Suzuki-Miyaura approach to JNJ-26076713, an orally active tetrahydroquinoline-containing alphaVbeta3/alphaVbeta5 integrin antagonist. enantioselective synthesis and stereochemical studies

• Published in: Journal of organic chemistry 2008-03, Vol.73 (6), p.2302-2310
• Main Authors: Kinney, William A, Teleha, Christopher A, Thompson, Andrew S, Newport, Maria, Hansen, Ryan, Ballentine, Scott, Ghosh, Shyamali, Mahan, Andrew, Grasa, Gabriela, Zanotti-Gerosa, Antonio, Dingenen, Jules, Schubert, Carsten, Zhou, Yong, Leo, Gregory C, McComsey, David F, Santulli, Rosemary J, Maryanoff, Bruce E
• Format: Article
• Language: English
• Subjects: Integrin alphaVbeta3 - antagonists & inhibitors; Integrins - antagonists & inhibitors; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Receptors, Vitronectin - antagonists & inhibitors; Stereoisomerism; X-Ray Diffraction
• ISSN: 0022-3263
• DOI: 10.1021/jo702551t

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.