Solution-phase combinatorial 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 ... 

Solution-phase synthesis has both advantages and disadvantages over solid-phase synthesis, and the preferred approach in a particular case will depend on a variety of considerations. Solution-phase expertise is currently the stock-in-trade of most synthetic organic chemists and much of the wealth of developed reactions is potentially available for combinatorial work. Whilst solution-phase reaction development has often been employed prior to transfer to solid phase, it occupies an important position in its own right in the combinatorial armoury. Solution-phase work is free from a number of the chemical constraints which currently limit the general application of solid-phase methods, but has clear disadvantages with respect to purification of products and pool generation. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

A convenient procedure for the solution phase preparation of a 2-aminothiazole combinatorial library has been reported. The Hantzch synthesis of 2-aminothiazoles has been adapted to allow the ready solution phase preparation of libraries of discrete 2-aminothiazoles <96BMC1409>. 

Also in this case, Curran and coworkers produced a library of 64 mappicine analogues by automated solution-phase combinatorial synthesis, as well as a 48-mem-ber library of mappicine ketone derivatives [88]. Furthermore, these authors were successful in building up a 115-member library of rac-homosilatecans 3-216 using different iodopyridones 3-214 and aryl isocyanides as substrates 3-215 (Scheme 3.56) [89]. 

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. 

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. 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

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). 

Scavenger-Based Purification of Combinatorial Libraries Generated by Solution Phase Synthesis... 

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. 

D. L. Boger, C. M. Tarby, P. L Myers, L H. Caporale, Generalized Dipeptidomimetic Template Solution Phase Parallel Synthesis of Combinatorial Libraries , J. Am Chem. Soc. 1996,118,2109. 

These results demonstrate that O-glycosyl trichloroacetimidate-based oligosaccharide synthesis on solid support may eventually become a valuable alternative to solution-phase synthesis because useful experience is available for the selection of the polymer support and choice of the linker system and the glycosyl donor. Further standardization of the building blocks and the protective group pattern will finally provide the yields and the anomeric control in order to successfully plan automated syntheses of oligosaccharides also in a combinatorial manner. 

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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