Influence of Chirality of the Preceding Acyl Moiety on the cis/trans Ratio of the Proline Peptide Bond

• Published in: Journal of organic chemistry Vol. 66; no. 21; pp. 7044 - 7050
• Main Authors: Breznik, Matej, Grdadolnik, Simona Golič, Giester, Gerald, Leban, Ivan, Kikelj, Danijel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.10.2001; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Crystallography, X-Ray; Dipeptides - chemistry; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Physical Sciences; Proline - chemistry; Science & Technology; Stereoisomerism; MULTIPLE-QUANTUM COHERENCE; DIPEPTIDES; CONFORMATIONAL ENERGY; THROMBIN INHIBITORS; SPECTROSCOPY; ACIDS; ISOMERIZATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0159439

We report that the cis/trans ratio of the proline peptide bond can be strongly influenced by the chirality of the acyl residue preceding proline. Acyl moieties derived from (2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) in acyl-Pro molecules influence isomerization of the proline peptide bond constraining the ω dihedral angle to the trans orientation. Structures of benzyl (2S)-1-{[(2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl}-2-pyrrolidinecarboxylate (3) derived from 2D 1H NMR conformational analysis and crystallographic data exhibit only the trans conformation of proline peptide bond. On the other hand the diastereomer 4, which contains an (R) acyl moiety, exhibits two sets of signals in 1H NMR spectra. The signals were assigned to trans (72%) and cis (28%) conformers. Crystallographic analysis of 4 showed that only the cis conformation is present in the crystalline state. The 1H NMR chemical shift pattern of three sets of signals observed in 2 was observed also in benzyl (2S)-1-[(2R/S)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate. (R)-Carboxylic acid 5, after coupling with (S)-ProOBn, yielded benzyl (2S)-1-[(2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate (6), which in DMSO-d 6 exhibited only the trans conformation of the proline peptide bond. These results suggest that in these particular cases acyl-Pro peptide bond isomerization is strongly influenced by the stereochemistry of the acyl residue preceding proline. (2S)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) are promising chiral peptidomimetic building blocks that can be used as acyl moieties to force the proline peptide bond into the trans conformation in a variety of acyl-Pro molecules.