Soluble polymer-supported combinatorial synthesis,

FIGURE 11.12 Prostaglandins E2 and Fj combinatorial libraries. (From Chen, S. and Janda, K.D., Synthesis of prostaglandin Ej methyl ester on a soluble-polymer support for the construction of prostanoid libraries, J. Am. Chem. Soc., 119, 8724, 1995 Chen, S. and Janda, K.D., Total synthesis of naturally occurring prostaglandin F2on a non-cross-linked polystyrene support. Tetrahedron Lett., 39, 3943, 1998.)... 

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. 

Soluble Polymer-Supported Methods for Combinatorial and Organic Synthesis... 

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. 

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). 

Soluble supports for solution-phase combinatorial synthesis were extensively covered in Section 8.5. A recent survey of available soluble supports, with respect to their use in the soluble supported synthesis of various classes of chemicals (90), highlights the wide range of physicochemical properties (especially regarding solubility, tendency to crystallize, and solubilization power) that are embedded in different polymers and copolymers. The assessment of a sort of S AR for the composition of copol5miers versus their physicochemical properties would require the preparation of a large number of examples. Combinatorial approaches to soluble support libraries could be highly beneficial in this perspective. 

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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