Challenging deprotection steps during the synthesis of tetra- and pentasaccharide fragments of the Le(a)Le(x) tumor-associated hexasaccharide antigen.

Abstract

We report the convergent synthesis of two novel tetrasaccharide and two novel pentasaccharide fragments of the Le(a)Le(x) TACA: the tetrasaccharides contain neither the galactose at the Le(a) nonreducing end nor the fucose at the Le(x) reducing end; the pentasaccharides only lack the galactose residue at the Le(a) nonreducing end. Two of the analogues were prepared as hexyl glycosides to be used in NMR experiments and as soluble inhibitors in binding studies and two as 6-aminohexyl glycosides to be conjugated to carrier proteins. Our strategy relied on stepwise extensions using excess monosaccharide glycosyl donors (trichloroacetimidates and thioglycosides) in sequential glycosylation reactions. The protecting groups were chosen to limit the number of deprotection steps required to obtain the final derivatives. While this strategy ensured that all glycosylation reactions proceeded in very good yields (70-84%), deprotection of the oligosaccharide intermediates was challenging. Global deprotection using Birch metal dissolving conditions did not remove the tert-butyldiphenylsilyl group, which indeed was incompatible with such reaction conditions. Attempts to remove the TBDPS with tetrabutylammonium fluoride was unsuccessful and led to a complex mixture of compounds that could not be separated. The desired hexyl and aminohexyl tetrasaccharides were finally obtained after four- and five-step deprotection sequences, respectively. Deprotection of the pentasaccharide intermediate to give the hexyl and aminohexyl analogues also led to unexpected results. Indeed, during Zemplén deacylation, a chloroacetamide chlorine atom was displaced by methoxide ions leading to the corresponding methoxyacetamide. Once the chloroacetamide was fully reduced to an acetamide the pentasaccharides were obtained in four and five steps, respectively.

• Authors: Mickaël Guillemineau, France-Isabelle Auzanneau
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 77 Issue 20 Pg. 8864-78 (Oct 19 2012) ISSN: 1520-6904 [Electronic] United States
• PMID: 23009725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Tumor-Associated, Carbohydrate
• Oligosaccharides

Topics

• Antigens, Tumor-Associated, Carbohydrate (chemistry)
• Carbohydrate Sequence
• Glycosylation
• Molecular Sequence Data
• Oligosaccharides (chemical synthesis, chemistry)