Split and recombine strategy

For linear multistep syntheses, the split and recombine strategy is a fast and effective method ofproducing large libraries. In fact, a synthesis with x inputs andy chemical steps gives rise to a library of xy components. Chemical tagging methods have been used extensively for the identification of active components in such libraries [6]. An alternative to chemical tagging is a coding system that uses radio frequency (rf) encodable microchips. 

In this technique, an rf encodable microchip is coupled with a capsule of derivatized polystyrene resin such that each unique synthesis site can be tagged with a unique identifier code. The inert nature of the rf transponder construction renders this tagging strategy compatible with virtually all synthetic methods. Additionally, the noninvasive transmission or retrieval of information from any capsule is unambiguous and instantaneous, avoiding the possibility of long reaction and/or analysis times associated with chemical tags. 

A successful lead optimization process is, in general, a result of careful and systematic analysis of structure-activity relationships (SAR) within an active series of compounds. The validity of the SAR obtained from screening a combinatorial library is a reflection of an accurate knowledge of the identity, purity and quantity of each library member. Also important is the ease and speed with which information can be relayed from the biological screen to the medicinal chemist. In fact, herein lies the main difference between the two techniques discussed so far. 

The OntoCODE system effectively combines the advantages of both the spatially dispersed and split and recombine strategies and allows the chemist to build large archiv-able combinatorial libraries with milligram quantities of each compound and without the need for chemical tagging. 

For a recent review on this subject, see Janda, K., Proc. Natl. Acad. Sci. USA, 91 (1994) 10779. 

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FIGURE 8.2 The generic representation of split-mix-recombine synthetic strategy with three unique monomers (A, B, and C) at each synthetic step. The final outcome for this example is the synthesis of all possible combinations, 27 unique compounds after three synthetic rounds. 

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