Synthesis of Unusual Sugar Library  

    Unusual sugars is a group of structurally diverse sugars bearing three types of modifications from a normal sugar scaffold including deoxygenation, amino group substitution, and branch chain modification. Unusual sugars are commonly found in the  naturally occurring antibiotics and play pivotal roles in the activity of these antibiotics.

Examples of Normal Sugar and Unusual Sugars

    Given the complexity of the unusual sugars found in the naturally occurring antibiotics, it is arduous to outline or predict the conclusions regarding the structure activity relationship of unusual sugars among the vast numbers of unusual sugar-containing antibiotics. In other words, there is no obvious rationale to which the synthesis of unusual sugar can follow. Fortunately, Wong and co-workers have proposed several binding motifs based on the commonly observed structural features of unusual sugars on aminoglycosides. These include gluco-/galacto-1,3-hydroxyl- amino and cis-/trans-1,2-hydroxylamino substructures. Mimicking these binding motifs, we propose four new natural and non-natural binding motifs, including gluco-/galacto-1,3-diamino and variants of gluco-/galacto-1,3-hydroxylamino substructures. These are the guidelines for the syntheses of our aminosugars and deoxysugars.

Binding Motif of Aminosugars/Deoxysugars

    Extensive studies have been done toward the synthesis of various aminosugars. However, there are two problems often associated with these results. First, the syntheses of most of the aminosugars/deoxysugars begin with different starting materials. For synthesizing a library of aminosugars, this will increase the burden of synthetic work. To alleviate this problem, we employ the philosophy of divergent synthesis for the expedient synthesis of a library of unusual sugars.

Philosophy Divergent Synthesis

    The second problem is the lack of convenient methodologies for converting the synthetic aminosugars/deoxysugars into glycosyl donors for glycosylation. This is the critical step that will permit the synthetic unusual sugars for practical applications. Many reported syntheses of aminosugars/deoxysugars make no attempts toward glycosylation. In fact, many protecting groups employed in these syntheses may not be compatible to the conditions that are required for converting aminosugars/deoxysugars into glycosyl donors. Therefore, there is a shortcoming in utilizing these unusual sugars for biological studies.

Problems encountered during the glycosylation of aminosugars

    On the other hand, most of the glycosyl donors are not stable enough in the conditions for amino group incorporation or deoxygenation. To avoid the complications during the glycosylation, Wong, Crich, and others have used phenylthio or ethylthio as the protecting group on C-1. Phenylthio or ethylthio groups are stable enough to endure the conditions for amino group incorporation and deoxygenation, and can be activated for glycosylation directly. However, the starting material, ethyl thioglucopyranoside or phenyl thioglucopyranoside, are difficult to prepare in the quantity we need (at least 200 g) for the preparation of the number of aminosugars/deoxysugars we designed. Commercially available thioglucopyranose is too expensive to be a practical option (ethyl thioglucopyranose: 1g for $230.7 from Sigma Co.). Therefore, we still mostly use methyl glucopyranoside (500g for $36) as the starting material; which means, we have to develop a reliable and general method for converting the methyl glycosides into glycosyl donors.

    After numerous attempts, we have developed a general method for converting the azidosugars into glycosyl donors concomitant with the protection of hydroxyl groups by acetyl groups. To expedite the synthetic work, the amino groups are masked as azido groups, which can be reduced at the final stage of synthesis. In summary, we are one of the few groups capable of synthesizing such a diverse but systematic unusual sugar library, and utilizing this library for practical applications. With the successful synthesis of the aminosugar/deoxysugar library, we began to work on one of the many envisioned applications: the synthesis of pyranmycin, a novel library of aminoglycoside antibiotics.

Synthesis of glycosyl donor and glycosylation of aminosugars

 A library of unusual sugars is available for glycosylation

 

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