title: S(N)1-type substitution reactions of N-protected β-hydroxytyrosine esters: stereoselective synthesis of β-aryl and β-alkyltyrosines.
abstract: The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N-dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman's catalyst delivered the unprotected β-hydroxytyrosine esters, which were further N-protected as N,N-phthaloyl (Phth) and N-fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel-Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH(2)) gave preferentially syn-products but the anti-selectivity increased when going from NHFmoc over NPhth to NBn(2). If the ester substituent was varied the syn-preference increased in the order Me < Et < iPr. The reactions were shown to be fully stereoconvergent and proceeded under kinetic product control. A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N-unprotected isopropyl ester, which gave Friedel-Crafts alkylation products with good syn-selectivity (anti/syn=21:79 to 7:93), and for the N,N-dibenzyl-protected methyl ester, which led preferentially to anti-products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)(3) -catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti-selectivitiy (anti/syn≥95:5).
authors.affiliation: Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Wilcke
authors.forename: Eberhardt
authors.initials: E
authors.lastname: Herdtweck
authors.forename: Thorsten
authors.initials: T
authors.lastname: Bach
mesh_terms: D000478:Alkylation; D000605:Amino Alcohols / Q000737:chemistry; D002412:Cations / Q000737:chemistry; D018360:Crystallography, X-Ray; D004295:Dihydroxyphenylalanine / Q000138:chemical synthesis / Q000737:chemistry*; D004952:Esters; D008956:Models, Chemical; D008968:Molecular Conformation; D009584:Nitrogen / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000605:Amino Alcohols; D002412:Cations; D004952:Esters; D004295:Dihydroxyphenylalanine; D009584:Nitrogen