A General Synthetic Route to Glycosidase Inhibitors

描述（申请人提供）：本研究的目的是研究钯催化的外消旋二烯单环氧化物向对映体纯的1，2-氨基醇的动态动力学不对称转化（DYKAT）的范围，并将该方法应用于天然产物2，5-二羟甲基-3，4-二羟基-吡咯烷、1-脱氧野尻霉素、苦马豆素、1-表阿来辛、和瓜拉霉素，它们是有效的糖苷酶抑制剂，代表了这些化合物的五种一般结构类型中的四种。该反应将通过扩大可以使用的氮亲核试剂和环氧化物的列表来研究。在优化反应过程中，将产生直接转化为这些抑制剂所需的高级中间体。通过灵活的路线，使用建议的DYKAT方法的有效的对映选择性化学合成将提供一个通用的合成策略，用于合成大量的结构相似的生物碱，已被确定为潜在的药物在治疗癌症，糖尿病，肥胖症和抗病毒药物。

DESCRIPTION (provided by applicant): The goal of the research outlined in this proposal is to investigate the scope of the palladium catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic diene monoepoxides to enantiomerically pure 1,2-aminoalcohols and to apply this methodology to the synthesis of the natural products 2,5-dihydroxymethyl-3,4-dihydroxy- pyrrolidine, 1-deoxynojiromycin, swainsonine, 1-epi-alexine, and gualamycin, which are potent glycosidase inhibitors and represent four of the five general structural classes of these compounds. The reaction will be investigated by expanding the list of nitrogen nucleophiles and epoxides that can be used. In optimizing the reactions, advanced intermediates necessary for straightforward transformation into these inhibitors will be generated. Efficient enantioselective chemical syntheses by flexible routes using the proposed DYKAT methodology will provide a general synthetic strategy for the synthesis of a multitude of structurally similar alkaloids, which have been identified as potential pharmaceuticals in the therapeutic areas of cancer, diabetes, obesity, and anti-virals.