title: Rapid Synthesis of Boc-2',6'-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics.
abstract: The unnatural amino acid 2',6'-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2',6'-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon-carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr(1) replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Bender
authors.affiliation: Department of Pharmacology, School of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Griggs
authors.affiliation: Department of Pharmacology, School of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, School of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Trask
authors.affiliation: Department of Pharmacology, School of Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States ; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
keywords: 2′,6′-dimethyl-l-tyrosine; Negishi coupling; microwave synthesis; opioid peptidomimetics; tetrahydroquinoline