A General Synthetic Route to Glycosidase Inhibitors

描述(由申请人提供)：本提案中概述的研究目标是考察钯催化的外消旋二烯单环氧化物动态动力学不对称转化(DYKAT)的范围，以生成对映体纯的1，2-氨基醇，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-脱氧诺吉罗霉素、苦马豆素、1-表阿列克辛和愈创木素的合成，这些化合物是有效的糖苷酶抑制剂，代表了这些化合物的五个一般结构类别中的四个。将通过扩大可使用的氮亲核试剂和环氧化物的名单来研究该反应。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。利用所提出的DYKAT方法通过灵活的路线进行高效的对映选择性化学合成，将为合成大量结构相似的生物碱提供一般的合成策略，这些生物碱已被确定为在癌症、糖尿病、肥胖和抗病毒治疗领域的潜在药物。

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.