title: Gamma2-, gamma3-, and gamma(2,3,4)-amino acids, coupling to gamma-hexapeptides: CD spectra, NMR solution and X-ray crystal structures of gamma-peptides.
abstract: There are numerous possible gamma-amino acids with different degrees of substitution and with various constitutions and configurations. Of these the gamma4- and the like- and unlike-gamma(2,4)-amino acids have been previously used as building blocks in gamma-peptides. The synthesis of gamma2-, gamma3-, and gamma(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 gamma-di-, tri-, and hexapeptides (12-23), which were fully characterized. The crystal structures of one of the gamma-amino acids (2,3-dimethyl-4-amino-pentanoic acid x HCl, 9a), of a gamma(2,3,4)-di- and a gamma(2,3,4)-tetrapeptide (20, 22) are described, and the NMR solution structure in MeOH of a gamma(2,3,4)-hexapeptide (3) has been determined (using TOCSY, COSY, HSOC, 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) 2.6(14) helices have thus been identified. NMR measurements at different temperatures (298-393 K) and H/D-exchange rates obtained for the gamma(2,3,4)-hexapeptide are interpreted as evidence for the stability of the 2.6(14) helix (no "melting") and for its non-cooperative folding mechanism. CD Spectra of the gamma-peptides have been measured in MeOH and CH3CN, indicating that only the protected and unprotected gamma(2,3,4)-hexapeptide is present as the 2.6(14) helix in solution. The structures of the gamma2- and gamma3-hexapeptides (1, 2) could not be determined.
authors.affiliation: Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule Zürich, ETH Hönggerberg, Switzerland. seebach@org.chem.ethz.ch
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
authors.forename: Meinrad
authors.initials: M
authors.lastname: Brenner
authors.forename: Magnus
authors.initials: M
authors.lastname: Rueping
authors.forename: Bernhard
authors.initials: B
authors.lastname: Jaun
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary / Q000187:drug effects; D012997:Solvents / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D012997:Solvents; D005680:gamma-Aminobutyric Acid