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

• 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

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1 α，25-二羟维生素D_3在调节细胞增殖和分化以及维持钙稳态方面具有重要作用，因此合成其结构类似物以分离和提高其各自固有的生物活性已引起人们的广泛关注。本研究的目的是开发高效实用的合成方法，用于多种维生素D_3类似物的聚合合成。因为涉及A环片段和C/D环片段偶联的会聚方法比基于胆甾-5，7-二烯衍生物的光解的方法更有益，因为容易获得其非天然变体。我们发展了一种制备20-表-22-氧杂维生素D_（20-epi-22-oxavitamin D）C/D环片段的有效方法。3种TMSOTf类似物在Et_3SiH存在下催化酮与烷氧基三甲基硅烷的还原醚化反应。基于以钯（0）为中心的新策略，我们发展了一种合成A环片段的简明方法，衍生自β-酮基酯的烯醇三氟甲磺酸酯的催化的分子内Heck型反应。第三，我们首次成功地通过偶联相应的A环片段和C/D环片段合成了1 α，25-二羟基-2 β-（3-羟基丙氧基）维生素D_3（艾德-71）。

项目成果

畑山 範: "A Facile Stereoselective Route to a C/D-Ring Synthon for 20-Epi-22-oxavitamin D_3 Analogues" J.Chem.Soc.,Chem.Commun.19. 1959-1960 (1995)

Norihiro Hatayama：“20-Epi-22-oxavitamin D_3 类似物的 C/D 环合成子的简便立体选择性路线”J.Chem.Soc.，Chem.Commun.1959-1960 (1995)。

畑山 範: "Convergent Synthesis of 1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D_3(ED-71)" Bioorganic & Medicinal Chemistry Letters. 7. 2871-2874 (1997)

Noriha Hatayama：“1α,25-二羟基-2β-(3-羟基丙氧基)维生素 D_3(ED-71) 的聚合合成”《生物有机与药物化学快报》7. 2871-2874 (1997)。

畑山 範: "A Facile Stereoselective Route to a C/D-Ring Synthon for 20-Epi-22-oxavitamin D_3 Analogues" J.Chem.Soc.,Chemical Communications. 1959-1960 (1995)

Norihiro Hatayama：“20-Epi-22-oxavitamin D_3 类似物的 C/D 环合成子的简便立体选择性路线”J.Chem.Soc.，化学通讯，1959-1960 年（1995 年）。