ENANTIOSELECTIVE SYNTHESIS OF MYO-INOSITOL DERIVATIVES

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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.