Combinatorial solid phase

Preparation of Memfield resin-bound nitro acetates, which is a suitable bndding block for the development of combinatorial solid phase synthesis, is repotted. The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylairunonium bromide as an electrolyte. Alkylaton of this anion with alkyl hahdes gives mono-alkylated products in 80% yield." ... 

Jung N, Wiehn M, Brase S (2007) Multifunctional Linkers for Combinatorial Solid Phase Synthesis. 278 1-88... 

McGhee AM, Procter DJ (2006) Radical Chemistry on Solid Support. 264 93-134 Mentel M, Breinbauer R (2007) Combinatorial Solid-Phase Natural Product Chemistry. 278 209-241... 

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

V. Wittmann and S. Seeberger, Combinatorial solid-phase synthesis of multivalent cyclic neoglycopeptides, Angew. Chem. Int. Ed., 39 (2000) 4348 -352. 

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

Here, we present an overview of the aspects of the design, synthesis, analysis, and screening of combinatorial solid-phase glycopeptide libraries as compared to parallel glycopeptide arrays. 

COMBINATION OF THE SCREENING APPROACH WITH COMBINATORIAL SOLID PHASE SYNTHESIS OF CATIONIC LIPIDS... 

In this section, an example will be given in which a (small) library of a new type of cationic lipids was synthesized and screened for TE (63). For synthesis, combinatorial solid phase chemistry was used. All cationic lipids of the example library are structurally based on 3-methylamino-1,2-dihydroxy-propane as the polar, cationic lipid part. As nonpolar lipid part, different hydrocarbon chains are boimd to the amino group of the scaffold and the amino group was further methylated to get constantly cationic-charged lipids. Lipids were synthesized in both configurations and as racemats, and the counterions were varied as well. Table 1 summarizes the structural features of these lipids. 

Figure 5 Combinatorial solid phase synthesis of A, Af-dialkyl-Af-methyl-amino-2, 3-propandiol with alkyl groups of different length.

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

The need for enhanced detection sensitivity and automation has steadily increased for the separation and analysis of peptides from natural sources or proteolytic digestion of low abundance proteins this is also partly a consequence of the greater usage of combinatorial solid-phase synthetic approaches. Narrow bore (1-2 mm i.d.), microbore (0.5-1.0 mm i.d.), and capillary (100-500 pm i.d.) columns have provided attractive solutions to these problems. 1221 An important attribute of very small particle diameter micropellicular, porous, or nonporous RPC sorbents is that they are ideally suited to such microbore or capillary... 

H. Gotfredsen, M. Grotli, M. Willert, M. Meldal and J. O. Duus, Single-bead structure elucidation. Requirements for analysis of combinatorial solid-phase libraries by Nanoprobe MAS-NMR spectroscopy, J. Chem. Soc. Perkin, 2000, 1, 1167-1171. 

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. 

Nielsen, J. Lynso, L. O. Combinatorial Solid-Phase Synthesis of Balanol Analogues, Tetrahedron Lett. 1996, 37, 8439. 

Combinatorial Solid-Phase Oligosaccharide Synthesis (CSPOS)... 

An efficient combinatorial solid-phase synthesis of asymmetric cyanine dyes was developed by Isacsson and Westman [17] using a Rink amide polystyrene resin. The picolinium and lepidinium salts 6 were linked to the solid-phase resin by amide coupling, then the benzothiazole derivatives 7 were subsequently condensed with the coupled picoline and lepidine moieties to give the yellow to blue (Amax ahs = 420-590 nm) asymmetric, fluorescent (Amax em = 480-650 nm) cyanine dyes 8 (Scheme 5.2, Fig. 5.3). As a consequence of restricted rotation upon intercalation, the fluorescence quantum yields increase significantly when these dyes are bound to DNA. 

Bunin BA. The combinatorial index. In Combinatorial Solid-Phase Synthesis. 1998. Academic Press, pp. 77-82. 

Based on a library-directed approach, Takahashi and co-workers developed a synthetic strategy for the combinatorial solid-phase synthesis of tree-type carbohydrate clusters using three types... 

Combinatorial solid-phase synthesis of tree-type carbohydrate clusters... 

Diaz-Garcia, M. E. Pina-Luis, G. Rivero, I., Combinatorial solid-phase organic synthesis for developing materials with molecular recognition properties, Trends Anal. Chem. 2006, 25, 112-121... 

Mentel, M., Breinbauer, R. Combinatorial solid phase natural product chemistry. Top. Curr. Chem. 2007, 278, 209-241. 

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