Combinatorial synthesis in solution

The main problem with preparing libraries using solution chemistry is the difficulty of removing unwanted impurities at each step in the synthesis. Consequently, many of the strategies used for the preparation of libraries using solution chemistry are directed to the purification of the products of each steps of the synthesis. This and other practical problems has usually restricted the use of solution combinatorial chemistry to synthetic pathways consisting of two or three steps. 

This method of identifying the structure of the most active component of combinatorial libraries of mixtures is known as deconvolution (see section 6.5). It depends on both the mixtures containing the active compound giving a positive result for the assay procedure. It is not possible to identify the active structure if one of the sets of mixtures gives a negative result. Furthermore, complications arise if more than one mixture is found to be active. In this case all the possible structures have to be synthesized and tested separately. However, it is generally found that the activities of the library mixtures are usually higher than those exhibited by the individual compounds responsible for activity after they have been isolated from the mixture. 

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In the literature, few examples exist for combinatorial synthesis in solution [68], with most being one- or two-step parallel synthesis of individual compounds or reagent-mixture synthesis of compound mixtures. Pools of dimeric compounds including esters, amides and carbamates have been successfully prepared without needing further purification. One example of a reaction which is particularly applicable to combinatorial synthesis in solution is a multicomponent reaction, such as the Ugi four-component reaction, as it can produce four points of diversity in a single step [69-71],... 

An extension of the combinatorial synthesis in solution is achieved by the use of soluble polymeric supports [80, 81], which combines some of the advantages of chemistry in solution and on solid phase. The so-called liquid-phase combinatorial synthesis is based on the physical properties of poly (ethylene glycol) monomethyl ether. The polymer is soluble in a variety of aqueous and organic solvents, which allows reactions to be conducted in homogeneous phase whereas the propensity to crystallize in appropriate solvents facilitates the isolation and purification of the compound at each step of the combinatorial synthesis. 

Scheme 3.9. Example of a convergent combinatorial synthesis in solution.

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

Wintner EA, Rebek J Jr, Combinatorial libraries in solution polyfunctionalized core molecules, in Combinatorial Chemistry Synthesis and Application (Eds. S.R. Wilson, A.W. Czarnik), pp. 95-118, 1997, John Wiley Sons, Inc., New York. 

Target selection and synthetic strategy in solution The retrosynthetic study to 3.83 (Fig. 3.32) identified compounds 3.84-3.88 as the precursors to the desired nucleus the aim of this project being the full combinatorial exploitation of a novel scaffold, an assessed SP protocol to general structures 3.89 was necessary. The synthesis in solution of related compounds (3.90a,b, Fig. 3.33 compare with 3.89, Fig. 3.32) being known (29), its adjustment to lead to 3.83 was deemed straightforward for this reason the authors moved directly to SPS. 

Some companies (75, 76) have developed their own automated instruments for combinatorial library synthesis in solution to produce large, purified arrays of discretes (up to several tens of thousands of individuals) the available information is obviously scarce, but an example of such a proprietary integrated synthesizer will be presented in section 8.2.6. 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this prupose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. Combinatorial chemistry had its beginning with the Merrifield synthesis, particularly when applied to peptide synthesis, and continues as an important part of modem organic chemistry. ... 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

Also in this case, Curran and coworkers produced a library of 64 mappicine analogues by automated solution-phase combinatorial synthesis, as well as a 48-mem-ber library of mappicine ketone derivatives [88]. Furthermore, these authors were successful in building up a 115-member library of rac-homosilatecans 3-216 using different iodopyridones 3-214 and aryl isocyanides as substrates 3-215 (Scheme 3.56) [89]. 

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