CONFORMATIONAL PROPERTIES OF THE UNNATURAL AMINO-ACID BETA-METHYLPHENYLALANINE IN A LINEAR OCTAPEPTIDE SYSTEM - CORRELATIONS OF C-13-NMR CHEMICAL-SHIFTS WITH THE SIDE-CHAIN STEREOCHEMISTRY OF THESE AMINO-ACID-RESIDUES

Conformational properties of the four stereoisomers ([2S,3S], [2S,3R], [2R,3S], and [2R,3R]) of a synthetic amino acid, beta-methylphenylana line (beta-MePhe), in a bioactive octapeptide sequence of CCK, )-beta- MePhe(3)-Gly(4)-Trp(5)-Nle(6)-Asp(7)-Phe(8) NH2, have been studied by using H-1 and C-13-2D NMR spectroscopy. beta-MePhe(3) residues introdu ce significant perturbations to the side-chain conformations. On the b asis of the rotamer populations determined by a combination of homonuc lear and heteronuclear vicinal coupling constants, each of the four di fferent stereoisomers of beta-MePhe residues virtually eliminates one of the three staggered side-chain conformations, trans for (2S,3S)and (2R,3R)-beta-MePhe, gauche(+) for (2S,3R)-beta-MePhe, and gauche(-) fo r (2R,3S)-beta-MePhe, respectively. It also was revealed that the side -chain rotamer populations of the Tyr(2) residue are influenced by dif ferent configurations of the beta-carbon in the adjacent beta-MePhe(3) residues. An empirical correlation between the C-13 chemical shifts o f the beta-CH3 and the stereochemistry of beta-methylphenylalanine sid e chains has been established, i.e., the delta(C) of the beta-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 rati onalized on the basis of the gamma-substituent effect in C-13-NMR chem ical shift, and it may become a useful probe for side-chain conformati ons of similar molecules. Furthermore, these beta-methylphenylalanine amino acids will provide useful side-chain conformational constraints in peptide and mimetic design.