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

本研究的主题是建立多种合成维生素D及其相关化合物的方法，并将其提交生理试验，以系统地研究其构效关系。本研究利用趋同策略，主要包括以下几个方面：开发了C、D和a环的不对称合成新方法，这些方法可以以前所未有的自然友好和捷径的方法耦合；以苯基甲基为手性助剂，采用非对映选择性分子内Wadsworth-Emmons反应，以98.3%的收率合成了C， d环。通过分子内1,3-偶极环加成反应得到了光学纯的-烯烃二羟基硝基氧化物，该化合物可由天然l -苹果酸的多克量光学纯乙基(3S) -3,4-二羟基丁酸衍生物方便地得到。此外，虽然仍处于模型反应阶段，但研究表明，α、β -不饱和醛与烯丙基硅烷之间的彼得森型烯烃化反应可能是即将到来的a环合子与C、d环合子偶联过程的重要组成部分。本研究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。我们将会参与到这个研究中这将有希望使方法在合成步骤上更好或者在C， d环合成的起始手性模板的可用性上更好。

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.