Facile synthesis of tetrasaccharide aided by fluorous chemistry toward a dengue virus vaccine
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Facile synthesis of tetrasaccharide aided by fluorous chemistry toward a dengue virus vaccine Yan Zhang · Bo Liu · Gang Liu
Received: 25 April 2013 / Accepted: 2 May 2013 / Published online: 22 May 2013 © Springer Science+Business Media Dordrecht 2013
Abstract We report the synthesis of a tetrasaccharide with side chain using a light-fluorous-tagged glycosyl donor through the double glycosylation and gradient fluorous solidphase extraction by adding a little of DCM to improve the solubility for retention for the first time. This convergent method has high efficacy by saving much time and solvent. Keywords Dengue vaccine · Tetrasaccharide · Fluorous chemistry · Double glycosylation · Gradient FSPE
Introduction The World Health Organization (WHO) estimates that 2.5 billion people are at risk of getting infected with dengue. Electronic supplementary material The online version of this article (doi:10.1007/s11030-013-9451-0) contains supplementary material, which is available to authorized users. The core tetrasaccharide with a side chain was synthesized using the excess fluorous-tagged mannosyl donor through double glycosylation. Purification of the resulting glycosides was rapidly and efficiently accomplished by a gradient fluorous solid-phase extraction (FSPE). Y. Zhang · B. Liu · G. Liu Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2 Nanwei Rd., Xicheng District, Beijing 100050, People’s Republic of China G. Liu Tsinghua-Peking Center for Life Sciences, Beijing, People’s Republic of China G. Liu (B) Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Haidian District, Beijing 100084, People’s Republic of China e-mail: [email protected]; [email protected]
There are at present four known antigenically distinct serotypes dengue virus. The designed vaccine must be tetravalent in formulation as a result of antibody-dependent enhancement (ADE) [1]. It is known that the four serotypes share the same 3D structure of their envelope glycoprotein [2,3] and the conserved oligosaccharide at the Asn-153 glycosylation site has been elucidated and modeled as a hexasaccharide consisting of three mannose, two N-acetyl glucosamine, known as the core pentasaccharide structure, and one fucose residue which often increases the overall immunogenicity in oligosaccharide [4] (Fig. 1). Thus, the ready availability of the glycopeptide with the conserved oligosaccharide and the peptides attached can greatly facilitate the exploration of biological functions of this glycopeptide and the development of a dengue vaccine. However, synthesis of glycopeptides on solid support usually has the drawbacks of requiring large excess of reagents and difficulty in monitoring the reaction process. Fluorous chemistry has been wildly used in biphasic catalysis, combinatorial and parallel synthesis of small molecules, and separation of bimolecules [5–7]. Since the Curran group first reported the utility of heavy-fluorous-tagge
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