Solution-Phase Combinatorial Chemistry

Most ordinary synthetic chemistry takes place in. solution. When a reaction must be modified to accommodate a solid support, it takes time and resources to develop and optimize the reaction conditions. Indeed, a combinatorial chemist may spend months designing a. solid-phu.se reaction and gathering (he necessary materials but then conduct (he entire synthesis in a mutter of hours or days Many reactions cannot ever be run on solid supports because of poor yields or failed reactions. For the.se reasons, (here has b n much intere.st in using solution-phase chemistry for the preparation of combinatorial libraries. Unlike one-bead one-compound synthesis 

An approach that is intermediate between solid-phase chemistry and solution-phase chemistry is to use soluble polymers as a support for the product. PEG is a common vehicle in many pharmaceutical preparations. Depending on (he degree of polymerization. PEG can be liquid or. solid at room temperature and show varying degrees of solubility in aqueous and organic solvents. Each molecule of PEG has an OH group at either end  

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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. 

The use of supported reagents has always been recognized as a powerful tool in classical organic chemistry for a large number of applications, and excellent reviews covered this topic in the past [103-105]. Recently, this technique has been applied to solution-phase combinatorial chemistry, where it looks really promising in terms of simpler work-up procedures, elimination of excess reagents, and isolation of pure reaction products. 

Bailey N, Cooper AWJ, Deal MJ, Dean AW, Gore AL, Hawes MC, Judd DB, Merritt AT, Storer R, Travers S, Watson SP, Solution-phase combinatorial chemistry in lead discovery, Chimia, 51 832-837, 1997. 

Coe DM, Storer R, Solution-phase combinatorial chemistry, in Annual Reports in Combinatorial Chemistry and Molecular Diversity (Eds. W.H. Moos, M.R. Pavia, B.K. Kay, A.D. Ellington), pp. 50-58, 1997, ESCOM Science Publishers, Leiden. 

An HY, Cummins LL, Griffey RH, Bharadwaj R, Haly BD, Fraser AS, Wilsonlingardo L, Risen LM, Wyatt JR, Cook PD, Solution phase combinatorial chemistry Discovery of novel polyazapyridinophanes with potent antibacterial activity by a solution phase simultaneous addition of functionalities approach, J. Am. Chem. Soc., 119 3696-3708, 1997. 

Boger DL, Ozer RS, Andersson CM, Generation of targeted C-2-symmetrical compound libraries by solution-phase combinatorial chemistry, Bioorg. Med. Chem. Lett., 7 1903-1908, 1997. 

These libraries contain a relatively small number of individuals (typically tens to hundreds) and are almost always prepared as discrete libraries using parallel synthesis and automated or semiautomated devices. Focused libraries are predominantly prepared in solution because of the easier shift from classical organic synthesis to solution-phase combinatorial chemistry, while automated purification procedures for relatively small arrays of discrete compounds in solution are common nowadays. The... 

Suto, M. T. Developments in solution-phase combinatorial chemistry. Curr. Opin. Drug Disc. Dev. 2 377-384, 1999. 

Solution-phase combinatorial chemistry so far has played a considerably lesser role than its solid-phase counterpart. This is probably due to the main problem of solution-phase combinatorial synthesis, i.e., to obtain pure products. In solid-phase synthesis, components such as auxiliary reagents and unreacted starting materials can be easily separated from the desired products by simple washing procedures since both reside in different phases. In solution-phase synthesis, all components occur in the same phase so that purification becomes a much more demanding task. With respect to side products derived from the resin-bound reaction component, the purification problems are, however, the same in both solution- and solid-phase synthesis. 

Nevertheless, the achievable purity will remain an important criterion for whether or not a reaction is suitable for solution-phase combinatorial synthesis. The extent to which this criterion can be fulfilled depends on the uniformity of the reaction and on the efficiency with which the products can be purified. Therefore, this chapter will focus on reactions that have been more or less successfully applied to solution-phase combinatorial chemistry (including parallel synthesis), and particularly on the purification techniques that have been used. 

Reactions Applied to Solution-Phase Combinatorial Chemistry... 

As has been mentioned above, there are principally no constraints in terms of reaction conditions in solution-phase combinatorial chemistry. However, the necessity to obtain sufficiently pure products may limit the types of reactions that are suitable for this purpose. These limitations may decrease with the advent of automated purification techniques, particularly those based on chromatography coupled with analytical tools such as mass spectrometry. 

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