1997 Fiscal Year Final Research Report Summary
Exploitation of an Efficient and Practical Method for the Synthesis of Active Vitamin D_3 Derivatives
| Project/Area Number |
07557290
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Nagasaki University |
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Principal Investigator |
HATAKEYAMA Susumi Nagasaki University Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (20143000)
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| Co-Investigator(Kenkyū-buntansha) |
KUBODERA Noboru Chugai Pharmaceutical Co., Ltd.Development Coordination Dep.Deputy Senior Manage, 研開推進部, 副部長
IWABUCHI Yoshiharu Nagasaki University Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (20211766)
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| Project Period (FY) |
1995 – 1997
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| Keywords | vitamin D / convergent synthesis / C / D-ring of vitamin D / reductive etherification / A-ring of vitamin D / palladium catalyzed reaction / 20-epi-22-oxavitamin D_3 / ED-71 |
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| Research Abstract |
Since 1alpha, 25-dihydroxyvitamin D_3 was found to play an important role in the modulation of cell proliferation and differentiation as well as in the maintenance of calcium homeostasis, a great deal of attention has been paid to the synthesis of its structural analogs to separate and improve its each inherent biological activities. In this research, we aimed to develop efficient and practical synthetic methods useful for the convergent synthesis of various vitamin D_3 analogs. Because a convergent approach involving coupling of a A-ring fragment and a C/D-ring fragment is much more beneficial than an approach based on photolysis of cholesta-5,7-diene derivatives due to easy access to its unnatural variants.
Firstly, we have developed an efficient method for the preparation of a C/D-ring fragment for 20-epi-22-oxavitamin D_3 analogs based on TMSOTf catalyzed reductive etherification of a ketone with an alkoxytrimethylsilane in the presence of Et_3SiH.Secondly, we have developed a concise method for the synthesis of A-ring fragments on the basis of the new strategy which centers around palladium (0) catalyzed intramolecular Heck type of reaction of the enol triflate derived from a beta-keto ester. Thirdly, we have succeeded in the first convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy) vitamin D_3 (ED-71) through coupling of the corresponding A-ring fragment and the C/D-ring fragment.
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