Peptide–Heterocycle Chimera: New Classes of More Drug‐Like Peptidomimetics by Ligations of Peptide–Bis(electrophiles) with Various Bis(nucleophiles)

Abstract

Abstract Several C‐terminal peptidyl‐substituted bis‐ and tris(electrophiles) were prepared by starting from polymeric phosphoranylidenacetates as acyl anion equivalents. After C ‐acylations with amino acids and peptide elongation, the obtained peptidyl‐phosphoranylideneacetate resins were either cleaved oxidatively, delivering peptidyl‐diketo esters, or saponified, leading to immediate decarboxylation. The generated peptidyl‐phosphorane could be treated with aldehydes to yield peptidyl vinyl ketones or could be cleaved oxidatively to yield peptidyl keto aldehydes. Ligation with various bis(nucleophiles) including hydrazines, hydroxylamine, diamines, amino‐thiols, amidines, and guanidines were investigated in the formation of peptide‐heterocycle chimera containing pyrazoline, pyrazole, isoxazole, isoxazoline, thiazepine, quinoxaline, and imidazolone heterocycles.