C-Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and

Review pubs.acs.org/CR

C‑Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and Bioactivity Focused on Antidiabetic Potential Éva Bokor,†,§ Sándor Kun,†,§ David Goyard,‡ Marietta Tóth,† Jean-Pierre Praly,‡ Sébastien Vidal,*,‡ and László Somsák*,† †

Department of Organic Chemistry, University of Debrecen, P.O. Box 400, Debrecen H-4002, Hungary Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 − Glycochimie, UMR 5246, Université Claude Bernard Lyon 1 and CNRS, 43 Boulevard du 11 Novembre 1918, Villeurbanne F-69622, France

‡

ABSTRACT: This Review summarizes close to 500 primary publications and surveys published since 2000 about the syntheses and diverse bioactivities of C-glycopyranosyl (het)arenes. A classification of the preparative routes to these synthetic targets according to methodologies and compound categories is provided. Several of these compounds, regardless of their natural or synthetic origin, display antidiabetic properties due to enzyme inhibition (glycogen phosphorylase, protein tyrosine phosphatase 1B) or by inhibiting renal sodium-dependent glucose cotransporter 2 (SGLT2). The latter class of synthetic inhibitors, very recently approved as antihyperglycemic drugs, opens new perspectives in the pharmacological treatment of type 2 diabetes. Various compounds with the Cglycopyranosyl (het)arene motif were subjected to biological studies displaying among others antioxidant, antiviral, antibiotic, antiadhesive, cytotoxic, and glycoenzyme inhibitory effects.

CONTENTS 1. Introduction 2. Synthesis of C-Glycosylation of Arenes 2.1. C-Glycosylation of Arenes by Unprotected Sugars and General Features of C-Glycosyl Compounds 2.2. Aromatic Electrophilic Substitution by O-Protected Glycosyl Donors 2.2.1. C-Glycosylation of Phenols through O → C-Rearrangement (Fries-Type Reactions) 2.2.2. C-Glycosylation of Nonphenolic Aromatic Compounds 2.2.3. Intramolecular Couplings toward C-Glycosyl Arenes and Fused Tricyclic Derivatives 2.3. C-Glycosyl Arenes by Arylmetal Derivatives 2.4. Cycloaddition Reactions To Form Aglycons of C-Glycosyl Arenes 2.5. Sugar Chain Closure Methods toward C-Glycosyl Arenes 2.6. Unsaturated C-Glycosyl Arenes from Glycals and Their Derivatives 2.6.1. 1,2-Unsaturated C-Glycosyl Arenes 2.6.2. 2,3-Unsaturated C-Glycosyl Arenes 2.7. Synthesis of SGLT2 Inhibitors 2.7.1. From Benzylated Gluconolactone 2.7.2. From Trimethylsilylated Gluconolactone 2.7.3. Through Chain Closure 2.7.4. Other Approaches

© 2017 American Chemical Society

2.8. Synthesis of Spiro-bicyclic C-Glycosyl Arenes: The Papulacandin Case 3. Synthesis of C-Glycopyranosyl Hetarenes 3.1. Five-Membered Heterocycles with One Heteroatom 3.1.1. Furans 3.1.2. Thiophenes 3.1.3. Pyrroles 3.1.4. Indoles 3.2. C-Glycopyranosyl Derivatives of Five-Membered Heterocycles with Two Heteroatoms 3.2.1. Isoxazolines and Isoxazoles 3.2.2. Pyrazoles 3.2.3. Thiazoles 3.2.4. Imidazoles 3.2.5. Benzazoles 3.3. C-Glycopyranosyl Derivatives of Five-Membered Heterocycles with Three Heteroatoms 3.3.1. Oxadiazoles 3.3.2. Thiadiazoles 3.3.3. Triazoles 3.4. Six-Membered Aromatic Heterocycles 3.5. Unsaturated C-Glycosyl Hetarenes 3.5.1. 1,2-Unsaturated Derivatives 3.5.2. 2,3-Unsaturated Derivatives 4. C-(1-C-Substituted-glycopyranosyl) (Het)arenes [Bis-C,C-glycopyranosyl (Het)arenes] 5. Biological Effects of C-Glycosyl (Het)arenes

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Received: July 21, 2016 Published: January 25, 2017 1687

DOI: 10.1021/acs.chemrev.6b00475 Chem. Rev. 2017, 117, 1687−1764

Chemical Reviews 5.1. Potential Antidiabetic Agents 5.1.1. Diabetes in a Nutshell 5.1.2. Glycogen Phosphorylase Inhibitors 5.1.3. Selective Inhibition of Sodium Glucose Cotransporter 2 (SGLT2) 5.1.4. Inhibition of Protein Tyrosine Phosphatase 1B (PTP1B) 5.1.5. Miscellaneous C-Glycosyl Derivatives with Antidiabetic Potential 5.2. Miscellaneous Biological Studies 6. Conclusions and Future Perspectives Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

biosynthesis has not yet been fully understood.38 Recent data indicate two possibilities, either via one of the polyketide synthase (PKS) pathways39 or by the action of glycosyltransferases and in particular C-glycosyltransferases.25,26,40−42 For the chemical construction of a C-glycosyl (het)arene derivative, three major possibilities arise from retrosynthetic analysis (Figure 1): (a) ring closure reactions of (het)aryl compounds having a side chain to form the pyranoid ring; (b) reactions between suitably functionalized glycopyranosyl derivatives (most frequently anomeric electrophiles) and aromatic compounds to formally couple the two rings; and (c) cyclizations of precursors already having a C−C bond attached to the “anomeric” carbon, also including ring transformations of Cglycosyl heterocycles to homo- and heteroaromatic ring systems. Ring-closing methodologies (a) are represented by the addition of a hydroxyl group to a carbonyl group to give hemiketals (route a1), which are usually reduced stereoselectively or O-alkylated to impede ring opening. Dehydrative cyclization of 1,5-diols (route a2) and electrophile-induced ring closure of vinyl (het)arenes (route a3) also lead to C-glycosyl (het)arene derivatives. Sporadically, cycloadditions and related pericyclic reactions have also been applied to the formation of a precursor of the pyranoid ring (as simplified in route a4). Among coupling methods (b) to attach a pyranoid sugar to an aromatic moiety, many sorts of anomeric electrophiles react with phenols as ambident nucleophiles, to produce O- and/or Cglycosyl compounds (route b1). Aryl O-glycosides can undergo acid-catalyzed rearrangement to C-glycosyl compounds (route b2), usually affording the more stable products under thermodynamic control. One of the main routes to C-glycosyl arenes involves electrophilic aromatic substitution catalyzed by a variety of Lewis acids, a reaction particularly efficient for electron-rich arenes and activated glycosyl donors (route b1). Electrophilic substitution can occur intermolecularly or, for appropriate precursors, intramolecularly, in such cases usually with high stereocontrol. Another entry to C-glycosyl arenes involves attack of carbon nucleophiles (e.g., metalated species) to sugar derivatives with an electrophilic anomeric center (e.g., glycosyl halides, glyconolactones, 1,2- or 1,6-anhydro derivatives, illustrated by routes b1, b3, b4, and b5). Glycals are also frequently used precursors (route b6, X = H) that can lead to Cglycosyl arenes through the Ferrier rearrangement, while metalated glycals (route b6, X = M) offer other possibilities for cross-coupling chemistry. Glycals with an electron-withdrawing group in position 2 can be transformed by aromatic nucleophiles (route b7). Cyclizations of various C-glycopyranosyl precursors (methods c) lead to homo- and heteroarene derivatives. Among them, Cglycosyl acetylenes (route c1), aldehydes (2,6-anhydro-aldoses, route c2), cyanides (2,6-anhydro-aldononitriles, route c3), as well as the intermediate nitrile oxides (route c4) are the most frequently used intermediates. Ring transformations of Cglycosyl heterocycles into homo- and heteroaryl derivatives (route c5) are also very important. In contrast to the case of C-glycosyl alkanes, radical-based routes13 found only limited applicability to access C-glycosyl arenes,43,44 and the same applies for approaches based on glycopyranosylidene carbenes45 as well as glycosyl carbanions.46 This Review includes data, most of which appeared after 2000, our main goals being to comprehensively summarize the preparative approaches and to emphasize the utility of synthetic C-glycopyranosyl (het)arenes in particular as investigational drugs with antidiabetic potential. Some structures are the results

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1. INTRODUCTION Among natural compounds, the highest diversity, as defined by the number of possible isomeric structures, can be observed with carbohydrate derivatives. In the form of O-glycosidically linked oligosaccharides, nature uses this enormous variability among others in diverse cellular recognition and signaling phenomena.1,2 Several kinds of mimicks of O-glycosides, first of all S-, N-, and C-glycosyl derivatives, may display similar biological activities; however, due to their significantly distinct chemical properties, such molecules can be valuable tools in deciphering the biological roles of natural sugars, and may also serve as leads for new drugs.3,4 Among glycomimetics, C-glycosides have attracted much attention due to the existence of a number of naturally occurring representatives.5,6 The term “C-glycoside”, often cited in the literature, is considered inaccurate stricto sensu because these compounds are not acetals, and IUPAC recommends “C-glycosyl compounds” or analogues instead. During the past two decades, C-glycosyl compounds in the broadest sense were the subject of books,7,8 and book chapters,9−11 while several reviews dealt with more specialized aspects of this compound class.12−19 The present account is devoted to C-glycopyranosylated (het)arenes, a subclass of Cglycosyl compounds for which occurrence, synthesis, and biological activities have been compiled in several reports, most of which are older than a decade.20−23 The abundance of new data can be judged from a recent review, which covers the synthesis of C-(D-mannopyranosyl)-alkanes, -arenes, and -hetarenes.24 Naturally occurring compounds of the C-glycosylated arene type have been reviewed, with focus on structure, activity, synthesis, and biosynthesis,25 and this applies also for bioactive C-glycosyl compounds from bacterial secondary metabolism.26 Glycomimetics of the C-glycosyl arene type were designed as selectin antagonists, and tested in view of their biological and pharmacological evaluation.27 Other comprehensive reports focus on C-glycosyl flavonoids.28−33 C-Nucleosides derived from nitrogen heterocyclic compounds and furanoid rings, being analogues of nucleosides and nucleotides, have received close attention.34−37 On the contrary, a similar account on Cglycopyranosyl arenes is missing, and especially the heterocyclic derivatives were not surveyed at all. How the C−C bond between a tetrahydropyranyl ring and the rest of the C-glycosylated compound is formed during the 1688


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Figure 1. General synthetic strategies to C-glycosyl arenes and hetarenes (see text for explanations).

which has met success with electron-rich arenes.15 The synthesis of C-β-D-glucopyranosyl phloroacetophenone 4, an important intermediate giving access to C-glucosyl flavonoids, was achieved by condensing D-glucose (1) with phloroacetophenone (2) in the presence of Sc(OTf)3 in aqueous organic media, with formation of variable amounts of the corresponding bis-C-β-Dglucosyl compound 6 (Scheme 1A).60,61 A 32% yield of 4 was obtained using scandium cation-exchanged montmorillonite.62

of our collaborative efforts, and they were designed or specifically investigated for antidiabetic properties due to their inhibition of glycogen phosphorylase (GP). The selective inhibition of renal sodium-dependent glucose cotransporter 2 (SGLT2) is receiving considerable attention in view of limiting hyperglycemia, and six of the developed compounds have been approved as marketed drugs in 2013 and 2014 (see Table 16 in Section 5.1.3).47−49 Interestingly, other structures were shown to have related applications, even though their mechanisms of action through inhibition of protein tyrosine phosphatase 1B (PTP1B) and other targets were quite different. We hope the information provided will help readers to better appreciate the recently developed synthetic methods, and the usefulness of C-glycosyl (het)arenes first of all in the context of type 2 diabetes,50 one of the major global health concerns at the moment, but also in other biomedical fields. In the synthetic parts of the survey, stress is laid on the C−C bond formation between the sugar and the arene as well as on the construction of the glycon or the aglycon from open-chain derivatives. Thus, in multistep syntheses of test compounds with potential biological activities, the final products usually need several additional steps to be reached, which will not be detailed except for some particularly important syntheses. Multivalency is at the heart of glycoscience, and multivalent glycostructures have been obtained also by C-glycosylation techniques. However, these topics have recently been summarized in several excellent reviews;51−59 therefore, this field is not included in the present treatise.

Scheme 1. C-Glycosylation of (A) Phenols or (B) 1,5Naphthalenediol by Unprotected Carbohydrates

2. SYNTHESIS OF C-GLYCOSYLATION OF ARENES 2.1. C-Glycosylation of Arenes by Unprotected Sugars and General Features of C-Glycosyl Compounds

Because of the polyol nature of carbohydrates, glycosyl derivatives are usually protected to achieve regioselective modifications. For glycosylation, protective group manipulation is particularly important for both reactivity and stereoselective formation of the desired anomer. However, as protection/ deprotection strategy results in multistep syntheses, direct glycosylation of O-unprotected sugars is an attractive approach, 1689


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Interestingly, in the presence of Sc(OTf)3, D-glucose (1) and methylphloroacetophenone (3), with a single substitution site, led to compound 5 in 65% yield.63 As the direct C-glycosylation of flavonoids with common sugars might offer a concise access to complex naturally occurring molecules, the coupling of D-glucose (1) and (±)-naringenin to afford compound 7 (Scheme 1A) has been evaluated systematically with commercially available rareearth metal triflates M(OTf)3 as catalysts (M = Sc, Y, La, lanthanides, except Pm). The yields observed were changing from 2% to 41%, independently of the metal order in the periodic table, but revealed Pr(OTf)3 as the most favorable catalyst.64 Besides D-glucose, also D-galactose, D-mannose, L-rhamnose, maltose, and lactose were applied, and the use of ultrasound slightly increased the yields.64 In the course of these studies, several bis-C-glycosyl derivatives (analogues of 6) with identical or different sugar residues were prepared among them precursors of vicenins.61 The C-glycosylation by unprotected sugars was particularly efficient when activated 2,6-dideoxy sugar 8 was reacted with electron-rich partners, for example, 1,5-naphthalenediol or 2-naphthol (not shown) to provide compound 10 (Scheme 1B).65 Similarly, the condensation of 2-deoxy-D-glucose 9 with 1,5-naphthalenediol provided the C-glycosyl compound 11, which was further converted into 5-aza-analogues of angucyclinones.66 A chemo-enzymatic approach is also possible as reported for the synthesis of nothofagin from UDP-glucose in the presence of a C-glycosyltransferase from rice (Oryza sativa, OsCGT).67 Similarly, conversion of acylphloroglucinol 2-Oglucosides into the corresponding 3-C-glucosides (e.g., Nothofagin) was accomplished with a C-glycosyltransferase from Mangifera indica (MiCGTb).68 There has been much work regarding the structure of C-linked disaccharides, in particular concerning their conformation about the C−C linkage, found essentially similar to that of Oglycosides.69−72 As polysubstituted or polycyclic arenes are bulky, the situation is different for C-glycosylated arenes, which experience restricted rotation around the exocyclic C−C bond and exist as different rotamers. Therefore, weak or broad signals for proton or carbon nuclei close to the C−C connecting bond in C-glycosyl arenes are frequently observed by NMR spectroscopy, unless heating the sample (ca. 60−120 °C) brings about the coalescence temperature.73−76 It is worth noting that in the course of the synthesis of a precursor of kendomycin, an intermediate C-glycosyl arene was obtained as a rotameric mixture, but after MOM protection of a phenolic hydroxyl, the conformation was frozen to the desired kendomycin-like atropisomer.77 Sterically demanding aryl moieties can influence also the glycosyl ring conformation. The synthesis of a series of Cglycopyranosyl phloroacetophenone derivatives differing in their sugar configurations73,74 and the study of their anomerization concluded that the conformation of the pyranosyl ring is dictated primarily by the preference of bulky aromatic aglycons to orient equatorially. Conformers with destabilizing 1,3-diaxial interactions are disfavored and are prone to acid-catalyzed anomerization toward thermodynamically stable compounds. Such anomerization involves cleavage of the endocyclic O5−C1 bond (Scheme 2). Hence, in the D-gluco, D-galacto, and D-manno series, β-anomers are the thermodynamically favored products, with their pyranosyl ring adopting a 4C1 conformation, while the sugar ring is usually distorted for α-anomers. For the D-manno series, see a more detailed discussion in section 2.2.1. The conversion of C-β-D-glucopyranosyl phloroacetophenone 4 and its D-galacto and D-allo configured analogues to spiropyran

Scheme 2. Anomerization through Cleavage of the C1−O5 Bond

(e.g., 12)- and spirofuran (e.g., 13)-type spiroketals has been reported.78 The detailed mechanism proposed involves an initial quinone-methide form, precursor of a hemiketal, which can undergo ring-closure through either the primary (path a) or the Scheme 3. Spiroketalization through Cleavage of the C1−O5 Bond

secondary (path b) hydroxyl, thus affording the respective spiropyran 12 or spirofuran 13 derivatives (Scheme 3). As the last ones were generally formed at the first stage of heating and comparatively in lower amounts, it was assumed that the formation of spirofuran and spiropyran was the respective kinetically versus thermodynamically controlled reaction, initiated by the cleavage of the C1−O5 bond.78,79 For highly hindered structures, cleavage of the C1−O5 bond in the pyranosyl ring appears to be facilitated if it results in decreased steric clashes. Consequently, while C1 bis-substituted pyranosyl moieties with either two alkyl groups or an alkyl group and a (het)aryl moiety as substituents are known,80 the gem-bis-C,Caryl-type analogues undergo ring opening.81,82 2.2. Aromatic Electrophilic Substitution by O-Protected Glycosyl Donors

Electrophilic aromatic substitution is a well-known method for synthesizing various C-glycosyl (het)arenes. The aromatic part influences greatly the reaction selectivity depending on the 1690


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to the synthesis and structure elucidation of deacetylravidomycin M.89 The Fries-type reaction for the C-glycosylation of phenols is not restricted to glycose acetates, and other glycosyl donors with the following type of anomeric substituents, OH, OMe, OC( NH)CCl3, OC(NPh)CF3, OPO(OPh)2, and F, have been successfully used. The available data have been compiled, according to the activating system utilized (and the anomeric substituent of the glycosyl donor): BF3·OEt2/CH2Cl2 (OMe, OAc, F); SnCl4/CH2Cl2 (OAc, F); Cp2HfCl2−AgClO4 (F); TMSOTf or TMSOTf/AgClO4 (OH, OMe, OC(NH)CCl3, OC(NPh)CF3, OPO(OPh)2); Sc(OTf)3 (OAc); protic acid and ionic liquid (OAc, OMe, F); Montmorillonite K-10 (OH, OMe).15 A benzylated glucosyl fluoride was employed for the preparation of 6-C-glucosylflavones,90 8-C-glucosylflavones,91 and flavocommelin.92 A benzylated glucosyl trichloroacetimidate and phloroacetophenone were condensed in the presence of TMSOTf to afford the corresponding C-glucosyl compound toward the synthesis of (iso)vitexin.93 The parent benzylated mannosyl trichloroacetimidate was reacted with a decorated 2naphthol toward sialyl-Lewis-X mimetics.94 Hemiacetal or 1-Oacetyl donors could be employed for the 2-deoxy-C-glycosylation of 2-naphthol toward angucyclin.95 Benzylated 2-deoxy-1thioglycosides provided the C-glycosyl compounds in high yields when reacted with 2-naphthol.96 A similar approach from 1-Oacyl 2-deoxy-glucose donors provided access to medermycin.97,98 Regioselective glycosylations of a complex dihydroxylated anthrapyran examplified other SnCl4-mediated couplings of sugar acetates that afforded a bis-C-glycosyl compound corresponding to the C-glycosidic pattern of kidamycin.99 In the presence of TMSOTf/AgClO4 or BF3·OEt2, benzyl protected glycosyl donors may lead to unexpected C-glycosyl arenes due to rearrangement within the sugar moiety into a bicyclic acetal in which the glycosyl donor had undergone an unusual 1,6-hydride shift.97 Interestingly, aryl C-glycosylations with a benzyl protected 2,6-dideoxy sugar acetate as well as benzylated glycosyl fluorides with electron-rich 3,4,5-trimethoxyphenol were achieved in high yield and selectivity in an ionic liquid containing HBF4, as a protic acid.100 Under similar conditions, O-unprotected methyl 2,6-dideoxy glycosides were also converted to C-glycosyl compounds.100 C-Glycosylation of phenols by 2,3-anhydro-1-thiopyranosides 14 and 15 can be readily achieved through TMSOTf activation (Scheme 5).101 The migration of the thioether to the 2-position was followed by O-glycosylation, and then a Fries rearrangement leading to the observed C-glycosyl compounds 16−18. Reductive removal of the 2-STol moiety by nBu3SnH/AIBN gave the corresponding 2-deoxy-C-glycosyl derivatives. It is agreed that, under thermodynamically controlled conditions, C-glycosylation of phenols occurs with a β-selectivity in the D-gluco,102 D-galacto, and 2-deoxy-D-arabino hexopyranose series.15 Earlier data exist for the D-manno series, but they need to be analyzed in the light of recent results on the β-selective Cmannosylation of electron-rich phenols.103 The reaction of tetraO-benzyl-mannosyl trichloroacetimidate 19 (Table 1) with 2naphthol carried out with TMSOTf gave compound 24 in 66% yield. The β-configuration was proved by NOESY NMR experiments, showing NOE interactions between H1, H3, and H5. Coupling to other electron-rich phenols led to the corresponding C-β-mannopyranosyl compounds (30, 32, 34) in yields increasing with the electron density and symmetry of the phenol. However, the coupling reaction of 2-naphthol with 19 afforded different products when carried out with BF3·OEt2, 2-

number of possible regio-isomers but also the rate of the reaction. Phenols can participate in similar reactions, although aryl Oglycosides are often intermediates that can be converted to CScheme 4. General Routes to C-Glycosyl Arenes by Aromatic Electrophilic Substitution

glycosyl phenols by Fries-type rearrangement reactions (Scheme 4).15 Electron-rich phenols such as 3,4,5-trimethoxyphenol and a glycosyl donor (e.g., trichloroacetimidate or phosphate) afford the direct coupling to the corresponding β-configured C-glycosyl arene.83 As phenols represent versatile synthetic compounds, the following section highlights specific aspects related to their Cglycosylation, before considering other aromatic compounds. 2.2.1. C-Glycosylation of Phenols through O → CRearrangement (Fries-Type Reactions). The Lewis acidcatalyzed rearrangement of O-glycosides to the corresponding Cglycosyl arenes (Fries-type reaction) with the C-glycosyl moiety in ortho position to the phenolic OH is a powerful method for the regio- and stereocontrolled construction of the target Cglycosyl compounds from simple precursors (Scheme 4). The choice of Lewis acid is critical to the yield and the stereoselectivity of the O → C-rearrangement, but other parameters such as temperature, time, additives, and solvent are also important for this transformation. The search for effective Lewis acids as activators for Cglycosylation revealed the interest of Sc(OTf)3 associated with Drierite for coupling benzyl protected glycosyl acetates and phenols.84 This system was superior to BF3·OEt2, TMSOTf, Cp2HfCl2/AgClO4, and Drierite performed better than molecular sieves, while 1,2-dichloroethane was superior to dichloromethane as the solvent. After the reagents were mixed at −30 °C, the temperature was raised and maintained for completing the O → C-rearrangement, and anomerization. In other cases, the O → C-rearrangement of O-glycosides was problematic.85,86 Attempted couplings of 2-deoxy-D-glucopyranose peracetate with two naphthol derivatives in the presence of TMSOTf/ AgClO4 yielded both the O-glycoside and the C-glycosyl compound in similar amounts (ca. 30%), but changing the solvent from CH2Cl2 to CH3CN raised the C-glycosyl compound yields to 82% and 97%, respectively. Therefore, a more coordinating medium must be highly favorable.85 The Sc(OTf)3-mediated Fries-type coupling procedure was developed to access resorcinol bis-C-glycosyl compounds,87 in one pot if the two sugar units were identical,88 and it was recently applied 1691


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purified and characterized, so that data for minor isomers were missing. Comparison of the optical rotations with those reported in the recent more detailed study103 using NOESY experiments points to a β-configuration in three of the four compounds initially reported to be α.106 In another synthesis of 2-C-Dmannopyranosyl-3,4,5-trimethoxyphenol 35, prepared from 3,4,5-trimethoxyphenol and fluoride 22 in an ionic liquid containing a protic acid, discrepancies exist for the configurations proposed in the text (α), and in the experimental section (β) (note 12 in the original manuscript).100 Again, β-selectivities were observed in the D-gluco and 2-deoxy-D-arabino-hexopyranose series. Earlier work on the synthesis of C-mannopyranosylphloroacetophenone from the benzyl protected α-fluoride 22 showed the initial formation of the C-α-mannopyranosyl compound 27 through an O → C-glycosyl compound rearrangement, and while the temperature was rising from −78 °C to rt, anomerization to 28 occurred at temperatures higher than −42 °C.73 Therefore, the very bulky di-tert-butyl resorcinol derivative 25, and the similar α-anomer derived from 3,4,5-trimethoxyphenol 35, should be prone to anomerization, and their proposed α-configuration should be checked.100 Although not derived from phenols, compounds 29 and 31 have been included in Table 1 for the purpose of comparison.107,108 Glycopyranosyl trichloroacetimidates are more reactive when protected by benzyl groups, as compared to their acetylated counterparts, which nevertheless permit direct C-glycosylation of electron-rich partners as the indole nucleus.109 As only two pairs of benzylated D-manno-configured anomers have been studied in detail (23 and 24, and 27 and 28),73,103 the anomeric configuration assignment requires closest attention for benzylated C-mannopyranosyl arenes (their 1H NMR spectra display overlapping signals), as compared to acylated analogues (the crystal structure of 2,3,4,6tetra-O-acetyl-β- D -mannopyranosylbenzene has been reported110). The recently published data103 indicate similarities in the gluco, manno, and galacto series in terms of preferred βstereoselectivity, and it is important to point out inaccuracies that otherwise might spread in the literature.15,24 2.2.2. C-Glycosylation of Nonphenolic Aromatic Compounds. A number of “classical” glycosyl donors (hemiacetal, fluoride, phosphate, trichloroacetimidate, N-phenyl trifluoroacetimidate) are in current use to achieve the C−C coupling of a carbohydrate to aryl moieties, and some representative examples will be discussed in the following. A coupling between Oglucosyl-N-phenyl trifluoroacetimidate 36 and xanthene derivatives111 (Scheme 6) allowed the formation of 37 and 38 from which 38 was transformed into homomangiferin in several steps. Analogous reactions were used for the preparation of mangiferin and isomangiferin. Other methods are illustrated by syntheses of trimethoxybenzene C-glycosyl compounds (Scheme 7). The recently introduced 2′-carboxybenzyl glycoside 39108 offered a stereocontrolled access to C-α-glycosyl arenes 40 (Scheme 7A). Compound 39 upon deprotonation with 2,6-di-tert-butyl-4methylpyridine (DTBMP) and in the presence of Tf2O underwent cleavage to afford a glycosylium ion able to react with resorcinol and phloroglucinol ethers to provide C-αglucosyl compounds (e.g., 40).108 S-Glycosyl phosphorothioates 41 in the presence of 1,3,5-trimethoxybenzene (TMB) afforded exclusively the β-configured anomer 42 in high yields, with either iodine or boron trifluoride etherate (Scheme 7B).112 The dehydrative C-glycosylation of TMB was also reported from the hemiacetal 2,3,4,6-tetra-O-benzyl-glucose 43 (Scheme 7C) activated by diphenyl sulfonium reagents to give 42 in high

Scheme 5. C-Glycosylation of Phenols by 2,3-Anhydro-1thiopyranosidesa

a

NI, not investigated; −, not formed.

naphthyl α-O-mannoside (25%), 23 (30%), 24 (10%), or with ZnCl2, α-O-mannoside (14%), 23 (42%). The coupling pattern observed by 1H NMR spectroscopy revealed a 1C4 conformation for the α-D-mannopyranosyl ring in 1-(tetra-O-benzyl-α-Dmannopyranosyl)-2-naphthol 23 (this is the sole work with precise assignment of all NMR signals), resulting in a strong NOE contact between H1 and H6a as shown by a cross-spot in the NOESY spectrum. This study confirmed that coupling to 2naphthol was a stepwise process that led first to the α-Omannoside, then to the C-α-mannosyl anomer, which anomerized easily73 to the more stable C-β-mannosyl anomer,24 thus releasing 1,3-diaxial interactions destabilizing C-α-mannosyl arenes. Measurement of the optical rotations of the pure α- and β-anomers showed the latter were more dextrorotatory (23, [α]26D −22.9; 24, [α]20D + 45.1). As the optical rotations spread over overlapping ranges (−22.9 to +20 for α-anomers; −1.3 to +68.1 for β-anomers) (Table 1), they do not provide reliable indication for anomeric configuration assignment, a task that is not straightforward by 1H NMR as the vicinal 3J1,2 couplings are close for both D-manno anomers. It was reported earlier that, upon reaction with TMSOTf, tetra-O-benzyl-α-D-mannopyranose phosphate 21 and 2-naphthol (and two other electron-rich phenols)104,105 gave exclusively the C-α-mannosyl arenes, while the β-anomers were obtained in the D-gluco series. The structure of product 33 obtained from 3-benzyloxyphenol (3-O-benzylresorcinol) is doubtful, as discrepancies exist about the anomeric configuration assigned in the text and experimental section. Similar confusion appeared for the product derived from 2naphthol, stated to be α-configured,104,105 while the reported optical rotation ([α] = +49.1) rather suggests the β-anomer, based on the optical rotations reported for 23 and 24 (Table 1).103 These facts cast doubt on the configuration assigned to 35 ([α] = +12.7, see below). Another study on the C-glycosylation of phenols with glycosyl N-phenyl trifluoroacetimidates in the presence of TMSOTf concluded to the preferred formation of β-configured C-glycosyl compounds in the D-gluco and D-galacto series, while for the four D-manno-configured analogues, the α-configuration was simply assumed.106 It was noted that all of the reactions led to a number of spots on TLC plates, but only the major products were 1692


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Table 1. Synthesis of C-D-Mannopyranosyl Phenols: Methods, Products, Optical Rotationsa

The O-α-D-mannosides were isolated in low amount when using BF3·OEt2 or ZnCl2 (see text); the C-α-mannosyl arenes are represented with either C4 conformation (when indicated by NMR analysis) or 4C1 conformation (if no specification); the indicated structures for the C-β-mannosyl arenes are supported by NMR data (NOE contact: H1 with H3, H5).73,103,108 bThe α-configuration initially proposed or assumed106 for compounds 24, 30, and 32 has to be changed on the basis of comparison of optical rotations.103 cThe authors did not provide the optical rotation106 for this compound but cited published data.104,105 dAnalogue obtained from 1,3,5-trimethoxybenzene. eAnalogue obtained from 1,3-dimethoxybenzene. fαConfiguration assigned in the text but noted β in the experimental section. a

1

yield.113 While investigating new diacylamino protecting groups for glucosamine,114 the use of diglycolyl-N-protected trichloroacetimidate 44 for the TMSOTf-catalyzed coupling to TMB afforded the expected β-configured anomer 45 in 86% yield (Scheme 7D).

The C-aryl glycosylation with glucose and galactose peracetates was performed with various electron-rich aromatic compounds (e.g., p-methoxytoluene, 1,2-, 1,3-, or 1,4-dimethoxybenzene, 2-methoxynaphthalene), affording predominantly the β-anomer (see Scheme 8 for some examples). The formation of glycosyl chloride intermediates upon reaction of glycopyranosy1693


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Scheme 6. Key Step of Synthesis of Mangiferin, Homomangiferin, and Isomangiferin Derivatives

Scheme 8. SnCl4/CF3CO2Ag-Mediated Coupling of Glucose Penta-acetate and 1,4-Dimethoxybenzene or Analogues

lium species with chloride anions from SnCl4 was observed.43,115,116 The reaction time and temperature were important parameters as optimized isolated yields call for full conversion of the glycosyl donors present, and completion of anomerization toward the thermodynamic product. In four cases shown in Scheme 8, coupling of glucose peracetate 46 occurred in yields above 60%, but it decreased to 75%) tetrahydroquinolines 86 (Scheme 15) in which the sugar residue was 1,3-linked to heterocyclic motif.135 A C-2-indium derivative was proposed as an intermediate to the isolated adducts. Several other examples of reaction of glycals with arylamines in the presence of indium bromide were reported with D-ribose136 or Scheme 15. Synthesis of Sugar-Annelated Tetrahydroquinolines from D-Glycal

2.3. C-Glycosyl Arenes by Arylmetal Derivatives

A different approach to C-glycosyl arenes involves nucleophilic metalated arenes (e.g., Grignard reagents or aryllithium 1697


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intermediates) reacting mainly with glycosyl halides and glyconolactones, but also other substrates with an electrophilic C-1 center. In the case of glycosyl chlorides or bromides, the reaction conditions require a fine-tuning, as the reactive polyfunctional glycosyl substrates can undergo a variety of possible reactions, notably hydrolysis, base, or metal-induced 1,2eliminations (involving the H2 proton or the 2-alk(acyl)oxy residue, respectively), competing with substitution. Treatment of ether- and/or acetal-protected glycosyl chlorides with phenyllithium even combined both processes, the chlorides 87−90

Scheme 17. Ionic and Pd-Catalyzed Grignard Reagent-Based Routes to C-β-D-Glycosyl Benzene from O-Peracetylated Donors

Scheme 16. Synthesis of 1-C-Phenyl Glycals from Protected Glycosyl Chlorides

Scheme 18. Arylation of Acylated Glycosyl Bromides by Aryl Zinc Reagents

being converted to 1-C-phenyl glycals 91−94 in good yields (Scheme 16).144,145 If 1,2-elimination can be minimized or avoided, this substitution method might lead in one step to the desired Cglycosyl arenes from easily accessible glycosyl halides, and much effort has been made to determine optimal conditions and mild reaction pathways compatible with high α/β stereoselectivity. Focus was first on Grignard146−148 and then aryl zinc reagents, according to a Ni-catalyzed Negishi149 or a transition-metal-free procedure.150 Moreover, recent findings, made with Grignard reagents reacting in the presence of Co salts or complexes and suitable ligands, provided novel mild protocols toward C-glycosyl arenes and deeper insight in the reaction pathways.151 Reaction of D-gluco-configured bromide 95 with excess PhMgBr, followed by acetylation of the crude reaction mixture, led to 99 in 45%,146 56%,147 and 73%148 (yields over three steps from the 1-O-acetate precursor of 95), the highest yield being the result of complete recovery of the product by crystallization followed by chromatography of the mother liquors (Scheme 17). The reaction proceeded similarly in the D-galacto series (96 → 100 43% yield), but afforded in the D-manno series a 1:1 β/α mixture (97 → 101 + 102 73% yield)147 separable by crystallization and column chromatography.152 Although direct, simple, and relatively high-yielding, this three-step process suffered from poor atom-economy, in particular regarding the large excess of Grignard reagent required. A related synthesis of 99 was based on a Corriu−Kumada-type cross-coupling between ethyl 1-thio-β-D-glucopyranoside 98 and PhMgBr, catalyzed by Pd(dba)2 and tri-2-furylphosphine (TFP).153 The lability of acyl protective groups to nucleophiles is a recurrent problem, which has received solutions, based on aryl zinc reagents as milder nucleophiles capable of displacing the bromine atom in benzoyl and pivaloyl protected bromides 103,

104 (Scheme 18). Under the substitution conditions, the benzoylated bromide 103 yielded the desired product 106 in low amount, together with the fused-bicyclic structure 107 resulting from the nucleophilic attack of a 1,3-dioxolanium intermediate formed by anchimeric participation of the benzoyl group. While pivaloates can control the substitution selectivity by anchimeric assistance, their bulkiness, as compared to acetyl or benzoyl esters, makes them more resistant to nucleophiles, and their cleavage can be avoided under optimized conditions. Applied to 104, the substitution with aryl zinc reagents afforded selectively various para- and ortho-substituted C-β-glucosyl arenes 105 in good yield, while the D-manno bromide 108 yielded 109 (J1,2 = 2.5 Hz; [α]20D = +38.2, c 1, CH2Cl2) considered to be the α-anomer.150 The scope and mechanistic aspects of this reaction were recently investigated154 and also further developed with furanosyl halides.155 It has been shown that transition metal-catalyzed crosscoupling of alkyl halides displaying β-hydrogens can be achieved under the guidance of suitable ligands to avoid β-elimination products. In particular, Ni-catalyzed Negishi cross-coupling conditions have been developed with pincer ligands to effectively inhibit detrimental β-elimination reactions. By assuming this applies also to the case of elimination-prone glycosyl-type electrophiles, this design might enable stereoselective formation of anomeric C−C bonds. To this end, various arylzinc and other 1698


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Scheme 19. Transition Metal-Catalyzed Negishi Cross-Coupling Approaches from Aryl Metal Derivatives to C-Glycosyl Arenes

chosen for a broader evaluation, with related acetylated glycosyl (D-gluco, D-manno, D-galacto) bromides. Applied to 97, the reaction was found rather general, yielding preferentially the αanomers 114.110,152 The α-anomers 114 had optical rotations in the range +40−50, and up to ∼85, except for the bulky 2,4,6trimethylphenyl derivative ([α] +7.1). While the first ones displayed 4C1 conformations (J3,4 ≈ J4,5 ≈ 9 Hz) and J1,2 ≈ 3 Hz, this 2,4,6-trimethylphenyl derivative adopted a distorted conformation (J1,2 = 10.8 Hz; J3,4 = 3.5 Hz; J4,5 = 1 Hz). Such an important structural change can possibly explain the lower optical rotation. Generally, the tetra-O-acetyl-D-glycopyranosyl arenes followed the Hudson rule (α-anomers were more dextrorotatory than β-counterparts) in the D-gluco, D-manno series, and most probably in the D-galacto series (as judged from data available only for α-anomers151,152,157). The preference for α-anomers was also observed in the D-gluco (118 + 112 α/β ≈ 2:1) and D-galacto (119 + 113 α/β > 9:1) series, as well as for the cross-coupling of alkenyl Grignard reagents. However, at variance with the data reported, similar α-stereoselectivities would be expected in the D-gluco and D-galacto series, for a typical free radical-based mechanism.158 More work should help in unravelling the details of this mild procedure with high αstereoselectivity, in sharp contrast to other routes cited before. The various catalyzed cross-coupling reactions reported recently appear to open new and mild approaches to the synthesis of Cglycosyl arenes, promising in terms of atom economy and versatile stereocontrol. The in situ formation of transient glycosyl-pyridinium salts 121 from 1-O-acyl 2-deoxy-glucose donor 120 can be readily accomplished with 2-methoxypyridine under Lewis acid catalysis. Subsequent C-arylation with an arylzinc reagent gave high α-selectivity toward C-glycosyl compounds 122 (Scheme 20).159 1,2-Anhydro (e.g., 123) or cyclopropanated (e.g., 126) derivatives (readily obtained from glycals), in which relief of the ring strain provides the driving force for different ringopening reactions, were also used as an entry to C-glycosyl arenes. Reactions of benzylated 1,2-anhydro-D-glucose 123 with PhMgCl or Ph2CuLi afforded the desired products 125 in good

reagents were coupled to different acyl protected glycosyl chlorides and bromides.149 Optimization of the conditions showed that the choice of Ni(COD)2, tBu-Terpy, and DMF (Scheme 19, route a) was optimal for coupling glucosyl αbromide 95 with PhZnI·LiCl, in terms of yield and selectivity (112: 71%, α/β 1:12). With this protocol, similar results were observed with other related glycopyranosyl bromides in the Dgluco, D-galacto, 2-amino-2-deoxy-D-gluco, and D-arabino series. In contrast, it was concluded that 114 contained predominantly the D-manno α-anomer, as good to excellent α-selectivities, strongly ligand-dependent, were achieved with Terpy (10:1) and PyBox (>20:1), as compared to tBu-Terpy (2.9:1). The reaction with PhZnI·LiCl in DMF gave poor results with benzyl protected (Dgluco, D-manno) glycosyl chlorides or failed with reactive acylated glycosyl halides (e.g., 2-deoxy-hexopyranosyl and furanosyl series) because they underwent hydrolysis.149 The potential of this method was further highlighted through a six-step synthesis toward salmochelin SX, the simplest representative of a family of siderophores. This paved the way to other more complex salmochelins, with either opened or macrocyclic polyamide backbones, linked to a variable number (n = 1−3) of D-glucosyl residues.156 Substitution of acetylated glycosyl bromides 95−97 with Grignard reagents in the presence of iron salts and ligands provided an access to C-glycosyl arenes 118, 119, and 114, respectively, with a good α-stereoselectivity (9:1 for D-gluco and 151 D-galacto, 1.3 to 3:1 for D-manno). These reactions were presumed to proceed by a free radical mechanism and have inspired further work with cobalt salts (CoCl2, Co(acac)2, and Co(acac)3), as cobalt-catalyzed coupling reactions are not prone to β-elimination. In attempted couplings (Scheme 19, route b) between 97 and PhMgBr to 114, promising results were obtained with each of these salts, in the presence of a catalytic amount of ligands such as N,N,N′,N′-tetramethyl-trans-cyclohexanediamine, 1,2-bis(diphenyldiphosphino)ethane, and N,N,N′,N′tetramethyl-ethylenediamine (tmeda). With Co(acac)3/tmeda, the catalyst load (5 mol %) could be decreased to 1 mol %, while use of 5 mol % Co(acac)2/tmeda decreased the yield slightly. For convenience, the couple Co(acac)3/tmeda (5 mol % each) was 1699


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Scheme 20. C-Arylation through Glycosyl-pyridinium Salts and Arylzinc Reagents

the presence of phenol-type nucleophiles (Scheme 22). This afforded a series of aryl 2-C-methyl glycosides, but electron-rich phenols yielded C-(2-C-methyl-mannosyl) arenes 127, 128, in variable amounts and selectivity, through a Fries-type rearrangement. The deuterium labeling experiment provided insight into the reaction mechanism.165 Much effort has been made to develop access to C-glycosyl arenes from glyconolactones and in particular from the inexpensive commercial D-gluconolactone. Its derivatives protected with acetyl, benzyl, or trimethylsilyl groups are accessible, but the acetylated derivative is not suitable for reactions with arylmetal derivatives (ArMgX, ArLi) due to reactivity of the protecting groups. With base-stable protecting groups the transformations are feasible, the first step being an attack by aryl anions, followed by reduction of the obtained hemiketal (Scheme 23). The silane-mediated reduction of 2,3,4,6-tetra-O-benzyl-1-C-phenyl-D-glucopyranose 131 was claimed to deliver exclusively the β-configured product 132 in 80% yield,166,167 but the gram-scale synthesis of C-glycosyl arenes, from benzyl protected D-gluconolactone 130 and PhLi,168 revealed a lower selectivity. On the basis of recent data obtained from pure anomers, the early reported optical rotation ([α]D +29.4)166,167 evidences contamination of the major β-anomer ([α]D +11.1) by the α-anomer ([α]D +95.5).168 In fact, reducing 131 with triethylsilane in the presence of BF3· OEt2 at −40 °C afforded 132 (99% yield), containing the αanomer (4:1 β/α ratio determined by HPLC). Tests with several silanes and DIBAL showed that the steric bulk of the silane influenced the selectivity of the reduction, which was up to 45:1 (β/α) when using triisopropylsilane (Scheme 23A). Coupling lithiated 1,3-dimethoxybenzene with 130 and subsequent reduction by triethylsilane afforded β-D-glucopyranosyl-2,6dimethoxybenzene 129 in 56% yield, which was further elaborated toward C-glycosyl isoflavone puerarin.169 The cost of 2,3,4,6-tetra-O-benzyl-D-gluconolactone 130 (accessible from D-glucose via a multistep sequence) makes the persilylated analogue 133 (one-step access from D-gluconolactone) more attractive due to the easily feasible silylation/desilylation steps, and the relative stability of this protecting group to strong bases. The addition of ArLi to lactone 133170 (Scheme 23B) occurred in enhanced yields by changing the solvent from THF171 to THF/toluene or THF/heptane combinations, and using low temperatures to minimize enolization169 and desilylation. Afterward, the labile 1-C-aryl hemiketals were converted to the desilylated methyl 1-C-aryl-glucosides in MeOH acidified with MeSO3H, which were then acetylated to 134 for further convenient manipulation. Reduction of methyl glycosides 134 to C-glycosyl compounds 135 with Et3SiH showed that the C-2 acetoxy group did not participate in the delivery of the hydride resulting in high β-selectivity of the transformations. A reaction calorimetry study revealed that the reactivity order according to the substituted phenyl/aryl moieties was 4-OMe > 3,4,5-tri-OMe > 4-Me > 2-naphthyl > 3-Me > 4-Cl. On multikilogram scale, reductions were sometimes incomplete, and to reach total conversion the addition of 1 equiv of water and more than 2 equiv of BF3·OEt2 was necessary. This system generated presumably a strong Brønsted acid, but the electron-rich 1-Canisyl methyl glucoside 134 (R = 4-OMe) reacted well under anhydrous conditions.170 With these improvements, this route appeared to be advantageous on any scale, and was developed further for preparing various SGLT2 inhibitors (see section 2.7). While the neighboring acetyl groups do not participate to stabilize the glycopyranosylium by anchimeric assistance, the

Scheme 21. C-Glycosyl Arenes from 1,2-Anhydro Carbohydrates

yield (Scheme 21), but only Ph2CuLi yielded the pure β-anomer, as expected according to a SN2-type substitution at the anomeric carbon atom. In contrast, use of the more oxophilic AlPh3 reagent favored the oxirane opening with formation of an ion pair 124, including a glycopyranosylium, preferentially attacked from the α-side possibly by directed addition. In this way, 123 was converted to either α- or β-anomers of 125 by simply changing the counterion on the aryl nucleophile.160 Similar preferential formation of 125 α-anomer was observed when Brønsted or Lewis acids were used as additives.161,162 Several other glucal and galactal derived epoxides with O-pivaloyl and O-silyl protection were studied under these conditions.162 1,2-Anhydro-glucoses and arylzinc derivatives (obtained in situ from boronic acids) gave similar products.163 1,2-Cyclopropanated carbohydrates164 are reactive analogues, and compound 126 has been ring-opened by [Pt(C2H4)Cl2]2 in Scheme 22. C-Glycosyl Arenes from 1,2-Cyclopropanated Carbohydrates

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spectra with earlier data obtained from a 4:1 α/β mixture,172 should be taken with caution.173 2-Deoxy and 2,6-dideoxy glyconolactones, for example, 136 and 137174,175 (and also the O-permethylated 2-deoxy-Dgluconolactone and O-perbenzylated 2-deoxy-D-galactonolactone), have been used for the synthesis of C-glycosyl arenes by reaction with Grignard or aryllithium reagents. Reducing the ensuing hemiketals with NaBH3CN afforded selectively the corresponding β-configured aryl derivatives (138, 139) in high yields (Scheme 24). On the other hand, dehydration of the hemiketals by use of the Martin sulfurane ([PhC(CF3)2O]2SPh2) or trifluoroacetic anhydride (TFAA) delivered

Scheme 23. Syntheses of C-Glycosyl Arenes from (A) Benzylated or (B) Trimethylsilylated Glyconolactones

Scheme 24. 2-Deoxy or 1,2-Unsaturated C-Glycosyl Arenes from 2-Deoxyglyconolactonesa

Method A: PhMgCl, THF, −78 °C; then NaBH3CN, EtOH, pH < 4.5, 50 °C.175 Method B: PhMgCl, THF, −78 °C; then [PhC(CF3)2O]2SPh2 (Martin sulfurane), CH2Cl2.175 Method C: ArLi, THF, −78 °C; then pyridine, DMAP, TFAA.174 a

the corresponding 1,2-unsaturated C-glycosyl arenes 92, 140 in high yields, regardless of the method applied (Scheme 24 and section 2.4 for other routes from glycals to related products). In this context, a 3-deoxy-gluconolactone was also used in the total synthesis of paecilomycin B.176 Treating 2-azido-2-deoxy-3,4,6-tri-O-benzyl-D-galactonolactone (141) with pOMePhMgBr to give 142, followed by reduction (Et3SiH, BF3·OEt2), afforded the corresponding βconfigured 1-C-anisyl intermediate 143 (72% yield), which, based on the well-developed chemistry of the azido group, was further elaborated to D-galactosamine derivatives (Scheme 25A).177 The benzylated 2-nitro-D-glucal 144 was predominantly converted into β-anomers of the corresponding C-(2-deoxy-2nitro-glucosyl)arenes 145 by using aryl-lithium reagents.178 Under the same conditions, the analogous D-galactal and Larabinal reacted less selectively. Transformation of 145 (Ar = Ph) into the N-acetyl-glucosamine derivative 146 was achieved by reduction with zinc metal in acidic conditions and subsequent acetylation of the crude mixture (Scheme 25B).

predominantly axial hydride attack has a stereoelectronic basis.170 This idea is supported by other data on the Lewis acid promoted silane reduction of the anomeric position in the case of 1-C-phenyl D-glycopyranoses (D-gluco, D-manno). These compounds were conformationally labile (2,3,4,6-tetra-O-benzyl) or rigid if a 3,4-diketal or 4,6-benzylidene moiety maintained the pyranosyl ring in the 4C1 conformation within a trans-decalin structure. The conformation restriction strategy improved the yields to 90−95% in both D-gluco and D-manno series. The two 2,3,4,6-tetra-O-benzyl-1-C-phenyl-D-glycopyranoses reduced with Et3SiH/TMSOTf (1.1 equiv each, CH2Cl2, −78 °C) afforded only β-configured products such as 132 in 50−60% yield, with ∼20% starting material recovered. However, in the Dmanno series, this allegation, based on comparison of 1H NMR

2.4. Cycloaddition Reactions To Form Aglycons of C-Glycosyl Arenes

The synthesis of C-glycosyl compounds bearing complex polycyclic aromatic moieties, such as gilvocarcins, kidamycins, or those derived from anthracyclinones, has created the need to elaborate methods for the construction of such complex aromatic systems on carbohydrate substrates. Diels−Alder cycloadditions were applied for the synthesis of C-glycosyl naphthalene derivatives through a benzyne generated in situ from 2-chloro1,4-dimethoxybenzene (Scheme 26).179,180 The reaction was performed either with 2-furyl180 (147) or with 3-furyl179−181 1701


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synthetic step for the formation of the anthraquinone precursor was achieved using nBuLi to generate the benzyne moiety, which underwent an intramolecular [4+2] cycloaddition to generate intermediate 157. Further basic treatment created the silanol 158 from which acidic treatment generated the desired C-glycosyl compounds 159. Saptomycin B and pluramycin A were also attained although through slightly different synthetic strategies.189,190 Access to C-glycosylated benz[a]anthraquinones was reported by addition of peracetylated 2-deoxy-glycosides to naphthalene moieties followed by [4+2] cycloaddition to afford angucycline antibiotics.191,192 C-Glycosyl anthraquinone could be obtained by cycloaddition of C-glycosyl-butadienes and naphthoquinones under InCl3 catalysis followed by oxidation.193 The [2+2+2] cycloadditions provided a general access to Cglycosyl arenes through Ru-catalyzed benzannulation,194−196 carried out on C-glycosyl acetylene 160 (Scheme 28). In the presence of 5 mol % of the catalyst, cycloadducts 161 were obtained in high yields195 from terminal diynes, whereas the use of an internal diyne required 10 mol % catalyst load to furnish the product 162 in a similar yield.194 Spirocyclic C-ribosyl arenes were also obtained by using this synthetic methodology.197 (C-Glycosyl-aryl)-O-glycosides 164 were prepared by benzannulation of C-glycosyl acetylene 163 and O-glycosidic chromium vinylcarbene complexes198 (Scheme 29).

Scheme 25. Approaches to C-Glycosaminyl Arene Derivatives from (A) a Glyconolactone or (B) a 2-Nitroglycal

2.5. Sugar Chain Closure Methods toward C-Glycosyl Arenes

Closure of a chiral polyhydroxylated chain attached to an aryl moiety represents another entry to C-glycosyl arenes (Scheme 30). Intramolecular cyclization often occurs through hydroxyl group addition to a carbonyl function when one or the other become unmasked. This was notably the case for ketone 165 after cleavage of the isopropylidene group,199 and for alkene 167,200 after oxidative cleavage of the exo-methylene group to generate a ketone. The hemiketals (like 168) formed primarily were converted in acidic methanol to the methyl glycoside 166 or reduced stereoselectively to afford C-2-deoxy-glycosyl arenes 169, respectively. Another strategy exploited the diol 170, which, in an appropriate solvent and at low temperature, cyclized stereoselectively upon Lewis-acid activation to deliver C-2deoxy-glycosyl arenes 171 again in high yields.201 In a different route, the Wittig−Horner adduct 172 easily cyclized in the presence of NIS202 to give two epimeric iodosugars 173 with the p-anisyl group projecting to the α-face, as determined by X-ray diffraction analysis. Subsequent transformations, among them notably the RuCl3−NaIO4 oxidation of the anisyl residue at controlled pH, afforded the β-methyl

(149) C-glycosyl compounds leading to isomeric structures 148 and 150, respectively, which were further elaborated into Cglycosyl antibiotics such as galtamycinone.180,181 A similar approach was also used involving Pd-catalyzed opening of a benzyne-furan cycloadduct with an intermediary Zn-glycal obtained from 1-iodoglycal 151 followed by oxidation and further elaboration into the dihydronaphthol and reduction of the glycal into the 2-deoxy C-glycosyl compound 152.180 Synthetic methods to get C-glycosyl furans are compiled in section 3.1.1. The Diels−Alder reaction could also be performed intramolecularly182 by using a silicon tether between the furan and the latent benzyne moieties (generated in situ with nBuLi) as an access to vineomycinone B2 methyl ester,183−185 isokidamycin,186,187 or 5-hydroxyaloin A188 (Scheme 27). The silicon tether was introduced in a general 3-(C-glycosyl)furan scaffold 153 by lithiation of the furan moiety. Next, hydroborationoxidation of the alkene 154 provided the alcohol intermediate 155, and Mitsunobu conjugation with the appropriate dihalogenated-phenol afforded the desired ether 156. The key

Scheme 26. Diels−Alder Cycloadditions as a Route to C-Glycosyl Naphthalene Derivatives

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Scheme 27. Intramolecular Diels−Alder Approach to C-Glycosyl Arenes and Representativesa

a

Gly corresponds to the sugar part or a precursor of it present in the natural products shown in the box.

Scheme 28. Synthesis of C-Glycosyl Arenes via Ru-Catalyzed [2+2+2] Cycloaddition

Scheme 29. C- and O-Diglycosylated Biphenyls by Chromium-Templated Benzannulation

glycoside of protected KDO 174 in good yield. This highlights the fact that aryl groups can be taken as masked carboxyl groups. Unsaturated alcohol 175 readily obtained from tri-O-benzyl-Dglucal (Scheme 30) was cyclized to the 2-deoxy-β-glucoside 138 by ring closing with phenyl selenyl chloride followed by reductive removal of the 2-selenophenyl moiety. Cyclization of 175 in the presence of NBS and reduction of the 2-brominated intermediate afforded the 2-deoxy-α-glycoside 122.203 Similarly, cyclization of

5-phenylpentenols with selenium electrophiles led to C-(2,3dideoxy-2-arylselenyl-D or L-glycosyl)benzenes.204 These ring-closure methods appear to be powerful tools for preparing elaborated carbohydrate derivatives. Most probably, this field will develop further, as suggested by a recent de novo approach to carbohydrates in which the acyclic precursors were obtained by tandem α-chlorination-aldol reactions with dynamic kinetic resolution.205 1703


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Scheme 30. Chain Closure Methods to C-Glycosyl Arenes

centers in one step (Scheme 31). The Z or E geometry of the enols 176 and 178 governs the stereochemistry at the allylic alcohol position in 177 and 179, respectively.207 Ring-closing metathesis was used for the formation of the pyranoid ring (Scheme 32). The diol 180 was converted into ketal 181, and then the alkyl bromide was converted to the alkene 182.208 Ring-closing metathesis afforded the pyranoid intermediate 183, which was converted to the polyol 184. The aromatic moiety was then oxidized to the carboxylic acid toward KDN 185209 or N-acetyl-neuraminic acid 186.210 An analogue of 183 with a 2-furyl moiety in place of the homoaromatic substituent was also prepared; however, the furan ring did not survive the attempted further functionalization.

The ene/intramolecular Sakurai cyclization was applied to the synthesis of pyranosyl C-nucleosides

206

creating four stereogenic

Scheme 31. Ene/Intramolecular Sakurai Cyclization toward C-Glycopyranosyl Arenes

Scheme 32. Ring-Closing Metathesis Strategy toward Neuraminic Acid Analogues

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Scheme 33. Pd-Catalyzed Cross-Couplings of C-1-Metalated Glycals and Glycal Boronic Acid Derivatives

2.6. Unsaturated C-Glycosyl Arenes from Glycals and Their Derivatives

papulacandins (see section 2.8). Compounds 187 (e.g., from 189) were reacted with chlorosilanes followed by a transformation to the corresponding silanol, which was coupled with elaborated iodoarene derivatives to yield 192 (route b). Formation of boronic esters was achieved by reacting 187 with B(OMe)3 followed by pinacol, and the intermediate was coupled with bromoarenes to give 192 in quantitative yields (route c).220 The method was also applied to the synthesis of di-Omethylbergenin.220 Formation of the above pinacol-boronate was controversial; therefore, 187 (from, e.g., 188) was transformed with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (iPrOBpin) to give the glycal derived boronic acid pinacolate almost quantitatively (route d).221 Both pinacolates (route d) and free boronic acids (route e) were subjected to cross-coupling to give 192 in high yields, and 187 derived from 190 was further elaborated toward papulacandin and bergenin.221 The boronic ester could also be installed at the C-1 position of glycal 191 through Ir-catalyzed C−H activation (Scheme 33, route f). Condensation of compound 193 with 2-chloro-benzyl alcohol under Pd-catalysis and subsequent spirocyclization under

Formation of C-glycosyl arenes with a 1,2-double bond was observed and even developed to a synthetic utilization in the reactions of aryl-metal reagents with glycosyl chlorides (Scheme 16) and with glyconolactones (Scheme 24). Nevertheless, the main routes to get C-glycosyl arenes with unsaturation in the sugar ring are based on glycals: (a) 1-C-substituted glycals retaining the 1,2-unsaturation can be obtained from C-1metalated or -iodinated glycals; and (b) the well-known Ferrier rearrangement when performed with arene nucleophiles gives 2,3-unsaturated derivatives; early aspects of both type of chemistries were incorporated in reviews.46,211,212 In several cases, the double bond was further functionalized by standard methods to get saturated sugar rings toward biologically active compounds; however, these transformations will not be detailed here. 2.6.1. 1,2-Unsaturated C-Glycosyl Arenes. C-Glycosyl arenes with a 1,2-unsaturation are most frequently made from C1-metalated glycals. Formation of C-1-lithiated glycals (e.g., 187 in Scheme 33), the general entry point to such precursors, was studied very carefully already in the nineties as to the base and suitable protecting groups (preferentially tBuLi and silyl, frequently TIPS).46 Early transmetalations, especially to stannyl derivatives, and ensuing cross-coupling were also reviewed.46 Additions of various C-1-lithiated glycals with TBS protection and also with a 3-deoxy-3-dimethylamino function to benzo- and naphthoquinones, as an extension of the “reverse polarity” approach to C-glycosyl natural products,46 were in particular applied toward the syntheses of ravidomycins and pluramycins.213,214 C-1-Lithio-glycals (187, Scheme 33) were also transmetalated, thereby modulating the nucleophilic character of the C-1 carbon atom, followed by cross-coupling with halogenated aromatic moieties under Pd-catalysis to afford the 1,2-unsaturated Cglycosyl compounds 192. Thus, in a one-pot procedure, 188 was converted into organoindium derivatives,215 which reacted with aryl iodides to give 192 (route a). C-Glycosyl silanes and silanols were extensively studied216−219 in the light of syntheses of

Scheme 34. Palladium-Mediated Synthesis of C-Glycosylated Phenylalanine Derivatives

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products 203.227 The reaction proceeded with poor stereocontrol slightly in favor of the β-anomer. The reaction with 2naphthol could also be catalyzed with Zn(OTf)2,228 Bi(OTf)3, Bi(OTf)3−SiO2,229 HClO4−SiO2,230 and H2SO4−SiO2231 leading predominantly to the α-anomer. Catalysis with molybdenum salts was also reported with phenol and anisole but provided moderate yields and stereoselectivities.232 The Lewis acid character of organoindium compounds has also been exploited to get 2,3-unsaturated C-glycosyl arenes 204 by using triaryl indiums (Scheme 37, route b also with D-galactal, 233 D-allal, and L-rhamnal besides 85). All three aryl groups participated in the reaction because substoichiometric amounts of triaryl indium delivered the corresponding products 204 in high yields (e.g., 86% with 0.33 equiv of InPh3), while the stereoselectivity strongly depended on the sugar configuration (e.g., α/β 1 to 6:1 for D-glucal and L-rhamnal, 10:1 for D-galactal). Reaction of in situ prepared arylzinc-chlorides with 85 in the presence of BF3·OEt2 also gave access to 204 (Scheme 37, route c).234 A similar transformation without Lewis acid was carried out on 202 to yield 205 with much better stereoselectivity wherein the steric bulk of the 6-O-TBS protecting group might play a role (Scheme 37, route c).235 The addition of diphenylzinc to 85 and 202 in the presence of trifluoroacetic acid led to C-glycosyl arenes 205 and 206, respectively, in high yields (Scheme 37, route d).234 With an areneboronic acid as the coupling reagent and Pd(OAc)2 as the catalyst,236 the C-glycosyl compound formation was possible due to the regio- and stereoselective syn-addition of ArPdOAc to the glycal 85 in CH3CN. This was followed by a βanti elimination of Pd(OAc)2 involving the acetoxy substituent at the 3-position, to generate the 2,3-unsaturated 1-C-substituted compounds 206 (Scheme 37, route e). In several other cases studied, formation of a byproduct 207 was observed, which even predominated when the aromatic moiety was electron-rich. Conversely, 206 was the sole product if the reaction was conducted in a 6:4 toluene/EtOH solvent mixture, or applied to 3,4-di-O-acetyl-6-deoxy-L-glucal. (−)-6-epi-Centrolobine was prepared using this methodology.237 An earlier study based on the same reaction conditions reported similar α-stereoselectivity and yield (except when the aryl was a p-anisyl group), without mentioning the formation of open byproducts.238 Further, 2,3dihydroxylation or epoxidation of the unsaturated bond in diversely protected analogues of 206 (Ar = phenyl) provided phenyl derivatives linked to C-D-allo- and -mannopyranosyl moieties, thus providing additional analytical data particularly interesting in the D-manno series.157 An efficient Heck-type C-glycosylation was achieved from glycal 85 by using aryl hydrazines to provide 206 in good yields (Scheme 37, route f).239 The stereoselectivity was in favor of the α-anomer for D-glucal and D-galactal, while mixtures of anomers were obtained with D-allal. Reactions of glycals (e.g., 85) under Pd-catalysis were also reported with arylsulfinates240 or arenesulfonyl chlorides241 (Scheme 37, route g) to give C-glycosyl arenes 206. Compounds of type 209 could also be prepared from a 2,3unsaturated glycoside 208 with Grignard reagents (Scheme 38): with Ni-catalysis242 β-anomers were obtained and further elaborated to liquid crystalline materials, while under Pdcatalysis,243 an α-anomeric derivative 210 was achieved and transformed into a C-mannopyranosyl-phenylalanine. Ferrier-type addition of arene nucleophiles was also investigated with 3,4-anhydro-glycals (Scheme 39). Specifically protected D-glucal 211 was treated with a strong base to give the

acidic conditions afforded a diastereosiomer of spiroacetal 194.222 Palladium-catalyzed cross-coupling reactions were used to create the carbon−carbon bond in C-glycosyl analogues of phenylalanine (Scheme 34). The cross-coupling of a metalated glycal 195 or 196 with an iodoaryl derivative afforded the desired C-glycosyl compound 197 (see section 3.1.4.1 for C-glycopyranosyl tryptophans synthesis). Both Stille223 (195, Z = Sn(nBu)3) and Negishi224 (196, Z = ZnCl) conditions were tried, and the latter proved more efficient in terms of yield of the product 197. Scheme 35. Desulfitative Stille Cross-Couplings from Glycals

Scheme 36. Ligand-Controlled C-Glycosylation of Arenes by Iodo-glycals

The use of arylsulfonyl chlorides under Stille conditions provided an additional access to C-glycosyl arenes 199 through desulfitative couplings of stannyl glycal 198 (Scheme 35).225 N-(8-Quinolyl)benzamides were C-glycosylated in the ortho position by O-TIPS-protected iodoglycals (D-glucal 151, and also D-galactal, L-rhamnal) in a ligand directed Pd-catalyzed C−H functionalization reaction (Scheme 36). Without ligand such as the L-proline derivative (L) and K2CO3 as the base, bis-Cglycosylated 201 was formed in high yield, while optimized conditions in t-amyl alcohol−water mixture in the presence of NaHCO3 gave the mono-C-glycosylated 200 as the main product, which was further transformed into spirocyclic and other compounds.226 2.6.2. 2,3-Unsaturated C-Glycosyl Arenes. 2,3-Unsaturated C-glycosyl arenes were synthesized from O-peracetylated glycals. Transformation of glucal 85 (Scheme 37, route a) using phenols under InCl3-catalyzed Ferrier rearrangement conditions provided the O-glycoside intermediates, which underwent an O → C rearrangement (see section 2.2.1) to the C-glycosyl 1706


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Scheme 37. Ferrier Rearrangements of Glycals with Arene Nucleophiles

Scheme 38. Syntheses of 2,3-Unsaturated C-Glycosyl Arenes from O-Glycosides

Scheme 40. Reaction of Glycals with Bromomagnesium Phenoxides under Ultrasonic Activation

rated C-glycosyl analogues with an inverted configuration of the 4-OH group.245 When hindered bromomagnesium phenoxides were reacted with glucal 85, the Ferrier products 214 were obtained in moderate to high yields and with high α-stereocontrol (Scheme 40).246 The open byproduct (207, Scheme 37) observed in Pdcatalyzed reactions of 85 with boronic acids236 was reinvestigated and further transformed selectively into 2,3-unsaturated C-aryl derivatives (for other ring closures, see Scheme 30).203 The Ni-

Scheme 39. C-Glycosylation from 3,4-Anhydro-glycals

Scheme 41. Ring-Opening−Ring-Closing Sequence toward 2,3-Unsaturated C-Glycosyl Arenes

3,4-epoxide 212, which, without isolation, was reacted with metalated arenes. While PhLi provided a high yield (93%) and complete β-stereocontrol, the selectivity was poorer with Grignard reagent PhMgCl to produce the corresponding 2,3unsaturated (C-glycosyl)benzene 213 with an inverted configuration of the 4-OH group.244 The same synthetic sequence starting from D-galactal provided the α-configured 2,3-unsatu1707


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with arylboronic acids using Pd(OAc)2 as catalyst and an oxidant.249 With benzoquinone 2-deoxy-3-keto-C-glycosyl compound (223, route a), with DDQ enone 224 (route b), and with Cu(OAc)2/O2 enol ether (225, route c) were formed from the silylated glucal 222 (D-galactal, L-rhamnal, and D-ribal were also studied). The O-acetylated analogue of C-glycosyl arene 223 could also be attained from the 3-keto-glycal under Rh(I)catalysis using an aryl boronic acid.250 These products are the result of carbopalladation and anti β-elimination (to afford 225), followed by desilylation and either hydrolysis (to afford 223), or another anti β-elimination to yield the enones 224. The condensation of 215 and 222 with an aryl halide was followed by a syn β-elimination with the substituent still present at the 3position to afford 225 (Scheme 43, route d).251,252 Benzyl (215) and silyl (222) protecting groups were required because acetyl moieties (85) did not perform in such reaction. Earlier studies of the Heck reaction applied to glucal 85 (acetyl and analogues) and the corresponding sugar-derived enones showed also the formation of mixtures of C-phenyl (and C-hetaryl) derivatives. In the products, the pyranosyl ring was 2,3-unsaturated, and/or of the ketone, enone, or enol ether types.253 Utilization of 2 equiv of boronic acid with Pd(OAc)2 and TEMPO as an oxidant provided access to 1,2-diaryl-substituted 1,2-dideoxy glycosides in good yields (60−80%) in a TEMPO-promoted domino Heck−Suzuki arylation.254 The reaction of glucal 222 with a more elaborated iodo-arene under Pd-catalysis (route d) was applied in syntheses of anomeric spiroacetals.255 Decarboxylative Pd-catalyzed cross-couplings were performed with a series of variously protected glycals of different configurations (e.g., 85) providing the corresponding 2,3unsaturated 2-deoxy-C-glycosyl compounds of type 225 with complete α-stereocontrol (Scheme 43, route e).256

catalyzed coupling of phenyl boronic acid with 3,4,6-tri-Obenzyl-D-glucal 215 provided the open-chain derivative 175 (Scheme 41). The reaction was much faster and gave optimal yields (93%) under microwave activation, and could be performed also with O-perbenzylated D-galactal, D-xylal, 2benzyloxy-D-glucal, and 2-acetoxy-D-glucal. The ring closure was Scheme 42. Unsaturated C-Glycosyl Arenes from 2-Formyl Glycals

then performed under acidic catalysis leading to either the 2,3unsaturated α- or β-glycosyl arenes 216 using Ph3PHBr or Sc(OTf)3, respectively. The benzylated 2-formyl glucal 217 was converted into the 2,3-unsaturated C-glucosyl benzene 218 with α-stereoselectivity by an organocopper reagent (Scheme 42).247 The O-methylated 2-formyl galactal 219 was transformed into the allylic acetate 220 as a π-allyl precursor. Further treatment with alcohols provided the expected O-glycosides, while only one example in the series afforded the C-glycosyl p-cresol 221 with β-stereoselectivity (Scheme 42).248 Several other parallel methodologies involving Pd-catalyzed Cglycosylation by glycals have been also developed (Scheme 43). Oxidative Heck-type C-glycosylations of glycals were studied

2.7. Synthesis of SGLT2 Inhibitors

The C-glycosyl arene scaffolds of the approved SGLT2 inhibitors (see section 5.1.3) were obtained mainly by nucleophilic addition of an aryl-metal to a conveniently protected D-gluconolactone but also from 1,6-anhydro-glucose derivatives or by using a ringopening−closure strategy. A recent and partial overview257 has been reported, but the present section will provide a more

Scheme 43. Miscellaneous Pd-Catalyzed C-Glycosylations with Glycals

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Scheme 44. (A) Synthetic Sequence toward Tofogliflozin and Ipragliflozin; and (B) Synthesis of Luseogliflozin

comprehensive survey of this specific, nevertheless highly valuable topic by summarizing the C-glycosylation chemistry. 2.7.1. From Benzylated Gluconolactone. The Operbenzylated D-gluconolactone 130 was mostly applied to the synthesis of tofogliflozin.258 The initial synthesis of tofogliflozin started from 130, which, upon addition of a lithiated aromatic intermediate, provided the hemiketal 226 (Scheme 44A). Subsequent detritylation and concomitant ketalization afforded the benzyl alcohol 227.258 Improved synthetic procedures were investigated separately on a chloro-substituted analogue starting from 130 and with a particular attention to the hydrogenolysis of the benzyl ethers to avoid reduction of the chloroaromatic moiety.259,260 Nevertheless, the multigram scale synthesis of tofogliflozin was finally designed from the trimethylsilyl protected D-gluconolactone 133 (see section 2.7.2) providing better yields, avoiding hydrogenolysis side-products and also several column chromatographies.261 Ipragliflozin262 (a nonspiro derivative, Scheme 44A) and luseogliflozin263 (a nonspiro and 5thioglucose analogue, Scheme 44B) were also attainable through this lactone 130 or its 5-thio analogue 228 but will not be discussed in detail here. 2.7.2. From Trimethylsilylated Gluconolactone. The 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone 133 is the most common intermediate used for the synthesis of SGLT2 inhibitors. It is a readily available starting material from the commercially available, cheap D-gluconolactone, and the O-silyl protecting groups are more suitable to large-scale synthesis264 than the benzyl ethers suffering from side-products formation during troublesome hydrogenolysis259,260 or during reduction of the methyl glucoside.264 The typical addition of a lithiated aryl derivative to 133 (Scheme 45) was influenced by the solvent composition, and a mixture of THF and toluene proved optimal for this step to provide the methyl glucoside 230.265−268 Reduction with triethylsilane provided the desired C-glucosyl arenes 231. This synthetic sequence was also applied to deuterium269 (dapagliflozin) or 13C/14C labeled analogues270 (empagliflozin) for in vivo biological evaluation and metabolism studies. Ton scale synthesis of the SGLT2 inhibitor empagliflozin by thorough optimization of this methodology resulted in a

Scheme 45. Synthetic Route toward SGLT2 Inhibitors from Trimethylsilylated Gluconolactonea

a *In a ton scale synthesis of empagliflozin, iPrMgCl·LiCl in THF and Et3SiH/AlCl3 in CH2Cl2/CH3CN were used in the 133 → 230 and 230 → 231 transformations, respectively.

process involving four chemical steps without isolation of the intermediates.264 A multidecagram scale synthesis of tofogliflozin was also reported with an overall yield of 50% in seven synthetic steps and without column chromatography.261 The influence of the substituents at the distal aryl ring was carefully investigated in vivo,271 while macrocyclic analogues with a chain connecting the 6-hydroxyl group with the aryl moiety provided a series of subnanomolar ligands of hSGLT2.272 Other tofogliflozin analogue inhibitors have been reported with modified aglycons, further nourishing the structure−activity relationships for this biological target.273,274 Syntheses of bexagliflozin,275 ertugliflozin,276 and canagliflozin277 were also based on this chemistry. The multikilogram scale synthesis of ertugliflozin was achieved in eight steps from the trimethylsilylated D-gluconolactone 133 (Scheme 46).276 The formation of the C-glycosidic bond was achieved as usual by addition of a lithiated aryl derivative, and then the methyl glycoside was installed and the trimethylsilyl 1709


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Scheme 46. Synthesis of Ertugliflozin and Henagliflozin from Silylated Gluconolactone

Scheme 47. Ring-Opening−Closure Strategy toward Ertugliflozin

Scheme 48. Synthesis of Canagliflozin from 1,6-Anhydro-Dglucose

ethers removed with sodium hydroxide to afford intermediate 232. Resilylation and regioselective removal of the 6-Otrimethylsilyl group was performed to obtain the primary alcohol 233, which was not isolated but immediately oxidized to aldehyde 234 under Parikh−Doering conditions. Subsequent aldol-Cannizzarro reaction afforded the pentol 235. The dioxabicyclic structure of ertugliflozin was then generated under acidic conditions using p-toluenesulfonic acid supported on silica (SilaBond tosic acid = Si−TsOH). In some cases, an Lphenylalanine complex was developed and used to purify and isolate the desired compound, and all steps were implemented at multikilogram scale.278 A synthetic route from O-perbenzylated D-gluconolactone 130 was reported on a multigram scale through similar key synthetic steps but organized differently.279 Henagliflozin, an analogue of ertugliflozin with a fluorine attached to the distal phenyl ring, was obtained analogously.49 2.7.3. Through Chain Closure. The chain closure strategy was applied successfully to obtain the SGLT2 inhibitor ertugliflozin280,281 with industrial scale syntheses.276,279 The synthesis was initially achieved from diacetone-D-mannofuranose, and the aryl substituent was introduced using a 2-aryl-1,3dithiane.281 Nevertheless, this strategy was abandoned, and the manno-configured starting material was replaced by glucosebased lactones (Scheme 47).276,279,280 The glucose-derived alcohol 236 was oxidized to the aldehyde, and a hydroxymethyl group was introduced in a one-pot aldol-Cannizzaro reaction to give 237.280 Protection of both primary alcohols, removal of the allyl ether, and oxidation provided the lactone 238. Ring opening of the lactone to the Weinreb amide intermediate 239 followed by addition of a lithiated aryl derivative afforded compound 240. Partial epimerization at the α-carbon to the ketone with the OBn group was observed. Acidic cleavage of the PMB ethers triggered

the ring closing to the desired dioxa-bicyclo[3.2.1] scaffold, and further hydrogenolysis of benzyl ethers afforded ertugliflozin. 2.7.4. Other Approaches. Arylalanes were recently applied to the synthesis of the canagliflozin SGLT2 inhibitor avoiding the use of conventional protecting groups on the glucose moiety (Scheme 48). The highly diastereoselective reaction was initially investigated with silyl ether protecting groups at positions 2 and 4 of 241 and also allowed for the preparation of the diaryl-chloroaluminum intermediate 243 from the corresponding brominated precursor 242.282 The study was then pushed to the limits using the nonprotected 1,6-anhydro-β-D-glucose 241 affording 61% yield (HPLC) of canagliflozin, which was then isolated in 50% yield along with a recovery of 33% of the starting material.283 The preparation could be performed in a single synthetic step and 1710


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2.8. Synthesis of Spiro-bicyclic C-Glycosyl Arenes: The Papulacandin Case

provided a high isolated yield of the desired C-glycosyl compound. This strategy has not yet reached industrial scale synthesis, and some aspects must be considered such as (1) the amount of arylating agent (2 equiv) should be diminished, and (2) lower temperatures should be used. The authors indicated that preliminary results in that direction might be possible with Ti- or Ga-based arylating agents.283 It is worth pointing out that a

Recent reviews have described the main routes to papulacadins,218,284 a series of antifungal agents with a glucose core conjugated to 1,3-dihydroxyphenyl moieties through a Cglycosidic bond and with a fatty acid chain attached by esterification of the glucose 3-OH group (Scheme 50). Several syntheses were reported for the formation of the bicyclic spiroketal moiety of these natural products. An original de novo approach was designed through the condensation of βphenylsulfonyl dihydrofuran 244 and D-arabinono-1,4-lactone 245 leading to the desired spiroketal 246 in good yield (40%) and complete stereocontrol.285 Another de novo approach started from the furan derivative 247, which was converted into the spiro-bicyclic core of papulacandins in three steps,286,287 leading to the 2,3-unsaturated intermediate 248, which was then dihydroxylated to the manno- or allo-configured C-glycosyl compounds. Further isomerization of the manno-diol provided in four synthetic steps the desired gluco-configuration of papulacandins.287 The galacto-configured analogue of papulacandin 250 was synthesized through another de novo strategy in which the carbon chain was prefunctionalized with hydroxyl groups and a ketone (249). Subsequent bis-acetalation under acidic catalysis with the hydroxyl groups of the benzylic alcohol and formation of the thermodynamically favorable pyranose ring on the other side of the molecule provided the desired galactoderivative 250.288 A similar strategy was then applied for the synthesis of gluco-, allo-, and altro-configured analogues.289

Scheme 49. Synthesis of Dapagliflozin and Canagliflozin from Pivaloyl Protected D-Glucosyl Bromide

synthesis of epi-canagliflozin was possible from the 1,2-anhydroD-glucose derivative although with O-pivaloyl protecting groups.162 The reaction of Ar2Zn species with the pivaloylated D-glucosyl bromide 104 (2−3 g scale) afforded the C-glucosyl intermediates 105, which were then deprotected under Zemplén conditions to yield dapagliflozin and canagliflozin (Scheme 49).150

Scheme 50. Retrosynthetic Strategies toward Papulacandin D Indicating the Sugar Precursors and Their Aromatic Reaction Partners Involved in the Key Step of the Synthesis

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Table 2. C-Glycosylation of Furans in Position 2

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Table 2. continued

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Table 2. continued

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Table 2. continued

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Table 2. continued

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Table 2. continued

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Table 2. continued

The most representative examples for the total synthesis of papulacandins are derived from the modification of a glucose

derivative for the formation of the anomeric C−C bond. The synthesis started from the trimethylsilylated gluconolactone 133, 1718


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Mg(ClO4)2) induced opening of the pyranose ring of the Cglycosyl-heterocycle, followed by the reaction of the formed benzylic type cation with a hetarene resulting in dihetaryl openchain sugar derivatives such as compound 278. A C-glycosylation strategy using 2-carboxybenzyl glycosides 39, 262 as glycosyl donors was reported (entry 8) to give, in the presence of at least equimolar amounts of 2,6-di-tert-butyl-4methylpyridine (DTBMP) and a heterocyclic acceptor, the corresponding furan derivatives 271, 272, respectively, with good α-stereoselectivity.108 In syntheses of C-glucosyl furans160,161 273 and 274 (entry 9) from glycal epoxide 123 and metalated furans, the temperature and the counterion had an important role in the stereochemical outcome of the reactions. Under properly chosen conditions, it was possible to obtain either β (273) or α (274) anomeric product from the same glycosyl donor. For more details about the ring opening of glycal epoxides by carbon nucleophiles, see section 2.3, Scheme 21. Reaction of aryl-alanes with a partially O-silylated 1,6-anhydroβ-D-glucose 263 (entry 10) to give 275 proceeded with complete β-stereoselectivity; however, an excess of the alane reagent or a preliminary deprotonation was required to block the free OH group of the starting sugar.282 A common method for the synthesis of C-glycosyl compounds is the addition of an organometallic reagent to a lactone followed by the stereoselective reduction of the resulting hemiketal. This procedure was applied to the synthesis of 2-glycosylfuran 276 from 264 (Table 2, entry 11)180 and 3-glycosylfurans 149, 281, and 282 from lactones 264, 136, and 280, respectively (Table 3, entries 1−3).180,181,183,184 Vineomycinone B2 methyl ester was synthesized from 282 in a multistep procedure (see section 2.4, Scheme 27).184 Spiroketal moiety can be found in many biologically important natural products. Multistep transformations of furyl ketose-type compounds, for example, 277 obtained from lactone 130 (Table 2, entry 12), offer access for complex spiroketal derivatives for example 279.297 Michael addition of lithiated furan to 2-nitroglucal 144 (Table 3, entry 4) gave exclusively the β-anomeric 3-glycosylfuran 283. It has been shown that 2-deoxy-2-nitroglucose derivatives are suitable precursors for the preparation of glucosamine derivatives (Scheme 25).178 A synthetic route toward the tetrahydropyran unit of Lasonolide A, a marine natural product with potent activity against several tumor cell lines, through 2-glycosylfuran 287 was reported (Scheme 51).298 Wittig olefination of hemiacetal 284 and isomerization of the geometrical isomeric mixture with tri-nbutyltin radicals gave the pure E-configured alkene 285. Electrophilic addition of phenyl selenyl chloride to 285 followed by intramolecular ring closure resulted in tetrahydropyran 286. The reaction proceeds via a chairlike conformation where the preferred equatorial position of the C-2 and C-6 substituents leads to the formation of a single diastereomer. Reduction of the selenide resulted in 287, which was transformed into the target molecule in several further steps. A unique dimerization upon action of a Lewis acid on 3-deoxyD-glucal (288 eq) or -galactal (288 ax) gave 2-C-glycosyl-glycals 289 (Scheme 52), which were transformed by ozonolysis and deformylation into hemiketals 290 whose acidic treatment furnished C-glycosyl furans 291.299 3.1.2. Thiophenes. Glycosylation methods using glycosyl bromides 95,149 104,150,154 chlorides 261,82 1,2- (292),162 and 1,6-anhydro glucose (263)282 derivatives, aldonolactones262,300

which was reacted with the lithiated anion of the bromo-aromatic derivative 251 to afford a lactol that was converted to the desired spiroketal under acidic catalysis in 45% yield.290 The same synthetic strategy was used for the study of the regioselective acylation of the glucose moiety,291 but also for the further elaboration of this intermediate into saricandin analogues.292 The lithiated glycal 252 was also engaged in a condensation with the quinone 253 to afford a C-glycosyl intermediate, which was further converted into the target papulacandin core.293 More recently, the preparation of a glucal silanol 254 provided a rapid and efficient access to the spiro-bicyclic core of papulacandins through condensation with the iodo-arene 255 and to the total synthesis of papulacandin D.219 A [2+2+2]-strategy294 was also used through the condensation of gluconolactone 130 with (2trimethylsilyl)ethynyllithium and reaction of the lactol intermediate with trimethylsilylated propargylic alcohol to afford the bis-silylated intermediate 257. Further condensation with acetylenes under Ru-catalysis afforded the desired cycloadducts 256 in good yields (78−86%). Similar spiro-bicyclic natural products were prepared by enyne metathesis followed by a Diels−Alder cycloaddition with quinone derivatives leading to Cglycosyl arenes.295

3. SYNTHESIS OF C-GLYCOPYRANOSYL HETARENES For the syntheses of C-glycopyranosyl hetarenes, most of the general methods to directly conjugate the sugar and the aglycon described in the previous sections were applied. On the other hand, for the construction of most of those C-glycopyranosyl hetarenes, which have more than one heteroatom in the ring, cyclizations of suitable C-glycosyl derivatives (e.g., glycosyl cyanides or acetylenes and many others) proved the method of choice. Therefore, to make the overview of this Review easier, the synthetic methods to furnish the target compounds are categorized according to heteroring types, and each of these sections includes all methods that were applied to prepare a particular C-glycopyranosyl heterocycle. 3.1. Five-Membered Heterocycles with One Heteroatom

The most common method for the synthesis of C-glycosyl compounds is the reaction of the electrophilic anomeric center of a glycosyl donor with carbon nucleophiles. Electron-rich fivemembered heterocycles with one heteroatom can themselves be nucleophilic enough to bring about the coupling; nevertheless, in many cases the more reactive metalated rings are used. The particular reactions are tabulated for furans (Tables 2 and 3), thiophenes (Tables 4 and 5), pyrroles (Table 6), and indoles (Table 7). 3.1.1. Furans. Glycosyl acetates179,186,296 258−260 (Table 2, entries 1−3) and glycosyl phosphorothioate112 41 (entry 4) in the presence of a Lewis acid and furan furnished the corresponding products 265, 147, 266, and 267, respectively. Diels−Alder cycloadducts of 2-glycosylfuran 147 were applied to the preparation of C-aryl glycosyl antibiotics186 (see section 2.4). Reactions of glycosyl bromides 95 and 104 (entries 5 and 6) with furylzinc reagents under Ni-catalyzed149 and transition metal free150,155 conditions gave the corresponding products 268, 269, respectively, in good yields (61−80%) and with high βstereoselectivity. 2-Deoxy-2-(p-tolylthio)-D-glycopyranosyl chlorides82 261 with a gluco:manno ratio of 88:12 (entry 7) were used to synthesize 2-glucopyranosyl furans 270. From the different Lewis-acid catalysts, Zn(CN)2 proved to be the best to promote the glycosylation. Other Lewis acids (e.g., SnCl4, TiCl4, FeCl3, 1719


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Scheme 51. Synthesis of a C-Glycosyl Furan by Closing the Sugar Ring

Scheme 53. Synthesis of C-Glycosyl Thiophene Derivatives by Cyclization of Open-Chain Precursors

Scheme 52. Synthesis of 2-(2,3-Dideoxyglycopyranosyl)furans by Way of 3-Deoxy-glycal Dimerization labeling biomolecules. Trichloroacetimidates 313, 315, and 316 were regio- and stereoselectively transformed into C-glycosyl dipyrromethanes 319−321 (Table 6, entry 1, R = pyrrol-2ylmethyl), which can be further converted into BODIPY derivatives.304 Stereoselective C-glycosylation of pyrrole by glycosyl bromide 95 (Table 6, entry 3) was achieved using InCl3 as a promoter305 to give a mixture of C-2 and C-3 monoglycosylated pyrroles, wherein 324 was the major component in a 3:1 ratio. Glucosyl fluoride 318 was reacted with a pyrrolyl Grignard reagent (entry 4) to give 2-β-D-glucopyranosyl pyrrole derivative 325 in 38% yield, which was further elaborated into SGLT2 inhibitors.262 (In the original publication, the structural formula and the chemical name of this compound do not correspond to each other.) 2-Deoxy-2-(p-tolylthio)-D-glycopyranosyl chlorides 261 (Table 6, entry 5) and N-methylpyrrole were reacted in the presence of Zn(CN)2 to get 2-glucopyranosyl pyrrole 326 together with diastereomeric open-chain byproducts such as compound 327.82 A glucopyranosyl analogue of the naturally occurring Cnucleoside showdomycin (331) was prepared from epoxide 123 (Scheme 54).306 N-TIPS-pyrrole was C-glucosylated in the sterically less hindered 3-position in the presence of InCl3 to give C-glucoside 329. Protecting group manipulations and oxidation yielded the target molecule 330. While showdomycin (331)

130, 133, and 2-nitroglucal 144178 as donors were applied for the C-glycosylation of thiophenes both in positions 2 (293−300) and 3 (301−304) (Tables 4 and 5, respectively). Peculiarities of these reactions were essentially the same as those described for the furan derivatives. A synthesis301 of thiophene derivatives as C-nucleoside analogues was reported in which cyclization of suitable Cglycosyl malononitrile derivatives 307, 308, obtained by silica gel-catalyzed Knoevenagel reactions of C-glycopyranosyl ethanals 305, 306, were ring closed by treatment with elemental sulfur and triethylamine to 2-glycosyl thiophenes 309, 310, which were further elaborated to thieno-pyrimidines 311, 312 (Scheme 53). 3.1.3. Pyrroles. For the direct C-glycosylation of pyrroles, glycosyl trichloroacetimidates and halides (Table 6) were reported as glycosyl donors. Pyrroles were reacted with peracetylated D-glucopyranosyl (313, 314), D-galactopyranosyl (315), D-mannopyranosyl (316), and maltosyl (317) trichloroacetimidates in the presence of boron trifluoride (entry 1) to give 2-(C-glycosyl)-pyrroles 319− 322 of 1,2-trans relative configuration.302,303 Interestingly, Cglycosylation of some 3-substituted pyrroles by 314 (entry 2) resulted in compounds 323; hence the sugar moiety entered the sterically more crowded 2-position instead of the expected 5position.303 Dipyrromethanes are precursors of 4,4-difluoro-4-bora-3a,4adiaza-s-indacene (BODIPY, 328)-type fluorescent dyes used for

Scheme 54. Synthesis of the β-D-Glucopyranosyl Analogue of Showdomycin

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anhydro-mannose 336, which was reacted with a C-2 lithiated indole derivative to afford 2-C-α-D-mannopyranosyl-indole 337 with high stereoselectivity (α/β 95:5). Compound 337 was transformed into the carboxylic acid derivative 338 in a threestep procedure. Trimethylsilyldiazomethane-mediated esterification of the carboxylic acid residue and transformation of the azido group into a Boc-protected amino group delivered an amino acid precursor. Subsequent removal of the benzyl and Boc protecting groups and alkaline hydrolytic cleavage of the ester as well as the sulfonamide groups yielded the desired product 339. Similar chemistry was performed to get D-gluco configured derivatives, and the transformation of 338 to 339 (acid) was simplified.310 Additionally, glycosylated derivatives 338 and 339 were shown to be suitable precursors for the construction of glycopeptides and glycoproteins.309−311 Other routes for the syntheses of both α- and β-Dglycosyltryptophan derivatives in the D-manno (377, 378), Dgluco (379, 380), and D-galacto (381, 382) configurations (Scheme 57) used protected glycosylacetylenes 163, 347−352 as starting materials. Sonogashira coupling with N-(2-iodophenyl)-p-toluenesulfonamide gave 340−346, which were cyclized to glycosylindole derivatives 354−360 in the presence of CuI and Et3N. After removal of the tosyl group by nBu4NF, the amino acid moiety was introduced in a Lewis acid-promoted reaction of 361−367 with chiral aziridine-2-carboxylate to give 370−376. Target compounds 377−382 were obtained after O- and Ndeprotection steps (alkaline hydrolysis and catalytic hydrogenolysis, respectively).312−315 O-Benzyl protecting groups of 365 were cleaved to obtain 2-(β-D-glucopyranosyl) indole (368), which exhibited weak GP inhibition.303 For the synthesis of 2-indolyl-C-glycosyl compounds, three modifications of the above method were reported. The first one is a cascade reaction in which the Sonogashira coupling and hydroamination were carried out in one step followed by a onepot detosylation.316 The second procedure used 2-nitroiodobenzene in the coupling reaction. Subsequent reduction of the nitro group and cyclization provided the target glycosylindole.317 The third modified procedure is a one-pot Sonogashira coupling and NaAuCl4-catalyzed heteroannulation in the presence of unprotected OH and NH2 groups.318 Formation of C-glycosyl-tryptophans was also envisaged by the Larock heteroannulation of C-α-glycosylpropargyl glycine 369 with N-protected o-iodoaniline (Scheme 57). Glucosylace-

displays antibacterial, antiviral, and antitumor activities, compound 330 did not show any meaningful activity. Biologically active pyranone derivatives often bear polyhydroxylated side chains or are fused to hydroxylated rings (e.g., compounds 66, 67 in section 2.2.3, Scheme 11). Structural analogues of such compounds were prepared from carbohydrate precursors (Scheme 55).307 Cycloaddition of alkynes 332 and a tetrazine yielded pyridazines 333, which were transformed into pyrroles 334 by a ring contraction reaction elicited by zinc dust. O-Debenzylation accompanied by spontaneous lactonization led to pyrano-pyrroles 335. Scheme 55. Synthesis of C-Glycopyranosyl Pyrroles by Heterocyclic Ring Transformation

3.1.4. Indoles. 3.1.4.1. 2-(C-Glycosyl)-indoles and Tryptophanes. α-C-Mannosyltryptophan (shown as a Na-salt 339 in Scheme 56) was discovered in 1994 as the first naturally occurring C-glycosyl amino acid derivative. It was found in ribonuclease 2 (RNase 2) isolated from human urine. Total synthesis of this molecule and related compounds was required to clear its biological functions.308 One of the first syntheses309,310 of 339, based on thorough studies of the C-glycosylation at the 2-position of variously protected indole moieties, started from O-perbenzylated 1,2-

Scheme 56. Synthesis of C-Mannosyltryptophan by C-Glycosylation

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Scheme 57. Synthesis of C-Glycosyltryptophans by Heterocyclic Ring Closure

tylene 350 was first transformed into iodoacetylene 353, which was coupled with an organozinc−copper derivative to obtain 369. Subsequent palladium-catalyzed ring closure with Ntosylated o-iodoaniline provided iso-tryptophan 383 instead of the expected C-glucopyranosyltryptophan.319 Further studies were carried out regarding the regioselectivity of Larock indole synthesis, but the factors determining the stereochemical outcome remained unclear.320 To clarify the role of C-mannosylation in peptides, a Cmannosylated and the corresponding nonglycosylated undecapeptide fragment of human erythropoietin receptor were prepared by solid-phase synthesis. Results of the comparative NMR study showed a considerable conformational difference. Enhanced NOE signals of the glycopeptide indicated a conformation stabilizing effect of C-mannosylation.321 3.1.4.2. C-Glycosylated Indoles. A specifically substituted indole was glucosylated by per-O-benzyl-D-glucopyranosyl trichloroacetimidate (384) to yield 3-glucopyranosyl indole 387 (Table 7, entry 1).322 Diversely substituted indoles were coupled with O-peracetylated glycosyl bromides 95−97, 110, and 385 in the presence of InCl3 to give the corresponding C-glycosyl derivatives 388−392 of 1,2-trans configuration in the sugar moieties (Table 7, entry 2).305 InCl3 has several advantages: it is not only a halide acceptor such as silver salts (e.g., Ag2O or Ag2CO3), but also a mild, water stable Lewis acid, which facilitates the rearrangement of the postulated indolyl-ethylidene intermediate to the desired C-

glycosyl compound. Indole and its N-methyl derivative gave poor yield of the product. Indoles having electron-withdrawing groups (e.g., 1-methyl-5-nitroindole) did not react under these conditions, while an electron-donating group (OMe) in the 5position decreased the stereoselectivity from >9:1 to 1.8:1 when the acceptor was conjugated with 95. All other substituted indole derivatives gave the desired coupled products in high yields (65− 85%) and with the expected stereocontrol. O-Perbenzylated 2′-carboxybenzyl glycosides 39, 262 and indoles (entry 3) gave, in the presence of DTBMP, C-glycosyl compounds 393, 394 (52−85%) with good α-stereoselectivity (α/β from 1.7:1 to 1:0).108 Addition of lithiated indoles to protected glucono 130322,323 (entry 4) and xylonolactone 386324 (entry 5) followed by reduction resulted in the corresponding β-configured glycosyl indoles 395 and 396, respectively. Diglycosylated heterocycles are regarded as metabolically stable mimetics of oligosaccharides.109 Both N-glycosyl (398− 402) and 2-C-glycosyl indoles (364, 366, and 412; for synthesis, see section 3.1.4.1) were C-glycosylated in position 3 with trichloroacetimidates 316 and 397 (Scheme 58) to yield the corresponding diglycosylated heterocycles 403−411, and 413− 417, respectively. These molecules may be precursors of functional glycomimetics.325 The galactose residue of the deprotected 408 was sialylated enzymatically to furnish a sialyl LewisX mimetic.326 1722


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Scheme 58. Synthesis of Diglycosylated Indolesa

a

*Combined yield.

3.2. C-Glycopyranosyl Derivatives of Five-Membered Heterocycles with Two Heteroatoms

the latter provided a 85:15 mixture of regioisomeric isoxazoles 478 and 479 in 69% yield.327 The synthesis of benzylated 3-(β-D-glucopyranosyl)-4,5dimethoxycarbonyl-isoxazole 476 was carried out from aldehyde 426 via aldoxime 434 (Scheme 59).328 In the presence of dimethyl acetylenedicarboxylate, nitrile oxide 454 was generated from 434 with N-bromosuccinimide (NBS) followed by addition of triethylamine to give C-glucosyl isoxazole 476 in 75% yield. The same procedure was applied for the synthesis of a special type of rigidified C-glycosyl amino acids in which an isoxazole ring was the linker between the sugar and the amino acid residue (480 75% and 481 68%).329 Acetonide removal followed by oxidation led to the target α-amino-acids 482, 483 in 78% and 75% yields, respectively. The direct conversion of oximes 434, 435 to 482, 483 with the corresponding ethynyl-functionalized α-amino-acid derivatives was also carried out in 72% and 66% yields, respectively.329 In the absence of dipolarophiles, dimerization of carbohydrate nitrile oxides 452-461 leads to the formation of 3,4-bisglycopyranosyl-1,2,5-oxadiazole N-oxides 462-471 in 60−96% yields (Scheme 59).327,328,330 These compounds may also appear as byproducts in the above 1,3-dipolar cycloadditions; nevertheless, their intentional preparation generally results in high yields of the bis-glycosyl derivatives. In a recent study, another ring-closing method to obtain 3glucopyranosylated isoxazole was also worked out (Scheme 60): the glucosylated phenylethynyl ketone 484 was cyclized with hydroxylamine affording the 5-phenyl-isoxazole 485 in moderate yield.333 Isoxazole derivatives C-fucosylated in the 4-position 489 and 490 (Scheme 61) were obtained from the corresponding Cglycosylated diketones 487 (R = Me and Ph) by their reaction with hydroxylamine.334 3.2.2. Pyrazoles. The preparation of two types of glycosylated pyrazoles was also accomplished from the same precursors that were used in the syntheses of the analogue isoxazole derivatives (see Schemes 60 and 61). The ring closure of ynone 484 with hydrazine acetate furnished the 3glucopyranosyl pyrazole 486 (Scheme 60),333 while the reaction of C-fucosylated diketones 487 and 488 (R = Ph) with hydrazine

3.2.1. Isoxazolines and Isoxazoles. For the syntheses of isoxazolines and isoxazoles C-glycosylated in position 3, the 1,3dipolar cycloaddition reactions of sugar nitrile oxides 452−461 with alkenes and alkynes, respectively, proved convenient methods (Scheme 59). Thus, in the presence of the corresponding dipolarophile, nitrile oxides 452−455, 458, and 459 were generated in situ from the corresponding oximes 432− 435, 438, and 439, respectively, either by base-induced dehydrohalogenation of the derived hydroximoyl chloride327 (Cl2, Et3N) or bromide328,329 (NBS, Et3N), or by oxidation with aqueous hypochlorite327 (NaOCl, Et3N). Anhydro-aldoximes (C-glycosyl formaldoximes) 430−439 can easily be prepared either from anhydro-aldoses (C-glycosyl formaldehydes) such as 426−429 in a condensation reaction with hydroxylamine,328 or from C-glycosyl nitromethanes327 440−443 with the complex [Et 3 NH][(PhS) 3 Sn] generated from SnCl 2 /PhSH/Et 3 N (Scheme 59). Direct dehydration of nitromethanes 441, 443− 445 to nitrile oxides 453, 459−461, respectively, by TDI (toluene-2,4-diisocyanate) was also reported.330 Anhydroaldononitriles (glycosyl cyanides) 418−421 can be converted to anhydro-aldose semicarbazones 422−425, respectively, with Raney-Ni and sodium−hypophosphite in water−acetic acid− pyridine in the presence of semicarbazide. Subsequent transimination with hydroxylamine in acetonitrile−pyridine yields the anhydro-aldoximes 430−432, respectively.331 C-Glycosyl isoxazolines 446−448 and 472−475 were prepared in reactions of oxidatively generated nitrile oxides 453, 458, and 459 (obtained from nitromethanes 441−443 via oximes 433, 438, and 439) with methylenecyclohexane, styrene, norbornene,327 and norbornadiene,332 respectively (Scheme 59). For the preparation of isoxazolines 448−451, the nitrile oxides 452, 458, and 459 were obtained from oximes 432, 438, and 439 by chlorination and subsequent HCl elimination, the latter step being carried out in the presence of styrene, allyl alcohol, and a 4C-vinyl furanose derivative, respectively.327 This method was extended to the syntheses of C-glucosyl isoxazoles 477−479 by reacting nitrile oxide 458 with dimethyl acetylenedicarboxylate (yield of 477: 98%) and ethyl propiolate, respectively, whereby 1723


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Scheme 59. Syntheses of 3-C-Glycosyl Isoxazoles and Isoxazolines

Scheme 60. Syntheses of 3-(C-Glucosyl) Isoxazole and 3-(CGlucosyl) Pyrazole

3.2.3. Thiazoles. The synthesis and synthetic uses of 2-Cglycopyranosyl thiazoles 495 (also as formyl C-glycosyl compound equivalents), accessible by addition of 2-lithiothiazole to aldonolactones 130 and subsequent deoxygenation of the resulting hemiketal 493 via acetate 494 (Scheme 62), were authoritatively reviewed.335 In the context of this survey, it is mentioned that compounds 495 and 496 were transformed in several steps via compounds 497−499 into variously substituted 2-(C-glucopyranosyl)-4- or 5-benzyl-thiazoles for evaluation as SGLT inhibitors.336 For the construction of 2-C-glucopyranosyl thiazoles, the Hantzsch reaction between thioamides and α-bromo-ketones provided another reliable method. 4-Aryl-2-glucopyranosylthiazoles 501 were produced by cyclization of glucosyl thioformamide 500 with α-bromo-ketones (Scheme 63).333 A

monohydrate gave the 4-fucosyl pyrazoles 491 and 492, respectively, in high yields (Scheme 61).334 1724


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Scheme 63. Syntheses of C-Glycosylated Thiazoles by RingClosing Methodology

Scheme 61. Syntheses of 4-C-Fucosyl Isoxazoles and Pyrazoles

Scheme 64. Synthesis of 4(5)-C-Glycopyranosyl Imidazoles (D/L)-2-deoxy-glucopyranosylated analogue of tiazofurin was achieved in a similar manner after building up the tetrahydropyrane unit by tandem ene/intramolecular Sakurai cyclization followed by crucial functionalization.206 Synthesis of thiazole derivative C-galactosylated at the 5position (503) was effected by a ring closure of C-galactosyl αbromoketone 502 with thiourea (Scheme 63). The resulting aminothiazole 503 was acylated, sulfonylated, or alkylated, and then the carbohydrate moiety was deprotected to provide ligands of Viscum album agglutinin and galectins (see section 5.2).338,339 3.2.4. Imidazoles. During the synthesis of a series of 6,7,8tri-O-benzyl-imidazolo[1,5]-D-gluco-piperidinoses, like 507 (Scheme 64) from the L-ido configured sulfonate 504, the formation of anomeric C-arabinopyranosyl imidazoles 505 and 506 as major products was observed.340 It is to be noted that similar cyclizations proved strongly configuration dependent: the analogous L-gluco, L-manno, L-gulo, and D-altro configured sulfonate derivatives gave the expected piperidinoses 507, while the D-allo compound gave 4(5)-α-L-lyxofuranosylimidazole exclusively.340 2-C-Glucosyl imidazoles 509 (Scheme 65) were achieved by ring-closure of amidine 508 with α-bromo-ketones in the presence of an acid scavenger.333 Somewhat better yields of 509 were obtained from imidate 510 with α-amino-ketones.303 It is to be noted that besides these imidazoles only one other can be Scheme 62. C-Glycosylation of Thiazolesa

a

*Et3SiH−TMSOTf and SmI2−(CH2OH)2 are other frequently applied reagent combinations for the preparation of compounds type 495.337 1725


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3.2.5. Benzazoles. The only direct C-glycosylation of a benzazole-type compound was reported for 2-glycopyranosyl benzothiazoles illustrated by 512 and 513 obtained from the respective aldonolactones 130 and 511 and 2-lithiobenzothiazole (Scheme 66).342,343 Analogous chemistry was also reported in the L-f uco series.344 C-Glycopyranosyl benzothiazoles 512 and 513 were transformed into the corresponding C-glycosyl aldehydes, which are versatile intermediates for the design of glycomimetics.335 Other C-glycosyl benzothiazoles 518, 519 were obtained by heterocyclic ring-closing reactions (Scheme 67): glucopyranosyl cyanide 514 was condensed with 2-aminothiophenol to give 518 (68%),345 while nitrile oxides generated from hydroximoyl chlorides 530 and 532 in the presence of 2-aminothiophenol produced C-glycosyl benzothiazoles 518 (81%) and 519 (90%), respectively.346 Hydroximoyl chlorides 530−532 were converted into the corresponding C-glycosyl benzoxazoles 515−517 (Scheme 67, yields 61−71%).346 The synthesis of C-glycosyl benzimidazoles was carried out by ring-closure methods in several different ways (Scheme 67). Glucopyranosyl cyanide 518 was converted to ethyl-thioimidate hydrochloride 534 by an acid-catalyzed addition of ethanethiol to the nitrile group.345 Reaction of 534 with o-phenylene-diamine (OPD) gave benzimidazole 520, albeit through a low yielding overall sequence (34%). Thioimidate 535 and imidate 510 were reacted with OPD to afford C-glycosyl benzimidazole 520 (62% from 535 and 89% from 510). Because of its higher stability, imidate 510 was used for the preparation of several other substituted benzimidazoles (yields: 46−83%).76 The analogous O-perbenzoylated 2-β-D-xylopyranosyl benzimidazole 521 was also obtained from the corresponding imidate 536 in 80% yield.347 The classical method for benzimidazole synthesis (i.e., reaction of a carboxylic acid with OPD under acidic conditions)

Scheme 65. Synthesis of 2-(C-Glucosyl) Imidazoles

Scheme 66. C-Glycosylation of Benzothiazole by Aldonolactones

found in the literature,341 which was prepared by addition of lithiated imidazole to O-perbenzylated D-glucono-1,5-lactone and subsequent reductive removal of the hemiacetalic OH.

Scheme 67. Syntheses of C-Glycosylated Benzimidazoles, Benzothiazoles, and Benzoxazoles

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Preparation of C-glycosyl-1,3,4-oxadiazoles 561−565 was carried out in two different ways. 1,3-Dipolar cycloaddition of cyanides 418, 514 with azide ions provided 5-glycosyl-tetrazoles 555, 556, which were converted into 2-glycopyranosyl-5substituted-1,3,4-oxadiazoles 561, 565, respectively, by acylation with acid chlorides, anhydrides, or carboxylic acids/DCC systems.345,351,352 Starting with cyanide 549 and applying the same synthetic strategy, tetrazole 557 and the corresponding 1,3,4-oxadiazole 566 were also prepared353 to form their cyclopentadienyl Ru(II) complexes for cytotoxic assays.354 Alternatively, reductive transformation of cyanides 418−421 in the presence of acylhydrazines351 or condensation of an Oisopropylidene protected β-D-arabino-hexos-2-ulo-2,6-pyranose with benzoylhydrazine353 yielded 2,6-anhydro-aldose acylhydrazones 550−554, respectively, from which oxidative ring-closure provided 2-aryl-5-D-glycopyranosyl-1,3,4-oxadiazoles 561− 564351 and 566,353respectively (Scheme 68). Syntheses of amino-oxadiazoles were also carried out. Thus, amidoxime 548 was reacted with carbodiimides or Vilsmeyer salts (obtained in situ from the corresponding ureas and oxalyl chloride) to give 3-β-D-glucopyranosyl-5-(mono- or dialkyl)amino-1,2,4-oxadiazoles 567 in variable yields (Scheme 69).355 2-Acylamino-1,3,4-oxadiazoles 571 (Scheme 70) were prepared by acylation of 2,6-anhydro-aldose semicarbazone 422 to compounds 569 whose oxidative cyclization resulted in the desired oxadiazoles 571.356 3.3.2. Thiadiazoles. Similarly to the synthesis of the above 2acylamino-1,3,4-oxadiazoles 571, construction of the analogous 1,3,4-thiadiazoles 572 was also investigated (Scheme 70). Acidcatalyzed trans-imination of 422 with thiosemicarbazide gave thiosemicarbazone 568, which was then acylated providing diastereomeric mixtures of the 4-acyl-2-acylamino-5-glucosyl-

was also studied. Anhydro-aldonic acid 533 failed to react even at elevated temperature.345 On the other hand, in the presence of triphenylphosphite and with microwave heating, acid 533 and OPD gave moderate yield of the expected 520 (45%).76 C-Glycopyranosyl benzimidazoles 525−529 were also achieved by acid-catalyzed condensation of O-unprotected Cglycopyranosyl methanals 537−541 obtained from the corresponding dimethyl acetals 542−546 with OPD (Scheme 67).348 Strongly acidic cation-exchange resin in the H+ form or hydrochloric acid were applied as catalysts. The reaction must proceed via benzimidazolines (not shown) whose spontaneous oxidation affords the final products 525−529 in 51−73% yields. Another route for the preparation of C-glycosyl benzimidazoles 522−524 was developed from hydroximoyl chlorides 530− 532 and OPD in ethanol via putative nitrile oxides (Scheme 67, yields 62−89%).346 3.3. C-Glycopyranosyl Derivatives of Five-Membered Heterocycles with Three Heteroatoms

For the syntheses of the title heterocycles, glycosyl acetylenes and glycosyl cyanides are widely used precursors. Their transformations are most frequently effected by 1,3-dipolar cycloadditions and/or by conversions into other functionalities suitable for heterocyclizations as detailed in the next sections. 3.3.1. Oxadiazoles. In searching for new glucose-based inhibitors of GP, our research groups have synthesized three series of isomeric C-glycosyl-oxadiazoles (Scheme 68). Amidoximes 547 and 548 treated with carboxylic acids or acid chlorides provided the 3-β-D-glucopyranosyl-5-substituted-1,2,4oxadiazoles 558 and 559.349 1,3-Dipolar cycloaddition of nitrile oxides to glucopyranosyl cyanide 418 furnished regioisomeric 3substituted-5-β-D-glucopyranosyl-1,2,4-oxadiazoles 560.350,351 Scheme 68. Syntheses of Isomeric C-Glycopyranosyl Oxadiazoles

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Scheme 69. Synthesis of 5-Amino-3-β-D-glucopyranosyl-1,2,4oxadiazoles

Scheme 72. Synthesis of 3,5-Bis-C-glycopyranosyl-1,2,4thiadiazoles and 3-C-Glycopyranosyl-Δ2-4,1,2-oxathiazolin5-ones

Scheme 70. Synthesis of 5-Acylamino-2-β-D-glucopyranosyl1,3,4-oxa- and -thiadiazoles

syl)-1,2,4-thiadiazoles 578−581 was observed: potassium bromate and sodium dithionite gave the best results in CH2Cl2−H2O biphasic solvent mixtures (Scheme 72).357 For the construction of 3,5-disubstituted-1,2,4-thiadiazoles 582, 583 with different substituents (Scheme 72), the use of 5(β-D-glycopyranosyl)-1,3,4-oxathiazol-2-ones 586, 587 as feasible sources of nitrile sulfides was investigated. Compounds 586, 587 were obtained from amides 584, 585 with chlorocarbonylsulfenyl chloride; however, preliminary attempts to get 1,2,4thiadiazoles failed.358 3.3.3. Triazoles. 3.3.3.1. 1,2,3-Triazoles. Development of the Cu(I)-catalyzed azide−alkyne cycloaddition359 (CuAAC) paved the way for the synthesis of carbohydrate-derived 1,4disubstituted-1,2,3-triazoles using relatively accessible azido and acetylenic carbohydrate derivatives.360−364 In this way, a large variety of 1-substituted-4-C-glycosyl-1,2,3-triazoles were prepared, which are collected in Table 8. Synthesis of chemically and metabolically stable mimics of glycopeptides may uncover new bioactive candidates for drug design. With this motivation, some 1,2,3-triazole-linked glycosyl amino acids 591−594 329,365,366 and glycopeptides 595, 596367,368 were prepared in the Cu(I)-catalyzed reaction of the corresponding glycosyl acetylenes 350, 163, 352, and 588 with azide-functionalized amino acids and dipeptides, respectively (Table 8, entries 1 and 2). For the inhibition of SGLT2, a series of 4-(β-D-glucopyranosyl)-1-(het)arylmethyl-1,2,3-triazoles 597 was synthesized from O-peracetylated glucosyl acetylene 588 with the corresponding azides (entry 3).369 Among a variety of rapamycin triazole glycoconjugates designed to modify the physicochemical properties of the natural product, C-galactopyranosyl-1,2,3-triazole was attached to the C40 position (598, entry 4).370 Among other sugar derivatives, C-galactopyranosyl ethyne 589 was used in a CuAAC-mediated ligation for the preparation of carbohydrate-coated silica gel (e.g., 599 in entry 5), which was applied as stationary phase in hydrophilic interaction chromatography to separate monosaccharides, amino acids, or flavonoids.371 Applicability of ionic liquids (ILs) in CuAAC reactions was investigated to find a new solvent system that suits the

Δ2-1,3,4-thiadiazolines 570. Subsequent oxidative transformation gave the target 2-acylamino-1,3,4-thiadiazoles 572.356 1-(2′-Amino-1′,3′,4′-thiadiazol)-5′-yl-β-D-arabinopyranose (574) was achieved by Fe(III)-mediated oxidative ring-closure of the corresponding thiosemicarbazone 573 (Scheme 71).353 In a study of the reactivity of 2,6-anhydro-aldonothioamides (C-glycosyl thioformamides) 500, 575−577 under various oxidative conditions, the formation of 3,5-bis(β-D-glycopyranoScheme 71. Synthesis of C-Glycosyl 2-Amino-1,3,4thiadiazole

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blocks and intermediates provided a set of further oligomers up to the length of hexadecamer.377,378 Construction of some cycloglucopyranosides having 1,2,3triazole linkers was performed with the use of suitable linear building blocks (Scheme 74).379 Cycloaddition of alkyne 613 with azide 614 and subsequent azidation of the resulting disaccharide at the C6 terminus followed by desilylation of the anomeric ethynyl moiety afforded the triazole-coupled disaccharide 615. This compound was subjected to intramolecular CuAAC yielding the target cyclodimer 617 (m = 2). The preparation of further cyclooligomers with larger cavities (617, m = 4, 6) was carried out in a similar manner after modular synthesis of the linear triazole-linked tetra- and hexaglucopyranosides 616 (n = 2, 4). The complexation peculiarities of the Odeprotected derivatives of 617 as cyclodextrin analogues were examined with the hope of having potential for applications in molecular recognition processes. A fluorescent assay of 617 (m = 2, 4, 6) with 8-anilino-1-naphthalene-sulfonate (ANS, an often used model ligand of cyclodextrins) revealed that the inclusion complex of cyclohexamer 617 (m = 6) with ANS had higher fluorescence intensity in comparison to the reference βcyclodextrin-ANS complex. In addition, the binding properties of cyclotetramer 617 (m = 4) in complex with phenylalanine hydrochloride determined by 1H NMR spectroscopy were found to be similar to those exhibited by the parent α-cyclodextrin.379 A series of O- and C-galactosylated divalent structures having C-glucopyranosyl-1,2,3-triazole spacers was designed for testing their inhibitory activity toward Pseudomonas aeruginosa lectin LecA. To this end, synthesis of the coupling cores was based on the cycloaddition of ethynyl C-galactoside 618 with azido

requirements of green chemistry. The test reactions between ethynyl C-galactoside 352 and different azide containing compounds (entry 6) revealed the superior effectiveness of a polyoxygenated ionic liquid, Ammoeng 100.372,373 Some 1,4-diglycosylated 1,2,3-triazoles were achieved for various biological assays. Treatment of O-perbenzylated α-Lfucopyranosyl acetylene 590 with O-peracetylated β-D-galactopyranosyl-azide in the presence of CuI gave the cycloadduct 601 in 75% yield (entry 7).109 A 1,4-diglycosylated 1,2,3-triazole having a pyrrolizidine-type iminosugar moiety at the N1 position of the triazole ring (602, entry 8) was formed for glycosidase inhibition.374 1,2,3-Triazole-containing sialyl Lewisx mimetics were constructed in the reaction of O-perbenzylated α-Dmannopyranosyl- and α-L-fucopyranosyl acetylenes with 3-Osialylated galactopyranosyl-azide (603, 604, entry 9).326 Extensive work was carried out to construct 1,2,3-triazolelinked (1,6)-α-D-oligomannoses.375 The alternating linear oligomers 607 were built up starting from alkyl 6-azido-α-Cmannoside 605 by applying repetitive CuAAC steps with the use of α-C-mannosyl ethyne 606. The intermediary azide-functionalized coupling partners 608 were achieved by azidation of the terminal C-6-OH group of cycloadducts 607 (Scheme 73A).376 1,2,3-Triazole-tethered 6-deoxy-α-1,6-oligomannosides 612 were also obtained from ethynyl 6-deoxy mannoside 609 with 3-hydroxy-3-methylbutynyl 6-azidomannoside 610, where the iterative cycle of the chain-elongation consisted of the cycloaddition and the liberation of the free ethynyl group of the resulting glycoconjugates 611 (Scheme 73B).377 Furthermore, combinations of the above orthogonally functionalized building

Scheme 73. Synthesis of 1,2,3-Triazole-Linked Oligomannosides from (A) an Alkyl 6-Azido-α-C-mannoside or (B) an Ethynyl 6Deoxy Mannosidea

a

Iteration of the reaction steps was performed n + 1 times. 1729


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Scheme 74. Synthesis of 1,2,3-Triazole-Linked Cycloglucopyranosides

have been relatively unknown until recent years. Cycloadditions (Scheme 77) and heterocyclic ring-closing reactions (Scheme 78) proved applicable to get such compounds. Glucosyl cyanide 514 treated with aromatic hydrazonoyl chlorides in the presence of Yb(OTf)3 furnished 1,3,5trisubstituted-1,2,4-triazoles 638 (Scheme 77).384 In contrast to an earlier procedure where analogous triazoles were obtained from unstable 1-aza-2-azoniaallene intermediates,385 this process required simpler reaction conditions. Several methods were elaborated for the synthesis of 3-β-Dglycopyranosyl-5-substituted-1,2,4-triazoles. Tetrazoles 555 and 639 were imidoylated by freshly prepared N-benzyl-carboximidoyl chlorides to give the fully protected Cglycosyl-1,2,4-triazoles 640 and 641 in moderate to good yields (Scheme 77). The N-benzyl protection was removed by catalytic hydrogenation.347,386 Ring-closing reactions toward 1,2,4-triazoles 643−645 were carefully studied (Scheme 78), because several unexpected transformations could be observed in the course of these investigations. 1,2,4-Triazoles 643 could be formed from acylamidrazones 642 (obtained from the corresponding acyl chloride 647) or imidoyl-amidrazones 646 at elevated temperature. Tosyl-amidrazone 655 and acyl chlorides gave N-tosyl-triazoles 648 which either lost the tosyl moiety spontaneously or could be detosylated by TBAF to furnish 643. On the other hand, acylation of amidrazone 656 (actually a transposition of the sugar moiety and the R1 substituent around the acylamidrazone core when compared to the 647 → 642 → 643 sequence) resulted in 1,3,4-oxadiazoles 561, which were also formed in reactions of amidine 508 or imidate 510 with acylhydrazines.387,388 These

compound 619 followed by terminal azidation of the cycloadducts as outlined in Scheme 75 for compounds 620 and 623. Attachments of the resulting linkers (e.g., 620 and 623) to the ethynylated galactose derivatives 624, 625, and 626, respectively, furnished the variously combined linear oligomers 627− 630.380,381 Formation of C-glycosyl-1,2,3-triazoles from unprotected glycosyl acetylenes was part of a set of “orthogonal” reactions used to selectively introduce carbohydrate moieties into suitably engineered proteins, thereby mimicking post-translational modifications and also allowing precise protein modifications in a designed manner.382 An efficient and regioselective method was worked out for the formation of trisubstituted 1,2,3-triazoles by applying Cu(I)/ Cu(II) as catalysts (Scheme 76).383 Perbenzylated glucosyl bromoalkyne 631 was treated with p-nitrobenzylazide in the presence of CuBr to give the 5-bromo compound 632 in 99% yield, while with the use of CuI, the 5-iodo derivative 633 was also observed as a byproduct (yield of a mixture of 632 and 633: 63% in 95:5 product ratio). 1,5-Disubstituted-1,2,3-triazoles (634−637, Figure 2) were also obtained using C-glycosyl ethynes and organic azides. Compounds 634, 635,329 and 636372 were achieved in uncatalyzed thermic reactions as concomitant regioisomeric pairs of the corresponding 1,4-cycloadducts 592, 593, and 600 (Table 8), respectively, while the 1,5-diglycosylated heterocycles 637 were solely produced by applying the Ru-catalyzed variant of the azide−alkyne cycloaddition.109 3.3.3.2. 1,2,4-Triazoles. Despite the multifaceted biological and other uses of the 1,2,4-triazole ring, its C-glycosyl derivatives

Figure 2. 5-(C-Glycosyl)-1-substituted-1,2,3-triazoles. 1730


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Scheme 75. Synthesis of 1,2,3-Triazole-Linked Pseudooligosaccharides

unexpected selectivity issues were explained by DFT calculations.387 In analogy with the oxidative ring closure of 2,6-anhydroaldose acylhydrazones to yield C-glycopyranosyl-1,3,4-oxadiazoles (Scheme 68), the behavior of 2,6-anhydro-aldose imidoylhydrazones 649−651 under oxidative conditions was also studied (Scheme 78). The use of several reagents (Pb(OAc)4, K3[Fe(CN)6], MnO2, KMnO4, HgO, DDQ,

PIDA) led to multicomponent mixtures in which the desired 1,2,4-triazole was present only in minor or trace amounts. Surprisingly, the reaction of 649−651 with NBS resulted in rather stable bromo derivatives 652−654, which could even be purified by silica gel column chromatography. Ring closure of 652−654 was effected under moderately basic conditions to give the expected triazoles 643−645. This method was also 1731


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Scheme 76. Cu(I)-Catalyzed Synthesis of 5-Halogeno-1,4disubstituted-1,2,3-triazoles

Scheme 79. Syntheses of 3-Glucopyranosyl-1,2,4-triazolones

Scheme 77. Cycloadditions toward C-Glycosyl 1,2,4-Triazoles

amidrazone 655 with ethyl chloroformate gave the 1-tosyltriazolone 658, while intramolecular cyclization of the N1carbamoyl-amidrazone 657 resulted in the unsubstituted heterocycle 659. The 1-aryl-substituted derivatives 662 were obtained either by Cu(II) catalyzed N-arylation of triazolone 659 or by ring-closure of N4-glucopyranosyl-semicarbazides 660 and 661.390 3.4. Six-Membered Aromatic Heterocycles

C-Glycopyranosyl derivatives of six-membered aromatic heterocycles have much less been studied in contrast to those of the five-membered rings. Syntheses of series of C-glycosylated dihydropyridines and dihydropyrimidines were performed by applying Hantzsch and Biginelli-type cyclocondensations, respectively, and this chemistry was authoritatively reviewed.391,392

generalized for the synthesis of 3,5-disubstituted-1,2,4-triazoles from alkylidene-amidrazones.389 Recently, some 3-glucopyranosylated 1,2,4-triazol-5-ones were also synthesized (Scheme 79). Treatment of N1-tosyl-

Scheme 78. C-Glycosyl 1,2,4-Triazoles by Heterocyclic Ring Closures

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Scheme 80. Syntheses of C-Glucopyranosyl Pyridine, Pyrazine, and Pyridazine Derivatives

preparation of C-glucopyranosyl pyridazine 666, an open-chain precursor (i.e., the γ-keto ester 663) was obtained starting from 130 in seven steps. Ring closure of 663 with hydrazine followed by oxidation and chlorination steps afforded the pyridazine derivative 666.336 Compounds 664−666 were further elaborated toward SGLT inhibitor candidates (see section 5.1.3). 4-Glycopyranosylated pyridazines as precursors of sugar-based pyrano-pyrroles were produced by inverse electron-demand Diels−Alder reaction of glycosyl ethynes with 1,2,4,5-tetrazine3,6-dicarboxylate (see 333 in Scheme 55).307 2-(2′-Deoxy-2′-nitro-β-D-glucopyranosyl)-pyridines 667 were formed by nitro-Michael addition of lithiated pyridines to 2nitroglucal 144 (Scheme 81).178 Preparation of some 2-glycosylated 3-aryl-quinoxalines 669 was accomplished by a consecutive three-step procedure (Scheme 82) consisting of a Sonogashira coupling of alkyne 668 with iodobenzenes, oxidation of the resulting arylated alkynes to diketones, and their cyclocondensations with 1,2diaminobenzene.393 Similarly to the preparation of C-glycopyranosyl benzimidazoles (Scheme 67), glycosyl nitrile oxides were successfully used for the construction of C-glycosyl perimidines 671−674 (Scheme 83).394,395 Treatment of 530−532, 670 with 1,8diaminonaphthalene at ambient temperature gave the target glycopyranosyl heterocycles 671−674 in moderate to good yields. At higher temperature, β-elimination of acetic acid from the 1,2-positions of the glycopyranosyl moieties also took place; thus the corresponding 1-C-hetaryl-glycal derivatives were isolated as the main products in 34−43% yields (see section 3.5.1, Table 11).

The construction of C-glucopyranosyl pyridine, pyrazine, and pyridazine scaffolds is shown in Scheme 80. Pyridine 664 and pyrazine 665 derivatives were achieved by the addition of the corresponding lithiated heterocyclic reagents to gluconolactone 130 followed by reduction of the resulting hemiketals.262 For the Scheme 81. Synthesis of 2-Glucosylated Pyridines from 2Nitroglucal

Scheme 82. Synthesis of 3-Aryl-2-glycosyl-quinoxalines

Scheme 83. Synthesis of C-Glycopyranosyl Perimidines

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3.5. Unsaturated C-Glycosyl Hetarenes

compounds 704−709 are listed in Table 11 describing the reaction conditions and indicating the scheme that shows the related main reactions. 3.5.2. 2,3-Unsaturated Derivatives. C-(2,3-Unsaturatedglycosyl) hetarenes 712 were obtained from variously protected D-glucals in Ferrier-type rearrangements elicited by various Lewis acids in the presence of the parent heterocycles (Table 12). The reactions proceeded with varying stereoselectivity; nevertheless, in many cases the β-anomers were reported as the main products. In several instances, the formation of isomers 713 was also observed. Uncatalyzed reactions of glycals 714, 715, and 202 with in situ prepared hetarylzinc derivatives gave the corresponding C-(2,3unsaturated-glycosyl)heterocycles 718−720 (Table 13, entries 1−3).235 Similar transformations were performed with Pdcatalysis between glycals 716, 717 and a furan boronic acid (entry 4)405 as well as an iodo-pyrimidine (entry 5)251 to give 3-(2,3unsaturated-glycosyl)-furan 721 and 6-(2,3-unsaturated-glycosyl)-pyrimidinedione 722 derivatives, respectively. Ru(II)-194,195,406 and Cu(I)407,408-catalyzed cycloaddition reactions were applied to form the heterocyclic aglycons of compounds 725−727 from 2,3-unsaturated C-glycosyl ethynes 160, 723, and 724 as summarized in Table 14.

Heteroaromatic C-glycosyl derivatives with an unsaturation in the sugar ring were prepared by the methodologies described for the homoaromatic counterparts; therefore, most of the available data are tabulated in this section. 3.5.1. 1,2-Unsaturated Derivatives. 2-Deoxy-glyconolactones 136, 137, 264, 675, and 676 were transformed into the corresponding C-(1,2-unsaturated-glycosyl)-furans 677−681 in a reaction sequence of furyl-lithium addition followed by trifluoroacetylation of the intermediary hemiketal-salt, which underwent an elimination under the basic conditions applied (Table 9).174 Several synthetic routes were elaborated toward KDO (Scheme 84) and analogues due to the potential biological activity of such compounds. In a synthetic sequence applying a chain closure strategy, a furyl glycal appeared as intermediate: acylation of thioacetal 682 yielded ester 683, which was methylenated by using the Tebbe reagent to result in the enolether 684. Methyl triflate-mediated cyclization yielded the furyl glycal 685 from which KDO and analogues were prepared by further transformations.396 Several 1-substituted glycals were converted to 1,2-unsaturated C-glycosyl heterocycles, which served as intermediates especially for the synthesis of SGLT inhibitors but also other compounds of potential biological activity. O-TIPS-protected glucal 151 (Table 10, entry 1) was coupled to furan, thiophene, and indole by a Pd-catalyzed, directed, oxidative CH functionalization yielding the respective 688−690 derivatives.226 Glycal-derived boronic acids or boronate esters 686 and 687 reacted with various heterocyclic halides under Pd-catalysis to give a variety of the corresponding C-glycosyl compounds 691− 696 (entries 2 and 3).220,221,397,398 A desulfitative cross-coupling of stannyl-glycal 198 led to the corresponding 8-substituted quinoline 697 (entry 4);225 however, the analogous 696 with different protecting groups could be prepared in much higher yield from glycal boronate (entry 3).220 To study the effect of the unsaturated glucose unit on the glycogen phosphorylase inhibitory activity, each isomeric oxadiazole ring was attached by a C−C bond to the C-1 center of glucal as depicted in Scheme 85. In the course of these studies, possibilities of constructing the heterocycle on preformed 1,2unsaturated precursors as well as the introduction of the double bond in a late stage, that is, into the C-glucosyl heterocycle, were investigated.399 Thus, bromination of 418400 to 698 followed by reductive elimination gave the glucal derived nitrile 699 (yield: 87% in two steps), which could also be obtained by a direct baseinduced elimination from 418, albeit in lower yield (50%). Transformation of 699 into the corresponding amidoxime (not shown) and subsequent acylation gave 3-(C-glucosyl)-5substituted-1,2,4-oxadiazoles 700. Oxadiazoles 560 (prepared earlier as shown in Scheme 68) on treatment by DBU gave 5-(Cglucosyl)-3-substituted-1,2,4-oxadiazoles 701 in good yields. These compounds were also obtained by 1,3-dipolar cycloaddition of nitrile-oxides with the unsaturated nitrile 699. A comparison of the overall yields showed route 418 → 560 → 701 was more advantageous. Finally, the 1,3,4-oxadiazoles 703 were achieved by introducing the double bond into the previously prepared C-glucosyl derivatives 561 (Scheme 68) in a radicalmediated bromination reductive elimination sequence via 702.399 Besides the intentional preparation of glycal derived heterocycles, in many cases the formation of such compounds occurred in undesired side-reactions. The isolated and characterized

4. C-(1-C-SUBSTITUTED-GLYCOPYRANOSYL) (HET)ARENES [BIS-C,C-GLYCOPYRANOSYL (HET)ARENES] Among the general features of C-glycopyranosyl derivatives, it was pointed out that two C-substituents attached to C-1 of pyranose rings are known with either two alkyl groups or an alkyl group and a (het)aryl moiety;80 however, the gem-bis-C,C-aryl type analogues undergo ring opening.81,82 In this section, syntheses for the existing bis-C,C-glycopyranosyl (het)arenes are surveyed categorizing the methods by the order of introduction of the aryl and the acyclic substituents. There are several methods to introduce the aromatic moiety first starting with suitably protected glyconolactones (Scheme 86). Thus, lactols 733−735 were obtained from ether protected lactones 130, 511, and 728, and the glycosidic OH was substituted by silylated nucleophiles in the presence of Lewis acids to give the bis-C,C-glycosyl compounds with cyano 736,409 allyl 737, 738,81,410 and phenacyl 739, 74081,410 groups in excellent yields. The newly introduced substituent enters from the α-face, so that the phenyl ring occupies the equatorial orientation, as evidenced by NMR analyses. In a similar approach starting with O-perbenzylated gluconolactone 130, aromatic groups ethynylated or vinylated in the ortho-position were introduced to give 729 and 731, respectively. Allyl substitution of the hydroxyl group of 729 gave the bis-C,C glycoside 730, which, after partial saturation of the ethynyl group, was cyclized to the SGLT2 inhibitor 732 (n = 2) by a ring-closing metathesis reaction. Upon reduction of 731 by Et3 SiH in the presence of BF 3·OEt 2, the intermediary glycosylium ion underwent ring closure with the vinyl substituent of the aromatic ring to give 732 (n = 1) after further manipulations.411 O-Trimethylsilylated gluconolactone 133 gave access to another SGLT2 inhibitor by a reaction with a lithiated arene derivative and subsequent treatment with methanol under acidic conditions providing the methyl glucoside intermediate412 232 (Scheme 46). Elaboration of the dioxabicyclic ring system was achieved in a long synthetic sequence providing compounds 742 (an isomer of ertugliflozin if n = 0). 1734


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Table 9. 2-(1,2-Unsaturated-glycopyranosyl)-furans from 2-Deoxy-glyconolactones174

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Table 9. continued

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Table 9. continued

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Table 9. continued

Scheme 84. Synthesis of an Unsaturated C-Glycosyl Furan by Closing the Sugar Ring

in diversification of carbohydrate derivatives. In addition, cobalt complex 752 was also prepared from alkynyl glucal 751 as a further entry to exploit the possibilities of a synthetic strategy based on the generation of Nicholas-type cations from 745, 746, and 752 in the presence of a Lewis acid. The D-gluco (745) and D-galacto (746) configured ketopyranoses showed different reactions. The hemiketalic OH in 746 was substituted with N-methylpyrrole as well as N-methylindole in the presence of a Lewis acid to yield 747 and 748, respectively. Interestingly, experiments with the D-gluco configured analogue 745 afforded Ferrier-type rearranged products 749 and 750 with an additional hetaryl substituent in position 4.80 Various C-3 branched bis-C,C-glycosyl derivatives were prepared from the complex 752. First the C-3 benzyloxy group was substituted with different C-nucleophiles to give glycals 753 in good yields and high stereocontrol. In the following step, the bis-C,C-glycosyl derivatives 754 were obtained by the regio- and stereoselective addition of pyrrole in the presence of BF3· OEt2.413,414 A 1-C-methyl glycal 755, upon oxidation by DMDO to 756 followed by nucleophilic substitution with a Grignard reagent, afforded derivatives 757 predominantly displaying an α-oriented phenyl group on the C-1 center (Scheme 88). Similar reactions

Glyconolactones were also used to introduce an aliphatic substituent first (Scheme 87). Thus, O-perbenzylated glyconolactones were the starting materials to get alkynyl ketopyranoses 743, 744, which were entry points to study the versatile applicability of the dicobalt-hexacarbonyl compounds 745, 746 1738


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Scheme 85. Synthetic Routes toward C-(1,2-Unsaturated-D-glucopyranosyl)-oxadiazoles

Scheme 86. Synthesis of C-(1-C-Substituted-glycosyl) Arenes from Glyconolactonesa

Method A: Me3SiCN, 1 equiv of I2, CH2Cl2.409 Method B: TMSAllyl or H2CC(OTMS)Ph, 0.2 equiv of TMSOTf, CH3CN, −40 °C.410 Method C: 1.5 equiv of TMSAllyl or H2CC(OTMS)Ph, 0.5 equiv of BF3·OEt2, CH2Cl2, T ≤ −15 °C.81 a

were highly dependent on the nucleophile and the 3-Oprotecting group, and variable stereoselectivities were observed.415 Reactions of allylic alcohol type derivatives of exo-glucal or -galactal 758 with areneboronic acids under Pd-catalysis (Scheme 89) gave bis-C,C-glycosyl compounds 759 from 758 (R = Ac or Me), while tautomerization of the primary product from 758 (R = H) resulted in 760 with the aryl moieties in the αposition in each case.416

A formal [4+2] cycloaddition of an aromatic imine to the electron-rich double bond (Povarov reaction) of exo-glucal 761 gave a mixture of the expected spiro-tetrahydroquinolines 762 and 763, and the quinoline 764 C-substituted by an open sugar chain (Scheme 90). Depending on the catalyst used, the product ratios were quite different: with Sc(OTf)3 764 was formed in ∼70%, while with lanthanoid triflate catalysis the ratio of the cyclic and open-chain products ((762+763)/764) was 1:1. The spiro compounds proved unstable even at room temperature and 1739


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Scheme 87. Synthesis of Bis-C,C-glycopyranosyl Hetarenes via Nicholas-Type Carbocations

Scheme 88. C-(1-C-Substituted-glycosyl) Benzenes from a 1,2-Anhydro Derivative

Scheme 89. Synthesis of Bis-C,C-glycosylidene Arenes from exo-Glycals

Scheme 90. Bis-C,C-glycosyl-spiro-quinolines by Povarov Reaction of exo-Glucal

slowly transformed into 764 by a tautomeric ring-opening/ oxidation sequence.417,418 A general strategy toward C-glycosyl analogues of neuraminic acid was designed from tri-O-isopropylidene-D-gluconate 765 with 2-phenyl-allylmagnesium bromide to provide the ketone

766 (Scheme 91).419 Reduction of the ketone, protection of the diol as a carbonate, and removal of the acetonides afforded intermediate 767, which was converted by PhSeCl into 768 by a 6-exo-trig heterocyclization. 1740


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be found among glycosidase inhibitors with either sugar derived or glycomimetic structures, such as acarbose, miglitol, and voglibose.425 Antidiabetic potential of C-glycosyl derivatives has been investigated in three main fields: inhibition of glycogen phosphorylase (GP),426 sodium-dependent glucose transporters (SGLT),47 and protein tyrosine phosphatase (PTP).427 5.1.2. Glycogen Phosphorylase Inhibitors. Glycogen phosphorylase (GP) in the liver is the main regulatory enzyme of glycogen metabolism and is directly responsible for the regulation of blood sugar levels. GP catalyzes the phosphorolytic degradation of the storage polysaccharide glycogen (glycogenolysis). On the other hand, glucose formed by the gluconeogenetic pathway is also cycled through the glycogen pool; therefore, GP is a suitable target to diminish elevated hepatic glucose production in T2DM.428 GPs (both the liver and muscle but not the brain isoforms) were thoroughly characterized by X-ray crystallography;429 therefore, these enzymes are ideal targets for structure-based430 and also for computationally driven drug design.431 GP inhibitors (GPIs) belong to extremely diverse classes of compounds,432−435 and among them glucose derivatives have been the most extensively studied inhibitors.428,436 Detailed structure−activity relationships of glucose derived GPIs can be found in the cited review articles. Figure 3 shows the most effective compounds 769−771 derived from Dglucose known to date with submicromolar Ki values, which also serve as comparisons to the GP inhibitory efficiency of C-glycosyl derivatives surveyed in this Review (Table 15).

Scheme 91. Chain-Closure Strategy toward Bis-C,C-glycosyl Derivatives as Neuraminic Acid Precursors

5. BIOLOGICAL EFFECTS OF C-GLYCOSYL (HET)ARENES 5.1. Potential Antidiabetic Agents

5.1.1. Diabetes in a Nutshell. Diabetes mellitus (especially its type 2, the so-called noninsulin dependent form: T2DM or NIDDM representing more than 90% of the cases) has become an endemic with 415 million people living with this disease in 2015 (approximately one-half of them may be undiagnosed). The corresponding data were 366 million in 2011, and the prediction for 2040 is 642 million. Healthcare expenditures are increasing accordingly from 465 (2011) to 673 (2015) and further to 802 (forecast for 2040) billion USD. Diabetes caused 5 million deaths in 2015 (4.6 million in 2011). One-half of the people who die from diabetes are under the age of 60. Deaths are mostly due to the long-term complications such as cardiovascular and kidney diseases, while other complications result in blindness and amputations. Approximately 20.9 million live births were affected by diabetes during pregnancy in 2015.420,421 All of these complications are consequences of the elevated blood sugar levels. Contrary to the etiology of type 1 diabetes, where due to the autoimmune destruction of the pancreatic β-cells insulin production is missing, T2DM is characterized by an insensitivity of tissues toward insulin-mediated uptake of circulating glucose. In addition, endogeneous glucose production of the organism, primarily in the liver, is a significant contibutor of hyperglycemia. Despite the growing knowledge of various chemical and biochemical aspects of the disease,422 the specific molecular mechanisms leading to T2DM are still unknown. Current pharmacological treatments are symptomatic and aim at maintaining the blood glucose levels close to the fasting normoglycaemic range of 3.5−6 mM. This can be achieved by an array of small molecule drugs (e.g., biguanides, sulfonylureas, thiazolidinediones, glycosidase inhibitors) and ultimately by administration of insulin.423,424 On the other hand, these antihyperglycaemic agents prove inefficient for some 40% of the patients; therefore, a lot of effort is directed toward finding new targets and drug candidates to combat diabetes.50 Both in established and in investigational therapies of diabetes, several sugar derivatives have been applied.425 Generic drugs can

Figure 3. Best glucose-based inhibitors of glycogen phosphorylase other than C-glycosyl derivatives.

C-Glucosyl benzoquinone 772 and -benzene derivatives 773− 778 proved modest GPIs (Table 15).43,437 Among heterocyclic derivatives, the first compounds studied as GPIs were 787, 525, 789, and 796.345 From these, benzimidazole 525 proved the best inhibitor due to a H-bond between the heterocyclic NH and the main chain CO of His377 located next to the active site of GP as revealed by X-ray crystallography.438 Substitution of the benzimidazole as in 788 slightly strengthened the inhibition.76 Systematic studies on oxadiazole derivatives 789−791 showed that the constitution of the heterocycle played an important role in the binding: the best inhibitors were 5-(β-D-glucopyranosyl)3-substituted-1,2,4-oxadiazoles (e.g., 791).351 Interestingly, bulky aromatic substituents resulted in inactive compounds among 1,3,4-oxadiazoles (789),351 while in the other two series 790349 and 791, the most efficient compounds featured the 2naphthyl substituent similarly to 769−771 (Figure 3). Appending side chains to either oxa- or -thiadiazoles via an amino group355,356 (792−794) or in other ways352 not depicted 1741


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Table 15. In Vitro GP Inhibition (Ki or *IC50 [μM]) of Various C-Glycosyl Arenes and Hetarenes

No inhibition at 1−8 mM concentrations. bCalculated data from the IC50 value of a mixture of 776 and 777 (140 μM, ratio of 776:777 = 0.6:0.4) and from the IC50 value of the pure 776. cNo inhibition if R is bulkier than a methyl group (e.g., Ph, 1- or 2-naphthyl). dNo inhibition at 625 μM. e Determined by N. G. Oikonomakos et al. (unpublished result in ref 351). fCalculated value from the IC50. a

786.333 In these compounds, the most probable reason for the strong inhibition is the H-bond donor capacity of the heterocycle. This can be figured out from comparisons to the analogous heterocyclic scaffolds (795 to 789−791, 786 to 785, 784 to 783), and has very recently been proven by X-ray

here gave inactive compounds. Changing the sugar part of each isomeric C-glucopyranosyl oxadiazoles to a D-glucal moiety led to a complete loss of the inhibitory effect.399 The most effective GPIs of C-glycosyl hetarenes with a nanomolar inhibition constant are the 1,2,4-triazoles (e.g., 795)386,388 and imidazoles 1742


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Figure 4. Trivalent compounds tested as inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb).

pharmacokinetics. From the SGLT2 inhibitors, which reached phase III clinical trials49,441 (Table 16, entries 1−8, 10), already six have been approved as marketed drugs (entries 1−6). Entries 11−32 feature examples of candidates obtained by the synthetic methods presented in the previous sections of this Review. Detailed surveys from the very recent years deal with the history, mode of action, syntheses, and structure−activity relationships as well as clinical advantages and concerns of SGLT inhibitors; therefore, the reader is kindly referred to those excellent articles for other peculiarities.47−49,442−457 5.1.4. Inhibition of Protein Tyrosine Phosphatase 1B (PTP1B). Insulin exerts its effects by binding to a receptor (IR) on the surface of a cell.458 The IR receptor then triggers a signaling cascade that involves sequential chemical reactions in which phosphate is added to target proteins by kinases. In fact, the insulin receptor is itself a kinase that phosphorylates target proteins or IR substrates (IRS) on specific tyrosine residues. Phosphorylation of this amino acid in target proteins serves as a switch to regulate function, thereby transmitting the effects of insulin to the machinery of the cell. The effects of the IR are countered by members of a family of enzymes called the protein tyrosine phosphatases (PTPs),459 which take the phosphate group back off tyrosine residues in proteins. Of particular importance to the downregulation of insulin signaling is the phosphatase PTP1B, which dephosphorylates the IR. In the diabetic state, an insulin molecule docks at a cell, but the cellular mechanism that sends its signal get altered. Therefore, rather than raising the insulin concentration, a more effective strategy would be to promote insulin signaling within the cell by favoring the phosphorylation events triggered by the IR, and, to this aim, inhibition of PTP1B may represent a practical strategy for the treatment of type 2 diabetes and obesity.460,461 Many PTP inhibitors contain a quinone functionality, while few carbohydrate-based structures are known as PTP1B inhibitors,459 and these facts were in line with the observed PTP1B inhibition of 850, found better than that of the Ounprotected D-gluco and D-galacto analogues (Table 17).116,462 These investigations were extended to a series of C-glucosyl 1,4benzo- and 1,4-naphtho-quinones that were found in general better PTP1B inhibitors than their analogues displaying 1,4dimethoxybenzene or -naphthalene residues.463 Most of these molecules were modified at the primary 6-position, transformed to either carboxylic, azido, or benzamido groups, or elongated by

Figure 5. Structure of the natural product phlorizin.

crystallography for 786.303 With a 3-(2-naphthyl)-1,2,4-triazole aglycon, even a xylopyranosyl derivative 797 exhibited weak inhibition,347 while several other xylose-based compounds (e.g., 798) remained inactive.347 C-Glycosyl heterocycles 779−782 with one nitrogen in the ring proved practically inactive against GP.303 Multivalent compounds were tested with glycogen phosphorylase to show very weak inhibition for the homotrivalent compounds 799 and 800 (Figure 4).439 Some other heterobivalent inhibitors of GP, based on N-glucopyranosylic conjugation, were also reported.440 5.1.3. Selective Inhibition of Sodium Glucose Cotransporter 2 (SGLT2). D-Glucose is a valuable nutrient for the body, and under normoglycaemic conditions its elimination by urinary excretion is prevented by a specific system of sodium-dependent glucose cotransporters (SGLTs), which reabsorb this sugar from the glomerular filtrate in the kidneys. SGLT2 is a low-affinity, high-capacity glucose transporter specifically expressed in the proximal tubules of the kidneys, and is responsible for ∼90% of the renal glucose reabsorption. On the other hand, SGLT1 is a high-affinity, low-capacity glucose transporter, which is also present in the intestine and heart besides the kidneys. Thus, selective inhibition of SGLT2 may result in diminishing blood sugar levels by a benign glucosuria, a mechanism independent of all other therapeutic approaches in diabetes. Development of SGLT2 inhibitors started with the natural product phlorizin (801, Figure 5) whose effect in lowering plasma glucose levels and improving insulin resistance by increasing renal glucose excretion had been known for a long time. However, its sensitivity toward hydrolysis by glucosidases, unselective inhibition of both SGLTs, and unfavorable effects of its aglycon phloretin on other glucose transporters prevented this compound from use as an antidiabetic drug. Among a wealth of molecules mimicking phlorizin’s structure, an array of C-glycosyl compounds, most of which belong to (het)aryl derivatives, exhibited the best features in terms of pharmacodynamics and 1743


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Table 16. Inhibitory Properties of Selected SGLT2 Inhibitors of the C-Glycosyl (Het)arene Type (Year of Approval and Trade Name)

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Table 16. continued

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Table 16. continued

a

ND: not determined. bUrinary glucose excretion (UGE) was measured in normal SD rats. cNI: no inhibition.

azide−alkyne click chemistry to triazole ring formation.464 As compared to acetyl groups, aryl-based protection (Bz, Bn) of the sugar hydroxyl groups proved beneficial, independent of the sugar configuration (see IC50: D-galacto 841, 1.12; D-gluco 847, 843, 848, 2.44, 2.36, 0.77; the latter showed the beneficial role of a 2-carbamoylbenzoic acid residue), and in general Ounprotected derivatives (e.g., 853, 854) were poor inhibitors. Similarly, when testing C-glycosyl 1,4-naphthoquinones for their cytotoxicity against A375 cell line (human melanoma cell), the structures displaying acetylated sugar (D-gluco, D-galacto) residues showed lower IC50 values than 1,4-naphthoquinone, while the O-unprotected ones were found inactive.115 This was also valid for triazolyl phenylalanine and tyrosine C-glucosyl hybrids 849−854 in which the amino acid carboxyl group, either free or as a methyl ester, played a role for the inhibitory activity (compare data for 849 and 851) more important than the tyrosine hydroxyl group (compare data for 851 and 852).465 To enhance the affinity to the enzyme by simultaneous binding at neighboring subsites, dimeric structures 855−862 were designed, but only the benzoylated ones 855−858 were

inhibitors, performing slightly better than a monomeric parent.464 Because of the number of existing PTPs, selectivity among this family of enzymes is crucial. PTP1B inhibitors 851 and 852 also inhibited TCPTP (T cell PTP), SHP-1, SHP-2 (SHP-PTP), but not LAR (leukocyte common antigen-related family receptor PTPs). Compound 851 exhibited a higher selectivity than 852 toward SHP-1 and SHP-2, suggesting that the OH group of the tyrosinyl residue may be involved in intermolecular contact with the SHP enzyme surface.465 Finally, alkyl- and benzyl-protected mangiferin derivatives were tested against PTP1B.466,467 Mangiferin, a natural C-glucosyl xanthone, which possess antidiabetic activity, appeared to inhibit poorly PTP1B (24% inhibition at 500 μM), but trialkyl and tribenzyl derivatives performed better (compare data for 863). 5.1.5. Miscellaneous C-Glycosyl Derivatives with Antidiabetic Potential. Antidiabetic activities (among others, like antiinflammatory, anxiolytic, antispasmodic, and hepatoprotective effects) of C-glycosyl flavonoids were reviewed.29,33 The in vivo antihyperglycemic activity of some phenolic C-glycosyl compounds including flavones468 proved comparable to that of 1746


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Table 17. In Vitro PTP1B Inhibition of Various C-Glycosyl Arenesa

a The data shown correspond to inhibition (%) for compounds tested at 20 μg/μL unless otherwise indicated, and/or IC50 (μM) given after the semicolon. bIC50 (μM). cWith sodium vanadate as control.

ity in a mouse model than the natural counterpart (R = OH, Figure 7).134 The C-glucosyl chromans or C-glucosyl vitamin E analogues 870−877 (with O-acetylated or O-unprotected sugar residues) were evaluated as antioxidants (Figure 8) in terms of their ability to inhibit the peroxidation of linoleic acid in SDS micelles. The position of the C-glucosyl moiety on the phenolic nucleus emerged as the critical determinant of their activity.75 2,3Unsaturated C-glycosyl phenols 878−883 were studied for inhibition of lipid peroxide formation in linoleate and ascorbic

the antidiabetic medication metformin. The glucose uptake enhancing activity of puerarin 864 together with C- (865) and Oglucosyl analogues469 (e.g., 866, 867) was studied (Figure 6) to show that the main effect could be attributed to the aglycon. 8-βD-Glucopyranosyl genistein 868 was shown to normalize hyperglycemia in STZ-induced diabetic rats and to prevent amyloid fibrillization occurring in diabetic patients.121 5.2. Miscellaneous Biological Studies

The synthetic fused tricyclic flavonoid 869 (R = H) displayed stronger anti-inflammatory effect against delayed hypersensitiv1747


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Figure 6. Antihyperglycemic isoflavone derivatives.

Figure 7. Chafuroside-type tricyclic flavonoids studied for antiinflammatory effect. Figure 10. D-Galactosamine derivatives binding to the asialoglycoprotein receptor (ASGPR) on hepatocytes.

acid-microsomes systems to show activity similar to that of 2(3)tert-butyl-4-hydroxyanisole (a food preservative) only in case of 881.246 Among various bicyclic C-glucosyl benzene derivatives (Figure 9), compound 884 showed strong and selective activity against cytomegalovirus,147 while the macrocyclic types 885 were screened for their antibiotic activity against Gram-positive and Gram-negative bacteria as well as yeasts and molds.148 Synthetic analogues of papulacandin 886 were tested against Candida albicans to show moderate inhibition for derivatives of linoleic (886-lin) and palmitic (886-pal) acids but no effect for those of retinoic (886-ret) and sorbic (886-sor) acids.217 An analogue of

saricandin corresponding to papulacandin D (886-sar) had no antifungal effect on the in vitro and cellular assays.292 Several 2glycosyl-benzimidazoles were screened as growth inhibitors against pathogenic yeasts, but none of them showed significant effect.348 D-Galactosamine derivatives 887−890 were tested for their affinity for the asialoglycoprotein receptor (ASGPR), a galactosebinding receptor expressed on hepatocytes (Figure 10).177 Compound 888 with a trifluoroacetamido group showed a 20-

Figure 8. Antioxidant studies with C-glucosyl chromanes (870−873), vitamin E analogues (874−877), and 2,3-unsaturated C-glycosyl phenols (878− 883).

Figure 9. C-Glucosyl benzene derivatives and papulacandin analogues studied for antiviral, antibacterial, and antifungal effects. 1748


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Figure 13. C-Galactosyl thiazoles as lectin binding blockers.

Figure 11. C-Glycosyl arenes and their complexes probed against malignant cell lines.

fold better affinity than the acetamide analogue 887, while the others 889 and 890 had affinities comparable to that of GalNAc. Several C-glycosyl (het)arenes were studied against malignant cells (Figure 11). Partially benzylated C-glucopyranosyl benzene 891 showed activity against human promyelocytic leukemia cell line (HL60), although several aliphatic C-glucosyl (but no galacto- or mannopyranosyl) derivatives were 3−6-fold more active and some of the latter type also induced apoptosis.470 Compound 891 proved inactive against human cervical carcinoma (HeLa) and osteosarcoma (HOS) cell lines, while aliphatic counterparts had low micromolar efficiencies (IC50 1− 10 μM).471 Unprotected C-glycosyl naphthoquinones 892 (R = H) were ineffective toward human melanoma cells (A375); however, with O-peracetyl as well as 2,3,4-tri-O-acetyl-6-O-

Figure 14. Inhibition of glycoenzymes by C-glycosyl compounds.

benzoyl protection, they showed in vitro cytotoxicity, which was independent of the sugar configuration.115 Ru(II) half sandwich complexes of tetrazole 893 and 1,3,4-oxadiazole 894 showed somewhat better activity against HeLa cells than cisplatin.354 In addition, the effect of 893 was also studied against HTC116 CC cells, showing weaker effect than the positive control oxaliplatin.472 Antimalarial activities of a large series of thiochroman sulfoxides (e.g., 895) and sulfones (e.g., 896) against chloroquine-sensitive (3D7) and chloroquine-resistant (FCR3) Plasmodium falciparum strains were tested to show submicromolar activities for the best compounds 895 and 896 (Figure 12), while epimers 897 were less efficient. Although this efficacy lags behind that of chloroquine, the widely applied antimalarial, the low cytotoxicity (>100 μM) and the novelty of the structures among antimalarial medications make these compounds very promising.129 Binding affinity of α-C-mannosyltryptophan (C-Man-Trp, compound 339 in Scheme 56) to mannose specific lectins such as Con A isolated from plant and MBL-C purified from mouse

Figure 12. Fused tricyclic C-glycosyl thiochromane oxides as antimalarials. 1749


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Figure 15. 1,2,3-Triazole-linked pseudooligosaccharide for lectin inhibition.

Table 18. Selectin Inhibition by Sialyl Lewisx Mimetics (IC50 [mM])326

serum was investigated;473 however, these lectins were not able to make contacts with C-Man-Trp. A series of C-galactosyl thiazoles as members of a library of 60 galactose derivatives were tested to block binding of the lectins Viscum album agglutinin and human galectin-3 to a ligand. CGalactosyl thiazoles 898 and 899 surpassed the inhibitory capacity of lactose by a factor of 1.1−1.3 (Figure 13).339 Bis-C-glycosyl thiadiazoles 900 and 901 showed moderate inhibitions against the indicated enzymes (Figure 14).357 CGlucopyranosylated 1,2,3-triazole derivative 902 had low micromolar inhibiton of an amyloglucosidase.374 Triazole-linked oligomannosides 903 were tested against a mycobacterial glycosyltransferase to show the highest activity for the hexamannoside derivative.378

From a series of divalent galactosides with C-glycosyl-1,2,3triazoles in the coupling moieties (Figure 15) to test the Pseudomonas aeruginosa lectin LecA inhibition, compound 904 proved the best (Kd 28 nM by ITC) being ∼800-fold more efficient than an analogous monovalent compound.380 Mimetics of the sialyl Lewisx tetrasaccharide containing 1,2,3triazole (905, 906) and indole (907) spacers in place of a monosaccharide unit showed higher activities against lectins (except for E-selectin) than the natural oligosaccharide 908 (Table 18).326 In a series of N- and C-galactosylated 1,2,3-triazoles (Figure 16) tested against cholera toxin, C-glycosyl derivatives 909−911 proved the most efficient: inhibition by the monovalent compounds 910 and 911 was stronger than that of D-galactose by a factor of ≥600.474

Figure 16. C-Galactosyl derivatives for cholera toxin inhibition.

6. CONCLUSIONS AND FUTURE PERSPECTIVES The need for powerful synthetic techniques toward C-glycosidic scaffolds has recently been evidenced by the growing number of reports in this field and, moreover, the pharmaceutical applications of such molecules. The surveyed general synthetic strategies toward C-glycopyranosyl (het)arenes rely (i) on the formation of a carbon−carbon bond between the anomeric carbon atom and a sp2-carbon of a (hetero)aromatic residue, (ii) on ring closure of the tetrahydropyrane ring from open-chain precursors, and (iii) on cyclization or/and ring transformation of suitable functional groups/rings attached to the anomeric center by a carbon−carbon bond. 1750


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The variety of strategies toward these C-glycosyl compounds afforded a wide range of chemical architectures and thereby permitted the development of numerous applications in biology. Among the studies reported, antihyperglycemic activities are based on inhibition of glycogen phosphorylase (GP), or protein tyrosin phosphatase (PTP) 1B, or sodium-dependent glucose cotransporter (SGLT) 2. While the first two effects are still in an investigational phase, several inhibitors of SGLT2 are now approved and marketed drugs targeting type 2 diabetes. Although carbohydrate-based drugs are scarcely represented in the pharmaceutical market to date, these SGLT2 inhibitors are now appearing as the next blockbusters for the pharmaceutical industry. It is highly probable that the onset of this research will bring other exciting findings in the very near future.

Marietta Tóth was born in Sátoraljaújhely (Hungary) in 1974. She received her Ph.D. in chemistry from the University of Debrecen in 2002, under the supervision of Prof. László Somsák. Her research topics were the syntheses of C-glycosyl-imine-type derivatives (such as anhydro-aldose-hydrazones, -semicarbazones, and -oximes) and the elaboration of a new synthetic method for exo-glycals. From 2001−2003 she was an assistant lecturer of the Department of Organic Chemistry at the University of Debrecen. She then gained a postdoctoral fellowship of the Hungarian Scientific Research Fund to study the syntheses of glycosyl and 5′-uridyl derivatives of N-glycosyl allophanic acid and biuret as glycosyl transferase inhibitors. In 2008 she was promoted to an assistant professor at the same department. She won the János Bolyai Research Scholarship of the Hungarian Academy of Sciences in 2011, and in 2013 the Zoltán Magyary Postdoctoral Fellowship supported by the European Union and the State of Hungary, cofinanced by the European Social Fund. Her research interests include transformation of C-glycosyl-imine-type molecules to C-glycosyl heterocycles, and the examination of Pd-catalyzed and metal-free cross-coupling reactions of anhydro-aldose-tosylhydrazones and aldonolactone tosylhydrazones.

AUTHOR INFORMATION Corresponding Authors

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

Jean-Pierre Praly received his Ph.D. in Organic Chemistry at the University of Lyon. In 1976, he joined the CNRS (Centre National de la Recherche Scientifique) as an academic researcher with Prof. G. Descotes. First, he studied free-radical routes (halogenation, reduction, C−C/C−O bond formation) shown to occur with high stereocontrol at the anomeric center of sugars. He held a 1-year position in a French company developing the industrial synthesis of vitamin E, then a 2-year postdoctoral position at the University of Alberta, Canada, with Prof. R.U. Lemieux for studying the anomeric effect by NMR spectroscopy. At Claude-Bernard University of Lyon, he started collaborations whereby organic syntheses by ionic, radical, photochemical, and concerted routes led to new sugar derivatives, glycomimics, and new amino acids. Many of them were valuable chemical tools for investigating glycosidases and glycosyltransferases, or potential drugs as oral antithrombotic 5-thioxylopyranosides. Recent synthetic strategies were designed toward potential glucose-based inhibitors of glycogen phosphorylase, a potential target for the pharmacological control of type 2 diabetes mellitus. The quest for hypoglycemic molecules benefited from a multidisciplinary collaboration with groups in France, Greece, and Hungary, where he had a several decades collaboration with Prof. L. Somsák. With the University of Monastir, Tunisia, he developed strategies toward enantiopure amino acids through dipolar cycloadditions of chiral nitrones and alkenes. These fields, including work in “click-chemistry”, benefited from the participation of Dr. S. Vidal and dedicated students.

Author Contributions

É.B. and S.K. contributed equally to this work.

§

Notes

The authors declare no competing financial interest. Biographies Éva Bokor was born in 1982 in Békéscsaba, Hungary. She received her M.Sc. (2006) and Ph.D. (2010) degrees in chemistry from the University of Debrecen under the supervision of Prof. László Somsák. From 2012−2015 she was a postdoctoral research fellow supported by the Hungarian Scientific Research Fund in the Department of Organic Chemistry of the above university, where she is currently working as an assistant professor. Her reasearch interests are the preparation and synthetic uses of 2,6-anhydro-aldonic acid-type derivatives as well as the syntheses of N- and C-glycosyl-heterocycles for the inhibition of glycogen phosphorylase and other glycoenzymes. In 2014 she received the Publication Prize of the University of Debrecen and the Prize of the Lajos Kisfaludy Foundation for two of her scientific papers related to the above research topics. In 2016 she was awarded the Győ ző Bruckner Prize endowed by the Gedeon Richter Plc. and the Hungarian Academy of Sciences. Sándor Kun was born in Debrecen (Hungary) in 1984. He obtained his M.Sc. degree in chemistry in 2008 and a Ph.D. in chemistry in 2014 from the University of Debrecen, where he worked on the synthesis of Cglycosyl heterocycles for the inhibition of glycogen phosphorylase under the supervision of Prof. László Somsák. Since 2016 he has been a postdoctoral research fellow of the Hungarian Scientific Research Fund in the same group. His current research interest is focused on the synthesis of glycopyranosylidene-spiro-heterocycles.

Sébastien Vidal currently holds a CNRS position at University of Lyon. He was born in Montpellier (France) in 1974. He received his Ph.D. in Organic Chemistry (2000) from the University of Montpellier (France). He studied under the direction of Prof. Alain Morère and synthesized mannose 6-phosphate analogues for drug delivery applications. He then moved to the group of Sir J. Fraser Stoddart as a postdoctoral fellow at UCLA to study the synthesis and characterization of glycodendrimers, but also the design of pseudorotaxanes and dynamic combinatorial chemistry. In 2003, he moved to the National Renewable Energy Laboratory (NREL, Golden, CO) and studied with Prof. Joseph J. Bozell the combination of organometallic and carbohydrate chemistries. After one year, he joined the group of Prof. Peter G. Goekjian at University of Lyon in 2004 where he started as a postdoctoral fellow and successfully applied to a CNRS position as “Chargé de Recherche”. He then started his own research projects dealing with carbohydrate chemistry and applications in biology. The main topics covered in his research are the design of glycoclusters for antiadhesive strategy against bacterial infections but also glycogen phosphorylase or glycosyltransferases

David Goyard graduated (Master degree in organic chemistry) from Université Claude Bernard Lyon 1. He then received his Ph.D. under the direction of Dr. Jean-Pierre Praly in 2011. His graduate work focused on the synthesis of glycosylated inhibitors of glycogen phosphorylase’s catalytic site. He then moved to the group of Prof. René Roy as a postdoctoral fellow at Université de Québec à Montréal (UQAM) where he worked on the synthesis of multivalent glycoclusters and neoglycolipids and their multivalent interactions with lectins. He is currently working as an ERC-funded postdoctoral fellow with Prof. Olivier Renaudet at Université Grenoble Alpes. His current research interests include the development of multivalent glycodendrimers and their interactions with lectins and antibodies. 1751


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DIAD DIPEA DMAP DMDO DMF DMP DMSO DPPA dppe dppf DTBMP EDCI

(OGT) inhibitors with applications in type 2 diabetes. He was awarded the Young Investigator Award from the French Glycoscience Group in 2014 and promoted “Directeur de Recherche” at CNRS in 2015. László Somsák received his Ph.D. under the guidance of the late Professors István Farkas and Rezső Bognár from the Lajos Kossuth University of Debrecen in 1983. He moved to Lyon (France) to join the research group of Prof. Gérard Descotes as a CNRS “poste rouge” fellow in 1990−91. Since that time a strong and long-standing collaboration has held between the members of the two groups. In 1992−93 he was the recipient of an Alexander von Humboldt Research Fellowship as a guest of Prof. Frieder W. Lichtenthaler in Darmstadt (Germany). After his return to Hungary, he was appointed to an associate professor of organic chemistry at the University of Debrecen and was promoted to full professor in 2003. Curently, he is Head of the Department of Organic Chemistry and Director of the Institute of Chemistry at the same university. His reasearch interests comprise radical-mediated transformations of carbohydrates; synthesis of C-glycosyl compounds; development of new methods for the preparation of glycals, exo-glycals, and anomeric spirocycles; preparation of glycosylidene- and glycosylmethylene carbene as well as glycosyl nitrene precursors and investigation of their reactivity; application of organometallic reagents and cross-coupling methodologies to carbohydrates; design and synthesis of glycosidase and glycogen phosphorylase inhibitors, study of their structure−activity relationships; and synthesis of glycomimetics and glycopeptidomimetics. Among others, he was awarded the George Oláh Medal and Prize (1999) and the Géza Zemplén Prize (2013) of the Hungarian Academy of Sciences.

Fmoc HOBt IDCP IL Im KDO LDA MOM MW NBS NMI NMO NMP NIS OPD PG PIDA Piv PMB Pyr rt SDS TBAF TBS TBDPS TDI TEA TEMPO Terpy TES Tf TFA TFAA TFP THF TIPS TMB tmeda TMS Tol Ts XPhos

ACKNOWLEDGMENTS Financial support from CNRS and University Claude Bernard Lyon 1 is gratefully acknowledged. The work was also supported by the Hungarian Scientific Research Fund (OTKA 105808 and 109450), by the University of Debrecen (5N5XBTDDTOMA320), and by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁ MOP-4.2.4.A/2-11/1-2012-0001 “National Excellence Program”. ABBREVIATIONS Ac acetyl acac acetylacetonate AIBN α,α′-azoisobutyronitrile 9-BBN 9-borabicyclo[3.3.1]nonane Bn benzyl Boc tert-butoxycarbonyl BocON 2-tert-butoxycarbonyloximino-2-phenylacetonitrile BODIPY boron-dipyrromethene or 4,4-difluoro-4-bora3a,4a-diaza-s-indacene Bz benzoyl CAN cerium(IV) ammonium nitrate cod 1,5-cyclooctadiene Con A concanavalin A Cp* pentamethylcyclopentadienyl CSA camphorsulfonic acid CuAAC Cu(I)-catalyzed azide−alkyne cycloaddition dba dibenzylideneacetone DBU 1,8-diaza-bicylo[4.5.0]undec-7ene DCC dicyclohexylcarbodiimide 1,2-DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone (DHQ)2AQN hydroquinine anthraquinone-1,4-diyl diether

diisopropyl azodicarboxylate diisopropylethylamine N,N-dimethyl-4-aminopyridine dimethyldioxirane N,N-dimethylformamide Dess−Martin periodinane dimethyl sulfoxide diphenylphosphorylazide 1,2-bis(diphenylphosphino)ethane 1,1′-ferrocenediyl-bis(diphenylphosphine) 2,6-di-tert-butyl-4-methylpyridine N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide 9-fluorenylmethoxycarbonyl 1-hydroxybenzotriazole iodonium di-sym-collidine perchlorate ionic liquid imidazole 3-deoxy-D-manno-2-octulosonic acid lithium diisopropylamide methoxymethyl microwaves N-bromosuccinimide N-methyl-imidazole N-methylmorpholine-N-oxide N-methyl-2-pyrrolidone N-iodosuccinimide o-phenylenediamine protecting group (diacetoxyiodo)benzene pivaloyl 4-methoxybenzyl pyridine room temperature sodium dodecyl sulfate tetra-n-butylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl tolylene-2,4-diisocyanate triethylamine 2,2,6,6-tetramethyl-1-piperidinyloxy 2,2′:6′,2″-terpyridine triethylsilyl trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride tri-2-furylphosphine tetrahydrofuran triisopropylsilyl 1,3,5-trimethoxybenzene N,N,N′,N′-tetramethylethylenediamine trimethylsilyl 4-tolyl 4-toluenesulfonyl 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

REFERENCES (1) Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.; von der Lieth, C.-W.; Seeberger, P. H. Exploring the Structural Diversity of Mammalian Carbohydrates (″Glycospace″) by Statistical Databank Analysis. ACS Chem. Biol. 2007, 2, 685−691. 1752


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