Venturing beyond Donor-Controlled Glycosylation: New Perspectives toward Anomeric Selectivity

Abstract

Glycans are complex compounds consisting of sugars linked glycosidically, existing either as pure polysaccharides or as part of glycoconjugates. They are prevalent in nature and possess important functions in regulating biological pathways. However, their diversity coupled with physiochemical similarities makes it challenging to isolate them in large quantities for biochemical studies, hence hampering progress in glycobiology and glycomedicine. Glycochemistry presents an alternative strategy to obtain pure glycan compounds through artificial synthetic methods. Efforts in glycochemistry have been centered on glycosylation, the key reaction in glycochemistry, especially with regards to anomeric stereoselectivity in polysaccharides and glycoconjugates. In particular, the stereoelectronic and steric properties of glycosyl donors are commonly used to direct the stereoselectivity in glycosylation reactions. Classic glycosylation strategies typically involve saturated glycosyl donors, proceeding either directly using hydrogen bonds and conformational constraints or indirectly by installing moieties covalently through neighboring group participation and intramolecular aglycon delivery. Over the past years, new glycosylation strategies, tapping on the foundations of transition metal catalysis, have emerged. To leverage the power of coordination chemistry, unsaturated glycosyl donors were introduced. Not only are the number of protection/deprotection steps reduced, the resultant unsaturated glycoside provides opportunities for downstream functionalizations, allowing quick access to a variety of sugars, including rare sugars. Alongside the glycosyl donor, an equally important but neglected aspect for targeting stereoselective glycosylation is the glycosyl acceptor. In the case of dual-directing donors, glycosyl acceptors have proved themselves capable of becoming the dominating factor for stereocontrol. Interestingly, rational manipulation or selection of glycosyl acceptors with particular nucleophilicity and p K values can lead to different stereoselectivities, thereby proving the tunability of such acceptors to favor the formation of one anomer over the other stereoselectively. By further venturing beyond substrate controlled stereoselectivity, we are presented with the opportunity to effect stereoselective glycosylation through glycosylating reagents. Of the key reagents, stereoselective catalyst stands out as a greener and efficient alternative to direct stereoselective control with stoichiometric substrates. Recently, investigations into this approach of stereocontrol presented an intriguing range of stereoselectivities, achieved by merely varying the nature of catalysts used. Another crucial effort in glycochemistry is enhancing the efficiencies of glycosylations, by reducing the number of preparative steps before or during glycosylation. Through using transient masking groups or one-pot synthetic strategies, these streamlined approaches provide enormous convenience and practicability for oligosaccharide syntheses. Th...

DBN‐Catalyzed Regioselective Acylation of Carbohydrates and Diols in Ethyl Acetate

“…The preparation of high value-added carbohydrates and building blocks for oligosaccharide synthesis still remains the most important scientific problem in carbohydrate chemistry. [1][2][3][4][5][6][7][8][9][10][11] Regioselective acylation is of great importance in the synthesis of valuable oligosaccharide structural units because it facilitates the protection and deprotection of hydroxyl groups and the synthesis of target building blocks. [12][13][14][15][16][17][18] Recently, many methods have been developed to make regioselective acylations highly efficient, green, and even controllable, and some metal catalysts and organic small molecules have been used for the regioselective acylation of carbohydrates and diols; for example, tin(IV), [19][20][21] boron(IV), [22] copper(II), [23][24][25] silver(I), [26] and iron catalysts have been recently reported.…”

“…[29,30] The organoboron catalysts can catalyze regioselective acylations of carbohydrates, but they are green but not suitable for transdiols. [22,31] Recently, Fe(acac) 3 was developed for the site-selective acylation of 1,2-cis-diols; [28] it is an efficient and green catalyst and has great research potentiality.…”

Phenanthroline‐Catalyzed Stereoretentive Glycosylations

“…As a result, the efficient preparation of well‐defined oligosaccharides has been a major focus in carbohydrate synthesis. Despite recent advances, the ability to forge α‐1,2‐ cis glycosidic bonds in a stereoselective fashion is not easily predictable (Scheme A) because of the reaction's high degree of variables and shifting S N 1‐S N 2 mechanistic paradigm . Most established methods have focused on tuning the steric and electronic nature of the protecting groups bound to the electrophilic partners to achieve α‐1,2‐ cis selectivity .…”

Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity

“…Thioglycosides 1 (Figure ) are the most commonly used glycosyl donors and can be easily activated chemoselectively by electrophilic promoter systems, among which N ‐iodosuccinimide (NIS, 6‐I )/TfOH is the most widely used . Ye, Huang, and Yoshida have developed a preactivation strategy that allows iterative one‐pot glycosylation . However, similar to all other glycosylation reactions, the poorly controlled stereoselectivity remains a long‐standing problem .…”

“…This discovery gives new insight to stereocontrolled glycosylation for carbohydrate/organic chemistry and presents a multidisciplinary direction that combines statistics. Since anomeric selectivity is simultaneously influenced by remote functional group participation, acceptor nucleophilicity, solvent polarity, temperature, and activation system, we are studying these permanent and environmental variables by using RRV as the analytic tools. Similar trends can also be observed when using TolSCl/AgOTf and BSP/Tf 2 O combinations as the promoters.…”