β-Turn and β-Hairpin Mimicry with Tetrasubstituted Alkenes

• Published in: Journal of the American Chemical Society 1999-03, Vol.121 (9), p.1806-1816
• Main Authors: Liang, Gui-Bai, Gellman, Samuel H
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9824526

Synthesis and conformational analysis are reported for molecules containing the trans-5-amino-3,4-dimethylpent-3-enoic acid residue (ADPA, 1). This amino acid is a glycylglycine mimic, in which the central amide group is replaced with an E-tetrasubstituted alkene. It was anticipated that this isosteric replacement would promote specific local (β-turn) and nonlocal (β-hairpin) conformational preferences. Previous work has shown that the most common β-turn conformations (type I and type II) are not strong inducers of β-hairpin formation, while the rare “mirror image” β-turns (type I‘ and type II‘) promote β-hairpin formation. We therefore sought an achiral unit with a strong turn-forming propensity, since the lack of stereogenic centers within such a unit would eliminate the energetic distinction between common and “mirror image” turn conformations. In, the ADPA unit, avoidance of allylic strain was expected to preorganize the backbone for adoption of folded conformations. A combination of NMR and IR data for di-, tri-, and tetrapeptide analogues containing the ADPA residue reveal that β-turn- and β-hairpin-like folding is promoted in methylene chloride solution.