Combinatorial Merrifield resins

Preparation of Merrifield resin-bound nitro acetates, which is a suitable building block for the development of combinatorial solid phase synthesis, is reported.4 The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylammonium bromide as an electrolyte. Alkylaton of this anion with alkyl halides gives mono-alkylated products in 80% yield.5... 

A Stille coupling of a bromopyridine on solid support was described by Snieckus group [101]. Merrifield resin 119 was esterified with 3-bromopyridine-5-carboxylic acid to afford ester 120. The Stille coupling of ester 120 on a solid support led to the expected hetero phenylpyridine 121, which was then cleaved via basic hydrolysis to produce 122. Snieckus work has the potential for application to combinatorial chemistry and high throughput screening. 

One of the most used resins in solid-phase combinatorial organic synthesis, which has found a myriad of applications, is the Merrifield resin (17).61 This resin is also the building block for a tremendous amount of novel resins being developed in combinatorial chemistry with applications in both solid-phase as well as solid-phase-assisted solution-phase combinatorial chemistry. A recent, useful, and novel example is the report of its being employed as a triphenylphosphine scavenging resin.76 During the conversion of azidomethylbenzene (51) into benzylamine, excess triphenyl-phosphine is allowed to react with Merrifield resin (17) in the presence of sodium iodide in acetone. A phosphonium-substituted resin (52) is thus formed. Upon simple filtration, pure benzylamine is isolated as shown in Fig. 22. 

This linker was originally developed by Leznoff and colleagues [77, 78]. Its preparation is outlined in Scheme 31. Commercial Merrifield resin was functionalized with the sodium alkoxide of isopropylideneglycerol. Hydrolysis of the acetonide yielded the desired entity 70, to which an aldehyde was coupled as starting material for a combinatorial synthesis. The final product bearing an aldehyde function was released by mild acid treatment. The linker was successfully applied in Suzuki-... 

Catalyst libraries for combinatorial screening of diimine-based nickel and palladium catalysts can be developed by attaching a diketone to a Merrifield resin, reacting with a variety of anilines in the presence of a dehydrating catalyst, and complexing with the metal (Scheme 25). After each variant is activated with MAO or borate salt, the 96-well microtiter plate is exposed to ethylene and polymerization activity is qualitatively determined by infrared imaging. 

The same authors demonstrated a solid-phase combinatorial synthesis of a muscone library starting from the monomethyl methanephosphonate 96 bovmd to the Merrifield resin. The key steps were the synthesis of the /1-ketophospho-nates 97, introduction of the aldehyde group, which was necessary for the cyclorelease, and final reduction of double bonds in 98 to the modified mus-cones 99 (Scheme 27). 

One-shot crosslinking of multifunctional monomers and copolymerization therefore is limited to the radical induced copolymerization of styrene and some derivatives with divinylbenzene or of methacrylates with ethyleneglycol dimethacrylate as crosslinker in suspension polymerization to form densely crosslinked polymer beads for applications such as ion exchange resins, Merrifield resins, polymer supports for chemical reagents especially with the aspect of combinatorial syntheses. 

An alternative to Merrifield resins, that is, the synthesis of ROMP spheres for use in combinatorial chemistry, was reported hy Barrett et Here, surface functionalization... 

However, as already mentioned above, the great majority of OPEs were prepared by Sonogashira-Hagihara reactions. Several useful modifications appeared in the literature, for example the application of phase transfer conditions [151], which suppress the Hay coupling. In order to obtain libraries of compounds, combinatorial protocols have been developed, where the CC coupling occurs in solution or on a solid support (modified Merrifield resin) [152, 153]. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Most important of all, however, is the possibility of running the Merrifield procedure on any number of resin beads (or other support systems) simultaneously in a number of reaction chambers. An example of this alternative is the so-called split and mix system of combinatorial chemistry. The first step in this kind of system is to prepare some number of monomer-support units (three in the example shown below), in which the monomer present differs from chamber to chamber. In the diagram below, the units are represented as -X, -Y, and -Z. These three units are washed and then mixed with each other in a single container. The mixture is then divided and placed into three separate containers. One of the most common containers used contains a number of wells in a plastic or glass dish that are miniature versions of the common petri dish used in biology experiments. 

Nucleoside chemistry is traditionally labor intensive and the output of compoxmds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the piupose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine diehloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two ehloro atoms by various amines. The purine heterocyclic bases were then condensed with Dd.-ribofuranosides following a classical Vorbruggen method to yield nucleosides of general formula 171. 

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. 

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). 

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