4′-Methoxyphenacyl-Assisted Synthesis of β-Kdo Glycosides

Abstract

3-Deoxy-β-d-manno-oct-2-ulosonic acid (β-Kdo) glycosides are mainly found in capsular polysaccharides and extracellular exopolysaccharides from Gram-negative bacteria. These compounds have profound biological implications in immune response and act as virulence factors. We have developed a novel methodology for the stereoselective synthesis of β-Kdo glycosides via the use of a 4'-methoxyphenacyl (Phen) auxiliary group at the C1 position of a peracetylated β-Kdo thioglycoside. Under the promotion of NIS/AgOTf in acetonitrile, a series of Kdo glycosides was synthesized in good yield and β-selectivity while minimizing the formation of undesirable glycals. Stereoselectivity of the glycosylation was shown to be modulated by various factors such as promotor, solvent, anomeric ratio of donor, nature of acceptor, and Phen substitution. Chemoselective cleavage of the Phen group was performed under the action of Zn/HOAc. DFT calculations together with experimental results suggested that α-triflate and a six-membered α-spiroPhen are plausible intermediates of the reaction, accounting for the enhanced formation of β-Kdo glycosides. The developed methodology could be applied to the synthesis of β-Kdo-containing glycans from pathogenic bacteria.

Glycosylation and Protecting Group Strategies Towards the Synthesis of Saponins and Bacterial Oligosaccharides: A Personal Account

“…Our research group was also interested in developing a synthetic approach to reach β ‐Kdo glycosides (Scheme 8D) [77] . To do so, we took advantage of a 4’‐methoxyphenacyl (Phen) auxiliary group at the C1 position of peracetylated thioglycoside donor 88 .…”

“…Our research group was also interested in developing a synthetic approach to reach β-Kdo glycosides (Scheme 8D). [77] To do so, we took advantage of a 4'-methoxyphenacyl (Phen) auxiliary group at the C1 position of peracetylated thioglycoside donor 88. Our hypothesis was that, once activated, the long-range participation of the Phen group could stabilized the oxocarbenium ion through the formation of an α-spirophenacylium intermediate that would be thermodynamically favoured over its β-counterpart.…”

Stereodirecting Effect of C5-Carboxylate Substituents on the Glycosylation Stereochemistry of 3-Deoxy-d-manno-oct-2-ulosonic Acid (Kdo) Thioglycoside Donors: Stereoselective Synthesis of α- and β-Kdo Glycosides

“…developed the peracetylated Kdo thioglycosides equipped with a 4′-methoxyphenacyl (Phen) group at C1-position with which a series of β-Kdo glycosides were synthesized in good yield but with moderate β-selectivity only. Additionally, the Phen auxiliary group has to be cleaved after the glycosylation, thereby lowering the synthetic efficiency . More recently, Yang et al reported a Au­(I)-catalyzed synthesis of β-Kdo glycosides using Kdo ortho -hexynylbenzoate as donor.…”

“…Additionally, the Phen auxiliary group has to be cleaved after the glycosylation, thereby lowering the synthetic efficiency. 11 that complete β-selectivity was realized in this direct glycosylation reaction, only one pyranosyl alcohol especially no Kdo alcohol was used as acceptor, which limits the application of the method. 12 Recently, a facile hydrogen-bond-mediated aglycone delivery (HAD) approach was uncovered by Demchenko and coworkers to synthesize stereoselectively various challenging 1,2cis-pyranosides.…”

Dimethylformamide-Modulated Kdo Glycosylation for Stereoselective Synthesis of α-Kdo Glycosides

“…As such, Kdo glycosylation usually led to a mixture of α/β-Kdo glycosides in low yields with the concomitant formation of Kdo glycals as side products. Aiming at this question, a range of approaches have been developed for the stereoselective synthesis of α- or β-Kdo glycosides by utilization of different types of Kdo donors such as glycosyl halides, thioglycosides, glycals, glycosyl N -phenyl trifluoroacetimidates, and phosphites. , The stereodirecting auxiliary iodo, thio, or phenylselenyl groups on the C-3 position were employed to improve the α-selectivity of Kdo glycosylation. , The cyclic 4,5- O -isopropylidene acetal or the 4,5-di- O - tert -butyldimethylsilyl ether was installed on the Kdo fluorides or N -phenyl trifluoroacetimidates for the α-selective synthesis of Kdo glycosides. , Remarkably, the cyclic 5,7- O -di- tert -butylsilylene-protected Kdo thioglycosides proved to be very effective donors for stereoselective synthesis of α-Kdo glycosides . Furthermore, the stereodirecting 5-carboxylate substituents on the Kdo thioglycoside donors resulted in varied α- and β-selectivities by fine-tuning the 5-ester groups and the acceptors .…”