Combinatorial syntheses

Instead of the conventional method of synthesizing individual trinucleotides for codon analysis, it is possible to couple a mixture of all 4 nucleotides to another mixture of 4 nucletotides to produce 16 dinucleotides. If these newly formed 16 dinucleotides are reacted with a mixture of 4 additional nucleotides, 64 trinucleotides that correspond to aU possible codons are obtained. The mixture of 64 trinucleotides is called a combinatorial library (nucleotide library). In this combinatorial synthesis, the number of products (P) increases exponentially according to 

Combinatorial synthesis has prompted an interest in rapid synthetic methods, particularly in the area of SPS and its application to the high-speed automated synthesis (Seneci, 2000). In solid-phase combinatorial synthesis, reagents can be used in excess without separation problems to attain complete conversion. Facile purification and automation provide further advantages. Two approaches for combinatorial synthesis of oligonu-clotides/peptides/saccharides will be considered. 

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HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed... 

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... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

R. J. Booth and J.C. Hodges, Solid-supported reagent strategies for rapid purification of combinatorial synthesis products, Acc Chem Res 32 18-26 1999. 

F. Balkenhohl, C. Vondembusschehunnefeld, A. Lansky and C. Zechel, Combinatorial Synthesis of Small Organic Molecules, Angew Chem, Int Ed Engl 35 2289-2337 1996. 

The Biginelli reaction has also been extended to solid phase and combinatorial synthesis. In a recent combinatorial approach Kappe and coworkers used 4-chloroacetoacetate as a building block to create a library of diverse DHPMs under... 

Combinatorial synthesis of heterocycles 96MI7, 97CRV449, 99AG(E)2494, 99CSR1. 

Combinatorial synthesis of multicomponent mixtures, among them mixtures of heterocycles, for screening of bioactive compounds 99JMC3743. 

Biologically important arylaimnes, various kinds of heterocycles, and macrocyclic potmds have been prepared by using resin-botmd nitro halo compotmds via S Such a process is very important for combinatorial synthesis of biologically important potmds Typical examples are presented in Eqs 9 13-9 31... 

Methods for Combinatorial Synthesis and Screening of Large Numbers of MIPs... 

Figure 16.21 The results of split combinatorial synthesis. Assuming that 4 different building blocks are used at each step, 64 compounds result after 3 steps, and more than 1 million compounds result after 10 steps.

Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

Rademann J, Jung G (2000) Integrating combinatorial synthesis with bioassays. Science 287 1947-1948... 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

Stmcturally novel pyrazole derivatives include the propellene 2,3,4,5,6-pentakis(pyrazol-r-yl)pyridine 1 and the corresponding 3 ,5 -dimethylpyrazole derivative 2<96T11075>. Poly(pyrazol-l-ylmethyl)benzenes, such as 3, have been prepared as multidentate ligands <95AJC1587>. Solid phase synthesis of structurally diverse 1-phenylpyrazolones was reported, with application to combinatorial synthesis <96SL667>. 

Tondi D, Costi MR Enhancing the drug discovery process by integration of structure-based design and combinatorial synthesis. In Viswanadhan AK, Chose VN, editors. Combinatorial library design and evaluation. New York Marcel Dekker, 2001. p. 563-604. 

For another investigation, amide formation was used as a model reaction to demonstrate the performance of parallel processing in micro-channel devices [23]. The target of such processing is combinatorial synthesis, the provision of multiple substances within one run. 

OS 30] ]R 30] [P 22] The synthesis of nine C-C bonded products was made from four carbamates and five silyl enol ethers [66, 67]. Conversions ranged from 49 to 69% the corresponding selectivities ranged from 67 to 100%. Similar performance was achieved when serially processing the same reactions (see Serial combinatorial synthesis). 

Figure 4.46 Schematic of serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers [66. ...

Liquid- and Liquid/Liquid-phase Reactions Serial combinatorial synthesis... 

OS 30] [R 30] [P 22] By simple flow switching, serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers was accomplished (Figure 4.46) [66, 67]. The conversions and selectivities were comparable to continuous processing using three feed streams only (see Conversion/yield/selec-tivity, above). 

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