Sialic acids are a family of over 50 naturally occurring 2-keto-3-deoxy-nononic acids in which the three most prevalent are N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc) and N-acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2). The most ubiquitous especially in human cells is Neu5Ac, which is expressed at the terminal position of glycoconjugates at the out face of cell membranes.
The numerous and important biological functions of these natural products, and therefore their use to drug design have been the driving force for the development of efficient chemical methodologies for their synthesis (chemical sialylations).
The stereoselective synthesis of sialic acid’s glycosidic bonds is today one of the major challenges in carbohydrate chemistry. Although a dramatic improvement has been recorded in the last decades, it is widely recognized that the field is still in need of more straightforward and efficient methods for the synthesis of these important compounds.
In particular, while the investigation of O-protecting groups is one of the most dedicated aspect in carbohydrate chemistry, for sialic acid very little is known on the effect of protecting groups at the O-positions. Recently, we proved that: 1) during sialylation reactions, the oxacarbenium ion can undergo a conformational change to all-axial conformation; 2) perbenzoylation of sialic acid creates a β-directing sialyl donor; 3) the introduction of tert butyl dimethyl silyl (TBDMS) group at C-4 is activating and α directing only in sialylations in acetonitrile as solvent (MeCN). These data strongly suggest an important influence of C-4 protecting groups during sialylations.
Herein we report the introduction of a picoloyl (Pico) group at C-4 and its testing as activating and/or stereodirecting group. Our rationale is based on the work of Demchenko et. al, who proved the high stereodirecting effect of Pico for several other monosaccharides, based on an Hydrogen-bond Aglycone Delivery (HAD), where the nuclephilic acceptor is Hbonded to the donor (via the Pico group) and is delivered in syn to it, controlling therefore the stereoselectivity of the reaction. When applied to sialic acid, we found that the HAD delivery is impeded by competing elimination reaction and reaction conditions (low temperature).
|Advisor:||De Meo, Cristina|
|Commitee:||Demchenko, Alexei, Dixon, Robert, O'Brien, Leah|
|School:||Southern Illinois University at Edwardsville|
|School Location:||United States -- Illinois|
|Source:||MAI 55/06M(E), Masters Abstracts International|
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