Combinatorial chemistry sequential synthesis

All issues about the preparation of inorganic solid catalysts that we have discussed above apply for the rapid sequential synthesis of inorganic solids by automated methodologies. As for HTE - and combinatorial approaches in organic chemistry, technical solutions for compound synthesis can be obtained commercially for a number of synthetic problems [42-45] and it is beyond the scope of this chapter to discuss all the technical details. 

Typically MCRs allow the synthesis of very many derivatives of a special scaffold. Since the number of possible products increases exponentially with the multiplicity of the MCR, very large chemical spaces can be inspected. These very large chemical spaces are not realistically accessible by classical sequential syntheses. As realized by Ugi in 1961 starting with 1000 each of the educts carboxylic acid, amines, aldehydes and isocyanides 10004 products are accessible [4]. In this seminal paper the roots of combinatorial chemistry are described. The authors noted that MCRs have huge variability. Although the paper describes the essentials of combinatorial chemistry, the time was not right for the great advances that only started 30 years later. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

Combinatorial chemistry evolved from the field of solid state peptide synthesis in which peptides are prepared on a polymeric solid phase support. Such supports are traditionally composed of polymeric resin beads on to which the synthesis of a peptide is undertaken in a stepwise fashion with each amino acid being added sequentially to the peptide chain (Figure 15.1). In order to avoid the formation of side products each... 

Combinatorial chemistry refers to the synthetic chemical process that generates a set or sets (combinatorial libraries) of compounds in a simultaneous rather than a sequential manner. The broader concept of combinatorial technologies includes all of the disciplines involved in the synthesis and the applications of synthetic chemical libraries, such as their attendant analytical and computational chemistry methods and high-throughput screening (HTS, vide infra), as well as the disciplines related to other... 

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

The principal difference between the synthesis of individual peptides and peptide libraries is that mixtures of amino acids, rather than individual amino acids, are incorporated into selected or all positions of the sequence of peptide libraries. However, all current peptide chemistry strategies can be used for the synthesis of peptide libraries. In general, library synthesis requires greater emphasis on simplicity and reproducibility of the synthesis process. Although soluble supports have also been used for peptide library synthesis,the majority of methods used to synthesize peptide combinatorial libraries utilize Merrifield s concept of solid-phase synthesis,which is based on the sequential assembly of peptides after covalent attachment of the C-terminal amino acid to a polymeric solid support. This enables the excess of reagents to be removed by simple wash and filtration processes, and avoids the... 

Nucleoside chemistry is traditionally labor intensive and the output of compoxmds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the piupose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine diehloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two ehloro atoms by various amines. The purine heterocyclic bases were then condensed with Dd.-ribofuranosides following a classical Vorbruggen method to yield nucleosides of general formula 171. 

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