Combinatorial chemistry, polymer solubility

The other major problem to be addressed in the combinatorial chemistry search to optimise recognition, is how the soluble libraries of macrocycles might be screened. An obvious way is to attach the "guest" to be recognised to a polymer, allow the most appropriate "host in the library to bind, and then exploit the major differences in physical properties between the polymers and macrocycles to facilitate the separation and... 

Soluble polymers have attracted recent attention in catalysis and combinatorial chemistry.1 3 When used in catalysis by organometallic compounds, soluble polymer ligands offer the following advantages The reaction is homogeneous in nature and separation of catalysts can be easily achieved by filtration or precipitation. We have now developed a new class of polymer ligands based on fluoroacrylate-arylphosphine copolymers for catalysis in periluorocarbon solvents and supercritical C02 (scC02). 

While PEG-based supports are widely used for liquid-phase combinatorial chemistry, other non-PEG-based soluble polymers have also been reported for combinatorial applications. A recent review (276) contains an exhaustive list of homo- and copolym-eric soluble supports used in peptide, oligonucleotide, and oligosaccharide synthesis, including combinatorial chemistry. Two of these supports have also been used for small organic molecule synthesis. Homopolymeric polyvinyl alcohol was used in conjunction with PEG for a protection/derivatization strategy in solution (284), and the copolymer between isopropylacrylamide and acrylic acid was used in the catalytic hydrogenation of a Cbz group (285). 

Although solid-phase synthesis is frequently linked to combinatorial chemistry, this is not a requirement. Other synthetic methodologies, such as solution-phase synthesis and soluble polymer-supported synthesis, have also been used to effect the combinatorial synthesis process. However, solid-phase synthesis allows the most efficient combinatorial synthesis. The advantages and problems with solid-supported synthesis are described in later chapters. Thus, combinatorial chemistry is not solid-phase chemistry, albeit combinatorial chemistry can be advantageously performed on the solid phase. 

Solution phase combinatorial chemistry continues to provide an important technique particularly to the medicinal chemist engaged in lead optimisation work. We anticipate that next year will see further development and application of purification technologies which will allow more complex chemistries to be employed. Although work on fluorous techniques has, currently, only been exploited by the original workers, the development of a solid phase extraction with fluorous reverse phase silica [31] and a soluble fluorous phase polymer support [32] indicates the opportunity for further innovative application of the strategy to solution phase approaches. 

A typical feature of combinatorial synthesis is the use of techniques that facilitate the isolation of products and intermediates. The most common example is the attachment to a solid support, such as a polymer bead, to allow isolation by simple filtration (solid-phase chemistry). A variety of solid and soluble supports have been developed. These may be attached to either the products or the reagents of a library. 

An extension of the combinatorial synthesis in solution is achieved by the use of soluble polymeric supports [80, 81], which combines some of the advantages of chemistry in solution and on solid phase. The so-called liquid-phase combinatorial synthesis is based on the physical properties of poly (ethylene glycol) monomethyl ether. The polymer is soluble in a variety of aqueous and organic solvents, which allows reactions to be conducted in homogeneous phase whereas the propensity to crystallize in appropriate solvents facilitates the isolation and purification of the compound at each step of the combinatorial synthesis. 

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