Synthesis of L-threo- and L-erythro-[1-13C, 2,3-2H2]amino acids: novel probes for conformational analysis of peptide side chains

An efficient and convenient route for the preparation of L-threo- and L-erythro-[1-l3C, 2,3-2H2]amino acids 5 as probes for the conformational analysis of peptide side chains by NMR spectroscopy is described. Stereoselective incorporation of deuterium into the α,β-positions of amino acid 5 was accomplished by catalytic deuteriation of dehydroamino acid derivatives 1 and 2 followed by a combination of enzymic optical resolution and the racemization at the 2-position. Using the doubly labelled amino acids, it was possible to obtain vicinal coupling constants between carbonyl carbon and prochiral β-protons, J(13C1–1Hβ1) and J(13C1–1Hβ2), through 13C NMR spectroscopy alone. We also demonstrate the determination of the fractional populations of rotamers in respect of the Cα–Cβ bond of the amino acids using the measured coupling constants.

[1]  J. L. Wood,et al.  RACEMIZATION OF BENZYL-l-CYSTEINE, WITH A NEW METHOD OF PREPARING d-CYSTINE , 1939 .

[2]  C. Griesinger,et al.  Peptide conformations. 42. Conformation of side chains in peptides using heteronuclear coupling constants obtained by two-dimensional NMR spectroscopy , 1987 .

[3]  E. Erlenmeyer,et al.  Zwei neue Synthesen des Tyrosins , 1899 .

[4]  U. Nagai,et al.  Solvent effect on side chain conformation of phenylalanine derivatives , 1977 .

[5]  F. L. Pyman.  XXII.—Derivatives of glyoxaline-4(or 5)-formaldehyde and glyoxaline-4(or 5)-carboxylic acid. A new synthesis of histidine , 1916 .

[6]  T. Miyazawa,et al.  Nuclear magnetic resonance analyses of side chain conformations of histidine and aromatic amino acid derivatives. Solvent and pH dependence. , 2009, International journal of peptide and protein research.

[7]  U. Schmidt,et al.  Amino Acids and Peptides; XLIII1. Dehydroamino Acids; XVIII2. Synthesis of Dehydroamino Acids and Amino Acids from N-Acyl-2-(dialkyloxyphosphinyl)-glycin Esters; II , 1984 .

[8]  M. Kainosho,et al.  Letter: Conformational analysis of amino acids and peptides using specific isotope substitution. II. Conformation of serine, tyrosine, phenylalanine, aspartic acid, asparagine, and aspartic acid beta-methyl ester in various ionization states. , 1975, Journal of the American Chemical Society.

[9]  Torsion angles in the cystine bridge of oxytocin in aqueous solution. Measurements of circumjacent vicinal couplings between proton, carbon-13, and nitrogen-15 , 1980 .

[10]  W. Steglich,et al.  Untersuchungen zur Reaktion von Acylaminobrommalonestern und Acylaminobromessigestern mit Trialkylphosphiten – eine einfache Synthese von 2-Amino-2-(diethoxyphosphoryl)essigsäure-ethylester , 1983 .

[11]  K. Pachler.  Nuclear magnetic resonance study of some α-amino acids—II. Rotational isomerism , 1964 .

[12]  U. Schmidt,et al.  Diastereoselective Formation of (Z)-Didehydroamino Acid Esters , 1992 .

[13]  J. Kelley,et al.  Attempted inhibition of histidine decarboxylase with beta-alkyl analogues of histidine. , 1977, Journal of medicinal chemistry.