ENANTIOSELECTIVE SYNTHESIS OF MYO-INOSITOL DERIVATIVES

肌醇衍生物的对映选择性合成

• 批准号: 3305688
• 负责人: A RICHARD CHAMBERLIN
• 金额: $ 12.02万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1993-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3305688
• 关键词: analog; biological signal transduction; chemical structure; chemical synthesis; cyclization; galactose; glucose; inositol phosphates; mannose; phosphatidylinositols; stereoisomer

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.

该研究的目标是开发多功能合成 制备对映体纯肌醇的方法 衍生物和相关化合物。 这种方法将是伟大的 对生物医学研究界的实用性， 高等生物中信号转导的细节。 以证明 该方法的实用性，几种肌醇多磷酸的合成， 提出了生物学意义。 靶分子包括 3，4，5-三磷酸磷脂酰肌醇，1，3，4，5-D-肌醇 四（硫代磷酸）和“笼状”1，3，4，5-D-肌肌醇 四（磷酸盐）。 初步研究已经确定，葡萄糖是一种可行的前体， 对映体纯的D-肌醇衍生物的合成。 关键 合成的步骤采用了费雷尔反应的新扩展， 其中吡喃糖环被转化为卡巴替林和两个立体异构体， 以正确的配置建立中心。 此外，一名刘易斯 已经发现酸促进的费雷尔反应， 为立体化学控制提供了额外的可能性。 与此 仿生方法，广泛的方法建立了 碳水化合物的保护、操作和再功能化可以 直接应用于肌醇衍生物的制备。 拟议 研究的重点是通过检查三种方法来确定方法的范围。 结构性修改的类型。 第一，保护群体的影响 将对Ferrier反应的结果进行检查。 第二，使用 用甘露糖和半乳糖代替葡萄糖， 获得D-肌醇的立体化学修饰的类似物 多磷酸盐 第三，几种功能修饰的D-吡喃葡萄糖苷 将被用来建立该方法的适用性 构建肌醇类似物， 常规方法。 此外，Ferrier的新型替代品 反应提出了进行关键的吡喃己糖，以肌， 肌醇转化 这些变化可以提供有用的替代方案， 在这种情况下，Ferrier反应要么不适用，要么效率低下。