Combinatorial methodology

AC Good, R Lewis. New methodology for profiling combinatorial libraries and screening sets Cleaning up the design process with HARPick. I Med Chem 40 3926-3936, 1997. 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

In addition, further automation will be needed in what is still very much a hands-on art. Autoinjectors coupled to complete analytical data systems and readers for 96-well plates are the beginning of what will continue to be a necessary trend of residue chemistry. The application of the techniques of combinatorial chemistry/biochemistry, which has produced screening methodology for handling many variables, might be appropriate to residue chemistry. 

Ozturk, S. and Senkan, S. (2002) Discovery of new fuel-lean NO reduction catalyst leads using combinatorial methodologies. Appl. Catal. B Environ., 38, 243. 

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

Perhaps the most important issues to consider now are the application of novel methodologies, molecular diversity, and synthetic convenience. There have been several reports of novel, one-pot procedures for the preparation of 1,2,4-triazoles with diverse structures. Synthesis of 1,2,4-triazoles on polymeric supports, in both solution and solid phase, represents a step toward the combinatorial synthesis of these heterocycles. It is these novel applications of technology to organic synthesis that perhaps lead the way in 1,2,4-triazole chemistry. 

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