γ2-, γ3-, and γ2,3,4-amino acids, coupling to γ-hexapeptides: CD spectra, NMR solution and X-ray crystal structures of γ-peptides

Dieter Seebach*, Meinrad Brenner, Magnus Rueping, Bernhard Jaun

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

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-γ2,4-amino acids have been previously used as building blocks in γ-peptides. The synthesis of γ2-, γ3-, and γ2,3,4-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, 9a), of a γ2,3,4-di- and a γ2,3,4-tetrapeptide (20, 22) are described, and the NMR solution structure in MeOH of a γ2,3,4-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 γ2,3,4-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 γ2,3,4-hexapeptide is present as the 2.614 helix in solution. The structures of the γ2- and γ3-hexapeptides (1, 2) could not be determined.

Original languageEnglish (US)
Pages (from-to)573-584
Number of pages12
JournalChemistry - A European Journal
Volume8
Issue number3
DOIs
StatePublished - Feb 2 2002

Keywords

  • Amino acids
  • Circular dichroism
  • Helical structures
  • Peptides

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Organic Chemistry

Cite this