Recent Progress On The Synthesis Of 2-Deoxyglycosides

Fig 1 Examples of natural products and drugs containing 2-deoxy sugars

2-Deoxysugars refer to those sugars with two hydrogen atoms at the C-2 position. Although the occurrence of these sugars in nature is not as abundant as common sugars such as glucose and galactose et al., they are still found to be presented in a plethora of bio-important natural products and clinical agents including marketed drugs. Most importantly, the existence of these rare sugars possibly played vital roles in the activities of these bioactive compounds. It has been found that modification of the sugar components of these compounds often affected their bioactivities.

This observation consequently intrigued a way to develop new therapeutic agents by systematic modification or replacement of the sugar components of these compounds. Despite successful examples, the discovery of new drugs by this method is a proverbial challenge from the synthetic point of view. It is because stereoselective attachment of 2-deoxysugars to other sugars or aglycons via glycosylation that makes this extremely difficult.

On the one hand, lack of the C-2 oxygenated functional group makes the glycosidic bonds less stable and thus much more sensitive to harsh conditions. On the other hand, C-2 functional groups in common sugars often participated to control the stereoselectivity of the glycosylation reactions, lack of this functional group in 2-deoxy sugar makes the glycosylation low or non-selective.

Fig 1 Examples of natural products and drugs containing 2-deoxy sugars

Despite great challenges encountered, the importance of 2-deoxysugars still attracted the widespread attention of carbohydrate chemists toward the stereoselective construction of 2-deoxyglycosidic bonds and enormous efforts have been devoted to this arena. These advances were recently reviewed by Wan and co-works (Science China. Chem. 2017, 60, 1162).

Fig 2. Strategies of 2-deoxyglycosides synthesis

Basically, most of the reported methods could be divided into a direct strategy and an indirect strategy. In a direct strategy, acceptors (aglycons or sugars with a free hydroxy group) were directly attached to 2-deoxyglycosyl donors (glycals or 2-deoxysugars with active anomeric leaving groups). Normally, the stereoselectivity was mainly controlled by anomeric effect which favors axial (usually α-) glycosidic bond formation. Besides, other factors such as solvent and reagent effect, steric-effect, conformational strain et al also participated to affect the selectivity.

Consequently, achieving exclusive α-selectivity was not an easy task. Nevertheless, some impressive works have been reported recently. For example, Mong used DMF as additive to modulate the α-selectivity (Eur. J. Org. Chem., 2014, 1827); Zhu applied an umpolung strategy with glycosyl lithium as intermediate to achieve exclusive α-selectivity (Angew. Chem. Int. Ed., 2013, 52, 8012); Bennett developed a cyclopropenium cation promoted dehydrative 2-deoxy-α-glycoside synthesis (Angew. Chem. Int. Ed., 2016, 55, 10088); Zhu elucidated a chelation controlled anomeric alkylation for α-selective 2-deoxyglycosyaltion (J. Am. Chem. Soc. 2014, 136, 3172).

On another hand, access to 2-deoxy β-glycosides via direct strategy is an extreme challenge due to the lack of the C2 participation group, furthermore, the β-glycosylation was also thermodynamically unfavorable. For years, the direct β-glycosylation of 2-deoxysugars were majorly relied on SN2 reaction pathway or steric effect by employing steric bulked groups to block the α-face. Recently, Mong applied the hydrogen-bond-mediated aglycone delivery (HAD) strategy (Chem Commun. 2015, 51, 5394) and Zhu established an umpolung strategy via kinetic anomeric effect (Angew. Chem. Int. Ed., 2013, 52, 8012) for 2-deoxy β-glycosides synthesis.

Unlike the direct strategy, the indirect strategy is much reliable with respect to the stereo-control, albeit less straightforward due to additional steps required. In an indirect strategy, a temporary functional group (TFG) was installed at the C2 position. It played as neighboring participation group to control the stereoselectivity (normally 1,2-trans) in the glycosylation step. After glycosylation, this TFG was removed. In this way, either α-or β-2-deoxy glycoside could be easily synthesized depending on the configuration of C2 TFG. Therefore, the stereoselective introduction of C2 TFG became one of the key points to the indirect strategy.

The most common used TFGs are halogen groups especially iodine group which was normally introduced by oxidative iodoglycosylation of glycals. However, the C2 TFGs installed via this way prefer to take the axial orientation thus led to α-selectivity, consequently, producing the β-selectivity is a greater challenge. This protocol was initially discovered by Lemieux and further well established by Roush and others. It has been successfully applied to a lot of complex naturally occurring oligosaccharides and glycoconjugates.

In conclusion, the review summarized the recent advancements on the methods and the rational in the stereoselective synthesis of 2-deoxyglycosides, which will undoubtedly benefit the preparation of oligosaccharides and glycoconjugates containing 2-deoxyglycoside skeletons.

These findings are described in the article entitled Recent progress on the synthesis of 2-deoxy glycosides, published in the journal Science China Chemistry. This work was led by Qian Wan & Jing Zeng from Huazhong University of Science and Technology.

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