Synthesis mixed library

The synthesis of libraries of structurally defined compounds can potentially be achieved either by split-mix synthesis or by parallel synthesis of individual compounds. The synthesis requires a reliable methodology of oligosaccharide synthesis, where stereochemistry and regioselectivity have to be achieved unlike other library approaches. Development of synthetic methodologies that can provide access to any oligosaccharide structure is underway. 

It is clear that the ideas of combinatorial chemistry could potentially be applied to identifying excellent matches of "hosts" and "guests", and that to achieve this requires the synthesis of libraries of macrocycles. As noted above, when cyclic oligomers are prepared under thermodynamic conditions the family of oligomers formed can equilibrate, Reactions 3 in Scheme 1, i.e. dimers can interconvert with trimers and tetramers etc. Use can be made of this to establish equilibria between cyclic oligomers of different families, i.e. to "mix" the different families, and in this way a soluble macrocyclic library may be prepared. 

A discrete library is a set of compounds that are obtained as individuals at the end of the library synthesis. Parallel synthesis leads to a discrete library by simultaneous addition of reactants in different reaction vessels and parallel handling of each library sample (see the example in Fig. 4.2, where 15 discretes are prepared from the common intermediate A with two parallel reaction steps). Conversely, a pool library is a set of compounds that are obtained as mixtures, or library pools, at the end of the synthesis. Mix and split (or divide and recombine) is the process leading to an SP pool library... 

Fluorous Split-Mix Library Synthesis and Preparative LC/MS De-Mixing... 

Mmray JK, Sadowsky JD, Scalf M et al (2008) Exploration of structure—activity relationships among foldamer ligands for a specific protein binding site via parallel and split-and-mix library synthesis. J Comb Chem 10 204-215... 

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. 

Modular Synthesis of a Mixed One-Bead - One-Selector Library... 

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

Because of their ease of synthesis and their structural similarity to peptides, many laboratories have used peptoids as the basis for combinatorial drug discovery. Peptoids were among the first non-natural compounds used to establish the basic principles and practical methods of combinatorial discovery [17]. Typically, diverse libraries of relatively short peptoids (< 10 residues) are synthesized by the mix-and-split method and then screened for biological activity. Individual active compounds can then be identified by iterative re-synthesis, sequencing of compounds on individual beads, or indirect deduction by the preparation of positional scanning libraries. 

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-... 

While parallel synthesis of arrays of glycopeptides is readily achieved by implementation of the building-block approach (Scheme 14.1, Strategy 2),101 glycopeptide library synthesis in a combinatorial manner via the split-mix method has yet to prove routine. The difficulty lies in the structural analysis of the vast number of compounds generated in picomolar quantities on a single bead. Whereas peptides on... 

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