Enzymatic acylation and ring-closing olefin metathesis: a convenient strategy for the lactone moiety of compactin and mevinolin.
Enzymatic acylation and ring-closing olefin metathesis: a convenient strategy for the lactone moiety of compactin and mevinolin.
复制标题
酶促酰化和闭环烯烃复分解：Compactin 和 Mevinolin 内酯部分的便捷策略。
DOI：
10.1021/jo000528m
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Lei,H
中科院分区：
文献类型：
--
作者：
Ghosh,AK;Lei,H
Compactin (1) and mevinolin (2) are potent inhibitors of HMG-CoA reductase, the rate-limiting enzyme involved in cholesterol biosynthesis. 1 Both of these compounds have been shown to reduce serum cholesterol levels in animals as well as in humans. 2 The therapeutic efficacy of mevinolin has been well documented. 3 One of the key structural features of these fungal metabolites is the presence of a (4R, 6R)-tetrahydro-2-pyrone unit that is essential for their biological properties. 4 As a consequence, a great deal of synthetic studies have been devoted to the optically active synthesis of the-hydroxy-δ-lactone, as well as on the replacement of the complex hexahydronaphthalene moieties of compactin or mevinolin. 5 This effort has resulted in the discovery of numerous very potent and selective HMG-CoA reductase inhibitors in which the δ-lactone moiety has been attached to simpler aromatic fragments. 6 As part of our interest in the enzymatic methodologies for 1, 3-diol synthons, we have developed an enantioselective synthesis of the δ-lactone unit of mevinolin (Figure 1). Herein, we report a convenient synthesis of (4R, 6S)-tetrahydro-2-pyrone derivative 3 in high enantiomeric excess, utilizing an immobilized lipase catalyzed selective acylation of (()-1-(benzyloxy)-4-penten-2-ol and a ringclosing olefin metathesis with Grubbs’ catalyst as the key steps.The key starting material, racemic homoallylic alcohol 5, was prepared in multigram quantities by treatment of commercial benzyloxyacetaldehyde with allyltrimethylsilane in the presence of TiCl4 in CH2Cl2 at-78 C for 30 min. Enzymatic acylation of the racemic alcohol 5 with immobilized lipase PS-30 (25 wt% with respect to lipase PS-30) in the presence of isopropenyl acetate in dimethoxy-
