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Synthesis of a tristearoyl lipomannan via preactivation-based iterative one-pot glycosylation.

ABSTRACT: A convergent and efficient strategy was developed for the synthesis of lipomannan (LM), useful for vaccine development. Thioglycosides were employed as glycosyl donors to construct two key pseudotrisaccharide and tetramannose intermediates through preactivation-based glycosylation strategy. These building blocks were then successfully coupled to form the LM core, which was lapidated, phospholipidated, and finally globally deprotected to afford the target molecule. The intermediate LM core involved in this synthesis contained orthogonal protections, which would facilitate its variable modifications for the preparation of other complex LM derivatives and for the synthesis of LM conjugates as LM-based vaccines.

SUBMITTER: Gao J

PROVIDER: S-EPMC3906423 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Synthesis of a tristearoyl lipomannan via preactivation-based iterative one-pot glycosylation.

Gao Jian J Guo Zhongwu Z

The Journal of organic chemistry 20131203 24

A convergent and efficient strategy was developed for the synthesis of lipomannan (LM), useful for vaccine development. Thioglycosides were employed as glycosyl donors to construct two key pseudotrisaccharide and tetramannose intermediates through preactivation-based glycosylation strategy. These building blocks were then successfully coupled to form the LM core, which was lapidated, phospholipidated, and finally globally deprotected to afford the target molecule. The intermediate LM core involv ...[more]

PMID: 24266397

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Project description:Heparin (HP) and heparan sulfate (HS) play important roles in many biological events. Increasing evidence has shown that the biological functions of HP and HS can be critically dependent upon their precise structures, including the position of the iduronic acids and sulfation patterns. However, unraveling the HP code has been extremely challenging due to the enormous structural variations. To overcome this hurdle, we investigated the possibility of assembling a library of HP/HS oligosaccharides using a preactivation-based, one-pot glycosylation method. A major challenge in HP/HS oligosaccharide synthesis is stereoselectivity in the formation of the cis-1,4-linkages between glucosamine and the uronic acid. Through screening, suitable protective groups were identified on the matching glycosyl donor and acceptor, leading to stereospecific formation of both the cis-1,4- and trans-1,4-linkages present in HP. The protective group chemistry designed was also very flexible. From two advanced thioglycosyl disaccharide intermediates, all of the required disaccharide modules for library preparation could be generated in a divergent manner, which greatly simplified building-block preparation. Furthermore, the reactivity-independent nature of the preactivation-based, one-pot approach enabled us to mix the building blocks. This allowed rapid assembly of twelve HP/HS hexasaccharides with systematically varied and precisely controlled backbone structures in a combinatorial fashion. The speed and the high yields achieved in glycoassembly without the need to use a large excess of building blocks highlighted the advantages of our approach, which can be of general use to facilitate the study of HP/HS biology. As a proof of principle, this panel of hexasaccharides was used to probe the effect of backbone sequence on binding with the fibroblast growth factor-2 (FGF-2). A trisaccharide sequence of 2-O-sulfated iduronic acid flanked by N-sulfated glucosamines was identified to be the minimum binding motif and N-sulfation was found to be critical. This provides useful information for further development of more potent compounds towards FGF-2 binding, which can have potential applications in wound healing and anticancer therapy.

Dataset Information

Synthesis of a tristearoyl lipomannan via preactivation-based iterative one-pot glycosylation.

Publications

Synthesis of a tristearoyl lipomannan via preactivation-based iterative one-pot glycosylation.

Similar Datasets

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