Exploitation of an Efficient and Practical Method for the Synthesis of Active Vitamin D_3 Derivatives

一种高效实用的活性维生素D_3衍生物合成方法的开发

基本信息

批准号：
07557290
负责人：
HATAKEYAMA Susumi
金额：
$ 0.83万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557290/
关键词：
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 活性型ビタミンD_3 骨粗鬆症治療薬キラル合成 Heck反応 A-環部エノールトリフラート活性型ビタミンD_3C 還元的エー

项目摘要

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.

由于1Alpha，发现25-二羟基维生素D_3在调节细胞增殖和分化以及维持钙稳态方面起着重要作用，因此对其结构类似物的合成引起了极大的关注，以分离并改善其每种固有的生物学活动。在这项研究中，我们旨在开发有效且实用的合成方法，可用于收敛的各种维生素D_3类似物。因为涉及涉及A圈碎片和C/D环碎片耦合的收敛方法比基于胆固醇5,7-7-二烯衍生物的光解相比，由于容易获得其非自然变体，因此我们开发了一种基于C/D ring fragmig的有效方法，因此我们开发了一种有效的方法。在ET_3SIH的存在下，我们已经开发了一种简洁的方法来基于钯（0）催化了eN型eSterem eSter eSter eStere eStere eStere eStere的eNOL TRIFFIFLAIE AROL eSTRAIE的eNOL TRIFFIFLAIE AROL eSTERARE的新策略，在ET_3SIH的存在下，用烷氧基三甲基硅烷的催化催化的酮的还原性醚化。第三，我们通过相应的A形片段和C/D环片段偶联，成功地将1α，25-二羟基-2Beta-（3-羟基丙氧基）维生素D_3（ED-71）取得了成功的合成。