PEG-based resins

Figure 14.5 The chemical structure of TentaGel and PEG-based resins. The open structure and the inert nature of PEG in biological systems confer ideal properties for bioassays to the PEG-based resins.24...

For the solid-phase synthesis of glycopeptides, both polystyrene and PEG-based resins have been successfully used. Experiments that compare the rates of reactions on various resins have revealed that the rate of reaction completely depends on the nature of the reaction itself 45 Some reactions perform better on hydrophobic resins, while others are better on hydrophilic resins. 

As of this writing, there are presently only two examples of successful synthesis of glycopeptide libraries in the literature, and these have been generated using PEG-based resins (PEGA and POEPOP), thus enabling rapid solid phase screening of the library (see Sections 14.8 and 14.7.2). 

M. Gr0tH, . H. Gotfredsen, J. Rademann, J. Buchardt, A. J. Clark, J. O. Duus and M. Meldal, Physical properties of polyethylene glycol) (PEG)-based resins for combinatorial solid phase organic chemistry A comparison of PEG-cross-linked and PEG-grafted resins, J. Comb. Chem., 2000, 2, 108 119. 

Grotli M, Grotfredsen CH, Radermann J, Buchardt J, Clark AJ, Duus J, Meldav M, Physical properties of polyethylene glycol) (PEG)-based resins for... 

The two epoxide enantiomers (i-) and (-) 7.71 were selected as chemical starting points for library generation Their synthesis from shikimic acid with reasonable overall yields was already known (248, 249), and they had a carboxylic acid handle for SPS. The other key intermediates were the three benzylnitrone carboxylic acids 7.72a-c, which were prepared from the corresponding benzyl alcohols (250,251) (Fig. 7.40). The two epoxycyclohexenols were supported onto a PEG-based resin, loaded with a photolabile linker, to give resin-bound 7.73a,b (from now on only one enantiomer will be shown in the figures, but the synthetic pathway was continued with both... 

Cross-linked polyamide (PA)-based resins and composite PS-polyethylene glycol (PEG)-based resins are much more hydrophilic supports exhibiting physical properties different from PS resins at microscopic and macroscopic levels (7). These supports, often with a lower loading capacity, may represent an alternative to standard cross-linked PS resins for the synthesis of difficult sequences and large peptides. 

Schleyer, A, Meldal, M, Manat, R, Paulsen, H, Bock, K, Direct sohd-phase glycosylations of peptide templates on a novel PEG-based resin, Angew. Chem. Int. Ed., 36, 1976-1978, 1997. 

Figure 8.5. The chemical structure of TentaGel and PEG-based resins.

The compatibility of all these PEG-based resins with aqueous buffers allows their use for biochemical applications such as on-resin screening of chemical libraries and in the development of affinity chromatography [58-61]. All these families of PEG-based resins, except POEPS, are free of aromatic rings. This feature makes these solid supports highly suitable for a broad range of applications where such rings can react with reagents or/and jeopardize the solid-phase NMR control of the reactions [62]. 

In conclusion, the concept of solid-supported chemistry has been extended from the preparation of peptides and other biomolecules to any organic molecule. PS-and PEG-based resins are the most widely used however, syntheses can be carried out in any solid support. The development of new solid supports and linkers/ handles is crucial to fulfill the new requirements of modem drag discovery programs. 

A range of PEG-based resins are available, including PEGA [24], POEPOP [25] and POEPS [26,27], that do not stand up to the harsh conditions employed during Friedel-Crafts reactions or acetolysis. To circumvent these drawbacks, the SPOCC that contains only primary ether bonds, secondary and quartemary carbon atoms was introduced. The synthesis of SPOCC resin is summarized in Scheme 20.3 [27]. 

Since the invention of SPPS, divinylbenzene-cross-linked polystyrene has been the predominant solid support used. There have been several alternatives developed along the way, with the most important advancement being the introduction of PEG, including PEG-grafted polystyrene resin [39, 40] and all-PEG-based resin (ChemMatrix) [41, 42]. PEG-based resins can produce crude products with better quality than the polystyrene resins, particularly in the case of difficult sequences [43]. This superiority is explained by the H-bond acceptor function of PEG which interrupts peptide inter-chain H-lxMiding, effectively inhibiting peptide chain aggregation [44],... 

The amount of cleavage cocktail used depends on the amount of resin and its ability to swell. The cleavage solution should cover the resin—approximately 5 mL per 0.5 g of resin— less for polystyrene (PS)-based resins and more for polyethylene glycol (PEG)-based resins. The reaction time is typically 2-4 h. Too long reaction times can cause side reactions, and too short... 

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