Solid-phase peptide synthesis polystyrene-divinylbenzene

FIGURE 27 14 A section of polystyrene showing one of the benzene rings modified by chloromethylation Indi vidual polystyrene chains in the resin used in solid phase peptide synthesis are con nected to one another at various points (cross linked) by adding a small amount of p divinylbenzene to the styrene monomer The chloromethylation step is carried out under conditions such that only about 10% of the benzene rings bear —CH2CI groups... 

Anchoring group, linker, a group bound to the polymeric support for the attachment of the first amino add in polymer-supported peptide synthesis. The chloromethyl group was the first anchoring moiety in the polystyrene/divinylbenzene resin for solid-phase peptide synthesis devdoped by Bruce Merrifield [R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149]. 

Fmoc-aminomethyl-3,5-dimethoxyphen-oxy)valeric acid PEG, polyethylene glycol PEG-PS, polyethylene glycol-cross-linked polystyrene graft copolymer PS, copoly-(styrene-1% divinylbenzene) polymeric support , resin SPPS, solid-phase peptide synthesis tBu, tert.-butyl TEA, trifluoro-acetic acid TFE, trifluoroethanol THF, te-trahydrofuran TLC, thin-layer chromatography. Amino acid symbols denote the L-con-figuration. All solvent ratios and percentages are v/v unless stated otherwise. 

Since the introduction of solid-phase peptide synthesis by Merrifield (1) nearly forty years ago, solid-phase techniques have been applied to the construction of a variety of biopolymers and extended into the field of small molecule synthesis. The last decade has seen the emergenee of solid-phase synthesis as the leading technique in the development and production of combinatorial libraries of diverse compounds of varying sizes and properties. Combinatorial libraries can be classified as biopolymer based (e.g., peptides, peptidomimetics, polyureas, and others [2,3]) or small moleeule based (e.g., heterocycles [4], natural product derivatives [5], and inorganie eomplexes [6,7]). Libraries synthesized by solid-phase techniques mainly use polystyrene-divinylbenzene (PS) derived solid supports. Owing to physieal and ehemical limitations of PS-derived resins, other resins have been developed (8,9). Most of these resins are prepared from PS by functionalizing the resin beads with oligomers to improve solvent compatibility and physical stability (8,9). 

One of the most developed methods used in combinatorial chemistry libraries preparation is solid-phase organic synthesis (SPOS) based on the Merrifield method for peptide synthesis [128]. A great number of such libraries have been prepared on a solid support, generally a functionalized polystyrene resin cross-linked with a small amount of divinylbenzene. Recently, it was demonstrated that micro-wave irradiation can be applied to solid-phase immobilized reagents to reduce significantly the reaction time. Those readers who are interested in such processes we would like to refer to more extensive reviews published by Chamberlin et al. [129] and Kappe [130], while in this chapter we are giving most common examples. 

Synthetic organic polymers, which are used as polymeric supports for chromatography, as catalysts, as solid-phase supports for peptide and oligonucleotide synthesis, and for diagnosis, are based mainly on polystyrene, polystyrene-divinylbenzene, polyacrylamide, polymethacrylates, and polyvinyl alcohols. A conventional suspension of polymerization is usually used to produce these organic polymeric supports, especially in large-scale industrial production. 

In the incipience of the methodical development, after some tests with different types of supports, Merrifield had already selected from the gigantic palette of organic and inorganic polymers the commercially available beaded polystyrene (200-400 mesh, 80—20 /i diameter), cross-linked by 2% divinylbenzene as the most suitable up to that time for the purposes of peptide synthesis on solid phase. Today there are series of investigations to find better supports for use in Merrifield s synthesis (for comparison, see the review articles of Merrifield [16, 35] and Meienhofer [33]). But in all cases the improved properties of novel carriers or modified polystyrenes concern only one or two of the above-mentioned necessary parameters — e.g., mechanical stability or strengthened C-terminal bond of an amino acid to the carrier — whereas nearly all the other characteristics for a suitable solid phase turn out to be less favourable, compared to the original Merrifield resin. 

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