Synthesis of Well-Defined Polystyrene Rink Amide Soluble Supports and Their Use in Peptide Synthesis

A soluble polystyrene-based support bearing a cleavable Rink amide moiety is synthesized and utilized for the iterative synthesis of an oligopeptide. This soluble support is obtained in three steps. First, a well-defined polystyrene segment is prepared by atom transfer radical polymerization (ATRP) using a fluorenylmethyloxycarbonyl (Fmoc)-protected amino-functional ATRP initiator. After polymerization, the Fmoc-protecting group is cleaved and the obtained primary amine is coupled to a commercial Knorr linker (also known as Rink amide linker). The formed Rink amide soluble support is characterized by size exclusion chromatography (SEC) and nuclear magnetic resonance (NMR) spectroscopy. As a proof of concept, this soluble support is used for the synthesis of a model tetrapeptide Glycine-Lysine-Serine-Arginine. This peptide is also prepared on a commercial Rink amide resin, in order to compare the advantages and drawbacks of soluble and solid supports. It is found that the soluble support allows efficient synthesis of the model oligopeptide. Interestingly, it also allows a precise monitoring of the oligomer synthesis by SEC and NMR.