Directed Split-and-Pool Method in Practice

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of 1000 compounds requires the handling of 1000 reaction vessels. To add sensitive reagents (e.g., butyl lithium) in timely manner at low temperature (—78°C) under an inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is used. Such syntheses can be performed easily in a manual fashion using the split-and-pool method, which requires only a limited number of reaction vessels. The split-and-pool methodology has been used for the synthesis of complex and diversity-oriented combinatorial libraries. 

To make the directed split-and-pool methodology practical, two issues need to be addressed (i) formulation of the solid support and (ii) tracking the chemical history of individual units of the solid support. 

7 Formulation of Solid-Phase Supports for the Directed Spiit-and- 

Pool Technique. Resin beads are the most frequently used formulation of insoluble support for solid-phase organic synthesis. However, the yield from one typical bead (100 jam) is only about lOOpmol. The need for substantially higher yield from one unit of solid phase triggered the development of different formulations of solid support. Two different scenarios were followed compartmentalization of resin beads (T-bags, wafers, Kans, capsules, and resin plugs) and development of modular solid support (SynPhase Lanterns, rods). 

PRACTICAL ASPECTS OF COMBINATORIAL SOLID-PHASE SYNTHESIS 

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