NEW AMINO-ACIDS FOR THE TOPOGRAPHICAL CONTROL OF PEPTIDE CONFORMATION- SYNTHESIS OF ALL THE ISOMERS OF ALPHA,BETA-DIMETHYLPHENYLALANINE AND A-DIMETHYL-1,2,3,4-TETRAHYDROISOQUINO-3-CARBOXYLIC ACID OF HIGH OPTICAL PURITY

The synthesis of all four diastereoisomers of alpha,beta-dimethylpheny lalanine (4) as well as those of alpha,beta-dimethyl-1 ,2,3,4,-tetrahy droisoquinoline-3-carboxylic acid (5 and 6) have been accomplished in high yield and high optical purity. Molecular mechanics calculations o n the N-alpha-acetyl and N- methylcarboxamide derivatives of (3R,4R)-6 and (3R,4S)-5 indicate large and moderate energy stabilization for th e gauche(-) but not the gauche(+) side-chain conformers of (3R,4S)-5 a nd (3R,4R)-6, respectively. By symmetry rules, the same holds for (3S, 4R)-5 and (3S,4S)-6, respectively. Thus, these amino acids are potenti al building blocks for the topographical design of peptides (Kazmiersk i et al., J. Am. Chem. Sec. 1998, 113, 2275-2283) by providing acylate d 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives in whic h a gauche(-) and not a gauche(+) side-chain conformation is energetic ally more stable for the L amino acid. Synthetic details and implicati ons of these new amino acids for peptide and protein design are discus sed.