糖醛酸脱羧氟代反应研究：稀有糖氟苷的制备及应用

Fluorinated carbohydrates are of considerable interest due to their potential applications in biological chemistry and medicinal chemistry. Among them , 4'- fluoro-furanoses and 5'- fluoro-pyranoses are attractive subsets, however, they are hard to prepare. In order to make them through a concise approach, this proposal aims to develop silver-promoted radical decarboxylative fluorination of uronic acids. The reaction features with mild reaction conditions, a broad substrate sccope and an excellent compatibility with different protecting groups and various functional groups. Various carhydrates both in furanoid and pyranoid forms, even oligosscharides including beta-cyclodextrin equipped with a wide range of protecting groups and substituents are amennable to the reaction thus providing fluorosugars in satisfactory yields..Rare sugars such as L-sugars and 6-deoxy-heptoses play important roles in bioactive natural products and medicines including oligosaccharides, glycopeptides, saponins and nucleosides. Glycosyl fluorides have proven to be powerful donor for synthesis of biologically relevant oligosaccharides and glycoconjugates. Decarboxylative fluorination of uronic acids also opens up a novel avennue to L-glycosyl fluorides from D-sugar derivatives by a head-to-tail inversion strategy.Thus the project focuses on convenient conversion of readily availble D-glucose and D-galactose derivatives into valuble L-xylo-, lyxo-, gluco- and mannopyranosyl fluorides. Additionally, 6-deoxy-D-ido-, gulo- and altro-heptopyranosyl fluorides as well as 6-deoxy-L-gluco-, galacto- and manno-heptopyranosyl fluorides are achieved with allyl gluco-, galacto- and alpha-D-mannosides as starting materials via fluorodecarboxylation of uronic acids. Finally L-glycero-4-deoxy-4-amino-L-manno-heptopyranosyl fluoride is prepared from allyl 2-deoxy-2-amino-beta-D-galatopyranoside. On the basis of the above results, penta-, tri- and hexasaccharide derivered from Sphingomonas and Campylobacter jejuni capsular polysaccharides as well as KRN-5500, a purine nucloside with unique structure and significant pain relief are accomplished by constructing challenging 1,2-cis-6-deoxy-beta-D-idopyranosidic bond and 1,2-cis-L-glycero-L-manno-heptopyranosyl linkage in this proposal.

氟代糖在生物化学和药物化学中占有重要地位。4'-氟代呋喃糖和5'-氟代吡喃糖是一类具有重要生物活性，但难于制备的分子。该项目旨在发展银促糖醛酸自由基脱羧氟代反应，为其制备提供反应条件温和、底物适用范围广和官能团耐受性好的新方法。该方法能将带有多种保护基和官能团的呋喃型和吡喃型单糖和寡糖糖醛酸转化为氟代糖。.L-糖和6-脱氧-七碳糖等稀有糖是多种活性糖类分子的组成部分。糖醛酸脱羧氟代反应为合成重要的稀有糖异头位氟代物-氟苷开辟了新途径。项目采用“头尾翻转”策略，通过脱酸氟代等反应由D-糖衍生物合成L-木糖/来苏糖/葡萄糖/甘露糖吡喃型氟苷、6-脱氧-D-艾杜/古洛/阿卓七碳糖氟苷和6-脱氧-L-葡萄/半乳/甘露七碳糖氟苷以及L-甘油-4-氨基-L-甘露七碳糖氟苷。藉此，完成来源于鞘氨醇单胞菌和空肠弯曲菌荚膜多糖中五糖、三糖和六糖糖苷以及具有独特结构和镇痛活性KRN-5500腺嘌呤核苷的合成。

由于反向氟苷和L-糖在生物化学和药物化学中的潜在应用价值，它们成为非常具有吸引力，但合成上有挑战性的合成目标分子。基于该项目的支持，通过形成C─F, C─N和 C─C键，我们建立了银促糖醛酸自由基脱羧和伯糖醇自由基脱羟甲基合成反向氟苷、稀有糖氟苷、4'/5'-叠氮取代呋喃糖/吡喃糖、糖基化的菲啶和异喹啉的新型方法。这些反应具有反应条件温和、底物适用范围广和官能团耐受性好等优点。.利用脱羧氟代反应，采用C1→C5翻转的策略，我们以易得的阿尔法-D-葡萄糖/半乳糖/甘露糖/阿洛糖烯丙基碳苷为原料，完成了8个6-脱氧-D/L-庚糖吡喃型氟苷的合成以及空肠弯曲菌CG8486荚膜六糖的构建。另外，我们也制备了3个L-己糖氟苷以及鞘氨醇单胞菌S-88多糖中五糖重复结构单元的合成。.我们也建立了金催化2-脱氧-2-DNsNH-D-葡萄糖和6-C-硝基-甘露糖邻炔基苯甲酸酯立体选择性-贝塔-糖苷反应的研究。该项目的实施为快速获得结构新颖的糖类化合物以及新型糖类药物的研发打下了方法学基础和提供了物质基础。