Zhang Ran, McCarter John D, Braun Curtis, Yeung Wai, Brayer Gary D, Withers Stephen G
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1.
J Org Chem. 2008 Apr 18;73(8):3070-7. doi: 10.1021/jo702565q. Epub 2008 Mar 18.
The synthesis of a series of 2-deoxy-2,2-dihaloglycosyl halides as potential alpha-glycosidase inactivators has been achieved via the halogenation of protected 2-fluoroglycal precursors. Direct chlorination of per-O-acetylated 2-fluoro-d-glucal and 2-fluoromaltal followed by basic deprotection yielded the corresponding 2-chloro-2-deoxy-2-fluoroglycosyl chlorides. Reaction of the per-O-acetylated 2-fluoroglycals with acetyl hypofluorite or Selectfluor yielded the 2-deoxy-2,2-difluoroglycosyl derivatives, which were converted to their alpha-chlorides using thionyl chloride and deprotected under basic conditions. Trinitrophenyl glycosides of the 2-deoxy-2,2-difluoro mono- and disaccharides were synthesized by arylation of the hemiacetals with picryl fluoride, then deprotected with HCl in methanol. All three monosaccharide derivatives caused active site-directed, time-dependent inactivation of yeast alpha-glucosidase via the trapping of covalent glycosyl-enzyme intermediates, and kinetic parameters for inactivation by each compound were determined. Surprisingly neither of the 2-deoxy-2,2-dihalomaltosyl chlorides caused time-dependent inactivation of human pancreatic alpha-amylase, despite the fact that the trinitrophenyl 2-deoxy-2,2-difluoromaltoside functioned in that mode. The trinitrophenyl glycosides appear to be approximately 1000-fold more reactive than the corresponding chlorides in the enzyme active sites.
通过对受保护的2-氟代糖醛前体进行卤化反应，成功合成了一系列作为潜在α-糖苷酶失活剂的2-脱氧-2,2-二卤代糖基卤化物。对全-O-乙酰化的2-氟-D-葡萄糖醛和2-氟麦芽醛进行直接氯化，随后进行碱性脱保护，得到相应的2-氯-2-脱氧-2-氟代糖基氯化物。全-O-乙酰化的2-氟代糖与乙酰次氟酸酯或Selectfluor反应，生成2-脱氧-2,2-二氟代糖基衍生物，该衍生物用亚硫酰氯转化为其α-氯化物，并在碱性条件下脱保护。通过用苦味氟化物对半缩醛进行芳基化反应，然后在甲醇中用盐酸脱保护，合成了2-脱氧-2,2-二氟单糖和二糖的三硝基苯基糖苷。所有三种单糖衍生物通过捕获共价糖基-酶中间体，导致酵母α-葡萄糖苷酶的活性位点定向、时间依赖性失活，并测定了每种化合物失活的动力学参数。令人惊讶的是，尽管三硝基苯基2-脱氧-2,2-二氟麦芽糖苷以这种方式起作用，但两种2-脱氧-2,2-二卤代麦芽基氯化物均未导致人胰腺α-淀粉酶的时间依赖性失活。三硝基苯基糖苷在酶活性位点的反应性似乎比相应的氯化物高约1000倍。
