Combinatorial chemistry Beads

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... 

Small-diameter packed columns offer (17) the substantial advantages of small volumetric flow rates (1-20 (p.L min )), which have environmental advantages, as well as permitting the use of exotic or expensive mobile phases. Peak volumes are reduced (see Table 1.1), driven by the necessity of analysing the very small (pico-mole) amounts of substance available, for example, in small volumes of body fluids, or in the products of single-bead combinatorial chemistry. 

Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to tfie different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

Introduced in the early 1990s, the split-and-recombine concept contributed much to the early success of combinatorial chemistry. Often, all combinatorial methods were identified with this concept. Split-and-recombine synthesis offered easy access to large number of individual compounds in few steps. If conducted on polymer beads, these are easily separated mechanically and can be identified subsequent to a screening step. 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

Swali, V., Wells, N.J., Langley, G.J., and Bradley, M. (1997) Solid-phase dendrimer synthesis and the generation of super-high-loading resin beads for combinatorial chemistry. J. Org. Chem. 62, 4902-4903. 

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... 

Most important of all, however, is the possibility of running the Merrifield procedure on any number of resin beads (or other support systems) simultaneously in a number of reaction chambers. An example of this alternative is the so-called split and mix system of combinatorial chemistry. The first step in this kind of system is to prepare some number of monomer-support units (three in the example shown below), in which the monomer present differs from chamber to chamber. In the diagram below, the units are represented as -X, -Y, and -Z. These three units are washed and then mixed with each other in a single container. The mixture is then divided and placed into three separate containers. One of the most common containers used contains a number of wells in a plastic or glass dish that are miniature versions of the common petri dish used in biology experiments. 

S. K. Sarkar, R. S. Garigipati, J. L. Adams and P. A. Keifer, An NMR method to identify nondestructively chemical compounds bound to a single solid-phase-synthesis bead for combinatorial chemistry applications, J. Am. Chem. Soc., 1996, 118, 2305-2306. 

The basis of the single-bead concept is the use of single shaped bodies as the catalytic material of interest. These particles may in principle be of any shape, but spherical particles are usually employed. In accordance with approaches known from combinatorial chemistry, such spherical particles are called beads , although they fulfil very different functions in comparison to their application in combinatorial setups in organic and bio-chemistry. 

Prion Protein Study of the target protein per se and selection of appropriate binding sites Solid-phase combinatorial chemistry (49 ligands) Affinity chromatography ELISA on beads 20... 

Stankova M, Strop P, Chen C, Lebl M, Mixtures of molecules versus mixtures of pure compounds on polymeric beads, in Molecular Diversity and Combinatorial Chemistry (Eds Chaiken IW, Janda KD), pp. 136-141, 1996, American Chemical Society, Washington. 

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. 

Sizemore CF, Seneci P, Kocis P, Wertman KF, Islam K, Combinatorial chemistry and natural products determination of the biological activity of on-bead, double cleavable teicoplanin aglycon (TD), Protein Pept. Lett., 3 253-260, 1996. 

Egner BJ, Rana S, Smith H, Bouloc N, Frey J, Brocklesby WS, Bradley M, Tagging in combinatorial chemistry the use of colored and fluorescent beads, Chem. Commun., pp. 735-736, 1997. 

Most of the mass spectrometry applications for combinatorial chemistry will be described in the following sections of this chapter. Here we will give a short overview of MS techniques utilized for the characterization of resin-bound molecules. The majority of publications in this field describe applications of matrix-assisted laser desorption ionization (MALDI), combined with time-of-flight (TOF) detection. The major difference of MS application for analysis of resin-bound molecules from the above-described NMR and IR applications is that analyte should not be covalently bound to solid support prior to mass measurement. Detachment of compound molecules from resin can be done chemically (for example, by bead exposure to TFA vapors) [30,31] or photochemically, such that cleavage, desorption, and ionization of molecules occur simultaneously upon stimulation by laser radiation [32], Since the... 

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