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

自从发现1alpha， 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中起重要作用以来，人们开始关注其结构类似物的合成，以分离和提高其固有的生物活性。在本研究中，我们旨在开发一种高效实用的合成方法，用于各种维生素D_3类似物的聚合合成。因为涉及a环片段和C/ d环片段耦合的收敛方法比基于胆碱-5,7-二烯衍生物光解的方法更有益，因为它更容易获得其非自然变体。首先，我们开发了一种基于TMSOTf催化酮与烷氧基三甲基硅烷在Et_3SiH存在下的还原醚化反应制备20-epi-22- ox维生素D_3类似物C/ d环片段的有效方法。其次，我们以钯(0)为中心，以分子内Heck型反应为中心，开发了一种简洁的合成a环片段的方法，该方法是由β -酮酯衍生的烯醇三酸酯。第三，通过a环片段与C/ d环片段的偶联，首次成功聚合合成了1 α， 25-二羟基-2 β -（3-羟基丙氧基）维生素D_3 （ED-71）。

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.