Chemical encoding strategies

After reporting the initial parallel experiments, the authors report a pooled approach using a chemical encoding strategy (176 and 177, see Fig. 3). Both the palladium and the nickel systems were screened in the same reaction vessel. Upon reaction, two different sized beads of polyethylene were observed. Deconvolution indicated the larger polymer granules were from catalysis by the nickel catalyst. 

Scott RH, Barnes C, Gerhard U, Balasubramanian S, Exploring a chemical encoding strategy for combinatorial synthesis using Friedel-Crafts alkylation, Chem. Commun., pp. 1331-1332, 1999. 

A family of chemical tags should ideally possess a number of features. It should be stable to all, or to the large majority, of the reaction conditions that may be used in an SP hbrary synthesis its synthesis should be easy and almost quantitative using commercially available precursors its presence should not interfere with the library synthesis scheme it should be inert in library screening when on-bead methods are used its structure should be determined with a fast and reliable method. We will now present the various chemical encoding strategies reported in the hterature and will comment on their fulfillment of the above criteria. 

Chemical encoding strategies rely on the assumption that the chemical analysis of a given member of the library is more difficult than the analysis of a chemical tag. In most cases this assumption is valid and justifies the described technique. Some libraries have been prepared and characterized by individual mass spectrometric analysis of each member of the library. However, to obtain unambiguous results, the following criteria must be fulfilled ... 

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-... 

Any chemically encoded library requires a double orthogonal chemical strategy, or the construction of elaborate tags/linkers on the solid support prior to the synthesis. Even when these are easily prepared and inert, the synthetic scheme becomes more complicated than direct deconvolution methods, where only the library synthesis is required. Sometimes the tag chemistry and the... 

All chemical tagging strategies are greatly limited by the additional synthetic transformations required to build up not only the product but also the tag. Consequently, this encoding method is only used exceptionally for the production of libraries [15-17]. 

Oligonucleotide tagging was developed and used successfully for the synthesis of peptides many methodological issues, related mostly to the chemical compatibility of the approach, were solved. However, the compatibility of this encoding strategy with the synthesis of other classes of organic molecules remains limited. 

Several laboratories have worked on the development of robust encoding strategies that can, be used for combinatorial synthesis of pharmacologically appealing chemical libraries. In... 

Figure 1. The solid phase construction of a 1300 compound di- and trisaccharide library using the mix and split combinatorial strategy. Anomeric linkage diversity, sugar building block diversity and substituent diversity were achieved. Chemical encoding was used to identity the structure of the active compounds la and lb which bound most tightly to the Bauhinia purpurea lectin.

---