1991 Fiscal Year Final Research Report Summary
Synthetic study of inhibitor of HMG-CoA reductase, Compactin
| Project/Area Number |
02640418
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
天然物有機化学
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
HAGIWARA Hisahiro Tohoku University, Institute for Chemical Reaction Science, Assistant, 反応化学研究所, 助手 (20006331)
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| Project Period (FY) |
1990 – 1991
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| Keywords | Compactin / Dihydrocompactin / Double Michael reaction / Hyperlipidaemia / Aldol reaction / Inhibitor of HMG-CoA reductase / Atherosclerosis |
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| Research Abstract |
Hypercholesterolaemia is one of the major factors to cause coronary disease which is the major reason of death in the developed countries. Since more than 60% of cholesterol in blood is biosynthesised in a liver, control of cholesterol biosynthesis is important to treat and prevent such diseases. Compactin and its congeners efficiently inhibit HMG-CoA reductase, a rate limiting enzyme in cholesterol biosynthesis. We now developed a new route to synthesize(+)-dihydrocompactin which is structurally divided in two portions, decalin and delta-lactone moieties having 5 and 2 asymmetric centers respectively. The basic framework of the decalin portion was synthesised via double Mhchael reaction of the kinetic enolate of 3-alkoxy- 1 -acetylcyclohexene and methyl crotonate. The decalin thus obtained equipped enough functionalities for further transformations, especially fulfilling syn stereochemistry of methyl group at C-9 and hydrogen atom at C- 15a. The unsaturation between C- 1 0 and 1 1 was
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introduced by pyrolysis of xanthate ester at C- 1 1. Stereochemistry of the alkoxy group at C- 15, was inverted by oxidation-reduction sequence. Remaining stereochemistry at C-8 was controlled by base catalyzed isomerization of aldehyde. After completion of decalin pardon, two carbon unit from C-7 was introduced by Homer-Emmons reaction. Two successive reductions, reduction of alpha, beta-unsaturation and ester group, provided alcohol which was resolved as(R)-O-methylmandelate. Removal of the chiml auxiliary followed by oxidation furnished the aldehyde. The requisite delta-lactone portion was introduced by using TiCl_4 promoted aldol condensation of bistrimethylsilylenol ether of methyl acetoacetate to give 5-hydroxy-3-ketoester. Since the secoacid of dihydrocompactin has syn-dihydroxy group at C-3 and 5, the resulting ketoester was reduced with the combination of Et_2BOMe-NaBH_4 to give syn-3, 5-diol. Final treatment of the dihydroxy-ester with BF completed the total synthesis of(+)-dihydrocompactin. The spectral data including optical rotational value and melting point were identical with reported ones. Less
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Research Products
(1 results)
