Principal Investigator: Hiromune Ando
Grant Title: Innovation of the glycosidation reaction of sialic acid
Abstract
1. Research objective: -Selective glycosidation of sialic acid has remained a grand challenge incarbohydrate chemistry. To surmount the sensitivity to the structure of reaction substrates andreaction conditions of the precedent methods, we envisioned a novel substrate-controlled system forproducing -sialosides, in which macrobicyclic sialic acid derivatives with -configuration wereused as the synthetic equivalent of bridgehead oxocarbenium ion of sialic acid that would restrict theattack of the nucleophile on the -face. The preliminary study revealed that a sialic acid donor with abicyclo[12.2.2] system provided the highest yield of the -glycoside with complete stereoselectivity.
Based on the proof-of-concept, this project aimed to establish a comprehensive method for making
-sialyl molecules.
2. Results
2.1. Substrate scope: Examination 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. Primary and secondary hydroxyl groups in an oligosaccharide acceptor weresimultaneously sialylated in a stereo- and regioselective manner to produce disialylated glycan inhigh yield. Due to its oxidant free condition, a phosphate sialyl donor ensured to glycosylate
unsaturated substrates. Furthermore, phosphate donor was reacted with carbon nucleophiles such as
metallyltrimethylsilane and silylenol to give the corresponding C-glycosides in high yields.
2.2. Selective cleavage of the tethering and subsequent modification of 5-NH2 group: Due to the2,2-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 acids: It was found that the 8-OH of macrobicyclized sialic acidwas exposed outward and showed ameliorated reactivity compared to that of normal sialic acid. Thisfinding allowed for the design of the synthesis of (2,8)-linked oligomeric sialic acid, which is mostchallenging in carbohydrate synthesis. A bicyclic sialic acid donor with tentative protection at the8-OH underwent the cycle of glycosidation and deprotection at 8-OH, producing a petameric sialic
acid derivative. Full deprotection has delivered unprotected pentasialoside.
3. Conclusion: A substituent of the sialic acid, the C-1 carboxyl group, which is generally
detrimental to the glycosidation, was instead harnessed as the key to solving the long-standing issueof -sialidation. These results also represent the achievement of a general, substrate-controlledstereoselective glycosidation. The prominent features of our method, including complete
stereoselectivity, high glycosidation yield, broad substrate scope and high applicability toward sialic
acid
congeners,
could
revolutionize the synthesis ofsialoglycans.
4. Publication
N. Komura et al. Science,
2019, 364, 677-680.