Solid-Phase Synthesis Combinatorial Methodology

A traceless solid-phase synthetic strategy has been developed. For example, a solid-phase Suzuki coupling of the Reissert intermediate 30 to 31 has been reported. The process consists of three steps (a) Solid-phase Reissert formation by the reaction of polymer-supported benzoic acid chloride resin with an isoquinoline, followed by reaction with TMSCN to afford the aryl bromide of Reissert 30, (b) Suzuki coupling of the solid-phase Reissert 30 with phenylboronic acid to provide the coupling product, and (c) subsequent treatment of the coupling product with aqueous KOH to produce 31 (86 % overall yield based on the starting bromide) (Eq. (62)) [99]. 

A 9-phenylfluoren-9-yl polystyrene-based resin has been described for the attachment of nitrogen and oxygen nucleophiles. Greater acid stability compared to the standard trityl resins that are widely used in solid-phase peptide synthesis make this solid support an interesting alternative in solid-phase organic synthesis. This resin can be used in Suzuki coupling reactions to furnish biaryls in good yields [100]. 

The scope and limitations of Pd(0)-mediated coupling reactions between aromatic halides linked to a polystyrene resin and boronic acid derivatives (Suzuki coupling) or arylstannanes (Stille coupling) have been reported. For all the reactions, the conditions were optimized and evaluated with various reagents. In most cases, products were obtained in excellent yields upon cleavage from the solid support (Eq. (63)) [101]. 

It is worthwhile pointing out that coupling results with electron-rich aryltin derivatives (Eq. (65)) were far inferior to those obtained with the corresponding boronic acids (Eq. (64)) [102], 

In combinatorial chemistry, the reaction times and reaction temperatures required are frequently crucial factors. Microwave irradiation is used to enhance reaction rates [105]. Larhed et al. recently reported that microwave-assisted, palladium-catalyzed coupling of aryl and heteroaryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored to Tenta-Gel S RAM, provides coupling products in excellent yields after a reaction time of just 3.8 minutes (45 W) [106]. The preparative results are summarized in Table 4. 

Solid-phase reactions play an important role in parallel synthesis and combinatorial chemistry, particularly in the area of medicinal chemistry, where their potential has emerged as a result of the possibility of automation. Considerable attention has been focused on adapting and exploiting the advantages of solid-phase synthesis (SPS) to produce libraries of such organic compounds. In this context, transition metal-pro- 

Human EP3 prostanoid receptors can be obtained by Suzuki coupling reaction of a solid-supported benzyl bromide using various boronic acids (Equation 73) [99], Yields obtained for the reaction were in the range of 24-95% of isolated arylmethyl cinnamic acid 42 after cleavage from the Wang resin. 

Suzuki couplings of aryl halides (eight varieties) and aryl- or vinylboronic adds (12 varieties) have been reported in water in the presence of a palladitmi complex of an amphiphilic polystyrene-poly(ethylene glycol) copolymer resin-supported N-an-chored 2-aza-l,3-bis(diphenylphosphino)propane ligand and potassium carbonate to give uniform and quantitative yields of the corresponding biaryls products (96 combinations) (Equation 75) [104]. 

Solid-phase syntheses of 1,2,4-trisubstituted urazole and thiourazole derivatives have been accomplished. Suzuki coupling of the immobilized reactant gives the expected coupling product. Subsequent heating of the resin in the presence of triethy- 

The usefulness of the diethanolamine polystyrene resin (DEAMPS) developed by Hall and co-workers [106] has been demonstrated in an example of resin-to-resin Suzuki coupling [107]. 

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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). 

Continuing with the approach of this chapter from previous years metal-mediated reactions, cycloadditions, radical processes and asymmetric applications will be highlighted. Syntheses using traditional approaches will not be covered, unless improvements are reported. Due to the volume of publications concerning pyridines and associated heterocycles many subject areas could not be covered. Combinatorial or solid-phase synthesis will not represented since the area is rather specialized and many of the processes utilize existing methodology. The synthesis and reactions of polyaza-fused systems of the pyridine class will also not be included in this review. 

The synthesis of the tetrasaccharide 17 proved to be a high yielding and facile synthesis. Analyses of cleavage solutions indicate that the on resin chemistry proceeds extremely clean. Accumulation of alternative anomers appears to account for the majority of reaction by-products. Similarly, the results for the solid-phase synthesis of 4 compare very favorably with those achieved via comparable solution-phase synthesis.17 Overall, 50 mg of the free trisaccharide 4 was prepared. While this system demonstrates a certain level of versatility, there are several criteria to be met to achieve fully generalized combinatorial methodology based on... 

Recent literature contains a multitude of examples of synthetic organic methodologies which have been optimized and applied to the solid-phase synthesis of combinatorial libraries [2]. In fact, the production of a number of these libraries has been realized on such systems as the Multipin SPOC [8], the DIVERSOMER [9] and the OntoBLOCK [10], All three apparatuses allow the automated production of spatially dispersed combinatorial libraries and facilitate the isolation, identification, screening and archiving of single compounds in distinct physical locations which are crucial factors during lead discovery and optimization. 

Recently, Fmoc-N-protected (3-amino acid synthons have been prepared and used for the synthesis of (3-peptides on solid phase [103]. This methodology facilitates enormously the search for new bioactive compounds, above all through the generation of combinatorial (3-peptide libraries. In this context, (3-amino acids have been used as building blocks for RGD cyclic peptides and for the synthesis of an inhibitor of human cathepsin L, previously identified by screening and deconvolution of pentapeptide amide collections [104,105]. 

The continuing development of solid-phase synthesis and combinatorial chemistry has led to solid-phase oxazole syntheses with a minimum of purification. Iso and co-workers generated ot-(trimethylsilyl)diazoketones on a Wang resin and employed rhodium-catalyzed diazo transfer methodology to prepare oxazoles (Scheme 1.47). Reaction of the resin-bound benzoyl chloride 169 with (trimethyl-silyl)diazomethane gave the corresponding a-(trimethylsilyl)diazoketone 170 in excellent yield. Treatment of 170 with an aryl nitrile in the presence of catalytic Rh2(OAc)4 then furnished a resin-bound 2,5-diaryl-4-(trimethylsilyl)oxazole 171. 

The use of soluble supports to generate combinatorial libraries has been reported in the literature, but complete automation for both synthesis and analysis must be effected to probe such methodology as a viable alternative to solid-phase synthesis protocols. The discussed results indicate that poly(ethylene glycol) samples could be handled under certain operation conditions as standard chemicals and subjected to high-throughput combinatorial analytical process. 

In searching for a possible lead for a drug, the idea is then to test libraries of peptides for potential activity, and here advances in biochemical screening technology play as important a role as the solid phase synthesis in making the whole combinatorial approach possible. Methodologies... 

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