Combinatorial chemistry solution-phase library synthesis

Human recombinant Factor Vila Complex tissue factor/factor Vila ligands designed to bind to the Gla-domain in Factor Vila. Solid-phase combinatorial chemistry solution-phase synthesis of a sub-library Affinity chromatography SPR 7,15 ... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Many of these new techniques are especially suited to the preparation of combinatorial libraries by solution phase parallel synthesis. This chapter provides a brief introduction to the concepts of strategy level purification, and then introduces fluorous chemistry with representative examples of reactions, reagents and techniques. 

Two general methods are used to build a library of compounds by the general techniques of combinatorial chemistry solid-phase synthesis (SPS) and solution-phase synthesis. 

In another approach, Hindsgaul et al. reported a combinatorial strategy to obtain glycohybrids (Scheme 5) [8]. Glycohybrids are derived from monosaccharides via a Michael reaction, followed by the derivatization of the carbonyl group with several amino acids. This chemistry was further extended to the solution phase parallel synthesis to obtain a library of several compounds. 

Having said this, the synthesis of solution-phase libraries is possible, and indeed is more appropriate, than the corresponding SP chemistry under certain circumstances. The value of such libraries is discussed in the following sections, but it is appropriate to stress the concept of complementarity, rather than mutual exclusivity of the solution and SP library formats. The goal for a combinatorial chemist is always to select the best library format according to the needs of the project without exclusion of individual options due to personal preference. 

We will start with classical solution-phase combinatorial chemistry with two examples, one of discretes and one of pools, describing the application of homogeneous phase library synthesis to multistep reaction sequences. The ex-... 

P. A. Keifer 1998, (New methods for obtaining high resolution NMR spectra of solid-phase-synthesis resins, natural products, and solution-state combinatorial chemistry libraries), Drugs Future 23, 301-307. 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

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