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n the support. A careful choice of the linker allows cleavage to be performed under appropriate conditions compatible with the stability of the compound and assay method'' [7].

The starting material for a solid-phase synthesis is attached reversibly to a linker, which is bound either directly or via a spacer to the resin (usually with divinyl-benzene cross-linked polystyrene). The choice of the linker is therefore very important in the design of a solid-phase chemical route. They must be stable in the presence of reagents and enable cleavage under mild conditions. Traditionally, linkers were designed to release molecules with one particular functional group and hence acted more or less as bulky protecting groups [8]. Initially, solid-phase

Microscopic view of resin beads

Reaction/ Washing it

Reaction/ Washing

Cleavage y Soluble Product J

Reaction/ Washing

Fig. 6.1.2. General scheme for synthesis on an insoluble polymeric support.

synthesis was mainly used to obtain peptides and the release of carboxylic acids and amines, which are essential for peptide synthesis, has therefore been studied extensively. However, small drug-like molecule libraries require linkers that are more versatile [9].

A particular linker should resist the entire synthetic sequence without bias to the diversity or structure of the target compound library and without limiting the chemical methodology. None of the reaction conditions used for construction of the building blocks should lead to a premature cleavage (orthogonality principle). Cleavage from the resin must be as mild as possible to ensure the product will not be affected. In general, linkers for various kinds of building blocks are known and different cleavage strategies have been developed, for example photocleavage, safety catch, and traceless linkers [10].

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