Venturing beyond Donor-Controlled Glycosylation - American

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Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

Venturing beyond Donor-Controlled Glycosylation: New Perspectives toward Anomeric Selectivity Wei-Lin Leng,†,‡ Hui Yao,†,‡ Jing-Xi He,†,§,‡ and Xue-Wei Liu*,† †

School of Physical & Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, 637371 Singapore § School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, 637459 Singapore CONSPECTUS: 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 pKa 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. This Account presents mainly our advancements beyond the conventional donor-controlled strategies over the past decade, with emphasis placed on mechanistic explanations of anomeric selectivities, thereby providing perspectives to inspire further progress toward a generalized unified strategy for preparing every type of glycan.

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INTRODUCTION

studies, severely hampering progress in glycobiology and glycomedicine. Hence, it is of great research significance to successfully mimic the natural biosynthetic processes of glycosylation artificially, in order to gain facile access to abundant amounts of glycans and glycoconjugates for in-depth studies. A glycosylation reaction typically involves constructing a glycosidic linkage between a glycosyl donor and a glycosyl

Glycosylation is the most important reaction in glycochemistry. It is an important biochemical process that gives rise to critical molecules in the cell, including glycans and glycoconjugates such as glycoproteins and glycolipids.1−3 As compared to other biologically important macromolecules, such as polypeptides and long-chain fatty acids, polysaccharides are structurally more complex, with both branched and linear structures, as well as αor β-anomeric stereochemistry. However, their structural complexity coupled with physiochemical similarities make it challenging to purify them in large quantities for biochemical © XXXX American Chemical Society

Received: September 13, 2017

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DOI: 10.1021/acs.accounts.7b00449 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Approaches to Stereoselective Glycosylation Using Saturated Glycosyl Donors

acceptor, in which the first step typically involves activation of the glycosyl donor at the anomeric position, followed by its reaction with glycosyl acceptor. Because there are two possible anomeric stereoselectivities, it greatly complicates the process of achieving pure glycans. Thus, tremendous effort has been dedicated to developing glycosylation methodologies with excellent control over anomeric stereoselectivity. The most well-established approach to achieve anomeric glycosylation stereoselectivity is perhaps through manipulating glycosyl donors. However, it is challenging to meet the growing demand for complex and diverse carbohydrates with this type of control alone. Through other strategies such as acceptor control, reagent control, or even combinations of these approaches, the field has developed new methodologies to provide indispensable insights in accomplishing stereocontrol. In this Account, we will be focusing on our and other related efforts in manipulating unsaturated donors and glycosyl acceptors. Due to the large volume of work that has been accomplished in this area, we are putting the emphasis mainly on contributions in developing stereoselective glycosylation methodologies. In particular, we focused on the chemistry of pyranosyl scaffolds, and only glycosylation methods relevant to our perspectives are discussed in this Account in which both αand β-glycosides are accessible.

centers, their corresponding hydroxyl groups are available for installation of directing moieties, which can direct the stereochemistry either directly or indirectly during the formation of glycosidic bonds.4 Many efforts have been made in this regard, and selected classic examples are illustrated as follows. Direct approaches to glycosylation typically involve the formation of weak interactions or direct interference of the glycosyl donor without installing additional groups by covalent bonding. In a demonstration by Demchenko, weak interactions between the remote pyridine functionality on glycosyl donor and the acceptor were utilized (Scheme 1a).5 Mechanistically, such approaches direct the nucleophile to one side of the sugar ring by forming hydrogen bonds with the directing moiety, resulting in α- or β-anomer selectively. In a conceptually distinct approach, selectivity of glycosylation is directly controlled by the conformation of the glycosyl donor. In Crich’s example of locking pyranose donors with benzylidene groups and fixing C5−O5 and C6−O6 bonds in an antiperiplanar manner, there is a potent electronwithdrawing effect on the oxocarbenium species, leading to increased bond covalency between the anomeric carbon and the triflate anion. As a result, the favored formation of contact ion pair and shielding effect of the α-leaving group impeded the approach of nucleophile from the same face, resulting in a selective formation of β-mannosides (Scheme 1b).6 By substitution of O4,O6-benzylidene with benzyl groups, the loss of ring-locked conformation led to reduced selectivity.7 A similar strategy was employed by Yamada, who used O-xylylene to lock a sugar ring into an axial-rich configuration.8 In this case, steric factors were used instead as 1,2-cis repulsion with 2O-benzyl can drive the formation of β-anomers through isomerization after glycosylation. Conversely, indirect strategies have been introduced to direct the nucleophile more efficiently. The additional steps introduced result in the formation of an intermediate linked by a covalent bond as opposed to weak interactions. A well-

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DONOR-CONTROLLED GLYCOSYLATION The complications associated with glycosylation, that is, α- and β-anomeric stereoselectivities, mainly stem from the chiral centers of the sugar ring. This is especially the case for glycosyl donor, as they closely surround the anomeric carbon and directly interfere with the construction of glycosidic bonds. Hence, most efforts have been devoted to the tuning of steric and electronic properties of these functionalities on the glycosyl donor to achieve stereoselective glycosylation. Classic glycosylation often involves using saturated pyranoses as glycosyl donors, as they can be directly isolated from natural sources in large quantities. Comprising up to five chiral carbon B


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Accounts of Chemical Research Scheme 2. Ferrier-Type Glycosylation Using Glycals

Scheme 3. Glycosylation by Aziridination Using Glycals

established example is the utilization of a nearby functionality to deliver a nucleophile instead of docking at the anomeric position. This intramolecular aglycon delivery approach (IAD) proceeds in a stepwise manner, in which the aglycon is first installed onto other positions of a sugar ring and then transferred to the anomeric carbon subsequently.9 A wellknown example was Ito’s use of PMB ethers (Scheme 1c).10 Aligned with our group’s long-standing interest in achieving effective glycosylation, we have focused our efforts on developing another type of glycosyl donors, the unsaturated glycosyl donor or glycal. The double bond of the donor means that it requires less protecting groups and it possesses the potential to utilize coordination chemistry, such as transition metal catalysis. In addition, the unsaturated glycal-generated glycoside allows facile transformations into diverse carbohydrates.11 However, the elimination of C2 stereodirecting effects increases the challenge of stereoselectivity. Thus, we are forced to rely on other effects.

Early efforts in using glycal donors could only direct glycosylation by the classic anomeric effect.12 Of them, the Ferrier rearrangement is the most well-studied direct approach. Besides the anomeric effect, the conformational effect also plays an important role in Ferrier glycosylation, especially in the absence of the anomeric effect (Scheme 2).13 The preferred conformation of activated oxocarbenium intermediate I over II as well as the favored half-chair conformation OH5 over the high-energy boat conformation 1,4B, leads to the preferred αselectivity, even for C-glycosylation, albeit not exclusively. Initial requirements of stoichiometric Lewis acids, such as BF3· OEt2, InCl3, or SnCl4 later evolved into catalytic amounts of Pd(II) complexes.14−17 Moving beyond the classic anomeric effect, we explored the possibility of extending to unsaturated sugars the wellestablished sugar chemistry methods. In order to harness such interactions, we installed a remote sulfamate ester at the C4 or C6 position to direct the transfer of an amine moiety in an IAD-like manner. The rhodium-catalyzed aziridination of glycals led to the formation of a tricyclic intermediate with a C


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Accounts of Chemical Research Scheme 4. Indirect and Direct Glycosylation by Decarboxylative Allylation Using Glycals

Scheme 5. Iterative Glycosylation towards Syntheses of Oligosaccharides Using Glycals

transition metal complex from the electron-rich glycal system. While this could be overcome by the addition of activators such as ZnEt2, there are limited options for reactive glycosyl acceptors. This severely limits the range of resultant glycosides.22 Drawing inspiration from our IAD-like tethering approach, we sought to address the problem of poor reactivity by IAD-like tethering of a glycosyl acceptor to the C3 position of the donor, next to the anomeric position, which could also be released in situ upon decarboxylation. Extension of this work to other types of nucleophiles proved the versatility of this reaction, in which C-, N-, and O-glycosides could be obtained with similar

conformationally strained aziridine ring, resulting in exclusive stereoselectivity and high yields (Scheme 3).18,19 Subsequent nucleophilic attacks resulted in diverse amination patterns on carbohydrates, which then served as important precursors for the syntheses of heparins, heparan sulfates, glycosaminoglycans, and drug molecules such as Tamiflu and sialic acid.20,21 Motivated by our success with the IAD-like tethering method, we envisaged the application of this approach to address other problems that are hindering the utilization of glycal as glycosyl donors. Ideally, owing to the coordinating ability of alkenes, transition metals can be used to exploit the reactivity of the glycal allylic system. However, this remains an elusive approach due to the challenge of generating a π-allyl D


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Accounts of Chemical Research Scheme 6. Acceptor-Controlled Approach Using Donor Bearing 2-Cyanobenzyl Ether Auxiliary

efficiency (Scheme 4a−c). In all cases, the reaction proceeded successfully to form β-glycosides stereoselectively.23−25 In our second generation design, we aimed to reduce the preparative steps for the unsaturated glycal donor. We achieved direct glycosylation using an exogenous glycosyl acceptor instead of aglycon installation, through careful consideration of the C3 leaving group and fine-tuning of the acceptors’ electronic properties (Scheme 4d−f).26−28 Overall, our approach demonstrated that C-, O-, and N-nucleophiles could be employed and all the reaction results were consistent with either the inner-sphere or outer-sphere mechanism raised by Trost,29 resulting in excellent selectivities. For the inner-sphere mechanism (Scheme 4b,c,e,f), the facial selectivity arises from the coordination between transition metals and hard nucleophiles prior to intramolecular nucleophilic attack of the anomeric carbon. In contrast, the outer-sphere mechanism (Scheme 4a,d) arises from the intermolecular attack of soft nucleophiles approaching the π-allylic system from the opposite face of the transition metal, also termed as double inversion. Furthermore, these methodologies could be applied to the formal synthesis of the macrolide aspergillide A, as well as the syntheses of specific disaccharides and trisaccharides (Scheme 5a).

Similarly, O’Doherty worked to enhance the reactivity of pyranone glycal donors toward glycosylation. In turn, the glycosylation step, is tandemly repeated for the synthesis of highly branched all-L-α-manno-heptapyranoside in 12 steps with a total yield of 11% from an achiral acylfuran (Scheme 5b).11 This achievement validated the idea that unsaturated donors are viable alternatives to saturated donors, especially in the synthesis of uncommon and complex sugars. As the most well-studied strategy to control stereoselectivity to date, the manipulation of glycosyl donors continues to see new progress. In addition, these above-mentioned concepts have paved the way for the development of other glycosylation methods.

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ACCEPTOR-CONTROLLED GLYCOSYLATION Despite being well-studied, the donor-controlled methodologies cannot satisfy the growing synthetic demand for diverse and complex carbohydrates, suggesting the need for other alternatives. One obvious alternative is to manipulate the acceptor instead of the donors. This concept was first explored by Woerpel in his works, relating nucleophilicity to stereoselectivity of glycosylation.30 Notably, this concept of using acceptors has also been explored by Crich, but no significant E


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Accounts of Chemical Research

Figure 1. 1H NMR studies of acceptor-controlled approach using donor bearing a 2-cyanobenzyl ether auxiliary: (a) temperature dependence of δH of EtOH and TFE and their pure samples in Tol-d8, respectively; (b) 1H NMR spectra of nitrilium intermediate at −78 °C; (c) concentration dependence of δH of TFE at −78 °C in Tol-d8; (d) concentration dependence of δH of EtOH at −78 °C in Tol-d8.

Figure 2. Effect of pKa values on stereoselectivity for acceptor-controlled approach.

anomers can be achieved stereoselectively via the rational selection of glycosyl acceptors, and this was successfully applied to 1 → 2, 1 → 3, 1 → 4, and 1 → 6 glycosidic linkages. Two mechanisms have been proposed for this dual-directing donor. When electron-deficient alcohols with decreased oxygen nucleophilicity and increased proton donor ability were employed, they coordinated with the nitrile group via hydrogen bonding, delivering the aglycon from the α-face. Conversely, electron-rich alcohols displaced the nitrilium ion via the SN2 pathway, leading to β-selectivity. Mechanistic studies showed the strong hydrogen bond interaction between trifluoroethanol and the BCN donor (Figure 1c) and the absence of such

effect on stereoselectivity was observed from the hypothesized hydrogen bonding between donor and acceptor.31 Thus, progress in using glycosyl acceptors to direct anomeric stereoselectivity has been slow hitherto. Hence, we turned away from hydrogen bonding to investigate the stronger coordinating effects of the acceptors. In pursuit of our fundamental aim of integrating current principles into carbohydrate synthesis, we developed the dualdirecting 2-cyanobenzyl ether (BCN) auxiliary, combining the principles of IAD, neighboring group participation, hydrogen bonding, solvent effect, and the arming−disarming strategy (Scheme 6).32,33 Using this dual-directed donor, both α- and βF


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Accounts of Chemical Research Scheme 7. Effect of Nucleophilicity on Stereoselectivity for Acceptor-Controlled Approach

Scheme 8. Reagent-Controlled Glycosylation

automated glycan assembly without having adverse effects on binding and immobilization. Codée then further probed the mechanisms of such glycosylation using a variety of acceptors and found that decreased acceptor nucleophilicity resulted in a shift from SN2- to SN1-type reactivity, accounting for the switched stereoselectivity.36 No doubt, this type of manipulation of anomeric stereoselectivity through modulating acceptors’ properties is a helpful addition to the repertoire of stereochemical glycosylation strategies. Challenging glycosylations can now be performed using dual control of the substrates.

interaction between ethanol and BCN donor (Figure 1d), as well as between the alcohol itself when BCN donor was introduced (Figure 1a). The direct observation of the nitrilium intermediate by low-temperature 1H NMR (Figure 1b) has further supported this proposed mechanism. Next, building on our work on unsaturated glycosyl donors, we went on to explore the effect of hardness−softness of acceptors in palladium-catalyzed decarboxylative allylation.34 Founded on our earlier works that the nature of nucleophiles dictates whether the bond breaking and forming processes occur inside or outside the coordination sphere of transition metals, we went on to develop a generalization of this trend using pKa values. In order to examine its relevance in predicting anomeric selectivity, the pKa values of various glycosyl acceptors were compared with their α-/β-stereoselectivities. The switchable anomeric selectivity in the case of trifluoroethanol proved that pKa 12.5 was an indicative value in distinguishing between hard and soft O-nucleophiles for effective acceptor-controlled O-glycosylation (Figure 2). Hard O-nucleophiles (pKa > 12.5) coordinated with the palladium ion to undergo inner-sphere attack while soft O-nucleophiles (pKa ≤ 12.5) favored outer-sphere attack on the soft allylic system. Seeberger and Pereira also studied the effect of nucleophilicity on α-/β-stereoselectivity.35 Usage of a difluorinated weak nucleophile led to α-stereoselectivity, while the nonfluorinated strong nucleophile yielded β-glycoside (Scheme 7). Notably, this strategy can be potentially utilized in

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REAGENT-CONTROLLED GLYCOSYLATION The glycosylation strategies discussed thus far focus on modulating the nature of substrates in directing and reversal of anomeric selectivity, meaning specific donors/acceptors of predetermined nature have to be decided and prepared prior to the glycosylation reaction. A more convenient and generalizable approach to achieve stereoselective control would be using the reacting reagents to modify any donor/acceptor during glycosylation. We discuss below some key examples showcasing the effects of changing solvents, promoters or catalysts on the reaction’s stereoselectivity (Scheme 8), with emphasis on important intermediates or transition states for the respective mechanisms and specific acceptors omitted. One of the most classic stereodirecting methods is by manipulating the solvent effect, commonly through the use of G


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Accounts of Chemical Research Scheme 9. Examples of Organocatalyzed Glycosylation with Controlled Anomeric Stereoselectivity

Table 1. Catalyst-Controlled Glycosylation Using Pd(0) and Pd(II) Catalysts

ethereal and nitrile solvents.37 Effects of other solvents were later explored, including computational calculations, which suggested the involvement of counterion coordination and oxocarbenium conformation in directing the stereoselectivity of glycosylation.38−40 In a unique streamlined approach by Mong, he proposed that the trapping of oxocarbenium ion using a DMF additive led to an equilibration between α- and β-glycosyl imidates, in which the more reactive β-glycosyl imidates favored α-glycosylation.41 In addition to targeting stereoselectivity by manipulating the solvent effects, the promoter or activator, applied in stoichiometric amounts, can be utilized as well. An example by Davis employed different activators to modify the nature of the sulfenium leaving group, either by retarding or promoting the SN2 pathway, hence achieving α- or β-glycosides, respectively.42 The elegance of reagent controlled glycosylation is perhaps best exemplified by using catalytic amounts of an activator to control the stereochemistry of reactants.43−45 This is well exemplified by our group’s work, in which the Nheterocyclic carbene (NHC) catalyst directed stereoselective β-

glycosylation (Scheme 9a).46 The Breslow intermediate generated from an aldehyde and the carbene catalyst attacked the β-face preferably due to its interaction with the nitro substituent on C2. Besides our work, Galan and McGarrigle have also reported thiourea catalyzed glycosylation, in which they proposed an alcohol−thiourea complex attacking the αface due to steric effects and anomeric effects.47 These stereodirecting approaches paved the way for dual-directing catalyst controlled glycosylation approaches developed later. Seminal work by Nguyen showed the potential of applying catalytic stereocontrol to the palladium−ligand complex, in which the anomeric selectivity of N-glycosylation could be reversed through the use of the cationic and neutral Pd(II) catalyst as shown in Scheme 8.48 Intrigued by the success of this catalyst-driven stereocontrol, we investigated the potential of targeting anomeric selectivity during the Pd-catalyzed decarboxylative allylation.49 When phenol was utilized as the glycosyl acceptor, α-/β-selectivity for the glycosides could be reversed by substituting the Pd(II) catalyst with Pd(0) catalyst, which was attributed to the catalysts’ differing preferences for H


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Accounts of Chemical Research Scheme 10. Comparison Study on Pd(0)/Pd(II)-Controlled Glycosylation

Figure 3. Tuning the reactivity of glycosyl donors through manipulation of (a) anomeric leaving groups or (b) combinations of protecting groups.

Scheme 11. Streamlining One-Pot Synthesis of Oligosaccharides through (a) Preactivation of Donor or (b) In Situ Protection/ Deprotection

dedicated to the streamlining of synthetic protocols, through the fine-tuning of reactivity or mimicking enzymatic glycosylation reactions, which could proceed without protection.50,51 The resulting convenience and practicability are especially desirable in oligosaccharide syntheses. A procedure for oligosaccharide synthesis typically involves protection−activation−glycosylation−deprotection, often with purification after each step. This procedure is then repeated for oligosaccharide elongation, making it laborious, expensive, and time-consuming. As such, the tuning of reactivity of glycosyl donors offers the advantage of eliminating deprotection steps (Figure 3). Yu and others designed anomeric leaving groups, such as N-phenyltrifluoroacetimidates (PTFAI), 3,3-difluoro3H-indol-2-yl (OFox), or 2-(2-propylsulfinyl)benzyl (PSB), which could be activated in a controlled manner to generate the reactive species.52−54 In addition, Wong and Hung extended the arming/disarming concept and performed programmable one-pot synthesis by mapping the relative reactivity values

coordination. Expansion to D-galactal, L-fucal, D-allal, and Ddigitoxal substrates with varying positional stereochemistry could be achieved (Table 1). To provide evidence for the catalyst-dependent stereoselectivity, a comparison study was conducted using Pd(II) catalyst with and without prestirring of ligand (Scheme 10). Although such reagent-controlled stereoselectivity is a wellconceived concept and has proven its ability to direct the stereoselectivity during glycosylation, in-depth investigation into tuning the properties and detailed mechanisms are required before it can serve as a powerful full-fledged glycosylation tool.

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OTHER ASPECTS OF GLYCOSYLATION Undoubtedly, the remarkable breadth of stereocontrol methodologies has maximized glycosylation efficiency by reducing or eliminating undesirable anomeric side products. In order to further enhance the synthetic efficiency, efforts have been I


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Figure 4. Boron-based transient masking groups in glycosylation.

(RRV) of each combination of protecting groups.55 These findings have significantly simplified oligosaccharide syntheses by reducing the number of steps required. Another approach to simplify the glycosylation procedure for oligosaccharides is to conduct reactions in a one-pot manner. This is often performed with a judicious choice of monomers based on their anomeric reactivities, which could be modulated with the above-mentioned strategies. Huang and Ye successfully overcame the reliance of such glycosylation reactions on glycosyl donor reactivities in their iterative one-pot synthesis through a preactivation of the donor followed by the introduction of the acceptor (Scheme 11a).56 Similarly, in situ protection/deprotection in the one-pot synthesis could contribute to streamlining glycosylation. However, deciding on the choice of such transient protecting group is not easy as it has to be sufficiently robust to mask the free hydroxyl groups regioselectively and effect reactivity during glycosylation, while remaining easy-to-remove after glycosylation. In reports by Aoyama, Kaji, and Taylor, arylboronic esters were successfully utilized as protecting group and their hydrolysis and removal were only made possible with phase changes (Scheme 11b).57−59 Inspired by these previous efforts, the idea of using a transient masking group was conceived, in which the glycosylation is independent of the monomer substrate’s intrinsic reactivity.60 Besides tapping on the unique coordinating ability in boron and their ease of removal as protecting groups, as in the case of arylboronates, dialkylboron as a transient masking group provides an additional steric factor, hence efficiently realizing the regio- and stereoselectivity of glycosylation. This strategy was then successfully applied to hydroxyl groups at various positions of the glycosyl donor, singly and multiply unprotected hydroxyl groups, and the syntheses of oligosaccharides through repeated couplings (Figure 4). Notably, the glycosyl donor is fully masked and activated before addition of the acceptor. It was then successfully demonstrated that, through reversing the stepwise

sequence of adding the two sugar components, their role in the glycosylation reaction, as either donor or acceptor, was interchangeable without the need for further derivatization. As exemplified in Figure 4, disaccharides with four different donor/acceptor combinations were all readily obtained with two partially protected sugar units, resembling the modular assembly of mechanical parts. Hence, by using transient masking groups, we are able to circumvent the tuning of protection or anomeric leaving groups of complex oligosaccharide blocks and accelerate the synthesis of glycan targets by using the powerful strategy of modular glycosylation.

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CONCLUSION AND OUTLOOK In consideration of the diversity and complexity of the glycoworld, there is an ongoing search for an efficient and unified glycosylation strategy for all specific stereoselectivities and branching patterns. In order to attain a comprehensive understanding of current glycosylation methodologies, our studies have spanned controlling anomeric selectivity by (1) donor-, (2) acceptor-, or (3) reagent-based methods. Classic donor-controlled glycosylation has offered us many opportunities to target the stereoselectivity, by using remote directing groups, conformational constraints, anomeric effects, neighboring group participation, and IAD. Another option is through the use of the other substrate, glycosyl acceptor. Interestingly, by careful choice of the donor, this acceptor-controlled stereoselectivity can be achieved while tapping the strengths of various donor-controlled strategies. Alternatively, pKa values of acceptors also empower us with predictive powers for anomeric selectivity. On top of substrate-dependent stereoselectivity, the nature of reagents, such as solvents and catalysts, can also be used to modulate α-/β-selectivity, thereby avoiding the laborious preparative syntheses of substrates. In addition, glycosylation efficiency can be further enhanced by fine-tuning of reactivity and protection/deprotection steps. While these methodologies have already opened up new possibilities to gain access to diverse oligosaccharides and glycoconjugates, their J


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applications remain scant due to various reasons such as practicability and convenience.61 Looking forward, our preliminary success in the search for a convenient, universal and versatile glycosylation strategy will continue to fuel advances in synthetic glycochemistry.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xue-Wei Liu: 0000-0002-8327-6664 Author Contributions ‡

W.-L.L., H.Y., and J.-X.H. contributed equally to this work.

Funding

Financial support from Nanyang Technological University (RG14/16 and COS RES SEED FUND), Ministry of Education, Singapore (MOE 2013-T3-1-002), and National Research Foundation, Singapore (NRF-NSFC002-005), is gratefully acknowledged. Notes

The authors declare no competing financial interest. Biographies Wei-Lin Leng was born in Singapore. She obtained her B.Sc. degree in Chemistry from NTU (2013) and continued to pursue her Ph.D. degree under the supervision of Prof. Xue-Wei Liu. Her research interests include glycosylation methods and their applications to glycopeptide and glycoprotein syntheses. Hui Yao was born in Anhui, China. He obtained his B.Sc. and M.Sc. in Medicinal Chemistry (2012) from Jinan University. After working for two years in CUHK, Hong Kong, he moved to NTU, Singapore, to join Prof. Xue-Wei Liu’s group as a Ph.D. candidate. He is interested in developing novel glycosylation methodologies and their applications. Jing-Xi He was born in Anhui, China. He obtained a B.Sc. degree from NTU in 2014. After working as a project officer for half a year, he started pursuing a Ph.D. degree under joint supervision of Prof. Mary B. Chan-Park and Prof. Xue-Wei Liu. His Ph.D. research focused on developing polysaccharide-based materials for antibacterial studies. Xue-Wei Liu received his B.Sc. and M.Sc. in Chemistry from China Agricultural University, China (1996), and Ph.D. degree from University of Southern California (2000). From 2000 to 2003, he worked in P&G Pharmaceuticals and Chugai Pharma USA, gaining insights to industrial applications. He carried out his postdoctoral research on carbohydrate chemistry and glycobiology at Caltech before he took up his current position as an associate professor of chemistry at Nanyang Technological University (NTU), Singapore. His research field covers carbohydrate chemistry, glycoproteins, and glycobiology in addressing problems of medicinal and biochemical significance.

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