2.2. Selective cleavage of the tethering and subsequent modification of 5-NH2 groupDue to the 2,2-dichloroethoxycarbonyl moiety, the tethering at the C-5 amino group was selectively cleaved upon treatment of zinc to give 5-NH2 intermediate, which was transformed to sialic acid congeners by acyl modification, giving N-Ac, N-Gc and N-FucosylGc derivatives. 2.3. Synthesis of oligomeric sialic acidsIt was found that the 8-OH of macrobicyclized sialic acid was exposed outward and showed ameliorated reactivity compared to that of normal sialic acid. This finding allowed for the design of the synthesis of α(2,8)-linked oligomeric sialic acid, which is most challenging in carbohydrate synthesis. A bicyclic sialic acid donor with tentative protection at the 8-OH underwent the cycle of glycosidation and deprotection at 8-OH, producing a pentameric sialic acid derivative. Full deprotection has delivered an unprotected pentasialoside.ganglioside synthesisTaking advantage of the prominent feature of the bicyclic sialyl donors, including complete stereoselectivity and high glycosidation yields with broad coupling partners, we envisioned a novel strategy toward ganglioside synthesis based on the late-stage sialylation. We developed a highly soluble lactosyl ceramide acceptor, which were highly protected with p-tert-butylbenzoyl (TBBz) group, which was used as an aggregation inhibitor3). Then, it was reacted with the bicyclic sialyl phosphate donor at lower temperature to produce the framework of ganglioside GM3 in a high yield. The protected GM3 was successfully derivatized to GM3 analogs differentiated by the modification of the C-5 amino group of the sialic acid residue via selective removal of the tether part and acylation of the retrieved amino group, delivering N-glycolyl, N-(13C)acetyl and N-trifluoroacetyl GM3s4). Following the abovementioned result, we next synthesized a 3. Progress after the granted period3.1. Development of the late-stage sialylation strategy toward 1. Research objectiveα-Selective glycosidation of sialic acid has remained a grand challenge in carbohydrate chemistry. In glycosylation, the sialic-acid oxocarbenium intermediate is destabilized by the C1 carboxyl group and readily converts into 2,3-ene byproduct via 1,2-elimination. Furthermore, neighbouring group participation is not available because of the deoxy structure at the C3 position, resulting in the preferential formation of thermodynamically stable β-glycosides in sialylations. To surmount the sensitivity to the structure of reaction substrates and reaction conditions of the precedent methods, we envisioned a novel substrate-controlled system for producing α-sialosides, in which macrobicyclic sialic acid derivatives with α-configuration were used as the synthetic equivalent of bridgehead oxocarbenium ion of sialic acid that would limit the attack of the nucleophile to the α-face. The preliminary study revealed that a sialic acid donor with a bicyclo[12.2.2] system provided the highest yield of the α-glycoside with complete stereoselectivity. Based on the proof-of-concept, this project aimed to establish a comprehensive method for making α-sialyl molecules. 2. Results1,2) (Figure 1)2.1. Substrate scopeExamination of the glycosidation reactions of bicylclic sialic acid donors bearing a phenylsulfenyl moiety and a dibenzylphosphate moiety as a leaving group revealed broad substrate scope, including primary to tertiary hydroxyl groups linked to sugar and nonsugar backbones. Our method also allowed for the double sialylation at the primary and secondary hydroxyl groups in an oligosaccharide acceptor in a stereo- and regioselective manner to produce disialylated glycan in high yield. Due to its oxidant free condition, a phosphate sialyl donor ensured to glycosylate unsaturated substrates. Furthermore, the phosphate donor was reacted with carbon nucleophiles such as metallyltrimethylsilane and silylenol to give the corresponding C-glycosides in high yields.44Innovation of the glycosidation reaction of sialic acidHiromune AndoInstitute for Glyco-core Research (iGCORE), Gifu University, Japan
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