Polystyrenes solid support chemistry

One major drawback of the current methods is the low atom economy45 of solid-supported chemistry with conventional resins in comparison to solution-phase synthesis. The low loadings are one important reason for excluding solid-supported methods from many resource-and cost-sensitive applications such as scale-up projects. Furthermore, polystyrene-based resins are restricted by solvent compatibility, thermal and chemical stability, and extensive adsorption of reagents. 

Combinatorial chemistry has significantly increased the nurnjjers of molecules that can be synthesised in a modern chemical laboratory. The classic approach to combinatorial synthesis involves the use of a solid support (e.g. polystyrene beads) together with a scheme called split-mix. Solid-phase chemistry is particularly appealing because it permits excess reagent to be used, so ensuring that the reaction proceeds to completion. The excess... 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

Immobilized catalysts on solid supports inherently have benefits because of their easy separation from the products and the possibility of recycling. They are also expected to be useful for combinatorial chemistry and high-throughput experimentation. The polystyrene-bound BINAP/DPEN-Ru complex (beads) in the presence of (CH3)3COK catalyzes the hydrogenation of l -acetonaphthone with an SCR of 12 300 in a 2-propanol-DMF mixture (1 1, v/v) to afford the chiral alcohol in 97% ee (Fig. 32.35) [113]. This supported complex is separable... 

In protein microarrays, capture molecules need to be immobilized in a functional state on a solid support. In principle, the format of the assay system does not limit the choice of appropriate surface chemistry. The same immobilization procedure can be applied for both planar and bead-based systems. Proteins can be immobilized on various surfaces (Fig. 1) (12). Two-dimensional polystyrene, polylysine, aminosilane, or aldehyde, epoxy- or thiol group-coated surfaces can be used to immobilize proteins via noncovalent or covalent attachment (13,14). Three-dimensional supports like nitrocellulose or hydrogel-coated surfaces enable the immobilization of the proteins in a network structure. Larger quantities of proteins can be immobilized and kept in a functional state. Affinity binding reagents such as protein A, G, and L can be used to immobilize antibodies (15), streptavidin is used for biotinylated proteins (16), chelate for His-tagged proteins (17, 18), anti-GST antibodies for GST fusion proteins (19), and oligonucleotides for cDNA or mRNA-protein hybrids (20). 

Ellman used silyl chemistry for the direct linkage of aromatics onto the solid support by converting an aryl bromide to aryl lithium and reacting this with a silyl resin.90 It is the production of the silyl resin that is of interest in the context of this review, since an in situ Suzuki coupling was used to link the allyl silane to bromomethyl polystyrene resin (Scheme 40). 9-BBN is used to carry out the regioselective hydroboration, and this is linked to the resin with palladium catalysis in the usual way. After brief exposure of this... 

Until now, the chemistry of radicals on solid supports has been investigated mostly in respect to intramolecular radical cyclizations and radical chain reactions. One reason for refraining from free radical transformations is the chemical nature of the polystyrene with its abundance of benzylic positions that are prone to H-radical abstraction and oxidation. 

To date the majority of polymer-supported chemistry is conducted only on a few solid support materials. Recently, it has been documented that specific solid-phase effects have significant impact on the success or failure of polymer-supported reactions.15 Considering the limitations of polystyrene, which is the standard material for most applications today, it becomes even more evident that innovations in the area of support materials will open the door to novel opportunities for polymer-supported chemistries. 

To address the purification issue, which frequently is a bottle-neck in the fast microwave chemistry, a solid-phase catch and release methodology was utilized in a two-component, two-step synthesis of l-alkyl-4-imidazolecarboxylates [45]. In the first step, a collection of isonitriles 25 was immobilized onto a solid support by the reaction with the commercially available N-mclhyl aminomethylated polystyrene 26. Subsequent treatment with various amines brought about simultaneous derivatization and release of the desired imidazoles 27 back into solution. Significantly, only derivatized material was released from the resin, thus ensuring high purity of the desired product. Both steps of the reaction were substantially accelerated by microwave dielectric heating, resulting in the overall reaction time reduction from 60 hours to 70 minutes (Scheme 18). 

While considerable efforts have been spent in the past few years in the field of solid supports for combinatorial chemistry [73], most of them were devoted to modified polystyrenic beads with different sizes, loadings or swelling properties [74], or carrying different functionalities or linkers for library synthesis [75], or to solid supports different from resin beads (pins [76], cellulose [77], soluble supports [78], and so on). Few reports dealt with labelled solid supports prepared by chemical reactions (see the previous paragraphs) and significant efforts in the field of material sciences to obtain intrinsically labeled, nonchemically encoded, easily readable, combinatorial solid supports have not been reported. 

Early reported applications of this technique were the preparation of a 24-member peptide library [83], of a 125-member tripeptide-substituted cinnamic acid library tested for inhibition of tyrosine phosphatase PTP1B [83], of a 64-member peptide-like library [83] and of libraries based on a natural product, epothilone, using also new polystyrene grafted solid supports [84], Other applications, ranging from l,5-benzodiazepin-2-one library synthesis [85] to chalcone library synthesis [86], were also recently reported. Commercialization of the basic components for this technique [87] (reaction supports and vessels, tags, software, sorters, reaction stations, and so on) will ensure its quick and effective use in combinatorial chemistry and also the implementation of new technical features and possibilities for more complex and demanding applications in future. 

Small-molecule libraries may be created by a variety of methods. These include traditional solution chemistry performed in parallel using multiple reaction vessels so that the individualized chemistry performed in each vessel is, in effect, spatially encoded and hence the structure of the product is implicit by vessel. Alternatively, the chemistry can be performed on a solid support, usually polystyrene beads, in individual vessels, or the supports can be combined into pools where each bead is viewed as a separate reaction vessel. This allows a whole range of design strategies to be employed (vide supra). According to a recent literature survey, two-thirds of reported libraries are prepared on solid support and one-third by solution chemistry. ... 

---