Suzuki-Miyaura approach to JNJ-26076713, an orally active tetrahydroquinoline-containing alphaVbeta3/alphaVbeta5 integrin antagonist. enantioselective synthesis and stereochemical studies.
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| 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.
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| Authors | William A Kinney, Christopher A Teleha, Andrew S Thompson, Maria Newport, Ryan Hansen, Scott Ballentine, Shyamali Ghosh, Andrew Mahan, Gabriela Grasa, Antonio Zanotti-Gerosa, Jules Dingenen, Carsten Schubert, Yong Zhou, Gregory C Leo, David F McComsey, Rosemary J Santulli, Bruce E Maryanoff |
| Journal | The Journal of organic chemistry (J Org Chem) Vol. 73 Issue 6 Pg. 2302-10 (Mar 21 2008) ISSN: 0022-3263 [Print] United States |
| PMID | 18278942 (Publication Type: Journal Article) |
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