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

Abstract

We describe the synthesis and side chain conformational analysis of a series of four 6-deoxy-2,3,5-tri-O-benzyl hexofuranosyl donors with the d-gluco, l-ido, d-altro, and l-galacto configurations. The conformation of the exocyclic bond of these compounds depends on the relative configuration of the point of attachment of the side chain to the ring and of the two flanking centers and can be predicted on that basis analogously to the heptopyranose analogs. Variable-temperature nuclear magnetic resonance (VT NMR) spectroscopy of the activated donors reveals complex, configuration-dependent mixtures of intermediates that we interpret in terms of fused and bridged oxonium ions arising from participation by the various benzyl ethers. The increased importance of ether participation in the furanoside series compared to the pyranosides is discussed in terms of the reduced stabilization afforded to furanosyl oxocarbenium ions by covalent triflate formation. The stereoselectivities of the four donors are discussed on the basis of the benzyl ether participation model.

Figure 1.

The staggered conformations of the side chains of gluco and galactopyranose and of methyl arabino and xylofuranosides and their approximate populations in the free solution.

Figure 2.

Relative hydrolysis rate of conformationally-locked gluco and galacto pyranosides.

Figure 3.

Predominant side chain conformation of glycosyl donors in the a) neuraminic acid and ulosonic series and b) 6-methyl hexopyranoside series with the approximate decomposition temperatures of the corresponding derived tetra-O-benzyl glycosyl triflates. The predominant conformations of the side chains are in blue and the relative configurations of the conformation-determining stereotriads are indicated on the Fischer projections.

Figure 4.

Literature Hexofuranose Derivatives and Their Approximate Side Chain Conformations.

Figure 5.

Thiofuranosides Targeted for Synthesis and their Predicted Side Chain Conformations.

Figure 6.

Diagnostic NOE and Coupling Constants for Side Chain Conformation Assignment.

Figure 7.

Variable temperature NMR spectra for sulfoxide donor 57 with characteristic signals a) = δ 0.87 and 0.94 (J = 6.1 Hz), and b) = δ 3.00–3.50 (J = 10.6 Hz).

Figure 8.

Variable temperature NMR spectra for sulfoxide donor 58 with characteristic signals a) δ 0.44 and 0.49 (J = 5.9 Hz), b) δ 0.68 and 1.06 (J = 6.1 Hz),and c) = δ 6.45 and 6.67 (J = 8.0 Hz).

Figure 9.

Decomposition products 59 and 60 from VT-NMR studies of donors 57 and 58, and literature precedent.

Figure 10.

Relative stabilities of intermediates on activation of glycosyl donors in the furanosyl and pyranosyl series in the presence of the triflate ion. Not to scale. Participation by the side chain ether is for illustrative purposes only and does not imply any preference.

Scheme 1.

Synthesis of 6-deoxy-D-glucofuranose and 6-deoxy-L-idofuranose donors.

Scheme 2.

Synthesis of 6-deoxy-D-altrofuranose and 6-deoxy-L-galactofuranose donors.

Scheme 3.

Assignment of relative configuration in 34-36.

Scheme 4.

Glycosylation of 1,2;3,4-Diacetone-α-D-galactopyranose by a) the D-Gluco Sulfoxide 57, and b) the L-Ido sulfoxide 58.

Scheme 5.

Model for the Rationalization of Stereoselectivity Observed with a) D-Gluco donor 18, b) L-Ido donor 19, and c) D-Altro and L-Galacto donors 20 and 21.