γ2-,γ3-, andγ2,3,4-Amino Acids, Coupling toγ-Hexapeptides: CD Spectra, NMR Solution and X-ray Crystal Structures ofγ-Peptides

Abstract

There are numerous possible γ-amino acids with different degrees of substitution and with various constitutions and configurations. Of these the γ⁴- and the like- and unlike-γ^2,4-amino acids have been previously used as building blocks in γ-peptides. The synthesis of γ²-, γ³-, and γ^2,3,4-peptides is now described. The corresponding amino acids have been prepared by Michael addition of chiral N-acyl-oxazolidinone enolates to nitro-olefins, with subsequent reduction of the NO₂ to NH₂ groups. Such additions to E-2-methyl-nitropropene provide (2R,3R,4R)-2-alkyl-3-methyl-4-amino-pentanoic acid derivatives (9, 10, 11). Stepwise coupling and fragment coupling lead to γ-di-, tri-, and hexapeptides (12–23), which were fully characterized. The crystal structures of one of the γ-amino acids (2,3-dimethyl-4-amino-pentanoic acid⋅HCl, 9 a), of a γ^2,3,4-di- and a γ^2,3,4-tetrapeptide (20, 22) are described, and the NMR solution structure in MeOH of a γ^2,3,4-hexapeptide (3) has been determined (using TOCSY, COSY, HSQC, HMBC and ROESY measurements and a molecular dynamics simulated-annealing protocol). A linear conformation (sheet-like), a novel (M) helix built of nine-membered hydrogen-bonded rings, and (M) 2.6₁₄ helices have thus been identified. NMR measurements at different temperatures (298–393 K) and H/D-exchange rates obtained for the γ^2,3,4-hexapeptide are interpreted as evidence for the stability of the 2.6₁₄ helix (no “melting”) and for its non-cooperative folding mechanism. CD Spectra of the γ-peptides have been measured in MeOH and CH₃CN, indicating that only the protected and unprotected γ^2,3,4-hexapeptide is present as the 2.6₁₄ helix in solution. The structures of the γ²- and γ³-hexapeptides (1, 2) could not be determined.