Combinatorial synthetic method

Any combinatorial synthetic method carried out with macroscopic solid support units, even if coding is omitted, has to ensure that the route of every unit in the entire multistep synthetic process can be traced. In string synthesis this can be achieved by... 

The combinatorial synthetic methods work according to the combinatorial principle, which means that they make possible to prepare compound libraries comprising all molecular structures that can be theoretically deduced from the monomers used in the synthesis as building blocks. These methods, at the same time, are very efficient. 

Libraries prepared by application of real combinatorial synthetic methods are usually submitted to screening experiments, either as soluble mixtures or as unknown discrete compounds cleaved from, or tethered to individual beads of the solid support. The task in deconvolution is to identify the substance that has a desired property. The deconvolution methods can be classified into two groups deconvolution of mixtures, cleaved from support and deconvolution of tethered libraries. 

The use of seven-membered ring heterocycles in new medicinal agent design is likely to continue, especially in the context of the search for greater structural novelty from combinatorial synthetic methods. This promises to be a challenging area for the future. 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

A set of chemicals that has been labeled or annotated for easy storage and retrieval and that is available for screening. Consists of compounds synthesized by combinatorial or standard synthetic methods, purchased from commercial or academic sources, or samples of natural products either as pure samples or as mixtures. 

Palladium-catalyzed coupling reactions are very efficient for the introduction of new carbon- carbon bonds onto molecules attached to solid support. The mild reaction conditions and compatibility with a broad range of functionalities and high reaction yields, have made this kind of transformation a very common tool for the combinatorial synthesis of small organic molecules. The literature for synthetic methods of palladium-catalyzed reactions on solid supports has recently been reviewed [237-239]. 

Adaptation of new synthetic methods for the solid-phase synthesis of combinatorial libraries. 

Adaptation of New Synthetic Methods for the Solid-phase Synthesis of Combinatorial Libraries... 

The advent of combinatorial techniques and solid phase organic synthesis may lead to preparation of large numbers of structurally related molecules in short periods of time. This is important especially for the optimization of lead structures in the pharmaceutical industry [40]. It is now well established and documented that the combinatorial technology and solid phase techniques could offer sufficient latitude for preparation of corresponding chemical libraries with broad structural diversity. The diverse potentiality of (3-lactam moiety as specific pharmacophores and scaffolds has attracted ample interests from pharmaceutical industries for the synthetic methods based on polymer-supported techniques. 

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process, but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of a thousand compounds requires handling of a thousand reaction vessels. The timely addition of sensitive reagents (e.g., butyl lithium) at low temperature (—78°) under inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is designed to handle and tolerate such reaction conditions. Such a synthesis can alternatively be performed easily in a manual fashion using a split-and-pool method that requires only a limited number of reaction vessels. Examples from Nicolaou s17 and Schrei-ber s18,19 laboratories have shown that the split-and-pool method is the methodology of choice for the synthesis of complex and diversity-oriented combinatorial libraries. 

Carlson, R. and Gautun, H. (2005) Combinatorial libraries and the development of organic synthetic methods. PLS modelling to discriminate between successful and failed reaction systems, Chemometr. Intell. Lab. Syst., 78, 113. 

Combinatorial synthesis may be carried out on a solid support (see section 6.2) or in solution (see section 6.4). In both cases synthesis usually proceeds using one of the strategies outlined in Figure 6.3. Both solid support and solution synthetic methods may be used to produce libraries that consist of either individual compounds or mixtures of compounds. Each type of synthetic method has its own distinct advantages and disadvantages (Table 6.1). 

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