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Design and synthesis of N-alkoxy analogues of deoxynojirimycin as glycosidase inhibitors.

机译：设计和合成脱氧野oji霉素的N-烷氧基类似物作为糖苷酶抑制剂。

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摘要

N-alkoxyl Deoxynojirimycin analogues were designed and synthesized as a new class of glycosidase inhibitors. Two practical procedures were developed for the synthesis of the N-alkoxy analogues of 3,4,5-trihydroxypiperidine (5-deshydroxymethyl-1-deoxynojirimycin). The key feature of these methods was the intramolecular N-cyclization of hydroxylamine derivatives which were readily obtained from the reduction of the corresponding oximes. One method was to reduce the oxime in the presence of a primary tosyl group and the resulting hydroxylamine was cyclized in situ after subsequent neutralization. The other method was to apply the Mitsunobu reaction to the synthesis of those compounds which contained the trans polyol structure. This intramolecular Mitsunobu coupling of hydroxylamine and alcohol is effective for the preparation of a variety of N-alkoxyazasugars.; The stereoselective synthesis of N-benzyloxy deoxynojirimycin started with bromination of the C-5 hydroxyl of 1,2-O-isopropylidene-{dollar}alpha{dollar}- scD-glucurono-6,3-lactone. The resulting bromolactone was reduced to a diol with the survival of the bromide. This diol was disilylated and monodesilylated to allow the formation of a benzyloxyhydroxamate at the C-5. The key intermediate 1,2-O-isopropylidene-5-benzyloxylamino-5-deoxy-{dollar}alpha{dollar}- scD-glucose was made by base-catalyzed cyclization and the following hydrolysis of the cyclized hydroxamate, i.e., the oxalidinone. The final product of N-benzyloxy deoxynojirimycin was obtained from the acidic hydrolysis of the acetonide and subsequent reductive cyclization of the above key intermediate. The correct stereochemistry of the final product was proved by removing the benzyloxy group to afford a synthetic deoxynojirimycin which has the identical proton nuclear magnetic resonance spectrum as the reported one.
机译：N-烷氧基脱氧野oji霉素类似物被设计并合成为一类新的糖苷酶抑制剂。为合成3,4,5-三羟基哌啶的N-烷氧基类似物（5-deshydroxymethyl-1-deoxynojirimycin）开发了两种实用的方法。这些方法的关键特征是羟胺衍生物的分子内N-环化，该羟胺衍生物可通过还原相应的肟而容易地获得。一种方法是在伯甲苯基存在下还原肟，然后中和后将所得羟胺原位环化。另一种方法是将Mitsunobu反应应用于那些含有反式多元醇结构的化合物的合成。羟胺和醇的这种分子内光延偶联有效地用于制备各种N-烷氧基天冬酰胺。 N-苄氧基脱氧野oji霉素的立体选择性合成始于溴化1,2-O-异亚丙基-{美元}α{美元} -scD-葡萄糖醛酸-6，3-内酯的C-5羟基。随着溴化物的存留，所得的溴内酯被还原成二醇。该二醇被二甲硅烷基化和单甲硅烷基化以允许在C-5处形成苄氧基异羟肟酸酯。关键中间体1,2-O-异亚丙基-5-苄氧基氨基5-脱氧-{美元}α{美元} -scD-葡萄糖是通过碱催化的环化反应和随后水解环化的异羟肟酸酯，即草酰丁酮制备的。 N-苄氧基脱氧野oji霉素的最终产物是从丙酮化物的酸性水解和随后的上述关键中间体的还原环化中获得的。最终产物的正确立体化学是通过除去苄氧基得到的，其合成的脱氧野rim霉素具有与所报道的相同的质子核磁共振谱。

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  • 作者

    Sun, Lihong.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Chemistry Organic.; Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 1998
  • 页码 254 p.
  • 总页数 254
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 有机化学;药物化学;
  • 关键词

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