Influence of Configuration at the 4- and 6-Positions on the Conformation and Anomeric Reactivity and Selectivity of 7-Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially Selective l-glycero-d-gluco-Heptopyranosyl Donor

Abstract

The preparation of four per-O-benzyl-D-or Lglycero-D-galacto and D-or L-glycero-D-gluco heptopyranosyl sulfoxides and the influence of their side-chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side-chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the D-and L-glycero-D-galacto glycosyl donors, the D-glycero-D-galacto isomer with the more electronwithdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the D-and L-glycero-D-gluco glycosyl donors, the L-glycero-D-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at −80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the L-glycero-D-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate, resulting in a high degree of S N 2 character in the displacement reaction.

Syntheses of Legionaminic Acid, Pseudaminic Acid, Acetaminic Acid, 8-epi-Acetaminic Acid, and 8-epi-Legionaminic Acid Glycosyl Donors from N-Acetylneuraminic Acid by Side Chain Exchange

“…Acetaminic acid and 8- epi -acetaminic acid donors 26 and 27 , respectively, on the contrary have the ribo configuration from C5–C7, adopt the gauche,trans ( gt ) conformation of the exocyclic bond to minimize dipolar interactions, and so have a sickle conformation of the C4–C8 chain as revealed by their 3 J H6,H7 coupling constants of 1.5 and 2.1 Hz, respectively. These observations are consistent with those from simple higher-carbon pyranosides and hexofuranosides and reinforce the notion that the side chain conformation in such molecules can be predicted by simple inspection of Fischer projections. , …”

Side Chain Conformation and Its Influence on Glycosylation Selectivity in Hexo- and Higher Carbon Furanosides

“… − , With occasional exceptions, these equilibrium populations are little affected by the nature of the protecting groups, by anomeric configuration, or by solvent . In the higher carbon sugars, however, the additional C–C bond extending the side chain and the associated additional stereogenic center result in equilibrium populations of the exocyclic bond that are more constrained as first revealed in studies of diastereomeric mixtures of sialic and ulosonic acid donors (Figure a) and then with a more uniform series of 6-methyl galacto- and glucopyranosyl donors (Figure b) …”

“…17 In the higher carbon sugars, however, the additional C−C bond extending the side chain and the associated additional stereogenic center result in equilibrium populations of the exocyclic bond that are more constrained as first revealed in studies of diastereomeric mixtures of sialic and ulosonic acid donors (Figure 3a) 2 and then with a more uniform series of 6methyl galacto-and glucopyranosyl donors (Figure 3b). 18 These studies, combined with an analysis of the crystal and solution phase conformations of the acyclic pentitols (arabinitol, lyxitol, ribitol, and xylitol), led us to develop a predictive model for the conformation of the exocyclic bond in the higher carbon hexopyranosides. This model predicts the conformation of the side chain on the basis of the relative configurations of a simple stereotriad composed of the point of attachment of the side chain to the ring and the two stereogenic centers flanking it (i.e., C5−C7 in neuraminic acids and C4−C6 in the simple pyranosides, Figures 3a and b, respectively).…”

Direct Experimental Characterization of a Bridged Bicyclic Glycosyl Dioxacarbenium Ion by 1H and 13C NMR Spectroscopy: Importance of Conformation on Participation by Distal Esters

“…Such bglycosyl dioxonium ions have yet to be observed spectroscopically,b ut their decomposition products (b-haloalkyl glycosides) have been isolated on multiple occasions. [29] The approximately two-fold increase in a-selectivity with acceptor 19 on going from the simple donor 8 to its 4-methyl analog 5 (Tables 2and 3) presumably arises from the observed change in conformation of the side chain on methylation, aphenomenon that is known to affect selectivity, [30] or greater steric shielding of the b-face by the conformationally more mobile tertiary ester in 5.…”