An Unnatural Amino Acid that Mimics a Tripeptide β-Strand and Forms β-Sheetlike Hydrogen-Bonded Dimers

Abstract

Unnatural amino acid 2 (5-HO2CCONH-2-MeO-C6H3-CONHNH2) duplicates the hydrogen-bonding functionality of one edge of a tripeptide β-strand. It is composed of hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid groups and is designated by the three-letter abbreviation “Hao” to reflect these three components. The 2,7-di-tert-butylfluorenylmethyloxycarbonyl (Fmoc*)- and tert-butyloxycarbonyl (Boc)-protected derivatives of Hao are prepared efficiently and in high yield by the condensation of suitably protected derivatives of hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid. Fmoc*-Hao and Boc-Hao behave like typical Fmoc- and Boc-protected amino acids and can be incorporated into peptides by standard solid- and solution-phase peptide synthesis techniques using carbodiimide coupling agents. Hao-containing peptide 9 (i-PrCO-Phe-Hao-Val-NHBu) forms a β-sheetlike hydrogen-bonded dimer in CDCl3 and CD3OD−CDCl3 solutions. Peptides containing Hao and natural amino acids display hydrogen-bonding surfaces that are complementary to the hydrogen-bonding edges of protein β-sheets.