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.

拟议研究的目的是开发多功能合成 制备对映体甲基肌醇的方法 衍生物和相关化合物。 这种方法将很棒 生物医学研究界的实用程序，该社区正在努力理解 较高生物体中信号转导的细节。 展示 方法论的实用性，几种肌醇多磷酸盐的合成 提出了生物学兴趣。 目标分子包括 磷脂酰肌醇3,4,5-三磷酸盐，1,3,4,5-D-myo-肌醇 俄罗斯蛋白酶（磷酸盐剂）和“笼” 1,3,4,5-d-myo-肌醇 四甲基（磷酸盐）。 初步研究已经确定葡萄糖是可行的前体 对映体pure d-myo-肌醇衍生物的合成。 钥匙 合成的步骤采用了Ferrier反应的新型扩展， 吡喃糖环将其转换为carbacycle和两个立体源性 中心以正确的配置建立。 此外，刘易斯 酸促进的Ferrier反应的版本已被发现 为立体化学控制提供了其他可能性。 与此 仿生方法，为建立的广泛方法 碳水化合物的保护，操纵和改建可以是 直接应用于肌醇衍生物的制备。 提议 研究重点是通过检查三个 结构修饰的类型。 首先，保护团体的影响 将检查有关Ferrier反应的结果。 其次，使用 将探索甘露糖和半乳糖代替葡萄糖获胜 访问D-myo-Inositol的立体化学修饰类似物 多磷酸盐。 第三，几种功能改性的D-葡萄吡喃糖苷 将被用来确定该方法的适用性 构建肌醇类似物，这些类似物很难由 常规方法。 此外，Ferrier的新颖替代品 提出了进行至关重要的六吡喃糖至myo-提出的反应 肌醇转换。 这些变化可能会提供有用的替代方案 Ferrier反应的情况是不适用或效率低下。