Synthesis and Scalable Conversion of L-Iduronamides to Heparin-Related Di- and Tetrasaccharides
Synthesis and Scalable Conversion of L-Iduronamides to Heparin-Related Di- and Tetrasaccharides
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DOI：
10.1021/jo300722y
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发表时间：
2012-09-21
影响因子：
3.6
通讯作者：
Gardiner, John M.
中科院分区：
文献类型：
--
作者：
Hansen, Steen U.;Miller, Gavin J.;Gardiner, John M.
一种非对映体纯的氰醇，可在千克规模上进行重结晶，在一步中有效地转化为新的L-艾杜糖酰胺。这种艾杜糖醛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使得能够短时间、可扩展地合成L-艾杜糖醛酸二乙酸酯C-4受体以及L-艾杜糖醛酸酯C-4受体硫代糖苷。描述了将这些有效转化为一系列肝素相关的葡萄糖-碘代二糖结构单元（各种C-4保护选择），包括有效地多克接近关键的肝素结构单元碘代-硫代糖苷供体。通过分化为受体和供体二糖，1- 0Ac二糖转化为肝素相关四糖。1，2-二乙酰基艾杜糖醛酸甲酯和类似物艾杜糖醛酰胺的X射线和NMR数据表明，虽然两者在溶液中均采用C-1（4）构象，但艾杜糖醛酸酯在固态时采用C-4（1）构象。还报道了新的C-4（1）-构象锁定双环1，6-脱水艾杜糖醛酸内酯的X射线结构沿着新的扭曲C-4（1）艾杜糖醛酸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醛酰胺水解成母体艾杜糖醛酸官能团期间内酯产物形成的机理见解。
A diastereomerically pure cyanohydrin, preparable on kilogram scale, is efficiently converted in one step into a novel L-iduronamide. A new regioselective acylation of this iduronamide and a new mild amide hydrolysis method mediated by amyl nitrite enables short, scalable syntheses of an L-iduronate diacetate C-4 acceptor, and also L-iduronate C-4 acceptor thioglycosides. Efficient conversions of these to a range of heparin-related gluco-ido disaccharide building blocks (various C-4 protection options) including efficient multigram access to key heparin-building block ido-thioglycoside donors are described. A 1-OAc disaccharide is converted into a heparin-related tetrasaccharide, via divergence to both acceptor and donor disaccharides. X-ray and NMR data of the 1,2-diacetyl iduronate methyl ester and the analogous iduronamide show that while both adopt C-1(4) conformations in solution, the iduronate ester adopts the C-4(1) conformation in solid state. An X-ray structure is also reported for the novel, C-4(1)-conformationally locked bicyclic 1,6-anhydro iduronate lactone along with an X-ray structures of a novel distorted C-4(1) iduronate 4,6-lactone. Deuterium labeling also provides mechanistic insight into the formation of lactone products during the novel amyl nitrite-mediated hydrolysis of iduronamide into the parent iduronic acid functionality.