Products, in combinatorial chemistry

N. K. Terrett, Chapter 8 Analysis of chemistry and products, in Combinatorial chemistry, in Oxford Chemistry Masters, eds. S.G. Davies, R.G. Compton, J. 

Mang C, Jakupovic S, Schunk S, Ambrosi H-D, Schwarz O, Jakupovic J. (2006) Natural products in combinatorial chemistry an andrographolide-based library. J Com Chem 8 268-274. 

Lowe, G., Oligomeric and biogenetic combinatorial libraries, Nat. Prod. Rep., 16, 641, 1999. Khosla, C., Combinatorial chemistry of unnatural natural products, in Combinatorial Chemistry and Molecular Diversity in Drug Discovery, Gordon, E.M and Kerwin Jr, J.F., Eds., Wiley-Liss, New York, 1998, chap. 21. 

Isolation and characterization of new indole alkaloids remains a fruitful avenue for the discovery of agents with the potential for biomedical application. The virtues of this age-old process, in light of advances in combinatorial chemistry, were brought to the community as part of the 231 ACS National Meeting symposium, Modern Natural Products Chemistry and Drug Discovery <06ORGN467>. 

In addition, SPOS can easily be automated using appropriate robotics for both filtration and evaporation of the volatiles from the reaction mixture to obtain the cleaved product. Furthermore, SPOS can be applied to the powerful split-and-mix strategy, which has proved to be an important tool in combinatorial chemistry [7]. 

Abstract In this chapter different types of domino-processes are described which consist of the combination of cationic, anionic, radical, pericyclic and transition metal-catalyzed as well other reactions. The methodology is used for the highly effective synthesis of carbocycles and heterocycles as well as of natural products and other interesting materials. It is also employed as an efficient tool in combinatorial chemistry. 

ATR FT-IR spectroscopy has also been employed to monitor the solid-phase synthesis of substituted benzopyranoisoxazoles [180]. Finally, Huber et al. [181] have also reported that this technique is particularly suitable for the characterization of supported molecules in combinatorial chemistry, as well as for the identification of side products and for Photoacoustic (PA) FT-IR. 

In general, organic chemistry on polymeric supports, which is the major tool in combinatorial chemistry with the implementation of organic compounds, can be divided into three parts the polymeric support, often a polystyrene resin the product, and the linker which enables a suitable connection between the two parts (Fig. 3.1) [5]. 

The multicomponent reactions have been widely used in solid and solution-phase chemistry during the last years. Multicomponent reaction strategies offer significant advantages compared with conventional liner type syntheses. Three or more reactants come together in a one pot reaction to form new products that contain portions of all the components [281]. There are several well-known multicomponent reactions that have been used in combinatorial chemistry. 

In fact, the distinction between solid-phase and solution-phase processes is largely of historical interest and does not necessarily describe the range of experiments now being carried out in combinatorial chemistry. Researchers are finding ways of using elements from both approaches through which a library of products can be synthesized and then purified and analyzed in the most effective manner possible. 

Nuclear magnetic resonance (NMR) measurements are usually considered to be slow processes, but recent advances in the design of flow-through NMR cells have allowed the method to be applied in combinatorial chemistry 97). These technological improvements were applied to the development of two NMR-based high-throughput ee assays for evaluating the products of enzyme- or transition metal-catalyzed reactions 98). 

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

With the intention to use AD reactions in combinatorial chemistry, polymer-attached substrates were dihydroxylated [15-18]. In general, these transformations worked well and products with high enantiomeric excesses were obtained. The selectivity trends remained the same as in solution. 

Typical examples with their yields are given in Scheme 3.15. It can be anticipated that this reaction will have much utility in combinatorial chemistry as well as in the total synthesis of natural products, especially if a stereo-selective variation can be established. 

Some reactions afford mixtures of products. Mixtures include diastereomers, such as endo and exo products (10.1 and 10.2) of a Diels-Alder cycloaddition, and regioisomers, such as ortho and para products (10.3 and 10.4) from an electrophilic aromatic substitution (Scheme 10.1). Even a reaction that forms products as subtly similar as enantiomers is technically a mixture of products. Isomeric mixtures violate the spirit of one compound, one well in combinatorial chemistry. Isomeric mixtures, however, are often unavoidable and therefore tolerated in compound libraries. Mixtures are also tolerated in libraries of compounds that have been derived from natural sources. Examples include extracts from finely ground vegetation and microbial broths. 

A complementary approach is afforded by the option to use reagents attached to suitable supports to allow the easy removal of excess or derived products. A useful review of this field was published in 1981 and recent advances in combinatorial chemistry have prompted a revival of interest [24],... 

There are basically three types of patent claims (i) product or compound claims (ii) process or method claims and (iii) product-by-process claims (see Table 3). The name of each type of claim is self-defining. Product claims cover devices such as robotics [2] which are used in combinatorial chemistry. In addition, these claims can cover a particular compound, group of compounds or even an entire library of compounds [3], Note that... 

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