Synthesis and Scalable Conversion of l‑Iduronamides to Heparin-Related Di- and Tetrasaccharides

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 1C4 conformations in solution, the iduronate ester
adopts the 4C1 conformation
in solid state. An X-ray structure is also reported for the novel, 4C1-conformationally locked bicyclic
1,6-anhydro iduronate lactone along with an X-ray structures of a
novel distorted 4C1 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.

一种可实现千克级规模制备的非对映异构纯氰醇（cyanohydrin），可经一步法高效转化为一种新型L-艾杜糖酰胺（l-iduronamide）。对该艾杜糖酰胺进行新型区域选择性酰化，并采用亚硝酸戊酯（amyl nitrite）介导的温和酰胺水解新方法，可实现L-艾杜糖酸二乙酸酯C-4受体（l-iduronate diacetate C-4 acceptor）以及L-艾杜糖酸C-4受体硫代糖苷（thioglycosides）的短路径、可规模化合成。本研究报道了将上述产物高效转化为一系列肝素（heparin）相关的葡萄糖-艾杜糖二糖结构单元（gluco-ido disaccharide building blocks，涵盖多种C-4保护策略）的方法，其中包括可高效实现多克级制备关键肝素结构单元——艾杜糖硫代糖苷供体（ido-thioglycoside donors）的路线。通过分支制备受体型与供体型二糖中间体，1-O-乙酰基二糖（1-OAc disaccharide）可被转化为一种肝素相关四糖（tetrasaccharide）。1,2-二乙酰基艾杜糖酸甲酯（1,2-diacetyl iduronate methyl ester）及其类似物艾杜糖酰胺的X射线衍射（X-ray）与核磁共振波谱（NMR）数据显示：尽管二者在溶液中均采取1C4构象（1C4 conformation），但该艾杜糖酸酯在固态下采取4C1构象（4C1 conformation）。本研究同时报道了一种新型4C1构象锁定双环1,6-脱水艾杜糖酸内酯（4C1-conformationally locked bicyclic 1,6-anhydro iduronate lactone）的X射线晶体结构，以及一种新型扭曲4C1构象艾杜糖酸4,6-内酯（distorted 4C1 iduronate 4,6-lactone）的X射线晶体结构。氘标记实验（Deuterium labeling）还为新型亚硝酸戊酯介导的艾杜糖酰胺水解生成母核艾杜糖酸（iduronic acid）官能团过程中内酯产物的形成机制提供了深入的机理见解。