Aminooxylated Carbohydrates: Synthesis and ... - ACS Publications

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Aminooxylated Carbohydrates: Synthesis and Applications Carlo Pifferi,†,‡ Gour Chand Daskhan,†,‡ Michele Fiore,† Tze Chieh Shiao,§ René Roy,§ and Olivier Renaudet*,†,∥ †

Université Grenoble Alpes, CNRS, DCM UMR 5250, F-38000 Grenoble, France Institut Universitaire de France, 103 Boulevard Saint-Michel, 75005 Paris, France § Pharmaqam, Department of Chemistry, Université du Québec à Montreal, P.O. Box 8888, Succursale Centre-ville, Montréal, Québec H3C 3P8, Canada ∥

ABSTRACT: Among other classes of biomolecules, carbohydrates and glycoconjugates are widely involved in numerous biological functions. In addition to addressing the related synthetic challenges, glycochemists have invested intense efforts in providing access to structures that can be used to study, activate, or inhibit these biological processes. Over the past few decades, aminooxylated carbohydrates have been found to be key building blocks for achieving these goals. This review provides the first in-depth overview covering several aspects related to the syntheses and applications of aminooxylated carbohydrates. After a brief introduction to oxime bonds and their relative stabilities compared to related CN functions, synthetic aspects of oxime ligation and methodologies for introducing the aminooxy functionality onto both glycofuranosyls and glycopyranosyls are described. The subsequent section focuses on biological applications involving aminooxylated carbohydrates as components for the construcion of diverse architectures. Mimetics of natural structures represent useful tools for better understanding the features that drive carbohydrate−receptor interaction, their biological output and they also represent interesting structures with improved stability and tunable properties. In the next section, multivalent structures such as glycoclusters and glycodendrimers obtained through oxime ligation are described in terms of synthetic design and their biological applications such as immunomodulators. The second-to-last section discusses miscellaneous applications of oximebased glycoconjugates, such as enantioselective catalysis and glycosylated oligonucleotides, and conclusions and perspectives are provided in the last section.

CONTENTS 1. Introduction 1.1. Generalities 1.2. Oxime Bonds 1.2.1. Stability 1.2.2. Formation 2. Synthesis of Aminooxylated Carbohydrates 2.1. Key Transformations 2.2. Aminooxylated Furanoid Sugars 2.3. Aminooxylated Pyranoid Sugars 2.3.1. Modification at C-1 2.3.2. Modifications at C-2 and C-3 2.3.3. Modification at C-4 2.3.4. Modification at C-6 3. Mimetics of Natural Structures 3.1. Oligosaccharide Mimetics 3.2. Oligomers 3.3. Glycoprotein Mimetics 4. Multivalent Structures 4.1. Glycoclusters 4.2. Immobilization of Glycoclusters on Solid Supports 4.3. Glycodendrimers 4.4. Heterofunctionalized Scaffolds and Orthogonality © XXXX American Chemical Society

4.5. Carbopeptides 4.6. Synthetic Vaccines 5. Miscellaneous Applications 5.1. Carbohydrate−Oligonucleotide Conjugates 5.2. Enantioselective Catalysis 5.3. Other Examples 6. Concluding Remarks and Perspectives Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

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1. INTRODUCTION 1.1. Generalities

Carbohydrates represent a fascinating class of biomolecules that are ubiquitous in all living organisms. Beyond their roles in energy storage, they are found as essential components of

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Received: November 1, 2016

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DOI: 10.1021/acs.chemrev.6b00733 Chem. Rev. XXXX, XXX, XXX−XXX

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natural products and are also associated with a large variety of soluble and membrane-bound lipids and proteins.1,2 It is now well-established that carbohydrates play crucial roles in countless biological communication events such as cellular adhesion, migration, development, disease progression, pathogen detection, and immune response.3−8 To study and exploit their functions, extensive efforts have been undertaken over the past few decades to synthesize these natural compounds and their structural analogues.9−13 In this context, aminooxylated carbohydrates have been shown to represent attractive building blocks for the preparation of natural products and for their conjugation into various entities such as oligomers, dyes, peptides, oligonucleotides, and even carbon nanotubes.14−19 Despite their significant potentials in bioorganic chemistry and other research fields, no review article dealing with this particular class of compounds has been published so far in the literature. The main objective of this review is to provide a comprehensive and critical overview covering all aspects of the synthesis and the utilization of aminooxylated carbohydrates. Oxime chemistry is discussed first, followed by a description of the synthetic methodologies available for introducing the aminooxy functionality. Special attention is devoted toward the incorporation of the aminooxy functionality at various positions of both glycofuranosyl and glycopyranosyl moieties. Next, we discuss the utilization of aminooxylated carbohydrates as key building blocks for the synthesis of antibiotics such as calicheamicin γ1 and esperamicin or modified oligosaccharides. These latter compounds indeed contain N−O interglycosidic linkages that control both their structural and conformational features. The next section describes the preparation of neoglycoconjugates displaying carbohydrates through oxime bonds that are easily formed by condensation with entities bearing ketone or aldehyde groups. In fact, this oxime-based approach undoubtedly represents a method of choice for providing a large variety of well-defined neoglycoconjugates in high yields and with predefined stereoisomeric glycosidic linkages. The disussion is focused on glycoengineered proteins or glycoprotein mimetics (i.e., using polymers, peptides, and nanotubes) that are important structures for fundamental research and biopharmaceutical developments. In the next section, the preparation of multivalent architectures using molecular scaffolds such as carbohydrates, peptides, cyclopeptides, and dendrimers is discussed. These multivalent glycoconjugates provide attractive tools for understanding the inherent complexity of biological phenomena, which is of crucial importance to the discovery of new diagnostic and therapeutic agents. In this section, particular emphasis is placed on antitumoral vaccines, lectin ligands, and cell-targeting agents. This review also discusses several glycosylated structures (i.e., oligomers, dynamers, foldamers, and aromatic species) that have been reported for purposes other than those mentioned above.

Figure 1. Chemistry of CN double bonds, including aminooxylated species in green.

If the instability of imines in aqueous media strongly limits their utilization for biological applications, hydrazones and, in a more meaningful way, oximes are hydrolytically more stable and are often used for this purpose.23 In alkylhydrazones, acylhydrazones, and oximes (Figure 2), electron delocalization

Figure 2. Relative stabilities of CN double bonds and the α-effect.

of the lone pairs of the heteroatom X adjacent to the nitrogen has been invoked as the leading cause for their improved stability through the so-called α-effect. The contribution of the resulting resonance forms (II and IV, Figure 2) decreases the electrophilicity of the sp2 carbon, thereby limiting its susceptibility to nucleophilic attack by water. In addition, the rate of acid-catalyzed hydrolysis is significantly decreased by the attractive inducting effect, which reduces the basicity of the sp2 nitrogen. In a recent study, Kalia and Raines unequivocally demonstrated that oxime linkages are hydrolytically more stable than hydrazones, while also presenting anomalous stabilities because of their resistance to protonation.24 In addition, several studies have highlighted that the nature of the carbonyl group is an important parameter for the stability of oximes.25−28 For example, Jencks previously demonstrated that the reactions of hydroxylamine with aromatic and glyoxylic aldehydes led to oxime conjugates with higher thermodynamic stabilities than reactions with ketones such as acetone and cyclohexanone.29−32 For these resons, strongly acidic conditions are required for the hydrolysis of oxime bonds, which makes this linkage ideal in vivo and for various biological uses.33−39 1.2.2. Formation. Oxime-based ligation was originally pioneered by Rose in 1994 for the conjugation of aminooxy peptides onto a linear polypeptide displaying aldehyde groups.15 Kinetic studies by Jencks demonstrated that this reaction occurs at an optimum pH of 3−4 and involves the formation of carbinolamine intermediates that undergo dehydration to form oxime linkages.29−32 The formation of oxime linkages also presents the advantage of being fast and quantitative, leading mainly to the formation of the Zstereoisomers and a mixture of E- and Z-stereoisomers when unsymmetrical ketones or aldehydes are used. Several studies have shown that aminooxylated derivatives can be conjugated to the anomeric center of reducing sugars,40−47 to provide a

1.2. Oxime Bonds

1.2.1. Stability. The condensation of nucleophiles such as amines, hydrazides, thiosemicarbazides, and oxyamines with carbonyl groups, leading to the formation of imines, hydrazones, and oxime linkages, represents a powerful and simple ligation methodology that provides access to a wide variety of bioconjugates under physiological conditions (Figure 1).20−22 B


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Scheme 1. Synthesis of Both α- and β-Aminooxylated Sugar Precursors Designed by Grochowski and Jurczak74

mixture of open-chain E- and Z-oxime isomers. Such reactions are beyond the scope of this review and are not further described in detail, except when aminooxylated derivatives are obtained. However, it should be mentioned that Dumy and coworkers48 demonstrated that the utilization of N,O-substituted oxyamines leads to the formation oxyiminium intermediates that provide cyclic sugars with high diastereoselectivity after ring closure with OH at position 5. With less reactive carbonyl compounds such as oligosaccharides, the condensation can be catalyzed with nucleophiles such as aniline,49−52 methoxyaniline,53,54 5-methoxyanthranilic acid,55 3,5-diaminobenzoic acid,55 and m-phenylenediamine,56 which mediate the formation of iminium intermediates that enhance the reactivity toward oxyamines, even at pH 7. Because of these considerations, a large variety of methods have been developed to introduce aldehydes and oxyamines into biomolecules to construct bioconjugates by oxime ligation.36,57−73

Later, two different approaches for the C-3 modification of furanoid sugars with the aminooxy function were reported by Tronchet et al.75−77 Treatment of keto sugar 4 with hydroxylamine hydrochloride in a 1:1 mixture of pyridine and ethanol at reflux gave the corresponding keto oxime, which was reduced with sodium cyanoborohydride to provide the desired furanoside 5 with high stereoselectivity (Scheme 2a). The

2. SYNTHESIS OF AMINOOXYLATED CARBOHYDRATES 2.1. Key Transformations

A wide variety of methodologies have been proposed for the introduction of the aminooxy functionality at different positions of sugar rings (Figure 3).

Scheme 2. Methods for the C-3 Modification of Furanoid Sugars with the Aminooxy Function Designed by the Tronchet Group75−77

second approach relied on the treatment of allofuranose 6 with triphenylphosphine, DEAD, and HONPhth in tetrahydrofuran (THF) to afford the related O-phthalimido compound, which subsequently underwent hydrazinolysis to give 7 (Scheme 2b). More recently, the synthesis of derivative 11 from precursor 8 derived from D-glucose was reported by Xie and co-workers (Scheme 3).78 Compound 9 was obtained in 85% yield under Mitsunobu conditions with HONPhth and then subjected to selective removal of the acetal protecting group at C-5 and C-6 with aqueous acetic acid. Treatment of the diol with NaIO4 followed by oxidation of the resulting aldehyde afforded derivative 10 in 84% yield. Esterification with tert-butyl trichloroacetimidate and deprotection of the phthalimido group with methyl hydrazine gave compound 11 in good yields. Hydrolytically stable aminooxyamide-linked oligoribonucleosides are analogous to the naturally occurring DNA or RNA backbone. In addition, such unnatural oligonucleotides have the ability to stabilize the secondary structure of DNA to the same extent as the native analogues. The first nucleoside aminooxy acids were synthesized from furanoid phthalimidooxy acids by N-glycosylation with uracil, thymine, N-benzoylcytosine, 6-Nbenzoyladenine, and 2-N-acetyl-6-O-diphenylcarbamoylguanine

Figure 3. Various synthetic approaches toward aminooxylated sugar derivatives.

Nucleophilic substitutions with N-hydroxysuccinimide (HONSu) or N-hydroxyphthalimide (HONPhth) using the Mitsunobu reaction, phase-transfer catalysis, stereoselective addition of hydroxylamine across the double bonds of glycals, direct oxidation of sugar amines, and deprotection of variously protected oxyamines represent key methodologies toward their syntheses, as described in detail in the following paragraphs. 2.2. Aminooxylated Furanoid Sugars

In 1976, Grochowski and Jurczak 74 first employed a straightforward strategy for synthesizing aminooxylated furanoid derivatives through implementation of the Mitsunobu reaction. Nucleophilic displacement of the anomeric free hydroxyl group of mannofuranose 1 by HONPhth in the presence of triphenylphosphine (Ph3P) and diethyl azodicarboxylate (DEAD) afforded separable mixtures of compounds 2 and 3 (Scheme 1) in yields of 11% and 65%, respectively. C


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Scheme 3. Synthesis of Furanoid Glycoaminooxy Acids Designed by Xie’s Group78

(Scheme 4).79 In that work, Xie and co-workers observed the instability of the phthalimido group in MeOH, leading to the

Scheme 5. Synthesis of C-6 Aminooxylated Furanosides Designed by Ruff and Lehn80

Scheme 4. Synthesis of β-Linked Aminooxylated Nucleoside Acids Designed by Xie’s Group79

first developed by the group of Beigelman.81 Starting from protected arabinonucleoside 23, nucleophilic displacement by HONPhth in the presence of diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2 afforded the corresponding phthalimido ribonucleoside derivative with inversion of the configuration in nearly quantitative yields. Removal of the Markiewicz protecting group in the presence of triethylamine trihydrofluoride and subsequent treatment with aqueous methylamine gave the desired aminooxy ribonucleoside 24 (Scheme 6). Scheme 6. Synthesis of Aminooxy Nucleoside 24 Designed by Beigelman’s Group81

imide ring-opening product in a reversible way. Later, the same group further extended the previous methodology to synthesize nucleoside aminooxy acid 18. The synthesis was achieved through N-glycosylation of various nucleic bases with preinstalled phthalimidoxy sugar acids in the presence of N,O-bis(trimethylsilyl)acetamide (BSA) and a Lewis acid. Thus, trimethylsilyl trifluoromethanesulfonate- (TMSOTf-) promoted N-glycosylation of derivative 12 with various nucleic bases in CH3CN or 1,2-dichloroethane afforded β-linked derivatives 13−17 in 41−71% yields. Esterification of 13 with tert-butoxytrichloroacetimidate also led to the formation of the N-tert-butyl side product, which was converted to the desired ester by treatment with acetic acid (AcOH) in CH2Cl2. Hydrazinolysis led to the fully deprotected aminooxy acid 18 and a small quantity of the trans-acetylation product on the aminooxy function. Ruff and Lehn80 reported an alternative route for the syntheses of aminooxylated arabinofuranosides 20 and 22 in two steps, including the nucleophilic substitution of the tosyl moiety by HONPhth and treatment with butylamine in methanol (Scheme 5). A facile three-step synthesis of aminooxy nucleosides by triflate replacement with HONPhth under basic conditions was

Modification of nucleosides by means of labeling with different fluorophores plays a crucial role in particular in DNA chip technology. Salo and co-workers introduced an aminooxy functionality on a pentyl linker-containing nucleoside (Scheme 7).82 The phthalimido derivative 26 was obtained by treating the nucleoside 25 with HONPhth in the presence of Ph3P and DEAD, followed by 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite in acetonitrile. The resulting phosphoramidite, bearing a masked aminooxy group, underwent oligonucleotide assembly, and the phthaloyl moiety was removed with hydrazinium acetate. D


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Scheme 7. Synthesis of a Terminal Aminooxy-Linked Deoxyribonucleoside Designed by Salo et al.82

Scheme 8. Synthesis of a Terminal Aminooxy-Linked Nucleoside83

Scheme 9. Synthesis of an Aminooxypropionate-Linked Deoxynucleoside84

Nucleosides bearing a terminal aminooxy function attached to the nucleobase were also reported by Lhomme and coworkers (Scheme 8).83 The incorporation of an aminooxy group linked through alkynyl spacer in the uridine triphosphate 31 was realized through coupling between 5-iodouridine 29 and a tert-butoxycarbonyl- (Boc-) protected aminooxy-containing alkynyl fragment under Hobbs conditions. Subsequent protection of the hydroxyl groups at positions 2′ and 3′ using ethyl orthoformate in acetone in the presence of a catalytic amount of p-toluenesulfonic acid gave protected nucleoside 28

in 45% overall yield. Acidolysis of intermediate 28 gave the free aminooxy-containing nucleoside 29. Along with nucleobase, Hu and co-workers reported the attachment of an aminooxy group connected through a spacer, namely, propionate ester, to the deoxynucleoside 5′ position (Scheme 9).84 The key step was the coupling between the fluoro deoxyuridine 32 and the aminooxy carboxylic acid 31 using Ph3P and DEAD. Compound 31 was obtained from HONPhth-protected derivative 30 in three steps, including the hydrazine-mediated ring opening of the phthalimide moiety, the carbobenzyloxy group (Cbz) protection of the free amine E


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Scheme 10. Gold(III)-Catalyzed Synthesis of Aminooxyglycosides85

Scheme 12. Strategy to Construct β-Linked Aminooxylated Sugars Designed by Danishefsky and Co-workers87

group, and trifluoroacetic acid-mediated ester hydrolysis. Hydrogenolysis of the Cbz protecting group of the resulting compound in the presence of Pd/C in MeOH under acidic conditions furnished compound 33. Recently, Hotha and co-workers reported the O-glycosidation of hydroxysuccinimides and hydroxyphthalimides with a variety of aldose-derived propargyl 1,2-orthoesters under gold(III)-catalyzed conditions.85 Performing the reaction with different solvents, they found that a mixture of CH2Cl2 and CH3CN in a 4:1 ratio was the most suitable for obtaining hydroxysuccinimidyl and hydroxyphthalimidyl derivatives in very good yields (70−80%). As an example, they reported the conversion of the furanoside donor 34 into its succinimidyl and phthalimidyl derivatives 35 and 36, respectively, in the presence of 7 mol % AuBr3 after 24 h of reaction. Deprotection of the benzoates was carried out using a 2 M solution of CH3NH2 in methanol at 65 °C for 24 h, to obtain aminooxy arabinofuranoside 37 in good yield (Scheme 10). In the case of oligosaccharides, however, the gold-catalyzed reaction was found to be very slow. Addition of 7 mol % silver triflate (AgOTf) was observed to be beneficial, probably because of the formation of more reactive catalytic Au-species.

derivative 41 was achieved through triphenylphosphine hydrobromide- (Ph3P-HBr-) mediated addition of 2-(trimethylsilyl)ethyl-N-hydroxycarbamate (TEOC-NHOH) to the less hindered face of the double bond of the glycal 40. An alternative straightforward route to the synthesis of βaminooxylated sugar derivatives from the sulfoxide precursor 42 was reported by Kahne and co-workers (Scheme 13).18 Treatment with ethyl hydroxycarbamate in the presence of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine furnished exclusively the desired derivative 43. Scheme 13. Synthesis of β-Linked Aminooxylated Sugars from a Sulfoxide Precursor Designed by Kahne and Coworkers18

2.3. Aminooxylated Pyranoid Sugars

2.3.1. Modification at C-1. The unusual N−O glycosidic linkage is present in the oligosaccharide fragment of enediyne antitumor antibiotics, such as esperamicin and calicheamicin. In an early attempt, Nicolaou and Groneberg86 reported a route for introducing the N−O glycosidic bond into the carbohydrate framework in a stereoselective fashion. Their synthetic approach (Scheme 11) involved the synthesis of β-amino-

Beau and co-workers88 described another method for the stereoselective synthesis of β-aminooxylated sugars by a Lewisacid-catalyzed reaction (Scheme 14). AgOTf-promoted glyco-

Scheme 11. Synthesis of β-Linked Aminooxylated Sugars Designed by Nicolaou and Groneberg86

Scheme 14. Lewis-Acid-Promoted Synthesis of β-Linked Aminooxy Sugars Designed by Beau and Co-workers88

oxylated derivative 39 from anomeric 38 in two steps: (i) treatment of derivative 38 with N-hydroxyphthalimide in the presence of Ph3P and DEAD and (ii) hydrazine-mediated deprotection of the phthalimido moiety. Shortly thereafter, Danishefsky and co-workers reported another strategy for introducing the aminooxy functionality at the C-1 position through the stereoselective addition of a hydroxylamine derivative across the double bond of glycal (Scheme 12).87 The synthesis of β-linked aminooxylated

sylation of the glycosyl bromide 44 with a nitrone salt gave an unstable nitrone intermediate that was immediately converted into the N-methyl hydroxylamine derivative 45 by acidic hydrolysis. Encouraged by the success of Lewis-acid-promoted reactions, Andersson and Oscarson developed another methodology64 for the stereoselective construction of both α- and β- aminoF


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included successive precipitations to avoid tedious purifications by column chromatography.90 More recently, Brunner and Keck91 reported the synthesis of aminooxy maltose and lactose from the corresponding bromo derivatives 51 and 52, respectively, following a procedure similar to that developed by Roy and co-workers (Scheme 18). Treatment of bromo derivatives 51 and 52 with HONSu in the presence of TBAHS gave succinimide glycosides, and finally, hydrazine-mediated ring opening in ethanol afforded compounds 65 and 66, respectively, in corresponding overall yields of 65% and 69%. Although several reports have documented the synthesis of β-aminooxylated sugars, stereoselective construction of the αanomer glycosides remains more tedious. In this regard, Bertozzi and co-workers established a strategy for prepareing N-acetylgalactosyl derivative 69 under conditions similar to those reported by Roy and co-workers (Scheme 19).92 Glycosylation of glycosyl chloride 67 with HONSu in the presence of a phase-transfer catalyst afforded α-linked derivative 68 in 52% yield. Reductive acetylation of the azide followed by de-O-acetylation and deprotection of the succinimido moiety gave 69 in 71% yield over two steps. In another report, using the same methodology, a series of β-linked aminooxylated analogues derivatives from the corresponding protected succinimidyl glycosides, including 62, 70, and 71, were successfully obtained in 55−58% overall yields (Scheme 19).93 Later, the strategy was efficaciously extended63 to prepare derivative 69 using glycosyl bromide instead of glycosyl chloride as an alternative glycosyl donor.94 Interestingly, modification with a bromide donor led to a 57% yield for the glycosylation step, thereby increasing the efficiency of the modified route. The synthesis of sialylated disaccharide 75, which is an STn antigen analogue, was accomplished by the same group through the glycosylation of sialyl phosphite donor 72 with masked aminooxyglycoside 73 in the presence of TMSOTf (Scheme 20). As expected, the absence of neighboring-group participation in 72 afforded a separable anomeric mixture (α/β = 3:1) of 74 in 44% yield. Further steps on α-isomer 74 provided the desired aminooxylated STn derivative 75 in 11% overall yield.94 As a synthetic alternative to N-hydroxysuccinimido and Nhydroxyphthalimido glycosides, the same group identified glycosyl N-pentenoylhydroxamates as synthetic precursors for

oxylated sugars (Scheme 15). Interestingly, the glycosylation of peracetylated glucoside 46 with HONSu in CH2Cl2 afforded Scheme 15. Synthesis of Both α- and β- Aminooxylated Sugars Designed by Andersson and Oscarson64

primarily the β-anomer 48, with good stereoselectivity. On the other hand, boron trifluoride diethyl etherate- (BF3·Et2O-) promoted glycosylation of 46 with HONSu in CH2Cl2 favored the formation of β-anomer 48. In addition, the utilization of AgOTf as promoter on a glucosyl bromide substrate, gave an anomeric mixture of 47/48 in 1:1.3 ratio. A similar selective reaction was also used for the preparation of α- and β-aminooxy galactosides from their peracetate precursor. To overcome the poor stereoselectivity (and instability) of the reaction intermediate, Roy and co-workers89 developed an elegant and reliable route for the construction of β-aminooxylated sugar derivatives using phase-transfer catalysis (PTC) (Scheme 16). The synthesis started with glycosylation of halides 44 and 49−52 with 4 equiv of HONSu and 1 equiv of tetra-n-butyl ammonium hydrogen sulfate (TBAHS) as the phase-transfer catalyst in the presence of CH2Cl2/Na2CO3 (1 M). Various monosaccharides, disaccharides (lactose, maltose), and sialylated succinimides 48, 53−56, and 58 were thus obtained in 59−90% overall yields. Several mono- and disaccharides 48, 54, and 56 were successively deprotected using either hydrazinolysis or treatment with sodium methoxide followed by sodium hydroxide to provide the corresponding aminooxy or N−O-linked prespacer glycosides, respectively (Scheme 17). An improved procedure for the preparation of the aminooxy galactosyl 62 was described more recently by the same group. It

Scheme 16. Stereoselective Glycosylation between Glycosyl Halides and N-Hydroxysuccinimide Using PTC Conditions Described by Roy and Co-Workers89

G


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Scheme 17. Synthesis of β-Aminooxylated Sugars under PTC Conditions Designed by Roy and Co-Workers89

Scheme 18. Synthesis of Aminooxy Maltose and Lactose Analogues91

Scheme 19. Synthesis of α-Aminooxylated Sugars Using Glycosyl Chloride as an Alternative Donor under PTC Conditions92,93

Scheme 20. Synthesis of the Aminooxylated 2,6-STn Derivative 7594

the free amino group, followed by tert-butyldiphenylsilyl (TBDPS) deprotection and I2-catalyzed hydrolysis of the hydroxamic ester gave the targeted trisaccharide derivative 78 in 25% overall yield from 76. In 2001, Dumy and Renaudet reported the synthesis of both the α- and β-aminooxy sugars in a single reaction by introducing glycosyl fluorides as more stable donors than the

the preparation of complex aminooxy glycans such as the aminooxy Lewis X derivative 78 (Scheme 21).95 For instance, TMSOTf- (1 equiv) promoted glycosylation of glycosyl Nphenyl trifluoroacetimidate 76 with N-pentenoylhydroxamic acid (NHPent) in CH2Cl2 at −20 °C afforded derivative 77 in 64% yield. Zinc-mediated removal of the trichloroethoxycarbonyl (Troc) protecting group and subsequent acetylation of H


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Scheme 21. Synthesis of Aminooxy Sugars Using NHPent as a Source of Masked Aminooxy Groups95

Scheme 22. Method to Introduce Both the α- and β-Aminooxy Sugars from Glycosyl Fluoride96

typical chloro- or bromohalides (Scheme 22).96 As an example, the tumor-associated carbohydrate antigen (TACA) analogues 69 and 82 were prepared from galactosyl fluoride 79. Glycosylation with N-hydroxyphthalimide in the presence of BF3·Et2O and Et3N afforded separable mixtures of both the αand β-phthalimido derivatives 80 and 81 in yields of 50% and 38%, respectively. Reductive acetylation of the azide functionality followed by de-O-acetylation and cleavage of the phthalimido moiety with methylhydrazine afforded 69 and 82, both in 90% yield after a single precipitation in MeOH/ CH2Cl2. Following this synthetic route, various aminooxylated carbohydrate derivatives (e.g., Gal-α-ONH2, 83; Gal-β-ONH2, 62; Glc-α-ONH2, 84; Glc-β-ONH2, 85; Man-α-ONH2, 86; and Lac-β-ONH2, 66) were obtained successfully. Later, the same group obtained the tumor-associated αaminooxy TF antigen 90 starting from disaccharide fluoro donor 89, by employing the procedure depicted in Scheme 23.97 Fluoro disaccharide 89 was first synthesized from 87 and the peracetylated galactosyl trichloroacetimidate 88 and was then glycosylated with HONPhth in the presence of Et3N and BF3·Et2O, after which azide reduction/acetylation and treatment with hydrazine afforded 90. Andreana and co-workers reported a convergent approach to obtain α-aminooxy TF antigen 90 using a key precursor,

Scheme 23. Synthesis of α-Aminooxy TF Antigen 9097

namely, D-GalN3−NHS glycoside 91, which contains a preinstalled α-N-hydroxysuccinimidyl function,98 and the peracetylated-galactosyl trichloroacetimidate donor 88 (Scheme 24a). In another work, Ghosh and Andreana synthesized α-aminooxy Gb3 derivative 9499 through (i) Niodosuccinimide (NIS)/TMSOTf-catalyzed glycosylation beI


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Scheme 24. Alternative Routes for the Preparation of (a) α-Aminooxy TF Antigen 90 and (b) Globotriose Gb3 9498,99

Scheme 25. Synthesis of α-Aminooxy-Containing Tetrasaccharide 98 Designed by Andreana’s Group100

Scheme 26. Synthetic Route to α- and β-Aminooxylated L-Fucopyranosides101

trichloroacetimidate disaccharide donor 95 and the disaccharide acceptor 96. Tetrasaccharide 97 was obtained using TMSOTf as the promoter at −15 °C in 53% yield with exclusive β-selectivity as a result of the anchimeric assistance of Troc protecting group. Final deprotections gave the αaminooxy-containing tetrasaccharide 98 in four steps. In a recent report, Renaudet and co-workers101 also demonstrated the first synthesis of both α- and β-aminooxylated L-fucopyranosyl derivatives 103 and 104 (Scheme 26).

tween NHS-protected glycoside 93 and ethyl-2,3,4,6-tetra-Obenzyl-1-thio-β-D-galactopyranoside, (ii) removal of the benzyl protecting groups, and (iii) hydrazine-mediated deprotection of the succinimide moiety (Scheme 24b). Following the same approach, the synthesis of the αaminooxy-containing tetrasaccharide 98, a repeat unit of a rhamnose-rich polysaccharide found in the cell envelope of S. dysgalactiae 2023, was reported in 19 steps and in ∼5% overall yield (Scheme 25).100 The final glycosylation involved the J


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Scheme 27. Synthetic Route to β-Aminooxylated Glycosides Developed by Yu and Co-Workers102

Fluoride derivatives 100 (α/β = 1.2:1) were prepared from peracetylated fucose 99 after fluorination with diethylaminosulfur trifluoride (DAST) in THF. Treatment of the anomeric mixture of 100 with HONPhth in the presence of BF3·Et2O and triethylamine afforded 101 and 102 in a 6:4 ratio. Final concomitant cleavage of the acetate and phthaloyl groups gave compounds 103 and 104. Interestingly, the stereoselectivity of the glycosylation between 100 and HONPhth was found to be strongly dependent on the solvent and the anomeric configuration despite the presence of an acetate participating group at carbon 2. The acetylated α-fluoride was indeed found to be the best donor in CH2Cl2, furnishing both the α- and βanomers in 88% yield in a 2.1:1 α/β ratio, whereas 1,2-cis glycosylation was largely favored in acetonitrile. An efficient and straightforward synthesis of aminooxyglycosides through the utilization of Fmoc-protected hydroxylamine as a source of aminooxy groups under Lewis acid conditions was developed by Yu and co-workers (Scheme 27).102 The synthetic strategy consisted of the Au(I)-catalyzed glycosylation of various ortho-hexynylbenzoate glycosides, such as 105, with N-Fmoc-hydroxylamine in CH2Cl2 and subsequent N-Fmoc removal to give β-aminooxylated derivative 106. Gold(III)-catalyzed glycosidation, as reported by Hotha and co-workers85 (see section 2.2), on pyranoid propargyl 1,2orthoesters represents another straightforward method for obtaining hydroxysuccinimidyl glycosides. 2.3.2. Modifications at C-2 and C-3. Although several strategies have been elaborated for the stereoselective synthesis of C-1 aminooxy carbohydrates, modifications at the C-2 and C-3 positions by aminooxy-group functionalization have also been a subject of investigations. A short and straightforward synthetic route for preparing C-2 aminooxylated sugar derivatives through direct 2,2-dimethyldioxirane (DMDO) oxidation of sugar amines was reported by Danishefsky and co-workers (Scheme 28).103

Treatment of 107 with DMDO in the presence of acetone furnished desired derivative 108. Similarly, C-2 and C-3 aminooxylated derivatives 109, 110, and 5 were synthesized from the corresponding amine precursors. 2.3.3. Modification at C-4. Kahne and co-workers104 developed an elegant strategy for introducing an aminooxy group at the C-4 position through nucleophilic replacement of the sugar triflate with an aminooxy substituent (Scheme 29). Scheme 29. Route for the Preparation of C-4 Aminooxylated Carbohydrates104

Displacement of the axial triflate at C-4 of 111 with Omethylhydroxylamine in dimethylformamide (DMF) afforded product 112 in 20% yield, along with undesired product 113 in 10% yield. Another possibility for derivatizing the C-4 position was realized by Tronchet and co-workers through oxime reduction as a key step (Scheme 30).76 Reduction of the oxime functionality of derivative 114 upon treatment with NaBH3CN gave separable epimeric mixtures of derivatives 115 and 116 in 84% yield and a 7:9 ratio. Beau and co-workers105 reported an alternative route for introducing an aminooxy group at the C-4 position. Pyridinium chlorochromate- (PCC-) mediated oxidation of hydroxyl group of derivative 117 in CH2Cl2 followed by addition of hydroxylamine furnished derivative 118 in 74% yield (Scheme 31). 2.3.4. Modification at C-6. Peri and co-workers proposed a method for introducing an unnatural aminooxy moiety at the C-6 position of the carbohydrate backbone.106−108 A very efficient synthesis of the C-6 aminooxy sugar 121, namely, methyl-6-deoxy-6-aminomethoxy-D-glucoside, was accomplished from a protected sugar derivative by Dess−Martin periodinane- (DMP-) mediated oxidation as a key step in 95% yield. Formation of derivative 121 in 67% overall yield was realized through reactions involving (i) I2-catalyzed detritylation of 119, (ii) oxidation with Dess−Martin periodinane to give aldehyde-containing derivative 120, (iii) nucleophilic attack with O-methylhydroxylamine, (iv) de-O-acetylation under Zemplén conditions, and (v) sodium cyanoborohydride-mediated oxime reduction (Scheme 32). Xie and co-workers reported the synthesis of a new class of glycoaminooxy acids as sugar building blocks bearing both aminooxy and carboxylic acid functional groups by using Mitsunobu reaction (Scheme 33).109 Treatment of derivative 122 with (i) HONPhth in the presence of Ph3P and DEAD,

Scheme 28. Synthesis of C-2 and C-3 Aminooxylated Sugar Derivatives through DMDO Oxidation103

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Scheme 30. Synthesis of C-4 Aminooxylated Gluco- and Galactopyranoside Derivatives76

before glycosylation. Interestingly, the aqueous solubility of neoglycoside 145 was found to be greater in aqueous buffer than that of the natural O-glycoside analogue, thereby leading to increased biological potency. However, the antagonistic activity of derivative 145 on MT2 macrophages showed an efficiency similar to that of the natural analogue (see Figure 7 below). It should be mentioned that similar compounds were obtained by Renaudet and Dumy.113 However, further attempts to reduce the N−O linkage to obtain the resulting amino glycosylated disaccharide failed. In another study, the aminooxy group of derivative 39 (Scheme 11) was utilized to build a bridge between the A and B rings of trisaccharide fragment 132 (Figure 5) of calicheamicin γ1 through nucleophilic attack by the hydroxylamine to the keto group of the A ring in the presence of acid, followed by oxime reduction with sodium cyanoborohydride.86 Core trisaccharide fragment 133 of esperamicin was prepared through the nucleophilic displacement of a sugar triflate by an aminooxy group as a key step, followed by the tetrabutylammonium fluoride- (TBAF-) mediated removal of the (trimethylsilyl)ethoxycarbonyl (TEOC) functionality.18 Other compounds having the same interglycosidic linkage have been obtained using the same strategy (see Figure 8 below).113 Porco and co-workers developed a stereocontrolled synthesis of complex chemical libraries through the utilization of angular epoxyquinol scaffolds.114 Important modifications of the epoxyquinol scaffold were made through the reaction of aminooxy glucose 85 with the ketone group present on the second six-membered ring. In a preliminary biological screening, it was observed that only six molecules (including the glycosylated compound 134) showed significant inhibition of heat-shock protein 72 (Hsp 72) induction (Figure 6). For the construction of pseudoglycopeptides, the synthesis of aminooxy and carboxylic acid moieties containing carbohydrate building block 124 (Scheme 33) was accomplished, and the utility of these precursors was verified through the formation of glycopeptide analogues.109 Coupling of derivative 124 with BocGlyOH amino acid and 6-phthalimido derivative 123 in the presence of diethyl cyanophosphonate (DEPC) and triethylamine afforded sugar amino acid 135 and N-oxyamide-linked disaccharide analogue 136 in yields of 71% and 92%, respectively (Figure 7).

Scheme 31. Synthesis of C-4 Aminooxylated Sugar Derivative 118105

followed by (ii) dihydroxylation with OsO4 and Jones oxidation gave derivative 123 in 44% overall yield. Next, (iii) dicyclohexylcarbodiimide- (DCC-) mediated esterification of phthalimido sugar aminooxy acid 123 and hydrazine-promoted ring opening of the phthalimido moiety afforded desired aminooxylated C-branched sugar ester 124 in 49% yield over two steps. However, the sensitivity of the N−O bond toward hydrogenation conditions did not allow the removal of the benzyl groups once building block 124 had ben introduced into an oligosaccharide structure.110 To circumvent this issue, the same group recently reported the synthesis of the para-methoxybenzyl- (PMB-) protected glycoaminooxy ester 126 through a Mitsunobu reaction with intermediate 125, for the synthesis of N-oxyamide-linked glycolipids (Scheme 34).111

3. MIMETICS OF NATURAL STRUCTURES 3.1. Oligosaccharide Mimetics

Hydrolytically stable carbohydrate analogues represent attractive targets for the development of pharmaceutically relevant agents. For this purpose, a new method for the synthesis of a class of unnatural aminomethoxy-linked oligosaccharide analogues was reported by Peri et al.,107 both in solution and on solid support. For this purpose, aminomethoxy-group-bearing unprotected derivative 121 (Scheme 35) was used to assemble oligosaccharide analogues in aqueous medium. Treatment of derivative 121 with D-glucose, D-galactose, and N-acetylglucosamine furnished the anticipated disaccharide analogues 127− 129 with almost complete stereoselectivity in yields of 82%, 75%, and 80%, respectively (Scheme 35). Similarly, this methodology was extended to construct trisaccharide analogue 130 (see Figure 4) through successive elongation of unprotected derivative 121 by an oxime-based strategy.106,107 Later, the same group reported the synthesis of a β-N(OMe) glycosidic-linked disaccharide mimic of Lipid A antagonist 131 (Figure 4) using a convergent procedure.112 Glycosyl bromide, instead of free reducing sugar, was used here as an effective donor for glycosylation with a hydroxymethyl glycoside. In both building blocks, lipid chains were preinstalled

3.2. Oligomers

Carbohydrate amino acids represent attractive building blocks for the construction of oligomers with diverse properties. In particular, structural studies have demonstrated that the

Scheme 32. Synthesis of C-6 Aminooxylated Carbohydrates106

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Scheme 33. Synthesis of Sugar Aminooxylated Acid Building Blocks109

Scheme 34. Synthesis of Orthogonally Protected Glycoaminooxy Ester 126111

Figure 4. Structures of aminomethoxy glycosidic-linked trisaccharide and disaccharide analogues.112

incorporation of these building blocks into oligomers promotes the formation of intramolecular hydrogen bonds that induce turns and helical structures. These observations led to the development of new foldamers with stable linkages for chemical and enzymatic hydrolysis. For example, peptidomimetics in which the sugar backbone influences the secondary structure of the carbopeptoid chain have been reported.115 Because of the presence of both aminooxy and acid functionalities, glycoaminooxy acids were demonstrated to be promising candidates for the preparation of oxyamide-linked disaccharide and higher oligosaccharide analogues. Thus, the synthesis of oxyamidelinked oligomers 137−141 (Figure 8) was performed through a coupling reactions between D-ribofuranoid glycoaminoxy acid derivatives 10 and 11 (Scheme 3) in the presence of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC)/1-hydroxybenzotriazole (HOBt) in DMF with 81% yield.78 Simultaneously, other homo-oligomers were also obtained by successive coupling steps. Modified oligonucleotides also represent an interesting class of oligomers. N-Oxyamide-linked oligonucleotides are hydrolytically stable oligonucleotide mimics. The first synthesis of Noxyamide-linked dinucleoside derivative 142 (Figure 8) was

Figure 5. Oligosaccharide fragment of natural products.18,86

Figure 6. Structure of the aminooxy-sugar-bearing angular epoxyquinol scaffold.114

performed by coupling nucleoside acid 13 and aminoxy derivative 18 (Scheme 4) in the presence of EDC and HOBt in DMF in 50% yield (Figure 8).79

Scheme 35. Synthesis of N(OMe)-Linked Disaccharides106,107

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used an oxime-based strategy to build a new class of oligoarabinofuranoside analogues of the naturally occurring polysaccharides. For this purpose, aminooxylated monomers 20 and 21 (Scheme 5) were identified as mono- and bivalent monomers for generating dynamic polymers 146 and 147. After deprotection of intermediates 20 and 148 by in situ acidolysis at pD < 1 at 50 °C for 24 h gave the hydrated forms 149 and 150, respectively, which underwent polycondensation under mildly acidic conditions to afford the desired polymers (Scheme 36). The authors next investigated the dynamic character of polymers 146 and 147 by adding 1 equiv of a termination agent (tert-butylhydroxylamine) to the polymers after equilibration. Following the integration ratio between the termination agent and the polymer signals by NMR spectroscopy, they observed a shorter half-life exchange at pD = 4 (244 min for 146 and 164 min for 147) than at pD = 6 (5440 min for 146 and 2410 min for 147), with an initial monomer concentration of 20 mM. The dynamic nature of these oligosaccharide analogues showed slower exchanges at pD = 6, whereas a rate increase occurred at the slightly acidic pD (4−5), thus allowing the polymer composition to be modified by controlling the incorporation and removal of new moieties. Synthetic glycopolymers have emerged as promising targets for a diverse range of medicinal applications. Taking advantage of a regioselective chemoenzymatic oxidative approach, Wang and co-workers prepared a series of low-molecular-weight hydrolytically stable glycopolymers in a highly efficient and straightforward way.120 This strategy relies on the utilization of galactose oxidase (GO) to mediate the oxidation of primary hydroxyl group of aminooxygalactose 62 (Scheme 17) to the corresponding aldehyde, leading to subsequent in situ polymerization by oxime formation. The reaction was carried out in an aqueous phosphate buffer at pH 5.5 in the presence of GO. Low-molecular-weight C-6 oxime-linked glycopolymer 148 (4000−8900 MW) was thus obtained with a polydispersity between 1.7 and 2.1 (Scheme 37).

Figure 7. Structures of aminooxy-sugar-acid-bearing mono- and disaccharide analogues of sugar amino acid 135.109

Figure 8. Structures of the N-oxyamide-linked furanoid oligosaccharide mimetics.78,79

Jagadeesh and co-workers utilized a strategy developed by the Tronchet group to obtain β-aminooxy furanoid sugar acids.116 Such unnatural building blocks have been used as nonpeptide scaffolds for the development of oligopeptides, namely, “foldamers” in peptidomimetics. In this regard, βaminooxy furanoid sugar acid 10 (Scheme 3) was used as a monomer for the construction of oligopeptides 143 and 144. Further, structural studies revealed that the presence of unusual N−O linkages tune the conformational geometry more specifically toward a preferred folding organization (145). Density functional theory (DFT), nuclear magnetic resonance (NMR), and molecular dynamics (MD) studies suggested the preference of 5/7 intramolecular hydrogen-bonded rings over 9-helical turns (Figure 9). The dynamic behavior of supramolecular polymers plays a pivotal role in a wide range of biological phenomena.117−119 Ruff and Lehn38 investigated the synthesis and characterization of various monomers capable of establishing reversible linkages in dynamic polymers, leading to so-called biodynamers. They

3.3. Glycoprotein Mimetics

Chemical manipulation of cell-surface glycans, called glycoengineering, is an attractive strategy for obtaining insight into the roles and functions of glycoconjugates. In this area, mucins represent a class of major interest. They play important roles in cell−cell communication and immunogenic responses, and they deeply influence the structure and stability of the protein in which they are expressed.121 In addition, their O-linked sugars are displayed on a polypeptide backbone that exhibits a rodlike extended conformation. Therefore, mimetics of mucins represent interesting tools for the study of this class of cellsurface glycoconjugates and secreted proteins. To this end, Bertozzi and co-workers63,94 exploited the simplicity of the oxime-based strategy to construct neoglycopeptide analogues through convergent oxime condensation between unprotected peptides bearing unnatural keto groups and aminooxy sugars. They chose two fragments of the endothelial mucin GlyCAM-1 and replaced six Ser or Thr residues with modified amino acid 149 displaying keto groups to react with aminooxy-Tn (69, Scheme 19) and aminooxy-STn (75, Scheme 20) antigens. The reactions were performed in the presence of 1 M NaOAc buffer (pH 5.5) at 37 °C for 24 h to afford compounds 150 and 151, respectively (Scheme 38).94 A similar strategy was described by the same group to obtain an oxime-linked neoglycopeptide analogue of drosocin, a

Figure 9. Structures of the aminooxy sugar and corresponding homooligomers designed by Jagadeesh and co-workers.116 N


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Scheme 36. Generation of Dynamic Polymers 146 and 14738

Scheme 37. Synthesis of β-Aminooxygalactose-Linked Glycopolymers120

Scheme 38. Synthesis of Mucin Mimics 150 and 151 Containing Tn and STn Antigens94

disaccharide 71 (Scheme 19) with the C-6 aldehyde-GalNAc residue of glycopeptide 152 gave the corresponding neoglycopeptides 153−155 in higher yields than 80%. Oxime ligation was performed in the presence of acetate buffer (100 mM, pH 5.5) at 37 °C for 24 h. This approach enables the steric hindrance problems often associated with the formation of sugar−peptide bonds within oligosaccharides to be overcome (Scheme 39).

glycosylation-dependent bacteriostatic agent. They showed how the retained biological activity of the neoglycopeptide compared to the native form allows for the replacement of the natural sugar−peptide linkage with an oxime bond.92 In another study,93 the same group investigated the use of oxime ligation to build an O-linked glycopeptide containing oligosaccharide analogues with native sugar−peptide linkages. A convergent strategy featuring oxime ligation between aminooxy monosaccharides 62 and 70 and aminooxy O


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Scheme 39. Chemoselective Synthesis of O-Linked Neoglycopeptides with Native Sugar−Peptide Linkages93

Figure 10. (a) Structure of oxime-linked C18 lipid-conjugated mucin mimic, (b) schematic representation of mucin mimic, and (c) model representation of CNTs with self-assembled synthetic mucin mimic glycosylated polymers.122

GalNAc moiety with β-GalNAc gave C18-β-MM-SWNTs that were unable to bind HPA, thus unequivocally demonstrating the anomeric sugar stereoselectivity. Specific interactions between modified CNTs and living cells have interesting potency for biological applications. Thus, the interactions between previously reported C18-terminated αGalNAc glycopolymers (C18-α-MM-CNTs, Figure 10c) and cells were realized by the same group by fluorescence microscopy and flow cytometry analyses.123 A highly efficient convergent route for the preparation of mucin mimetic-functionalized glycopolymers with suitable hydrophobic tails was elaborated by Bertozzi and co-workers; these glycopolymers were next incorporated into synthetic lipid bilayers.124 The introduction of a terminal phospholipid tail onto a methyl vinyl ketone- (MVK-) derived keto polymer gave key intermediate 156, which was demonstrated to be a suitable precursor allowing the incorporation of mucin mimetics into artificial supported bilayers. The coupling of derivative 156 with 2.8 equiv of compounds 69 (Scheme 19), 82 (Scheme 22), and 66 (Scheme 18) along with 0.03 equiv of fluorescent probe Texas Red hydrazide in a water/acetonitrile (3:1) mixture in the presence of 0.1% of acetic acid at 95 °C for 96 h gave glycopolymers 157, 158, and 159, respectively. Biophysical characterizations indicated fluid behavior similar to that of membrane-associated proteins. The authors next assessed the recognition ability of mucin mimics 157 and 158 toward lectins HPA and Bauhinia purpurea agglutinin (BPA). The second lectin is specific for βGalNAc and does not interact with αGalNAc, unlike HPA. After incubation of mucin mimetic 156

Appropriate functionalization of carbon nanotubes (CNTs) with biomolecules provides access to numerous applications in materials science and biology by increasing their aqueous solubility. Bertozzi and co-workers modified CNTs using glycosylated polymers, designed to mimic cell-surface mucins (Figure 10).122,123 The strategy consisted in the chemoselective ligation of aminooxy α-GalNAc moieties to the poly(vinyl methyl ketone) backbone of the polymer through oxime bond formation to give a 75000 g/mol mucin mimic, which was subsequently functionalized with a C18 lipid fragment at one end of the polymer backbone. Single- and multiwalled carbon nanotubes (SWNTs and MWNTs, respectively) were lipidfunctionalized by ultrasonication in the presence of an aqueous solution of the C18-functionalized mucin mimic bearing αGalNAc residues (C18-α-MM). Characterization of the CNTs was performed using atomic force microscopy (AFM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). AFM experiments highlighted the mucin coating and the uniform tube diameter of 65−70 nm. SEM and TEM analyses also provided evidence of the mucin coating. According to TEM, a coating thickness of 10−25 nm was obtained. The binding efficiency of C18-α-MM-functionalized nanotubes (C18-α-MM-SWNTs) was next assessed toward the lectin Helix pomatia agglutinin (HPA). C18-α-MM-SWNTs were incubated with a solution of HPA conjugated to fluorescein isothiocyanate (FITC), and the bound lectin was analyzed by fluorescence spectroscopy. HPA−FITC labeling of the C18-α-MM-SWNTs was inhibited when 0.2 M free GalNAc was present in solution; moreover, replacement of the αP


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carbohydrate epitope is accessible for recognition by protein receptors (Scheme 40). Homogeneously glycosylated proteins are important targets for fundamental studies of glycosylation-dependent protein folding and stability and biological processes. Approaches that rely on glycosidases to convert heterogeneous natural glycoprotein into a simple homogeneous core are limited, because of the predetermination of the primary glycosylation sites imposed by the cell line in which the protein is expressed. Direct chemoselective methods to modify proteins with saccharides would greatly facilitate this task. Schultz and coworkers exploited the site-specific incorporation of unnatural amino acids into proteins directly in living cells128 to introduce the keto-containing amino acid p-acetyl-L-phenylalanine, which is prone to react with aminooxy saccharide derivatives. The authors explored two routes for generating glycoprotein mimetics 161−163 (Scheme 41). In route A, aminooxy GlcNAc 70 (Scheme 19) was first coupled with the Z domain of the staphylococcal protein A, modified with a keto group (160) in the presence of aqueous sodium acetate buffer (pH 5.5) to afford derivative 161 in 95% yield, which subsequently underwent enzymatic glycosylation with uridine diphosphate galactose upon treatment with β-1,4-galactosyltransferase in N2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid buffer system to give compound 162 in 60% yield. Further, a similar sequence of α-2,3-silyltransferase attachment with CMP-sialic acid furnished derivative 163 in a 65% yield. Alternatively, employing convergent route B, featuring a condensation between aminooxy analogue 164 and 165 with the Z-domain protein derivative 160 in the presence of aqueous sodium acetate buffer (pH 5.5) gave glycoproteins 162 and 163 with yields of 76% and 60%, respectively. Aminooxy analogues 164 and 165 were synthesized starting from aminooxy GlcNAc 70 through a stepwise glycosylation under enzymatic conditions as described above in 70% and 80% yields, respectively. Still with the same objective, Bertozzi’s group exploited the aldehyde tag method95 to combine the synthetic aminooxy SLex 166 with recombinant human growth hormone (hGH) containing two aldehyde tags at the C- and N-termini. Oxime coupling between 166 and aldehyde-tagged hGH to give glycoprotein 167 (Scheme 42) was found to be more efficient using a sodium citrate buffer at pH 3.5, improving the conjugation efficiency from 20% to 25% to 64% compared to the previous conditions (5% aqueous MeCN with 0.02% formic

or 157 or no polymer with FITC-labeled lectin, membraneassociated fluorescence was quantified by microscopy. The results confirmed the specificities of the lectins, indicating structural similarities between these mucin mimetic polymers and natural mucins. Bertozzi and co-workers further investigated the biophysical behavior of their oxime-linked mucin-mimetic glycopolymers featuring additional hydrophobic groups (Figure 11) on living

Figure 11. Structures of oxime-linked mucin mimic glycopolymers.125,126

cells.125,126 Fluorescence correlation spectroscopy (FCS) experiments highlighted the role of the end-functional hydrophobic group for correct incorporation into ldlD CHO cell membranes, whereas the glycan structure seemed to be irrelevant in terms of incorporation and diffusion phenomena. Nevertheless, flow cytometry and fluorescence miscoscopy experiments assessed the capability of the membrane-associated mucin mimics to interact specifically with the HPA lectin. In another report, the same group127 described a general strategy for engineering the display of nascent neoglycoconjugates on cell surfaces. The intrinsic substrate promiscuity of the enzymatic sialyltransferase biosynthetic pathway was exploited to perform the conversion of the unnatural derivative Nlevulinoylmannosamine (ManLev) to the ketone-containing Nlevulinoyl sialic acid (SiaLev). The keto function was subsequently reacted with aminooxygalactose 62 (Scheme 17) to obtain the chemically defined oligosaccharide epitope, and the remodeled HeLa and Jurkat cells acquired the ability to bind the ricin lectin, thus demonstrating that the novel

Scheme 40. Glycoengineering of Cell Surface Glycoprotein by ManLev with the Ensuing Aminooxygalactosylation of the Sialic Acid Analog by 62127

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Scheme 41. Synthesis of Oxime-Linked Glycoprotein Conjugates128,129

antiparallel β-sheet constrained by two L-proline−glycine βturns and stabilized into a locked and rigid conformation by intramolecular hydrogen bonds.131 Conjugations with binding entities are commonly accomplished through anchoring sites provided by orthogonally protected lysine side chains that are pointed outward on both sides of the platform, thus preventing undesired steric hindrances among the assembled moieties.132−134 Synthetic multivalent glycostructures represent attractive molecular tools for diverse applications in glycosciences.9 RAFT cyclopeptides have been used by Renaudet and Dumy over the past decade135 for this purpose. A straightforward oxime-ligation strategy was developed from scaffold 168 displaying four oxoaldehyde groups on lysine side chains that was prepared by using both solid-phase and solution-phase strategies (Scheme 43). Chemoselective ligations with both the series of β- and α-aminooxy carbohydrates in the presence of sodium acetate buffer (pH 4.0) afforded the desired tetravalent glycoclusters 169−172 and 173−177, respectively, which were isolated by reverse-phase high-performance liquid chromatography (RP-HPLC) in excellent yields and purities. Further evaluation of the mannosylated glycocluster 175 using fluorescence anisotropy revealed a modest 20-fold increase in binding potency compared to the corresponding monovalent control, with a half-maximal inhibitory concentration (IC50) value of 62 μM to concanavalin A (from Canavalia ensiformis, ConA). Recently, the binding potencies of previously reported oxime-linked tetravalent glycoclusters 169, 176, and 177 (Scheme 43) were compared with those of their triazole-linked analogues.136 The inhibitory potencies of both the oxime- and triazole-linked glycoclusters were investigated by enzyme-linked lectin assay (ELLA) with Con A and Ulex europaeus I agglutinin (UEA-I), a vegetal lectin specific for fucose. Interestingly, no significant difference in inhibition was observed between the two series and Con A. In contrast, oxime-linked derivative 177 showed a 16-fold increase in binding affinity with UEA-1 (IC50

Scheme 42. Structure of the Oxime-Linked Glycosylated SLex-hGH Conjugate95

acid). In 2014, the same group applied the aldehyde tag technique to perform chemoenzymatic glycosylation on the crystallizable fragment (Fc) of IgG.130 Finally, chemical modification of peptide libraries obtained by phage display represents a straightforward method for elucidating a variety of non-natural moieties. Derda and coworkers produced a library of 108 peptides containing aldehyde functionalities within 30 min through the NaIO4-mediated oxidation of the Ser and Thr residues, which could be readily derivatized using aminooxy-containing ligands.68

4. MULTIVALENT STRUCTURES 4.1. Glycoclusters

Over the past few decades, regioselectively addressable functionalized templates (RAFTs) have been recognized as versatile scaffolds for the attachment of biomolecular ligands on two addressable domains. RAFTs are composed of an R


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Scheme 43. Structures of Oxime-Linked Multivalent Glycoconjuagtes135

Figure 12. Structures of (a) labeled Cu(I)-chelating multivalent glycocluster140 and (b) labeled multivalent vector for hepatocytes.141

Scheme 44. Structure of the Aminooxylated Divalent Cluster89,142

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Scheme 45. Synthesis of Tetravalent O-Linked Glycoconjugates 183−188143

Scheme 46. On-Bead Synthesis of Oxime-Linked Neoglycoconjugates144

value of 1 μM) compared to the triazole-linked analogue. More impressive linker effects were observed with the wheat germ agglutinin (WGA) β-GlcNAc-terminated tetravalent glycoclusters and thioether linker.137 The same group designed series of labeled glycoclusters based on sequential attachment of various aminooxy sugars through an oxime bond onto the upper domain of the scaffold, having preinstalled either a biotin or a fluorescein molecule on the lower face, both in solution138 and in the solid phase,139 without mentioning biological properties. Aiming to decrease the intracellular copper concentration in the liver, Delangle and co-workers designed a cysteine-based glycoconjugate wherein clusters of α-GalNAc were assembled onto a cyclopeptide scaffold through oxime ligation to target asialoglycoprotein receptors (ASGP-R).140 This glycocluster also contained two cysteines oxidized to disulfide bridge to chelate Cu(I) and a D-lysine to attach fluorescent probe 178 (Figure 12a). Binding studies with HepG2 and WIF-B9 cells showed the efficient uptake of this derivative by hepatocytes. More interestingly, these studies clearly revealed a decrease of the intracellular copper concentration under conditions of metal excess, particularly in the WIF-B9 cell line. Further flow cytrometry experiments with compound 179 (Figure 12b) highlighted that this effect can be attributed to a dissociation constant in the nanomolar range, suggesting that such compounds have a promising potential for drug delivery in the liver.141 Amine-terminated bivalent sugar ligands have been used as promising intermediates in glycodendrimer synthesis.89 Efforts were undertaken to synthesize the fluorescent cluster glycoside 181 (Scheme 44) through ring opening of the succinimidyl moiety of derivative 54 (Scheme 17) in the presence of tris(2aminoethyl)amine, to give the divalent cluster in nearly quantitative yield. The authors reported that, even in the presence of a large excess of succinimide 54, no trisubstituted

product was observed. Finally, addition of primary amine 180 to fluorescein isothiocyanate (FITC) in a methanol/THF mixture gave glycoprobe 181. Recently, Dhavale and co-workers reported the synthesis and recognition properties of a series of oxime-based clusters grafted on a 314-helical peptide scaffold.143 The tetravalent βgalactopeptide 182 represents the site-specific key intermediate that underwent oxime bond formation by reacting with aminooxy sugars α-Gal-ONH2 83, α-Glc-ONH2 84, α-ManONH2 86, β-Glc-ONH2 85 (Scheme 22), β-Gal-ONH2 62 (Scheme 17), and β-Lac-ONH2 66 (Scheme 18). The reactions were performed in 0.1 M sodium acetate (AcONa) buffer at pH 4.1 for 24 h to provide glycoconjugates 183−188 in 90−95% yields (Scheme 45). Circular dichroism (CD) spectra confirmed a 314-helical conformation for all glycoconjugates, and fluorescence anisotropy experiments showed that tetravalent mannopeptide 185 reached a 6.5-fold binding enhancement per glycan toward ConA compared to the mannose monomer. 4.2. Immobilization of Glycoclusters on Solid Supports

A fully solid-phase synthesis of glycocyclopeptides and their onbead recognition with diverse lectins were also reported by Renaudet and Dumy.144 The strategy included the head-to-tail cyclization of linear decapeptide 189 with D-glutamic acid as the attachment site of TGR resin beads and lysines protected by an N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) group. Final incorporation of aminooxy sugars 66 (β-LacONH2, Scheme 18), 69 (α-GalNAc-ONH2, Scheme 19), and 86 (α-Man-ONH2, Scheme 22) was performed by an oximebased strategy onto the solid-supported cyclopeptide scaffold presenting four glyoxyaldehyde groups to give derivatives 190− 192 (Scheme 46). On-bead recognition of these compounds with specific lectins showed increased binding efficiency with tetravalent T


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Figure 13. Oxime-linked multivalent neoglyconjugates immobilized in a capillary tube.147

Figure 14. Oxime-linked fucose-terminated glycoconjugates.152

Figure 15. General structures of oxime-linked neoglycodecapeptides based on a cyclopeptide scaffold.153−156

glycoconjugates 190 and 192 compared to the monovalent analogues, whereas GalNAc-terminated derivative 191 and its monovalent control exhibited similar affinities. Electrochemical impedance spectroscopy145 experiments with immobilized oxime-linked biotinylated lactoclusters on polypyrrole films and the lectin from Arachis hypogaea (PNA, galactoside-binding lectin) showed similar binding properties. In addition, nanogravimetry (quartz crystal microbalance with dissipation monitoring, QCM-D) and surface plasmon resonance (SPR)

studies on gold surfaces allowed the determination of kinetic and thermodynamic parameters of the binding process.146 Lab-in-a-capillary devices were recently identified as efficient alternatives to lab-on-a-chip devices for several biological applications. Among them, one interesting application is the detection of bimolecular movement inside capillary tubes. For this purpose, Defrancq and co-workers designed an efficient method for immobilizing glycoclusters inside glass capillaries.147 Derivative 193 (Figure 13), displaying a cluster of oxime-linked mannose residues at the upper face of the U


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Figure 16. Structures of oxime-linked heteroglycoclusters.159

assays with adhesion/growth-regulation human galectins and plant toxins showed promising inhibitory activity, thereby reflecting that the valency, density, and defined topological presentation need to be finely tuned. Later, another class of glycodendrimers displaying different aminooxy sugars was developed by the same group by employing a similar strategy.155 The authors self-condensed cyclopeptides and prepared similar structures with the polylysine core using a divergent approach. The binding potencies of the resulting compounds were investigated with different lectins. In particular, studies with LecB, a specific lectin for L-fucose produced by Pseudomonas aeruginosa, were performed using competitive ELLA tests and isothermal titration calorimetry (ITC) studies with both the α- and βfucose-terminated glycodendrimers.155 Among all of the tested molecules, compound 201, featuring α-linked L-Fuc residues and having a more flexible geometry, showed the highest binding affinity (IC50 value of 0.6 nM) in comparison with the other glycodendrimers. ITC experiments indicated a binding constant of 28 nM and a stoichiometry with a ligand-toreceptor ratio at 1:6. This observation was further rationalized using molecular dynamics simulations, which led the authors to suggest that the high affinity observed might be due to an aggregative chelate binding mode. Such synthetic multivalent ligands might represent an attractive alternative to traditional antibiotic treatments against P. aeruginosa infections. To evaluate the potential of the divergent and iterative protocol mentioned above, the same group synthesized series of 64-valent cyclopeptide-based glycodendrimers.156 The synthesis of cyclopeptide-core glycodendrimers was achieved by successive oxime ligation, serine oxidation, and final attachment of 64 copies of aminooxy sugars, namely, α-Man-ONH2 (86, Scheme 22) and α-Fuc-ONH2 (103, Scheme 26), on the periphery of the scaffolds. As observed previously with hexadecavalent structures, the mass spectrometry (MS) characterization of such compounds was found to be impossible because of the fragmentation of the oxime linkage during the analysis. To confirm the exact number of sugar residues, the authors finally used diffusion-ordered spectroscopy (DOSY) and circular dichroism (CD) experiments. Lectin-binding

cyclopeptide scaffold and a methyl ketone at the lower face, was synthesized from aminooxy mannose 86 (Scheme 22). Immobilization in the capillary tube was performed by oxime ligation to give the functionalized surface 194. Binding efficiency was studied with FITC-labeled ConA. Analysis of the fluorescence inside the capillary tube revealed specific immobilization of carbohydrates and thereby validated the efficiency of this methodology. To close this section, one should note that a few glycoarrays based on the immobilization of reducing glycans onto aminooxylated surfaces have been published.148−151 This approach is not discussed further in this review. 4.3. Glycodendrimers

Glycodendrimers are branched glycosylated structures of high interest for the study of multivalent interactions or the prevention of pathogen infections. The syntheses of first- and second-generation bivalent and tetravalent α-L-fucose-terminated oxime-linked dendrons have been reported.152 Compounds 195 and 196 were prepared by the condensation of aminooxy fucose 103 (Scheme 26) to methyl ketonefunctionalized dendrons in citrate buffer. The authors suggested that the terminal double bond could be used for further moficiation by thiol−ene coupling (Figure 14). It is now well-known that the optimal biological potency of a synthetic glycoconjugate mainly relies on its valency, density, and topological architechure. To assess the importance of peripheral sugar headgroups in protein binding avidity, Renaudet’s group employed a divergent and iterative strategy based on oxime ligation to prepare cyclopeptide-based glycodendrimers, namely, dendri-RAFTs.153−155 The iterative strategy consisted on the initial conjugation of serinefunctionalized polylysine denron onto a cyclopeptide core. Subsequent serine oxidation afforded clusters of aldehyde groups, which were then functionalized with aminooxy carbohydrates, namely, α-Gal-ONH2 (83, Scheme 22), β-LacONH2 (66, Scheme 18), α-TF-ONH2 (90, Scheme 23), αMan-ONH2 (86, Scheme 22), α-Fuc-ONH2 (103, Scheme 26), and β-Fuc-ONH2 (104, Scheme 26) to afford hexadecavalent derivatives 197−208 (Figure 15a). Preliminary lectin-binding V


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range of heterofunctionalized glycoconjugates (215, 216) were thus prepared through a protocol combining oxime ligation, CuAAC reaction, thiol−ene coupling, thiol−chloroacetyl coupling, amide coupling, and/or disulfide bond formation. The tetravalent glycosylated platform displaying oxime-, thioether-, triazole-, and thioacetyl-linked sugar motifs, 214, was first synthesized in either a stepwise or a sequential one-pot fashion. Furthermore, this tetravalent scaffold was further functionalized with a diverse set of biomolecules such as biotin, fluorescein (through an amide bond), a poliovirus peptide fragment (through disulfide bond formation), and CpG (tolllike receptor) oligonucleotide (OL) to afford heteroglycoconjugates 215 and 216. In addition, through a convergent strategy based on oxime ligation, synthesis of a hexadecavalent heteroglycocluster 217 was also accomplished (Figure 18).

assays were next evaluated using ELLA tests with Con A and UEA-1 for derivatives 209 and 210, respectively, in comparison with compounds with lower valency (Figure 15b). Binding of α-mannose-terminated glycodendrimer 209 to Con A showed a modest improvement. By contrast, derivative 210 showed a nanomolar IC50 value and a 40000-fold higher binding potency than the monosaccharide, which corresponds to a 625-fold increase in inhibition per sugar unit. 4.4. Heterofunctionalized Scaffolds and Orthogonality

Heteroglycoclusters (hGCs) represent relevant classes of molecules for mimicking the expression of heterogeneous carbohydrates in biological environments. Renaudet and coworkers described a randomized combinatorial strategy to synthesize libraries of neoglycoconjugates that differed in terms of the compositions and relative positions of glycans on a synthetic scaffold.157,158 For example, tetravalent hGCs comprising sugars and amino acids were prepared and screened with ConA by affinity chromatography. SPR experiments demonstrated that the presence of hydrophobic amino acids, such as tyrosine, together with mannose enhanced the binding affinity toward Con A. It was hypothesized that the increased binding affinity arose from secondary hydrophobic interactions. However, to avoid problems related to the separation of regioisomers of this randomized approach, the same group designed orthogonal chemoselective processes to construct similar types of hGCs in a controlled manner.159 By combining both oxime ligation and the copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction, a cyclopeptide scaffold containing two aldehyde and two azide groups was functionalized with aminooxylated and then propargylated carbohydrates. This protocol thus led to the synthesis of new series of 2:2 and 3:1 hGCs (e.g., 211 and 212) comprising α-Man, αFuc, and β-Lac in excellent yields and purities (Figure 16). More sophisticated combinations of chemoselective ligation have given access to multifunctional glycosylated compounds. Boturyn and co-workers reported the use of orthogonal oxime ligation and the CuAAC reaction in a successive one-pot fashion to prepare multivalent cyclic RGD glycoconjugate (Figure 17).160 Glycoconjugate 213 was thus prepared from the aminooxy glucoside 85 (Scheme 22) by oximation followed by thiol−maleimide coupling of the KLA peptide and the CuAAc reaction of the cycloRDG bearing an azide function. Later, the same group reported the first multiclick approach involving up to five different coupling reactions.161 A diverse

4.5. Carbopeptides

The utilization of the carbohydrate backbone as a molecular scaffold for the de novo design of artificial three-dimensional macromolecules, namely, carbopeptides, has emerged as subject of interest in the area of bioorganic chemistry. Brask and Jensen first reported an interesting use of an aminooxy-functionalized methyl α-D-galactopyranoside as a molecular template for this purpose (Scheme 47).162 Treatment of methyl α-D-galactoside with Nβ-Boc-aminooxy acetic acid (Nβ-Boc-Aoa-OH) and N,N′-diisopropylcarbodiimide (DIPCDI) in pyridine/CH2Cl2 (1:1) in the presence of DMAP afforded the protected tetravalent derivative 218. Removal of the Boc groups furnished aminooxy precursor 219 bearing four aminooxy functionalities, which underwent an oximation reaction with a slight excess of C-terminal aldehyde of peptide (H-Ala-Leu-Ala-Lys-Leu-GlyGly-CHO) to give derivative 220. Furthermore, 1H NMR spectroscopy studies of compound 220 revealed that pyranose retained its 4C1 conformation. Improved activity and specificity of an antimicrobial peptide primarily relies on both the length and the charge of its amino acid sequence. The multivalent presentation of the peptides was also demonstrated to be essential for bioactivity. Toward this aim, Jensen, Planas, and co-workers used the oxime-ligation method to assemble multiple copies of antimicrobial peptides onto a carbohydrate skeleton functionalized with aminooxy linkers (Figure 19).163 The peptide sequences KKLFKKILKYLNH2 (BP100) and KKLfKKILKYL-NH2 (BP143) were functionalized with aldehyde groups to cyclodithioerythritol and D-galactose aminooxylated scaffolds to furnish carbopeptide conjugates 221−223. The antibacterial potencies of derivatives 221−223 were verified against the plant and human phytopathogenic bacteria. The study showed that all of the carbopeptides 221−223 exhibited significant bacterial growth inhibition compared to their monovalent analogues. Surprisingly, BP100-functionalized di- and tetravalent derivatives 221 and 223 were up to 8 times more efficient against human phytopathogenic bacteria than the monovalent control. The synthesis of a mono- and tetravalent carbopeptides 224−226 by a similar strategy and the elucidation of their structural features using CD and NMR spectra were also reported by the same group. Interestingly, derivative 226 exhibited a 4-α-helix bundle structure as confirmed by the CD spectrum and H−D exchange experiments, whereas derivative 225 showed a higher degree of α-helicity (Figure 19). 4.6. Synthetic Vaccines

Glycoclusters displaying tumor-associated carbohydrate antigens in association with peptide antigens have the potential to

Figure 17. Aminooxy-carbohydrate-functionalized neoglycopeptide.160 W


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Figure 18. Aminooxy-carbohydrate-functionalized heteroglycoclusters.161

Scheme 47. Synthesis of Oxime-Linked Carbopeptides162

induce potent immune responses against cancer cells.164 In this context, Renaudet and co-workers developed an oxime-based approach to functionalize both addressable domains of the cyclopeptide scaffolds with a combination of sugars and oxoaldehyde peptides.165 The resulting vaccines comprised the aminooxylated Tn antigen 69 (Scheme 19) as a B-cell epitope and a peptide sequence from the type 1 poliovirus as CD4+ helper T-cell in a cyclopeptide scaffold. This scaffold displayed four serine residues as masked glyoxylyl aldehyde functions and one or two copies of aminooxy acetyl groups to ligate the poliovirus (PV) peptide aldehyde through the oxime-

ligation method.166 Further immunization experiments with glycoclusters 227 and 228 in mice showed that both of the derivatives elicited Tn-specific immunoglobulin G (IgG) antibodies that recognized native Tn expressed on human cancer cells (Figure 20a).166 It should also be mentioned that only 0.1% of the antibodies were directed against the scaffold itself, which confirms the potential of cyclopeptide as a carrier for the development of cancer vaccine candidates. This encouraging study prompted the same group to develop another generation of four-component vaccine candidates (229) with improved immunological properties (Figure X


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Figure 19. Structures of the oxime-linked carbopeptide conjugates described by Jensen, Planas, and co-workers.163

Figure 20. Structures of oxime-linked multivalent cyclopeptide-based vaccine candidates.166−169

Figure 21. Structures of PS A1 230 and Tn−PS A1 231 conjugates.170,171

20b).167−169 These new constructions display a cluster of Tn antigens linked by an oxime linkage, a helper T-cell peptide epitope (PADRE) in line with a cytotoxic T-cell peptide epitope (OVA257-264), and a TLR-2 agonist (palmitic acid) to induce both humoral and cellular responses without the need for an external adjuvant. More interestingly, immunological studies in mice indeed showed potent tumoral regression and a

strong increase in survival. Further investigations of immunological mechanisms demonstrated that the position of the palmitic tail in the peptide has a significant impact on the magnitude of the responses by B-cell and cytotoxic T lymphocytes, presumably because of different cross-presentation pathways.169 Y


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Figure 22. Structures of α-and β-aminooxylated oligonucleotide glycoconjugates.176,179

more efficient and practical method. Coupling between the aminooxy derivatives of α-GalNAc (69, Scheme 19), α-Man (86, Scheme 22), β-Gal (62, Scheme 22), and β-Glc (85, Scheme 22) with an oligonucleotide having 5′-CHO group anchored through a phosphoramidite moiety in phosphate buffer at pH 4 afforded conjugates 232−235 (Figure 22).176−179 These oxime-linked glycoconjugates were found to be hydrolytically stable when incubated with phosphate buffer at pH values of 4 and 7 over a period of 72 h at 37 °C. Assessments of the thermal degradation stabilities of conjugates 232−235 indicated that the melting temperatures (Tm) remained identical to those of unmodified oligonucleotide analogues, which reflects the effectiveness of the ligation strategy. In a subsequent report, the same group extended the oximation procedure to prepare a similar class of carbohydrate−oligonucleotide conjugates using an oligonucleotide bearing a 3′-CHO group. Likewise, α-Man-ONH2 (86, Scheme 22) was conjugated with 3′-modified undecamer (5′CGCACACGC3′)−O−CH2CHO under conditions similar to those described above to afford derivative 236 (Figure 22).176,180 The authors anticipated that these new classes of bioconjugates might target dendritic cells. Later, the same group described the incorporation of aminooxy carbohydrates at both the 3′- and 5′-termini of an oligonucleotide displaying a dialdehyde through a successive oxime-condensation strategy to give 237 and 238 (Figure 22).178 Another example of biglycosylated oligonucleotide conjugates was achieved by combining both oxime ligation and the CuAAC reaction.181 Oligonucleotide derivative 239 functionalized with 3′-aldehyde and 5′-alkyne groups was conjugated with aminooxy-β-lactose and azido glucose according to route A or route B in Figure 23 to afford derivative 240 in 50% yield. Interestingly, route A, involving

Zwitterionic polysaccharides such as the PS A1 motif are tetrameric repeating sugars units (∼120 units) carrying an electrostatic charge that adopt an α-helical secondary structure in solution. When conjugated with tumor-associated carbohydrate antigens (TACAs), these structures can elicit MHC-II activation for a T-cell-dependent immune response without using any carrier proteins. Along these lines, the Tn antigen was conjugated to PS A1 230 by Andreana’s group and used for immunizations on 22C57BL/6 mice to determine antibody specificity.170,171 In this study, Tn−PS A1 conjugate 231 was obtained from 230 (Figure 21) by sequential NaIO4-mediated oxidation of the vicinal diol and oxime ligation with aminooxy Tn antigen 69 (Scheme 19). Immunization data showed that oxime-linked Tn−PS A1 conjugate 231 elicited a 200-fold increase in antibody production in the absence of an immune adjuvant compared to 230. Moreover, the conformational behavior was monitored by circular dichroism (CD). The CD spectra of pure PS A1 motif 230 and Tn−PS A1 conjugate 231 were compared, and the results revealed that the presence of the Tn antigen with the PS A1 polysaccharide fragment altered the α-helical secondary structure of the conjugate without hindering the immune response.

5. MISCELLANEOUS APPLICATIONS 5.1. Carbohydrate−Oligonucleotide Conjugates

Synthetic carbohydrate−oligonucleotide conjugates are subjects of interest for many biological applications.172 For instance, the presence of a sugar unit increases the poor cellular uptake efficiency, stability against nucleases, and specific delivery of oligonucleotides.173,174 Among other synthetic routes developed so far,175 it was demonstrated that the utilization of aminooxy sugars by the oxime-ligation protocol represents a Z


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5.2. Enantioselective Catalysis

Because of the presence of polyfunctional hydroxyl groups, carbohydrate-based chiral ligands are employed for transitionmetal catalysis in bioinorganic chemistry. In 2001, Brunner et al. reported the covalent conjugation of various aminooxy βglucose and β-galactose derivatives, 85 (Scheme 22) and 62 (Scheme 19), with heterocyclic aldehydes through oxime bond formation (Scheme 48).184,185 Condensation was performed under acidic conditions (0.1 equiv of HCl) in H2O/THF to afford the hydrolytically stable ligands 244−247 in good yields and purities. Similarly, synthesis of bivalent ligands 248 and 249 was also accomplished from derivative 244 using dialdehyde under identical reaction conditions. These ligands were tested for transition-metal-catalyzed reactions, such as palladium-mediated allylic alkylation and hydrosilylation and transfer hydrogenation reactions.185 First, in the reaction of 1,3-diphenylallyl acetate with dimethyl malonate, none of the chiral ligands were able to show efficient catalytic activity. This is presumably due to the inability of the oxime ether group to bind with Pd metal. In contrast, ligand 244 exhibited the highest catalytic efficiency in the rhodium-catalyzed hydrosilylation of acetophenone with diphenylsilane. In another report, the same group utilized aminooxy β-glucose 85 (Scheme 22), β-galactose 62 (Scheme 22), D-maltose 65 (Scheme 18), and D-lactose 66 (Scheme 18) along with their acetylated analogues for coupling with various heterocyclic and aromatic-ring-bearing aldehyde groups.91 Oxime derivatives 250a−d, 251a−d, 252a−d, and 253a−d and their acetylated analogues were obtained by condensation between aminooxy sugars and the 2-carbaldehyde of 2diphenylphosphanyl benzene, pyridine, pyrrole, and phenol, and the resulting conjugates were tested as catalysts for the enantioselective hydrogenation of folic acid into 5,6,7,8tetrahydrofolic acid (which is spontaneously converted into 5formyltetrahydrofolic acid because of its light and air sensitivity) in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer {[Rh(COD)Cl]2} as a metal procatalyst (Figure 26). The results showed that the acetylated analogue of pyridine derivative 251b exhibited highest efficiency compared to other derivatives, with a turnover of 64% and a stereoselectivity of 25.8%.

Figure 23. Structures of bis-glycosylated oligonucleotide conjugates.181

initial reaction with aminooxy lactose at pH 4.5 followed by the CuAAC reaction with the azido derivative at pH 7−8, was realized by a successive one-pot strategy, whereas route B required purification before the oximation reaction. The same group next conjugated glycoclusters to oligonucleotide to enhance the binding affinity to a target lectin.182 For this purpose, a successive oxime-based ligation strategy was employed to prepare compound 241 through regioselective attachment of tetravalent aminooxy lactose residues and oligonucleotide-5′CHO (Figure 24). First, thermal denaturation experiments confirmed the stability of the duplex formed with the complementary sequence. Moreover, binding properties were further evaluated against horseradish peroxidase(HRP-) labeled lectin PNA obtained from Arachis hypogaea (peanut lectin). The studies showed that the tetravalent lactose−oligonucleotide conjugate exhibited increased binding potency in comparison to its monovalent control 242. Karskela et al. described a solid-supported oxime-ligation protocol to synthesize oligodeoxyribonucleotide glycoconjugate bearing both the trivalent β-glucose and α-mannose clusters. The strategy included oxime coupling of aminooxy-functionalized oligonucleotide with mannose and glucose clusters bearing benzaldehyde functions to give 243 (Figure 25).183

Figure 24. Structure of a tetravalent glycopeptide−oligonucleotide conjugate.182 AA


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Figure 25. Structure of an oligonucleotide glycoconjugate.183

Scheme 48. Structures of Oxime-Linked Carbohydrate-Based Mono- and Bivalent Ligands184,185

5.3. Other Examples

In 2003, the first synthesis of oxime-linked oligomers from commercially available building blocks was elaborated by Renaudet and Reymond.186 The synthetic strategy consisted of an iterative process involving the O-amination of phenol followed by oxime conjugation with hydroxybenzaldehyde. Oligomeric chains of various sizes were thus prepared and terminated with diverse aminooxy building blocks including the glucose derivative 85 (Scheme 22) to provide compound 254 (Figure 27). The resulting library of 43 oxime-linked oligomers was tested against protease inhibition with α-chymotrypsin. The study showed that sulfonate-terminated pentameric oligomer 254 had the best inhibitory ability among the oligomers and that the presence of the sugar unit (255) did not improve the inhibition activity. A series of GalNAc mimetics was reported by Nilsson and co-workers.187 These derivatives are O-galactosyl aldoximes

Figure 26. Structures of the oxime-linked ligands for the hydrogenation of folic acid.91

AB


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Figure 27. Structures of the oxime-linked oligomers 254 and 255.186

6. CONCLUDING REMARKS AND PERSPECTIVES Aminooxylated carbohydrates have been widely employed over the past few decades in diverse research areas. In addition to being easy to synthesize, their utility as building blocks has been demonstrated for the synthesis of antibiotics, modified oligosaccharides, and glycoprotein mimetics and for the conjugation to diverse platforms such as polymers, oligonucleotides, carbon nanotubes, and multivalent (cyclo)peptides through oxime ligation. Such reactions are indeed advantageous because they require mild reaction conditions, short reaction times, and no coupling reagents, and they ensure excellent reproducibilities, yields, and purities. The resulting compounds provide attractive tools for studying, activating, and inhibiting a variety of biological phenomena as exemplified by antitumoral synthetic vaccines, antiadhesive, and cell-targeting agents. In addition, because of the stability and synthetic versatility of oxime-based conjugates, aminooxylated carbohydrates undoubtedly represent key chemical tools for the construction of varieties of glycoconjugates endowed with diverse biological functions. More interestingly, the development of more effective and selective biomolecular systems is of the utmost importance for medicinal, diagnostic, and even theranostic applications. This purpose might be achieved through the construction of heterofunctionalized macromolecules with accurate molecular definition and encompassing multiple biofunctional groups. In our opinion, the recent advances in the development of orthogonal chemoselective ligation strategies make such strategies among the most viable for synthesizing such biomacromolecular systems in a controlled manner, which is crucial to ensuring the reproducibility of biological effects. Because of their high reactivity and stability, aminooxylated carbohydrates undoubtedly represent major building blocks in this field, together with glycans and other derivatives bearing compatibles functional groups such as alkenes, alkynes, thiols, and azides. For example, such approaches might provide access to synthetic multiantigenic vaccines composed of multiple tumor-associated carbohydrate and peptide antigens. In addition, the high modularity and compatibility of orthogonal ligations with carbohydrates, peptides, and nucleic acids might lead to the development of new biomolecular systems with unprecedented biological functions.

that contain hydrolytically stable oxime ether as glycosidic linkages. Synthesis of the library was achieved through a onepot coupling between β-aminooxy N-acetylgalactose 82 and various aromatic and nonaromatic heterocycles bearing Scheme 49. Synthesis of Oxime-Ether-Linked O-Galactosyl Aldoxime Derivatives187

aldehydes. Inhibition studies against galectin-3 revealed that indole analogue 256 showed a 24-fold higher affinity than methyl N-acetyl-β-D-galactopyranoside (Scheme 49). Renaudet and Dumy utilized various aminooxy sugars to synthesize chromogenic and fluorogenic oligosaccharide analogues by oxime ligation as a key step.188 Toward this end, they conjugated aminooxy α-Man 86 (Scheme 22), α-Fuc 103 (Scheme 26), β-Lac 66 (Scheme 18), and Tn antigen 69 (Scheme 19) with dansyl and dabsyl moieties bearing masked aldehyde groups in the presence of aqueous acetic acid to furnish the desired oxime-linked fluorogenic and chromogenic carbohydrate derivatives 257−260 and 261−264, respectively. UV−vis absorbance and fluorescence emission spectra revealed the expected optical properties for each conjugate. In addition, fluorescence anisotropic studies of mannose- and lactoseterminated conjugates against ConA and PNA showed efficient binding (Figure 28).

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Figure 28. General structures of aminooxy-sugar-linked fluorogenic and chromogenic carbohydrate probes.188

Olivier Renaudet: 0000-0003-4963-3848 AC


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Author Contributions

René Roy. His main research interests are carbohydrate-based synthetic vaccines and glycochemistry. He has over 30 publications to date.

‡

C.P. and G.C.D. contributed equally to this research

Notes

René Roy was born in Québec (Canada). He has held a Canadian Research Chair in Therapeutic Chemistry at the Department of Chemistry of the Université du Québec à Montréal (Montreal, Qc, Canada) since 2004. He has more than 40 years of experience in carbohydrate chemistry. After obtaining his Ph.D. degree in 1980 from the Université de Montréal (Montreal, Qc, Canada) in carbohydrate chemistry under the expert guidance of Prof. Stephen Hanessian, he joined the National Research Council of Canada in Ottawa (Canada) from 1980−1985, where he became acquainted with carbohydratebased vaccines. He then served as a professor in the Department of Chemistry at the University of Ottawa from 1985 to 2002. He was the recipient of the 2003 Melville L. Wolfrom Award from the ACS Division of Carbohydrate Chemistry for his contributions to the design of vaccines and glycodendrimers. He has published over 340 publications and has contributed to the development of two commercial carbohydrate-based vaccines against meningitis. His research interests are in multivalent carbohydrate−protein interactions, medicinal chemistry, and nanomaterials.

The authors declare no competing financial interest. Biographies Carlo Pifferi was born in Italy. He obtained his Master’s degree in pharmaceutical chemistry and technology under the supervision of Prof. C. Nativi, Dr. S. Roelens, and Dr. O Francesconi at the University of Florence. His Master’s work focused on supramolecular chemistry and the synthesis of synthetic receptors for the molecular recognition of carbohydrates. He is currently a Ph.D. student in Prof. Renaudet’s group, and his project concerns the design of carbohydratebased fully synthetic anticancer immunomodulators. The main aspects of his current work concern carbohydrate chemistry, peptide chemistry, and click chemistry for the design of multivalent homoand heteroglycoconjugates. His research relies on a chemical-biology context, with particular interest in immunochemistry and interdisciplinary collaborations. Gour Chand Daskhan was born in India. In January 2013, he received his Ph.D. degree in synthetic organic chemistry under the supervision of Prof. N. Jayaraman, Department of Organic Chemistry, Indian Institute of Science, Bangalore, India. His Ph.D. thesis was focused on the synthesis and application of C-2 and C-4 branched carbohydrates. After that, he worked as a Postdoctoral Fellow in Prof. Olivier Renaudet’s group at University of Grenoble-Alpes, Grenoble, France. During this period, he gained research experience focused on the synthesis of cyclopeptide-based multivalent homo- and heterofunctional glycoclusters and their in vitro lectin-binding behaviors. Currently, he is a postdoctoral researcher in Prof. Christopher W. Cairo’s group at the Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. His current research is centered on the development of a bioconjugation strategy for the construction of multivalent homo- and heterobifunctional glycoconjugates and their application in B cell activation. His research interests include the synthesis of oligosaccharides, development of carbohydrate-based antiadhesive agents, and synthesis and applications of macrocyclic hosts.

Olivier Renaudet was born in Niort (France) in 1973. He received his Ph.D. degree in 2002 in the field of peptide and carbohydrate chemistry at the Université Joseph Fourier (Grenoble, France). Thereafter, he pursued postdoctoral researches in the group of Prof. J.L. Reymond at the University of Berne (Switzerland) then he returned to Grenoble to obtain an Assistant Professor (2004) and a full Professor position (2012) at the Department of Molecular Chemistry. He was awarded junior member at the Institut Universitaire de France in 2011 and ERC Consolidator Grant in 2014. He has co-edited a themed issue on “Multivalent Scaffolds in Glycoscience” published in the Chemical Society Reviews (RSC Publishing) in 2013. He has published over 90 publications, and he coedited a themed issue on “Multivalent Scaffolds in Glycoscience” published in the Chemical Society Reviews (RSC Publishing) in 2013. His current research activities focus on the development of polyfunctional homo- and heteroglycoclusters as antitumoral synthetic vaccines, immunomodulators, nanovectors, or antipathogenic agents.

Michele Fiore, Associate Professor at the University of Lyon (ICBMS, Lyon, France), graduated from the University of Naples “Federico II” (Naples, Italy), where he obtained a Ph.D. degree in Agrochemistry and Agrobiology in 2007. He served in several postdoctoral positions focusing on research into chemoselective ligations and glycochemistry with Prof. Dondoni and Prof. Marra at the University of Ferrara (2008−2011, Ferrara, Italy) and then with Prof. Renaudet at the University Grenoble-Alpes (2011−2014, Grenoble, France). His current activities focus on system chemistry and prebiotic chemistry. He applies chemoselective ligations for the preparation of clickable fluorescent probes for the monitoring of the evolvability of synthetic prebiotic protocells.

ACKNOWLEDGMENTS O.R. acknowledges ICMG FR 2607, LabEx ARCANE (ANR11-LABX-0003-01), the “Communauté d’agglomération Grenoble-Alpes Métropole” (Nanobio program), the French Agence Nationale de la Recherche (ANR-12-JS07-0001-01 “VacSyn”), and the European Research Council Consolidator Grant “LEGO” (647938) for the funding of part of the reported research. R.R. thanks the Natural Sciences and Engineering Research Council of Canada (NSERC) for a Canadian Research Chair in Therapeutic Chemistry. REFERENCES

Tze Chieh Shiao was born in Taiwan (R.O.C.) in 1965. He grew up in Argentina. He started his study of medicine at Universidad de Buenos Aires (UBA, Buenos Aires, Argentina) from 1986 to 1988. He also obtained an informatics diploma at the same time. In 1989, he returned to Taiwan and obtained his certificate in administration (MBA degree) at the University of Taiwan (Taipei City, Taiwan) in 1991. He then moved with his family to Québec (Canada) in 1992. He return to university in 2000 and obtained his B.Sc. degree in Biochemistry and M.Sc. degree in Chemistry (honours) at Université du Québec à Montréal (Montreal, Qc, Canada) in 2009 under the supervision of Prof. René Roy. He then became the assistant of Prof.

(1) Crick, F. Central dogma of molecular biology. Nature 1970, 227, 561−563. (2) Chen, Q.; Chen, Y.; Bian, C.; Fujiki, R.; Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 2013, 493, 561−564. (3) Varki, A. Biological roles of oligosaccharides: All of the theories are correct. Glycobiology 1993, 3, 97−130. (4) Varki, A., Cummings, R. D., Esco, J. D., Freeze, H. H., Stanley, P., Bertozzi, C. R., Hart, C. W., Etzler, M. E., Eds. Essentials of Glycobiology, 2nd ed.; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2009. AD


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