Combinatorial chemistry solution-phase parallel synthesis

Many of these new techniques are especially suited to the preparation of combinatorial libraries by solution phase parallel synthesis. This chapter provides a brief introduction to the concepts of strategy level purification, and then introduces fluorous chemistry with representative examples of reactions, reagents and techniques. 

In another approach, Hindsgaul et al. reported a combinatorial strategy to obtain glycohybrids (Scheme 5) [8]. Glycohybrids are derived from monosaccharides via a Michael reaction, followed by the derivatization of the carbonyl group with several amino acids. This chemistry was further extended to the solution phase parallel synthesis to obtain a library of several compounds. 

Tietze and coworkers developed two new domino approaches in the field of combinatorial chemistry, which are of interest for the synthesis of bioactive compounds. Combinatorial chemistry can be performed either on solid phase or in solution using parallel synthesis. The former approach has the advantage that purification of the products is simple and an excess of reagents can be used. This is not possible for reactions in solution, but on the other hand all known transformations can be used. The Tietze group has now developed a protocol which combines the... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

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. 

The tremendous development of combinatorial chemistry during the last few years has contributed to increasing steadily the options for a chemist to synthesize a chemical library, and many excellent reviews have dealt extensively with different aspects of this exciting new discipline. Solid-phase [1] or solution-phase [2] libraries, parallel synthesis [3] or mixtures of compounds [4] and large or small libraries, are only a few of the alternatives, and each one of... 

These libraries contain a relatively small number of individuals (typically tens to hundreds) and are almost always prepared as discrete libraries using parallel synthesis and automated or semiautomated devices. Focused libraries are predominantly prepared in solution because of the easier shift from classical organic synthesis to solution-phase combinatorial chemistry, while automated purification procedures for relatively small arrays of discrete compounds in solution are common nowadays. The... 

Combinatorial Chemistry. The application of high-throughput, parallel methods to the synthesis, analysis, screening, and testing of materials. This approach relies on robotics and computer-assisted methods to generate and analyze the results. Synthesis, analysis, and testing of samples occurs in the wells of microtiter plates, which may contain as few as 96 samples or as many as a few thousand. Solid-phase and solution methods are used, and samples may be one-bead-one-com-pound" or they may contain mixtures, which require "deconvolution" to determine which component is responsible for observed activity. 

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