“One-Pot” Protection, Glycosylation, and Protection–Glycosylation

Review Cite This: Chem. Rev. 2018, 118, 8025−8104

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“One-Pot” Protection, Glycosylation, and Protection−Glycosylation Strategies of Carbohydrates Suvarn S. Kulkarni,*,† Cheng-Chung Wang,*,‡ Narayana Murthy Sabbavarapu,§ Ananda Rao Podilapu,† Pin-Hsuan Liao,‡ and Shang-Cheng Hung*,§ †

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan § Genomics Research Center, Academia Sinica, Taipei 115, Taiwan Chem. Rev. 2018.118:8025-8104. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/13/18. For personal use only.

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ABSTRACT: Carbohydrates, which are ubiquitously distributed throughout the three domains of life, play significant roles in a variety of vital biological processes. Access to unique and homogeneous carbohydrate materials is important to understand their physical properties, biological functions, and disease-related features. It is difficult to isolate carbohydrates in acceptable purity and amounts from natural sources. Therefore, complex saccharides with well-defined structures are often most conviently accessed through chemical syntheses. Two major hurdles, regioselective protection and stereoselective glycosylation, are faced by carbohydrate chemists in synthesizing these highly complicated molecules. Over the past few years, there has been a radical change in tackling these problems and speeding up the synthesis of oligosaccharides. This is largely due to the development of one−pot protection, one−pot glycosylation, and one−pot protection−glycosylation protocols and streamlined approaches to orthogonally protected building blocks, including those from rare sugars, that can be used in glycan coupling. In addition, new automated strategies for oligosaccharide syntheses have been reported not only for program-controlled assembly on solid support but also by the stepwise glycosylation in solution phase. As a result, various sugar molecules with highly complex, large structures could be successfully synthesized. To summarize these recent advances, this review describes the methodologies for one-pot protection and their one-pot glycosylation into the complex glycans and the chronological developments associated with automated syntheses of oligosaccharides.

CONTENTS 1. Introduction 2. One-Pot Protection of Carbohydrates 2.1. Differentiation of Primary Alcohols Using Bulky Protecting Groups 2.2. Regioselective Protection-Catalyzed by Metal Coordination and Organocatalysts 2.3. Regioselective Protection of the TMS-Protected Sugars 2.4. One-Pot Protection Protocols Involving Formation of Orthoester or Acetal Protecting Groups 2.4.1. Orthoesters and Acetals from Unprotected Glycosides 2.4.2. One-Pot Protection Using TMS Protected Sugars 2.5. Orthogonally Protected Glycosamine and Rare D/L-Deoxy Amino Sugar Building Blocks via One-Pot Nucleophilic Displacement of OTriflates 3. Glycosylation 3.1. One-Pot Glycosylation 3.2. One-Pot Glycan Assembly from the Nonreducing End to Reducing End 3.2.1. Reactivity-Based One-Pot Glycosylation

© 2018 American Chemical Society

3.2.2. Orthogonal One-Pot Glycosylations 3.2.3. Preactivation-Based Iterative One-Pot Glycosylation 3.2.4. Photochemical One-Pot Glycosylations 3.3. One-Pot Glycan Assembly from the Reducing End to Nonreducing End 3.4. Hybrid One-Pot Glycosylation 4. Glycosylation and Protecting Group Manipulations in One-Pot 4.1. Glycosylation−Deprotection−Glycosylation in One-Pot 4.2. Protection−Glycosylation in One-Pot 4.3. Protecting Group Manipulation and Glycosylation in One-Pot Using Borinic Esters 5. Toward Development of Automated Approaches in Oligosaccharide Synthesis 5.1. Automated Solid-Phase Oligosaccharide Synthesis 5.2. Automated Solution-Phase Synthesis of Oligosaccharides

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Received: January 15, 2018 Published: June 5, 2018 8025

DOI: 10.1021/acs.chemrev.8b00036 Chem. Rev. 2018, 118, 8025−8104

Chemical Reviews 5.2.1. Fluorous-Tag-Assisted Automated Oligosaccharide Synthesis 5.2.2. HPLC-Assisted Automated Oligosaccharide Synthesis 5.2.3. Automated Electrochemical Assembly of Oligosaccharides 5.3. Ionic Liquid Supported Oligosaccharide Synthesis 6. Summary and Future Directions Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations References

Review

cells, are found to be involved in cell−cell interactions26 based on several carbohydrate−protein or carbohydrate−carbohydrate binding studies. Moreover, carbohydrates exert their antibacterial effects by binding to the decoding aminoacyl site (A-site) of the bacterial 16S rRNA and interfering with translational fidelity during protein synthesis. However, unlike DNA and proteins, which are gene-encoded, oligosaccharides are synthesized in a stepwise manner via posttranslational enzymatic modifications in the endoplasmic reticulum and Golgi apparatus.27 This lack of gene-regulated synthesis results in a highly heterogeneous and extremely diverse repertoire of carbohydrate structures,28 which makes isolation of pure samples from natural sources arduous. Because isolation of carbohydrates from nature can become a daunting, if not impossible, task, carbohydrate molecules are mostly accessed synthetically. General strategies used for the preparation of oligosaccharides include enzymatic, chemoenzymatic, and chemical syntheses. In enzymatic synthesis, glycan assembly can be carried out with absolute regio- and stereocontrol with high efficiency (Scheme 1A).29 However, the success and scope of glycosyltransferase-catalyzed sugar couplings are still limited due to the lack of readily available enzymes and their lack of promiscuity toward different substrates. Therefore, chemical approaches have gained prominence over enzyme-based routes, as chemical syntheses (Scheme 1B) offers exceptional flexibility to assemble natural and non-natural oligosaccharide scaffolds that allow the detailed interrogation of cell-surface carbohydrate−receptor binding events. Research in oligosaccharide synthesis encompasses both the discovery and development of formidable glycosylation methods and the invention of novel technologies that control regio- and stereochemical outcomes in each glycosidic bond formation.30 Indeed, the discovery of the Koenigs−Knorr glycosylation31 fueled the field of carbohydrate chemistry. Since then, chemists have made remarkable efforts for the syntheses of oligosaccharide sequences from suitably protected monosaccharide building blocks involving a minimal number of synthetic operations.32−39 Of these, one-pot multistep glycosylations, where glycosylation reactions of several glycosyl donors are sequentially coupled with acceptors in a single reaction vessel, have attracted attention from the synthetic community. This technique has witnessed tremendous development and growth mainly because the target oligosaccharides are easily afforded with minimal protecting group manipulations and devoid of tedious intermediate isolations.40,41 Aside from convenient access to a vast array of oligosaccharide structures, chemical synthesis guarantees substance homogeneity. As synthetic chemists continuously explore carbohydrate chemistry and develop versatile methods to streamline the synthesis of complex glycans, a variety of structurally diverse complex glycoconjugates have been synthesized with the aid of sophisticated analytical tools for structural determination. Hence, synthetic studies toward complex oligosaccharides provide access not only to desired homogeneous stereodefined structures but also to sufficient amounts of pure synthetic oligosaccharides for biological evaluation. In general, traditional glycosylation methods involve the preparation of individual monosaccharide building blocks in the synthesis of complex glycans (Scheme 2A). This, however, requires extensive protection and deprotection manipulations during oligosaccharide chain elongation. To expedite glycan assembly, one-pot procedures for multistep transformation have gained prominence, which obviates the need to carry out

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1. INTRODUCTION Carbohydrates are indispensable in eliciting a myriad of key biological processes such as viral and bacterial infection, cell signaling, cell proliferation and differentiation, angiogenesis and metastasis, immune-responses, and neurodegenerative diseases.1−4 These glyco-moieties are mediators of various physiological functions and modulate the physicochemical properties of proteins, including their structures, stability, flexibility, and functions after post-translational modifications.1 For example, O-glycan-rich proteins, which have significant antifreeze properties, can allow Arctic fishes to survive at low temperatures (−2 °C) by preventing nucleation of ice.5−7 Remarkable advances have been made in understanding the role of oligosaccharide domains of the glycolipids, glycoproteins, and bacterial lipopolysaccharides in recent years. Although their functions are still not yet fully understood, the sugar-epitopes of glycoconjugates found on the cell surface and in the basement membrane and extracellular matrix play key roles in recognition events including cell−virus, cell−bacterium, and cell−cell interactions. Moreover, the trove of structural information stored in the carbohydrate scaffolds dictates the blood group activities and their ontogenic and oncogenic properties as differentiation antigens.8,9 In addition, there are other overwhelming data supporting and showing the relevance of carbohydrates in numerous complex biological processes. All of these can help advance the field of glycobiology and provide important breakthroughs in deciphering the so-called “sugar code”.10 The carbohydrates of host cells are often involved in pathogen recognition, inflammation, innate immune responses, and the development of autoimmune diseases and cancer.11−14 Of these, cell-surface carbohydrate-receptor binding events with oligosaccharides and glycoconjugates are increasingly used to address the important issues in glycobiology and for therapeutic cancer vaccines15−18 and drug development.19 Consequently, new technologies such as glycan microarrays (e.g., the consortium for functional glycomics, CFG) came into existence for highthroughput screening to determine the affinity and specificity of cell surface receptor glycans for the identification of their specific roles.20−24 For example, the widespread use of glycan array technologies in recent years has enabled rapidly assessing the nature of the interaction between the influenza virus and host glycans.25 Eukaryotic cell-surface glycoconjugates, which are assembled from the nine monosaccharides found in mammalian 8026


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Scheme 1. (A) Enzymatic Glycosylation: Glycosyltransferases-Catalyzed Formation of Glycosidic Bonds from Sugar Nucleotide Donors; No Protecting Groups Are Required in This Approach and (B) Chemical Glycosylation: Glycosylations Involve the Reaction between a Suitably Protected Glycosyl Donor Equipped with a Leaving Group at the Anomeric Position and a Glycosyl Acceptor under the Agency of a Suitable Promotera

The formation of a particular stereoisomer (α or β anomer) during the glycosylation depends on the substituents mainly at the 2-O-position and nature of leaving group at the anomeric position.

a

preactivation-based glycosylation approach is independent of donor reactivity, and it involves activation of the donor using a stoichiometric amount of promoter to form a reactive intermediate, which is subsequently coupled with the acceptor to form a new glycosidic linkage [Scheme 2B (iii)].61 The resulting tailor-made glycosyl building blocks can allow successful one-pot assembly of oligosaccharides.40,41,62−64 Automated oligosaccharide synthesis on solid phase addresses the two major challenges encountered frequently in carbohydrate synthesis: regioselective protection and deprotection of polyhydroxylated molecules and the stereoselective assembly of glycosidic linkages. Most importantly, solid phase synthesis offeres powerful advantages in comparison to conventional solution phase syntheses by circumventing multiple purification steps resulting in rapid, one-pot protocols for the synthesis of linear and branched oligosaccharides.57,65 Pioneering studies have been initiated on the solid phase synthesis of oligosaccharides,66 and progress made in this direction has led to the development of a number of different platforms that include fluorous,67−70 imidazolium cations,71−73 and gold nanoparticles74,75 as supports to harness the modular synthesis of oligosaccharide libraries to integrate them into glycoproteins. In the present review, we provide a comprehensive overview of numerous synthetic approaches for building carbohydrate sequences based on regioselective one-pot protection of carbohydrates, concomitant glycosylation strategies, automated and programmable chemical glycosylations for rapid assembly of

intermittent workups, time-consuming purifications, and greatly reduces chemical waste.42,43 Nevertheless, application of one-pot procedures for oligosaccharide acquisition is a formidable task as it requires absolute regio- and stereochemical control during the formation of each glycosidic bond during the assembly (Scheme 2B). The success of chemoselective one-pot sequential glycosylation strategies44−51 [Scheme 2B(i)] is based on the reactivity differences between competing glycosyl donor building blocks of the same class during the sequential addition. In the reactivity based one-pot glycosylation, the most reactive glycosyl donor, which serves as the nonreducing end, is used to initiate the one-pot glycosylation reaction. Essential to this approach is the presence of an unreactive glycosyl donor, appended at the reducing end of a given oligosaccharide that can later be coerced to undergo glycosylation in the single reaction vessel. The underlying one-pot process is propelled by the concept of “armed” (reactive) and “disarmed” (less reactive) glycosyl donors.52,53 A reactivity based one-pot sequential glycosylation method was also developed, which relies on quantitative measurement of relative reactivity values (RRVs) of various glycosyl donors and acceptors for commonly used protecting groups.54−56 This database of RRVs (“OptiMer”) enabled the one-pot assembly of many important oligosaccharides of biological relevance in excellent yields based on different thioglycoside reactivities.57−59 Alternatively, the orthogonal glycosylation approach involves the variation of leaving groups for chemoselective activation 60 [Scheme 2B (ii)]. The 8027


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Scheme 2. (A) Traditional Glycosylation Approach and (B) One-Pot Chemical Glycosylation Strategies: (i) Chemoselective OnePot Glycosylation Strategy, (ii) Orthogonal One-Pot Glycosylation Strategy, (iii) Pre-Activation Based One-Pot Glycosylation Strategy

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Scheme 3. Carbonyl Neighboring Group Participation Effect

To establish a successful one-pot protecting group scheme, each step requires the use a stoichiometric amount of reagents and has excellent regioselectivity to afford the desired product in high yield in each step. The conditions of sequential reactions in one flask should be compatible with each other. It is preferable that the reactions are either acid- or base-catalyzed, and that the intermediates are stable in each step. Acid−base neutralization should occur only once, otherwise a simple workup, filtration, or solvent evaporation might be necessary, and the protocol is no longer considered a real one-pot process. Nevertheless, such preparative routes are also important to obtain sugar building blocks with well-differentiated hydroxyl groups. Numerous strategies have been developed in the past few years to efficiently synthesize either partially- or fully protected monosaccharide building blocks in a few steps or via one-pot protocols. The topic has been extensively discussed in recent reviews.93,94 Traditionally, after anomeric protection, the most commonly used methodologies for the protection of hexopyranosides are (1) the treatment with bulky reagents to generate O6 protected products, (2) the introduction of acetal protecting groups as sixmembered rings on O6 and O4 or as five-membered rings on vicinal cis-diols, and (3) the inversion of stereochemistry of the key hydroxyl groups to access orthogonally protected rare sugars. The following section on the one-pot protocols is classified into these three major strategies.

complex oligosaccharides, and their applications in the development of microarrays and therapeutics.

2. ONE-POT PROTECTION OF CARBOHYDRATES Chemical synthesis of carbohydrates involves two major challenges: the differentiation of individual hydroxyl groups of each monosaccharide76,77 based on the structure of the target molecules and stereoselective glycosylation.78 The former is necessary to transform unprotected free sugars into either the glycosyl donors or the acceptors for their assembly into oligosaccharides. It is challenging to produce orthogonally protected monosaccharides as the secondary hydroxyl groups present in saccharides that show similar reactivity. Separation and characterization of the regioisomers at each step is laborious and greatly lowers the overall yields and efficiency. Moreover, in designing the protecting group pattern of the building blocks, one has to consider not only the structures of the target molecules but also inductive and neighboring group participation effects.79−82 The electron-donating or electron-withdrawing nature of the protecting groups directly influences the activation of the glycosyl donors and the participation of the acceptors and in turn controls the efficiency and the yields of the glycosylation reactions. The protecting group at the 2-O-position of the donor is essential for controlling the stereochemistry of the new glycosidic bond (Scheme 3). Generally, an ester or carbonatetype protecting group, such as acetyl (Ac), benzoyl (Bz), or 9fluorenylmethoxycarbonyl (Fmoc), leads to the 1,2-trans-linkage because of neighboring group participation by the carbonyl group. On the other hand, donors with allyl- or benzyl-type ethers at this position tend to be unselective in the absence of other factors, such as acetal protectng groups, catalysts, or glycosylation modulators but slightly favor the formation of axially oriented glycosidic bonds due to the anomeric effect (∼1.5 kcal/mol).83,84 In other words, the protecting groups at the 2-O-position have to be determined in the retrosynthetic design and installed exactly according to the stereochemical configuration of the glycosidic bond.52,85−92 The orthogonal protecting group pattern is also crucial for sugar chain elongation and functional group modifications. Traditional chemical synthesis of oligosaccharides requires long preparative steps and takes months or years to be carried out. The associations with protecting group installations and modifications seem to be the most time-, labor-, and material-consuming processes in the synthesis of glycans. The desired product is usually obtained in low yields due to the poor regio-selectivity or reactivity. The lack of common intermediates and methodologies also impedes the preparation of glycans. Each monosaccharide is in equilibrium between the furanosyl and pyranosyl configurations, each with different orientations of hydroxyl groups requiring unique strategies to prepare building blocks. In addition, inefficient protection−deprotection sequences taking additional steps are usually needed. Therefore, strategies that simplify the regioselective protection of carbohydrates via one-pot protocols greatly expedite glycan synthesis.

2.1. Differentiation of Primary Alcohols Using Bulky Protecting Groups

The primary hydroxyl group at C6, which is less hindered, has a higher reactivity than the secondary hydroxyl groups at C2, C3, and C4. It can be regioselectively protected by bulky protecting groups, such as tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr), to generate the 6-O-protected monosaccharides in good yields.95−100 Discrimination of the remaining three secondary hydroxyl groups relies on their relative spatial orientation (axial or equatorial) and electronic properties. Therefore, different sugars or even anomers usually offer different ratios of regioisomers. These factors can be modulated and exploited properly via appropriate reagents, solvents, and temperatures to obtain high regioselectivity. In 2000, Kong and co-workers developed a sequential regioselective one-pot tritylation, silylation, and diacylation protocol for the hexopyranosyl tetraols 1−7 (Table 1) under basic conditions.101 Initially, treatment of the hexopyranoside with trityl chloride in the presence of a catalytic amount of 4(dimethylamino)pyridine (DMAP) at 80 °C yielded the 6-Otritylated intermediate, which underwent regioselective silylation with TBDMSCl and imidazole at either O2 or O3, depending on the relative spatial orientation of the secondary hydroxyl groups and the anomeric configuration. Subsequent per-O-acetylation or benzoylation in the same reaction vessel gave the fully protected monosaccharides 8−15 in 71−86% overall yields after a single column chromatography. In general, the hydroxyl group 8029


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Table 1. One-Pot Protection of Sugar Tetraols

Scheme 4. Me2SnCl2-Catalyzed Regioselective Esterifications

Me2SnCl2-catalyzed highly regioselective benzoylation of various monosaccharides to afford the monobenzoylated products in good yields (Scheme 4a).110 The excellent selectivity can be attributed to (1) the reversible interaction between Me2SnCl2 with the 1,2-cis-dioxygen atoms of the α-glucoside 5 or the 4,6dioxygen atoms of the β-glucoside 17; (2) the increase of the proton acidity in the tin-coordinated intermediate which can be deprotonated easily by a weak base, such as N,N-diisopropylethylamine (DIPEA) or 1,2,2,6,6-pentamethylpiperidine (PEMP);111 and (3) the nucleophilic addition with benzoyl chloride at the less hindered alkoxide to provide the 2-O-Bz derivative 16 and 6-O-Bz derivative 18 in 82% and 79% yields, respectively. A similar phenomenon was observed in the case of the α-mannoside 2 (Scheme 4b). The 3-O-functionalized product 20 was isolated via the proposed 2,3-cis-oriented fivemembered ring intermediate 19, presumably formed via elimination of 2 equiv of HCl and further activation of the C-3 hydroxyl group.111 Application of this strategy to the 3,4,6-triol 16 to regioselective tosylation, as illustrated in Scheme 4c, gave the corresponding 6-OTs derivative 21 in 88% yield. Interestingly, differentiation of the remaining 3,4-trans-diequatorial dihydroxyl groups in 21 using Boc2O as the reagent under similar Me2SnCl2-catalyzed conditions was successfully achieved to yield the 3-O-bocylated product 22 in excellent regioselectivity. Subsequent phosphorylation of 22 eventually afforded the fully protected glucoside 23. Although this sequential protocol was not carried out in a one-pot manner, all of the consecutive steps were under the same catalyst as well as

at C4 is less reactive, and none of the 4-O-silylated products were isolated. In cases of the α-mannosides 1 and 2, β-glucosides 3 and 4, and β-galactoside 6, the silylation took place at O3. The regioselectivity is attributed to steric effects, which directly affect the approach of the hydroxyl group toward the silylation reagent. This is different from the methyl α-glucoside 5, which preferred the 2-O-position because of the inductive effect of the ring oxygen atom. Poor O2/O3 regioselectivity was obtained for the α-galactoside 7. Replacement of the trityl group by the TBDPS group at O6 in the mannoside 2 gave similar regioselectivity in the second step of TBDMS-silylation. These building blocks have been applied to synthesize the 3,6-branched mannopyranosyl penta- and hexasaccharides and β-1,3-glucans.101 It should be noted that the 3-O-TBDMS group of the glucosides was found to undergo migration to the 2-O-position under strong basic conditions.102 2.2. Regioselective Protection-Catalyzed by Metal Coordination and Organocatalysts

With the use of coordinating catalysts, one can use the relative spatial orientation of the hydroxyl groups and the anomeric configurations to achieve regioselective protection of carbohydrate polyols. The history of this chemistry can be traced back to the 1970’s.103−109 In 2008, Onomura and co-workers reported a 8030


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Scheme 5. Proposed Mechanism for the Benzylation Catalyzed by an Organotin Reagent and TBAB

base. The protocol can be potentially transformed into a one-pot procedure. The first organotin-catalyzed benzylation and allylation of sugar polyols using a catalytic amount of Bu2SnO under solventfree conditions was developed by Iadonisi and co-workers.112 Dong and Pei further demonstrated that regioselective benzylation could also be executed in toluene in the presence of organotin reagents, such as Bu2SnO, Bu2SnCl2, or Me2SnCl2, and also proposed a catalytic cycle (Scheme 5).113 Recently, orthogonal protection of saccharide polyols through solvent-free and regioselective one-pot sequences employing TBDPS- or TBDMS-silylation at O6 followed by Bu2SnOcatalyzed benzylation or allylation was reported by Iadonisi and co-workers (Scheme 6).114 This one-pot two-step protocol worked for the 2,3,4,6-tetraols 2, 5, and 24, affording the 6-Osilylated and 3-O-benzylated/allylated diols 25, 26, 27, and 29 and 6-O-silylated and 3-O-benzylated diol 28 in moderate to good yields (42−62%). The lower yields could be the results of the competitive reaction in the second silylation reaction due to residual etherification reagents from the first step for compounds 25−27 and 29 or the cleavage of the TBDPS group in the second benzylation step under high temperature 28. The Me2SnCl2-catalyzed procedure has been applied to the indirect preparation of orthogonally protected D-glucosamine building blocks from D-mannosides by Kulkarni and co-workers (Scheme 7).115 The Me2SnCl2-catalyzed regioselective acylation (Bz or Ac) worked well for the β-thiomannoside 30 and gave the 3-O-acylated thiomannoside 31a or 31b in excellent yields, which was further benzylidenated at the O6 and O4 positions to furnish 32a or 32b. Inversion of the remaining C2-hydroxyl group via triflation and subsequent SN2 displacement with an azide provided the orthogonally protected D-glucosamine building

Scheme 6. Bu2SnO-Catalyzed Regioselective One-Pot Protection of the 2,3,4,6-Tetraols

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Scheme 7. Efficient Preparation of Orthogonally Protected DGlucosamine Building Blocks from β-Thiomannoside

Scheme 8. Regioselective O4-Acylation Using the Chiral DMAP as Organocatalyst

blocks 33a or 33b. Although the synthesis was not carried out in the one-pot manner, the whole protocol could be completed with only a single column chromatographic purification and 33b was obtained in a day with an overall yield of 44% over four steps. This route circumvents the use of a cumbersome diazo transfer reaction to convert the amino group of D-glucosamine hydrochloride to access 2-azido glucosides. Compounds 33a and 33b could be easily converted into the corresponding galactosamine building blocks by subsequent benzylidene hydrolysis, regioselective O6-silylation, and C4-epimerization. Regioselective acylation of monosaccharides has been a topic of great interest as seen from a number of very useful methodologies published in recent years employing various reagents,116 (organotin,117−119 organoboron,120−124 organosilicon,125 and organobases126−129), transition metal catalysts [copper(II),130−134 silver(I),135 nickel(II),136 molybdenum(V) and (II),137,138 and iron(III)139 ], and tetrabutylammonium salts.140,141 These reports have revealed that the hydroxyl groups at O6 and O4 in a pyranoside are the most and least reactive positions, respectively. Kawabata and co-workers recently described a C2-symmetric, chiral DMAP derivative (34) as an excellent catalyst (1.0 mol %) to achieve the regioselective acylation of n-octyl β-D-glucopyranoside 35 at O4, yielding the corresponding 2,3,6-triol 36 (99%) as a single isomer (Scheme 8).142−145 It is proposed that multiple noncovalent interactions between catalyst 34 and substrate 35, including hydrogen bonding between the carbonyl group of the amide and the indole NH with the 6-OH and 3-OH groups, probably fixes the conformation of the substrate and allows the 4-OH group to react with the acylpyridinium ion. However, high yield and selectivity could only be achieved when using chloroform as the solvent, and the n-octyl group or related substituent is necessary for the solubility of the substrates. Furthermore, the equatorially oriented 4-OH and β-anomeric configuration are essential for obtaining high regioselectivity, such as n-octyl β-D-glucopyranoside, β-D-thioglucopyranoside, and β-D-mannopyranoside. The selectivity was decreased in the case of α-D-glucopyranoside, however. Moreover, for n-octyl α-D-galactopyranoside, the regioselectivity changed to the O6 position. Consecutive TBDPS-protection of the 2,3,6-triol 36 at O6 provided the 2,3diol 37 (98%), Boc-protection at O2 furnished 38 (98%), and final benzyloxymethyl (BOM) protection at O3 afforded the fully

orthogonally protected monosaccharide 39 (99%) in good regioselectivity.142 2.3. Regioselective Protection of the TMS-Protected Sugars

In the methods discussed so far, prior to the chemical modification of the polyols, the anomeric position of the monosaccharides has to be substituted due to the solubility issues of free sugar substrates in organic solvents. To solve this problem, Hung and co-workers introduced per-O-trimethylsilyl (TMS) derivatives of glycosides to greatly improve the solubility of carbohydrates in organic solvents, such as CH2Cl2, to carry out regioselective one-pot protection of carbohydrates40,41 (vide infra section 2.4.2). Traditional introduction of the TMS group uses TMSCl and multiequivalents of the Et3N as base. However, this method generates a large amount of Et3N/HCl salt, which needs to be removed. Therefore, it is necessary to isolate these per-O-trimethylsilylated substrates before the sequential one-pot procedures, and the preparation of per-O-trimethylsilylated saccharides takes an additional step. Wang and co-workers developed a trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed 1,1,1,3,3,3-hexamethyldisilazane (HMDS) mediated per-O-TMS protection of carbohydrates.146 A proposed catalytic cycle is depicted in Scheme 9. TMSOTf and HMDS initially react to generate a complex A with its Si−N bond polarized and activated, and then the trimethylsilyl group migrates to one equivalent of alcohol to afford the corresponding TMS-ether and complex B, which further reacts with another equivalent of alcohol to produce another equivalent of TMSether. Finally, complex C is formed and turned into gaseous ammonia and TMSOTf. The former evolves, and the latter triggers the next catalytic cycle. The strongly basic conditions turned to neutral when the reaction proceeded to completion as basic HMDS is transformed into NH3 and then released. Sequential Lewis acid-catalyzed one-pot reaction in the same vessel is feasible, and the subsequent reactions can be started from free sugars employing the per-O-trimethylsilylated derivatives as intermediates. The reaction time was shortened from hours to minutes and monosaccharides 2 and 40−43 were 8032


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Scheme 9. Postulated Catalytic Cycle of TMSOTf-Catalyzed HMDS Silylation of Alcohols

Table 3. Streamlined Regioselective One-Pot Acetylation of Free Sugars

Table 2. TMSOTf-Catalyzed HMDS per-OTrimethylsilylation of Sugars

Scheme 10. ReSET Acetylation of per-O-TMS NAcetylneuraminic Acid (Neu5Ac) Benzyl Ester 55

TMS Neu5Ac benzyl ester 55 was used as the substrate and was treated with pyridine, acetic anhydride, and 1.0 equiv of acetic acid under microwave-assisted conditions to give the 4-OAc derivative 56, 4,9-di-OAc derivative 57, 4,8,9-tri-OAc derivative 58, and 2,4,8,9-tetra-OAc derivative 59 in 28%, 31%, 16%, and 11% yields, respectively. The silyl ether/acetate exchanged in the order of C4 (2°) > C9 (1°) > C8 (2°) > C2 (anomeric). Subsequent hydrogenolysis of the benzyl ester along with hydrolysis of the TMS groups afforded a series of naturally occurring and unnatural Neu5Ac derivatives for chemical biology studies. The one-pot silylation−acetylation protocol has been extended to silylation−phosphorylation of free sugars. Accordingly, after the TMSOTf-catalyzed HMDS per-O-trimethylsilylation of free D-glucose 42, D-galactose 43, and D-mannose 41,

transformed into their corresponding per-O-trimethylsilylated sugars 44−48 in excellent yields (Table 2).146 By extending this method, anomerically unprotected free sugars can also be modified in one-pot at the C6 position. As indicated in Table 3, after the TMSOTf-catalyzed HMDS per-Otrimethylsilylation of free D-glucose 42, galactose 43, and mannose 41, without any purification or workup, pyridine, AcOH, and Ac2O were added to the same reaction vessel and the 6-OAc products 49−51 were furnished in moderate to good (64−81%) yields.146−148 Minor amounts of 1,6-di-OAc products 52−54 (15−18%) were also isolated. Gervay-Hague and co-workers proposed a regioselective silylexchange technology (ReSET)147,148 and have applied it to regioselective acetylation of sialic acid (Scheme 10).149 Per-O8033


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Scheme 11. Chemoselective HMDS per-O-Trimethylsilyltion of Aminosugars Table 4. One-Pot Regioselective O6 Phosphorylation of Free Sugars

Scheme 12. Concise One-Pot Synthesis of Glucosamine-6Phosphate

HCl, and hydrogenolysis of the diphenylphosphate group yielded the glucosamine-6-phosphate 71 in 93% yield. 2.4. One-Pot Protection Protocols Involving Formation of Orthoester or Acetal Protecting Groups

without purification or workup, pyridine and diphenyl phosphoryl chloride were added to furnish the O6-phosphorylated derivatives 60−62 in 78−85% yields (Table 4). After the hydrogenolysis of the two phenyl groups along with the hydrolysis of the TMS groups by the solvent, a series of biologically potent sugar 6-phosphates could be obtained. It is noteworthy that for disaccharides, such as lactose and cellobiose, the phosphorylation took place regioselectively at the O6 position of the nonreducing end. Moreover, for symmetric trehalose, the phosphorylation was selective on only one of the two primary C6 hydroxyl groups, and thus this method is useful for trehalose desymmetrization.150 Wang and co-workers later found that by treating aminosugar hydrochlorides with HMDS in acetonitrile as the solvent, without any additional catalyst, a chemoselective per-Otrimethylsilylation of glucosamine hydrochloride 63, galactosamine hydrochloride 64, and mannosamine hydrochloride 65 could be performed to give the corresponding free amines 66− 68 in quantitative yields (Scheme 11).151 The ensuing amine functionalization could therefore be performed homogeneously. A one-pot two-step reaction, involving diazotransfer and O6 phosphorylation of 66 was demonstrated in the synthesis of biologically potent glucosamine-6-phosphate (Scheme 12).151 Per-O-trimethylsilylated glucosamine 66 was first treated with azido trifluoromethanesulfonate (TfN3), followed by the subsequent regioselective O6-phosphorylation, to give the glucosamine-6-phosphate derivative 70 in 78% yield. Reducing the azido group of 70, neutralizing the amino group with aqueous

Acetals and orthoesters are frequently used protecting groups152−155 in carbohydrate chemistry. They protect two hydroxyl groups at a time by forming either a five-membered (dioxolane) or six-membered (dioxane) ring usually, but not always, with high regioselectivity toward a specific set of diols. Depending on the structure of the monosaccharide, this leaves only two remaining hydroxyl groups to be differentiated. 2.4.1. Orthoesters and Acetals from Unprotected Glycosides. Cyclic orthoesters can selectively protect cis-diols simultaneously. This protecting group is base-resistant and can be further rearranged into esters with reasonable regioselectivity under acidic condition. Field and co-workers developed a onepot protocol that introduced orthoester to cis-diol, followed by benzylation of the remaining hydroxyl groups and successive orthoester rearrangement under acidic conditions.156 In the case of methyl α-L-rhamnose 72 (Scheme 13), the orthoester formation fixed the adjacent cis-dihydroxyl groups at C2 and C3 to yield the intermediate 73, and the C4-hydroxyl group was further benzylated using benzyl bromide and sodium hydride to give intermediate 74. Consecutive treatment of 74 with 1 M aqueous HCl enabled the regioselective opening of the orthoester, and the C2-acetate 75 (83%) was afforded in a one-pot manner. Cleavage of the cyclic orthoester exposes the equatorial hydroxyl group, leaving the ester (in this case acetate) at the axial position. Similar results were obtained in the monosaccharides containing the cis-dihydroxyl groups, and the products 76−79 were obtained in good yields. Finally, in a study of methyl α-D-glucopyranoside, the orthoester was formed at the 8034


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regioselectivity and have intrinsic advantages in protecting diols. The importance of benzylidene acetals has been further demonstrated by their regioselective ring opening, which selectively releases either the primary C6 or secondary C4 hydroxyl groups by using different combinations of reducing agent, solvent, and acid.157−174 Moreover, they can also be hydrolyzed to reveal the diol moiety, which can then be selectively protected at the primary C6 hydroxyl group with an orthogonal protecting group. Alternatively, the benzylidene group can also be cleaved with N-bromosuccinimide (NBS) to give the corresponding 4-OBz, 6-bromo derivatives in high regioselectivity.175 Many one-pot acetalation−acetylation reactions using various acid catalysts have been reported. The acetalation with dimethyl acetal or ketal, followed by acidcatalyzed acetylation using acetic anhydride gave the fully protected monosaccharides. The catalysts include p-toluenesulfonic acid,176 Cu(OTf)2,177 I2,178,179 cyanuric chloride,180 HClO4,181 and H2SO4182 on silica. Taking the β-glucoside 17 and β-thiogalactoside 81 as the examples, using Cu(OTf)2 as the catalyst, after consecutive benzylidenation and acetylation, the fully protected glucoside 82 and galactoside 83 were obtained in

Scheme 13. One-Pot Protection Using Orthoester Rearrangement

Scheme 15. Cu(OTf)2-Catalyzed One-Pot AcetalationAcetylation-O4 Benzylidene Opening of Glycosides

92% and 75%, respectively (Scheme 14).177 As shown in Scheme 15 for the thioglucoside 84, thiogalactoside 81, and thioglucosamine 85, after the acetylation, further regioselective reductive opening of the benzylidene group using Et3SiH afforded the corresponding C4 alcohols 86−88 in good (50−60%) yield over three steps in a one-pot manner.

O4 and O6 positions. After the benzylation, the rearrangement gave a mixture of the 6-acetate 80a and 4-acetate 80b in 7:3 ratio. Benzylidene and isopropylidene acetals and their derivatives are important protecting groups for monosaccharide building block synthesis because they can be introduced in high

Scheme 14. Cu(OTf)2-Catalyzed One-Pot Acetalation-Acetylation of Glycosides

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Scheme 16. Hung’s Regioselective One-Pot Protection of Carbohydrates

2.4.2. One-Pot Protection Using TMS Protected Sugars. As mentioned earlier, one of the problems faced while dealing with sugar polyols is their poor solubility in organic solvents. Hung and co-workers pioneered the introduction of TMS protecting groups into one-pot protection of carbohydrates.40,41,94,183 The TMS protection was carried out by using Et3N and TMSCl, and these groups can be removed by using a fluoride source or acidic resin in methanol as solvent. The per-Otrimethylsilylated sugars exhibit excellent solubility in organic solvents, such CH2Cl2 or even n-hexane, as compared to free sugars. Moreover, the reactivity of per-O-trimethylsilylated sugars is elevated thermodynamically in the ensuing one-pot reactions by the formation of TMSOTMS or TESOTMS. Hung and co-workers employed α-OMe or β-STol per-O-trimethylsilylated glucosides 89a or 89b as the starting material and incorporated a TMSOTf-catalyzed arylidenation of TMS ethers184 and a TMSOTf-catalyzed regioselective reductive etherification185,186 as the key steps to get access to hundreds of fully orthogonally protected building blocks or 2-, 3-, 4-, and 6OHs, useful for glycan synthesis, with high overall yields and regioselectivity (Scheme 16). Treating the per-O-trimethylsilylated glucosides 89a or 89b with an aryl aldehyde in the presence of a catalytic amount of TMSOTf formed the O4,O6-arylidene intermediate in situ, which was subsequently added with another

equivalent of aryl aldehyde and Et3SiH in the same vessel to introduce a benzyl-type ether at O3 by reductive etherification to generate intermediates 90a or 90b. The formation of the acetal does not need the corresponding dimethyl acetal but only the aryl aldehyde, and the reaction is driven by the formation of TMSOTMS.184 The excellent regioselectivity of the O3 reductive etherification can be attributed to a thermodynamic effect187 and also the weaker nucleophilicity of the O2 due to a stronger electron-withdrawing inductive effect from its adjacent oxygen atoms. The key intermediate 90 could be further treated with tetrabutylammonium fluoride (TBAF) to obtain the C2alcohol 91, which can be further acylated or alkylated under basic conditions to synthesize the fully protected building blocks 92. When the benzyl type group of 92 is p-methoxybenzyl (PMB) or 2-naphthylmethyl (2-NAP), the oxidative removal of the O3 using DDQ furnished the 3-alcohols 93. On the other hand, after O4, O6-arylidenation, O3-arylmethylation, and acidic O2acylation using acyl anhydride catalyzed by TMSOTf, fully protected building blocks 94 could also be obtained. Successive ring-opening of the arylidene ring in the same vessel using BH3· THF as a reducing agent and TMSOTf as the catalyst gave the C6-alcohols 95, whereas using NaCNBH3 and HCl furnished the C4-alcohols 96. Hung and co-workers extended this protocol to produce a series of diols as well.64 Arylidine ring opening of 28036


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Figure 1. Chemical structures of heparan sulfates, alginate, and influenza trisaccharide.

Scheme 17. One-Pot Protection of Glucoside Using Cu(OTf)2 or FeCl3·6H2O as Catalysts

OTMS 90 under suitable conditions gave 2,6- or 2,4-diols in high yields. Similarly, removal of the 2-NAP group of the intermediate 94 at O3 followed by the arylidene ring opening generated 3,4- or 3,6-diols, and the hydrolysis of the arylidene moiety of 94 gave the 4,6-diol. Due to the greatly improved solubility using per-Otrimethylsilylated sugar as the starting materials, three to five steps can be integrated in a one-pot manner, and various building blocks can be prepared in high yields after a single column chromatography step. Building blocks, which were prepared by

this protocol, had been applied to the synthesis of heparin and heparan sulfates,64,188 alginates,189 and influenza trisaccharides (Figure 1).190 This protocol has been further streamlined by Wang and co-workers by incorporating a TMSOTf-catalyzed HMDS silylation by generating the per-O-trimethylsilylated glucosides 89 in situ. Therefore, tetraols could be used directly as the starting material for this elegant one-pot protocol.146 Beau and co-workers later reported that a similar tandem process could also be catalyzed by Cu(OTf)2191 and nonair8037


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Scheme 18. One-Pot Protection of Glucosamine Building Blocks

sensitive FeCl3·6H2O192 at room temperature instead of −86 °C.40,41 Scheme 17 illustrates the approach, with per-Otrimethylsilylated thioglucoside 97. Using Cu(OTf)2 or FeCl3· 6H2O as the catalyst for the tandem reactions, benzaldehyde as the reagent for benzylidenation and reductive benzylation, and acetic acid for the subsequent acetylation afforded 98 in good yield. Moreover, after O3 benzylation to generate C2-alcohol intermediate 99 in situ, opening of the benzylidene acetal at O4 or O6 gave the 2,4-diol 100 or 2,6-diol 101 in good yields as well. The use of BH3·THF to perform the O6 ring opening was not compatible with FeCl3·6H2O. Beau and co-workers proposed a different reason for the regioselectivity of O3 benzylation. At room temperature, a 4,6-O- and 2,3-O-dibenzylidene intermediate could be generated, which was not observed by Hung et al. at −86 °C. After regioselective reductive ring opening of the more unstable 2,3-O-dibenzylidene acetal, the O3 benzylated compound 99 was formed exclusively. Glucosamine derivatives could also be orthogonally protected by using this one-pot protocol, although the amine protecting groups, which are essential for controlling the anomeric selectivity of ensuing glycosylation reactions,193,194 need to be installed in advance. As shown in Scheme 18, Hung and coworkers modified the 2-azido glucosamine derivative 102 by 4,6O-benzylidenation, O3 acetylation, and O6 ring opening of the acetal to give C6-alcohol 103 in 71% yield. Marques and coworkers carried out the one-pot protection of NH-Troc protected α-O-allyl and β-4-thiotolyl (STol) glucosamine derivatives 104a and 104b by using TMSOTf as the catalyst for the tandem reactions.195 Similarly, 4,6-O-benzylidenation, O3 benzylation, and O4 ring opening of the acetal using a combination of Et3SiH and BF3·OEt2 furnished the C4-alcohols 104a and 104b in 60% and 33% yields, respectively. Beau and coworkers also reported the one-pot protection of α-O-methyl-, NHTFA-protected glucosamine derivative 106 by using TfOH as the catalyst following a similar strategy. After the 4,6-Obenzylidenation, O3-benzylation, and O4-ring opening of acetal, the 4-alcohol 107 was obtained in one-pot in 67% yield. Wang and co-workers also streamlined this one-pot glucosamine protection protocol by integrating their TMSOTfcatalyzed HMDS silylation into the orthogonal regioselective protection of carbohydrates (Scheme 19).146 The NHTCAprotected glucosamine-derived triol 108 was used as the starting material. Sequential TMSOTf-catalyzed silylation, 4,6-O-benzy-

Scheme 19. Wang’s Streamlined One-Pot Protection of Glucosamine Derivative

lidenation, O3-benzylation, and ring opening under different conditions gave either the C4-alcohol 109 (87%) or the C6alcohol 110 (88%), respectively. These protocols have been adopted in Hung’s synthesis of the anticoagulant drug Fondaparinux.196 Scheme 20. Microwave-Assisted Preparation of Thioglucoside for One-Pot Protection of Glucose

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substituted galactoside 115 as the starting material for the onepot protection. When the O6 position was blocked, the benzylidene was formed to block the C3 and C4-hydroxyl groups. After the TMSOTf-catalyzed benzoylation at O2, the O6-TBDPS group was removed by using TBAF to produce the C6-alcohol 116 in 68% yield.63 In the case of D-xyloside 117, regioselective benzylation took place at the O3 position, and the intermediate was regioselectively benzoylated at O2 in the presence of Yb(OTf)3 as catalyst to yield the C4-alcohol 118 (45%) in a one-pot manner. In the investigation of the glucosamine-derived tetra-O-TMS ether 69, 4,6-O-benzylidenation followed by 1,3-di-O-acetylation provided the 1,3-diacetate, which was treated with ammonia gas to regioselectively remove the anomeric acetyl group to furnish reducing sugar 119 in 59% yield. This protocol could be scaled up and has been applied in the total synthesis of potential anti-inflammatory antigen MECA79 by Kulkarni and co-workers.199 1,6-Anhydrohexopyranoses are important starting materials for preparing building blocks for the carbohydrates synthesis.200 The conversion of hexopyranoses into 1,6-anhydrohexopyranoses forms a bicyclo[3.2.1]octane structure, which not only converts the 4C1 chair conformation of D-form pyranoses into 1 C4 conformation but also reverses the axial−equatorial orientations of the hydroxyl groups exactly opposite to those of the ordinary hexopyranoses; thus, the whole reactivity pattern is altered. By fixing O1 and O6 in the 1,6-anhydro ring, the tedious separation and identification of α- and β-anomeric isomers can be avoided. In addition, protecting groups at O1 and O6 are eliminated, and only three remaining hydroxyl groups need to be discriminated. The high conformational rigidity of the bicyclo[3.2.1] skeleton also offers advantages in the regioselective protection reactions. A new method for preparing the 1,6anhydrosuagrs was reported by Wang, Hung, and co-workers. Treatment of free sugars with HMDS in the presence of TMSOTf followed by additional treatment with TMSOTf under microwave irradiation gave per-O-trimethylsilylated 1,6-anhy-

Using the TMSOTf-catalyzed HMDS silylation of free sugars, the Wang and Hung groups further advanced the regioselective one-pot protection of carbohydrates to free glucose 42 (Scheme 20).197 Free glucose 42 was first converted into its per-Otrimethylsilylated version 47, which was further treated with TMSSTol in the presence of ZnI2. With the assistance of microwave irradiation, 47 could be converted into thioglycoside 89b in a one-pot manner in 71% in a 5:1 α/β ratio. Without isolating 89b, continuing the tandem one-pot reactions using TMSOTf as the catalyst successfully afforded the fully protected thioglucoside and the C2-, C3-, C4-, or C6-alcohols in a one-pot manner directly from free sugars. This protocol obviates the need Scheme 21. One-Pot Protection of Various per-O-TMS Glycosides

Scheme 22. One-Pot Synthesis of 1,6-Anhydrosuagrs from Free Sugars

of transforming the anomeric group of free sugars before the modification of the other four hydroxyl groups. This one-pot strategy can also be applied to other sugars by carrying out the protection sequences based on their intrinsic spatial relationships of the hydroxy groups (Scheme 21). In the case of the mannoside 111, the 2,3:4,6-di-O-benzylidene intermediate with the exo-configuration at the acetal spanning O2 and O3 was generated by treatment with 2.1 equiv of benzaldehyde in acetonitrile. It was subsequently opened by DIBAL-H, and the 2-alcohol 112 was afforded in 70% yield.40,198 The galactoside 113 with a bulky anomeric isopropyl substituent was also orthogonally protected via the one-pot protocols. 4,6-OBenzylidenation followed by regioselective Et3SiH-reductive PMB protection with anisaldehyde at O3 afforded the C2alcohol 114 in 53% yield. To ensure the formation of the 3,4-Obenzylidene group, Hung and co-workers used a O6-TBDPS8039


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drosugars in a short time in excellent yields (Scheme 22).197 When D-glucose 42 and D-mannose 41 were used as the starting material, this one-pot protocol provided the corresponding 1,6anhydropyranoses 120 and 121 in 92% and 86% yields, respectively. In the case of D-galactose 43, microwave irradiation in CH3CN gave the 1,6-anhydrogalactofuranosyl derivative 122 (95%), whereas the 1,6-anhydrogalactopyranosyl compound 123 was isolated in 61% yield when chloroform was used as the solvent. Interestingly, applying the same method to sialic acid gave the 2,7-anhydrosialic acid derivatives.201

sugars 128a and 128b in 84% and 85%, respectively. When the bis-triflate was treated with a stoichiometric amount of tetrabutylammonium azide (TBAN3) at −30 °C in CH3CN, the displacement took place exclusively at the axial C2 triflate. Successive C4 triflate displacement by adding tetrabutylammonium nitrite (TBANO2) in the same vessel afforded the orthogonally protected galactosamine building blocks derivatives 129a and 129b in 60% and 61% yields, respectively, over three steps with only a single column chromatography. The higher reactivity of the C2 triflate over that at C4 could be attributed to its trans-axial effect, because the axial C2 triflate blocks the top face of D-mannoside and thus allows the nucleophile to attack more easily from the bottom face.203 Likewise, switching the order of addition of TBAN 3 and TBANO 2 gave the corresponding 4-azido-2-hydroxy-galactose derivatives 130a and 130b in 54% and 56% yields, respectively. Moreover, after the triflation of 125a and C2 inversion using TBAN3, adding H2O into the reaction mixture and heating up to 65 °C afforded the 3-hydroxy galactosamine derivative 131 (56%) over three steps in a one-pot manner. Similarly, the D-rhamnose-derived diol 132, obtained by C6deoxygenation of the D-mannose thioglycoside, could be transformed into a series of rare sugars using this one-pot sequential inversion strategy (Scheme 25). Inverting the C2-OTf using azide, followed by the inversion of C4 using N3−, NPhth−, NO2−, and OAc (intramolecular) as nucleophiles furnished compounds 133a,b, 134, and the fucosamines 135a,b and 136 in excellent overall yields. In the intramolecular version (transformation of 132 to 136), the C4-OTf is displaced by C3-OAc via a water-mediated ring opening of an orthoester intermediate. Inversion of the C2 of 132 using TBAN3, followed by the double inversion of C4 (using NO2−, triflation and then inversion using NaN3) gave 137a,b in 45% and 49% yields over 5 steps, respectively.194,214,215 The orthogonally protected rare sugar and glycosamine building blocks have been used in the assembly of various conjugation-ready bacterial oligosaccharides, including a trisaccharide fragment of Neisseria meningitides glycopeptide,202 a pseudotrisaccharide of Bacillus cereus,194 and phosphorylated trisaccharide of Providencia alcalifaciens O22,216 as well as archaeal N-linked hexasaccharide211 (Figure 2).213−215,217,218 The azide containing rare sugars were shown to be especially useful for selective metabolic glycan labeling in pathogenic bacteria.219 By extending their methodology, Kulkarni and coworkers transformed L-rhamnose and L-fucose into various bacterial, rare deoxy amino L-sugars.220 As shown in Scheme 26, the β-L-rhamnothioglycoside 2,4-diol 144 underwent bistriflation followed by a highly regioselective sequential SN2 displacement of the C2 axial triflate followed by C4 equatorial triflate by various nucleophiles to generate the L-f uco-configured sugars 139−143 in a one-pot manner. Likewise, similar triflate displacements of the corresponding Lfucosyl 2,4-diol derivative 144 (Scheme 27) afforded the Lrhamno-configured rare sugars 145−147. On the other hand, regioselective triflation at O2 of the 2,4-diol 144 and sequential O2-triflate displacement with sodium azide, furnished the Lpneumosamine derivatives 148 and 149. In the case of the latter, the free C4-OH was capped with acetate prior to the displacement reaction to check the migration of OBz from C2 to C3, which occurred in the case of 148. These building blocks have been applied in glycan assembly to synthesize various bacterial oligosaccharides, including conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229 and the

2.5. Orthogonally Protected Glycosamine and Rare D/L-Deoxy Amino Sugar Building Blocks via One-Pot Nucleophilic Displacement of O-Triflates

As introduced previously in Scheme 3,115 inverting the stereo configuration of a hydroxyl group via its transformation into a sulfonate, such as mesylate (OMs) and triflate (OTf), followed by nucleophilic SN2 displacement, provides access to rare sugar or expensive building blocks, such as bacterial sugars202 or galactosamine derivatives.203 A few examples for stepwise conversion to galactosamine into protected derivatives have been reported by Toth,204 Ramströ m,205−209 Bundle,210 Kulkarni115,211 and Wang.212 Recently, Kulkarni and co-workers developed an elegant protocol to access orthogonally protected D-galactosamine Scheme 23. Kulkarni’s Strategy to Transform D-Mannoside into Orthogonally-Protected Galactosamine Thioglycosides

building blocks ready for use as donors for glycan chain elongation from inexpensive and naturally abundant Dmannose.213 The strategy involved a sequential double inversion of β-thiomannoside 124 at C2 and C4 by azide and nitrite nucleophiles, respectively (Scheme 23). Regioselective TBDPSsilylation at O6 followed by Me2SnCl2-catalyzed regioselective acylation at O3 gave the 2,4-diol 125a or 125b. The C2 and C4 dihydroxyl groups of 125a or 125b were triflated using Tf2O to give the 2,4-bis triflates 126. By fine-tuning of the reagent equivalents and order of addition of nucleophiles, the inversion could be regioselective at C2 first and then at C4, and therefore the double inversion could be carried out in a one-pot manner. By varying the order of the addition of the nucleophiles, such as azide, nitrite, and acetate, various building blocks (127) could be generated. As presented in Scheme 24, triflation of diols 125a and 125b and concomitant displacement of the C2 and C4 triflate with excess NaN3 in DMF at room temperature gave the 2,4-diazido 8040


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Scheme 24. One-Pot Sequential Nucleophilic Displacement of Triflate to Prepare Glycosamine Building Blocks

Scheme 25. One-Pot Transformation of D-Rhamnose into Rare Sugar Building Blocksa

Conditions: (1) Tf2O, pyr, CH2Cl2, 2 h; (b) NaN3, DMF, 8 h; (c) TBAN3 (1.0 equiv), CH3CN, −30 °C, 20 h; (d) PhthNK, DMF, 10 h; (e) TBANO2, 1.5 h; (f) H2O, 65 °C, 1.5 h.

a

trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain M71 (Figure 2b).220 Similar procedures were extended to

transform L-rhamnose into all its isomeric 6-deoxy-L-sugars via efficient SN2 displacements.221 Thus, one-pot protection of 8041


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Figure 2. Structure of some rare sugar-containing bacterial and archaeal glycans.

A typical glycosylation reaction (Scheme 28) entails a coupling of an electrophilic glycosyl donor and a nucleophilic glycosyl acceptor (an OH group), upon activation by an activator/ promoter, via mostly SN1 or sometimes SN2 as well as SNi reaction pathways.78,82,241−245 Usually, the remaining hydroxyl groups are selectively masked with protecting groups as dictated by the branched structure of the desired target oligosaccharide. Sometimes, semiprotected or unprotected sugars are employed as acceptors or donors and the selectivity obtained takes advantage of subtle reactivity differences between two or more hydroxyl groups. What makes sugar coupling challenging is that the protecting groups that are used to mask the hydroxyl groups alter the electronic properties of the coupling partners, which in turn modulate the speed and stereoselectivity of the reaction. In a glycosylation reaction, activation of the glycosyl donor by a promoter, enabling leaving group departure, yields an oxocarbenium ion (SN1 type), which is then intercepted by the nucleophilic sugar alcohol (acceptor). Moreover, the ester type protecting groups present on the C-2 position of the donor participate in the glycosylation leading to stereoselective formation of 1,2-trans glycosidic bonds (vide supra Figure 3). On the other hand, C-2 auxiliaries have been used to install 1,2-cis glycosidic bonds.246 Ester type groups at the C6 position,247 and

carbohydrates provides rapid and easier access to the building blocks that can be used in one-pot glycosylation.

3. GLYCOSYLATION Glycosylation, the formation of a new glycosidic bond between two sugar units, has remained the central reaction in carbohydrate synthesis. Since the first report on glycoside synthesis by Michael in 1879222 and Fischer glycosylation223 in 1893, followed by the advent of the Koenigs−Knorr reaction in 1901,31 glycosylation has undergone many changes over the years.78,224−240 Glycosylation is probably the most intriguing reaction that has mesmerized the carbohydrate community for such a long time. In contrast to the synthesis of other biomolecules such as proteins and nucleic acids, wherein no regio or stereochemical issues are involved in the coupling step, sugar coupling has to be controlled such that only one of several reactive hydroxyl groups is coupled with the other partner and with the desired stereoselectivity (α or β). While the former requirement can be met by masking the remaining hydroxyl groups with suitable protecting groups, the latter part (i.e., glycosylation) demands much experimentation and subtle tuning of reaction conditions. 8042


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Scheme 26. One-Pot Transformation of L-Rhamnose into Rare L-Amino Sugar Building Blocks

Scheme 27. One-Pot Transformation of L-Fucose into Rare L-Amino Sugar Building Blocks

Scheme 28. Typical Glycosylation Procedure of a Glycosyl Donor and a Glycosyl Acceptor

axially oriented esters at C4220,248,249 (D-galactose, L-fucose, etc.) and C3250 have been also shown to engage in remote participation imparting face selectivity. Recently, Demchenko and co-workers showed that O-picolinyl and O-picoloyl groups at

C-3, C-4, and C-6 participate in glycosylation reactions via Hbonding, thereby providing high or even complete facial selectivity for the attack of the glycosyl acceptor and allow installation of 1,2-cis or 1,2-trans linkages.251,252 In addition to 8043


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Figure 3. Structures of tricolorin and Lewis X derivative.

Scheme 29. Typical Approaches for the Assembly of Oligosaccharides from (a) the Nonreducing to Reducing End and (b) Reducing End to Nonreducing End

nature and orientation of anomeric leaving group, promoter, additives, temperature, conformation and reactivity matching of donor and acceptor, orientation of various functional groups on the sugar, stereoelectronic factors, and solvent. Any changes made in the protecting groups of the coupling partners have a direct impact on the selectivity and efficiency of glycosylation. In

this, some solvents (such as acetonitrile, DMF, ether, and dioxane) do participate in the reaction. For example, diethyl ether (also dioxane or DMF) offers α-selectivity, whereas acetonitrile leads to formation of the β-isomer.253 Thus, the stereoselectivity of a glycosylation is a consequence of a complex interplay between various factors such as protecting groups, the 8044


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general, the α/β isomers of saccharides formed in any glycosylation are difficult to separate using column chromatography. So, achieving clean selectivity in this reaction is crucial. Over past 125 years, a tremendous amount of effort has gone into developing newer methods of glycosylation. A vast array of glycosyl donors have been developed, among which thioglycosides254,255 and glycosyl trichloroacetimidates (TCAI)89,239 are the most widely used. Other donors include glycosyl bromides, chlorides, and fluorides,92 glycosyl iodides,256 glycosyl phosphates257 and phosphites,258 sulfoxides,259,260 pyranones,261,262 glycals,263 n-pentenyl glycosides,44 and selenoglycosides.78 In recent years, several novel donors have been introduced, such as glycosyl thioimidates,264,265 2(benzyloxycarbonyl)benzyl (BCB) glycosides,266 hemiacetals via dehydrative glycosylation,267,268 or via SN2 displacement of in situ generated anomeric tosylates.269 N-Phenyl trifluoroacetimidate (PTFAI)270,271 and regenerative glycosylation using in situ generated 3,3-difluoro-3H-indol-2-yl (OFox),272 ortho-(methyltosylaminoethynyl)benzyl glycosides,273 glycosyl o-alkynylbenzoate (ABz),274−276 propargyl glycosides,277 propargyl orthoesters,278 and alkynyl carbonates, 2 7 9 2-(2-propylsulfinyl)benzyl (PSB)/S-2-(2propylsulfinyl)benzyl (SPSP) glycosides methods,280,281 phenyl glycosides,282−285 o-(p-methoxyphenylethynyl)phenyl (MPEP) glycosides,286 hydroxybenzotriazolyl glycosides,287 and glycosyl isoquinoline-1-carboxylate.288 In the past few years, novel promoters and conditions have been introduced for the activation of existing donors.289−303 Recently, a β-selective ring closing glycosylation via a nonglycosylating pathway was also described.304

lished.42,94,225,255,305−308 The one-pot glycosylation approach exploits subtle reactivity differences of glycosyl donors or acceptors, and it is most often performed from the nonreducing end to the reducing end. However, it can also be carried out from the reducing end to the nonreducing end or through a combination of strategies. 3.2. One-Pot Glycan Assembly from the Nonreducing End to Reducing End

In this approach, a bifunctional glycosyl acceptor (also referred to as donor−acceptor) bearing a nucleophilic alcohol as well as an activatable leaving group is used. In the first cycle, a glycosyl donor is reacted with the alcohol carrying an activatable leaving group, which remains stable under the first glycosylation conditions and is only activated in the second cycle of glycosylation upon addition of a promoter. In other words, the bifuctional building block acts only as an acceptor in the first step and upon completion of the first glycosylation, the formed glycoside is able to act as a donor. These approaches are mainly based on three concepts: (1) chemoselective activation of same type donor by making use of anomeric reactivity differences, (2) orthogonal glycosylation by taking advantage of the differences in activation conditions of different types of donors (leaving groups), and (3) preactivation of glycosyl donors. 3.2.1. Reactivity-Based One-Pot Glycosylation. Glycosyl building blocks have different anomeric reactivities that can be tactically used for designing a reactivity-based one-pot glycosylation by reacting donors sequentially in decreasing order of reactivity. Several factors influence the anomeric reactivity of a glycosyl donor including, protecting groups, the orientation of various substituents, conformation, the anomeric leaving group and its orientation, temperature, and solvent. Fraser−Reid in his seminal work on n-pentenyl glycosides observed that the C2 substituent of the donor remarkably influences the outcome of glycosylation.53,56 The electronwithdrawing ester type protecting groups at C2 makes the donor less reactive (disarmed), whereas electron-donating ether-type groups at C2 make it more reactive (armed). This effect was later extended to thioglycosides,309 as well as glycals,310 and was found to be generally applicable to other types of donors. The armed− disarmed concept revolutionized the field of glycan synthesis and laid the foundation for reactivity-based one-pot glycosylation. The protecting groups used to mask different hydroxyl groups influence the anomeric reactivities of the sugar building blocks through electronic and conformational effects. As a result, glycosyl donors carrying the same leaving group can have very different anomeric reactivities. The reactivity difference between different building blocks can be used in designing a reactivitybased one-pot protocol, wherein a donor having the higher anomeric reactivity can be activated over the bifunctional donor−acceptor bearing the same leaving group but with a lower reactivity. This can be achieved by controlling the amount of promoter, temperature, and type of solvent. The process can be reiterated, each time using a building block with lower anomeric reactivity, in the same flask to obtain the desired oligosaccharide [vide supra Scheme 2B (i)]. Ley and co-workers were the first to apply the reactivity-based one-pot strategy to assemble a trisaccharide unit from the polysaccharide antigen of group B Streptococci, by exploiting conformational/torsional disarming ability of the cyclohexane1,2-diacetal (CDA) protecting group.311 A cyclic acetal, such as CDA, imparts rigidity to the chair conformation of the donor via annulation thereby impeding the formation of the half-chair

3.1. One-Pot Glycosylation

Traditionally, oligosaccharide assembly is carried out in a stepwise manner, either from the nonreducing end to the reducing end or vice versa (Scheme 29). After the formation of a glycosidic bond, the elongation of glycan is carried out either by transformation of the anomeric protecting group of the glycan into the leaving group (donor) and its coupling with a suitable acceptor (Scheme 29a) or by selectively removing a protecting group to create a glycosyl acceptor and its subsequent coupling with a suitable donor (Scheme 29b). This process is repeated until the desired target chain length of glycan is reached. The time to procure orthogonally protected donor and acceptor sugar building blocks, their stepwise elongation, and the need to carry out tedious work ups and column chromatography after each step makes the oligosaccharide synthesis an arduous and timeconsuming task. To reduce time and effort, and to improve the overall efficiency, one-pot strategies have been designed. In the one-pot approach, a monosaccharide building block is sequentially reacted with other sugar building blocks and reagents in the same pot without any intermittent work ups or purification. Thus, several glycosylations can be integrated into a single operation, at the end of which, the target glycan can be obtained after a single purification. In such a sequential one-pot process, the losses due to handling during work ups and purifications are minimized and higher yields can be expected. Moreover, a considerable amount of time is saved and the overall process is more cost-effective. For the success of any one-pot glycosylation, it is necessary that every reaction goes to completion, giving mainly one product in excellent yield and stereoselectivity, and that the protecting groups as well as generated side products are compatible with all the reagents that are added in the same pot. Over the past 20 years, a variety of novel one-pot glycosylation protocols have been estab8045


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Scheme 30. Ley’s One−Pot Synthesis of Trisaccharide 154 Based on Torsional Disarming

tool and a guide for the selection of suitable building blocks for the reactivity-based one-pot assembly of linear or branched oligosaccharides.317,318 For example, the tumor-associated antigen Globo H was synthesized by this methodology (Scheme 31).319 The three-step synthesis involves two independent onepot reactions separated by a selective deprotection step. The first one-pot reaction of 155, 156, and 157 in the presence of NIS/ TfOH as the promoter afforded trisaccharide 158 (67%). The levulinoyl (Lev) protecting group was selectively cleaved to reveal the acceptor 159 (95%). The second one-pot reaction between 160, 159, and 161 installed the two α-linkages and furnished the hexasaccharide 162 (62%). Global deprotection delivered p-methoxyphenyl (PMP)-linked hexasaccharide moiety of Globo-H (45%). The building blocks 155, 156, and 157 as well as compounds 159, 160, and 161 showed sufficiently large RRV differences to allow their one-pot assemblies in excellent yields. The reactivity-based one-pot methodology has been applied to the assembly of an impressive array of complex oligosaccharides such as dimeric Lewis X,59 Lewis Y fragments,315,320 fucosyl GM1,321 heparin,322 tumor-associated antigen stage-specific embryonic antigen-4 (SSEA-4),323 tumor-associated antigen N3 minor octasaccharide,324 KH-1 epitope,59 N-acetyllactosamine oligomers,325 α-Gal oligomers,326,327 vancomycin,328 oligomannoses,329 lactotetraose (Lc4),330 and oligosaccharide libraries331 (Figure 4). The RRVs may serve as a useful guide in designing the synthesis of a particular glycan. It should, however, be emphasized that the RRVs are experimentally measured via competition experiments using methanol as an acceptor, and these values may not be the same for glycosylations with secondary alcohols. Huang and co-workers found that factors such as acceptor structure and solvent significantly influence the relative reactivities.332 Some useful arming effects for one-pot synthesis have been recently identified. Tony Mong and co-workers showed that deoxy sugars (e.g., 2-deoxy-D-glucose and 2,6-dideoxy sugars)80 display higher donor reactivity (Figure 5A).333 Interestingly, Demchenko and co-workers discovered that 2-O-benzoyl-3,4,6tri-O-benzyl (S-Box, S-benzoxazolyl) donors are, in fact, much more reactive (superarmed) than the conventional armed donor due to an O2/O5 co-operative effect (Figure 5B).79 The conformational arming effect of bulky silyl groups on donor reactivity was first observed by Bols and co-workers. Through a series of mechanistic investigations aimed at probing the influence of the orientation of sugar substituents on anomeric reactivities,334,335 they discovered that axial groups are less electronegative than equatorial groups. By extrapolating this concept, Bols and co-workers developed super-armed donors by

conformation adopted by oxocarbenium ion intermediate upon activation.312 Thus, the L-rhamno-thioethylglycoside donor 150 could be activated over the conformationally disarmed CDAprotected rhamnoside 151 (Scheme 30) in the presence of Niodosuccinimide (NIS) and catalytic triflic acid (TfOH) to afford the disaccharide intermediate 152. Concomitant reaction of 152 with acceptor 153 and NIS/TfOH in the same flask furnished trisaccharide 154 in 62% yield. Similar to the torsional disarming effect, the electronic disarming also paved the way to one-pot synthesis. Yu and co-workers used the electronic armed− disarmed effect in the one-pot assembly of the 19-membered macrolactone-containing tricolorin A.313,314 Similarly, Kondo and co-workers accomplished the one-pot assembly of Lewis X derivatives (Figure 3).315,316 To synthesize longer and complex oligosaccharides using the armed−disarmed concept in a one-pot setting, it was deemed necessary to quantify the anomeric reactivity of several glycosyl donors. This knowledge was essential for chemists to design building blocks with substantial reactivity differences so that they can be used in a chemoselective glycosylation process. To address this problem, Ley and co-workers quantified the influence of protecting groups, monosaccharide type, and anomeric leaving groups on the reactivity of various glycosyl donors. They assigned the RRVs to various fully protected manno- and rhamnosyl donors using 1H NMR spectroscopy as a tool.43 Specifically, two donors were made to compete for a single acceptor, and their product ratio (RRV) was determined by measuring the integration of the anomeric proton peaks. Subsequently, the Wong group made a great contribution to this effort by conducting a systematic study on thiotolyl donor of various sugars (glucose, GlcNAc, galactose, GalNAc, fucose, and mannose). In an alternative approach, Wong and co-workers determined donor RRVs by using an HPLC-based competition assay by subjecting two thiotolylglycosides to a substoichiometric amount of a promoter and methanol as the acceptor.54 The RRVs of thioglycoside building blocks were obtained from the HPLC integration of the respective glycoside products. They synthesized hundreds of mono and disaccharide thiotolylglycoside building blocks and measured their respective RRVs.54 It was observed that different types of monosaccharides have different anomeric reactivities. For instance, in the case of thioglycosides having the same substituents on the sugar ring, the reactivity order was found to be fucose > galactose > glucose > mannose. They also established a general protocol for the quantitative measurement of the relative reactivity of various thioglycoside donors and donor−acceptors (a thioglycoside with one hydroxyl exposed). The generated reactivity database was used to develop the computer program “OptiMer” for use as a database search 8046


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The Hung and Wong groups330 carried out a systematic study to probe the influence of bulky silyl and acyl protecting groups on donor reactivity of thiotolylglycosides by RRV analysis. They observed that silyl groups on different positions of monosaccharides lead to the strong arming of the donor. This observation was used in one-pot synthesis of linker attached embryonic stem cell surface carbohydrate Lc4. The reactivity tuning can be also achieved by making modifications in the aglycone. Subtle variations in the leaving group structure in turn offer different levels of reactivities that can be exploited for the one-pot synthesis of oligosaccharides. For example, Sulikowski and co-workers used two types of phosphites; the more reactive diethyl glycosyl phosphite was activated over pinacol phosphite to synthesize a trisaccharide in a one-pot manner.338 Similarly, Iadonisi and co-workers observed that due to strong electron-withdrawing nature of the trifluoromethyl group, glycosyl trichloroacetamidates can be preferentially activated over (N-phenyl)trifluoroacetimidates at a low temperature using small amounts of mild catalyst [Yb(OTf)3 or Bi(OTf)3].339,340 This reactivity difference allowed one-pot synthesis of two trisaccharides and also a three-step assembly of the antitumor PI-88 pentasaccharide. Likewise, Kobayashi and co-workers observed that N-trichloroacetylcarbamate donor could be selectively activated over the bifunctional glycosyl trichloroacetate by TMSOTf at 0 °C. This reactivity difference has been used in the one-pot synthesis of a α-1 → 6-glucan trisaccharide (Figure 6).341 Stable thioglycosides are the pick of the lot when it comes to tuning anomeric leaving groups for reactivity-based one-pot assembly (Scheme 33). The electron-donating or -withdrawing properties of the thio substituent affects the reactivity of the donor, and by using different substituents on sulfur, various reactivity levels are accessible for one-pot endeavors. Sialoside donors are difficult to glycosylate owing to their poor reactivity mainly because of the anomeric carboxyl group. Crich and coworkers342 developed a highly reactive adamantanyl thiosialoside donor 167 that could be readily activated over a thioglycoside with the p-chloro-thiophenyl leaving group at lower temperature. Thus, the thioadamantanyl donor 167 could be regio- and stereoselectively glycosylated with the thioglycoside 3,4-diol 168 at −78 °C using the NIS/TfOH system to generate the corresponding 3-O-linked disaccharide donor. The resulting intermediate could, in turn, be sequentially activated in the same pot at 0 °C and coupled with the glucosamine acceptor 169 to obtain the trisaccharide 170 in 45% yield. This method was used to synthesize four trisaccharides by changing the acceptor in the second cycle. Huang and co-workers introduced a divergent protocol to tune the anomeric reactivity by postsynthetic modification of glycan.343 By using S-(4-aminophenyl) thioglycoside as the key intermediate, they were able to easily convert the amino function into substituents bearing various groups (NEt2, N3, NHPhth, NHAc, Br, etc.). Within the thioaryl types of donors, modulation of the electronic properties of the phenyl ring through different substitutions provided enough reactivity difference to allow one-pot four-component assembly. Recently, Madsen and co-workers have employed chemoselective activation of a superarmed thioethyl galactoside over thiophenyl donor−acceptors of 3-OH/4-OH glucosamine to carry out onepot syntheses of human milk oligosaccharides.344 Yet another level of reactivity tuning can be achieved by using donors of different types (e.g., selenoglycosides), which are more reactive than the corresponding thioglycosides.43,49,51 By using a combination of selenoglycosides, thioglycosides, and the

Scheme 31. Wong’s Relative Reactivity-Based One-Pot Synthesis of Globo-H Glycosidea

a NBz = p-nitrobenzoyl, ClBn = p-chlorobenzyl, and PMP = pmethoxyphenyl.

placing bulky silyl groups on neighboring 2,3,4 equatorial hydroxyl groups of monosaccharides. The unfavorable gauche interactions force the pyranose ring to undergo conformational switching from lower energy 4C1 conformation to a twisted boat conformation. This conformational flipping places the substituents into the less electronegative pseudoaxial orientations and makes the donor much more reactive.336 Thus, bulky silyl groups on pyranoses prefer the pseudoaxial position and cause conformational arming of the donor. This conformational arming nicely augments the armed−disarmed concept and has been successfully integrated in the one-pot synthesis of trisaccharide 166 (Scheme 32).337 Glycosylation of the superarmed donor 163, armed donor−acceptor 164, and disarmed donor−acceptor 165 with 2.1 equiv of NIS and catalytic TfOH, performed by sequential temperature-controlled activation of donors afforded trisaccharide 166 in 64% yield. 8047


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Figure 4. Chemical structures of complex oligosaccharides.

phosphate,346 and 2-O-acylated SBox80,347,348 donors. Very recently, Zhu and co-workers349 studied the influence of anomeric configuration on the reactivity of thioglycoside donors by comparing pairs of α and β-configured thioethylglycosides. They conducted a series of competitive glycosylations with a 6OH galactosyl acceptor using 1 equiv of NIS as a promoter and TMSOTf as catalyst with slow warming from −78 to 0 °C. The reactivity ratio was determined by recovery of the donor starting materials and comparing relative intensities of the respective

conformationally disarming CDA group, Ley and co-workers were able to generate donors with four different levels of reactivities, which were used in the three-component one-pot synthesis of a high mannose-type oligosaccharide, a part of the glycoprotein gp120 of the viral coat of HIV-1. Anomeric reactivity tuning can also be achieved by merely changing the α/β configuration of the glycosyl donor. In general, it is the β-isomer of a glycosyl donor that reacts faster than αisomer as observed with halides,345 n-pentenyl glycosides,312 8048


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activation, is shown in Scheme 34. Thus, the superarmed βthioethylglycoside donor 171 reacted with the α-thioethylglycoside 6-OH donor−acceptor 172 at −78 to −20 °C in the presence of the NIS/TMSOTf system generated the disaccharide 173, which upon subsequent addition of the 6-OH thioethylglycoside 174 (disarmed) and NIS/TMSOTf afforded the trisaccharide thioglycoside 175 (49%), in a one-pot manner. By changing the acceptor 174 to other acceptors, two more trisaccharides have been synthesized. Lastly, anomeric reactivity tuning can be attained by changing solvents. An elegant example of solvent effects in one-pot glycosylation was presented by Oscarson.350 Dichloromethane is one of the preferred solvents for glycosylation owing to the higher rate of glycosylation it usually offers. On the other hand, participating solvents such as acetonitrile and diethyl ether slow down the glycosylation by coordinating with the oxacarbenium ion, and thus offer better chemoselectivity in donor activation. Capitalizing on this effect, Oscarson and co-workers designed a one-pot synthesis of several trisaccharides by conducting the first glycosylation in diethyl ether and subsequent glycosylation in dichloromethane. For example, the thioethyl glycoside donor 176 (Scheme 35) was selectively activated over the thiophenyl donor−acceptor 177 in diethyl ether and sequentially coupled with the acceptor 178 in CH2Cl2 to afford the trisaccharide 179 in a remarkable 84% yield. It should be noted that when the first glycosylation was performed in CH2Cl2, a complex mixture of products was formed, while the second glycosylation did not proceed in Et2O. Subsequently, Bassov and co-workers integrated this solvent effect with the armed−disarmed glycosylation strategy. They achieved reactivity tuning by the use of N-(2,2,2-trichloroethyl)carbonate (Troc) and N-phthaloyl (Phth) protected D-glucosamine thioglycosides, as well as by tuning anomeric leaving groups (SEt and SPh), to accomplish a one-pot synthesis of glucosamine oligosaccharides.351 3.2.2. Orthogonal One-Pot Glycosylations. Orthogonal glycosylation, which makes use of different types of donors (leaving groups) that require distinct activation conditions, is among one of the most popular one-pot glycosylation strategies. One-pot sequential glycosylations of this type involve chemoselective activation of one type of leaving group over another present in a building block that also bears a free hydroxyl group (donor−acceptor or bifunctional acceptor). The donor−acceptor building block acts as an acceptor in the first glycosylation, and its anomeric leaving group is activated in the second. For example, glycosyl trichloroacetimidates can be activated by using TMSOTf catalysis, whereas thioglycosides are stable under such acidic conditions and requires stronger electrophilic promoters

Figure 5. Structures of some deoxy glycans and superarmed donors showing co-operative effect.

Scheme 32. Bols’ Reactivity Tuning through Conformational Arming Effecta

a

TBS = tert-butyldimethylsilyl.

peaks in 1H NMR spectrum. They observed that a respective βthioethylglycoside of the anomeric pairs containing a 2-O-acyl moiety are more reactive and can be selectively activated over a related α-thioglycoside. An application of a pair of super−armed thioglycosides to one-pot oligosaccharide, synthesis in which selectivity is a result of configuration-based orthogonal

Figure 6. Structures of PI-88 pentasaccharide and α-1 → 6-glucan. 8049


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Scheme 33. Crich’s Reactivity Tuning by Aglycone Functionalization

Scheme 34. Zhu’s Configuration-Based Orthogonal Activation Approach

Scheme 35. Oscarson’s One-Pot Synthesis Based on Reactivity Tuning through Solvent Effect

like NIS/TfOH, dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST), or MeOTf. Thus, a trichloroacetimidate donor can be chemoselectively activated in the presence of a thioglycoside donor−acceptor by TMSOTf. Similarly a glycosyl bromide can be selectively activated by AgOTf over a thioglycoside,46 whereas a glycosyl fluoride can be selectively triggered over a thioglycoside by HfCp2Cl2/AgOTf,352 thus forming an orthogonal set of activatable leaving groups. Additionally, one can tune the reactivity by changing the substituent on the leaving groups (e.g., use of SEt and SPh) to obtain more levels of reactivity. The potential of the orthogonal activation approach can be gauged from Takahashi’s one-pot syntheses of a phytoalexin elicitor-active hexasaccharide47 and

heptasaccharide.353 Synthesis of the heptasaccharide (Scheme 36) incorporates a one-pot six-glycosylation process via sequential activation of the glycosyl bromide 180, the ethylthio glycosides 181, 183, and 185, the glycosyl fluoride 182, and the phenylthioglycoside 187 as glycosyl donors. The one-pot reaction was sequentially activated by the addition of AgOTf, MeOTf, HfCp2Cl2/AgOTf, and DMTST, respectively. Thus, chemo- and regioselective synthesis of the branched tetrasaccharide 184 was accomplished by the subsequent reactions: (1) AgOTf promoted glycosylation of the glycosyl bromide 180 with the key 3,6-diol thioethyl glycoside 181 at the O6 position, (2) chemoselective activation of the thioethyl group of the formed 1 → 6 disaccharide by MeOTf and coupling with the glycosyl fluoride donor−acceptor 182, and (3) the sequential coupling of SEt glycoside 183 at the remaining O3 position. Without isolating 184, the sequential addition of the thioethyl donor− acceptor 3,6-diol 185 and HfCp2Cl2/AgOTf, excess DMTST, and acceptor 186, and finally the thiophenyl glycoside 187 furnished the heptasaccharide 188 in 24% yield. This remarkable one-pot reaction coupled the highest number of building blocks using chemoselective activation with selective activators. It should be noted that the total synthesis including six sequential glycosylations and deprotections was carried out using a parallel manual synthesizer (Quest 210). Takahashi’s synthesis of the hexasaccharide of β-glucan47 involves chemoselective coupling of a trichloroacetimidate donor with a thioglycoside acceptor. This donor combination has been 8050


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Recently, Hung and co-workers employed selective activation of N-phenyl trifluoromethyl imidate over a thioglycoside using TMSOTf as a promoter (Scheme 37). Glycosylation of the imidate 189 with the thioglycoside donor−acceptor 190 afforded the intermediate α-sialoside 191 with a thiotolyl group in place. This sialoside was further activated under NIS/TMSOTf conditions to couple with the acceptor 192, furnishing trisaccharide 193 in 64% yield and excellent stereoselectivity.190 Boons and co-workers incorporated their α-selective glycosylation methodology by using (1S)-phenyl-2-(phenylsulfanyl) ethyl moiety at O2 position as the participating group in the chemoselective one-pot glycosylation endeavor.91 As shown in Scheme 38, the imidate donor 194 bearing (1S)-phenyl-2(phenylsulfanyl)ethyl moiety, upon activation with TMSOTf, led to the formation of the quasi-stable anomeric sulfonium ion 195 with a trans-decalin ring system. SN2 displacement of the sulfonium ion by the hydroxyl group of the acceptor 196 resulted in the formation of the α-glycoside 197 having the anomeric SPh group intact for sequential activation. Addition of the acceptor 198 and NIS in the same reaction flask afforded the trisaccharide 199 in 52% yield. Ito and co-workers developed a method for α-selective glycosylation of 2-deoxy-2-amino donors using a N-benzyl-2,3oxazolidinone group190 in orthogonal one-pot glycosylation processes using a bromide/thioglycoside pair (Scheme 39).365 Accordingly, bromide 200 was selectively activated by AgOTf and coupled with the thioglycoside donor−acceptor 201 to generate the corresponding thioglycosyl disaccharide. The disaccharide was then concomitantly coupled with acceptor 202 to afford the trisaccharide 203 with two consecutive αlinkages in an excellent 81% yield in a one-pot manner. Glycosyl phosphites and phosphates can be activated by a catalytic amount of TMSOTf and can be coupled to selenoglycosyl or thioglycosyl donor−acceptors. For example, Wu and co-workers achieved the one-pot synthesis of a tetrasaccharide glycosyl glycerol by using activation of a glycosyl phosphite over selenoglycoside.366 More recently, Mong’s group reported a one-pot synthesis of the same tetrasaccharide using a low concentration glycosylation of thiotolylglycosides.367 Wong and co-workers also synthesized the SSEA-4 hexasaccharide 207 in a one-pot manner using selective activation of glycosyl phosphates.323 As shown in Scheme 40, the dibutyl sialyl phosphate 204 was coupled with the thioglycoside donor−acceptor 205 with TMSOTf as the activator to generate the corresponding α-sialyl thioglycoside, which upon sequential coupling with the acceptor 206 in the presence of NIS in the same pot afforded the SESA-4 207 in 78% yield. Demchenko and co-workers developed two novel types of glycosyl thioimidates: SBox368−370 and S-thiazolyl (STaz)264 thioglycosides having unique chemoselectivity over other thioglycosides. The SBox could be activated over SEt by AgOTf, SEt could be activated over STaz by NIS/TfOH, and STaz could be activated by using excess AgOTf. Thus, orthogonal glycosylation between the S-Box donor 208 and the thioethylglycoside 209 promoted by AgOTf, followed by sequential glycosylations by activating SEt (in 209) and STaz (in 210) employing NIS/TfOH and AgOTf, respectively, afforded tetrasaccharide 212 in 73% overall yield (Scheme 41).371 By capitalizing on this selectivity, Takahashi and co-workers used the combination of SEt and SBox sialoside building blocks to synthesize α-(2 → 9)-linked trisialic acid.372 In addition to the orthogonal, selective activation of glycosyl thioimidates and

Scheme 36. Takahashi’s One-Pot Synthesis of Heptasaccharide by Chemoselective Activationa

a

MBz = p-methoxybenzoyl and Piv = pivaloate.

extensively used in one-pot assembly of several oligosaccharides and natural products including diosgenyl saponin,354,355 Galili trisaccharide,91 PSGL-1 hexasaccharide,356 a pentasaccharide against Helicobacter pylori,357 oligosaccharide fragments of the mycolyl-arabinogalactan complex, 358,359 hyaluronic acid oligomers,360 flaccidoside II,361 β-glucosyl chitobiose,362 trisaccharide motif of natural saponin,363 and a D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa364 (Figure 7). 8051


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Figure 7. Chemical structures of oligosaccharides and natural products.

thioglycosides,373 the concept of reverse orthogonal strategy based on orthogonal protecting groups was envisioned and applied for the oligosaccharide synthesis.374 In the reverse orthogonal strategy, Demchenko and co-workers employed PMB and 4-pentenoyl groups as a pair of orthogonal protecting groups that can be removed under the glycosylation conditions required for activation of STaz (TMSI, AgOTf) and SEt (NIS/ TfOH/H2O) donors, respectively. Hung and co-workers used S-benzoxazolyl (SBox) as a suitable anomeric leaving group for chemoselective activation using AgOTf and established more challenging α-sialylation process.40

AgOTf-activated assembly of 213 and 214 in the mixed solvent of CH2Cl2/Et2O = 3/1, followed by second coupling with alcohols 215, 216, 217, and 218 via in situ generated p-TolSOTf by the adddition of p-TolSCl in one-pot manner afforded the expected trisaccharides 219, 220, and 221 as well as the glycoconjugate 222 (Scheme 42), respectively. Owing to the neighboring group participating effect of the galactose O2 benzoyl functionality, the stereochemistry of the second glycosylation is exclusively β. Likewise, isopropenyl glycosides can be selectively activated by TMSOTf in the presence of an n-pentenyl glycoside, which, in 8052


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Scheme 38. Boons’ α-Selective One-Pot Orthogonal Glycosylation

Scheme 37. Hung’s One-Pot Synthesis of Trisaccharide via Orthogonal Activation

Scheme 39. Ito’s One-Pot Synthesis of the α-Linked Trisacharide 203 turn, can be activated by the NIS/TfOH promoter system.48 This selectivity was applied to a one-pot synthesis of a trisaccharide (Figure 8). Mukaiyama and co-workers showed that phenylcarbonate glycoside can be selectively activated over a thioethylglycoside using TrB(C6F5)4 as a promoter in trifluoromethylbenzene (TFB) as a solvent. The donor pair was used in the one-pot assembly of the mucin-related F1α-antigen.375 Their group also combined one fluoride donor and two thioglycosides in the one-pot synthesis of the phytoalexin elicitor heptasaccharide.376 Very recently Sun and co-workers reported a novel alkyneactivation-based glycosylation protocol using stable o-(pmethoxyphenylethynyl)phenyl (MPEP) glycoside donors, which can be efficiently prepared from the corresponding oiodophenyl (IP) glycosides by employing the Sonogashira reaction.286 Due to their stability, MPEP as donors and IP glycosides as acceptors can be conveniently used in sugar couplings via a latent−active protocol, with IP glycosides as the latent form and MPEP donors as the active form. The MPEP donors are more stable than usual thioglycosides, are inert to catalytic TMSOTf and Au(1) complex, and can be activated by NIS/TMSOTf promoter system. The authors reported that MPEP donors are superior to thioglycosides owing to the preparation from an odor-free starting material and the absence of aglycon transfer side reactions commonly encountered in thioglycosides. Moreover, they form a set of orthogonal donors with imidates, and o-alkynyl benzoates (ABz), and thus, can be used in one-pot oligosaccharide synthesis. For example (Scheme 43), chemoselective activation of the imidate 223 over ABz

donor−acceptor 224 in the presence of TMSOTf led to the corresponding disaccharide with the alkenyl benzoate moiety intact for activation with the Ph3PAuNTf2 promoter to couple with the MPEP donor−acceptor 225 and generate the MPEP glycoside 226. Without isolating the trisaccharide 226, sequential glycosylation with 4-OH acceptor 227 with NIS/TMSOTf promoter system in the same pot furnished the tetrasaccharide 228 in 65% overall yield. These new developments show great promise in oligosaccharide synthesis. 3.2.3. Preactivation-Based Iterative One-Pot Glycosylation. This type of glycosylation is independent of the donor reactivity. Although reactivity-based one pot glycosylation has greatly advanced oligosaccharide assembly, limitations still exist. 8053


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Scheme 40. Wong’s One-Pot Synthesis of SESA-4 Oligosaccharide

ease of one-pot assembly is reduced by the need of carrying out extensive protecting group manipulations. On the other hand, the chemoselective orthogonal glycosylation strategy is based on activation of different type of donors and thus overcomes the limitation that the glycosyl donor must possess higher anomeric reactivities than the donor−acceptor. However, this approach still requires the preparation of building blocks containing different types of aglycones. Preactivation-based glycosylation combines the advantages of both approaches. In this approach, the one-pot glycosylation reactions can be performed independent of anomeric reactivities using building blocks containing the same aglycone, under the same reaction conditions. The selectivity is achieved by activating the donor using a stoichiometric amount of promoter in the absence of an acceptor to form a reactive intermediate, which is coupled with the acceptor to form a new glycosidic bond.377 Van der Marel and co-workers developed a new preactivationbased one-pot glycosylation procedure employing reducing sugars and thioglycosides (Scheme 44).378 Accordingly, preactivation of hemiacetal donor 229 with Ph2SO/Tf2O at −60 °C followed by the addition of acceptor 230 and warming up to room temperature led to a thioglycosyl disaccharide and concomitant regeneration of Ph2SO. Without separation, the reaction mixture was cooled to −60 °C and Tf2O was added, which generated a new thiophilic promoter. Addition of the second acceptor 231 to the reaction produced the protected α-Gal epitope 232 in an excellent 80% yield. Using a similar procedure, a protected hyaluronic acid trisaccharide was obtained in 32% yield. The Huang and Ye groups established the concept of iterative one-pot synthesis of oligosaccharides based on the preactivation technique.379 In this strategy, thioglycosides are used as the only type of donor and TolSOTf (prepared in situ from p-TolSCl/ AgOTf) is used as the sole promoter. First, a thioglycoside is activated in the absence of acceptor to form a reactive

Scheme 41. Demchenko’s Orthogonal Coupling Protocol Using the Thioglycosyl Groups: S-Ethyl, S-Benzoxazolyl, and S-Thiazolyl

Several protecting group and aglycone modifications are required to prepare building blocks with desired anomeric reactivities, which is not feasible at all times. Moreover, the installation of protecting group pattern required for reactivity-based one-pot glycosylation is often more complicated than what is needed for stepwise oligosaccharide assembly. Thus, the advantage of the 8054


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Scheme 42. Hung’s Orthogonal One-Pot Coupling Protocol Using the S-Benzoxazolyl Sialyl Donor

Figure 8. Structures of isopropenyl glycoside, F1α-antigen, and phytoalexin elicitor heptasaccharide.

intermediate. After the addition of the acceptor to the preactivated donor, a disaccharide is formed with an identical activatable anomeric leaving group. By reiteration of this process in the same pot, longer oligosaccharides can be constructed in a one-pot manner. In this strategy, the use of a stoichiometric amount of promoter is essential. The reaction works so well because TolSOTf in a stoichiometric amount is capable of activating a wide range of thioglycosyl donors and is completely consumed by the donor, an essential prerequisite to prevent the activation of the subsequent building blocks. Moreover, the intermediate generated after preactivation is stable in the absence of the acceptor and can rapidly react when the acceptor is added to the reaction mixture. Importantly, the steps for activation of the donor and glycosylation with the acceptor are separated, so donor reactivity is not a concern. This feature is particularly

useful in the modular assembly of complex oligosaccharides. For instance, the disaccharide building blocks used in the assembly of the heparin-based hexasaccharide 236 possess the same protecting group combination (Scheme 45).380 Activation of the thioglycoside 233 by using the in situ generated stoichiometric TolSOTf was followed by addition of acceptor 234 along with a hindered base tritert-butylpyrimidine (TTBP), which prevents the activation of the thiotolyl functionality of the acceptor. The temperature was then increased to −10 °C to decompose any remaining intermediate from donor 233. Subsequent coupling with the terminal acceptor 235 under similar conditions efficiently delivered the hexamer 236 in 50% yield. Over the past ten years, the one-pot iterative glycosylation strategy has become a powerful tool for oligosaccharide synthesis 8055


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Scheme 43. Sun’s Orthogonal One-Pot Synthesis of the Tetrasaccharide 228 Using MPEP Donor

Scheme 45. Huang’s Iterative One-Pot Approach for the Assembly of Heparin Oligosaccharides

as witnessed from the elegant assembly of many complex oligosaccharides and glycoconjugates such as chitotetraose,381 Globo H hexasaccharide,382 Man5 oligosaccharide,383 iGb3 oligosaccharide,384 Lewis X and dimeric Lewis X,385 hyaluronic acid oligosaccharides,386,387 influenza virus-binding sialyl trisaccharides,40 biantennary N-glycan dodecasaccharide,388 heparin/ heparan sulfate oligosaccharide,380 and syndecan-1 heparan sulfate glycopeptide389 (Figure 9). More recently, Guo and co-workers390 used a preactivationbased one-pot [2 + 1 + 4] glycosylation strategy to achieve the first chemical synthesis of the heptasaccharide repeating unit of type V group B Streptococcus capsular polysaccharide (CPS). The synthesis of heptasaccharide 241 (Scheme 46) involves iterative glycosylation using the thioglycoside building blocks 237 and 238 and the reducing end tetrasaccharide acceptor 240, which was also synthesized via a similar [1 + 2 + 1] iterative onepot reaction and TBS deprotection. Thus, TolSOTf-promoted regioselective O4-glycosylation of 237 with the 3,4-diol acceptor 238 generated the trisaccharide thioglycoside 239, which was activated in the same pot and coupled with the tetrasaccharide 240 to obtain the fully protected heptasaccharide 241 in 59% yield. The O4-regioselectivity in the glycosylation is due to the well-known steric effect of the N-phthalimide group. The Guo group also employed the preactivation-based one-pot methodology for the synthesis of an arabinomannan heptasaccharide intermediate in their total synthesis of a miniature lipoarabinomannan.391 Inspired by Huang and Ye’s iterative one-pot synthesis based preactivation,379 Hung and co-workers directed their efforts to extrapolate the concept further and synthesized β-1,6-glucan oligosaccharides (Scheme 47). The monosaccharide building

Scheme 44. Van der Marel’s Iterative One-Pot Glycosylation for Synthesis of an α-Gal Epitope

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Figure 9. Structures of complex oligosaccharides synthesized via one-pot iterative glycosylation.

series of efficient preactivation-based one-pot glycosylation reactions and stereoselective β-arabinofuranosylation reactions. Several linear and branched oligosaccharide/polysaccharide fragments ranging from a 5-mer to a 31-mer in length were rapidly synthesized in a one-pot manner, and the target 92-mer was assembled through a highly convergent [31 + 31 + 30] coupling reaction. The 92-mer is composed of 30 D galactofuranose residues (Galf 30) connected to two arabinan chains each having 31 D-arabinofuranose residues (Araf 31). Both Galf 30 and Araf 31 fragments were synthesized starting from thiotolyl monosaccharide building blocks employing iterative one-pot glycosylation. As an example, the synthesis of Galf 30 is delineated in Scheme 48. An efficient six component, one-pot, iterative glycosylation using three thioglycoside building blocks 249, 250 (twice), and 251 (twice) and the p-TolSCl/AgOTf promoter system afforded hexasaccharide 252 in an excellent 63% yield on a gram scale (Scheme 48a). This is the largest number of sequential glycosylations performed in one-pot reported to date. Next, a sequential, iterative, five-component one-pot glycosylation using hexasaccharide building blocks 254, 253 (thrice), and 256 delivered the protected Galf 30 257 in 68% yield (Scheme 48b). Having a viable one-pot approach for the efficient synthesis of Galf 30 in place, construction of Galf 30 acceptor 262 was realized via a four-component one-pot iterative coupling

blocks 242, 243, and 244 were strategically employed in iterative one-pot protection methodology. The starting nonreducing end unit 242 was coupled with 244 by the promotion of p-TolSOTf, generated from the reaction of AgOTf and p-TolSCl in situ, to afford disaccharide 245 in very good yield (91%). To synthesize longer saccharide chains, chemoselective activation of the thioglycoside 242 was first done using in situ generated pTolSOTf at −80 °C, and after the complete activation of 242 (15 min), the acceptor 243 was injected into the reaction mixuture (n = 1). The solution was slowly warmed to form the disaccharide intermediate without disturbing the reducing end anomeric thiotolyl group. The anomeric function of the so-formed disaccharide intermediate was again activated by the addition of another stoichiometric promoter at low temperature to couple with the terminating sugar unit 244 to afford trisaccharide 246 (72%) efficiently. Similar, couplings were performed by the repetitive addition of the elongation unit 243 (n = 2,3) and resulted in the rapid construction of tetrasaccharide 247 and pentasaccharide 248 in a one-pot manner and in good overall yields, respectively.40 The power of the iterative one-pot glycosylation is nicely portrayed in the first chemical synthesis of a 92-mer mycobacterial arabinogalactan achieved by Ye and co-workers.392 This is, to date, the longest well-defined carbohydrate chain synthesized by chemical means. The heroic synthesis involves a 8057


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Scheme 46. Guo’s Preactivation-Based One-Pot Synthesis of the Heptasaccharide 241

in the oligosaccharide 277 (Scheme 51) were established by reacting preactivated 3,5-O-tetraisopropyldisiloxanylidene-protected thioglycoside 274393 with branched pentasaccharide 273, which was subsequently converted into the appropriate building block 277, using standard functional group manipulations. Synthesis of Araf 31 donor 278 was done from oligosaccharide building blocks 277, 272, and 266 via preactivation-based onepot glycosylation events. Final assembly of the Galf 30 diol acceptor 262 and Araf 31 278 (twice) in one-pot protocol, employing benzenesulfinyl morpholine/Tf2O,384 promoted double glycosylation, and global deprotection furnished the arabinogalactan 92-mer (280) (Scheme 52). Although the preactivation-based glycosylation is generally applicable to a diverse group of oligosaccharides, like other onepot glycosylation protocols, iterative glycosylation also suffers from some limitations. For example, donors such as per-Obenzoylated thiotolyl galactoside failed to give coupling products with sterically hindered, less reactive acceptors.394 To address this problem, Huang and co-workers probed the reactive

between 249, 258 (twice), and 250 to obtain the hexasaccharide 259 (Scheme 49a). Desilylation of the hexasaccharide 259 followed by strategic use of the so-formed hexasaccharide acceptor 260 in the proposed order along with the other oligosaccharide fragments 254, 253, 253, and 256 in a five component one-pot manner afforded the oligosaccharide 261, which upon treating with hydrazine acetate successfully furnished the desired Galf 30 acceptor 262 (Scheme 49b). Likewise, steroselective one-pot assembly of building blocks 263 and 264 (5 times) furnished the hexasaccharide 265, which upon removal of TBS group, afforded acceptor 266 (Scheme 50a). Alternatively, coupling of 265 with n-octanol as an acceptor followed by TBS removal generated the reducing end hexasaccharide acceptor 267. In a separate experiment, the thioglycoside building blocks 263 or 268, 269, and 264 were iteratively assembled to procure 270 and 271, which upon treatment with TBAF and hydrazine, respectively, afforded acceptors 272 and 273 (Scheme 50b). Stereocontrolled installation of the more challenging β-arabinofuranosyl linkages 8058


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Scheme 47. Hung’s Iterative One-Pot Synthesis of β-1,6-Glucan Oligosaccharides

3.2.4. Photochemical One-Pot Glycosylations. In the view of green and sustainable chemistry, chemists have a profound interest in light as a source of energy for synthetic transformations. The practice of using photochemistry in synthetic chemistry eliminates the need of using additional reagents as well as the formation byproducts. Hence, photochemical reactions become particularly interesting and increasingly important in the context of sustainable chemistry. Recently, the power of photocatalysis has made remarkable strides in organic synthesis.401−403 However, its practice in the field of carbohydrate chemistry has not been exploited as much. In recent years, significant advancement has been made toward the development of photoinduced glycosylation methods.297,404,405 In the process of photoinduced glycosylations,297 activation of thioglycoside donors primarily relies on the redox potential of the photocatalyst. Unfortunately, application of this approach is hampered as a result of limited substrate scope and low glycosylation yields. To circumvent some of the existing limitations, excess amounts of glycosyl acceptors and longer reaction times were employed. Ye and co-workers406 recently envisioned that the photochemical activation of thioglycosides by the use of Umemoto’s reagent407 as a radical precursor and subsequent glycosylation with glycosyl acceptors can be used for this approach. This novel photoinduction strategy uses both UV and visible light effectively to activate thioglycoside donors via a radical pathway. The Ye group proposed that the interdependent light-induced glycosylation pathway with the additional radical precursor can activate glycosyl donors regardless of their redox potentials. The underlining principle of light-induced glycosylation methodology was further successfully extended to onepot assembly of the trisaccharide 289 and the tetrasaccharide 290. As shown in Scheme 55, the thioglycosides (285, 286) and 287 were irradiated with a specified light energy source in the presence of the Umemoto’s reagent (288) followed by glycosylation with an acceptor enabled the synthesis of trisaccharide 289 and tetrasaccharide 290 without any intermediate isolation (Scheme 55).

intermediates formed after preactivation by low-temperature NMR studies. Their studies indicate that the more electron-poor donor forms the glycosyl triflate intermediate, whereas the electron-rich donor generates a more reactive dioxolenium ion. Therefore, this work suggested that in challenging glycosylation reactions, donors bearing fewer electron-withdrawing protecting groups would perform better. Another limitation of this methodology is that p-TolSCl is a moisture sensitive reagent, which requires careful handling for long-term storage. Many promoters have been tested for this purpose, which include 1benzenesulfinylpiperidine (BSP)/trifluoromethanesulfonic anhydride (Tf2O),395 benzenesulfinylmorpholine (BSM)/Tf2O,384 diphenyl sulfoxide/Tf2O,396 p-NO2PhCl/AgOTf,397 and O,Odimethylthiophosphonosulfenyl bromide (DMTPSB)/ AgOTf.398 Among them, BSM shows great promise as it is more stable than p-TolSCl and is odorless too. The reagent has already proved its worth in the assembly of the 92-mer arabinogalactan 280 via a double glycosylation that did not work with other reagents, including TolSOTf.392 Huang and co-workers also developed a separation protocol based on fluorous “catch and release” to expedite the purification process.399 In this method (Scheme 53), the last acceptor in the sequential one-pot synthesis is appended with a functionalized linker (e.g., ketone-containing linker), which can react with a fluorous tag, postglycosylation, and is easily separated from nonfluorous impurities by fluorous solid-phase extraction (FSPE). Subsequently, the tag can be released, and F-SPE affords the desired pure oligosaccharide product without the need to carry out silica gel column purification. Using this method, a four component one-pot assembly of a tetrasaccharide has been achieved in an expeditious manner. Recently, Ye and co-workers developed a preactivation-based protocol using protected 2-pyridyl donors and applied it to onepot synthesis of a β-1,6-glucan trisaccharide.400 As illustrated in Scheme 54, the preactivation-based glycosylation of 2-pyridyl donor 281 with the acceptor 282 generated a disaccharide intermediate bearing the same 2-pyridyl leaving group, which was then activated by Tf2O and further reacted with the acceptor 283 in the same flask to afford the trisaccharide 284 in 84% yield. 8059


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Scheme 48. Ye’s Iterative Assembly of Galf 30

3.3. One-Pot Glycan Assembly from the Reducing End to Nonreducing End

OH group of a saccharide is more reactive than other secondary (the C2, C3, and C4) hydroxyl groups. Takahashi and coworkers exploited this reactivity difference to synthesize 2,6sialyl-T antigen (Scheme 56). Regioselective glycosylation of the sialyl thioglycoside donor 291 with the 3,6-diol acceptor 292 led

In this approach, the glycan assembly relies on reactivity differences between different hydroxyl groups on sugars to achieve regioselective glycosylation. For example, the primary 68060


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Scheme 49. Ye’s Iterative Assembly of Galf 30 Acceptor

to the formation of the corresponding 1 → 6 linked disaccharide, which upon one-pot sequential glycosylation of the remaining 3OH group with the thiogalactoside donor 293, afforded the fully protected trisaccharide 294 in 77% yield (α/β = 78:22).408,409 Regioselective one-pot glycosylation has been applied to the synthesis of trisaccharide fragment present in the Mycobacterium tuberculosis cell wall410 and oligofuranoses.411 Galan’s regioselective synthesis of branched model trisaccharides incorporates a novel ionic liquid-based cosolvent/promoter [bmim][OTf], which, in conjunction with NIS, activates thioglycosides at room temperature.412 Similarly, secondary sugar hydroxyl groups also show reactivity differences. For example, the equatorial 3-OH of galactose and

mannose is more reactive than the axial 4-OH and 2-OH in galactose and mannose, respectively. It is also possible to finetune the subtle reactivity difference between 3-OH and 4-OH on the glucosamine scaffold by placing appropriate protecting groups on the remaining functionalities. For example, Field and co-workers employed trichloroacetimidate activation, promoted by HClO4 immobilized on silica gel, in their one-pot synthesis of Lewis X and Lewis A trisaccharides.413 Regioselective glycosylation of the 3,4-diol acceptor 295 with L-fucosyl donor 296 generated the α-1 → 3-linked disaccharide intermediate 297, which upon sequential addition of the galactosyl imidate donor 298 in the same flask afforded the trisaccharide 299 in 62% yield (Scheme 57). By merely changing the order of addition of donors 8061


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Scheme 50. Ye’s Iterative Assembly of β-Araf-Containing Oligosaccharides

in situ using the same silica gel column. The “on-silica” method is yet to be tested for one-pot glycosylation. One-pot glycosylation can also be carried out by capitalizing on the reactivity differences of the hydroxyl groups on different building blocks. For example, Galan’s one-pot synthesis of a branched trisaccharide412 and Fang’s414 one-pot syntheses of timosaponin AIII and its analogues are based on the higher reactivity of the acceptor alcohol over the 2-OH group present on the donor. Very recently, based on this concept, Kulkarni and Podilapu accomplished the first total synthesis of the phosphorylated trisaccharide repeating unit of O-polysaccharide

in the glycosylation (i.e., by conducting the reaction of diol 295 first with galactosyl trichloroacetimidate 298), followed by the fucosyl trichloroacetimidate 296, LeA trisaccharide derivative 300 was obtained in 59% yield. The regioselectivity between 3OH and 4-OH of 295 could be perhaps attributed to the presence of bulky TBDPS group at O6, which blocks access to the 4-OH group. Because the HClO4 promoted glycosylation essentially involves adding silica to the reaction, the entire process can be conveniently carried out on a column containing HClO4-impregnated silica gel and the product could be purified 8062


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Scheme 51. Ye’s Iterative Assembly of Araf 31 Donor

of Providencia alcalifaciens O22 via one-pot glycosylation.216 In their synthesis, a bifunctional thioglycoside building block 301, which also bears a free 4-OH group, acts as a donor in the first glycosylation and as acceptor in the second (Scheme 58). Thus, a regioselective coupling of the donor 301 with the rare sugar AAT acceptor 302 led to the formation of 1 → 3-linked disaccharide 303. Sequential glycosylation of the remaining 4′-OH group with

thioglycoside donor 304 and subsequent addition of triethylamine afforded the trisaccharide unit 305 in 72% yield in a onepot manner. In this case, triethylamine served the dual purpose of quenching the reaction as well as removal of the Fmoc protecting group to reveal the 3″-OH group of the trisaccharide for further phosphorylation. 8063


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Scheme 52. Ye’s Iterative Assembly of Arabinogalactan

Scheme 53. Fluorous Solid-Phase Extraction of One-Pot Oligosaccharide Synthesis

3.4. Hybrid One-Pot Glycosylation

building block 308 (Scheme 59). This elegant synthesis portrays many layers of selectivities. First, a catalytic amount of TfOH is incapable of activating a thioglycoside so that the bifunctional thioglycoside 308 acts only as an acceptor under the conditions. Second, due to the electron-donating para-methoxy group, the aglycone of 307 is more reactive than that of 306. Third, the C-4 alcohol of 308 reacts faster than the C-4 silyl ether (of 307), which is cleaved under the conditions and allows 307 to act as a donor in the first step and the acceptor in the next. Thus, the

To expedite oligosaccharide assembly, the one-pot approaches discussed in the previous section can be combined to develop a hybrid one-pot glycosylation. In fact, the first one-pot glycosylation reported in 1993 by Kahne45 was a hybrid of reactivity-based approach and orthogonal glycosylation. They assembled the protected Ciclamycin 0 trisaccharide 309 in a onepot manner in 25% yield by adding catalytic TfOH to the mixture of the glycosyl sulfoxides 306 and 307 and the thioglycosyl 8064


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Scheme 54. Iterative Glycosylation Approach Using 2-Pyridyl Donors

Scheme 56. Takahashi’s One-Pot Synthesis of 2,6-Sialyl T Antigen

reactivity of both the glycosyl donors and the glycosyl acceptors was manipulated to control the order in which glycosylation takes place. Methyl propiolate was added as an electrophile to prevent the undesired activation of the thioglycoside product by phenylsulfenyl triflate, which was formed as a side product of sulfoxide activation. Scheme 55. Photochemical Glycosylation Strategy for the Synthesis of Tetrasaccharide 290

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Scheme 57. Field’s Strategy to the One-Pot Synthesis of Lewis X and Lewis A

Scheme 58. Kulkarni’s One-Pot Synthesis of an AATContaining Trisaccharide

Scheme 59. Kahne’s One-Pot Synthesis for the Preparation of Cyclamycin 0

Similarly, Ley and co-workers415 combined orthogonal activation (fluoroglycoside, seleno-, and thioglycoside) with reactivity-based armed−disarmed glycosylation (1,2-diacetal protecting groups) to create three reactivity levels from five building blocks. A four-step, one-pot synthesis via sequential coupling of the glycosyl fluoride 310, the torsionally disarmed fluoride donor−acceptor 311, the selenoglycoside 313, the torsionally disarmed selenoglycoside 315, and the disarmed thioglycoside 316 was achieved for the assembly of the linear pentamannoside 317 in 8% yield (Scheme 60). In a similar manner, Mong and co-workers416 constructed a 1,6-β-glucan trisaccharide through combination of orthogonal activation using a phosphate/thioglycoside pair and armed−disarmed approach. 8066


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Scheme 60. Ley’s One-Pot Synthesis of Pentasaccharide 317a

a

TIP = 2,4,6-triisopropylbenzenesulfonyl.

(Scheme 62).423 The key building block in this synthesis was the bifunctional donor−acceptor 323, which acts as a disarmed acceptor with the armed donor and as a donor with a reactive acceptor. Glycosylation of the armed thioglycoside donor 324 with the disarmed acceptor 323 in the presence of NIS/TMSOTf generated the nonreducing end trisaccharide 325. In a separate flask, regioselective coupling of 323 with the reactive acceptor 326 furnished the reducing end trisaccharide 327. Next, the reaction mixture holding 325 was added to the flask containing 327 together with NIS/TMSOTf to afford the hexasaccharide 328 in 53% overall yield. Other examples include Fraser-Reid’s double differential glycosylation invoking the principle of reciprocal donor−acceptor selectivity424 and Wong’s synthesis425 of sialyl Lewis X hexasaccharide. A combination of iterative one-pot glycosylation and regioselective glycosylation is seen in Huang’s one-pot synthesis of Lewis X trisaccharide (Scheme 63).385 Thiotolylgalactoside 329 was preactivated at −78 °C by in situ formed p-TolSOTf, and the 3,4-diol acceptor 330 was added to it along with the sterically hindered base TTBP. The N-phthalamide protecting group in 330 makes the 3-OH sterically less accessible, and thus the more reactive 4-OH group of the two acts as a nucleophile in this reaction. Upon completion of the reaction, a highly reactive fucosyl donor 331 was then added as a solution in diethyl ether to

A more convenient approach to one-pot synthesis is to combine chemoselective activation with regioselective glycosylation. For instance, Fraser−Reid and Jayaprakash showed that n-pentenyl orthoester (NPOE) can be activated over n-pentenyl glycosides (NPG) in a regioselective manner using the Yb(OTf)3/NIS promoter system.417 As shown in Scheme 61, the glycosylation of NPOE glycoside 318 with the 2,6-diol NPG acceptor 319 led to the formation of 1 → 6 linked NPG disaccharide 320, which upon subsequent one-pot glycosylation of the remaining 2-OH with the thioglycoside 321 afforded the trisaccharide 322 in 61% yield. The corresponding trichloroacetimidates also worked well and afforded the trisaccharide 322 in similar yield. Takahashi and co-workers employed this strategy for the onepot syntheses of the core 2 class glycosyl amino acid (Figure 10),418 a branched trisaccharide,419 dibranched heptasaccharide with phytoalexin elicitor activity,353,420 and a library of dimeric Lewis X derivatives.421 Recently, Zhang and co-workers reported a one-pot assembly of 3,6-branched hexaarabinogalactan using an imidate/thioglycoside pair in an orthogonal and regioselective glycosylation combination setting.422 Boons and co-workers combined regioselective glycosylation with the reactivity-based glycosylation approach in their bidirectional one-pot synthesis of the hexasaccharide 328 8067


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favor the formation of the thermodynamically more stable αisomer. Because the armed fucosyl donor 331 has high anomeric reactivity compared to the formed disaccharide, the addition of another equivalent of p-TolSCl chemoselectively activated 331 leading to trisaccharide 332 in 68% yield. The sequence was continued further to synthesize Lewis X pentasaccharide and dimeric Lewis X in a one-pot manner in 40−60% yield.

Scheme 61. Fraser-Reid’s One-Pot Synthesis of Trimannoside 322

4. GLYCOSYLATION AND PROTECTING GROUP MANIPULATIONS IN ONE-POT 4.1. Glycosylation−Deprotection−Glycosylation in One-Pot

The success of regioselective glycosylations depends on reactivity differences between the free hydroxyl groups on sugars. However, it is not always possible to have enough reactivity difference between various secondary hydroxyl groups (e.g., 2-OH, 3-OH, and 4-OH of glucose), and one often ends up getting mixtures of regioisomers in such glycosylations. To tackle the problem of regioselectivity, protecting group strategies are designed to temporarily block a reactive hydroxyl group to ensure that the glycosylation takes place at the desired position. The temporary protecting group is then removed in situ to carry out the ensuing glycosylation in the same flask. For this purpose, temporary protecting groups that are not very stable under acidic conditions (e.g., TBS, PMB, and TBDPS) are typically employed. Glycosylations are usually conducted at subzero temperatures under acidic conditions. The temporary protecting group is removed postglycosylation either by warming up the temperature or by adding more acid such as TfOH, TMSOTf, or BF3·Et2O. For example, Hung and co-workers employed a TBS protecting group as a temporary masking group in their one-pot synthesis of the tetrasaccharide linkage region of proteoglycans (Scheme 64). The reactive 3-OH group of the galactosyl donor was blocked by a TBS group. Glycosylation of 3′-OH disaccharide acceptor 333 with the TBS-bearing galactosyl donor 334 led to the trisaccharide, which was converted to acceptor 335 in situ by removal of the TBS protecting group with additional TfOH. Coupling of 335 with donor 336 afforded the tetrasaccharide 337 in 37% yield over three steps.63 Similarly, a

Figure 10. Chemical structures obtained from one-pot syntheses. 8068


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Scheme 62. Boons’ Bidirectional Synthesis of Hexasaccharide 328

of D-glucosamine building block to achieve the synthesis of the tetrasaccharide repeating unit of the O-antigen of Escherichia coli O163 via sequential glycosylation by thioglycoside activation using sulfuric acid immobilized on silica (H2SO4−silica) and NIS as a Brønsted acid catalyst.431 In this case, the glycosylations using thioglycosides were carried out at −20 °C and the PMB group at O3 was removed by raising the temperature to 10 °C. Besides the PMB and TBS ethers, other acid-labile protecting groups have been employed in the one-pot assembly of glycans. The trityl ester group was used by Li and co-workers in the synthesis of flaccidoside II361 and also in Yu’s one-pot synthesis of a bidesmosidic triterpene saponin.432 Sen and co-workers employed the TBDPS group at the O6 position and the NIS/TfOH, TMSOTf promoter system for thioglycoside activation in their one-pot assembly of a branched pentamannoside (Figure 12).433 Alternatively, regioselective ring-opening of benzylidene acetals can provide access to branched trisaccharides.434−436 The ring-opening reaction transforms a fully protected compound into an alcohol that would act as acceptor for the ensuing glycosylation in the same vessel, as glycosylation and ring-opening are both conducted in acidic medium. Boons and co-workers434 integrated this reaction in the one-pot synthesis of several di- and trisaccharides (Scheme 65). For instance, the L-

TBS group was used as a temporary protecting group in the onepot synthesis of a branched mycobacterial arabinogalactan by Gallo-Rodriguez.426 The TMS group has played a remarkable role in carbohydrate synthesis as evidenced from Hung’s one-pot protection protocol. Gervay-Hague and co-workers established a novel one-pot glycosylation method employing per-O-TMS glycosyl iodides with fully functionalized diglyceride and ceramide as well as cholesterol as acceptors for accessing α or β-glycosides such as α-GalCer KRN-7000,427 BBGL-1,428 and others (Figure 11).256,429 Their methodology cleverly incorporates the arming effect of the TMS group and its acid lability by carrying out the stereoselective coupling of per-O-TMS glycosyl iodides in the presence of either TBAI or AgCO3 to achieve α or β selectivity, respectively, and the immediate removal of TMS ethers in the same vessel by using Dowex. Nilsson and co-workers employed PMB ether as an in situ removable protecting group in the one-pot synthesis of a globotetraose analogue wherein the thioglycoside coupling was done at −45 °C using NIS/TfOH. After coupling a lactoside acceptor with a β-thiogalactoside donor, the p-methoxybenzyl ether at O3 position was conveniently cleaved by increasing the reaction temperature to 0 °C to expose 3-OH group for subsequent glycosylation with β-D-GalNAc donor.430 Likewise, Mondal and co-workers installed a temporary PMB group at O3 8069


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trisaccharide 342 in 63% yield. HClO4 on silica gel was also found to catalyze the same one-pot ring-opening-glycosylation sequence.436 A few other reports on combining deprotection and glycosylation are also noteworthy. Iadonisi’s group executed debenzylation using I2/Et3SiH and glycosylation in one pot.437 Examples of removal of the Fmoc group216,438 and benzylidene acetals,152 immediately after glycosylation in the same flask, have been also reported. Nokami’s team nicely incorporated glycosylation and the Fmoc deprotection cycle in their electrochemical one-pot synthesis of a β-1 → 6-glucan pentasaccharide.439

Scheme 63. Huang’s Iterative One-Pot Assembly of Lewis X Trisaccharide

4.2. Protection−Glycosylation in One-Pot

Protecting group installation and glycosylation can also be carried out in a one-pot manner, provided that the protection steps are conducted in an acidic environment. In 2002, the Hung group for the first time developed such a protocol by performing a TMSOTf-catalyzed regioselective reductive monobenzylation of a di-O-TMS protected sugar, followed by coupling with an imidate donor under the prevailing acidic conditions.186 In a similar manner, Galan’s group performed the simultaneous blocking of the O4 and O6 positions of triol 343 with a benzylidene acetal, generating acetal 344.177 The remaining C3OH was subjected to sequential one-pot glycosylation using the imidate 345 to afford the 1 → 3-linked disaccharide 346 (Scheme 66). These procedures allow in situ formation of glycosyl acceptors for sequential one-pot glycosylation. Alternatively, one-pot methods for regioselective protection to fashion the fully protected donors and their subsequent glycosylation were also demonstrated. For example, Beau and co-workers conducted a one-pot 4,6-O-benzylidene formation and 3-O-benzylation catalyzed by TfOH on molecular sieves to afford a fully protected glucosamine-derived thioglycoside,192 which upon activation by the addition of NIS in the presence of an acceptor afforded the requisite disaccharide. Apart from a one-pot benzylidenation and regioselective benzylation of a persilylated thioglucoside,94 Hung and coworkers also performed a 2-O-acetylation under acidic conditions to form a donor that was easily activated in the same flask for the ensuing glycosylation.440 Alternatively, instead of carrying out 2-O-acetylation, a one-pot protection−glycosylation−glycosylation sequence was performed as shown in Scheme 67. Reactivity-based 2-O-glycosylation by the thiomannoside 349 generated the disaccharide donor 350, which upon subsequent activation and glycosylation with the glycerolderived acceptor 351 led to the glycerate 352. These one-pot procedures hold great promise for future endeavors in oligosaccharide synthesis. Recently, Guo and Zhu explored a novel strategy for chemical synthesis of GPI anchored peptide, wherein the suitably protected mannose-derived acceptor 353 was glycosylated with the Schmidt glycosyl donor 354 in the presence of TMSOTf as a promoter. In the same pot, 2′-O-deaceylation of the resultant disaccharide using NaOMe under Zemplen’s conditions provided the α-linked disaccharide 355. The disaccharide 355 was further used as an acceptor to elongate the sugar chain via subsequent glycosylation followed by selective desilylation to furnish the trimannoside 358. Subsequent phosphorylation of the resulting trimannoside 358 with phosphoramidite 359 and global deprotection under acidic conditions gave the GPI core trimannose 361 (Scheme 68).441 In the repertoire of sequential glycosylation strategies developed over the years, the power of transition metal catalysis

Scheme 64. Hung’s One-Pot Strategy for the Assembly of the Tetrasaccharide Linkage Region of Proteoglycans

fucosyl imidate 338 was coupled with the 4,6-O-benzylidene acetal-protected 3-OH glucoside acceptor 339 using TfOH as a promoter, and the 4,6-O-benzylidene acetal was subsequently opened at the O4 position by adding TfOH, Et3SiH at −78 °C to generate the disaccharide acceptor 340. Subsequent glycosylation with the imidate 341 in the same flask provided the branched 8070


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Figure 11. Structures of glycolipids synthesized via one-pot glycosylation.

Figure 12. Structures of complex glycans synthesized by one pot sequential glycosylation−deprotection−glycosylation.

amounts of TMSOTf or BF3·Et2O are generally employed for the activation of O-glycosyl trichloroacetimidate glycosyl donors

has been successfully harnessed for stereoselective synthesis of glycoconjugates.235,243 In glycosylation reactions, catalytic 8071


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Scheme 65. Boons’ One-Pot Glycosylation-Ring-OpeningGlycosylation Protocola

a

Scheme 67. Hung’s One-Pot Protection−Sequential Glycosylations Protocol

yield of the glycosylation, due to their low affinity toward glycosyl donor leaving groups and high affinity to glycosyl acceptors. The high affinity of Lewis acid species toward a glycosyl acceptor generate reversible formation of acceptor−catalyst adducts. The proton transfer then triggers a cascade of events such as an increased in the proton acidity and acceptor nucleophilicity, as well as donor activation.243 Pastore and co-workers, demonstrated that Bi(OTf)3 can be used as moisture-stable activator for mannosyl trifluoroacetimidate donors. With this approach, iterative one-pot glycosidation followed by removal of temporary Fmoc protection in the same vessel can be performed to synthesize biologically important linear and branched mannans incorporated in the HIV gp120 glycan.438,443 Initially, Bi(OTf)3mediated glycosylation of the mannosyl trifluoroacetimidate donor 362 equipped with an Fmoc group was done with glycosyl acceptor 363. In situ Et3N-mediated removal of Fmoc protection just after the glycosylation furnished the α-linked disaccharide 364. Further coupling of 364 with the imidate donor 362, followed by Fmoc cleavage in a one-pot sequence, turned out to be an effective one-pot iterative method for constructing the target compound 366 (Scheme 69). Fucosylation is an important feature of protein Nglycosylation as it has been reported to influence the efficacy of therapeutic proteins, as well as a potential biomarker for some diseases such as cancer.444−446 Fucosylated derivatives isolated from variety of natural sources have been found to possess a broad range of biological activities including anticoagulant, antithrombotic, antitumor, immunostimulatory, antihyperglycemia, antiangiogenic, antibacterial, antiviral, among others.447−452 Due to the biological relevance associated with fucosyl moieties, numerous synthetic attempts have been made to append fucose to oligosaccharide skeletons to achieve specific functions. Boons and co-workers presented a meticulous demonstration of the challenging α-fucosylation and β-mannosylation reactions in the synthesis of orthogonally protected Staphylococcus aureus-type trisaccharide using a one-pot glycosylation−deprotection strategy.453 MeOTf-mediated α-fucosylation using the 2-azido-

dfBz = 2,6-difluorobenzoyl.

Scheme 66. Galan’s One-Pot Benzylidene Protection− Glycosylation Procedure

in the presence of glycosyl acceptors.82,442 Because these catalysts have a high affinity toward the imidate leaving group, a highly reactive glycosyl cation intermediate is generated. This, however, is unfavorable in some cases because of the possible occurrence of competing side reactions, which can inherently diminish their glycosyl donor potential. To tackle these problems, a new variation in the glycosylation reaction scheme was designed employing Lewis acid catalytic systems. Activation of O-glycosyl trichloroacetimidates by these Lewis acid metal salts have a profound impact on the anomeric selectivity and 8072


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disaccharide intermediate with excellent α-stereoselectivity, which was subjected to Et3SiH/TfOH-catalyzed regioselective benzylidene ring-opening434 in the same pot to generate the glycosyl acceptor 374 in 84% yield (Scheme 71). The concept of one-pot glycosylation and in situ reductive opening of benzylidene acetals to provide 4-hydroxy sugars combined with trichloroacetimidate glycosylation was further extended by Kakiuchi’s group for the first synthesis of a novel glycospingolipid435 from the marine ascidian M. sulcatus (Scheme 72). In addition, many new methods have been developed based on one-pot glycosylation and regioselective deprotection of masked functionality to elongate carbohydrate chains with one or more sugar scaffolds. On the basis of this strategy, recently, the Boons group synthesized a tetra-antennary N-glycan intermediate, which was further enzymatically extended to an array of complex structures using glycosyltransferases.455 The key building block 393 (Scheme 73) is a versatile precursor for the regioselective extension of each antenna for the synthesis of highly complex asymmetric tetra-antennary N-linked glycans through enzymatic diversification. The synthesis of the core structure 393 was achieved from the glycosylation of acceptor 381 with the Nphenyl trifluoroacetimidate donor 382 in the presence of TMSOTf at −20 °C to obtain the heptasaccharide 383, which was then treated with HF/pyridine for the regioselective removal of TBS group in one-pot to secure acceptor 384. The obtained acceptor was subjected to sequential glycosylations and selective deprotection/functional group manipulation using suitably protected N-phenyl trifluoroacetimidate donors (385, 388, and 391). Here, the order of protecting group removal and glycosylation was critical for the successful synthesis of a tetraantennary N-glycan. Analogously, Misra and Bhaumik carried out a one-pot assembly of a pentasaccharide derivative employing two stereoselective glycosylations and in situ removal of a PMB group.456 Here the thioglycosides are attractive building blocks because both glycosyl donors and acceptors can be activated by NIS in the glycosylation process. As outlined in Scheme 74, the Lfucosyl thioglycoside donor 395 was preferentially activated by NIS and coupled to the trisaccharide acceptor 394. Upon HClO4−SiO2 addition to the glycosylation mixture at low temperature, the tetrasaccharide intermediate was furnished. The hydrolysis of the PMB group was achieved by raising the reaction temperature to reveal the desired tetrasaccharide acceptor for the next glycosylation event. Subsequent coupling of the resulting acceptor with the galactosamine thioglycoside donor 396 under identical conditions afforded the protected pentasaccharide 397 in 65% overall yield (Scheme 74). The Wang and Hung groups’ continuous work on one-pot TMSOTf-mediated regioselective transformations of various per-O-trimethylsilylated scaffolds into acceptable building blocks40,41,62,63,198,440 shed light into the development of diversified strategies in the field of carbohydrate chemistry. As an example, a microwave-assisted one-pot synthesis of thioglycosides by reacting trimethyl(4-methylphenylthio)silane and ZnI2 with in situ generated per-O-trimethylsilylated monosaccharides from free sugars was previously reported.197 This methodology was further applied to evaluate the acceptor potential of persilylated thioglycosides in a one-pot glycosylation with Nphenyl trifluoroacetimidate donors. Trimethylsilylation of free sugars was studied using HMDS under TMSOTf catalysis146 and later used in MW-assisted one-pot thioglycosylation to provide a number of differentially substituted thioglycosides. Glycosylation

Scheme 68. Guo’s One-Pot Synthesis of a Disaccharide Module in the Azido Derivative of the GPI Core Trimannose

454 L-fucose 367 as glycosyl donor, and the fucopyranoside acceptor 368 failed to secure the desired product due to the decomposition of the acid sensitive anomeric TDS group in the acceptor 368. The use of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as an acid scavenger did not improve the fucosylation. The use of a standard thioglycoside activator system, NIS/ TMSOTf, promoted the α-fucosylation, albeit, in a very low yield. It was then observed that the target α-fucoside 369 was obtained in moderate yield and with exclusive α-stereoselectivity when the glycosylation was performed under neutral conditions using BSP/Tf2O (Scheme 70). Addition of the thiourea to the same vessel resulted in the selective removal of chloroacetyl (CA). To study the installation of β-mannosamine, the resulting α-fucoside 369 was coupled with the mannoside donor 370 under the similar neutral condition to afford the desired βmannoside 371. In a similar fashion, combining protecting group manipulations with glycosylation as a one-pot synthetic operation, the PSGL-1 hexasaccharide was synthesized.356 This strategy streamlined the oligosaccharide assembly by combining protecting group manipulations and glycosylations as one-pot multistep synthetic procedures. The synthesis entailed the coupling of properly protected fucosyl trichloroacetimidate donor 372 with phenylthioglycosyl acceptor 373 in the presence of TMSOTf as a promoter. This furnished the corresponding

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Scheme 69. Pastore’s One-Pot Synthesis of Oligosaccharides Related HIV gp120

Scheme 70. Boons’ One-Pot Glycosylation−Deprotection−Glycosylation Protocol

Scheme 71. Boons’ One-Pot Glycosylation-Reductive Opening of Benzylidene Acetal

as an activator. Desilylation using TBAF provided the α-1 → 6 disaccharides (399−401) in moderate yields (Scheme 75). It was also observed that the formation of thiomannoside 402 in a one-

of the in situ-generated persilylated thioglycosides was also studied as acceptors in glycan assembly using N-phenyl trifluoroacetimidate donor 398 under the influence of AgOTf 8074


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Scheme 72. Kakiuchi’s One-Pot Glycosylation−Reductive Opening of Benzylidene Acetal−Glycosylation Methodology

coordinated organoboron adducts using either arylborinic acids123,476 or boronic acid/Lewis base combinations.124,477 The concept of borinic ester formation with carbohydrates followed by Lewis base mediated generation of tetracoordinate adduct was utilized by the Taylor group in a stereoselective onepot synthesis of disaccharide and trisaccharide derivatives.478 It was proposed that the tetracoordinate borinic ester increases the nucleophilicity of the oxygen relative to free alcohol during the coupling sequence with a second electrophile in one-pot operation. In this approach, the α-rhamnopyranoside 418 was reacted with arylborinic acid and the so obtained borinic esterprotected rhamnose was treated with p-methoxybenzyl trichloroacetimidate in the presence of Lewis acid BF3·OEt2 to install the PMB protecting group. The PMB-protected intermediate was subsequently treated with Et3N to form acid−base adducts of tetracoordinate borinic ester, which then triggered its sequential coupling with the glycosyl bromide 419 in the presence of Ag2O as halide scavenger and base. The reaction sequence provided the protected disaccharide 420 in 60% yield (Scheme 77).

pot operation occurred because of the remaining TMSSTol reagent and not by intermolecular aglycon thioglycoside transfer.355,457,458 The one-pot glycosylation strategies discussed here so far basically rely on these three approaches: (a) an orthogonal strategy, which relies completely on the selective activation of one leaving group over another;47 (b) a chemoselective approach, which makes use of the electronic properties of protecting groups in glycosyl donors having the same type of leaving group at the anomeric position;44,419 and (c) a preactivation strategy, which involves activation of a glycosyl donor with a suitable promoter in a stoichiometric amount at low temperatures to generate highly reactive glycosylating species. However, these protocols normally consume more than stoichiometric amounts of expensive and sensitive reagents such as NIS, Tf2O, and AgOTf, among others, to activate glycosyl donors, thereby limiting their application. Recently, novel approaches were reported to differentiate similarly protected glycosyl trichloroacetylimidate and (N-phenyl)-trifluoroacetylimidate donors using various Lewis acids as activators by changing the reaction temperature.339,340 Kobayashi and co-workers341 devised a one-pot direct dehydrative glycosylation of a glycosyl carbamate derived from reducing sugars in situ (Scheme 76).459 Hemiacetal 403 was derivatized in situ by treatment with a slight excess of trichloroacetyl isocyanate to generate a more reactive donor (glycosyl carbamate 404). This was subsequently coupled with the glycosyl trichloroacetate 405, followed by reaction with the reducing end acceptor 406 to furnish trisaccharide 407 in 55% yield. The compatibility of this approach was studied with properly protected galactose and mannose hemiacetals to obtain their corresponding galactosyl trisaccharide 412 and mannosyl trisaccharide 417, both in 71% yield.

5. TOWARD DEVELOPMENT OF AUTOMATED APPROACHES IN OLIGOSACCHARIDE SYNTHESIS The development of automated approaches advanced the field of oligosaccharide synthesis and provided access to structurally well-defined complex carbohydrate structures. Notably, the automated assembly of oligosaccharides involves the rapid construction of structures of interest by performing repetitive chemical transformations at various temperatures precluding laborious isolations and purifications. Efforts have been directed toward designing an automated oligosaccharide synthesizer to create designated oligosaccharides using established monosacharide building blocks. This major technological breakthrough catapulted the assembly of well-defined oligosaccharides by greatly reducing the labor needed for the preparation of glycoconjugates.

4.3. Protecting Group Manipulation and Glycosylation in One-Pot Using Borinic Esters

The application of boronic esters as protecting groups for 1,2- or 1,3-diol scaffolds is well-documented.460,461 The phenomenon of molecular recognition between boronic acids and sugars led to the formation of tri-coordinated boronic esters as temporary protecting groups, allowing numerous site-selective chemical transformations such as acylations, glycosylations,462 sulfations, alkylations, and silylations of appropriately functionalized carbohydrate derivatives.463−471 However, limited precedent exists for the activation of hydroxyl functionalities through the formation of tetra-coordinated adducts to achieve regio- and stereoselective glycosylations.472,473 A related effect has been employed by Aoyama and co-workers toward the reaction of electrophiles by the activation of tetra-coordinated boronic esters of carbohydrates using Lewis base.474,475 But, recent explorations by Taylor’s group in this direction uncovered a handful of methods for site-selective activation of carbohydrates via tetra-

5.1. Automated Solid-Phase Oligosaccharide Synthesis

The use of polymer support in the field of solid-phase synthesis of oligosaccharides and glycoconjugates465,479−485 has seen tremendous development from the inception of similar work on oligopeptides486,487 and oligonucleotides.488 Solid phase synthesis has demonstrated its efficacy by eliminating the need for necessary repetitive purification of reaction intermediates and excess reagents, which can be removed by simple filtration. In general, solid-phase oligosaccharide synthesis uses different approaches for the elongation of oligosaccharide sequence.65 For example, in the donor-bound strategy, oligosaccharide assembly starts from the nonreducing end to reducing end by reacting a glycosyl donor anchored to solid support via a linker with a glycosyl acceptor.263,489,490 On the other hand, a glycosyl acceptor anchored to a solid support through its anomeric 8075


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Scheme 73. Boons’ Chemical Assembly of the Asymmetric Tetra-Antennary N-Glycan Intermediate 393 Using One-Pot Glycosylation−Deprotection

tends to hydrolyze or undergo other decomposition pathways during the course of the glycosylation. Combinations of both strategies have been evaluated as a bidirectional approach for the preparation of several branched oligosaccharides.492−494 Applications of glycosyl trichloroacetimidates,239,482,495,496 glycosyl

position can be reacted with activated donors in the acceptorbound strategy.491 In principle, the acceptor-bound strategy produces higher yields of the target oligosaccharide in comparison to the donor-bound strategy due to the fact that the resin bound glycosylating agent is the limiting agent and 8076


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temporary protecting groups such as Fmoc and Lev groups were used to elongate oligosaccharide sequences, as well as to attain branching by cleaving them under mild basic conditions. The automated solid-phase oligosaccharide synthesis typically involves a TMSOTf-activated coupling of the initial glycosyl phosphate with a monosaccharide building block anchored to a solid support through a linker. The temporary Fmoc protecting group is then removed using 20% piperidine in DMF as nonnucleophilic base. The furnished disaccharide acceptor is glycosylated again with a glycosyl phosphate, followed by a subsequent removal of temporary protecting groups; this process is continued until the desired oligosaccharide is obtained. This iterative coupling strategy assembled the fully protected Lex-Ley nonasaccharide in 6.5% yield. The use of an octenediol-linker and Merrifield resin together with automated solid phase synthesis approach accelerated the synthetic efficiency to address the current demands for diverse carbohydrates and their use for interesting applications. Moreover, efforts toward the efficient removal of oligosaccharides from the solid support using olefin cross metathesis enabled the synthesis of complex carbohydrates.504−508 The automated solid-phase approach has also been extensively studied to synthesize carbohydrates like the protected core of N-linked pentasaccharide using trichloroacetimidate donors, 509 and β-mannosides, 510 α-linked oligomannosides,508,511 oligorhamnosides, and β(1 → 3)/β(1 → 6) phytoalexin elicitor β-glucans using glycosyl phosphates.512 Controlling α/β stereoselectivity can be a challenge in automatic solid-phase synthesis. In spite of this, automated solid-phase assembly has been successfully employed in the synthesis of the tumor-associated carbohydrate antigens Gb3 and Globo-H hexasaccharide vaccine candidate, which currently are in advanced clinical trials.513,514 Both of these molecules have 1,2-cis-galactosidic linkages, which were formed in high αselectivity.515 The versatility of stereoselective automated solidphase synthesis of biologically important oligosaccharides with multiple 1,2-cis-glycosidic linkages with complete anomeric control using the (S)-(phenylthiomethyl)benzyl chiral auxiliary at the C2 of the glycosyl donor was reported by Boons and coworkers.91,516 In this chiral-auxiliary-mediated 1,2-cis-glycosylation approach, the neighboring group effect provided by the C2 auxiliary stabilizes the oxocarbenium ion through the formation of β-sulfonium ion. The trans-decalin conformation avoids unfavorable steric interactions and concomitant glycosylation with the resin bound acceptor led to the formation of 1,2-cisglycoside.

Scheme 74. Misra’s One-Pot Glycosylation−Deprotection− Glycosylation Procedure

phosphates,497 and glycosyl thioethers498,499 as building blocks were carried out to show the power of automated assembly on solid support. Seeberger and co-workers designed an automated solid-phase oligosaccharide synthesizer based on a modified peptide synthesizer to expedite the synthesis of defined oligosaccharide structures.500,501 The robust automated solidphase design technology was meticulously demonstrated in the synthesis of Ley−Lex (KH-1) antigen (Figure 13),502 a complex nonasaccharide derivative found on tumor cells. By using five different substituted glycosyl phosphates497,503 as glycosylating agents, different glycosidic linkages were made in the target molecule. In this automated coupling process, octenediol was chosen as a stable linker and was functionalized with polystyrene resin via esterification. Strong basic conditions were used to cleave the linker at the end of a coupling cycle. Due to their excellent stability toward acidic glycosylation conditions,

Scheme 75. Wang’s and Hung’s Microwave-Assisted One-Pot Glycosylation Strategy from Free Sugars

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Scheme 76. Kobayashi’s Sequential One-Pot Dehydrative Glycosylation Strategy

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Similarly, automated iterative glycosylations incorporating monomer building blocks with remote participating groups were performed, which afforded the Globo-series oligosaccharides 450 and 452 (Scheme 79). Analogously, α-glucans (459, 461, 463, 465, and 467) with multiple 1,2-cis-glucosidic bonds were procured from AGA iterative protocols using thioglucoside building blocks (453−457). In analogy to the galactose monomer building block series, glucosyl donors with acetyl groups at the C3 and C6 positions provided the best α-selectivity through neighboring group effect (Scheme 80). Over the years, the first prototype automated solid phase synthesizer was gradually modified to a fully automated version equipped with advanced tailor-made syringe pump systems for precise and accurate addition of reagents to obtain oligosaccharides in high chemical yield. By using these features, the Codee group reported the automated synthesis of hyaluronan and mannuronic acid alginates.522,523 The salient aspects of the synthesis involve stereoselective formation of the β-(1 → 4) linkage of mannuronic acid from functionalized Merrifield resin using the butenediol linker 468. The N-phenyltrifluoroacetimidate glycoside 469 was used as glycosyl donor for the coupling, which was performed at low temperatures. After the initial coupling, the Lev protecting group of 470 was removed using H2NNH2·HOAc and subsequent repetitive coupling were performed. The products were cleaved from the solid support via cross-metathesis reaction to furnish hepta-, undeca-, and pentadecasaccharide fragments (471−474) of hyaluronan acid. Deprotection of silylidene ketals were carried out using HF·Et3N, and the resulting hydrophilic derivatives (475−477) were analyzed and purified by HPLC. Global deprotection followed by acetylation afforded the set of hyaluronan acid oligomers (478−480)522 (Scheme 81). Although there is much more to improve, the concept of automated solid-phase synthetic platform has advanced into commercial technology to render structurally defined oligosaccharides of biological relevance for glycan arrays, diagnostics, and carbohydrate-based vaccines.524−532

Scheme 77. Taylor’s One-Pot Protection and Glycosylation Using Borinic Esters

Initially, the resin bound hydroxyl 421 was coupled with trichloroacetimidate donor 422 using a catalytic amount of TMSOTf in anhydrous CH2Cl2 at low temperature. The Fmoc protecting group of the synthesized disaccharide intermediate was then selectively cleaved to yield the resin bound acceptor 423. Prior to the coupling of acceptor 423, the auxiliarycontaining glucosyl donor 424 was preactivated in a separate flask to form the intermediate sulfonium ion, which ensured the requisite 1,2-cis-linkage in excellent stereoselectivity. The resulting disaccharide was then subjected to palladium-mediated transfer of allyl group followed by glycosylation with the preactivated trichloroacetimidate glycosyl donor 425, thus generating the resin-bound trisaccharide 426. This glycosylation protocol was repeated to obtain a pentasaccharide with multiple α-glucosides at the primary and secondary positions (Scheme 78).479 Recently, Seeberger and co-workers demonstrated that automated glycan assembly (AGA) can be used for the efficient preparation of biologically relevant oligosaccharides with 1,2-cisglycosidic linkages by exploiting the stereochemical aspects of remote participation of protecting groups in the monosaccharide building blocks.517 In this study, mammalian and bacterial glycans518 bearing α-galactosidic linkages519 and α-glucans were selected as prime targets for automated solid-phase technology. It has been previously reported that the protecting groups positioned at C3, C4, and C6 of glucose and galactose building blocks can control the stereoselective construction of glycosidic bonds.520,521 Thus, the thiogalactoside monomer building blocks (434−443) decorated with diverse protecting groups capable of remote participation were chosen for the selective formation of α-Gal epitopes of trisaccharide 445 and pentasaccharide 447 using AGA (Scheme 79). In AGA, the polystyrene resin anchored to the photocleavable linker 433 was coupled with monosaccharide 434 by the NIS/ TfOH promoter system, which was followed by Fmoc removal. Programmable iterative glycosylation of the derived acceptor with the selected donors furnished the fully protected oligosaccharide targets 444 and 446, which were released from the solid support by ultraviolet irradiation. After the automated assembly, the fully protected oligosaccharides 444 and 446 were deprotected by methanolysis and hydrogenolysis and purified by reversed-phase HPLC to secure the α-Gal epitopes of trisaccharide 445 and pentasaccharide 447, respectively.

5.2. Automated Solution-Phase Synthesis of Oligosaccharides

5.2.1. Fluorous-Tag-Assisted Automated Oligosaccharide Synthesis. The advancement of solid-phase automation in carbohydrate synthesis achieved prominent milestones in the carbohydrate research field. However, the fundamental stumbling block for this strategy is the use of a large excess of glycosyl donors (≈ 10 equiv) to obtain appreciable reaction yields at each coupling step. In addition, the synthesis of such glycosyl donors most likely requires more synthetic transformations, which typically involve orthogonal protection and deprotection steps from their naked sugar scaffolds. To circumvent the situation, fluorous chemistry involving fluorous solid phase extraction (F-SPE) protocol has gained prominence and became amenable to automated carbohydrate synthesis. FSPE technique is based on the strong affinity of fluorous compounds toward fluorinated silica gel, thereby making it useful for a variety of synthetic applications. Fluorous-protecting tags attached to a glycosyl donor are quite stable and inert to standard glycosylation and deprotection conditions. Moreover, this kind of technique was realized to be of great potential for the synthesis of oligosaccharides as well as other glycoconjugates because it minimizes the time needed for tedious isolation procedures, as well as offers relative ease of NMR spectroscopic characterization of carbohydrate intermedi8079


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Figure 13. Representative examples of glycans synthesized by automated solid phase approach.

branching points and the application of the fluorous tag method for the synthesis of a branched mannose pentasaccharide.537 Besides the use of fluorous tag in iterative glycosylations, a linker with an alkene design in the fluorous tag was modified through a series of synthetic transformations such as ozonolysis, oxidation, reduction, and radical elongations to prepare neo-glycoconjugates.538 Oligosaccharides or glycoconjugates with a fluorous tag easily allowed the creation of microarrays to screen different carbohydrate-binding proteins.539,540 Moreover, the fluorous tag method was meticulously exploited in a one-pot synthesis of oligosaccharides.399 The fluorous tag automated solution-phase synthesis was further extended to the synthesis of β-1,4-mannan oligomers.541 To demonstrate the proposed automated strategy, the glycosyl trichloroacetimidate donor 481 was activated with TMSOTf and coupled with the fluorous tag 482. The resultant tagged product was then subjected to TBS removal using a mixture of TBAF and TEA·3HF to provide a glycosyl acceptor for further automation.

ates.533−536 Pohl and Jaipuri reported the first solution phase automated synthesis of linear α-(1 → 2)-linked and branched mannose oligosaccharides using C8F17 fluorous tag incorporated with an oxygen spacer. The oxygen spacer was essential as it mitigated solubility issues associated with oligosaccharides and linkers in the organic solvents commonly used for glycosylations. After each glycosylation, based on adequate solubility properties, the desired glycosylated fluorous-tagged products could be easily isolated from deletion sequences by passing the crude compound through a F-SPE column. Iterative glycosylation and deprotection steps were carried out using this methodology to obtain a linear α-(1 → 2)-linked mannose tetrasaccharide in 79% overall yield from its monosaccharide precursor using 6.0 equiv of glycosyl imidate donor, a significant decrease compared to automated solid-phase strategy.500 Employing suitable temporary protecting groups such as TBDPS at the 6-position, Ac at the 3-position, and Piv at the 2-position for α-stereoselectivity through neighboring group participation allowed the creation of 8080


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Scheme 78. Boons’ Stereoselective Solid-Phase Synthesis of α-(1 → 6)-Linked Tetraglucoside Branched with an α-(1 → 3)-Linked Glucosea

a

The imidate donors 424, 425, 427 and 428 were preactivated during each iteration by TMSOTf at −40 °C in a separate reaction flask.

leading to impacts in the field of glycobiology4,542,543 and glycomics.544 Of these technologies, the design, and development of an HPLC-assisted automated oligosaccharide synthesizer, which is based from fundamental concepts of solid−phase synthesis, 545 has improved oligosaccharide assembly. In comparison to traditional manual synthesis, the HPLC-assisted automated oligosaccharide synthesizer designed by the Demchenko group enables faster reaction times, real time reaction monitoring by the HPLC detection system, operational simplicity, and eliminates multiple iterative glycosylation, which is common in most manual and automated techniques. Similar to classical glycosylations, the glycosyl acceptor, which is bound to a polymer support in a column connected to a HPLC, was made to react by passing through a mixed solution of glycosyl donor and activator to generate the desired saccharide chain length. The HPLC-assisted automated approach was employed in the synthesis of a pentasaccharide.546 As depicted in Scheme 83, the synthesis commenced with the coupling of TentaGel MB-

Iterative glycosylation−deprotection cycles were performed to afford the fully protected β-mannuronate hexasaccharide, which was then treated with diisobutylaluminum hydride (DIBAL-H) for the global reduction of esters into alcohols to afford protected β-mannan. After cleavage of fluorous tag by an olefin crossmetathesis reaction employing the Grubbs catalyst II, hydrolysis of the esters and concomitant Pd/C-catalyzed hydrogenolysis provided the β-1,4-mannuronate hexamer 483. For completing the synthesis of β-1,4-mannan hexamer (484), protected βmannan was subjected to an olefin cross-metathesis reaction to cleave the fluorous tag followed by hydrogenolysis to remove benzyl groups (Scheme 82). The noteworthy advantage of this solution-phase approach over the solid-phase approaches is that intermediate purifications can be applied whenever necessary during the chain elongation sequence. 5.2.2. HPLC-Assisted Automated Oligosaccharide Synthesis. Oligosaccharide synthesis has been streamlined by employing various high-throughput expeditious strategies,60 8081


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Scheme 79. Seeberger’s AGA of Oligosaccharides Containing 1,2-cis-Galactosidic Linkage

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Scheme 80. Seeberger’s AGA of α-Glucans with Multiple 1,2-cis-Glucosidic Linkage

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Scheme 81. Codee’s Automated Solid-Phase Synthesis of Hyaluronan Oligosaccharides

highly reactive synthetic reagents. Of these, electrochemical reactions are considered as green protocols for the generation of reactive species such as radical cations, radical anions, carbocations, carbon free radicals, and carbanions under mild conditions. Hence, this strategy has received significant research interest in carrying out important transformations in organic synthesis. In an electrochemical process, the oxidation and reduction potentials of the substrates are essential to elicit chemical transformations. In general, similar to using chiral auxiliaries to control strereochemistry, intramolecular electroauxiliaries are used to accomplish a favorable electron transfer process in a more selective manner to yield the desired product. A substituted arylthio group at the α-position of heteroatom compounds was observed to have a substantial decrease in oxidation potential.548,549 This can be used for selective C−S bond cleavage due to internal stabilization of the oxacarbenium ion intermediate, which, in turn, reacts with a nucleophile to complement the electrochemical process.550−552 Therefore, an arylthio group was considered as internal electroauxiliary (EA), and its reactivity was studied by substituting appropriate functional groups on the aromatic ring. This strategy was applied to the generation of glycosyl triflates at −78 °C from aryl thioglycosides using tetrabutylammonium triflate (Bu4NOTf)

NH2 resin-bound glycosyl acceptor 486 and Fmoc-protected trichloroacetimidate donor 485. The glycosylation was performed by programmable addition of mixed solution of donor 485 and TMSOTf to the HPLC column with resin-bound acceptor 486. This reaction afforded the disaccharide 487. Subsequent Fmoc removal from the disaccharide 487 was carried out by purging the column with 20% solution of piperidine in DMF, releasing dibenzofulvene-pyridine complex, which indicates a successful Fmoc deprotection. The solid-phase resinbound disaccharide acceptor 488 was then glycosylated with the donor 485. Again, the resulting oligosaccharide was subjected to Fmoc cleavage to provide the trisaccharide acceptor 489. Repetition of similar transformations as above with the trisaccharide 489 furnished the protected pentasaccharide 491. Recently, a prototype version of an automated HPLC-assisted synthesizer was complemented with a standard autosampler system. This allowed a programmable delivery of reagents and was applied to the efficient synthesis of a β-1,6-glucan pentasaccharide.547 5.2.3. Automated Electrochemical Assembly of Oligosaccharides. In the field of synthetic organic chemistry, electron transfer reactions serve as viable synthetic tools for selectively transforming various organic compounds without the need for 8084


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Scheme 82. Pohl’s Automated Solution-Phase Synthesis of β1,4-Mannuronate and β-1,4-Mannan Oligomers

Subsequent glycosylation with the building blocks 492b, 493b, and 493c at −50 °C furnished the chitotriose trisaccharides 498, 499a, and 499b with exclusive β-glycosidic linkages in moderate yield. Similarly, Itoh and Nokami560 combined the electrochemical anodic oxidation of disaccharide module 500 to generate activated α-glycosyl triflates with the immediate coupling with thioglycoside 501 to furnish the trisaccharide 502. Anodic oxidation of the intermediate trisaccharide 502 to obtain the corresponding α-glycosyl triflate and subsequent coupling with thioglycoside acceptor 501 at low temperature afforded the protected target tetrasaccharide 503 in 41% yield (Scheme 85). Employing an identical strategy of automated electrochemical assembly, the synthesis of a GPI anchor core trisaccharide was achieved from mannothioglycoside building blocks.561 5.3. Ionic Liquid Supported Oligosaccharide Synthesis

To meet the ever-growing demand for the homogeneous oligosaccharides in sufficient purity and quantity to carry out biological studies, different strategies for the assembly of oligosaccharides on polymeric supports have been reported.65 Of these, solid-supported synthesis has received considerable attention due to the ease of product purification from excess reagents and side products. In contrast, polyethylene glycolsupported synthesis has been used successfully as an alternative to solid-supports in the synthesis of oligosaccharides and oligopeptides.562,563 Recently, fluorous supports have been introduced into the solution-phase paradigm for the construction of oligosaccharides based on the preferential solubility of fluorous support in fluorinated solvents. On the basis of this partitioning, the nonfluorous reagents can be removed from the supported oligosaccharides through fluorous−organic solvent extractions or fluorous silica gel based solid-phase extraction (SPE).541 However, this approach is restricted due to lack of fluorinated compounds, which are otherwise difficult to prepare, and solubility issues associated with large oligomers in the fluorinated solvents. During the past decade, ionic liquid supported oligosaccharide synthesis emerged as a viable alternative to the classical solid- and fluorous-phase synthesis strategies. This appoach combines the advantage of performing homogeneous chemistry on a relatively large scale while avoiding large excesses of reagents and allows for chromatography-free isolation of products.71 Due to their unique physical and chemical properties, ionic liquids are considered as a new class of benign reaction media for numerous organic transformations to support the concept of green chemistry.564−567 However, the intriguing properties of ionic liquids can be tuned by modifying the structure of cation or anion, which makes them as new vehicles for immobilization and offers a great deal of potential as soluble functional supports for the organic synthesis. Over the years, the concept of ionic liquid supported synthesis (ILSS) has been demonstrated elegantly for the synthesis of small molecules568 and peptides.569 Very recently, ionic liquid supported synthesis (ILSS) was further extended to the field of carbohydrate chemistry and showcased the use of ionic liquids as soluble functional supports in oligosaccharide synthesis. In a new strategy based on the use of ionic liquids as soluble functional supports, ionic liquids are covalently attached as purification labels to either the glycoside donor or acceptor (ITag-substrates) to differentiate I-Tag-products from non-I-Tagmaterials eventually after glycosylation. Then, a simple biphasic

acting as the supporting electrolyte.92,255,553,554 The intermediate triflates produced by electrochemical thioglycoside oxidation were further studied using low temperature NMR spectroscopy. It was confirmed that α-glycosyl triflates were generated based on the measured coupling constant (doublet, 3JH1H2 = 2.9 Hz) of the anomeric proton.555 This intriguing idea was extrapolated further to automated solution phase synthesis of oligosaccharides via electrochemical oxidative assembly of thioglycosides. The pioneering work reported by Yoshida and Nokami 439,556−558 opened a new avenue of electrochemical glycosylation reactions as an alternative method to construct glycosidic bonds with higher selectivity without tedious purifications. As shown in Scheme 84, the automated electrochemical assembly of chitotriose trisaccharide559 from the corresponding thioglycosides is illustrated. Prior to electrochemical glycan assembly, the oxidation potential (Eox) of the corresponding thioglycoside building blocks were measured to predict their order of reactivity. Thioglycosides having lower oxidation potentials, such as compounds 492a and 493a, with 4-fluorophenyl and 2,4difluorophenyl substitutents, respectively, were used as building blocks for anodic oxidation at −80 °C to generate the corresponding α-glycosyl triflate intermediate 494. Reaction of this intermediate with the thioglycoside acceptors 492b, 493b, and 493c at −50 °C afforded the disaccharides 495, 496a, and 496b, respectively. In the same pot at −80 °C, anodic oxidation of the disaccharides 495, 496a, and 496b was performed and this generated the corresponding α-glycosyl triflates 497a/497b. 8085


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Scheme 83. Demchenko’s HPLC-Assisted Automated Synthesis of the Pentasaccharide 491

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Scheme 84. Yoshida and Nokami’s Automated Electrochemical Assembly of Chitotriose Trisaccharides

sodium tetrafluoroborate. Oxidation of monosaccharide I-tagged substrate 505 was done to form activated sulfoxide 506 using mCPBA and then subjected to sulfoxide glycosylation conditions using acceptor 504 to yield ionic liquid bound disaccharide 507. By repeating the oxidation protocol on disaccharide 507 followed by glycosylation and concomitant cleavage of ionic liquid moiety from 508 with Cs2CO3 trisaccharide 509 was obtained in quantitative yield. Initial work done in the area of ionic liquid supported oligosaccharides synthesis involves the incorporation of I-Tag to carbohydrate precursor via the formation of transient ester

extraction or precipitation method can be used for the isolation of product after each reaction step using appropriate solvents. As a proof of concept to show the application of ionic liquids as a soluble functional support in oligosaccharide synthesis, Chan570 reported that an imidazolium cation via an ester linkage was covalently appended to form I-Tag-substrates as suitable parteners for glycosylations. As illustrated in Scheme 86, ITagged thioglycoside donor 505 was smoothly prepared from acylation of thioglycoside 504 with bromoacetic acid under DCC coupling, followed by SN2 halide displacement from the corresponding bromoacetate with 1-methylimidazole and 8087


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Scheme 85. Itoh and Nokami’s Automated Electrochemical Assembly of TMG-Chitotriomycin

building blocks including those of the rare sugars are readily made accessible through efficient one-pot or partial one-pot procedures. Numerous new methodologies have been developed for the solution-phase synthesis of oligosaccharides, the impact of which can be gauged from the complexity and size of the structures of oligosaccharides that have been synthesized. It is now possible to carry out a sequence of five to six reactions in one-pot. The success in developing one-pot methodologies has come from in-depth studies leading to deeper mechanistic understanding of glycosylation reactions. Further, in over the past ten years, iterative glycosylation has emerged as a powerful method for glycan assembly, which allows a maximum of up to five glycosylations in single flask to generate a fragment of six to ten sugar units. Several of such fragments can be then stitched together to obtain large, more complex glycans. Although all of these methods have seen great advancement in recent years, we are still far from finding a general solution to the problem of oligosaccharide synthesis, as installation of certain linkages remains to be a daunting task. Nevertheless, the expedient access to orthogonally protected monosaccharide building blocks provided by one-pot protocols will hopefully speed up automated solid phase oligosaccharide assembly65,529 and enzymatic42,307 one-pot procedures. This work will allow a major goal of the carbohydrate community, to be able to rapidly synthesize biologically relevant glycans that can lead to

linkage. However, ester protecting groups are often used for masking the hydroxy functionalities during oligosaccharide synthesis and are labile under mild basic conditions, which limit the use of ester-linked ionic supports. Moreover, a large excess of I-tagged glycosyl donor is needed, which is converted to unwanted side products due to hydrolysis and degradation of the donor during the glycosylation reaction. To overcome these issues, Galan and co-workers developed ionic liquid supports with alkyl-type functionalities introduced at the anomeric position of the reducing end to grow the carbohydrate chain. After the desired oligosaccharide sequence is reached, the product can be released as a hemiacetal, which can be used for further oligosaccharide elaboration by the introducing the appropriate leaving group. The versatility of this “ionic catch and release oligosaccharide synthesis” (ICROS) strategy was elegantly employed for both chemoselective protecting group manipulations and oligosaccharide synthesis.571 Eventually, the novel concept of ICROS was further extrapolated for the combinatorial synthesis of small libraries of oligosaccharides.572

6. SUMMARY AND FUTURE DIRECTIONS Over the past 25 years, there has been a paradigm shift in the way chemists synthesize oligosaccharides. Novel one-pot protection, one-pot glycosylation, and one-pot protection−glycosylation protocols have been developed. Several orthogonally protected 8088


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Scheme 86. IL-Supported Synthesis of Oligosaccharides

breakthrough research in carbohydrate-based vaccine development, diagnostics, and drug discovery, to be achieved more readily.

devising newer ways for efficient chemical synthesis of complex glycoconjugates implicated in various infectious diseases for the development of vaccines, therapeutics, and diagnostics. His group actively pursues the development of one-pot methods for the synthesis of a variety of bacterial rare D/L-sugars and their stereoselective assembly into biologically important complex bacterial oligosaccharides and is also involved in the preparation of diverse trehalose glycolipids and oligosaccharides of mycobacterial origin via regioselective functionalization of trehalose.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Dr. Cheng-Chung Wang is an Associate Research Fellow at the Institute of Chemistry, Academia Sinica. He received both his B.Sc. and M.Sc. from the National Sun-Yat Sen University in 1997 and 1999, respectively. He then joined Prof. Shang-Cheng Hung’s group at the Academia Sinica as a research assistant and worked on the synthesis of rare L-form sugars and regioselective protection of carbohydrates. In 2002, he was admitted by the Chemical Biology and Molecular Biophysics Program of Academia Sinica in cooperation with the National Tsing Hua University to pursue his Ph.D. studies on regioselective, orthogonal, and combinatorial one-pot protection of carbohydrates and the synthesis of heparan sulfate saccharides under the supervision of Prof. Shang-Cheng Hung. In early 2008, he joined Prof. Peter H. Seeberger’s laboratory and worked on the automated synthesis of carbohydrates for his postdoctoral research at the ETH Hönggerberg, Swiss Federal Institute of Technology. He then moved to the MaxPlanck-Institute of Colloids and Interfaces with Prof. Seeberger before he started the independent career at the Institute of Chemistry, Academia Sinica, in the end of 2009. His group is currently focusing on

Suvarn S. Kulkarni: 0000-0003-2884-876X Shang-Cheng Hung: 0000-0002-8797-729X Notes

The authors declare no competing financial interest. Biographies Dr. Suvarn S. Kulkarni is a Professor in the Department of Chemistry at the Indian Institute of Technology Bombay, India. After receiving his Ph.D. in Organic Chemistry from the University of Pune in 2001, he pursued his postdoctoral research in the laboratory of Professor ShangCheng Hung at the Academia Sinica on chemical synthesis of complex glycans via one-pot protection of sugars. In 2005, he moved to the University of California at Davis to work with Professor Jacquelyn Gervay-Hague and was engaged in glycosyl iodide mediated one-pot synthesis of glycolipids. He returned back to India in late 2008 and held a faculty position at IACS Kolkata prior to joining the Indian Institute of Technology Bombay in 2009. His current research interests include 8089


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BCB BSP Boc CDA DMAP DIPEA DMTST

2(benzyloxycarbonyl)benzyl benzenesulfinyl piperidine tert-butoxycarbony cyclohexane-1,2-diacetal 4-N,N-dimethylaminopyridine diisopropylethylamine dimethyl(methylthio)sulfonium trifluoromethanesulfonate DMTPSB o,o-dimethylthiophosphonosulfenyl bromide DTBMP 2,6-di-tert-butyl-4-methylpyridine Fmoc 9-fluorenylmethoxycarbonyl HMDS 1,1,1,3,3,3-hexamethyldisilazane Lev levulinoyl MeOTf methyl trifluoromethanesulfonate Ms methanesulfonyl MPEP o-(p-methoxyphenylethynyl) phenyl 2-NAP 2-naphthylmethyl NBS N-bromosuccinimide NIS N-iodosuccinimide OFox 3,3-difluoro-3H-indol-2-yl PTSA p-toluenesulfonic acid PMB p-methoxybenzyl PMP p-methoxyphenyl PTFAI N-phenyltrifluoroacetimidates PSB 2-(2-propylsulfinyl)benzyl Phth phthalate ReSET regioselective silyl-exchange technology RRVs relative reactivity values SPSP S-2-(2-propylsulfinyl)benzyl S-Box S-benzoxazolyl STaz S-thiazolyl TBAF tetra-n-butylammonium fluoride TBDPS tert-butyldiphenylsily TBS or TBDMS tert-butyldimethylsilyl TMS trimethylsilyl Tr trityl TMSOTf trimethylsilyl trifluoromethanesulfonate TfN3 trifluoromethanesulfonyl azide Tf trifluoromethanesulfonyl TBAN3 tetrabutylammonium azide TBANO2 tetrabutylammonium nitrite TfOH trifluoromethanesulfonic acid Troc 2,2,2-trichloroethoxycarbonyl Tol tolyl TFB trifluoromethylbenzene TTBP tritert-butylpyrimidine

the chemistry of free sugars, stereoselective glycosylation reactions, and the synthesis of bacterial CPS and glycoproteins. Dr. Narayana Murthy Sabbavarapu obtained his Ph.D. on the development of novel synthetic methodologies and total synthesis of natural products under the supervision of Prof. Y. V. D. Nageswar at the Indian Institute of Chemical Technology (IICT)-Hyderabad in 2013. He then joined Prof. Timor Baasov’s laboratory for his postdoctoral research at the Technion-Israel Institute of Technology and worked on the design and synthesis of new classes of aminoglycoside derivatives for treatment of human genetic diseases. In 2016, he moved to the Genomics Research Center, Academia Sinica, where he is currently working with Prof. Shang-Cheng Hung as the Postdoctoral Research Associate. His research interest is concerned with the development of viable synthetic strategies for the preparation of sialylated oligosaccharides to investigate their important biological functions. Ananda Rao Podilapu received his B.Sc. from the SSSS Degree College, Vizianagaram, in 2008 and M.Sc. from the University of Hyderabad in 2011. He then joined the group of Professor Suvarn S. Kulkarni at the IIT Bombay for the Ph.D. studies and had recently submitted his Ph.D. thesis. His present studies involve the total synthesis of rare sugarcontaining bacterial glycoconjugates and archeal glycans. Pin-Hsuan Liao was awarded her B.Sc. and M.Sc. from the Tamkang University and the Taiwan University of Science and Technology in 2014 and 2016, respectively. She is currently a Research Assistant in Dr. Cheng-Chung Wang’s laboratory working on the development of stereoselective glycosylation reactions. Dr. Shang-Cheng Hung is a Distinguished Research Fellow and Director at the Genomics Research Center, Academia Sinica. He obtained his Ph.D. in synthetic organic chemistry with cosupervisions of Prof. ChunChen Liao and Prof. Biing-Jiun Uang from the National Tsing Hua University of Taiwan in 1992. After a two-year military service, he carried out postdoctoral studies with Prof. Andrew Streitwieser at the University of California at Berkeley in 1994 and subsequently with Prof. Chi-Huey Wong at the Scripps Research Institute in 1995. He began his independent career at the Institute of Chemistry, Academia Sinica, in 1998 and was appointed as an Associate Professor at the National Tsing Hua University in 2005. In 2009, he was recruited back to the Genomics Research Center, Academia Sinica, where he became the Distinguished Research Fellow in 2012. His research interests focus on the development of “one-pot” strategies for carbohydrate synthesis and the preparation of cell-surface heparan sulfate saccharides to probe their specific interactions with various proteins.

ACKNOWLEDGMENTS This review is dedicated to Professor Chi-Huey Wong on the occasion of his 70th birthday. We greatly thank Professor Todd L. Lowary for careful proofreading and editing of this manuscript. We are grateful to the Ministry of Science and Technology of Taiwan (MOST 106-2745-M-001-001-ASP, MOST 106-2113M-259-009, and MOST-106-2113-M-001-009-MY2), the SERBDST of India (Grant EMR/2014/000235), and the ISF-UGC joint research program framework (Grant 2253/15) for financial support of our work. A.R.P gratefully acknowledges financial support from CSIR New Delhi.

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ABBREVIATIONS ABz o-alkynylbenzoate Ac acetyl Bz benzoyl BOM benzyloxymethyl BSM benzenesulfinyl morpholine 8090


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