Suzuki−Miyaura Approach To JNJ-26076713, An Orally Active Tetrahydroquinoline-Containing αVβ3/αVβ5 Integrin Antagonist: Enantioselective Synthesis And Stereochemical Studies
Journal Of Organic Chemistry
An improved scale-up synthesis was required for the αVβ3/αVβ5 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.
W. A. Kinney, C. A. Teleha, A. S. Thompson, Maria Gallagher Newport, R. Hansen, S. Ballentine, S. Ghosh, A. Mahan, G. Grasa, A. Zanotti-Gerosa, J. Dingenen, C. Schubert, Y. Zhou, G. C. Leo, D. F. McComsey, R. J. Santulli, and B. E. Maryanoff.
"Suzuki−Miyaura Approach To JNJ-26076713, An Orally Active Tetrahydroquinoline-Containing αVβ3/αVβ5 Integrin Antagonist: Enantioselective Synthesis And Stereochemical Studies".
Journal Of Organic Chemistry.