ENANTIOSELECTIVE SYNTHESIS OF MYO-INOSITOL DERIVATIVES

提出的研究目标是开发多功能合成材料。 对映体纯肌醇的制备方法 衍生物和相关化合物。这种方法论将是非常有用的 对正在努力理解的生物医学研究社区的效用 高等生物体中信号转导的细节。要演示 方法学的实用性，几种肌醇多聚磷酸盐的合成 提出了生物兴趣的概念。目标分子包括 磷脂酰肌醇3，4，5-三磷酸，1，3，4，5-D-肌醇 四(硫代硫酸盐)和笼养的1，3，4，5-D-肌醇 四(磷酸盐)。 初步研究证实，葡萄糖是一种可行的前体 对映体纯D-肌醇衍生物的合成。钥匙 该合成步骤采用了费里尔反应的新扩展，In 其中吡喃糖环转化为碳环和两个立体生成物 中心建立在正确的配置中。此外，一位刘易斯 酸促进的费里尔反应已被发现 为立体化学控制提供了额外的可能性。有了这个 仿生方法，为 碳水化合物的保护、操纵和再官能化可以是 直接应用于肌醇衍生物的制备。建议数 研究的重点是通过考察三个方面来确定该方法的范围 结构修改的类型。第一，保护群体的影响 关于费里尔反应的结果，将进行检查。其次，使用 用甘露糖和半乳糖代替葡萄糖酒作为一种手段进行探索 获得D-肌醇的立体化学修饰类似物 聚磷酸盐。第三，几种官能化的D-吡喃葡萄糖苷 将被用来确定该方法对 很难制备的肌醇类似物的结构 传统的方法。此外，渡轮的新替代品 提出了进行关键的己糖转化为肌醇的反应. 肌醇转化。这些变化可能在以下方面提供有用的替代方案 费里尔反应不适用或效率低下的情况。

The goal of the proposed research is the development of versatile synthetic methodology for the preparation of enantiomerically-pure myo-inositol derivatives and related compounds. This methodology will be of great utility to the biomedical research community that is striving to understand the details of signal transduction in higher organisms. To demonstrate the utility of the methodology, syntheses of several inositol polyphosphates of biological interest are proposed. The target molecules include phosphatidylinositol 3,4,5-trisphosphate, 1,3,4,5-D-myo-inositol tetrakis(phosphorothioate), and "caged" 1,3,4,5-D-myo-inositol tetrakis(phosphate). Preliminary studies have established that glucose is a viable precursor for the synthesis of enantiomerically-pure D-myo-inositol derivatives. The key step of the synthesis employs a novel extension of the Ferrier reaction, in which the pyranose ring is converted to a carbacycle and two stereogenic centers are established in the correct configuration. In addition, a Lewis acid-promoted version of the Ferrier reaction has been discovered that offers additional possibilities for stereochemical control. With this biomimetic approach, the extensive methodology established for the protection, manipulation, and refunctionalization of carbohydrates can be directly applied to the preparation of inositol derivatives. The proposed studies focus on establishing the scope of the method by examining three types of structural modification. First, the impact of protecting groups on the outcome of the Ferrier reaction will be examined. Secondly, the use of mannose and galactose in place of glucose win be explored as a means of accessing stereochemically-modified analogues of the D-myo-inositol polyphosphates. Thirdly, several functionally-modified D-glucopyranosides will be employed to establish the applicability of the method for the construction of inositol analogues that are very difficult to prepare by conventional methods. In addition, novel alternatives to the Ferrier reaction are proposed for carrying out the crucial hexopyranose-to-myo- inositol conversion. These variations may offer useful alternatives in cases in which the Ferrier reaction is either inapplicable or inefficient.