Synthesis of methylated phenylalanines via hydrogenolysis of corresponding 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. Synthesis and biological activity of oxytocin analogs with methylated phenylalanines in position 2.
A new method of synthesizing ortho-methylated phenylalanines has been developed. Phenylalanines with at least one free ortho-position undergo a Pictet-Spengler cyclization with formaldehyde followed by hydrogenolytic splitting of the endocyclic benzylic C--N bond of 1,2,3,4-tetrahydroisoquinolines and afford corresponding ortho-methyl derivatives. Repeating this reaction sequence on the ortho-substituted phenylalanines yielded ortho,ortho-disubstituted derivatives, and para-substituted phenylalanines yielded ortho,para-disubstituted analogs. Our modified method of cyclization preserved the configuration at the chiral center: hydrogenolysis, on the other hand, led to racemization. Incorporation of the methylated phenylalanines into position 2 of oxytocin led to, in the case of the D-isomers, potent uterotonic inhibitors.
Majer
P
P
Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague.
Slaninová
J
J
Lebl
M
M
D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006859:Hydrogen / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry*; D008745:Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis*; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry*; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014599:Uterus / Q000187:drug effects
D007546:Isoquinolines; D009842:Oligopeptides; D044005:Tetrahydroisoquinolines; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D010649:Phenylalanine; D010121:Oxytocin; D006859:Hydrogen