Enantioselective total synthesis of (+)-6-epi-mevinolin and its analogs. Efficient construction of the hexahydronaphthalene moiety by high pressure-promoted intramolecular Diels-Alder reaction of (R,2Z,8E,10E)-1-[(tert-butyldimethylsilyl)oxy]-6-methyl-2,8,10-dodecatrien-4-one
Enantioselective total synthesis of (+)-6-epi-mevinolin and its analogs. Efficient construction of the hexahydronaphthalene moiety by high pressure-promoted intramolecular Diels-Alder reaction of (R,2Z,8E,10E)-1-[(tert-butyldimethylsilyl)oxy]-6-methyl-2,8,10-dodecatrien-4-one
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DOI：
10.1021/jo970444m
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发表时间：
1997-08-08
影响因子：
3.6
通讯作者：
Konoike, T
中科院分区：
文献类型：
--
作者：
Araki, Y;Konoike, T
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（+）-6-epi-mevinolin（2a）和（+）-6-epi-4a，5-dihydromevinolin（2b）是通过将两个非外消旋单元膦酸酯3和十氢萘4（分别由对映体纯的3-取代戊二酸单酯5a和5 b制备）合并而制备的。每种酸都是由环酸酐7a和7 b通过非对映选择性开环合成的，所述开环是借助于（S）-扁桃酸苄酯作为常见的手性助剂。十氢萘部分4的构建是通过带有甲基作为手性控制器的非外消旋三烯酮6的不对称分子内Diels-Alder（IMDA）反应完成的。三烯酮6的IMDA非对映选择性是根据（E）-和（Z）-双烯亲体的构型来讨论的，它们被内源性羰基活化。（R）-（Z）-6在高压下的IMDA反应是高度选择性的，并且仅产生顺式-十氢化萘，其中4优先于16形成。将（+）-6-表-美维诺林（2a）和几种类似物对HMG-CoA还原酶的抑制活性与美维诺林（1b）进行比较。（+）-6-表-美维诺林（2a）的效力为美维诺林（1b）的一半，而（+）-6-表-4a，5-二氢美维诺林（2b）的效力与美维诺林相同。
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a) and (+)-6-epi-4a,5-dihydromevinolin (2b), were prepared by combining two nonracemic units, phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by means of (S)-benzyl mandelate as a common chiral auxiliary. The construction of decalin moiety 4 was accomplished by asymmetric intramolecular Diels-Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller. The IMDA diastereoselectivity of trienone 6 is discussed in terms of the configuration of(E)- and (Z)-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of(R)-(Z)-6 under high pressure is highly selective and gives cis-decalins exclusively with preferential formation of 4 over 16. The inhibitory activity of (+)-6-epi-mevinolin (2a) and several analogs against HMG-CoA reductase was compared with mevinolin (1b). (+)-6-epi-Mevinolin (2a) was shown to be half as potent as mevinolin (1b) while (+)-6-epi-4a,5-dihydromevinolin (2b) was as potent as mevinolin.