Influence of solid support, solvent and coupling reagent on the head-to-tail cyclization of resin-bound peptides.

Abstract

Head-to-tail cyclization of peptides attached to insoluble supports by means of the side chains of aspartic acid or glutamic acid allows the rapid synthesis of cyclic peptides of widely varied amino acid sequence. However, two side reactions dramatically reduce the yield of the desired compound; these are (1) interpeptide condensation that creates dimers, trimers and higher-order oligomers and (2) racemization of the C-terminal residue. A comparison was made between benzotriazoyloxy-tris-(dimethyl-amino)phosphonium hexafluorophosphate (BOP) and diisopropylcarbodiimide (DIPCDI) as cyclization reagents on kieselguhr-supported polydimethylacrylamide, chloromethyl-PolyHipe, and two commercially available polystyrene supports using DMF, CH2Cl2 and THF as cyclization solvents. Both of the side reactions are dependent on the amino acid sequence, the reagent used to couple the ends of the peptide and the solid support.