P-61 (+)-6-エピメビノリンの不斉合成(ポスター発表の部)
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概要
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Recognizing that structural modification on 6 position of compactin led to two therapeutically useful HMG-CoA reductase inhibitors, mevinolin and pravastatin, we have synthesized 6β-methylated derivatives of compactin (6-epi-mevinolin) and discussed their structure-activity relationships. (+)-6-epi-Mevinolin 2a and analogs were prepared by an enantioselective total synthesis which employed a chiral benzyl mandelate as a sole chiral auxiliary. The key feature of our strategy is connecting two chiral synthons, Horner-Wadsworth-Emmons reagent 3 and octalin aldehyde 4. These two chiral synthons were obtained by asymmetric ring opening of prochiral 3-substituted glutaric anhydrides and with a chiral benzyl mandelate. The octalin moiety was assembled by an intramolecular Diels-Alder reaction of a chiral enone 15, which is highly stereoselective under super high pressure. The ring opening amide formation from lactone was also accelerated under super high pressure, and these high pressure transformations offer the several advantages over conventional methods in terms of the yields of products, selectivity, and operational simplicity. This is the first synthesis of (+)-6-epi-mevinolin 2a and our strategy would offer a general approach for other 6β-substituted derivatives of compactin. The inhibitory activity of (+)-6-epi-mevinolin 2a and analogs against HMG-CoA reductase was evaluated, and (+)-6-epi-4a,5-dihydromevinolin 2b was shown to be the most potent inhibitor.
- 天然有機化合物討論会の論文
- 1995-09-01