DEUSS: a perdeuterated poly(oxyethylene)-based resin for improving HRMAS NMR studies of solid-supported molecules

A novel resin called DEUSS (perdeuterated poly(oxyethylene)-based solid support) has been prepared by anionic polymerization of deuterated [D4]ethylene oxide, followed by cross-linking with deuterated epichlorohydrin. DEUSS can be suspended in a wide range of solvents including organic and aqueous solutions, in which it displays a high swelling capacity. As measured by proton HRMAS of the swollen polymer, the signal intensity of the oxyethylene protons is reduced by a factor of 110 relative to the corresponding nondeuterated poly(oxyethylene)poly(oxypropylene) (POEPOP) resin, thus facilitating detailed HRMAS NMR studies of covalently linked molecules. This 1H NMR invisible matrix was used for the solid-phase synthesis of peptides, oligoureas, and a series of amides as well as their characterization by HRMAS NMR spectroscopy. On-bead NMR spectra of high quality and with resolution comparable to that of liquid samples were obtained and readily interpreted. The complete absence of the parasite resin signals will be of great advantage, for example, for the optimization of multistep solid-phase stereoselective reactions, and for the conformational study of resin-bound molecules in a large variety of solvents.     

固相合成及组合化学用的高聚物载体

综述了用于固相合成及组合化学的高聚物载体的制备方法、特征、应用和最新进展,重点介绍了目前广泛用作固相载体的交联聚苯乙烯树脂、聚酰胺树脂和TentaGel树脂,并对几类新型载体如聚乙二醇、聚四氢呋喃衍生物交联剂改性的聚苯乙烯树脂、非芳环体系的POEPOP,树脂和SPOCC树脂作了简要的概述。     

Synthesis and evaluation of poly(oxyethylene glycol) polymer (POP) supports

Mono- and alpha,omega-bis-styryl-oligo(oxyethylene glycol) ethers have been constructed in an efficient two-step synthesis. From these precursors, poly(oxyethylene glycol) polymer (POP) supports of varying monomer and cross-linker composition have been produced. The swelling properties and mass-solvent uptake of these novel materials have been evaluated in a variety of solvents, demonstrating that POP supports exhibit enhanced solvent compatibilities over the commercial resins TENTA-GEL, ARGO-GEL, and Merrifield's resin. The utility of POP supports in solid-phase organic chemistry has also been demonstrated successfully. It is anticipated that these high-loading polymeric supports will have generic application in the solid-phase synthesis of combinatorial libraries and the in situ screening of these libraries in the aqueous environment of a bioassay.     

Recent advances in liquid-phase combinatorial chemistry

In combination with high throughput screening, combinatorial organic synthesis of large numbers of pharmaceutically interesting compounds may revolutionize the drug discovery process. Although combinatorial organic synthesis on solid supports is a useful approach, several groups are focusing their research efforts on liquid-phase combinatorial synthesis by the use of soluble polymer supports to generate libraries. This macromolecular carrier, in contrast to an insoluble matrix, is soluble in most organic solvents and has a strong tendency for precipitation in particular solvents. Liquid-phase combinatorial synthesis is a unique approach since homogeneous reaction conditions can be applied, but product purification similar to the solid-phase method can be carried out by simple filtration and washing. This method combines the positive aspects of classical solution-phase chemistry and solid-phase synthesis. This review examines the recent applications (1995-1999) of soluble polymer supports in the synthesis of combinatorial libraries.     

Dendritic aliphatic polyethers as high-loading soluble supports for carbonyl compounds and parallel membrane separation techniques

This paper describes the use of dendritic polyglycerol as a new high-loading polymeric support. The soluble polyether skeleton allows the parallel synthesis of small libraries on a large scale (1-5 mmol). Purification of polymer-bound products is easily achieved by a parallel dialysis apparatus, which was developed to separate up to 12 reaction mixtures simultaneously. The terminal 1,2-diol groups of polyglycerol (loading capacity: 4.1 mmol diol/g) can be directly coupled with carbonyl compounds without additional linker groups. At the same time the polyglycerol support acts as a polymeric ketal protecting group. The coupling of the carbonyl compounds occurs in high yields, and effective loading capacities of up to 3.5 mmol of ketone/g can be reached. The obtained polymeric acetals can easily be characterized by standard analytical techniques, such as NMR, IR, UV, and SEC. The versatility of this new polymeric support for solution-phase organic synthesis is demonstrated by two efficient polymer-supported syntheses: nucleophilic substitutions of gamma-chloroketones with amines and Suzuki-coupling on p-bromobenzaldehyde. The acid-catalyzed acetal cleavage with a solid-phase acidic ion-exchange resin in methanol demonstrates the orthogonal use of these soluble polymeric supports with conventional solid-phase reagents. Cleavage of products occurs in high yields, and almost complete recovery (>95%) of the polyglycerol support has been demonstrated after phase separation or ultrafiltration.     

Resin capsules: permeable containers for parallel/combinatorial solid-phase organic synthesis

A resin capsule is a permeable container for resin beads designed for multiple/combinatorial solid-phase organic synthesis. Resin capsules consist of a high density polyethylene ring sealed with peek mesh on both sides. The cylindrical shape of resin capsules enabled space-saving packing into plastic columnlike reaction vessels commonly used for solid-phase organic synthesis. Resin capsules have been evaluated for their use in combinatorial synthesis, and a set of model compounds with excellent purity was prepared.     

大孔聚丙烯醛-呋喃-2-硫代酰腙螯合树脂的合成及其性能的初步研究

合成了一新型高分子骨架，大孔内烯醛－苯乙烯－二乙烯苯三元共聚物树脂骨架，通过其含有的活泼醛基与呋喃－2－硫代酰肼螯合剂进行高分子反应，制备了一种含氮、硫配位原子的螯合树脂，聚丙烯醛－呋喃－2－硫代酰腙。对其与贵金属离子的吸附性能进行了初步研究，结果表明，该树脂对金、钯及铂具有选择性吸附作用，吸附容量分别为1.20mmol/g干树脂，0.37mmol/g干树脂及0.28mmol/g干树脂。     

Microwave-assisted solid-phase synthesis of 2,5-diketopiperazines: solvent and resin dependence

Solid-phase synthesis of diketopiperazines (DKPs) was preformed using various combinations of resins (polystyrene, TentaGel, ArgoGel, and PEGA) and solvents (toluene, tert-butyl alcohol, water, and toluene/2-butanol (1:4, v/v). The DKPs were synthesized from solid-phase bound dipeptides via intramolecular aminolysis. Both thermal and microwave-assisted solid-phase synthesis of DKPs gave high yields of products independently of resin and organic solvent used; however, only the PEGA resin resulted in high yields of DKPs in water independent of heating method. The short reaction times, high yields, and the possibility to run reactions in water when an appropriate resin is used makes the microwave-assisted solid-phase synthesis the method of choice. The method should be suitable for solid-phase synthesis of diketopiperazine-based libraries.     

Multistep synthesis of 2,5-diketopiperazines on different solid supports monitored by high resolution magic angle spinning NMR spectroscopy

The solid-phase synthesis of 2,5-diketopiperazines containing the trans-4-hydroxy-L-proline amino acid residue (Hyp) was performed on Ellman polystyrene, polyoxyethylene-polyoxypropylene (POEPOP), polystyrene-polyoxyethylene NovaSyn, and Wang resins, respectively. The reaction pathway allowed the introduction of different functional groups around the bicyclic scaffold in a combinatorial approach, and it generated mixtures of isomers. A detailed characterization of the single reaction steps by high resolution magic angle spinning (HRMAS) NMR spectroscopy was performed. The NMR spectral resolution of the resin-bound intermediates and final products was greatly influenced by the polymer matrix. The POEPOP resin permitted to obtain HRMAS NMR spectra with a resolution comparable with that of the spectra of the molecules in solution. Moreover, configurational and conformational isomers formed during the solid-phase reaction steps could be detected and easily assigned. Therefore, the combination of the HRMAS NMR technique with the use of nonaromatic resins may become an extremely powerful tool in solid-phase organic synthesis. This approach will allow the monitoring of multistep reactions and the conception of on-bead structural studies either on small molecules or on natural and/or synthetic oligomers.     

Synthesis of monofunctionalized gold nanoparticles by fmoc solid-phase reactions

In this communication, solid-phase reactions for the synthesis of Lys-monofunctionalized gold nanoparticles are described. A controlled and selective fabrication of linear nanoparticle arrays can be achieved through peptide linkage systems, and therefore it is essential to prepare Fmoc amino acid nanoparticle building blocks susceptible to Fmoc solid-phase peptide synthesis. Gold nanoparticles containing carboxylic acids (2) in the organic shell were covalently ligated to Lys on solid supports through amide bond coupling reactions. We employed Fmoc-Lys-substituted polymer resins such as Fmoc-Lys-Wang or Fmoc-Lys-HMPA-PEGA. The low density of Lys on the matrix enabled 2 nm-sized gold nanoparticles to react with Lys in a 1:1 ratio. Subsequent cleavage reactions using 60% TFA reagent resulted in Lys transfer from the solid matrix to gold nanoparticles, and the Fmoc-Lys-monofunctionalized gold nanoparticles (5) were obtained with 3-15% yield. Synthesis using HMPA-PEGA resin increased productivity due to the superior swelling properties of PEGA resin in DMF. Monofunctionalization of nanoparticles was microscopically characterized using TEM for the ethylenediamine-bridged nanoparticle dimers (6). By counting the number of 6, we found that at least 60% of cleaved nanoparticles were monofunctionalized by Lys. This method is highly selective and efficient for the preparation of monofunctionalized nanoparticles.     

乙酰丙酮基聚苯乙烯在萃取金属离子上的应用

大孔的苯乙烯-二乙烯苯共聚物经氯甲基化后,分别与乙酰丙酮镍、乙酰丙酮钠和四正丁基乙酰丙酮铵三种不同的乙酰丙酮盐反应,可制得聚3-(p-乙烯苄基)戊二酮-[2,4]。其中以由乙酰丙酮镍制得的聚合物最好,除二乙烯苯外,78%左右的苯环乙酰丙酮化了。该聚合物螯合Fe~(3 )和Ni~(2 )的能力与β-二酮基高聚物相仿或稍优。还比较了此类高聚物的物理机械性能。     

Suspension ring-opening metathesis polymerization: the preparation of norbornene-based resins for application in organic synthesis

A series of norbornene-based resin beads were obtained by aqueous suspension ring-opening metathesis polymerization (ROMP) and used as polymeric supports for organic synthesis. These resins were prepared from norbornene, norborn-2-ene-5-methanol, and cross-linkers such as bis(norborn-2-ene-5-methoxy)alkanes, di(norborn-2-ene-5-methyl)ether, and 1,3-di(norborn-2-ene-5-methoxy)benzene. The resulting unsaturated ROMP (U-ROMP) resins containing olefin repeat units were chemically modified using hydrogenation, hydrofluorination, chlorination, and bromination reactions to produce saturated ROMP resins with different chemical and physical properties. The hydrogenated ROMP (H-ROMP) resin was found to be highly resistant to acidic, basic, Lewis acid, and Birch reduction conditions and was assessed as a polymeric support in a series of solid-phase synthetic applications. The H-ROMP resin was found to have superior performance compared to polystyrene-divinylbenzene (PS-DVB) copolymers in aromatic nitration and acylation reactions. In a conventional five-step solid-phase synthesis of a hydantoin, similar results were obtained for both the H-ROMP and PS-DVB resins. The U-ROMP resin was also shown to be effective in the solid-phase syntheses of benzimidazoles and benzimidazolones.     

Chemically modified resins for solid-phase extraction

The packings most widely used for solid-phase extraction are hydrophobic and make poor surface contact with aqueous samples unless the resins are first treated with an activating organic solvent such as methanol. Insertion of an acetyl- or hydroxymethyl group into a porous polystyrene-divinylbenzene resin provides a more hydrophilic surface that is easily wetted by water alone. Small columns of the chemically modified resins were found to be very efficient for the solid-phase extraction of many types of organic solutes from aqueous samples. Comparative recovery studies showed that the modified resins are superior to both silica packings and unmodified organic resins for the solid-phase extraction of organic compounds, and especially for polar organics such as phenols.     

Preparation and Properties of Sol–Gel Thin Film Containing Rhodamine B Derivative with Ethoxy Silano Group on Organic Substrate and its Application to Surface-Treatment Thin Film for Display

A thin film containing rhodamine B derivative with ethoxy silano group was formed on organic film substrate using the sol–gel method. Rhodamine B derivative with a triethoxysilano group, SiO₂ sol and acrylic polymer having a triethoxy group were reacted in alcohol to give a coating solution for film formation, followed to be roll-coated on polyethylene terephthalate (PET) film and heat-treated at 130°C. This thin film consists of inorganic polymer (SiO₂), organic polymer (acrylic resin) and organic dye. These component parts become interconnected through mutual chemical bonding. This thin film has an absorption peak at 578 nm and superb water resistant characteristics (almost no dye elution in 50°C water for 150 min) as a result of chemical bonding between the organic dye and the matrix skeleton. It also has good flexibility. The film can be used as a wavelength-selective absorption film for displays to improve contrast.     

Solid-phase Synthesis of a Novel Kind of Hydroxylated Heterocyclic Ketene Aminals

An efficient solid-phase synthesis method for novel heterocyclic ketene aminals containing a hydroxyl group has been developed. The loading of the substrate on the resin through the hydroxyl group and the protection of the amine by the Schiff base were the key steps in the synthesis.     

Tailoring ultraresins based on the cross-linking of polyethylene imines. Comparative investigation of the chemical composition, the swelling, the mobility, the chemical accessibility, and the performance in solid-phase synthesis of very high loaded resins

Ultraresins have been prepared from polyethyleneimines and cross-linking molecules and have been provided with various degrees of cross-linking. The total nitrogen loading and the loading with secondary and with tertiary amines have been determined in all products. Nitrogen loadings of the novel resins were up to 15 mmol/g, reactive secondary amines up to 13.8 mmol/g. In addition to the exceptionally high loading, the novel resins displayed efficient swelling volumes in polar and nonpolar solvents. The mobility of resin-bound species as determined by EPR-spectroscopy, depending on the amount of cross-linker, indicated good flexibility and reactivity of this resin type. The novel, high-loaded resins have been investigated subsequently in solid-phase synthesis. The Rink amide linker and two different hydroxy linkers (hydroxyacetamide, HMPB) have been attached to the resin. Despite the high loadings, the secondary amines were easily accessible and could be functionalized exhaustively. Reactivity of the linker-coupled resins was found to be closely related to the resin composition. Increased resin cross-linking led to reduced swelling, reduced mobility, and reduced reactivity in the synthesis of a medium-sized model peptide. As the result of the systematic investigation of structure-property relations in Ultraresins, a support material was identified that combined high reactivity and a mobility in the range of the extremely flexible Tentagel supports. In the optimized Ultraresin, >95% of all available secondary nitrogens could be coupled with Rink linker or with the small 2-hydroxyacetamide anchor, resulting in loadings from 2.7 to 6.8 mmol/g, respectively. A resin with an attached HMPB linker and spacer delivered analytically pure peptides in solid-phase synthesis, fully exploiting the exceptionally high loadings.     

Synthesis, characterization and evaluation of sulfonic resins as catalysts

Ion-exchange resins have been often used as catalysts especially those based on styrene-divinylbenzene copolymers with sulfonic acid groups in the aromatic rings of polymer chains. That is due to the advantages of heterogenous catalysis over the homogeneous acid catalysis. Moreover, resin catalysts can often lead to high selectivity in organic reactions due to the matrix effects. Therefore, the study of copolymers synthesis conditions to determine the type of polymer structure produced as well as the characterization of sulfonic resins obtained thereof are of great interest. The current paper describes the synthesis, characterization and evaluation as catalysts of sulfonic resins derived from polymer supports synthesized by aqueous suspension polymerization of styrene and divinylbenzene. The reaction conditions were varied and polymer supports with different physical properties and morphological characteristics were obtained. The polymer supports were chemically modified by sulfonation. The resultant sulfonic resins had their catalyst activity evaluated in the esterification of acetic acid with n-butanol.     

Application of multivariate analysis to the screening of molecularly imprinted polymers (MIPs) for ametryn

Among the solid-phase extraction (SPE) techniques, a novel system for a triazine herbicide named ametryn, has been developed based on a molecular imprinted polymer (MIP) phase. Through this method, the synthesis of the complementary to ametryn MIP was accomplished and the factors influencing its efficiency have been optimized. Through the optimization process, the type and the amounts of functional monomer and solvents, template amount, cross-linker, initiator as well as the polymerization temperature were considered to be evaluated. Based on the obtained results, the optimum conditions for the efficient polymerized sorbent, considering the recovery efficiency were solvent: acetonitrile, 6.41 mL; monomer: methacrylic acid, 5.41 mmol; template: 1.204 mmol; cross-linker: 27.070 mmol; initiator: 2.03 mmol; temperature: 40.86 degrees C. The optimum molar ratio among the template, monomer and cross-linker for ametryn was 1:4.49:22.48. The reversed-phase HPLC-UV was used for the ametryn determination, using an isocratic solvent delivery system (acetonitrile: H(2)O, 60:40), flow-rate of 0.8 mL min(-1) and a UV wavelength of 220 nm. In line with the obtained results, using central composite design (CCD) can increase the precision and accuracy of synthesis and optimization of MIP to ametryn and possibly other similar analogues.     

树脂吸附对红酵母催化苯乙酮不对称还原反应的促进作用

以红酵母静息细胞催化苯乙酮不对称还原合成(S)-α-苯乙醇为模型反应, 研究了在反应体系中加入吸附树脂对反应的影响. 结果表明, 水相中较高浓度(＞50 mmol/L)的苯乙酮对红酵母细胞具有显著毒性; 加入适量的吸附树脂可以降低水相中苯乙酮的浓度从而减小对细胞的毒害作用. 考察了3种不同极性的吸附树脂(HZ-801, HZ-806和HZ-816)对底物和产物的吸附能力, 发现在3种树脂中疏水性最强的HZ-816树脂对反应底物和产物具有相对较高的吸附能力. 进一步研究结果表明, 当底物浓度为100 mmol/L, 细胞湿重为500 g/L时, 与不加树脂的对照实验相比, 加入100 g/L HZ-816树脂后, 使得48 h的反应转化率从54%提高到91%, 与此同时细胞的死亡率从99%下降为10%. 含有产物的树脂经乙醇解吸后即可循环使用.     

Preparation and Adsorption Ability of Molecularly Imprinted Polymer Microspheres for Malachite Green

Molecularly imprinted polymer (MIP) microspheres were synthesized through precipitation polymerization using malachite green (MG) as template, methacrylic acid (MAA) as monomer, and trimethylolpropane trimethacrylate (TRIM) as cross-linker. The microsphere structure of MIP was characterized by IR spectroscopy and SEM. The influence of preparation conditions such as monomer and cross-linker dosages on the polymer absorption of MG in acetonitrile solution was also explored. Under the optimum synthesis conditions (0.25 mmol MG, 1.5 mmol MAA, 2.5 mmol TRIM, 40 mL acetonitrile), the prepared MIP microspheres have a binding capacity as high as 2000 µg g^?1 of MG with an imprinting factor of above 4.0. The result suggests that the prepared MIP microspheres are promising material for the selective extraction of MG in complicated matrix solutions.