准品做串联质谱分析，以得到该类化合物的裂解规律并给出解析该类化合物的流程图。在此利用计算化学的方法讨论了离子的丰度与裂解活化能之间的关系。然后应用APCI-MS/MS 方法探讨了四对同分异构体和几个已知的化合物，并最后用液质联用对其进行确认，同时还给出了4 个未知化合物的可能结构。 第二部分报道通过质谱和串联质谱发现并合成新型的PdPincer 催化剂，同时对其活性进行测试。钯催化的交联反应是有机合成中C-C 键形成的最有效的方法，且硫脲是一类对空气和水都稳定的化合物，因此我们设计并合成了一系列的硫脲钯催化剂并得到了很好的催化活性。我们在对其中一类环状双硫脲化合物进行质谱实验的时候，在正离子模式下发现了反常的[M.H]+，通过串联质谱进一步确定了它是一种新型的PdPincer 结构。我们将其合成出来并通过X-ray 衍射实验确定了它的结构。同时测定其催化活性并与未形成pincer 的类似物进行比较发现该类化合物具有较宽的底物适用性。 第三部分为串联质谱自动解析软件的设计及应用。通过前面两部分的启示，独立设计开发了AuMass（1.0）。其算法是：先通过查找特殊的碎片离子，中性丢失或碎片离子质量差来确定某类化合物的骨架结构，然后利用该类化合物的自动解析流程来对其周边取代基进行确认。通过它快速地对白芍中的化学成分进行解析，并对未知的化合物进行了推测。为了增加它的解析能力，我又对其它类型的化合物裂解规律进行总结，并给出了自动解析流程。实践证明该软件具有相当好的应用价值。 第四部分综述了应用在质谱上的各类母离子的碎裂技术。这里包括了碰撞诱导裂解（CID）、光诱导碎裂（LID）、电子捕获裂解/电子转移裂解（ECD/ETD）、红外多光子解离（IRMPD）、黑体辐射解离（BIRD）和PQD 裂解技术。 This dissertation consists of four chapters. The first chapter reports the rapidanalysis of trace impurities from synthetical medicine and analysis of the chemicalconstitutents from Chinese herb medicines. The second chapter elaborates the studieson the discorvery and synthesis of new type of Pd Pincer catalyst by using MS andtandem MS together with the testing of its catalyst activity. The third chapter dwellson the designation and development of automatic tandem mass spectrometry analysissoftware. The last chapter presents a review on the dissociation technique of massspectrometry. The first chapter reports the rapid analysis of trace impurities from synthesismedicine and analysis of the chemical constitutents from Chinese herb medicines. The fission mechanism of 5-bromotetrandrine was obtained by analysis of the dissociationpathways of major product, by using which the possible structure of the two traceimpurties was assumed. There are lots of saponins in Sapindus mukurossi. Except forthe good spumescence and decontamination，it possesses the bioactivity of antigenand antitch. First of all, the high resolution mass information was obtained by ESI-QTOF. Hence the possible molecular formulars were acquired too. Then weconducted the further detection of the structures of its saponins by using ESI-ITtechnology. In the same manner, first the molecular formulars of every constituentfrom Dioscorea panthaica in total saponins were obtained by ESI-QTOF, and thenacquired the fission mechanism of this type of compounds by tandem massexperiment on a series of known and available saponins. In the same time, theanalysis flowchart was concluded. Here the relationship between the ion intensity andthe corresponding dissiociation activation energy was studied by computer chemistry.Then the four pairs of isomers were differentiated by APCI-MS/MS, as well as thecharacterization of known and unknown compounds. The assumption was confirmed by HPLC-MS/MS. Among them the possible structures of four unknown saponinswas presented. The second part was discovery and synthesis of a new type of Pd pincer catalystby MS and tandem MS. The coupling reaction catalyzed by Pd is the most effectivemethod in C-C formation in organic synthesis. Apart from that, thiourea is type ofcompounds that are stable to atmosphere and moisture. Hence we designed a series ofPd thiourea catalysts. Some of them show the excellent catalyst activity. The abnormalparent ion [M.H]+ was founded in positive ESI mode when we conduct some massspectrometry experiments on the bicyclical thiourea Pd complex. The structure wasproposed by mass and tandem mass spectrometry. Because it was a new type of pincer,we want to test its catalyst activity. So the Pd pincer was synthesized and the detailstructure was obtained by x-ray experiment. It shows the more fitness in catalysis ofSuzuki reaction by comparison with the analogue. The third chapter dwells on the design and development of automatic tandemmass spectrometry analysis software. Inspired by the former two chapters, theAuMass (version 1.0) was developed. Its algorithm is: first check the diagnostic ion,diagnostic neutral loss or diagnostic ions mass intervals in database to find out whatthe analyst’s skeleton belongs to, then identify the peripheral functional group by thecorresponding analysis flowchart. The chemical constituents of Paeonia lactiflorawere identified rapidly by using AuMass. To increase the analysis ability, the othertypes of compounds from Chinese herbs was concluded. Actually, the software isproven to have the much valuable application. The last chapter presented the review on the some kinds of fission technique ofmass spectrometry. It involves the collision induced dissociation (CID), laser induceddissociation (LID), electron capture dissociation/electron transfer dissociation(ECD/ETD), infrared multiple photons dissiociation, black body irraditiondissociation and PQD fission technique from Finnigan.

An electroosmotic pump for packed capillary liquid chromatography

An electroosmotic pump (EOP) capable of generating pressure above 3 MPa and mul/min flow rate with reverse phase mobile phases of HPLC was constructed and evaluated. The pump consisted of three parallel connected fused silica capillary columns (25 cm x 320 mum I.D.) packed with 2 mum silica materials, hollow electrodes, a high voltage DC power supply, and. a liquid pressure transducer. The EOP was applied in a capillary liquid chromatographic system for mobile phase delivery instead of a mechanical pump. Standard samples containing thiourea, naphthalene, anthracene, phenanthrene and acetonitrile were separated on a 15 cm x 320 mum I.D. 5 mum Chromasil C-18 packed capillary column with acetonitrile/water as mobile phase. (C) 2003 Elsevier Science B.V. All rights reserved.

赤霉素、硫脲处理对黄精根状茎和须根发生的影响

为诱导无芽黄精根状茎产生不定芽,选择不同的化学物质进行诱导处理。结果表明,GA3处理效果明显,选用0.4 mg/L的GA3浸泡25 min对黄精根状茎不定芽的产生和须根生长有明显促进作用,高浓度抑制其生长;1%硫脲浸泡处理对黄精无顶芽根状茎萌发新芽和须根有明显的抑制作用。

Morphology control of nanoscale PbS particles in a polyol process

Nanostructured PbS with different morphologies and particle sizes have been prepared through a polyol process. Narrow size distribution for star-shaped, octahedral, tetradecanehedral, and cubic products were achieved by slowly introducing the source materials using a peristaltic pump in the presence of poly(vinylpyrrolidone) (PVP) as additive. Systematic variation of the kinetic factors, including the additive, the reaction temperature, the duration time, the ratio of source materials, the Sulfur sources, and the Pb(Ac)(2)center dot 3H(2)O concentration, reveals that the morphology depends mainly on the supersaturation degree of the free sulfur ions released from thiourea under elevated temperature.

Shape-Controlled Synthesis of Wurtzite ZnS Microstructures Under Mild Solvothermal Condition

Through a facile solvothermal route using zinc chloride and thiourea as reactants, wurtzite ZnS and its precursor ZnS center dot (en)(0.5) (en = ethylenediamine) with various morphologies and sizes were grown, which were characterized by XRD, SEM, TEM and N-2 adsorption and so on. The phase evolution, composition and morphologies of the products are highly dependent on the concentration of en. By keeping the en-water volume ratio at 1/2 to 1, the nanostripes-flower or nanorod-spheric wurtzite ZnS were easily obtained under 120 degrees C for 6-24 h, which possess relatively higher specific surface area and larger total pore volume.

Low-temperature synthesis of oil-soluble CdSe, CdS, and CdSe/CdS core - Shell nanocrystals by using various water-soluble anion precursors

Colloidal CdSe and CdS quantum dots were synthesized at low temperatures (60-90 degrees C) by a two-phase approach at a toluene-water interface. Oil-soluble cadmium myristate (Cd-MA) was used as cadmium source, and water-soluble Na2S, thiourea, NaHSe, Na2SeSO3, and selenourea were used as sulfur and selenium sources, respectively. When a cadmium precursor in toluene and a selenium precursor in water were mixed, CdSe nanocrystals were achieved at a toluene-water interface in the range of 1.2-3.2 nm in diameter. Moreover, we also synthesized highly luminescent CdSe/CdS core-shell quantum dots by a two-phase approach using poorly reactive thiourea as sulfur source in an autoclave at 140 degrees C or under normal pressure at 90 degrees C. Colloidal solutions of CdSe/CdS core-shell nanocrystals exhibit a photoluminescence quantum yield (PL QY) up to 42% relative to coumarin 6 at room temperature.

Amperometric biosensor for tyrosinase inhibitors in a pure organic phase

The determination of benzoic acid, thiourea and 2-mercaptoethanol in three pure organic solvents, viz., chloroform, chlorobenzene and 1,2-dichlorobenzene, by using an amperometric cryohydrogel tyrosinase biosensor is described. Measurements were carried out with phenol as the enzyme substrate. Kinetic parameters (K-i and I-50) were determined in the three solvents for various inhibitors. The sensor showed the most sensitive measurements to these inhibitors in pure chloroform. The solvent-induced deviation of the biosensor to thiourea was evaluated by means of Hill coefficients. The smallest deviation as observed in 1,2-dichlorobenzene, owing to the high hydrophobicity of this solvent. The nature of the inhibition process and its reversibility mere also examined.

Large-pore mesoporous SBA-15 silica particles with submicrometer size as stationary phases for high-speed CEC separation

A new mesoporous sphere-like SBA-15 silica was synthesized and evaluated in terms of its suitability as stationary phases for CEC. The unique and attractive properties of the silica particle are its submicrometer particle size of 400 nm and highly ordered cylindrical mesopores with uniform pore size of 12 nm running along the same direction. The bare silica particles with submicrometer size have been successfully employed for the normal-phase electrochromatographic separation of polar compounds with high efficiency (e.g., 210 000 for thiourea), which is matched well with its submicrometer particle size. The Van Deemeter plot showed the hindrance to mass transfer because of the existence of pore structure. The lowest plate height of 2.0 mu m was obtained at the linear velocity of 1.1 mm/s. On the other hand, because of the relatively high linear velocity (e.g., 4.0 mm/s) can be generated, high-speed separation of neutral compounds, anilines, and basic pharmaceuticals in CEC with C-18-modified SBA-15 silica as stationary phases was achieved within 36, 60, and 34 s, respectively.

Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents

This thesis describes work carried out on the design of new routes to a range of bisindolylmaleimide and indolo[2,3-a]carbazole analogs, and investigation of their potential as successful anti-cancer agents. Following initial investigation of classical routes to indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycons, a new strategy employing base-mediated condensation of thiourea and guanidine with a bisindolyl β-ketoester intermediate afforded novel 5,6-bisindolylpyrimidin-4(3H)-ones in moderate yields. Chemical diversity within this H-bonding scaffold was then studied by substitution with a panel of biologically relevant electrophiles, and by reductive desulfurisation. Optimisation of difficult heterogeneous literature conditions for oxidative desulfurisation of thiouracils was also accomplished, enabling a mild route to a novel 5,6-bisindolyluracil pharmacophore to be developed within this work. The oxidative cyclisation of selected acyclic bisindolyl systems to form a new planar class of indolo[2,3-a]pyrimido[5,4-c]carbazoles was also investigated. Successful conditions for this transformation, as well as the limitations currently prevailing for this approach are discussed. Synthesis of 3,4-bisindolyl-5-aminopyrazole as a potential isostere of bisindolylmaleimide agents was encountered, along with a comprehensive derivatisation study, in order to probe the chemical space for potential protein backbone H-bonding interactions. Synthesis of a related 3,4-arylindolyl-5-aminopyrazole series was also undertaken, based on identification of potent kinase inhibition within a closely related heterocyclic template. Following synthesis of approximately 50 novel compounds with a diversity of H-bonding enzyme-interacting potential within these classes, biological studies confirmed that significant topo II inhibition was present for 9 lead compounds, in previously unseen pyrazolo[1,5-a]pyrimidine, indolo[2,3-c]carbazole and branched S,N-disubstituted thiouracil derivative series. NCI-60 cancer cell line growth inhibition data for 6 representative compounds also revealed interesting selectivity differences between each compound class, while a new pyrimido[5,4-c]carbazole agent strongly inhibited cancer cell division at 10 µM, with appreciable cytotoxic activity observed across several tumour types.

Ionic liquid S-alkylthiouronium salts

The prepn. and characterization of a series of ionic liqs. based on S-alkylthiouronium cations prepd. from thiourea, 1,3-dimethylthiourea, 1,3-diethylthiourea and 1,3-tetramethylthiourea coupled with bis{(trifluoromethane)sulfonyl}imide, bromide, methylsulfate or ethylsulfate anions are reported. All are liqs. at room temp. or solids with m.ps. close to room temp., except for the bromide salts, which have m.ps. below 92 °C. Systematic variation in the N- and S-alkyl substituents demonstrates how the phys. properties of these ionic liqs. can be readily controlled. The mutual miscibility limits of representative examples with octane, dodecane and toluene have been detd. as a function of temp., and the extn. of dibenzothiophene from dodecane as a model for desulfurisation of diesel has been investigated.

Chiral thiouronium salts: synthesis, characterisation and application in NMR enantio-discrimination of chiral oxoanions

Chiral thioureas and functionalised chiral thiouronium salts were synthesised starting from the relatively cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine. The introduction of a delocalised positive charge to the thiourea functionality, by an alkylation reaction at the sulfur atom, enables dynamic rotameric processes: hindered rotations about the delocalised CN and CS bonds. Hence, four different rotamers/isomers may be recognised: syn-syn, syn-anti, anti-syn and anti-anti. Extensive H-1 and C-13 NMR studies have shown that in hydrogen-bond acceptor solvents, such as perdeuteriated dimethyl sulfoxide, the syn-syn conformation is preferable. On the other hand, when using non-polar solvents, such as CDCl3, the mixture of syn-syn and syn-anti isomers is detectable, with an excess of the latter. Apart from this, in the case of S-butyl-N,N'-bis(dehydroabietyl)thiouronium ethanoate in CDCl3, the H-1 NMR spectrum revealed that strong bifurcated hydrogen bonding between the anion and the cation causes global rigidity without signs of hindered rotamerism observable on the NMR time scale. This suggested that these new salts might be used as NMR discriminating agents for chiral oxoanions, and are indeed more effective than their archetypal guanidinium analogues or the neutral thioureas. The best results in recognition of a model substrate, mandelate, were obtained with S-butyl-N,N'-bis(dehydroabietyl) thiouronium bistriflamide. It was confirmed that the chiral recognition occurred not only for carboxylates but also for sulfonates and phosphonates. Further H-1 NMR studies confirmed a 1 : 1 recognition mode between the chiral agent (host) and the substrate (guest); binding constants were determined by H-1 NMR titrations in solutions of DMSO-d(6) in CDCl3. It was also found that the anion of the thiouronium salt had a significant influence on the recognition process: anions with poor hydrogen-bond acceptor abilities led to the best discrimination. The presence of host-guest hydrogen bonding was confirmed in the X-ray crystal structure of S-butyl-N,N'-bis(dehydroabietyl)thiouronium bromide and by computational studies (density functional theory).

Histamine H3 receptor-mediated inhibition of sympathetically evoked mydriasis in rats

This study was designed to determine if the histamine H3 receptor agonist R-alpha-methylhistamine would play a role in modulation of sympathetically evoked mydriasis in anesthetized rats, and if so, to ascertain the specific receptor subtype(s) involved. Reproducible frequency-response curves of pupillary dilation were generated by stimulation of the cervical preganglionic sympathetic nerve (1-32 Hz). Systemic administration of R-alpha-methylhistamine (0.3-3.0 mg kg(-1)) produced a dose-related inhibition of the evoked mydriasis. The greatest inhibition was seen at lower frequency levels, with about 43% depression observed at 2 Hz. The specific histamine H3 receptor antagonist, clobenpropit (3.0 mg kg(-1), i.v.), blocked the inhibitory effect of R-alpha-methylhistamine, whereas neither the histamine H2 receptor antagonist, cimetidine (5.0 mg kg(-1), i.v.), nor the histamine H1 receptor antagonist, chlorpheniramine (0.5 mg kg(-1), i.v.), was effective. The histamine H2 receptor agonist, dimaprit (10 mg kg(-1), i.v.), was also without effect on the evoked mydriasis. R-alpha-methylhistamine (3.0 mg kg(-1)) did not inhibit phenylephrine-induced mydriasis. These results support the conclusion that R-alpha-methylhistamine produces inhibition of sympathetically evoked mydriasis via histamine H3 receptor stimulation, presumably by an action on presynaptic histamine H3 receptors.

Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe.

Exploring molecular recognition pathways within a family of gelators with different hydrogen bonding motifs

We report the synthesis of a family of gelators in which alkyl chains are connected to the amino groups of L-lysine methyl ester using a range of different hydrogen bonding linking groups (carbamate, amide, urea, thiourea and diacylhydrazine) using simple synthetic methodology based on isocyanate or acid chloride chemistry. The ability of these compounds to gelate organic solvents such as toluene or cyclohexane can be directly related to the ability of the linking group to form intermolecular hydrogen bonds. In general terms, the ability to structure solvents can be considered as: thiourea <carbamate <amide <urea similar to diacylhydrazine. This process has been confirmed by thermal measurements, scanning electron microscopy (SEM) and infrared and circular dichroism spectroscopies. By deprotecting the methyl ester group, we have demonstrated that a balance between hydrophobic and hydrophilic groups is essential-if the system has too much hydrophilicity (e. g., diacylhydrazine, urea) it will not form gels due to low solubility in the organic media. However, the less effective gelators based on amide and carbamate linkages are enhanced by converting the methyl ester to a carboxylic acid. Furthermore, subsequent mixing of the acid with a second component (diaminododecane) further enhances the ability to form networks, and, in the case of the amide, generates a two-component gel, which can immobilise a wide range of solvents of industrial interest including petrol and diesel (fuel oils), olive oil and sunflower oil (renewable food oils) and ethyl laurate, isopropyl myristate and isopropyl palmitate (oils used in pharmaceutical formulation). The gels are all thermoreversible, and may therefore be useful in controlled release/formulation applications.