Stereoselective 1,2-cis glycosylation via intramolecular aglycone delivery: Opportunities and challenges.

Review: about 100 refs.

Methodology toward the stereoselective 1,2-cis glycoside linkage using intramolecular aglycon delivery (IAD) has been extensively developed. In the last two decades, progress has been made using various mixed acetal linkages and a number of glycosyl donor moieties to develop novel IAD strategies, mainly based on formation of acetal linkages. This account summarizes the newest naphthylmethyl (NAP) ether-mediated IAD as well as all the types of mediations for stereospecific construction of various 1,2-cis linkages, not only for beta-mannopyranoside, but also for other linkages almost without exception, including beta-L-rhamnoside.

The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective fashion. 2-O-Allyl protected thioglycoside donors are excellent substrates for IAD, and may be glycosylated stereoselectively through a three-step reaction sequence. This sequence consists of quantitative yielding allyl bond isomerisation, to produce vinyl ethers that can then undergo N-iodosuccinimide mediated tethering of the desired glycosyl acceptor, and subsequent intramolecular glycosylation, to yield either alpha-glucosides or beta-mannosides accordingly. Although attempted one-pot tethering and glycosylation is hampered by competitive intermolecular reaction with excess glycosyl acceptor, this problem can be simply overcome by the use of excess glycosyl donor. Allyl mediated IAD is a widely applicable practical alternative to other IAD approaches for the synthesis of beta-mannosides, that is equally applicable for alpha-gluco linkages. It is advantageous in terms of both simplicity of application and yield, and in addition has no requirement for cyclic 4,6-protection of the glycosyl donor.

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ConspectusThe limited availability of structurally well-defined diverse glycans remains a major obstacle for deciphering biological functions as well as biomedical applications of carbohydrates. Despite tremendous progress that has been made in past decades, the synthesis of structurally well-defined complex glycans still represents one of the most challenging topics in synthetic chemistry. Chemical synthesis of glycans is a time-consuming and labor-intensive process that requires elaborate planning and skilled personnel. In contrast, glycosyltransferase-catalyzed enzymatic synthesis provides a more efficient, convenient, low-cost, and sustainable alternative to affording diverse and complex glycans. However, the existing methods are still insufficient to fulfill the increasing demand for specific synthetic glycan libraries necessary for functional glycomics research. This is mainly attributed to the inherent character of the glycan biosynthetic pathway. In nature, there are too many glycosyltransferases involved in the in vivo glycan synthesis, but only a small number of them are available for in vitro enzymatic synthesis. For instance, humans have over 200 glycosyltransferases, but only a few of them could be produced from the conventional bacterial expression system, and most of these membrane-associated enzymes could be overexpressed only in eukaryotic cells. Moreover, the glycan biosynthetic pathway is a nontemplate-driven process, which eventually ends up with heterogeneous glycan product mixtures. Therefore, it is not a practical solution for the in vitro enzymatic synthesis of complex glycans by simply copying the glycan biosynthetic pathway.In the past decade, we have tried to develop a simplified and transformable approach to the enzymatic modular assembly of a human glycan library. Despite the structural complexity of human glycans, the glycoinformatic analysis based on the known glycan structure database and the human glycosyltransferase database indicates that there are approximately 56 disaccharide patterns present in the human glycome and only 16 disaccharide linkages are required to account for over 80% of the total disaccharide fragments, while 35 disaccharide linkages are sufficient to cover over 95% of all disaccharide fragments of human glycome. Regardless of the substrate specificity, if one glycosyltransferase could be used for the synthesis of all of the same glycosidic linkages in human glycome, it will require only a few dozen glycosyltransferases for the assembly of entire human glycans. According to the glycobioinformatics analysis results, we rationally designed about two dozen enzyme modules for the synthesis of over 20 common glycosidic linkages in human glycome, in which each enzyme module contains a glycosyltransferase and a group of enzymes for the in situ generation of a nucleotide-activated sugar donor. By sequential glycosylation using orchestrated enzyme modules, we have completed the synthesis of over 200 structurally well-defined complex human glycans including blood group antigens, O-mannosyl glycans, human milk oligosaccharides, and others. To overcome the product microheterogeneity problem of enzymatic synthesis in the nontemplate-driven glycan biosynthetic pathway, we developed several substrate engineering strategies to control or manipulate the outcome of glycosyltransferase-catalyzed reactions for the precise synthesis of structurally well-defined isomeric complex glycans.

1,2-cis Glycosidic linkages are prevalent in natural glycans. Although key factors that control stereoselectivity of glycosylation have been largely understood, stereoselective synthesis of 1,2-cis glycosides is potentially problematic. To achieve exclusive formation of desired isomer, approaches based on intramolecular aglycon delivery (IAD) are of special promise. In the last two decades, various mixed acetal linkages and a number of glycosyl donor moieties have been making much progress to develop novel IAD strategies, mainly based on formation of the acetal linkages.The methodology toward the strereoselective 1,2-cis glycosylation using naphthylmethyl (NAP) ether-mediated IAD has been developed. Namely, 2-O-NAP protected donor was cleanly converted to the mixed acetal upon oxidative activation with DDQ. Subsequent activation of thioglycosidic linkage initiated the rearrangement of an aglycon from mixed acetal moiety to give a desired 1,2-cis glycoside. Stereospecific constructions of various 1,2-cis linkages, which are not only β-mannopyranoside but also other linkages such as β-L-rhamno-, α-glucopyrano- and β-arabinofurano-sides, were achieved through NAP-IAD. This methodology was successfully applied to the synthesis of various fragments of natural glycans.

For the stereoselective assembly of bioactive glycans with various functions, 1,2-cis-O-glycosylation is one of the most essential issues in synthetic carbohydrate chemistry. The cis-configured O-glycosidic linkages to the substituents at two positions of the non-reducing side residue of the glycosides such as α-glucopyranoside, α-galactopyranoside, β-mannopyranoside, β-arabinofuranoside, and other rather rare glycosides are found in natural glycans, including glycoconjugate (glycoproteins, glycolipids, proteoglycans, and microbial polysaccharides) and glycoside natural products. The way to 1,2-trans isomers is well sophisticated by using the effect of neighboring group participation from the most effective and kinetically favored C-2 substituent such as an acyl group, although high stereoselective synthesis of 1,2-cis glycosides without formation of 1,2-trans isomers is far less straightforward. Although the key factors that control the stereoselectivity of glycosylation are largely understood since chemical glycosylation was considered to be one of the useful methods to obtain glycosidic linkages as the alternative way of isolation from natural sources, strictly controlled formation of these 1,2-cis glycosides is generally difficult. This minireview introduces some of the recent advances in the development of 1,2-cis selective glycosylations, including the quite recent developments in glycosyl donor modification, reaction conditions, and methods for activation of intermolecular glycosylation, including the bimodal glycosylation strategy for 1,2-cis and 1,2-trans glycosides, as well as intramolecular glycosylations, including recent applications of NAP-ether-mediated intramolecular aglycon delivery.

2-O-Allyl protected glycosyl donors may be glycosylated stereoselectively via a three step sequence involving double bond isomerization, N-iodosuccinimide mediated tethering to a glycosyl acceptor and subsequent intramolecular glycosylation (intramolecular aglycon delivery, IAD).

2-O-Allyl protected glycosyl donors may be glycosylated stereoselectively via a three step sequence involving double bond isomerization, N-iodosuccinimide mediated tethering to a glycosyl acceptor and subsequent intramolecular glycosylation (intramolecular aglycon delivery, IAD).

The synthesis of β-mannopyranosides by intramolecular aglycon delivery is shown to proceed with complete stereoselectivity in six separate cases. This strategy has been successfully applied to the synthesis of several disaccharides, including octyl 3,6-di-O-benzyl-4-O-(3,4,6-tri-O-benzyl-β-D-mannopyranosyl)-2-deoxy-2-phthalimido-β-D-glucopyranoside, a precursor of the naturally occurring β-D-Man-(1→4)-β-D-GlcNAc linkage, present in all N-linked glycoproteins. Exclusive formation of the β-mannosidic linkage has been confirmed in all six cases, since independently synthesized α-linked mannopyranoside standards were shown to be absent from the reaction products. The intramolecular stereocontrolled reaction proceeds even in the presence of competing methanol. The extension of this strategy to the synthesis of the core pentasaccharide of N-linked glycoproteins has revealed limitations to the methodology, especially when a block synthesis approach is investigated.

Synthetic oligosaccharides are objects of interest as model compounds in studies on the biological activity of natural compounds, but also as components for new drugs, glycoconjugate vaccines, carbohydrate diagnostic agents and various other products. The key stage in oligosaccharide synthesis is the glycosylation reaction, which leads to the formation of a linkage between carbohydrate fragments. This review highlights a current problem in modern glycochemistry – the methods of stereocontrol in the glycosylation reaction. Protecting groups within the structure of glycosyl donors are considered as stereocontrolling factors, affecting the reaction mechanism by means of (1) participation or anchimeric assistance, (2) deactivation, (3) intramolecular aglycone delivery. The well-established mechanism of neighboring group participation at O-2 for the synthesis of 1,2- trans glycosides is shown, as well as its modern modifications, including activating ethers, chiral protecting groups and achiral bicyclic glycosyl donors. The mechanisms of remote participation from O-3, O-4 and O-6 of the glycosyl donor are discussed in detail. In addition, approaches to stereocontrol using deactivating protection (conformation constraining and electron withdrawing groups) are described. Finally, synthetic approaches based on intramolecular aglycone delivery are considered. Both classical and novel protecting groups used to control the steric outcome of glycosylation are presented, the mechanisms underlying the presented approaches are discussed in detail, while also showing how the described strategies apply to the synthesis of complex structures.

A novel use of polymer supported glycosyl donor for stereoselective synthesis of β-manno glycoside is described. This system features the use of polymer support in an unprecedented manner, in which the polymer sector serves as a “gatekeeper”. Polymer supported thiomannoside 10 that carries a p-alkoxybenzyl group as a linker at C-2 position was synthesized. This compound was subjected to the conditions of β-mannosylation according to the procedure of p-methoxybenzyl assisted intramolecular aglycon delivery (IAD) to react with glycosyl acceptor 11. Treatment with DDQ afforded the mixed acetal 12 which was followed by the activation of the anomeric C-S linkage to initiate the IAD step. This process allows the product derived from IAD to be specifically released from the polymer to give the mixture which is highly enriched with the β-manno glycoside 13. Compatibility with the orthogonal glycosylation strategy was confirmed by the reaction with the glycosyl fluoride 11c, and resultant disaccharide 14 was furth...

Allyl protecting group mediated intramolecular aglycon delivery (IAD): synthesis of α-glucofuranosides and β-rhamnopyranosides

β-Mannosylation of N-acetyl glucosamine by propargyl mediated intramolecular aglycon delivery (IAD): synthesis of the N-glycan core pentasaccharide

Stereospecific 1,2-cis-glycosylation of 2-O-allyl protected glucosyl and mannosyl fluorides can be achieved via a sequence of allyl isomerization, N-iodosuccinimide mediated tethering, and intramolecular aglycon delivery (IAD). Fluoride is advantageous as an anomeric leaving group since extended reaction times can be employed to tether hindered aglycon alcohols without competitive anomeric activation. Tin(II) chloride mediated intramolecular glycosylation furnishes the desired α-glucosides and β-mannosides in an entirely stereoselective manner.