Design and asymmetric synthesis of unusual amino acids for incorporation into peptide hormones.
AuthorRussell, Keith Casey.
AdvisorHruby, Victor J.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractOne of the central goals of peptide and protein chemistry is the development of peptides with specific biological, chemical, and physical properties. An important method directed towards attaining this goal is the use of conformationally restricted amino acids. The conformationally restricted amino L-isomers of 2'-methyltyrosine, 2',6'-dimethyltyrosine, erythro- and threo-2',β-dimethyltyrosine, and erythro- and threo-2',6',β-trimethyltyrosine were asymmetrically synthesized in good yields and high optical purities. The synthesis of these compounds was based on the chiral boron imidate methodology. Acid precursors were prepared from either 5-methyl-2-nitrophenol, 3-methylanisole, or 3,5-dimethylansole and coupled to optically active 4-phenyl-2-oxazolidinone. Unsaturated coupled products were subjected to 1,4 conjugate additions to set the stereochemistry at the β-carbon with superior stereoselectivity (88-99% de). The Michael adducts and other acyloxazolidinones were asymmetrically brominated to set the chirality at the α-carbon also with excellent stereoselectivity (80-98% de). The bromides were displaced with azide ion to afford the α-azidocyloxazolinones without any detectable racemization. The chiral auxiliary was hydrolyzed and recovered. The azido acids were reduced and methyl ether hydrolyzed to yield the tyrosine derivatives with high optical purity. The absolute stereochemistry of three of the bromide intermediates was determined by X-ray crystallography providing evidence for the selective reactions. The superiority of 4-phenyl-2-oxazolidinone over 4-phenylmethyl-2-oxazolidinone for asymmetric induction was also demonstrated. To examine the sensitivity of the 2' position of tyrosine in oxytocin, (D,L-2'-methylTyr²) oxytocin was synthesized using the standard techniques of solid phase synthesis. Racemic 2'-methyltyrosine was prepared via the classical malonate synthesis. Computer models suggest that the [L-2'-methylTyr²] oxytocin should be a weak agonist.