Combinatorial libraries decoration

The structure of 3.25 looks suited for the introduction of decorating functions in various positions to create a combinatorial library based on a natural rigid scaffold ... 

Figure 5 Examples of scaffold decoration for the solution-phase synthesis of pooled combinatorial libraries from Rebek and Isis. In both cases, biologically active compounds were identified...

The full combinatorial exploitation of 3.25 requires an assessed SP synthetic method to build and decorate the scaffold for SP library generation ... 

Another decoration pool library L23 was reported by Nestler (49), who presented the appendage of a peptidic chain to the two hydroxylic functions of a steroid scaffold (Fig. 4.15). The library was made up of 10 x 10 x 10 x 10 = 10,000 individuals using a chemical encoding method (39) and L-a-amino acids as monomer sets (R1-R4). The assay of the library as a source of artificial two-armed receptors for enkephalin-related peptides produced positives with micromolar affinity. Much larger libraries could be obtained by simply increasing the monomer sets and the length of the two arms this could lead to a primary library of peptide-binding artificial receptors similar scaffolds have been repeatedly exploited for combinatorial purposes (50-52). 

A classic illustration of scaffold decoration is the trisubstituted 1,3,5-triazine. The starting material trichloro-l,3,5-triazine is inexpensive, and the halogens can be displaced by nucleophilic aromatic substitutions one by one. Such chemistry was well precedented in pre-combinatorial days, and used on a large scale for the synthesis of colour-fast reactive dyes. The overall reaction sequence has an appeal in its simplicity, and both academic and industrial practitioners have reported a steady trickle of such triazine-based libraries over the last 20 years. Novelty will come either from the particular set of nucleophiles employed or the assay targets. 

The combinatorial decoration or derivatization of existing natural products is a popular method for library creation. Among targets for such exercises are the alkaloids yohimbine and scopolamine, terpenoids and steroids, and the heterocyclic peptide antibiotic GE-2270A (Figure 11). In the latter case, combinatorial variation was instrumental in the discovery of a developmental candidate now in clinical trials at Vicuron. Pfizer, the world s largest pharmaceutical company, recently acquired Vicuron for the sum of 1.9 billion, a mark of approval for natural product-based combinatorial chemistry. 

Other analogs were also prepared from oxomaritidine by hydrogenation to give 24, which on reductive amination with polymer-supported cyanoborohydride afforded a small library of unnatural analogs based on the structure of 25. Obviously, many other derivatives would be possible given the efficiency of this route to the natural products, and clearly many of the intermediates, such as the spirodienone 23, could usefully be diverted to other combinatorial chemistry programs for further elaboration and decoration. 

MCRs can be considered the cradle of combinatorial chemistry [56]. Other than the stepwise library synthesis described in the library design section above, MCRs have the advantage of the very short reaction sequence. This allows for the possibility to apply extreme cherry-picking of the desired products, resulting in very low matrix coverage and high structural diversity regarding the decoration of the scaffold. 

Emergence of combinatorial chemistry and parallel synthesis in early nineties and synthesis of small molecules inspired by the structural architectures of natural products in the beginning of this century called for further developments in the solid-phase synthesis protocols. Synthesis of compound libraries possessing enantiopure molecules embodying a complex framework and decorated with more than one stereocenters in a combinatorial and parallel fashion calls for highly feasible solid-phase synthesis methods." In particular, these efforts must address the stereocontrol of the reaction course in order to minimize isomer... 

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