Synthesis of Enaminone‐Based Vinylogous Peptides

Vinylogous peptides 3 with a vinyl fragment inserted into the peptide C–N bond were prepared from ynones 6 and enaminones 7 that are easily available from Boc‐protected α‐amino acids 4 . Coupling at the C terminus was achieved by 1,4‐addition of amino esters 5 to the C≡C bond in 6 or by substitution of the NMe 2 group in 7 to give N‐terminal vinylogues 3a – p . Coupling at the N terminus of 3 and 7 , in contrast, required temporary protection of the acidolytically labile enamino moiety. Thus, cyclization of 6 or 7 with hydroxylamine, removal of the Boc group with HBr–AcOH, acylation of free amine 10 with BocGlyOH ( 4a ), and hydrogenolytic deprotection of the enamino moiety in the presence of GlyOMe ( 5a ) led to tripeptides 3q – s with vinylogous amide as the central building block.