Solid-phase approaches

The example clearly demonstrates the main advantages of solution chemistry over the solid-phase approach ... 

Solid-phase chemistry is an efficient synthetic tool that, compared with solution-phase chemistry, simplifies the work-up of the reaction, allows the process to be driven to completion by using excess of reagents, and can be automatized [2a]. In recent years, many studies have been devoted to developing both surface-mediated and resin-supported synthesis. Today the solid-phase approach is not limited to peptides and oligonucleotides but is also used to synthesize molecules of lower molecular weight. 

Merriman and colleagues have reported the cydization of N-acyl-l,2-diaryl-l,2-ethanediamine derivatives, obtained by way of a solid-phase approach, to 4,5-diaryl-imidazolines by treatment with trimethylsilyl polyphosphate (TMS-PP) in dichloro-methane solution (Scheme 6.204) [367]. The best results were obtained by micro-... 

For this solid-phase approach, conventional iPrOCH2-functionalized polystyrene resin (Merrifield linker) was employed. After attachment of the requisite substrate, the resin was pre-swollen in a solution of barium(II) hydroxide in N,N-dimethyl-formamide within an appropriate sealed microwave vial. The vial was heated in the microwave cavity for 5 x 2 min cycles (overall 10 min) with the reaction mixture being allowed to cool to room temperature in between irradiation cycles (Scheme 7.50), leading to comparatively modest isolated yields of hydantoins. 

A successful solid-phase approach to libraries of asymmetrically disubstituted furazano[3,4-7 ]pyrazines 244 has been developed. By using these solid-phase synthetic protocols, 320 fused heterocyclic derivatives were synthesized (Scheme 63) <2002TL4741>. 

Abstract Described are the synthetic routes to precisely defined molecular wires which are of discrete length and constitution. They are fully conjugated systems and are expected to have nearly linear current-voltage response curves. Their ends are functionalized with molecular alligator clips, based on chalconides and isonitriles, for adhesion between proximal probes. Both solution and solid-phase approaches have been used to prepare these molecular wires that are based on oligofthiophene ethynylene)s and oligofphe-nylene ethynylene)s. Molecular device syntheses are also described that would be expected to have nonlinear current-voltage responses. 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

In 1983, Prasad et al.12 first reported the condensation of chloromethyl polystyrene with /V-hydroxyphthalimide to give the ester, hydrazinolysis of which yielded the desired resin-bound hydroxylamine. However, the sole purpose of this reagent was to react with, and hence extract ketones from, a complex steroidal mixture, and its use for the solid-phase synthesis of hydroxamic acids was not explored. Recently, the exploitation of the above solid-phase approach for the synthesis of hydroxamic acids was independently reported by three groups,7-9 all of which differ only in the method for the initial anchoring of TV-hydroxyphtha-limide to an 4-alkoxybenzyl alcohol functionalized polystyrene or trityl chloride polystyrene. Subsequent /V-deprotection was... 

Scheme 1.1 Early solid-phase approaches to a-(l —>6)-linked oligosaccharides.

One alternative would be to use isotopically labeled intermediates to trace incorporation of groups in to the catalyst. In spite of the drawbacks I feel that the solid-phase approach will be used successfully in the synthesis of catalysts with enzyme-like properties. 

The solution phase synthesis of peptides often results in mixtures of labelled, unlabelled compounds along with other impurities and requires extensive purification. A route using a solid phase approach [polyethylene glycol-poly-styrene PEG-PS derivatised with a xanthen-2-oxovalerate (XAL) linker] was recently developed [193] (Scheme 44). 

The rationale behind the synthesis of phosphohomoserine-containing peptides [Hse(P)] is that this phosphorylated residue is inert to base-mediated (3-elimination and thereby may provide an interesting surrogate for the study of Ser(P)-based processes. In initial work, Boc-Hse[PO(OPh)2]-OH[21l was prepared by a simple four-step procedure but was found to be unsuitable for use in Boc-based solution synthesis due to extensive amine-mediated intramolecular dephosphorylation of the Hse[PO(OPh)2] residue during mixed anhydride coupling of its N-terminus. This side reaction was subsequently minimized through the use of Fmoc-Hse[PO(OPh)2]-OH in a Fmoc-based solid-phase approach in which the use of a large... 

With the advent of HPLC, a new tool was born that revolutionized peptide/protein chemistry as a whole as it allowed not only purification of biologically active peptides and proteins from complex mixtures of tissue or plant extracts/231 but also allowed purification of synthetic unprotected peptide mixtures analytically and preparatively.124-261 This was particularly significant in that purity could be assessed of peptide intermediates made by the classical solution-phase methodology that promoted characterization of all intermediates, as well as the purity of final products made by the solid-phase approach of MerrifieldJ27 ... 

A logical extension of the synthetic strategy underlying our solid-phase approach toward 1,5-benzothiazepinones was to replace the [3-mercapto acids (cysteine, penicillamine) by a-mercapto acids, such as mercaptoacetic acid 54a or thiolactic acid 54b. This change would facilitate access to the corresponding [6,6]-fused systems, i, e. 1,4-benzothiazin-3-ones 57. As with the benzothiazepines, no solid-phase synthesis of benzothiazines has been reported to date. 

Several comparisons can be made between the solution- and solid-phase approaches. Yields of oligomers formed on the solid phase fluctuate more than solution methods, though both are similar. Solution yield calculations were compiled from isolated yields for each of the three transformations,... 

Takahashi, T. Ebata, S. Doi,T. Solid Phase Approach to Muscone Synthesis Rh(I)-Catalysed Hydroformylation of a 1,1-Disubstituted Alkene on the Multipin1 System, Tetrahedron Lett. 1998, 39, 1369. 

A Multiple Solid-Phase Approach to /V-Alkylhydroxamic Acids, J. Chem. Soc. Chem. Commun. 1997, 2005. 

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