【作者】 丰巍伟；

【导师】 吕春绪；

【作者基本信息】 南京理工大学 ， 化学工程与技术， 2013， 博士

【摘要】 碳苷作为一类非常重要的合成砌块,常被用于合成一些具有重要生物学意义的天然产物及人工化合物。由于其具有较好的化学与生物学稳定性,即耐酸碱性及对糖苷酶的稳定性,而倍受人们的关注,但是碳苷的立体选择性合成一直是有机化学家所面对的巨大挑战。之前报道的方法对于芳基酮-p-碳苷的合成而言,存在明显的缺陷：反应时间长(12h)、产率普遍较低(6-64%)等。因此,需要开发一种快速高效的方法来合成芳基酮-β-碳苷。以D-葡萄糖为底物模型,详细研究了微波辅助立体选择性合成芳基酮-p-碳苷的方法,验证其普适性,拓展应用范围。在NaHCO3的EtOH-H2O (4:1, V/V)体系中,游离的醛糖与二苯甲酰基甲烷经微波辅助发生Knoevenagel缩合,生成芳基酮-β-碳苷,具有较高的产率(D-葡萄糖的产率高达99%,D-甘露糖的产率为98%)和立体选择性(p-构型>95%),反应时间大大缩短(仅90min),该合成方法优于之前报道的文献。立体选择性地合成羟基部分保护的芳基酮-p-碳苷及其衍生物3-乙酰氨基-3-脱氧-β-碳苷酮,有效地解决了碳苷2-或3-位羟基区域选择性保护相对困难的问题,避免了差向异构和端基异构。详细研究了1-C-(4’,6’-D苄叉基-β-D-吡喃葡萄糖基)-丙酮、2-C-(4’,6’-O-苄叉基-p-D-吡喃葡萄糖基)-苯乙酮和2-C-(4’,6’-O-苄叉基-β-D-吡喃葡萄糖基)-乙苯的2,3-位羟基区域选择性对甲苯磺酰化。相对于氧苷而言,由于碳苷没有端基效应,区域选择性保护其糖环的2-或3-位羟基就显得非常困难。以3-位对甲苯磺酰化的产物为原料,合成了3-乙酰氨基-3-脱氧-p-碳苷酮。利用上述方法合成了p-碳苷氨基糖衍生物、糖苷酶抑制剂α-溴代丙酮-β-碳苷以及治疗心血管类疾病的潜在药物β-碳苷硝酸酯。三者在有机化学、生物化学、药物化学及不对称催化领域具有良好的应用前景。以2,3-脱水-p-碳苷为原料,利用环氧化合物的选择性亲核开环反应,合成了一系列结构新颖的p-碳苷氨基糖,获得了较高的产率(37-97%)；以廉价易得的醛糖为原料,利用高效、环保的1,3-二溴-5,5-二甲基海因(DBDMH)为溴化试剂,经过碳苷化和α-溴代反应,两步法简便合成了β-糖苷酶抑制剂α-溴代丙酮-β-碳苷,总产率是文献值的2倍；以β-碳苷酮为母体化合物,经选择性保护糖环4,6-位羟基及在发烟硝酸-乙酸酐体系中的硝化反应,合成了一系列结构新颖的β-碳苷硝酸酯类化合物,为新药研发及构效关系的研究提供新的候选化合物。更多还原

【Abstract】 C-Glycosides are being used as building blocks for the synthesis of a variety of biologically important natural products and synthetic compounds. The interest in C-glycosides lies on the stability of the C-glycosidic linkage, which is resistant to both enzymatic and chemical hydrolysis. However, stereoselective synthesis of C-glycosides has been a challenging task for organic chemists.The previous conventional methodologies for the synthesis of aryl ketone β-C-glycosides have some obvious defects, including long reaction time (12h), low yields (6-64%), and so on. As a result, we need faster and more efficient methods for the synthesis of aryl ketone β-C-glycosides.This paper described a detailed optimization procedure for the microwave-assisted stereoselective synthesis of aryl ketone β-C-glycoside in D-glucose case and investigated the scope of this methodology for the preparation of several C-glycoside derivatives. This one-step protocol involved Knoevenagel condensation between unprotected aldoses and dibenzoylmethane catalyzed by NaHCO3in the co-solvents EtOH-H2O (4:1, V/V) under400W microwave irradiation, which gave aryl ketone β-C-glycosides with higher yields (99%with C-glucoside,98%with C-mannoside) and better anomeric selectivities (β-configuration>95%) in a shorter reaction time (90min), compared with previous conventional methodologies.Using this method, partially protected aryl ketone β-C-glycosides and its derivatives3-acetamido-3-deoxy-β-C-glycosidic ketones were synthesized from the corresponding partially protected aldoses and aminosugars. This methodology provided an attractive alternative to the existing means for the regioselective protection of C-glycoside2-or3-hydroxyl group, and avoided the epimerization and anomerization.Regioselective tosylation of2,3-hydroxyl groups for2-C-(4’,6’-O-benzylidene-P-D-glucopyranosyl)-acetone,2-C-(4’,6’-O-benzylidene-β-D-glucopyranosyl)-acetophenone and2-C-(4’,6’-O-benzylidene-β-D-glucopyranosyl)-ethylbenzene were investigated detailedly. Compared with O-glycosides, it was very difficult to protect2-or3-hydroxyl group of C-glycosides selectively, because C-glycosides had no anomeric effect.3-Acetamido-3-deoxy-β-C-glycosidic ketone was synthesized from the nucleophilic substitution of3-tosyl product.Based on the above methodologies, β-C-glycosidic aminosugars, β-glucosidase inhibitors a-bromoacetone-β-C-glycosides and the potential drug for the treatment of cardiovascular disease β-C-glycosidic nitrates were synthesized, which have good application prospects in organic chemistry, biochemistry, medicinal chemistry and asymmetric catalysis.β-C-Glycosidic aminosugars were synthesized through selective nucleophilic ring-opening reaction of2,3-anhydro-β-C-glycosides with good yields (37-97%). a-Bromoacetone-β-C-glycosides were synthesized concisely from cheap and available aldoses, by the two reactions of C-glycosylation and a-bromination using1,3-Dibromo-5,5-Dimethylhydantoin (DBDMH) as an efficient and environment-friendly brominating agent. The overall yield was twice as many as that of the previous literature reported. β-C-glycosidic nitrates were synthesized from β-C-glycosidic ketones, through selective protection of the4,6-position hydroxyl of pyranose ring and nitration using fuming nitric acid in acetic anhydride, which were new candidate compounds for new drug development and structure-activity relationship study.更多还原