Polymer-supported chemical Solid-phase synthesis

Structural analysis of linear polymers molecularly dissolved in a suitable solvent using and solution phase NMR spectroscopy is long established [87-89]. Not surprisingly therefore when a linear soluble polymer is used as a support in solid phase synthesis and solution phase NMR spectroscopy can be a powerful tool in following the chemical synthesis on the support [90]. Figure 15.3.58, for example, shows a series of H NMR spectra of dissolved linear polymer samples taken at various stages in the solid phase synthesis of oligoethers on soluble polystyrene [91]. The various chemical steps Fig. 15.3.59 are clearly demonstrated. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

High selectivity and substrate specificity of glycosyl transferases make them valuable catalysts for special linkages in polymer-supported synthesis. There is, however, still a rather limited set of enzymes available to date, and the need to synthesize a variety of natural and non-natural oligosaccharides prevails. Particularly with regard to combinatorial approaches, chemical solid-phase oligosaccharide synthesis promises to meet the demands most effectively. 

Subsequently, solid-phase strategies were developed for the synthesis of oligonucleotides, as well as for nonbiopolymer small molecules, such as synthetic drugs and natural products. In a solid-phase synthesis, the starting material (e.g., first residue or molecular scaffold) is attached to an insoluble solid support, such as a polymer or glass bead, via a chemical linker that can be cleaved under specific, orthogonal reaction conditions... 

Nevertheless, the primary tool used in solution-phase synthesis for structural elucidation is NMR spectroscopy. There has been some interest in developing NMR methods for analyzing resin-bound compounds and monitoring the progress of chemical reactions on solid-phase by on-bead analysis (without cleavage of the product from the resin). Many improvements have been achieved in NMR for SPS, but hmitations remain. On the one hand, the limited mobility of polymers, as well as the poor mobility of attached compounds, leads to broad bands with low spectral resolution. On the other hand, the broad signals due to the polymer matrix can mask or overlay with bands from the desired product. The main advantage of this technique is its nondestructive nature, as the sample can be easUy recovered. The next section will focus on the most powerful technique developed to monitor and characterize polymer-supported compounds gel-phase HR-MAS NMR spectroscopy. 

This bead-based procedure is a derivative of the solid-phase chemistry that has proven its merits in automated peptide synthesis [74], combinatorial chemistry [75] and also small-molecule synthesis [76]. The basic principle behind solid-phase synthesis is the attachment of a substrate to a polymer bead by a covalent linker and subsequently performing a chemical reaction on the substrate. Because the substrate is tightly bound to the polymer, excess reagents and by-products can simply be washed away, after which further chemical elaboration of the product may be performed. Finally, the dean product is deaved from the polymeric support, which usually can be regenerated for re-use. 

Although an enantioselective reaction carried out on solid phase, in principle, also includes the reactions wherein a chiral catalyst or a chiral auxiliary is polymer bound, in this chapter we have mainly focused on reactions wherein a substrate is bound to a solid support and the chemical transformation is carried out by chiral reagents. However, we have included few examples of employing solid-supported catalyst and auxiliaries to give readers an idea of these alternative synthesis strategies. Readers are, however, advised to refer to Refs 6 and 7 for a review on the applications of immobilized chiral catalysts and solid-phase-bound chiral auxiliaries, respectively, and Refs 1,5, and 8 for diverse solid-phase synthesis approaches directed toward small molecules and natural products. ... 

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