Influence of Side Chain Conformation and Configuration on Glycosyl Donor Reactivity and Selectivity as Illustrated by Sialic Acid Donors Epimeric at the 7-Position

Abstract

Two N-acetyl 4O,5N-oxazolidine-protected sialyl thioglycosides epimeric at the 7-position have been synthesized and their reactivity and stereoselectivity in glycosylation reactions compared. It is demonstrated that the natural 7S-donor is both more reactive and more α-selective than the unnatural 7R-isomer. The difference in reactivity is attributed to the side chain conformation and specifically to the proximity of O7 to the anomeric center. In the natural 7S-isomer O7 is closer to the anomeric center than in its unnatural 7R-epimer and therefore better able to support incipient positive charge at the locus of reaction. The difference in selectivity is also attributed to the side conformation, which in the unnatural 7R-series is placed perpendicularly above the α-face of the donor and so shields it to a greater extent than in the 7S-series. These observations are consistent with earlier conclusions on the influence of the side chain conformation on reactivity and selectivity derived from conformationally locked models in the glucose and galactose series and corroborate the suggestion that those effects are predominantly stereoelectronic rather than torsional. The possible relevance of side chain conformation as a factor in the influence of glycosylation stereoselectivity by remote protecting groups and as a control element in enzymic processes for glycosidic bond formation and hydrolysis are discussed. Methods for assignment of the anomeric configuration in the sialic acid glycosides are critically surveyed.

Oxidative Deamination of N-Acetyl Neuraminic Acid: Substituent Effects and Mechanism

“…42-47 Comparable participation of more remote esters through six-membered dioxenium or larger cyclic ions is hotly debated in carbohydrate chemistry, 48-52 but the premise of dioxenium ions as intermediates in simple systems rests securely on a labelling study. 53 In the present oxidative deamination reaction participation through the dioxenium ion 61 would appear to be especially favorable in view of the extended zig-zag conformation of the side chain 54-60 and the ideal location it imposes on the 7- O -acetyl group. Notwithstanding this precedent, the complete retention of configuration observed when the 4- O or 7- O -acetyl groups are replaced by benzyl ethers or a silyl group (Table 1, entries 4-6) excludes the need for ester participation through either a dioxalenium or dioxenium ion.…”

Stereoselective Synthesis of 5-epi-α-Sialosides Related to the Pseudaminic Acid Glycosides. Reassessment of the Stereoselectivity of the 5-Azido-5-deacetamidosialyl Thioglycosides and Use of Triflate as Nucleophile in the Zbiral Deamination of Sialic Acids

“…As each of the glycosides isolated were found, on the basis of NMR coupling constant analysis, to exist as the 2 C 5 conformers depicted, their anomeric configuration was determined by measurement of the 3 J C,H heteronuclear coupling constant between the C1 carboxyl carbon and the axial H3. 32,61–65 …”

“…Indeed, we have previously demonstrated that even the simple inversion of configuration at the 7-position in NeuAc affects the reactivity and selectivity of the widely used O4,N5-oxazolidinone-type sialyl donors, 32 due to the imposed change in side chain conformation. 33 Moreover, the influence of the N5 protecting group on the stereoselectivity in the formation of NeuAc glycosides is widely reported, 34–40 and the replacement of an equatorial substituent (typically a C-O bond) by the axial equivalent typically influences reactivity and selectivity of glycopyranosyl donors.…”

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…53 The natural 7 S -isomer was found by NMR spectroscopy to adopt predominantly the gg -conformation of its C6-C7 bond and to be activated more rapidly than its 7 R epimer which displays the gt conformation (Scheme 9). The gg conformation with the C7-O7 bond perpendicularly above the mean plane of the pyranose ring and optimally placed to stabilize any developing positive charge at the anomeric center was therefore found to be the most reactive conformation consistent with the observations in the conformationally locked systems (Fig.…”

“…The authors speculated that restriction of the conformation of the side chain in other monocyclic systems by adjacent protecting groups may play a role in controlling the reactivity and selectivity of glycosyl donors, and that, through the correct placement of suitable hydrogen bonding networks, that glycosidase and glycosyl transferase enzymes might also adopt such strategies. 53 …”