Chemical and chemoenzymatic syntheses of sialyl Lewisa tetrasaccharide antigen.

ABSTRACT

Sialyl Lewisa (sLea), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a tetrasaccharide glycan 1 structurally derived from sLea are reported. Challenges involved in the chemical synthesis include the highly stereoselective construction of 1,2-cis-α-L-fucoside and α-D-sialoside, as well as the assembly of the 3,4-disubstituted N-acetylglucosamine subunit. Perbenzylated thiofucoside and N-acetyl-5-N,4-O-oxazolidinone protected sialic acid thioglycoside were employed as glycosyl donors, respectively, for the efficient preparation of the desired α-fucoside and α-sialoside. The 3,4-branched glucosamine backbone was established through a 3-O and then 4-O glycosylation sequence in which the 3-hydroxyl group of the glucosamine moiety was glycosylated first and then the 4-hydroxyl. A facile chemoenzymatic approach was also exploited to synthesize the target molecule. The chemically obtained free disaccharide 30 was sequentially sialylated and fucosylated in an enzyme-catalyzed regio- and stereospecific manner to form 1 in high yields. The linker appended 1 can be covalently attached to a carrier protein for further immunological studies.