Using a Noncovalent Protection Strategy to Enhance Solid-Phase Synthesis

Since the introduction of solid-phase peptide synthesis by Merrifield (
1
) nearly forty years ago, solid-phase techniques have been applied to the construction of a variety of biopolymers and extended into the field of small molecule synthesis. The last decade has seen the emergence of solid-phase synthesis as the leading technique in the development and production of combinatorial libraries of diverse compounds of varying sizes and properties. Combinatorial libraries can be classified as biopolymer based (e.g., peptides, peptidomimetics, polyureas, and others [
2
,
3
]) or small molecule based (e.g., heterocycles [
4
], natural product derivatives [
5
], and inorganic complexes [
6
,
7
]). Libraries synthesized by solid-phase techniques mainly use polystyrene-divinylbenzene (PS) derived solid supports. Owing to physical and chemical limitations of PS-derived resins, other resins have been developed (
8
,
9
). Most of these resins are prepared from PS by functionalizing the resin beads with oligomers to improve solvent compatibility and physical stability (
8
,
9
).