Split synthesis strategy

Fig. 6. Split synthesis strategy using the OntoCODE system.

The word library is used to define a collection of compounds usually built around a common structural motif. There are three general approaches to library preparation parallel synthesis, mixture synthesis and split synthesis. One of these preferred strategies, parallel synthesis, is the approach where the compounds are made individually by automated or semi-automated methods. The library members may be made either in solution by classical methods, in solution attached to a polymeric carrier or on solid support. In parallel synthesis there must be linkage to a spatially defined position. The structure of the product is inferred from the position of the reactor and by the order of addition of the synthons and reagents at that position in space. Every possible member, resulting from the combinatorial mix of the synthons, need not be included in the library. 

Using a split-and-pool combinatorial synthesis strategy, Tamanoi and coworkers developed a library of approximately 4000 heterocycles generated from resin-bound allenoates by means of phosphine catalysis [36,37]. This library was initially screened to identify GGTase I inhibitors (Table 8.1), and some potent GGTase I inhibitors with novel... 

Diversity Sciences developed a library synthesis strategy that combines the simplicity of parallel synthesis and the power of resin-mixing techniques. The general format is four 96-well plates that give rise to 384 synthetic wells, as shown in Figure 8.9. The layout of the synthesis blocks enables 16 unique monomers in monomer position A (across rows) and 24 unique monomers in monomer position B (down the columns). All of the 384 wells are preloaded with off-the-shelf resin where each well has a unique binary code embedded in the analytical construct. The first two points of diversity (monomer A and monomer B) is added in all possible combinations by parallel synthesis. Each spatial location has a unique binary-mass code that encodes for a particular combination of monomer A and monomer B. For example, binary code number 8 represents monomer Al and monomer B8. After the addition of monomer B, the resin from all 384 wells is mixed together and split into 96 identical pools, to which monomer C is added. The third monomer, monomer C, is spatially encoded, since the 96 pools are not mixed after the last step and screened as pools. Upon decoding, the identification of the binary code reveals the combination of monomer A and monomer B on each bead. 

The solid-phase technique of split and mix synthesis relies on the efficiency of mixture-based synthesis to provide very large libraries (millions) of discrete compounds (Figure 4).[161 In this approach, each resin bead is treated with a single building block for each synthesis step. Thus any single resin bead possesses identical copies of one library member, but the identity of the library member on any bead is lost due to the mix step of the process. Elegant strategies have been developed to chemically encode the syn-... 

While parallel synthesis of arrays of glycopeptides is readily achieved by implementation of the building-block approach (Scheme 14.1, Strategy 2),101 glycopeptide library synthesis in a combinatorial manner via the split-mix method has yet to prove routine. The difficulty lies in the structural analysis of the vast number of compounds generated in picomolar quantities on a single bead. Whereas peptides on... 

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