Synthesis of Constrained C‐Glycosyl Amino Acid Derivatives Involving 1,3‐Dipolar Cycloaddition of Cyclic Nitrone as Key Step

Abstract

An efficient two‐step strategy for the synthesis of constrained C‐glycosyl amino acid derivatives from C‐vinylglycosides involving a 1,3‐dipolar cycloaddition using l‐(–)‐menthone‐derived nitrone as the key step is described. After optimization of 1,3‐dipolar cycloaddition conditions, various C‐vinylglycosides were tested leading exclusively to one diastereoisomer of the corresponding cycloadduct in good to excellent yields. The total facial selectivity observed was also studied by DFT calculations. Original conformationally restricted C‐glycosyl amino acid derivatives (8 examples) were isolated after simple cleavage of the chiral auxiliary.

Synthesis, conformational analysis and GalNAc–lectin interactions of a constrained C-glycoside analogue of the TN antigen

“…10 In that context, we recently described the synthesis of constrained C-glycosyl amino acids in different series involving a 1,3dipolar cycloaddition between L-menthone-derived nitrone 4 and C-vinyl-N-acetylgalactosylamine 3 as the key step (Scheme 1). 11 Herein, we describe the synthesis, the conformational analysis and the interactions with a GalNAc-specific lectin of the constrained T N antigen analogue 2. In addition, the constrained analogues of T N antigen in vaccines have already been described and a promising anticancer immune response was observed.…”

“…In that context, we recently described the synthesis of constrained C -glycosyl amino acids in different series involving a 1,3-dipolar cycloaddition between l -menthone-derived nitrone 4 and C -vinyl- N -acetylgalactosylamine 3 as the key step (Scheme 1). 11…”

“…1,3-Dipolar cycloaddition between nitrone 4 and the C -vinyl- N -acetylgalactosylamine 13 3 led to only one diastereoisomer of the corresponding cycloadduct with high regio- and stereoselectivity in 77% yield. 11 Based on NMR analyses and DFT calculations, the excellent stereoselectivity was attributed to an exo approach from the Si face (the less hindered) of the nitrone. This total facial selectivity was only driven by the strong discrimination imposed by the isopropyl group of the chiral auxiliary of the nitrone.…”

“…This total facial selectivity was only driven by the strong discrimination imposed by the isopropyl group of the chiral auxiliary of the nitrone. 11 Then, chiral auxiliary was removed under acidic conditions. The nitrogen atom was acylated in the presence of acetic anhydride and pyridine affording compound 6 (Scheme 2).…”