Conformational properties of the unnatural amino acid β-methylphenylalanine in a linear octapeptide system; correlations of 13C-NMR chemical shifts with the side-chain stereochemistry of these amino acid residues

K. Kövér, Ding Jiao, Sunan Fang, Victor J. Hruby

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Abstract

Conformational properties of the four stereoisomers ([2S,3S], [2S,3R], [2R,3S], and [2R,3R]) of a synthetic amino acid, β-methylphenylanaline (β-MePhe), in a bioactive octapeptide sequence of CCK, H-Asp1-Tyr2-β-MePhe3-Gly 4-Trp5-Nle6-Asp7-Phe 8-NH2, have been studied by using 1H and 13C-2D NMR spectroscopy. β-MePhe3 residues introduce significant perturbations to the side-chain conformations. On the basis of the rotamer populations determined by a combination of homonuclear and heteronuclear vicinal coupling constants, each of the four different stereoisomers of β-MePhe residues virtually eliminates one of the three staggered side-chain conformations, trans for (2S,3S)-and (2R,3R)-β-MePhe, gauche(+) for (2S,3R)-β-MePhe, and gauche(-) for (2R,3S)-β-MePhe, respectively. It also was revealed that the side-chain rotamer populations of the Tyr2 residue are influenced by different configurations of the β-carbon in the adjacent β-MePhe3 residues. An empirical correlation between the 13C chemical shifts of the β-CH3 and the stereochemistry of β-methylphenylalanine side chains has been established, i.e., the δC of the β-MePhe in (2S,3S)- and (2R,3R)-isomers is at lower field by ca. 3 ppm relative to those in (2S,3R)- and (2R,3S)-isomers. This correlation can be rationalized on the basis of the γ-substituent effect in 13C-NMR chemical shift, and it may become a useful probe for side-chain conformations of similar molecules. Furthermore, these β-methylphenylalanine amino acids will provide useful side-chain conformational constraints in peptide and mimetic design.

Original languageEnglish
Pages (from-to)991-998
Number of pages8
JournalJournal of Organic Chemistry
Volume59
Issue number5
Publication statusPublished - 1994

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Stereochemistry
Chemical shift
Linear systems
Conformations
Stereoisomerism
glycyl-glycyl-glycyl-glycine
Nuclear magnetic resonance
Amino Acids
Isomers
Nuclear magnetic resonance spectroscopy
Carbon
Peptides
Molecules

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{3d2fea11b6714e319ded15f1a4c29784,
title = "Conformational properties of the unnatural amino acid β-methylphenylalanine in a linear octapeptide system; correlations of 13C-NMR chemical shifts with the side-chain stereochemistry of these amino acid residues",
abstract = "Conformational properties of the four stereoisomers ([2S,3S], [2S,3R], [2R,3S], and [2R,3R]) of a synthetic amino acid, β-methylphenylanaline (β-MePhe), in a bioactive octapeptide sequence of CCK, H-Asp1-Tyr2-β-MePhe3-Gly 4-Trp5-Nle6-Asp7-Phe 8-NH2, have been studied by using 1H and 13C-2D NMR spectroscopy. β-MePhe3 residues introduce significant perturbations to the side-chain conformations. On the basis of the rotamer populations determined by a combination of homonuclear and heteronuclear vicinal coupling constants, each of the four different stereoisomers of β-MePhe residues virtually eliminates one of the three staggered side-chain conformations, trans for (2S,3S)-and (2R,3R)-β-MePhe, gauche(+) for (2S,3R)-β-MePhe, and gauche(-) for (2R,3S)-β-MePhe, respectively. It also was revealed that the side-chain rotamer populations of the Tyr2 residue are influenced by different configurations of the β-carbon in the adjacent β-MePhe3 residues. An empirical correlation between the 13C chemical shifts of the β-CH3 and the stereochemistry of β-methylphenylalanine side chains has been established, i.e., the δC of the β-MePhe in (2S,3S)- and (2R,3R)-isomers is at lower field by ca. 3 ppm relative to those in (2S,3R)- and (2R,3S)-isomers. This correlation can be rationalized on the basis of the γ-substituent effect in 13C-NMR chemical shift, and it may become a useful probe for side-chain conformations of similar molecules. Furthermore, these β-methylphenylalanine amino acids will provide useful side-chain conformational constraints in peptide and mimetic design.",
author = "K. K{\"o}v{\'e}r and Ding Jiao and Sunan Fang and Hruby, {Victor J.}",
year = "1994",
language = "English",
volume = "59",
pages = "991--998",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
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T1 - Conformational properties of the unnatural amino acid β-methylphenylalanine in a linear octapeptide system; correlations of 13C-NMR chemical shifts with the side-chain stereochemistry of these amino acid residues

AU - Kövér, K.

AU - Jiao, Ding

AU - Fang, Sunan

AU - Hruby, Victor J.

PY - 1994

Y1 - 1994

N2 - Conformational properties of the four stereoisomers ([2S,3S], [2S,3R], [2R,3S], and [2R,3R]) of a synthetic amino acid, β-methylphenylanaline (β-MePhe), in a bioactive octapeptide sequence of CCK, H-Asp1-Tyr2-β-MePhe3-Gly 4-Trp5-Nle6-Asp7-Phe 8-NH2, have been studied by using 1H and 13C-2D NMR spectroscopy. β-MePhe3 residues introduce significant perturbations to the side-chain conformations. On the basis of the rotamer populations determined by a combination of homonuclear and heteronuclear vicinal coupling constants, each of the four different stereoisomers of β-MePhe residues virtually eliminates one of the three staggered side-chain conformations, trans for (2S,3S)-and (2R,3R)-β-MePhe, gauche(+) for (2S,3R)-β-MePhe, and gauche(-) for (2R,3S)-β-MePhe, respectively. It also was revealed that the side-chain rotamer populations of the Tyr2 residue are influenced by different configurations of the β-carbon in the adjacent β-MePhe3 residues. An empirical correlation between the 13C chemical shifts of the β-CH3 and the stereochemistry of β-methylphenylalanine side chains has been established, i.e., the δC of the β-MePhe in (2S,3S)- and (2R,3R)-isomers is at lower field by ca. 3 ppm relative to those in (2S,3R)- and (2R,3S)-isomers. This correlation can be rationalized on the basis of the γ-substituent effect in 13C-NMR chemical shift, and it may become a useful probe for side-chain conformations of similar molecules. Furthermore, these β-methylphenylalanine amino acids will provide useful side-chain conformational constraints in peptide and mimetic design.

AB - Conformational properties of the four stereoisomers ([2S,3S], [2S,3R], [2R,3S], and [2R,3R]) of a synthetic amino acid, β-methylphenylanaline (β-MePhe), in a bioactive octapeptide sequence of CCK, H-Asp1-Tyr2-β-MePhe3-Gly 4-Trp5-Nle6-Asp7-Phe 8-NH2, have been studied by using 1H and 13C-2D NMR spectroscopy. β-MePhe3 residues introduce significant perturbations to the side-chain conformations. On the basis of the rotamer populations determined by a combination of homonuclear and heteronuclear vicinal coupling constants, each of the four different stereoisomers of β-MePhe residues virtually eliminates one of the three staggered side-chain conformations, trans for (2S,3S)-and (2R,3R)-β-MePhe, gauche(+) for (2S,3R)-β-MePhe, and gauche(-) for (2R,3S)-β-MePhe, respectively. It also was revealed that the side-chain rotamer populations of the Tyr2 residue are influenced by different configurations of the β-carbon in the adjacent β-MePhe3 residues. An empirical correlation between the 13C chemical shifts of the β-CH3 and the stereochemistry of β-methylphenylalanine side chains has been established, i.e., the δC of the β-MePhe in (2S,3S)- and (2R,3R)-isomers is at lower field by ca. 3 ppm relative to those in (2S,3R)- and (2R,3S)-isomers. This correlation can be rationalized on the basis of the γ-substituent effect in 13C-NMR chemical shift, and it may become a useful probe for side-chain conformations of similar molecules. Furthermore, these β-methylphenylalanine amino acids will provide useful side-chain conformational constraints in peptide and mimetic design.

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