Synthesis of 4-O-Alkylated N-Acetylneuraminic Acid Derivatives

Abstract

The synthesis of 4- O -alkyl analogues of N -acetylneuraminic acid (Neu5Ac) and the scope of the reaction are described. Activated alkyl halides and sulfonates and primary alkyl iodides give products in useful yields. The utility of the methodology is exemplified using a thiophenyl Neu5Ac building block to synthesize a 4- O -alkyl DANA analogue. These results expand the toolbox of Neu5Ac chemistry with value in drug discovery and for the design of novel tools to study the biology of Neu5Ac lectins.

Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction

“…However, the canyon that interconnects the Neu5Ac binding sites is directly accessible from the C4 hydroxyl via a narrow passage making it highly interesting as a point of connection as interactions to, or steric clashes with, the protein backbone of the virion are forced. Further, 4- O -alkynyl Neu5Ac building blocks are accessible via etherification of appropriately protected building blocks 19 and after deprotection conjugated to a C9 modified azido Neu5Ac compound to yield C4–C9 linked divalent Neu5Ac compounds. Another, more straightforward method, of assembling divalent Neu5Ac compounds is preparation of a common Neu5Ac building block, e.g.…”

“…That is, Pfp esters 22, 22 23, 23 and 24 were used, respectively, in the amide coupling to compound 1 to afford azido derivates 25–27 in 29–62% yield over the two steps, including O -deacetylation. The azido containing derivatives 25–27 were then, respectively, “clicked” to the alkyne building block 28 19 affording the corresponding C4–C9 linked divalent sialic acid methyl esters 29–31 in 35–78% yields. Subsequent saponification provided the corresponding C4–C9 linked divalent Neu5Ac compounds 32–34 in 83–92% yields after neutralization.…”