Combinatorial chemistry split synthesis

There are two main approaches to combinatorial chemistry—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 the different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

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... 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

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. 

There are two basic combinatorial chemistry techniques (1) parallel synthesis and (2) split and mix methods. They are illustrated next. 

Combinatorial chemistry has moved from specially centralized laboratories, often equipped with multimillion-dollar robots, onto the bench of individual medicinal chemists. This change in direction requires the availability of personal chemistry tools that are simple to operate, easy to arrange in the laboratory, and reasonably priced. Such instruments are now available for the effective synthesis of combinatorial libraries. The Encore synthesizer represents a simple and efficient personal chemistry tool that allows the execution of directed split-and-pool combinatorial synthesis. The current version of the Encore synthesizer is designed for solid-phase synthesis on SynPhase Lanterns however, it can be modified for synthesis on alternative solid supports such as resin plugs from Polymer Laboratories (e.g., StratoSpheres Plugs). 

When performing a synthetic combinatorial chemistry experiment, several basically different strategies may be followed to create a library of compounds. The most commonly used are mixelsplU (or split and pool) synthesis [1] masking strategies [15, 16] and parallel synthesis. In this chapter, the attention is focussed on the application of parallel synthesis to catalysis in the liquid phase. 

Much of the early work in combinatorial chemistry focused on the preparation of large mixtures of compounds. The most widely used technique for mixture synthesis is the split/recombine method which assures that each component of the mixture is present in approximately equimolar concentrations. The structures of the bound ligands are determined either through an iterative, or reclusive, deconvolution strategy or through the use of encoded libraries. 

The extension of the application of combinatorial chemistry from lead discovery to lead optimization has resulted in a gradual shift from split-pool protocol-based libraries generating mixtures of compounds to the parallel synthesis of discrete analogs (see Fig. 5). The emphasis in the latter case is not on the size of the libraries but rather on the yield, purity,... 

Combinatorial chemistry is the production of libraries of compounds that represent permutations of a set of chemical variables. These variables include the nature of the substituent in a particular molecule, both in type and size, changes in the components in a mixture of materials, e.g. in ceramics and changes in process parameters, e.g. temperature, pH etc. Chemical libraries are usually created by one of two methods split and mix or parallel synthesis . Split and mix synthesis is used to produce small quantities of a relatively large number of compounds and requires assays to be performed on pools of compounds. Parallel synthesis is used to produce libraries... 

Approximately 100 mg of resin was distributed to each of the reaetion bloek wells (of an ACT block or a Bohdan block) by pipetting a slurry of the resin in DMF/DCM (3 1) or as dry resin into each IRORI kan. The peptides were then assembled by the combinatorial chemistry apparatus suited for parallel or split-and pool-synthesis (34) using in situ neutralization/HBTU activation protocols for BOC chemistry. The resin was initially washed with DCM and the BOC protecting group removed by washing twice with a 40% solution of TFA in DCM. 

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