The synthesis, characterization, and application of a poly(N-acrylylpyrrolidine) resin as an improved insoluble support for the preparation of peptides is described. The three-dimensional polymer was obtained by reverse-phase suspension co-polymerization of the water-soluble monomers N-acrylylpyrrolidine, N, Nʹ-bis(acrylyl)-1, 2-diaminoethane, and N-acrylyl-1, 6-diaminohexane hydrochloride to yield a resin in beads of predetermined size. This method of polymer preparation appears to be generally applicable for water-soluble monomers. The particular resin studied contained 4.4% cross-linking, 0.7 mmol of primary amine per g of polymer and was prepared with a monomer-to-solvent dilution ratio of 1: 4. The resin has favorable swelling properties in solvents covering a broad range of polarities (CH2CI2, alcohols, AcOH, DMF, and H2O), which allow the adaptation of most of the techniques developed for the Merrifield method of solid-phase peptide synthesis as well as the use of procedures not previously compatible with polystyrene. The feasibility of amino acid and peptide attachment and detachment has been demonstrated with three types of polymer-to-peptide bridging groups: (1) a new S-carbamoyl group for the side-chain attachment of cysteine was used for a high yield bidirectional synthesis of deaminooxytocin, a potent biologically active analogue of oxytocin; (2) the dinitrophenylene group for the side-chain attachment of histidine was used for the bidirectional synthesis of thyrotropin-releasing hormone; (3) the benzyl ester group for COOH-terminal attachment and, moreover, for the side-chain attachment of glutamic acid. Nʹ-Benzyloxycarbonylprolylglutamyl-O5-[4-(oxymethyl)phenylacetamidopoly(N-acrylylpyrrolidine)]glycinamide was assembled bidirectionally to demonstrate the feasibility of preparing both glutamic acid and glutamine-containing peptides from the same polymer-attached peptide intermediate; saponification and ammonolysis were the respective methods of choice for the liberation of the Z-Pro-Glu-Gly-NF2 and Z-Pro-Gln-Gly-NH2 model peptides. Reaction conditions used for detachment are nonacidic and different from those normally used for removal of Nα-amino group protection. Coupling reactions on the resin have been demonstrated in such diverse solvents as CH2CI2, DMF, and aqueous media. © 1979, American Chemical Society. All rights reserved.
