Solution phase combinatorial libraries

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 ... 

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 solution-phase cycloadditions of (1Z,4R, 5R )-4-benzoylamino-5-phenylpyrazolidin-3-on-l-azomethine imines 320 to 3-keto esters afforded a library of 26 highly pure bicyclic pyrazolidinones 713 in 6-89% yields and in 14-100% de. Most of the products were isolated as mixtures of the major (13, 23, 3/ , 5/ , 6/ )-epimers 713 and the minor (1R, 2A, 3R, 5R, 6R )-epimers 714 (Scheme 113). Epimerization of these cycloadducts at the anomeric position in solution was confirmed by H NMR spectroscopy <2007MI717>. 

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. 

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. 

Since glycosylated derivatives of this porphyrin core have been shown to be effective photosensitisers, inducing necrosis and/or apoptosis in several cancer cell lines, Drain s group used TPPF20 as a core platform to efficiently generate a variety of solution-phase combinatorial libraries.83 This... 

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... 

Zhao, Y.-Z., van Breemen, R.B., Nikolic, D., Huang, C.-R., Woodbury, C.P., Schilling, A., Venton, D.L. Screening solution-phase combinatorial libraries using pulsed ultrafiltration/electrospray mass spectrometry. J. Med. Chem. 1997, 40, 4006-4012. 

Schilling A, Venton DL Screening solution-phase combinatorial libraries using pulsed ultrafiltration/ electrospray mass spectrometry. J Med Chem 1997, 40, 4006-4012. 

Ludlow, R. F. Otto, S. Two-vial, LC-MS identification of ephedrine receptors from a solution-phase dynamic combinatorial library of over 9000 components. J. Am. Chem. Soc. 2008,130, 12218-12219. 

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 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. 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

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