Practical Synthesis of Chiral Synthons for the Preparation of HMG-CoA Reductase Inhibitors
Practical Synthesis of Chiral Synthons for the Preparation of HMG-CoA Reductase Inhibitors
复制标题
用于制备 HMG-CoA 还原酶抑制剂的手性合成子的实用合成
DOI：
10.1021/jo00104a049
复制
发表时间：
1994
影响因子：
3.6
通讯作者：
Y. Araki
中科院分区：
文献类型：
--
作者：
T. Konoike;Y. Araki
A practical procedure for the enantioselective preparation of opticallypure (R)-and (S)-monomethyl esters of 3-[(Łert-butyldimethylsilyl) oxy] pentanedioic acid has been developed by diastereoselective ring-opening of 3-[(Łeri-butyldimethylsilyl) oxy] pentanedioic anhydride 5 by benzyl (R)-and (S)-mandelate, respectively. These half-esters afforded chiral Wittig reagent 2 and Homer-Wadsworth—Emmons (HWE) reagent 1 efficiently which have been proved to be useful in the synthesis of HMG-CoA reductase inhibitors. The method is applied to the synthesis of the (R)-3-methylglutaric acid, monomethyl ester.Since the recognition of hypercholesterolemia as a primary risk factor of atherosclerosis and coronary heart disease,* 1 intense efforts havebeen made to identify the chemical entity that is capable of regulating the plasma level of this sterol. These effortsresulted in the discovery of compactinand mevinolin, 2 two potent inhibitors of cholesterol biosynthesis at the level of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Comparison of compactin, mevinolin, and other known HMG-CoA reductase (HMGR) inhibitors revealed that the 3, 5-dihydroxyheptanoic acid moiety 4 is present in all compounds, and it is well-documented that this group represents a pharmacophore for HMGR inhibitor recognition. There have been many reports on the synthetic methods of this functional group. 3 Heathcock and co-workers have demonstrated the utility of the optically active Homer—Wadsworth—Em-mons (HWE) reagent I4 in their synthesis of compactin and its analogues. This synthon allows for the direct introduction of a highly functionalized side chain keto-ester 3, which eventually leads to the chiral 3, 5-dihydroxyheptanoic acid moiety 4 essential for HMGR inhibition activity (Scheme 1). They reported two routes to HWE reagent 1 that relied on the highly diastereoselec-tive reaction5 of commercially available prochiral anhydride 5 with either CR)-1-phenylethanol or(S)-l-(l'-naphthyl) ethanol for the introduction of asymmetry (88—95% diastereomeric excess(de)). Subsequent trans-formations gave HWE reagent 1 in moderate yield. The same reagent 1 was prepared by Karanewsky and co-
