1992 Fiscal Year Final Research Report Summary
New Method for Construction of Contiguous Chiral Centers with Hetero-atom Substituent
| Project/Area Number |
03671022
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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 |
Chemical pharmacy
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| Research Institution | Kobe Women's College of Pharmacy |
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Principal Investigator |
NAITO Takeaki Kobe Women's College of Pharmacy, Professor, 薬学部, 教授 (00068339)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATA Okiko Kobe Women's College of Pharmacy, Lecturer, 薬学部, 講師 (90102110)
KIGUCHI Toshiko Kobe Women's College of Pharmacy, Lecturer, 薬学部, 講師 (70068344)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Nucleophilic Addition / Thiophenol / Benzyl Mercaptan / Unsaturated Acid / Diltiazem / Isositsirikine / gamma-Lactone / Stereoselectivity |
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| Research Abstract |
Considering that contiguous stereogenic centers with hetero-atom substituent are shown in the structures of not only many medicinals but also the biologically active compounds, we investigated to explore a new method for the construction of contiguous stereogenic centers via the route involving the stereospecific nucleophilic addition reaction of hetero-atom centered nucleophiles to electron-withdrawing olefins. Among the nucleophilic addition reactions investigated, the addition of thiols to alpha, beta- unsaturated esters proceeded stereospecifically in the presence of small amount of lithium thiophenoxide to give the erythro- and threoadducts from E- and Z-olefins, respectively.
Adducts prepared by the addition reaction were found to be potential synthons by demonstrating the synthesis of natural alkaloids with ethylidene group and asymmetric synthesis of a famous drug (+)-diltiazem. Combination of the newly developed stereospecific nucleophilic addition of thiols and syn-elimination of the corresponding sulfoxide of the resulting adducts completed the total synthesis of the whole alkaloids of isositsirikine group.
Addition reactions of thiols to the unsaturated acid derivatives having chiral auxiliary proceeded smoothly to give the chiral adducts diastereoselectively which was effectively converted into (+)-diltiazem, a cardiac drug. The other chiral ad-duct was also effectively converted to (+)-trans-whisky and cognac lactones via stereoselective nucleophilic substitution of the corresponding sulfonium group.
Thus, we have now developed a new strategy for construction of the contiguous stereogenic centers with hetero-atom substituent via stereospecific nucleophilic addition reaction of thiols.
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