Synthesis and X-ray crystallographic investigation of N-(3-deoxy-3-acetamido-β-D-glycopyranosyl)alkanamides as analogs of N-glycoprotein linkage region

Abstract

As part of our ongoing program aimed at understanding the structural significance of GlcNAcβAsn linkage conserved in all eukaryotic N-glycoproteins, the present study reports on the synthesis and X-ray crystal structures of N-(3-deoxy-3-acetamido-β-D-glycopyranosyl)acetamide (Glc3NAcβNHAc) and the corresponding propionamide (Glc3NAcβNHPr). Comparative analysis of these structures with those of the corresponding GlcNAc (C2 acetamido) compounds showed that the bifurcated anti-parallel pattern involving N-H…O and C-H…O hydrogen bonds, the hallmark feature of the N-glycoprotein models, GlcNAcβNHAc and GlcNAcβAsn, is absent in both the C3 acetamido analogs. The extended (anti) conformation of the amido aglycon moiety as defined by χ(2) seen in the case of C2 acetamido derivative, GlcNAcβNHPr, turns into gauche for the C3 acetamido analog (Glc3NAcβNHPr). This observation is consistent with the earlier work on the critical role of the C2-NHAc group of GlcNAcβAsn in controlling χ(2) at the linkage region of N-glycoproteins.

Exploring the Effect of Bioisosteric Replacement of Carboxamide by a Sulfonamide Moiety on N‐Glycosidic Torsions and Molecular Assembly: Synthesis and X‐ray Crystallographic Investigation of N‐(β‐D‐Glycosyl)sulfonamides as N‐Glycoprotein Linkage Region Analogues

“…Further studies on the various glycosyl alkanamides illustrated the influence of the substituent at C2 and C5 as well as environmental factors particularly inter‐ and intramolecular interactions involving hydrogen bonds and the weak CH⋅⋅⋅O contacts on the energy preference of the ϕ N torsion angle 8. The critical role of C2‐NHAc was also confirmed by the study of C3‐NHAc analogues, which showed the gauche conformation of the amido aglycon moiety 10. A comprehensive analysis of both the regular hydrogen bonds and the weak interactions involving CH⋅⋅⋅O hydrogen bonds present in the crystal structures of N ‐glycoprotein models and analogues revealed a cooperative antiparallel network of bifurcated hydrogen bonds consisting of NH⋅⋅⋅O and CH⋅⋅⋅O interactions seen uniquely for the models, GlcNAcβAsn and GlcNAcβNHAc, and not for any analogue including the propionamide derivative, GlcNAcβNHPr.…”

“…A major program of our laboratory is focused on the synthesis, crystallography, and ab initio calculations of the Nglycoprotein linkage region models and analogues. [4][5][6][7][8][9][10][11] A systematic investigation pertaining to the effect of structural variation in the linkage region sugar and its aglycon moiety, among several N-(b-glycopyranosyl)alkanamido derivatives, on the N-glycosidic torsion, f N (O5-C1-N1-C1') revealed that f N (Figure 1) is influenced to a larger extent by the structural variation in the sugar part than that of the aglycon moiety. [4] X-ray crystallographic analysis and ab initio calculations on the N-(b-d-glycopyranosyl)alkanamides showed that the N-acetyl group at C2 controls the side chain torsion angle c 2 (N1-C1'-C2'-C3') at the linkage region and helps in establishing the extended aglycon conformation.…”

Synthesis and X-ray crystallographic investigation of N-(β-d-glycosyl)butanamides derived from GlcNAc and chitobiose as analogs of the conserved chitobiosylasparagine linkage of N-glycoproteins

“…10 (4)(5)(6) was started with chitin (Scheme 1). The powdered chitin (7) was subjected to acetolysis using H 2 SO 4 and acetic anhydride under sonication condition to give the chitobiose octaacetate (8), 11 which was de-O-acetylated using catalytic amount of sodium methoxide in methanol to give the GlcNAcb(1-4)GlcNAc (9). The chitobiose (9) was converted to 1,b-aminochitobiose by Kochekov amination, followed by reaction with acetic anhydride to give (GlcNAcb(1-4)GlcNAc)NHAc (4) 12 in 7% yield.…”

“…The chitobiose (9) was converted to 1,b-aminochitobiose by Kochekov amination, followed by reaction with acetic anhydride to give (GlcNAcb(1-4)GlcNAc)NHAc (4) 12 in 7% yield. In the case of GlcNAcb(1-4)GlcNAcbNHPr (5) and GlcNAcb(1-4)GlcNAcbNHBu (6) derivatives, amination of chitobiose (9) was carried out with ammonium carbamate for 24 h at 37°C in dry methanol. The chitobiosamine-salt precipitated out as a white solid, which was transformed into the corresponding b-chitobiosamine after brief drying under high vacuum.…”

“…6,7 Ab Initio Quantum Chemical Calculations and X-ray crystallographic studies on propionamido and chloroacetamido derivatives showed the critical role of the C2-acetamido group of GlcNAc in controlling v 2 at the linkage region of N-glycoproteins and conserving the extended side chain conformation. 8,9 As a logical extension of the above systematic investigation, the newer analogs GlcNAcbNHBu (3) and (GlcNAcb(1-4)GlcNAc)alkanamides (4-6) have been synthesized to understand the influence of aglycon as well as additional GlcNAc on the linkage region (Fig. 1).…”