The Solid Support

One should keep two things in mind when choosing a support (1) structure and (2) surface characteristics. Structure contributes to the efficiency of the support, whereas the surface characteristics govern the support s participation in the resulting separations. The perfect column material would be chemically inert towards all types of samples. It would have a large surface area so that liquid phase could be spread in a thin film and structure of the surface would be such that it would properly retain the liquid film. However, large surface area is not a guarantee of an efficient column. 

The most commonly used column support materials are made from diatomite. Other materials include sand. Teflon, inorganic salts, glass beads, porous layer beads, porous polymers, carbon blacks, etc. We will discuss the diatomite supports in some detail and additional information may be obtained in Chapter 3. 

The pink or brick diatomite has been crushed, blended and pressed into bricks, which are calcined (burned) at temperatures greater than 900°C. During the process the mineral impurities form complex oxides and/or silicates. 

It is the oxide of iron which is credited for the pink color. 

The elimination of adsorption sites (i.e, deactivation of surface) can be performed several ways  

A key element of solid-phase-assisted chemistry, which has been underscored by most chemists, is the support itself However, it is evident from the discussion so far that the supports used are still far from ideal in several respects and that there is considerable scope to prepare improved supports [8]. Indeed, this has become a very active interdisciplinary area of research. Many reviews have been devoted to the various supports employed in solid-phase-assisted synthesis [9, 10] together with some reviews devoted to the physical properties of resins [11]. 

With respect to the polymeric backbone, two approaches exist for the preparation of functional polymers, the polymerization or copolymerization of monomers which carry the desired functionality, and secondly the chemical modification of preformed polymers. The former concept, the polymerization of prefunctionalized monomers, was often tested in the early days of polymer-assisted syntheses, e. g. in the preparation of polymers containing pyridine [12] or quinone [13] residues, and benzaldehyde [14] or phosphine [15] functionalities. Although the latter approach demands that the synthetic organic chemist acquires profound knowledge of polymers and polymerization, this strategy can have advantages because 

The merging of the properties of cross-linked polystyrene and soluble PEG is achieved in so called tentagels. Here, the hydrophobic properties of cross-linked 

Typical examples of some catalysts which are attached to different polymeric supports discussed here are listed in Fig. 4.1. 

Along this line, sol-gel materials based on Si02find increasing use in solid-phase assisted synthesis. The sol-gel synthesis creates well ordered porous glasses which retain a rigid and exposed surface area (300-1000 m g ) [56]. Gelation occurs after a sol is cast into a mold so that the monolithic samples can be tailored to a desired size or shape [57]. 

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Section 27 18 In the Memfield method the carboxyl group of an ammo acid is anchored to a solid support and the chain extended one ammo acid at a time When all the ammo acid residues have been added the polypeptide is removed from the solid support... 

What protected ammo acid would you anchor to the solid support m the first step of a syn thesis of oxytocin (see Figure 27 8) by the Memfield method" ... 

Protect glycine as its Boc derivative and anchor this to the solid support Remove the pro tecting group and treat with Boc protected phenylalanine and DCCI Remove the Boc group with HCl then treat with HBr in tnfluoroacetic acid to cleave Phe Gly from the solid support... 

MATHEMATICAL MODELING OF THE PROCESS TAKEN PLACE IN THE SOLID SUPPORT - SOLUTION , TYPE INDICATOR PIPES... 

A recent report demonstrates that trisubstituted furans can be prepared on a solid support using the Paal-Knorr condensation. Raghavan synthesized a variety of triaryl and alkyl diary] furans, one of which is highlighted below. Dione 50 was cyclized using p-toluenesulfonic acid in refluxing toluene followed by cleavage from the solid support to yield furan 51. ... 

High-speed synthesis of thiadiazoles has been recently completed on a solid support system using a catch and release technology to provide novel thiadiazoles. The solid-supported sulfonylhydrazine reacts with ketones to provide the solid phase hydrazones (catch) and formation of the thiadiazole with subsequent release of the... 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

Combinatorial approaches have been applied to this chemistry. In a method amenable to split and pool, PAL, or Rink resin, 89 is modified with an acetoacetate to generate the solid supported aminocrotonate 90. Either a two- or three-component Hantzsch protocol is followed to produce 91. Treatment with TFA carries out the cleavage from the resin and the cyclization to dihydropyridine 92. 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

Flash chromatography is widely employed for the purification of crude products obtained by synthesis at a research laboratory scale (several grams) or isolated as extracts from natural products or fermentations. The solid support is based on silica gel, and the mobile phase is usually a mixture of a hydrocarbon, such as hexane or heptane, with an organic modifier, e.g. ethyl acetate, driven by low pressure air. (Recently the comparison of flash chromatography with countercurrent chromatography (CCC), a technique particularly adapted to preparative purposes, has been studied for the separation of nonchiral compounds [90].)... 

A chiral separation medium is a complex system. Ideally, interactions that lead to enantioseparation are maximized while nonspecific interactions should be completely suppressed. Typically, a medium for chromatographic separations involves the solid support, the selector, and the linker connecting the two, as shown in scheme 3-1. 

DNA synthesizers operate on a principle similar to that of the Merrifield solid-phase peptide synthesizer (Section 26.8). In essence, a protected nucleotide is covalently bonded to a solid support, and one nucleotide at a time is added to the growing chain by the use of a coupling reagent. After the final nucleotide has been added, all the protecting groups are removed and the synthetic DNA is cleaved from the solid support. Five steps are needed ... 

The column. The actual separation of sample components is effected in the column where the nature of the solid support, type and amount of liquid phase, method of packing, length and temperature are important factors in obtaining the desired resolution. 

The most reliable methods of the preparation of stable adsorbents involve, however, a covalent attachment of the polymeric stationary phases to the solid supporting material. In addition, the more diffuse interfaces formed in this case (see Sect. 2.2) are often favourable for the separation of proteins. 

However, the polymerization of monomers in the gaseous phase by first procedure (1) mentioned above leads to the formation of considerable amounts of homopolymers. It is caused by low molecular weight radicals H and OH , not bounded chemically with the solid support [70, 73], In this case the subsequent... 

Porous glass (PG) modified with covalently adsorbed poly(p-nitrophenyl acrylate), as described in Sect. 4.1, turned out to be a highly suitable carrier for immobilization of various biospecific ligands and enzymes. When the residual active ester groups of the carrier were blocked by ethanolamine, the immobilized ligands when bound to the solid support via hydrophilic and flexible poly(2-hydroxyethyl acrylamide). The effective biospecific binding provided by the ligands... 

The described bioaffinity separations demonstrate that polyacrylamide spacers aid the selective binding of highly complex and delicate biomacromolecules and their associates. Moreover, these solutes remain biologically active after desorption probably due to the high inertness and flexibility of the surrounding polymer chains fixed on the solid support. The unbound parts of serum usually show no loss of the activities of their constituents. Thus we evaluate the surface of inorganic supports coated with chemisorbed iV-hydroxyethyl polyacrylamide and its derivatives as being biocompatible. 

The cells activities have been described based on a multi-species biofilm model, and the microbial kinetics by a mathematical model. Using this model predicts that the biomass on the external surface of the biofilm has higher activity than the biomass near the solid support surface, and that condition may occur, after the biofilm has reached a critical dept or formed... 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

In place of N-methylimidazole (Melm), only dimethylaminopyridine (DMAP) could be substituted. The solid-supported amines piperidinomethyl- or morpholinomethyl polystyrene resins, pyridine, and tertiary amines like triethylamine andN-methylmorpholine were not effective. 

To generate molecular libraries, a series of 5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs were prepared via a stereospecific Diels-Alder reaction by reacting Wang-resin-bound diene 35 with a variety of dienophiles [28]. After removing the solid support with a strong acid, adducts 36 were isolated examples of reactions that have furnished the best yields are reported in Scheme 4.6. 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

Benzofurans have been prepared by microwave-accelerated cyclocondensation of differently substituted salicylaldehydes 182 with esters of chloroacetic acid 183 in the presence of K2CO3 (used as the solid support) and tetrabutyl-ammonium bromide (TBAB) as phase transfer catalyst [120]. This method seemed general regarding the variations at the benzene ring and the nature of the ester moiety (Scheme 66). 

A very detailed comparison for every single step of the whole sequence (linking of a pyrazinone to the solid support, Diels-Alder reaction with acetylenic dienophile and cleavage of a formed pyridinone from the resin) was made between microwave irradiation and conventional heating conditions [115]. 

To perform the cycloaddition on solid-phase, N-l-unprotected pyrazi-nones were coupled with the solid support by treatment of the brominated linker in DMF for 6h at ambient temperature, using CS2CO3 as a base (Scheme 43). The reaction time for complete loading could be dramatically shortened to only 5 min under microwave irradiation at a pre-selected maximum temperature of 70 °C. 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

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