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제107회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Enantioselective Total Synthesis of (+)-Fluvastatin via Catalytic C-C and C-O Bond Formation Reactions

2011년 2월 18일 15시 03분 39초
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목 <발표Ⅱ>
저자 및
김애진, 문영규, 김미림, 김인수
울산대학교 화학과, Korea
Statins are a class of drugs that lower the cholesterol level in the blood by blocking hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) in the liver. Statins have become the most frequently prescribed agent for the treatment of hypercholesterolemia due to their effect on reducing the rates of cardiovascular events. Fluvastatin (LescolTM) inhibits the enzyme that reduces 3-hydroxy-3-methylglutaric acid to mevalonic acid, thus blocking cholesterol biosynthesis and lowers low-density lipoprotein cholesterol levels by 20-30% at a daily dose of 20-40 mg. It has also been shown to exhibit antiviral activity against Hepatitis C. Due to their potent pharmacological effects and the unique structural features, statins have attracted considerable attention as powerful synthetic targets. The majority of synthetic approaches have focused on efficient construction of the stains side chain. In 1997, the Novartis research group described a practical asymmetric synthesis of fluvastatin via a highly selective reduction of optically pure δ-hydroxyl-β-ketoesters with a subsequent Horner-Wadsworth-Emmons reaction. In addition, they developed a manufacturing process for the production of fluvastatin in racemic form. Recently, Hayashi and coworkers reported enantioselective total synthesis of (+)- and (–)-fluvastatin and their analogues through the reaction of an aldehyde with diketene in the presence of Ti(OiPr)4 and a chiral Schiff base ligand as the key step. In this paper, we present a new strategy for the asymmetric total synthesis of (+)-fluvastatin, that includes catalytic carbon-carbon bond formations, such as Cu-catalyzed C-3 arylation, Ir-catalyzed asymmetric allylation and Ru-catalyzed intermolecular metathesis, and diastereoselective Michael addition for the preparation of 1,3-syn-diol.