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

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

ASJC Scopus subject areas

  • Organic Chemistry

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