The design and synthesis of 2,5-linked pyrrolinones. A potential non-peptide peptidomimetic scaffold

The de novo design and initial synthetic studies directed toward construction of a novel non-peptide scaffold for β-strand/sheet and related secondary peptide structural mimics are described. The scaffold, consisting of a repeating array of 2,5,5-trisubstituted pyrrolinone (enaminone) units punctuated with appropriate amino acid side chains, is conceptually related to our previously successful 3,5-linked polypyrrolinone non-peptide peptidomimetic scaffold. Construction of the 2,5,5-trisubstituted pyrrolinone ring system proceeds via intramolecular condensation of an N-protected amino dione. The latter is prepared from a protected α-amino ketone and aldehyde via an aldol-oxidation reaction sequence. The de novo design and initial synthetic studies directed toward construction of a novel non-peptide scaffold for β-strand/sheet and related secondary peptide structural mimics are described. The scaffold (22), consisting of a repeating array of 2,5,5-trisubstituted pyrrolinone (enaminone) units punctuated with appropriate amino acid side chains, is conceptually related to our previously successful 3,5-linked polypyrrolinone non-peptide peptidomimetic scaffold. Construction of the 2,5,5-trisubstituted pyrrolinone ring system [(+)-55] proceeds via intramolecular condensation of the N-protected amino dione (+)-52.