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Synthesis and Scalable Conversion of L?Iduronamides to Heparin-Related Di- and Tetrasaccharides

机译:L?Iduronamides的合成和可扩展转化为肝素相关的二糖和四糖

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A diastereomerically pure cyanohydrin, preparablenon kilogram scale, is efficiently converted in one step intona novel L-iduronamide. A new regioselective acylation of thisniduronamide and a new mild amide hydrolysis methodnmediated by amyl nitrite enables short, scalable syntheses ofnan L-iduronate diacetate C-4 acceptor, and also L-iduronate C-n4 acceptor thioglycosides. Efficient conversions of these to anrange of heparin-related gluco-ido disaccharide building blocksn(various C-4 protection options) including efficient multigramnaccess to key heparin-building block ido-thioglycoside donorsnare described. A 1-OAc disaccharide is converted into a heparin-related tetrasaccharide, via divergence to both acceptor andndonor disaccharides. X-ray and NMR data of the 1,2-diacetyl iduronate methyl ester and the analogous iduronamide show thatnwhile both adopt 1C4 conformations in solution, the iduronate ester adopts the 4C1 conformation in solid state. An X-raynstructure is also reported for the novel, 4C1-conformationally locked bicyclic 1,6-anhydro iduronate lactone along with an X-raynstructures of a novel distorted 4C1 iduronate 4,6-lactone. Deuterium labeling also provides mechanistic insight into the formationnof lactone products during the novel amyl nitrite-mediated hydrolysis of iduronamide into the parent iduronic acid functionality.
机译:可制备的非对映体纯的氰醇,非公斤级,一步一步就能有效地转化为新型的L-艾杜糖酰胺。该亚硝酰胺的新的区域选择性酰化和由亚硝酸戊酯介导的新的温和酰胺水解方法可短而可扩展地合成南L-异氰酸酯二乙酸酯C-4受体,以及L-异氰酸酯C-n4受体硫代糖苷。将它们有效地转化为各种肝素相关的葡萄糖基双糖构筑物n(各种C-4保护选项),包括对关键的肝素构筑基糖基-硫代糖苷供体的有效多价访问。 1-OAc二糖通过与受体二糖和供体二糖的分歧而转化为肝素相关的四糖。 1,2-二乙酰基异丁酸酯甲酯和类似的异丁烯酰胺的X射线和NMR数据表明,虽然溶液中均采用1C4构型,但固态时异丁酸酯采用4C1构型。还报道了新颖的4C1构象锁定的双环1,6-无水异戊二酸酯内酯的X射线结构,以及新颖的扭曲的4C1异丁酸酯4,6-内酯的X射线结构。氘标记还提供了在新的亚硝酸戊酯介导的艾杜糖酰胺水解为母体艾杜糖酸官能团期间内酯产物形成的机理的机理。

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