An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics

The synthesis and use of an alkylsilyl-tethered large (500-600 mum) polysty rene resin (1) are disclosed. An optimized Suzuki coupling of bromine-funct ionalized polystyrene and a silicon-functionalized alkylborane generates th e silicon-substituted polystyrene 1 in large scale (> 100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an auto mated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-poo l synthesis on a per bead basis for use in both forward and reverse chemica l genetic assays. This technology satisfies many requirements of a one bead -one stock solution approach to chemical genetics.