Synthesis of Discrete Compounds

The parallel synthetic methods, while being very slow and expensive when compared to the split-mix procedure, have two advantages  

There were successful efforts to modify the split-mix method, in order to eliminate the disadvantages while preserving the high efficiency. 

FIGURE 2.9 Two-stage identification of beads carrying active organic molecule. The arrow shows the vessel containing the active substance. 

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All the molecules in a DNA-encoded library are selected simultaneously. As shown in Ensemble Discovery and GSK s data analyses, a comprehensive view of SAR can be rapidly generated from the lines and planes formed in the SAR plot, high priority structural elements can be identified and applied to the next generation of library design, or to the synthesis of discrete compounds. In addition, a clear correlation between related structural elements with binding potency strongly validates the selection itself. 

The solid-phase technique of split and mix synthesis relies on the efficiency of mixture-based synthesis to provide very large libraries (millions) of discrete compounds (Figure 4).[161 In this approach, each resin bead is treated with a single building block for each synthesis step. Thus any single resin bead possesses identical copies of one library member, but the identity of the library member on any bead is lost due to the mix step of the process. Elegant strategies have been developed to chemically encode the syn-... 

Figure 14.1 The conceptual difference between the synthesis of a combinatorial library with exponential increase in number of compounds and the synthesis of parallel arrays of discrete compounds.

Parallel synthesis is the term loosely applied to the preparation of discrete compounds in the format of a spatially addressable array. It is often used in contrast to "mixture-based" combinatorial synthesis. While it is hue that the term "parallel synthesis" may encompass the preparation of a fully combinatorial multidimensional array of compounds, in practice, it most... 

Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds... 

This issue highlights the characterization difference between parallel synthesis and combinatorial synthesis. Parallel synthesis is automated traditional organic chemistry. Each compound is made in a separate reactor, purified and characterized. There is no excuse for not fully characterizing compounds made by parallel synthesis. Jonathan Ellman s laboratory at UC Berkeley has been a pioneering academic center for solid-phase chemistry development. His philosophy is to synthesize libraries of discrete compounds in a spatially separate fashion, rather than libraries of compound mixtures, to allow for rigorous analytical characterization [48,49],... 

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,... 

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... 

The main purpose of parallel high-throughput organic synthesis (HTOS) is, as already mentioned in Chapter 4, to prepare focused libraries of discrete compounds that can be used to assess a fast, preliminary stmcture-activity relationship for a specific target. The components of these libraries may vary in number from tens to thousands of compounds therefore different instrumentation and expertise are required depending on the library size. 

Despite using array-based technologies in combinatorial chemistry, most of the current synthesis methods in research laboratories or industry are based on highly automated plate-based technologies. The concept of parallel synthesis in combinatorial chemistry involves the generation of discrete compounds in spatial separated reaction compartments. The typical employed format is the 96-well microtiter plate. 

Referring to catalysis studies, academic research focused on the synthesis of thio-compounds involving MS4 or MS5 active cores. Discrete clusters or complexes... 

The structure elucidation of the active compounds depends critically on the library format. A library of discrete compounds, prepared by multiple parallel synthesis, can be characterised routinely by standard means such as TLC, IR, NMR and MS. As for conventionally synthesised compounds, the identity of these products is determined by its site of synthesis. 

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