Studies on the development of new, practical synthetic methods for the synthesis of physiologically active compounds related to vitamin D

本研究的目的是建立一套通用的维生素D及其相关化合物的合成方法，并对其进行生理测试，以系统地研究其构效关系。这项研究利用收敛策略，涵盖以下几个方面：开发不对称合成C、D-和A-环的新方法，这些方法可以通过具有自然友好和快捷过程的前所未有的方法学进行耦合。以苯基薄荷基为手性助剂，通过非对映选择性分子内Wadsworth-Emmons反应，在98.3%De中合成了C，D-环合成子。光学纯的(3S)-3，4-二羟基丁酸乙酯衍生物可以方便地从天然的L-苹果酸中获得光学纯的(3S)-3，4-二羟基丁酸乙酯衍生物，通过分子内1，3-偶极环加成反应，高效地获得了光学纯的A环合成子。此外，虽然仍处于模型反应阶段，但已表明α，β-不饱和醛与烯丙基硅烷之间的Peterson类型的烯化反应可能是即将到来的A-环合成子与C，D-环合成子的偶联过程。本研究中开发的方法似乎适用于合成结构多样化的维生素D衍生物。我们将暂时参与这项研究，希望在涉及的合成步骤或C，D-环合成子的起始手性模板的可用性方面使方法更好。

The subject of this research is to establish versatile methods for the synthesis of Vitamin D and related compounds which can be submitted to physiological tests to systematically investigate the structure-activity relationship. The research takes advantage of convergent strategy and covers following categories : the development of novel methods for the asymmetric synthesis of C,D- and A-rings, which can be coupled by unprecedented methodology featuring nature-friendly and short-cut processes. The C,D-ring synthon has been prepared in 98.3 %de based on diastereoselective intramolecular Wadsworth-Emmons reaction relying on phenylmenthyl group as a chiral auxiliary. The optically pure A-ring synthon has been in hand efficiently by means of intramolecular 1,3-dipolar cycloaddition reaction of optically pure omega-olefinic dihydroxylnitriloxide which can be derived conveniently from optically pure ethyl (3S) -3,4-dihydroxybutanoate derivative available in multigram quantities from natural L-malic acid. Also, though remained at the stage of model reaction, it has been shown that Peterson-type olefination reaction between alpha, beta-unsaturated aldehyde and allylsilane may be promising for the forthcoming coupling process of the A-ring synthon with C,D-ring synthon. The methods developed in this research seem applicable to the synthesis of structurally diversed vitamin D derivatives. We will get involved in this research for the time being whcih would hopefully make the methods much better in terms of synthetic steps involved or availability of starting chiral templates for the C,D-ring synthon.