title: Suzuki-Miyaura approach to JNJ-26076713, an orally active tetrahydroquinoline-containing alphaVbeta3/alphaVbeta5 integrin antagonist. enantioselective synthesis and stereochemical studies.
abstract: An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477-0776, USA. wak@pei3.com
authors.forename: William A
authors.initials: WA
authors.lastname: Kinney
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Teleha
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.forename: Maria
authors.initials: M
authors.lastname: Newport
authors.forename: Ryan
authors.initials: R
authors.lastname: Hansen
authors.forename: Scott
authors.initials: S
authors.lastname: Ballentine
authors.forename: Shyamali
authors.initials: S
authors.lastname: Ghosh
authors.forename: Andrew
authors.initials: A
authors.lastname: Mahan
authors.forename: Gabriela
authors.initials: G
authors.lastname: Grasa
authors.forename: Antonio
authors.initials: A
authors.lastname: Zanotti-Gerosa
authors.forename: Jules
authors.initials: J
authors.lastname: Dingenen
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Leo
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Santulli
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D014961:X-Ray Diffraction
chemical_list: D039302:Integrin alphaVbeta3; D016023:Integrins; C527479:JNJ-26076713; D009287:Naphthyridines; D011804:Quinolines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5