A Protocol for Metal Triflate Catalyzed Direct Glycosylations with GalNAc 1-OPiv Donors

Abstract

Herein we report on the development of novel glycosylation methodology for the concise synthesis of naturally occurring glycoconjugate motifs containing N-acetylgalactosamine (GalNAc) from the cheaper and commercially available N-acetylglucosamine (GlcNAc). The stereoselective glycosylations proceed with catalytic amounts of a promoter and without the need for N-protection other than the biologically relevant N-acetyl group. Among the catalysts explored, both Bi(OTf)3 and Fe(OTf)3 were found to be highly active Lewis acids for this reaction. It was also found that other less reactive metal triflates such as those of Cu(II) and Yb(III) can be beneficial in glycosylation reactions on more demanding glycosyl acceptors. We have furthermore demonstrated that it is possible to control the anomeric stereoselectivity in the glycosylation via postglycosylation in situ anomerization to obtain good yields of α-galactosides. The present protocol was used to prepare important naturally occurring carbohydrate motifs, including a trisaccharide fragment of the naturally occurring marine sponge clarhamnoside.

3-(Dimethylamino)-1-propylamine: A Cheap and Versatile Reagent for Removal of Byproducts in Carbohydrate Chemistry

“…It is well known that the solubility of acetamido-2-deoxysugars can be problematic in practice. 30 Octaacetyl lactose (12) gave similar results (1 1 / 2 h, 89%) as found for the monosaccharides described above.…”

Glycosylation: The Direct Synthesis of 2‐Acetamido‐2‐Deoxy‐Sugar Glycosides

“…It has also been demonstrated that catalytic amounts of triflic acid activated the β‐donors 1β and 88 for the glycosylation of the 6‐OH glycosidic acceptor 45 and octanol 77 , respectively (Scheme ).…”

“…Similar conditions were described for the activation of the GalNAc donor 88 bearing a pivaloyl group at the anomeric position . This donor 88 was easily synthesized from N ‐acetylglucosamine in three steps .…”

Glycosylation via Transition‐Metal Catalysis: Challenges and Opportunities

“…This method tolerates per‐benzylated glucal and a variety of alcohol acceptors. In addition, Fe(OTf) 3 was also reported as an effective Lewis acid catalyst for direct glycosylation of GalNAc 1‐ pivalate donors with alcohols to afford corresponding O ‐glycosides …”