Broadening the Scope of the Reverse Orthogonal Strategy for Oligosaccharide Synthesis.

The reverse orthogonal strategy was invented in 2011 in an attempt to address drawbacks of other strategies for glycan assembly. Different from the classical orthogonal approach that relies on the orthogonality of leaving groups, the reverse strategy is based on orthogonal protecting groups that could be removed during the glycosylation step. This strategy remained largely unexplored due to only one combination of orthogonal protecting groups that would fit into this concept. Reported herein are new orthogonal combinations of leaving and protecting groups that help to streamline the glycan assembly. Also reported is further refinement of the previously reported reaction conditions.

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

Advances in synthetic carbohydrate chemistry have dramatically improved access to common glycans. However, many novel methods still fail to adequately address challenges associated with chemical glycosylation and glycan synthesis. Since a challenge of glycosylation has remained, scientists have been frequently returning to the traditional glycosyl donors. This review is dedicated to glycosyl halides that have played crucial roles in shaping the field of glycosciences and continue to pave the way toward our understanding of chemical glycosylation.

Picoloyl protecting group in synthesis: focus on a highly chemoselective catalytic removal.

The picoloyl ester (Pico) has proven to be a versatile protecting group in carbohydrate chemistry. It can be used for the purpose of stereocontrolling glycosylations via an H-bond-mediated Aglycone Delivery (HAD) method. It can also be used as a temporary protecting group that can be efficiently introduced and chemoselectively cleaved in the presence of practically all other common protecting groups used in synthesis. Herein, we will describe a new method for rapid, catalytic, and highly chemoselective removal of the picoloyl group using inexpensive copper(ii) or iron(iii) salts.

A Highly Efficient Glycosidation of Glycosyl Chlorides by Using Cooperative Silver(I) Oxide-Triflic Acid Catalysis.

Following our discovery that silver(I) oxide-promoted glycosylation with glycosyl bromides can be greatly accelerated in the presence of catalytic TMSOTf or TfOH, we report herein a new discovery that glycosyl chlorides are even more effective glycosyl donors under these reaction conditions. The developed reaction conditions work well with a variety of glycosyl chlorides. Both benzoylated and benzylated chlorides have been successfully glycosidated, and these reaction conditions proved to be effective in coupling substrates containing nitrogen and sulfur atoms. Another convenient feature of this glycosylation is that the progress of the reaction can be monitored visually; its completion can be judged by the disappearance of the characteristic dark color of Ag2 O.

Comparative Study on the Effects of Picoloyl Groups in Sialylations Based on Their Substitution Pattern.

A novel 8-O-picoloylated sialyl donor has been developed, and the performance of various picoloylated sialyl donors in glycosylations with primary glycosyl acceptors has been evaluated. 8-O-Picoloyl and 4,9-di-O-picoloyl sialyl donors produced moderate to excellent yields of disaccharides with complete α-stereoselectivities. Synergistic effects between picoloyl and the accompanying O-protecting groups (benzoyl vs acetyl) were evaluated, as well as the effects of triflic acid concentration on the 8-O-picoloyl donor. 1H NMR analysis was also carried out to assess differences in the hydrogen-bonding net between sialyl donors.

Manual and Automated Syntheses of the N-Linked Glycoprotein Core Glycans.

Presented herein are two complementary approaches to the synthesis of the core N-glycan pentasaccharide. The first, a traditional manual approach in solution, makes use of the H-bond-mediated aglycone delivery method for the highly diastereoselective introduction of the ß-mannosidic linkage at room temperature. The synthesis of the core pentasaccharide was also accomplished using an high-performance liquid chromatography-assisted automated approach. The overall assembly was swift (8 h) and efficient (31%).

Iron(iii) chloride-catalyzed activation of glycosyl chlorides.

Glycosyl chlorides have historically been activated using harsh conditions and/or toxic stoichiometric promoters. More recently, the Ye and the Jacobsen groups showed that glycosyl chlorides can be activated under organocatalytic conditions. However, those reactions are slow, require specialized catalysts and high temperatures, but still provide only moderate yields. Presented herein is a simple method for the activation of glycosyl chlorides using abundant and inexpensive ferric chloride in catalytic amounts. Our preliminary results indicate that both benzylated and benzoylated glycosyl chlorides can be activated with 20 mol% of FeCl3.

Regenerative Glycosylation.

Previously, we communicated 3,3-difluoroxindole (HOFox)-mediated glycosylations wherein 3,3-difluoro-3H-indol-2-yl (OFox) imidates were found to be key intermediates. Both the in situ synthesis from the corresponding glycosyl bromides and activation of the OFox imidates could be conducted in a regenerative fashion. Herein, we extend this study to the synthesis of various glycosidic linkages using different sugar series. The main outcome of this study relates to enhanced yields and/or reduced reaction times of glycosylations. The effect of HOFox-mediated reactions is particularly pronounced in case of unreactive glycosyl donors and/or glycosyl acceptors. A multistep regenerative synthesis of oligosaccharides is also reported.

Combined Effect of the Picoloyl Protecting Group and Triflic Acid in Sialylation.

The stereoselective synthesis of sialosides is still one of the major challenges in carbohydrate chemistry. The synthesis and glycosidation of novel sialyl donors bearing a picoloyl substituent at C-4 are reported. High stereoselectivities and faster reactions were observed in the presence of an excess of triflic acid. The acid excess does not have the same effect on conventional sialyl donors, which suggests a possible synergistic effect of the picoloyl substituent and the triflic acid.

Synthesis and elimination of C-3-labeled thiosialosides.

The synthesis of C-3-labeled phenylthio sialic acid derivatives and an investigation of stereoselectivity in elimination reactions for the synthesis of 2,3-dehydro derivatives (glycals) is described. The experimental results are consistent with the existence of a conformational change and may be indicative of the intermediacy of an all-axial oxacarbenium ion.