A helical arrangement of β‐substituents of dehydropeptides: Synthesis and conformational study of sequential nona‐ and dodecapeptides possessing (Z)‐β‐(1‐naphthyl)dehydroalanine residues

Abstract

Sequential nona- and dodecapeptides possessing three and four (Z)-β -(1-naphthyl)dehydroalanine (ΔZNap) residues, Boc–(L-Ala–ΔZNap–L-Leu)n–OCH3 (n = 3 and 4; Boc = t-butoxycarbonyl), were synthesized to design a rigid 310-helical backbone for a regular arrangement of functional groups using dehydropeptides. Their solution conformations were investigated by NMR and CD analyses, and theoretical energy calculations. Both peptides were found to adopt a 310-helical conformation in CDCl3 from their nuclear Overhauser effect spectroscopy (NOESY) spectra, which showed intense cross peaks for NiH–Ni+1H proton pairs, but no cross peaks for CαiH–Ni+4H pairs. The predominance of a 310-helix was also supported by solvent accessibility of NH resonances. CD spectra of both peptides in tetrahydrofuran showed strong exciton couplets at around 228 nm assignable to naphthyl side chains, which are regularly arranged along a right-handed helical backbone. Chain-length effects on conformational preference in sequential peptide –(Ala–ΔZNap–Leu)n– were discussed based on spectroscopic analysis, energy minimization, and molecular dynamics simulations. Consequently, the repeating number n ≥ 3 forms predominantly a right-handed 310-helical conformation. The energy calculation also revealed that the midpoint naphthyl groups of peptide n = 4 are highly restricted to one stable orientation. In conclusion, β-substituted α,β-dehydroalanine is expected to be a unique tool for designing a rigid molecular frame of 310-helix along which β-functional groups are regularly arranged in a specific manner. © 2001 John Wiley & Sons, Inc. Biopolymers 59: 356–369, 2001