Combinatorial parallel

Referring to highly parallel synthesis, the smallness of the micro-channel dimensions enables one to combine several micro imit operations on one chip [23]. By using multi-layered chip architecture complicated fluidic circuits with nx m combinations of fluid streams can be made. By this means, truly combinatorial parallel processing can be achieved. 

Chemistry as a subject has developed through the synthesis of individual compounds in a number of distinct steps. Recently it has benefited from the introduction of combinatorial/parallel chemistry techniques as well as microwave-enhanced technology but so far these studies have not been combined [80]. Lockley and coworkers [81-83] have shown very nicely how parallel chemistry techniques can be used for the rapid screening and ranking of catalysts using the hydrogenation of 3-methyl-3-butenylisonicotinate as the model reaction (Scheme 13.8). 

Thompson LA (2000) Recent applications of polymer-supported reagents and scavengers in combinatorial, parallel, or multistep synthesis. Curr Opio Chem 4 324-337... 

Combinatorial-Parallel Approaches to Catalyst Discovery and Development... 

Gibb, Thomas, R. P., Jr., Primary Solid Hydrides Gilbertson, Scott R., Combinatorial-Parallel Approaches to Catalyst Discovery 3 315... 

The Pd-catalyzed carbonylation of o-vinylaryl bromides using Mo(CO)6 as CO source with microwave irradiation gave indanone 338 and 3-acylaminoindanone 340, which are key intermediates for the synthesis of inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and Plasmepsin I and II (Scheme 46). These polycyclic compounds were obtained in less than 30 min in high yields. The results clearly indicate the power and advantage of this protocol, especially for the combinatorial parallel synthesis of a library of compounds. 

OBRECHT Solid Supported Combinatorial Parallel Synthesis of Small Molecular-Weight Compound Libraries... 

Solution-phase combinatorial synthesis provides a homogeneous reaction medium and overcomes the drawbacks of a solid-phase strategy. An easy and reliable purification method is required in solution-phase combinatorial (parallel) synthesis to facihtate automation. The throughput in solution-phase automated synthesis is directly related to the facility of performing a purification process (work-up), compound separation, etc.15... 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

Alternatively, drug candidates may be combined for coanalysis in the same sample. Although this combinatorial analysis approach may have previously resulted in impossible analysis complexity, the capabilities of LC/MS and LC/MS/MS for providing detailed information from highly complex samples are an excellent fit with combinatorial parallel processing. 

Purity assessment of combinatorial hbraries is an important issne. It has led to the nse of alternative detectors next to MS, snch as UV-DAD and ELSD. Stractural characterization and pnrity assessment of compound libraries obtained by combinatorial parallel synthesis using LC-APCI-MS and MS-MS, UV-VIS DAD, and NMR has been reported by Dulery et al. [18]. 

Finally combinatorial methods for the fabrication of chemical sensors have been proven to enhance significantly the performance of differential sensors. In this chapter, we show the use of a combinatorial parallel fabrication of fluorescent SAMs. 

The unpredictability of what components will constitute a successful sensing layer underlines the power of utilizing a 2D combinatorial parallel approach to the discovery of successful sensing systems in aqueous media. The library response toward metal cations can be used to search for either a unique response (individual hit ) or a whole fingerprint of responses. Here, the fingerprint is the collection of the individual responses of each sensing layer to one cation. Rapid inspection of the library fingerprint (Fig. 4.11) provides a unique response for each cation. 

Combinatorial parallel synthesis of head-to-tail bisbenzimidazoles 41 has been performed using polymer-immobilized 1,2-diaminobenzenes (Fig. 2). The PEG-bound diamines were hf-acylated at the primary aromatic amino group with 4-fluoro-3-nitrobenzoic acid. The substituted amides were cy-clized to benzimidazoles under acidic conditions. Successive reduction and cyclization with various aldehydes yielded 5-(benzimidazol-2-yl)benzimid-azoles. Finally, the desired products 41 were released from the polymer support to afford the bisbenzimidazoles in good yields and with high purity [46]. 

Ideally, a fully automated process exists from the combinatorial parallel synthesis to compound isolation, delivering the compounds in a standard 96-well microtiter plate for the following biological high-throughput screening. 

Fig. 7.9. Representation of a combinatorial parallel synthesis of a 96-member library of dipeptides in a typical plastic microtiter plate of eight rows and 12 columns only the upper left three rows and three columns are shown. Step 1 shows three rows of wells containing three different amino acids that are already attached to a polymeric solid phase, as represented by the solid circles. In step 2, all eight rows are treated with the particular protected amino acids shown in each of the 12 columns, giving rise to 96 different polymer-bound dipeptides. In step 3, the dipeptides are cleaved from the solid support in preparation for testing them for biological activity.

The recent interest in organic solid phase synthesis, triggered by the advent of chemical combinatorial methods (1-7), also accelerated methodology development. Simplification of chemical protocols, their robustness, and amenability to handling large arrays of compounds, prepared by combinatorial/ parallel solid phase synthesis, is one area that witnessed numerous novel contributions. This chapter describes an apparatus and method for gaseous cleavage of compounds from solid phase supports. 

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