Suzuki-Miyaura Approach to JNJ-26076713, an Orally Active Tetrahydroquinoline-Containing V3/V5 Integrin Antagonist. Enantioselective Synthesis and Stereoche
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- 作者：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 ; Carste
- 刊名：Journal of Organic Chemistry
- 出版年：2008
- 出版时间：March 21, 2008
- 年：2008
- 卷：73
- 期：6
- 页码：2302 - 2310
- 全文大小：194K
- 年卷期：v.73,no.6(March 21, 2008)
- ISSN：1520-6904
文摘
An improved scale-up synthesis was required for the 
V
3/V5 integrin antagonist 1, which haddemonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. Astereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyauracoupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiralhydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor andthe (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. Theundesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. Theabsolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemicalmeans.
V3/V5 integrin antagonist 1, which haddemonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. Astereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyauracoupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiralhydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor andthe (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. Theundesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. Theabsolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemicalmeans.