Application in Solid-phase Synthesis

One of the most exciting applications of this copper-mediated reaction is in solid-phase synthesis and combinatorial chemistry. Two approaches have been reported solid-supported catalyst and resin-supported substrates. 

Combs and co-workers have pioneered the effort in the use of resin-supported substrates, reporting many examples of efficient cross-coupling of solid-supported sulfonamides [28c], primary and secondary aliphatic amines [28d], as well as het-eroarenes such as benzimidazoles, imidazoles, pyrazoles, and benzotriazoles [28e]. 

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The ready alkylation of heterocyclic thiols lends this link to applications in solid-phase synthesis. Although much more work has been done in other heterocyclic systems, a prototype solid-phase synthesis has been described in which the pteridine is built from a 2- or 4-alkylthiopyrimidine attached to a cross-linked polystyrene support <20030BG1909, 2003TL1267> Oxidative cleavage was preferred using DMDO to avoid unwanted by-products... 

Trichloroacetimidates are the only type of imino ethers to have found some application in solid-phase synthesis. Trichloroacetimidates can readily be prepared from support-bound alcohols by treatment with trichloroacetonitrile and a base (Entry 6, Table 13.18). Because trichloroacetimidates are good alkylating agents, this reaction offers a convenient alternative for converting support-bound aliphatic alcohols into alkylating agents. Trichloroacetimidates prepared from Wang resin or from hydroxymethyl polystyrene are quite stable and can be stored for several months without decomposition [253],... 

The single-electron-transfer reagent samariiun(II) iodide (SmH) has been used extensively to intitiate radical reactions in solution and has now begun to find application in solid-phase synthesis. 

Diaryl ketones are important scaffolds in biologically active compoimds, and although several synthetic pathways are available in solution, their application in solid phase synthesis is rare. Yun et aL [85] have developed a high-throughput synthesis of diaryl ketones via a Stille carbonylation on solid phase. Immobilized arylstannanes 39 were subjected to Stille coupling with aryl halides in presence of carbon monoxide (Scheme 23). Not only did the reaction afford products of high yield and purity, but it was also tolerant towards most functional groups. 

Over the past number of years, solid-phase synthesis has become a synthetic mainstay as it avoids the tedious and costly parallel purification processes of the solution-phase products. Impurities can be removed just by washing with appropriate solvents and desired final products can be obtained by cleaving the resin link in high purity. Thus, MCRs as well as IMCRs involving CICs have found their application in solid-phase synthesis. 

Kupihar Z, Varadi G, Monostori E, Toth GK (2000) Preparation of an asymmetrically protected phosphoramidite and its application in solid-phase synthesis of phosphopeptides. Tetrahedron Lett 41 4457-4461... 

Representative examples of the recent applications of controlled microwave heating in solid-phase synthesis of heterocychc compounds are summarized. The preparation of monocyclic compoimds is presented hrst, followed by a description of the synthesis of polycyclic structures. 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Scheme 5.10 Application of NPGs in solid-phase synthesis (a) immobilization of the glycosyl donor (b) immobilization of the glycosyl acceptor.66...

Infrared and Raman spectroscopy are nondestructive, quick and convenient techniques for monitoring the course of solid-phase reactions, and have therefore been widely used for the characterization of polymer supports and supported species [156-160]. In fact, the application of infrared spectroscopy in solid-phase synthesis has received much attention and has been the subject of several recent reviews [127, 128, 161-164]. Reactions involving either the appearance or disappearance of an IR-active functional group can be easily monitored using any of the IR techniques described in this section. Some beads are typically removed from the reaction mixture, then they are quickly washed and dried prior to IR analysis. Traditionally, polymer supports are diluted and ground with KBr, then conventional FT-IR analysis of the KBr disk is carried out Although this is a commonly used... 

There are many examples that demonstrate the useful application of ester and amide moieties in solid-phase synthesis. They can be used in the benzyl and allyl... 

The sulfonimidoyl group acts in the asymmetric synthesis of the unsaturated oxiranes shown in Schemes 1.3.20 and 1.3.21 as both a chiral auxiliary and a nucleofuge. These results suggested the application of the sulfonimidoyl group as a chiral linker in solid-phase synthesis. 

The first applications of solid phase synthesis were to peptides, hence it is no surprise that there have been several reports of HRMAS studies of peptide systems attached to a support. One of the earliest reports of HRMAS in a supported sample was that of Wang-bound lysine, whose structure was determined by TOCSY and HMQC HRMAS NMR.38 More recently, HRMAS NMR has been used to identify several peptidomimetic inhibitors of hepatitis C virus NS3 protease while on the resin.79 However, it is perhaps a bit surprising that more has not been made of HRMAS in attacking problems of relevance to peptide synthesis, although most recent interest is moving that way. Combinatorial chemistry and solid phase organic chemistry has been a much more active area using HRMAS techniques. 

M. J. T. Ditty, H. N. Hunter, R. M. E. Mainville and W. P. Power, NMR applications for solid-phase synthesis Part I. suppression of residual polymer signals in ID H NMR spectroscopy of polymer-supported species, Magn. Reson. Chem., 2001, 39, 241-248. 

Scheme 45 Application of Mitsunobu reaction in solid phase synthesis of [1-lactam...

Thus, gel-type polystyrene-sulfonyl-hydrazide resin 20, which originally was developed for carbonyl scavenging applications [30] can also serve as a linker for carbonyl compounds in solid phase synthesis and gives access to support-bound sulfonyl hydrazones 21 (Scheme 8)... 

An application of a diazete has been disclosed in a patent application <1995WO9501347>, as a novel cross-linking agent. Water-soluble cross-linking agents have various applications in separation techniques, that is, chromatography, electrophoresis (separation technique used for peptides and proteins), etc. These water-soluble cross-linking polymers are stable, inert, and are used in solid-phase synthesis of peptides. 

In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or V-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in. 

The application of ultrasound in solid-phase synthesis has been shown to be useful in several cases such as carboxylic acid attachment to Merrifield resin,condensation... 

Stewart, J. M. and Klis, W. A. (1990) Peptides, polypeptides and oligonucleotides. Macro-organic reagents and catalysts and biomedical applications, in Innovation and Perspectives in Solid Phase Synthesis and Related Technologies (Epton, R., ed.), Mayflower Worldwide Ltd, Birmingham, UK, pp. 1-9. 

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