Suzuki−Miyaura Approach To JNJ-26076713, An Orally Active Tetrahydroquinoline-Containing αVβ3/αVβ5 Integrin Antagonist: Enantioselective Synthesis And Stereochemical Studies
Document Type
Article
Publication Date
3-21-2008
Published In
Journal Of Organic Chemistry
Abstract
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.
Recommended Citation
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.
(2008).
"Suzuki−Miyaura Approach To JNJ-26076713, An Orally Active Tetrahydroquinoline-Containing αVβ3/αVβ5 Integrin Antagonist: Enantioselective Synthesis And Stereochemical Studies".
Journal Of Organic Chemistry.
Volume 73,
Issue 6.
2302-2310.
DOI: 10.1021/jo702551t
https://works.swarthmore.edu/fac-chemistry/199