Total Synthesis of Aryl CâGlycoside Natural Products: Strategies and

Review Cite This: Chem. Rev. 2018, 118, 1495−1598

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Total Synthesis of Aryl C‑Glycoside Natural Products: Strategies and Tactics Kei Kitamura,† Yoshio Ando,‡ Takashi Matsumoto,§ and Keisuke Suzuki*,‡ †

Department of Applied Chemistry for Environment, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan ‡ Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan § School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan ABSTRACT: The aryl C-glycoside structure is, among the plenty of biologically active natural products, one of the distinct motifs embedded. Because of the potential bioactivity as well as the synthetic challenges, these structures have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review focuses on the synthetic strategies and tactics employed in the total synthesis of this class of natural products. The Introduction describes the historical background, structural features, and synthetic problems associated with aryl C-glycoside natural products. Next the Review summarizes the methods for constructing the aryl C-glycoside bonds. Completed total synthesesand, in some cases, selected examples of incomplete synthesesof natural aryl C-glycosides are also summarized. Finally described are the strategies for constructing polycyclic structures, which were utilized in the total syntheses.

CONTENTS 1. Introduction 1.1. Historical Background 1.1.1. Early History 1.1.2. After 1970 1.2. Structural Diversity and Biosynthesis 1.2.1. Diversity of Sugars 1.2.2. Diversity of Polycyclic Skeletons 1.2.3. Carbohydrate Modifications 1.3. Synthetic Problems 1.3.1. Stereochemistry 1.3.2. Regioselectivity 1.4. List of Contents 2. Methodologies for Constructing Aryl C-Glycoside Linkages 2.1. General Considerations 2.2. C-Glycosylation of Arenes (Approach A) 2.2.1. Methods Using Electrophilic Sugar Derivatives 2.2.2. Methods Using Glycosyl Anions 2.2.3. Transition-Metal-Mediated Coupling Reactions 2.3. De Novo Construction of the Sugar Moiety 2.3.1. Hetero-Diels−Alder Reaction 2.3.2. 1,3-Dipolar Cycloaddition 2.3.3. Metathesis 2.4. De Novo Construction of the Aromatic Moiety 2.4.1. Biomimetic Polyketide Condensation Approach © 2017 American Chemical Society

2.4.2. Use of Furyl Glycosides 2.4.3. Use of Acetonyl Glycosides 2.4.4. Use of Alkynyl Glycosides 2.4.5. Use of Nitromethyl Glycosides 3. Natural Product Syntheses 3.1. Polyketides 3.1.1. Vineomycins 3.1.2. Angucyclines 3.1.3. Gilvocarcins 3.1.4. Medermycin 3.1.5. Galtamycinone 3.1.6. Pluramycins 3.1.7. Griseusins 3.1.8. Granaticin 3.1.9. Nogalamycin 3.1.10. Anthrone C-Glycosides 3.1.11. Xanthone C-Glycosides 3.2. Flavonoid/Isoflavonoid/Chalcone 3.2.1. C-Glycosyl Flavones 3.2.2. C-Glycosyl Isoflavones 3.2.3. C-Glycosyl Chalcones 3.3. Miscellaneous 3.3.1. Indole C-Glycoside 3.3.2. Bergenins 3.3.3. Proposed Ardimerin 3.3.4. Papulacandins 4. Strategies for Constructing Polycyclic Structures 4.1. Diels−Alder Reaction

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Received: June 27, 2017 Published: December 27, 2017

1532 1495

DOI: 10.1021/acs.chemrev.7b00380 Chem. Rev. 2018, 118, 1495−1598

Chemical Reviews General BackgroundRegioselectivity Juglone Derivatives in the Angucycline Synthesis 4.2. Naphthaldehyde Synthesis via Bradsher Cycloaddition 4.3. Benzyne−Furan [4 + 2] Cycloaddition 4.3.1. Use of α-Alkoxybenzyne 4.3.2. Use of Intramolecular Reaction 4.4. Benzyne [2 + 2] Cycloaddition 4.5. Hauser Reaction and the Related Reactions 4.6. Pinacol Cyclization 4.7. Claisen Condensation and Aldol Reactions 4.8. Pd-Catalyzed Cyclization 4.9. Baker−Venkataraman Rearrangement 4.10. Construction of the Anthrapyranone Framework of Pluramycin-Type Natural Products Approach I Approach II

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Approach III Approach IV Approach V Approach VI Approach VII 4.11. Castro Indole Synthesis 5. Conclusion Associated Content Special Issue Paper Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

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Figure 1. Selected natural aryl C-glycosides.

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1. INTRODUCTION The aryl C-glycoside designates the structure having an aromatic moiety and sugar(s), which are directly connected through a C− C bond. This particular structure is one of the distinct motifs embedded in various biologically active natural products as illustrated in Figure 1. Because of the potential bioactivity as well as the synthetic challenges, these natural products have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review will cover strategies and tactics on the chemical syntheses of aryl C-glycoside natural products. A very early review in 1985 focused on the chemistry and biochemistry of C-nucleosides and aryl C-glycoside.1 The chemical synthesis of aryl C-glycoside antibiotics, including the methodological aspect of the aryl C-glycoside bond formation and the total synthesis of this class of antibiotics, were reviewed in 19932 and 1994,3 whereas books dealt with a broad range of methods for the construction of aryl C-glycoside bonds in 1995− 1998.4−6 The structure, bioactivity, and biosynthesis of naturally occurring aryl C-glycosides were reviewed in 2005.7 A recent review in a book chapter, published in 2008, focused on general methods to construct C-glycosides, giving some examples for the synthesis of natural products.8 The chemical structures of naturally occurring glycosylated secondary bacterial metabolites, including C-glycosides, were highlighted in 2015,9 and very

recently, in 2017, a review covered the synthesis and diverse bioactivities of C-glycosyl (het)arenes, including natural and non-natural compounds.10 Although an important class of C-glycosidic compounds, Cnucleosides (Figure 2) will not be discussed in this Review. Readers interested in these compounds are encouraged to see the pertinent review.11 Our Review will discuss the aryl C-glycoside natural products starting from a brief history of this compound class, biosynthetic aspect, and development of various strategies and tactics in their chemical syntheses. 1.1. Historical Background

1.1.1. Early History. Early history of aryl C-glycosidic compounds traces back to the turn of the 20th century, when Perkin scrutinized a plant sample from New Zealand, isolating polyphenolic compounds later called vitexin (1) and isovitexin (2) (Figure 3).12,13 Although he had just assigned the structures of the aglycons, apigenin and luteolin, the structure elucidation of these nonhydrolyzable, C-glycosidic congeners remained elusive for a long time. Even half a century later, these were erroneously assigned as A or B.14,15 This is not surprising in view of the limited analytical tools available in the 1950s−1960s, when NMRs were not found in organic laboratories. Along the same lines, for orientin (3) and homo-orientin (4), erroneous structures C and D were originally assigned.16 However, a dramatic yet positive change happened to organic chemists due to the availability of NMR spectroscopy. Horowitz and Gentili17 and Koeppen18,19 had now been able to identify the currently accepted structures of 1−4 (vide supra), and, in due course, the C-pyranoside and the aryl C-glycoside structures were born. Remarkable and pioneering contribution by Haynes and coworkerswho, before the NMR era, assigned the correct structure to some aryl C-glycosidic natural products, including aloin,20 carminic acid,21 and homonataloin22deserves great acknowledgment (Figure 4). He also corrected the wrong structures E and F, previously proposed for bergenin.23 Comparing the Fischer formulas in the original papers and Mills formulas, which are currently accepted, it is noteworthy

Figure 2. C-nucleosides.

Figure 3. Flavonoid C-glycosides 1−4 and erroneously assigned structures A−D. 1497


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Figure 4. Aryl C-glycoside structures correctly assigned by Haynes and co-workers.

antitumor action and (2) lesser vulnerability toward deglycosylation. X-ray crystallography also played a key role around the 1970s for the assignment of the aryl C-glycoside structure. For example, although pluramycins were already isolated in the 1950s by Umezawa and co-workers,25 their structure remained unassigned for quite some time. However, the structure determination of kidamycin by X-ray crystallography by Furukawa et al.26 served as the basis for determining the unusual bis-C-glycoside structure by NMR spectroscopic correlation.27 These compounds exhibit diverse biological activities, such as antibacterial activity, enzyme inhibitory effects, inhibition of platelet aggregation, and antitumor activities. Because of such significant biological activities and also because of the synthetic challenges posed by the characteristic structural features, these compounds were put to the forefront of chemical synthesis, and indeed, many synthetic studies have been conducted. In this Review, the relevant synthetic efforts and the total synthesis will be highlighted by particularly stressing the strategy and tactics.

Figure 5. Aquayamycin, adriamycin, and pluramycins.

1.2. Structural Diversity and Biosynthesis

The structural diversity of aryl C-glycosides originates from the multiplication of the diversity in the polycyclic nucleus and that of the carbohydrate appendages. 1.2.1. Diversity of Sugars. The sugars in polyphenolic compounds are often typical carbohydrates, mostly D-glucose (Figure 6). For example, vitexin is a flavonoid having a C-linked glucose at the C8 position, while flavocommelin has two Dglucose molecules, one C-linked at the C6 position and another as an O-linked one. Aloin A is an anthrone C-glycoside, in which the sugar is D-glucose as well. In contrast, the carbohydrates included in the antibiotics derived from type-I and -II biosynthesis are often “rare sugars”.28−30 Although the starting material of biosynthetic pathways is D-glucose, the final status of the sugar residues often

that the stereochemical assignments relied on the later contributions. 1.1.2. After 1970. The dawn of aryl C-glycoside chemistry was the 1970 landmark report on the structure elucidation of aquayamycin, an antitumor antibiotic with an angular tetracyclic framework containing an anthraquinone nucleus that is directly connected to a sugar, D-olivose (Figure 5).24 This C-glycosidic structure quickly attracted the attention of biological and medicinal interests in comparison with a class of clinically important anthracyclines as represented by adriamycin. Note that anthracyclines consist of O-glycosylated hydrotetracene cores. The structure similarity and difference of C-glycosides, like aquayamycin, with O-glycosidic drugs, such as adriamycin, were of great interest in view of two main issues: (1) the mechanism of 1498


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Figure 6. Normal and rare sugars.

Figure 7. Conformation of α-C-glycosyl vancosamine.31−33

medermycin and pluramycin A. Some compounds feature the coexistence of C- and O-linked sugars as exemplified by vineomycin A2 and benzanthrin B. Kidamycin manifests an extraordinary structural feature in which the vancosamine moiety, one of the carbohydrates, adopts a boatlike conformation, as suggested by the X-ray and the NMR

manifests the results of extensive modifications, particularly deoxygenation; D-Olivose, a 2,6-dideoxy sugar, is frequently embedded in this class of compounds, as displayed by aquayamycin and vineomycin A2. Furthermore, amino sugars, such as D-angolosamine, and/or branched sugars, such as Lvancosamine derivative, are also incorporated as shown in 1499


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Figure 8. Decaketide-derived aglycons and C-glycosides.

analyses (Figure 7).31 On the other hand, the vancosamine moiety in hedamycin adopts a chair conformation, disposing the aryl group axial in crystal (X-ray analysis), while the NMR analysis suggests the prevalence of a twisted conformation in solution.32 Furthermore, such conformational preference seems delicate as inferred by the deacetylation of saptomycin D to deactetylsaptomycin D, which induces a conformational change, from chair to boat, in the C-vancosaminyl moiety.33 1.2.2. Diversity of Polycyclic Skeletons. The polycyclic moieties discussed in this Review are derived from the polyketide biosynthesis (section 3.1), as well as from the flavonoids (section 3.2) and miscellaneous (section 3.3). Let us take the decaketide biosynthesis as a first example (Figure 8).34,35 Assembly of 10 acetate units generates a polyketide chain A, which is cyclized into a curved tetracycle B, as represented by tetrangomycin. Because of this characteristic scaffold, these compounds are called angucyclines. A prominent C-glycosyl derivative is aquayamycin, a compound with quite a history, as it is the first

antibiotic compound bearing C-glycoside whose structure elucidation was accomplished in 1970. This early biosynthetic platform B serves as an important branching point, because three distinct modification modes a−c generate diversity and hence lead to linear tricycle C, linear tetracycle D, or curved tetracyclic lactone E, respectively. The prototypical aglycons include fridamycin, SS-228R, and defucogilvocarcin M, C-glycosylations of which give vineomycinone B2, galtamycinone, and gilvocarcin M, respectively. The glycosylation is not restricted to C-glycosylation, but Oglycosylation occurs as well, as featured by benzanthrins A and B, possessing distinct and same sugars as O- and C-glycosides. The decaketide pathway with a different initial folding mode provides a class of oxygen-containing tetracycles, i.e., the anthrapyranones as represented by saptomycin F (Figure 9). C-Glycosylation gives saptomycin D, or even dual Cglycosylations are seen among the pluramycin-class antibiotics as represented by pluramycin A. 1500


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Figure 9. Bis-C-glycosides with anthrapyranone skeleton.

Figure 10. Octaketide-derived aglycons and C-glycosides.

1.3. Synthetic Problems

Figure 10 shows the octaketide pathway that produces a class of oxygen-containing tricycles, i.e., pyranonaphthoquinones as represented by kalafungin, and also a class of tricycles, i.e., anthrones. The C-glycosyl congeners of these tricycles are also found, as represented by medermycin and cassialoin, respectively. The mixed biosynthesis of the polyketide−shikimic pathways produces flavonoid natural products with tremendous diversity (Figure 11).36 Again, O/C-glycosylations further enhance the diversity as represented by, inter alia, vitexin and vicenin-2 by dual C-glycosylations. 1.2.3. Carbohydrate Modifications. Nontrivial carbohydrate-derived compounds further multiply the diversity of glycosylated polyaromatic natural products as seen in doubly bridged structures, granaticin and nogalamycin. Athough griseusin A is not a C-glycoside from the biosynthetic viewpoint, the authors took the liberty of including it here, due to the intriguing structure, in which the pseudo-C-glycoside attached as a spirocycle to the pyranonaphthoquinone core, which has synthetic relevance in this Review (Figure 12).37−41

Regarding the formation of the aryl C-glycoside linkages, one needs to address two fundamental selectivity issues: (1) the α/β stereoselectivity of the C-glycoside and (2) regioselectivity for installing the sugar(s) onto a specific position of the polycyclic scaffold. In the following, we will comment on these delicate issues. 1.3.1. Stereochemistry. Although aryl C-glycosides significantly differ in their polycyclic and carbohydrate portions, a rough sketch of the stereochemical trend is shown in Figure 13. Let us take C-D-olivoside as an example.42−44 The primary factor that influences the conformation of each anomer is the strong preference of the C(1)-aryl group to orient itself in an equatorial position, and here the anomeric effect is negligible, if any. Thus, of two optional conformers of the α-olivoside, i.e., 4C1 (A) and 1 C4 (B), the latter prevails despite forcing three substituents in an axial position. In contrast, the β-olivoside can adopt an ideal conformer, 4C1 (D) with all four substituents equatorial, which is in general thermodynamically more stable than the α-anomer. 1501


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Figure 11. C-Glycosyl favonoids derived from polyketide−shikimic pathway.

Figure 12. Carbohydrate modification. Figure 14. Stereochemical mutation of gilvocarcin antibiotic.45,46

It should be noted, however, that the anomeric configuration in natural products is not necessarily the thermodynamically favored one, as exemplified by gilvocarcin V (Figure 14).45,46 Since the sugar part is a furanoside, the thermodynamic preference is not that obvious. Indeed, upon acid treatment at an elevated temperature, anomerization occurs to give a 1/1 mixture of α/β-furanosides, suggesting the parent compound was not the thermodynamically favored one. Notably, the major product observed was the pyranosyl derivative generated by the ring enlargement, suggesting quinone methide A as the intermediate. From a synthetic point of view, the control of this unusual stereochemistry would be challenging. 1.3.2. Regioselectivity. The aryl C-glycoside bonds in the majority of aryl C-glycoside natural products are located ortho to a phenolic hydroxy group, as seen in aquayamycin (Figure 1) and vineomycin (Figure 1). However, some members possess a paraC-glycoside, such as the gilvocarcins (Figure 1), and the ones with both ortho- and para-C-glycosides can be found, too, such as hedamycin (Figure 7). Thus, the regiocontrolled formation of the aryl C-glycoside bond is an issue of particular difficulty in

Figure 13. Conformational preference of aryl C-glycosides: general tendency.

Indeed, Lewis acid-mediated equilibration exclusively gives the β-anomer via quinone methide species E. 1502


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Scheme 1. Three Approaches to Aryl C-Glycoside Structures

terms of C-glycosylating the usually densely functionalized polycyclic aromatic core. Of no less importance is the selective construction of the complex and highly functionalized aromatic framework, which is by no means trivial but rather synthetically challenging, even in the synthesis of the “aglycon” lacking the carbohydrate moiety. This topic will be covered within the context of natural product syntheses in section 3 and strategies for construction polycyclic structures in section 4.

Scheme 3. Normal Polarity

1.4. List of Contents

Along these lines, this Review will cover two aspects of the synthesis of aryl C-glycosides: synthetic methodologies and the application to total synthesis of natural products. Section 2 will outline the synthetic methodologies to generate aryl C-glycoside structures, including C-glycosylation of arenes (section 2.2), which is further divided into three parts, methods using electrophilic sugar derivatives (section 2.2.1), methods based on glycosyl anions (section 2.2.2), and methods based on crosscoupling reactions (section 2.2.3). Other methods, including de novo construction of sugar moiety or aromatic moiety, will be discussed in sections 2.3 and 2.4, respectively. Section 3 covers the total syntheses of natural products, including the mostly-finished ones, and is further subdivided according to the biosynthetic origin of polycyclic moiety discussed, i.e., polyketides (section 3.1), flavonoids (section 3.2), and miscellaneous (section 3.3). Section 4 will provide a brief overview and glossary of the ring-forming strategies en route to the polycyclic skeletons in the aryl C-glycoside natural products.

Scheme 4. Hurd−Bonner Report in 194547−50

2. METHODOLOGIES FOR CONSTRUCTING ARYL C-GLYCOSIDE LINKAGES 2.1. General Considerations

This section will outline the synthetic methodologies to construct aryl C-glycosides. Three formal approaches are present Scheme 2. Three Approaches to Aryl C-Glycoside Linkage as shown in Scheme 1, differing in the point of time for forming the aryl C-glycoside linkage (red), i.e., the C−C bond between the sugar and the arene moiety. Approach A presents the installation of a sugar moiety to a full or partial aromatic structure. Most methods fall into this category, constituting a sort of standard approach, which will be discussed in section 2.2. As for other possible methods, approach B comprises the de novo construction of the sugar moiety and will be described in section 1503


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Scheme 5. Early Example by Kalvoda (1970)51

two-carbon unit by ozonolysis and was utilized in the synthesis of a C-nucleoside, showdomycin. Table 1 shows selected examples of the Friedel−Crafts reaction of trialkoxybenzenes with various combinations of glycosyl donors and activators. O-Acylated glycal derivatives constitute a class of good glycosyl donors for Friedel−Crafts C-glycosylations as exemplified in the report by Grynkiewicz and Zamojski in 1980 (Scheme 6).65 Reaction of triacetyl glucal (11) and anisole promoted by SnCl4 gave C-glycoside 12. The stereochemistry of 12 was originally assigned as α but later was corrected as β by Casiraghi et al. in 1988.66 Scheme 7 shows an incidental finding in the reaction of glycosyl acetate 13 with SnCl4, where the 2-O-benzyl protecting group intercepted the oxonium species to give cyclic ether 14.67 This issue demanded precaution to potential side reaction using benzyl-protecting groups. However, this intramolecular arylation also implied the potential of 13 (or derivatives) for an approach toward aryl C-glycoside synthesis.68−70 Indeed, Martin and coworkers reported a series of useful intramolecular aryl Cglycosidations as exemplified by Scheme 8,71,72 and one of those was applied to an efficient access to 8,10-di-O-methylbergenin triacetate (19) (Scheme 9).73 In a broader context of C-glycoside synthesis, the nucleophilic reaction partners are not restricted to arenes. Other nonaromatic nucleophiles include electron-rich alkenes; allyl-, alkenyl-, and alkynyl silanes or stannanes; enol silyl ethers; silyl cyanide; and enamines. The moieties thus installed to the anomeric position of carbohydrates serve as the platforms to aryl (or heteroaryl) Cglycosides (Scheme 10). See section 2.4 for the de novo construction of (poly)aromatic moiety. Regiochemistry. Let us get back to the Friedel−Crafts approach and focus on the regiochemistry in the C-glycosylation. In terms of a convergent synthetic strategy, it would be ideal if one could install the sugar(s) onto the fully elaborated polyaromatic aglycon. However, it poses challenging problems in view of the regiochemical control in the C-glycosylation. A report by Suzuki, Matsumoto, and Katsuki in 1989 is illustrative: while the most reactive positions in the aryl C-glycosylations of protected naphthalene derivatives are basically the carbon atoms possessing the highest HOMO (highest occupied molecular orbital) coefficient, the steric effects are also operative (Scheme 11).56 Furthermore, prediction of the regiochemistry of the aryl Cglycosylation becomes even more difficult, in case the polyaromatic substrates become larger and more complicated, possessing multiple potential reaction sites. An illustrating example of such difficulty in regiochemical control can be found in the report by Yu and co-workers on the synthesis of xanthone C-glycosides (Scheme 12):74,75 Reaction of 24 with glycosyl imidate 23 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) gave a mixture of regioisomers 25 and 26. After separation, each compound was converted into isomeric natural products, mangiferin and isomangiferin (see Figure 15 and Scheme 159). One of the ways to overcome this issue is to carry out the Cglycosylation with a simpler glycosyl acceptor followed by incremental development of the full polycyclic skeleton. A concrete example of such an “early-stage C-glycosylation approach” can be seen in the Li synthesis of neomangiferin, a related C-glycosyl xanthone natural product, starting with a Friedel−Crafts C-glycosylation of 1,3,5-tribenzyloxybenzene followed by construction of the full skeleton (see Figure 15 and Scheme 160).76

2.3. Vice versa, in approach C the sugar is linked to a small substructure, like an alkynyl group or furyl group, as a progenitor that serves as a platform for constructing the aromatic core. This de novo construction of aromatic moiety will be discussed in section 2.4. 2.2. C-Glycosylation of Arenes (Approach A)

Approach A exploits the installation of a sugar moiety to a full or partial aromatic structure. Let us first consider the formal polarity, needed for the formation of the aryl C-glycoside linkage. Scheme 2 shows, in a retrosynthetic fashion, the disconnection of the particular C−C bond, suggesting the synthons for the ionic transforms. The contents described in section 2.2.1 assign (+) to the carbohydrate fragment A and (−) to the aromatic fragment B; namely, the sugar is an electrophile and the arene moiety acts as a nucleophilic reaction partner. On the contrary, the umpolung approach uses the charge-inverted species, i.e., glycosyl anion equivalent C and aryl cation equivalent D, as will be discussed in section 2.2.2. Furthermore, section 2.2.3 will describe approaches using transition-metal catalyzed crosscoupling reactions of E and F. 2.2.1. Methods Using Electrophilic Sugar Derivatives. This section describes the reaction patterns, in which the sugar is an electrophile and the arene moiety is a nucleophilic reaction partner (Scheme 3). The latter is further divided into subgroups, depending on the nature of arene nucleophiles, including πnucleophiles (section 2.2.1.1), phenols (section 2.2.1.2), and σnucleophiles and phenolates (section 2.2.1.3). In this relation, a historic report by Hurd and Bonner appeared in 1945, describing the Friedel−Crafts reaction of glycosyl chloride 5 using AlCl3 in benzene (Scheme 4).47−49 The yields were low, though, due to the incompatibility of the acetyl protecting groups under the reaction conditions. It is interesting to note, however, that the authors also reported the reaction of glycosyl chloride 5 with a phenyl Grignard reagent, giving Cglycosyl benzene 6 (see section 2.2.1.3).50 2.2.1.1. Friedel−Crafts Reactions. Since the Hurd−Bonner report in 1945, subsequent studies on the Friedel−Crafts approach focused on the variation of glycosyl donors with different leaving groups, which could be activated by various Lewis acids or electrophilic reaction promoters. Phloroglucinol (1,3,5-trihydroxybenzene) is a structure motif embedded in the flavonoid class of natural products. Numerous studies have been conducted on the reaction of phloroglucinol derivatives, such as trimethoxybenzene, which are electron-rich, reactive benzene derivatives, serving as particularly good nucleophiles in the Friedel−Crafts reaction with the oxonium species generated by the activation of glycosyl donors. An early example reported by Kalvoda et al. in 1970 is representative for this aspect (Scheme 5).51 The aromatic part was processed into a 1504


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Table 1. Selected Examples of Friedel−Crafts Reaction of Trialkoxybenzenesa, 52−64

a

DTBMP = 2,6-di-tert-butyl-4-methylpyridine; DBSA = dodecylbenzenesulfonic acid [CH3(CH2)11C6H4SO3H].

compounds. In the synthetic study toward kidamycin,77 Fei and McDonald attempted the reaction of anthrapyranone derivative

Scheme 13 shows another example of an unpredicted regioselectivity in the C-glycosylation of elaborated polyarene 1505


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Scheme 11. Reactive Sites in C-Glycosylation of Naphthalene Derivative (1989, Suzuki−Matsumoto)56

Scheme 6. Friedel−Crafts Reaction with Glycal (1980, Grynkiewicz)65

Scheme 7. Intramolecular Friedel−Crafts Reaction 1 (1985, Martin)67

Scheme 8. Intramolecular Friedel−Crafts Reaction 2 (1988, Martin)71

Scheme 12. Nonregioselective C-Glycosylation with Xanthene Derivative (2010, Yu)74

Scheme 9. Intramolecular Friedel−Crafts Approach to 8,10Di-O-methylbergenin (2000, Martin)73

Scheme 10. Various Progenitors of the Aromatic Moiety At the end of this section, Figure 15 showcases total syntheses of aryl C-glycoside natural products accomplished by means of Friedel−Crafts aryl C-glycosylation as a key step. 2.2.1.2. O → C-Glycoside Rearrangement. The use of phenols as π-nucleophiles in aryl C-glycosylation reactions paved the path to a new class of useful reactions called the “O → Cglycoside rearrangement”, which was discovered independently by two groups in 1988. Kometani et al. noted that naphthol Oglycoside 36, prepared by the Mitsunobu reaction, was converted to C-glycoside 37 upon treatment with BF3·OEt2 (Scheme 16).85 At the same time, this reaction pattern was observed by Suzuki, Matsumoto, and Katsuki in the formation of a phenol Cglycoside via its O-glycoside (Scheme 17).86 In the presence of Cp2HfCl2 and AgClO4, glycosyl fluoride 38 reacted readily with phenol 39 at −78 °C to give O-glycoside 40. Upon gradual warming, O-glycoside 40 was in situ converted to the corresponding C-glycoside 41. Other Lewis acids, such as BF3· OEt2 or SnCl4, worked as well, but with different reactivities and stereoselectivities (vide infra). The latter group uncovered several important aspects of this reaction, which are the bases for the wide use of this reaction for

27 with glycosyl acetate 28 in the presence of SnCl4, where the Cglycosylation occurred not at the desired C10 position but at the C7 position, giving C-glycoside 29 unexpectedly. Thus, successful examples of installing a sugar moiety onto an almost completely aromatic core are limited. Two examples are shown, in which fairly good regiochemical control was achieved in Friedel−Crafts C−C bond formation of the polyaromatic systems, i.e., the report in 1991 by Allevi et al. on the total synthesis of carminic acid (Scheme 14)78 and the report by Suzuki and co-workers on the total synthesis of saptomycin B (Scheme 15).79,80 1506


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Figure 15. Total syntheses of aryl C-glycoside natural products accomplished by means of Friedel−Crafts C-glycosylation as a key step.

aryl C-glycoside synthesis.87 The following summary will comprise (a) mechanistic view, (b) reactivity and stereoselectivity of the processes involved, (c) regioselectivity, and (d) role of Sc(OTf)3 as an especially effective Lewis acid. 2.2.1.2.1. Mechanistic View. Scheme 18 outlines a rough mechanistic view of this three-step process that is involved in the O → C-glycoside rearrangement. Note that, albeit not apparent at first glance, step 3, that is the stereomutation, does occur and

proceeds after or in parallel with step 2. More detailed explanations of this issue follow. Step 1 is the activation of glycosyl donor A (Scheme 18) by Lewis acid (LA) to generate oxonium species F, which is trapped with the phenolic oxygen to give O-glycoside C. As long as the glycosyl donor A is sufficiently activated by Lewis acids or other reaction promoters, this facile process proceeds even at −78 °C (typically employed in the initial studies). Thus, various glycosyl donors, including glycosyl fluorides as above,42,43,86,88−96 and 1507


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Scheme 13. Undesired Regioselectivity in C-Glycosylation of Anthrapyranone Derivative (2007, McDonald)77

Scheme 16. Discovery of O → C-Glycoside Rearrangement (1988, Kometani)85

Scheme 17. Discovery of O → C-Glycoside Rearrangement (1988, Suzuki−Matsumoto)86

Scheme 14. Regioselective C-Glycosylation of an Anthracene Derivative in Carminic Acid Synthesis (1991, Allevi)78 Scheme 18. Three-Step Mechanism of the O → C-Glycoside Rearrangement

Scheme 15. Regioselective Friedel−Crafts Reaction of an Anthrone Derivative in Saptomycin Synthesis (2014, Suzuki−Kitamura−Ando)80

Scheme 19. Various Glycosyl Donors Used for the O → CGlycoside Rearrangement (only pyranosyl core shown)

glycosyl acetates,44,79,80,97−112 1-OH sugars,113−121 methyl glycosides,113,122,123 thioglycosides,124 glycosyl imidates,125−128

glycosyl phosphates,127,129,130 and glycals,131,132 have been used in combination with suitable activators (Scheme 19). 1508


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Scheme 20. Insightful Example of O → C-Glycoside Rearrangement (1989, Suzuki−Matsumoto)42

Scheme 24. Stereoselectivity of the O → C-Glycoside Rearrangement of Furanosyl Derivative in Gilvocarcin Synthesis (1992, Suzuki−Matsumoto−Hosoya)98

Scheme 21. Conformation of α- and β-C-Olivoside

Scheme 25. ortho-Selective C-Glycosylation by the O → CGlycoside Rearrangement in Vineomycinone B2 Synthesis (1991, Suzuki−Matsumoto)43 Scheme 22. O → C-Glycoside Rearrangement of Flipped Glycosyl Donor 45 (1996, Suzuki−Matsumoto−Hosoya)44

Scheme 23. Stereoselectivity of the O → C-Glycoside Rearrangement in Ravidomycin Synthesis (2000, Suzuki−Matsumoto−Hosoya)88

This mechanistic framework via ion pair G presents several characteristic features of the reaction. (1) Ion pair G embodies an ideal matching of reactive species in that the nucleophilic phenolate is in proximity to the electrophilic oxonium species. (2) Ion pair G is in equilibrium with O-glycoside C. In the event that the C−C bond formation in G fails, facile reversion to O-glycoside C serves as a backup, allowing the repeated generation of the reactive species G. In contrast, the situation is quite different in the Friedel−Crafts aryl C-glycosylation of fully protected arene substrates (section 2.2.1.1): In the case where the π-nucleophilicity of the arene is not sufficient, the

Step 2 is the in situ conversion of O-glycoside C to C-glycoside D, which is responsible for the oxonium−phenolate ion pair G being generated by Lewis acid activation of C. Recombination by C−C bond formation gives C-glycoside D. 1509


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Scheme 26. ortho-Selective C-Glycosylation by the O → CGlycoside Rearrangement in C104 Synthesis (1995, Suzuki−Matsumoto)100,101

Scheme 29. Resorcinol Trick in the Gilvocarcin Synthesis (1992, Suzuki−Matsumoto−Hosoya)98

Scheme 27. Resorcinol Trick Scheme 30. Divergent Use of Selectively Protected Resorcinol C-Glycoside

Scheme 28. Versatility of Selectively Protected Resorcinol CGlycoside (1991, Suzuki−Matsumoto)89

oxonium species will not be trapped, therefore undergoing decomposition. Thus, highly electron-rich arenes are needed. (3) Early studies showed that the ion pair is fairly distant in nature, as evidenced by a crossover experiment.86 (4) The ion pair mechanism also accounts for the regioselectivity in that the C-glycoside is formed at the orthoposition to the phenol. Even when the reaction appears to proceed without forming the apparent intermediary O-glycoside, the ortho-selectivity is faithfully followed. Step 3 is the anomerization of aryl C-glycoside D via the intermediary quinone methide species H, generated by the Lewis acid activation of the endocyclic oxygen in D coupled with the electron donation by the ortho-hydroxy lone pair. 2.2.1.2.2. Reactivity and Stereoselectivity. Scheme 20 is an insightful example pointing out the Lewis acid dependency of steps 2 and 3 (see Scheme 18).42,43 The reaction of 3,4-di-Obenzoyl-D-olivosyl fluoride (42) with β-naphthol in the presence of Lewis acid upon gradual warming from −78 to 0 °C proceeded via the O-glycoside 43, giving C-glycoside 44. Notably, the yields and the α/β-selectivities were different based on the Lewis acid employed. 1510


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Scheme 31. O → C-Glycoside Rearrangement in Total Syntheses of Galtamycinone (1997, Suzuki−Matsumoto)104 and Aquayamycin (2000, Suzuki−Matsumoto)133−135

Scheme 34. Sc(OTf)3-Promoted Bis-C-glycosylation (2006, 2010, Suzuki−Matsumoto)107−109

Scheme 32. Sc(OTf)3 in O → C-Glycoside Rearrangement (2004, Suzuki−Matsumoto)105 Scheme 35. Sc(OTf)3-Promoted C-Glycosidation of Nitrogen-Containing Sugar in Isokidamycin Synthesis (2010, Martin)110

Scheme 33. Sc(OTf)3-Promoted Aryl C-Glycosylation of Nitrogen-Containing Sugar (2011, Suzuki−Matsumoto−Ohmori)106

In summary, (1) The stronger Lewis acid Cp2HfCl2−AgClO4, which is capable of activating glycosyl fluorides and other oxygen functionalities, gave a quantitative yield of 44 with complete βselectivity. (2) The weaker Lewis acid BF3·OEt2 gave 70% yield of 44, in which the α-anomer prevailed. At the final temperature of 0 °C, the O → C-glycoside rearrangement was not complete, and Oglycoside 43 was obtained in 28% yield. Further warming to room temperature completed the conversion of 43 into 44. 1511


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Scheme 36. Sc(OTf)3-Promoted C-Glycosylation in Saptomycin B Synthesis (2014, Suzuki−Kitamura−Ando)79,80

Scheme 39. Total Synthesis of Kendomycin via O → CGlycoside Rearrangement (2004, Lee)137

Scheme 37. Sc(OTf)3-Promoted Bis-C-Glycosylation of Nonprotected Glucose in Flavonoid Synthesis (2004, Sato)114−116

Taking this trend into account, the representing conformers of αand β-olivosides are as shown. The conformation of α-44 is an unusual 1C4 conformation, where the aryl group disposes at the equatorial position even by sacrificing three axial substituents. In contrast, β-44 can adopt an ideal 4C1 conformer with all four substituents equatorial, and thus, β-44 is thermodynamically more stable than α-44. The complete β-selectivity of the reaction by using Cp2HfCl2−AgClO4 can be rationalized by the strong Lewis acidity, which creates an equilibrium via quinone methide A. Interestingly, when the C3- and C4-hydroxy groups were protected as t-butyldiphenylsilyl (TBDPS) ethers, D-olivosyl donor 45 adapted a flipped conformation, in which all substituents except for the one at the anomeric position are in an axial position (Scheme 22).44 The C-glycosylation gave the αC-glycoside 46 exclusively. The rationale here is the severe gauche interaction that would be experienced in the β-anomer, rendering the α-anomer with a flipped sugar ring favorable. The pronounced small A-values of siloxy groups may also be relevant. This tendency was exploited in the total synthesis of ravidomycin (Scheme 23; see also Scheme 140).88 When the sugar portion is a furanoside, as in the synthesis of the gilvocarcin-class antibiotics, the thermodynamic preference is not obvious. The α/β-selectivity differed greatly depending on the Lewis acid used without obvious reasons (Scheme 24).98,99 Relevant factors include the Lewis acidity to induce the anomerization, and the relative stability of the coordination complex may also be relevant. 2.2.1.2.3. Regioselectivity. The key advantage of the O → Cglycoside rearrangement is the reliable regioselectivity: the Cglycoside is selectively formed at the position ortho to the phenolic hydroxy group. A telling example is seen in the total synthesis of vineomycinone B2 (Scheme 25).42,43 Anthrol 52 reacted with glycosyl fluoride 42 at the desired position, ortho to the free phenolic hydroxy group, among other potential reactive sites. By contrast, random regioselectivity was seen in the reaction of the corresponding tetramethyl ether 54, giving a mixture of positional isomers in low yields. From the stereochemical standpoint, the aryl C-glycoside 53 was solely the β-anomer, as discussed above. The ortho-selective glycosylation reaction was employed as the key step in the total synthesis of antibiotic C104 as well,

Scheme 38. Pr(OTf)3 for O → C-Glycoside Rearrangement (2013, Rauter)117

Stereoselectivity. Scheme 21 shows the general behavior of aryl C-glycosides in terms of the stereochemistry.42,43 The bottom line is the strong preference of the C(1)-aryl group to adapt an equatorial orientation. The anomeric effect is negligible. 1512


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Figure 16. continued

1513


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1514


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1515


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Figure 16. Accomplished total syntheses via the O → C-glycoside rearrangement.

Scheme 40. Grignard Reaction of Glycosyl Chloride (1945, Hurd−Bonner)50

Scheme 43. Reaction of Ribofuranosyl Chloride with Aryl Cuprate (2003, Seitz)144

Scheme 41. Reaction of Glycosyl Chloride with Aryl Grignard Reagent in Flavonoid Synthesis (1975, Eade)139

Scheme 44. Reaction of Glycosyl Bromide with Diarylzinc Reagent (2012, Lemaire−Knochel)146

Scheme 42. Reaction of Ribofuranosyl Chloride with Ph2Cd and Ph2Zn (1995, Kool)141

Scheme 45. 3-Ketoglycal as an Electrophilic Sugar Unit (1987, Bellosta−Czernecki)148

allowing the installation of a D-olivose unit onto the curved tetracycle (Scheme 26).100,101 This ortho-selective C-glycosylation was indirectly exploited in the regioselective approach to the gilvocarcin−ravidomycin antitumor antibiotics, possessing C-glycosides located at the para-position to a phenol; namely, an approach called resorcinol trick was applied to the O → C-glycoside rearrangement of

monoprotected resorciniol A (Scheme 27). The C-glycoside bond formation occurred selectively at the less-hindered orthoposition of the free phenol in A, giving C-glycoside C. The selective protection pattern of the two phenolic hydroxy groups in C could be used for further elaboration. 1516


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Scheme 50. Sugar-Derived Lactone in Aryl C-Glycoside Synthesis (1988, Kraus)160

Scheme 46. Acyclic Sugar as an Electrophilic Reaction Partner (1989, Schmidt)151

Scheme 51. Use of Sugar-Derived Lactone in Medermycin Synthesis (1990, Tatsuta)162

Scheme 47. Use of Acyclic Sugar as an Electrophilic Reaction Partner in Griseusin Synthesis (1983, Yoshii−Takeuchi)152

Scheme 52. Use of Sugar-Derived Lactone in Vicenin-2 Synthesis (2016, Suzuki−Ohmori)171

Scheme 48. Use of Acyclic Sugar as an Electrophilic Reaction Partner in 7-Con-O-methylnogarol Synthesis (1986, Terashima−Matsuda)153

Scheme 49. Nucleophilic Addition−Reduction of SugarDerived Lactone: Prototype (1982, Kishi)159

Scheme 53. 1,2-Anhydro Sugar as an Electrophilic Reaction Partner: Prototype (1982, Hirata−Kishi−Uemura)175

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Scheme 54. 1,2-Anhydro Sugars in Aryl C-Glycoside Synthesis ((a) 1989, Czernecki176; (b) 2002, Rainier178)

Scheme 28 shows a concrete example of the resorcinol trick.89 Reaction of glycosyl fluoride 38 and mono-O-acetyl resorcinol (58) in the presence of BF3·OEt2 gave C-glycoside 59 in a regioand stereoselective manner. After conversion of 59 into triflate 60, deoxygenation by hydrogenolysis gave a para-phenol Cglycoside 61. Using the triflate in 60 for cross-coupling reactions, introduction of a vinyl group or an aryl group by Stille reaction gave styryl C-glycoside 62 or biaryl C-glycoside 63, respectively. The resorcinol trick was strategically exploited in the total synthesis of ent-gilvocarcin M (Scheme 29).98,99Although the α/ β-stereoselectivity at this step was not straightforward, as the furanoside C-glycoside was concerned, it was nicely controlled by the judicious choice of Lewis acid employed (see section 3.1.3). The O → C-glycoside rearrangement of iodoresorcinol derivative 48 gave C-glycoside 51 regioselectively. After conversion of the f ree ortho-phenol in 51 into the corresponding triflate, the vicinal iodotriflate functional array was used to generate benzyne species 65, undergoing [4 + 2] cycloaddition with methoxyfuran en route to the target, ent-gilvocarcin. Note that the protected phenol group in 48 (highlighted in red) became the “para”-hydroxy group in the final product. For the full synthetic scheme and the [4 + 2] benzyne−furan cycloaddition, see sections 3 and 4. Furthermore, the selective protection of each phenol group in the iodo-resorcinol C-glycoside A could be strategically exploited to prepare benzyne precursors D, allowing the generation of benzyne E with an ortho-oxy functionality (Scheme 30), which was used for the total syntheses of galtamycinone102−104 and aquayamycin (Scheme 31; also see sections 3 and 4).102,133−135 2.2.1.2.4. Sc(OTf)3 As an Especially Effective Lewis Acid. Sc(OTf)3 is among the rare-earth triflates developed by Kobayashi in 1999, showing unique characteristics, such as stability and therefore utility in protic solvents.136 In 2004, Matsumoto, Suzuki, and co-workers employed Sc(OTf)3 in aryl C-glycoside chemistry, discovering its special efficacy in the O → C-glycoside rearrangement.105 Many reports later appeared on the special advantages of Sc(OTf)3 in aryl C-glycoside synthesis regarding substrate scope and extraordinary tolerance of a variety of functional groups, as will be described in the following section.79,80,106−111,114 Scheme 32 shows two advantages: (1) Applicability to the sugars that bear nitrogen functionalities as 71.

Scheme 55. Use of 1,2-Anhydro Sugar in the Synthesis of α-CMannosyltryptophan (1999, Ito−Manabe)179

Scheme 56. 1,2-Anhydro Sugar in Aryl C-Glycoside Synthesis: A Recent Example (2015, Mukherjee)181

(2) Applicability to phenols having electron-withdrawing groups, such as 72. These two features stand in contrast to common Lewis acids used before that time, which are often deactivated by the presence of coordinating functional groups in the substrates or the reaction media. These features allowed strategic changes: Sc(OTf)3 allowed an early-stage incorporation of nitrogen-containing sugars as illustrated in the synthesis of deacetylravidomycin M (Scheme 33; see also Scheme 141).106 This stands in contrast to the earlier synthesis of ravidomycin in 2000 (see Schemes 23 and 140),88 in which the aryl C-glycoside bond formation was carried out on a neutral sugar and the amino functionality was installed at a late stage by a substitution reaction. Scheme 34 shows another example of the viable installation of two distinct amino C-glycosides within the same benzene ring, related to the synthetic study of saptomycin B.107−109 Schemes 35110,111 and 3679,80 show further examples of the Cglycosidations of nitrogen-containing sugars in relation to the synthesis of the pluramycin-class bis-C-glycoside antibiotics,

Scheme 57. Magnesium Phenolate in Aryl C-Glycoside Synthesis (1988, 1990, Casiraghi)182,183

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Figure 17. Accomplished total syntheses via formation of C-glycoside linkage using an aromatic anion.

Scheme 58. Reverse-Polarity Approach

Scheme 59. Generation of Glycosyl Anion by Deprotonation (1982, Vasella)187

showing the viability of the late-stage C-glycosylation, that is, installation of a sugar onto the tetracyclic aglycon 82 and tricyclic intermediate 86.

An additional feature of Sc(OTf)3 is its tolerance to multiple oxygen functions, which often deactivate the Lewis acidic 1519


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Scheme 60. Generation of Glycosyl Anion by Reduction (1985, Beau)192−194

Scheme 64. Reverse-Polarity Approach to Aryl Bis-Cglycoside (1994, Parker)211

Scheme 61. Generation of Glycosyl Anion by Tin−Lithium Exchange (1987, Beau)200

Scheme 65. Use of Glycal Anion in Cassialoin Synthesis (2008, Suzuki−Koyama)212 Scheme 62. Reductive Aromatization of Glycal/Quinone Monoacetal Adduct (1991, Parker)207

bis-C-glycoside did not form under these conditions.117 Ultrasound irradiation improved the yield and shortened the reaction time, and this protocol further allowed the installation of a disaccharide, lactose. It is interesting to show an example in which the O → Cglycoside rearrangement, although not for an aryl C-glycoside synthesis, was exploited for a macrocyclization (Scheme 39): the first total synthesis of kendomycin by Lee and co-workers.137 By using BF3·OEt2 as Lewis acid, phenol 91 was converted to macrocycle 93 via O-glycoside 92. In contrast, attempts at the Friedel−Crafts cyclization of a fully protected derivative of 91 were unsuccessful. To close this section, Figure 16 summarizes the accomplished total syntheses of aryl C-glycoside natural products by means of O → C-glycoside rearrangement. 2.2.1.3. Methods Using Aryl Anions. This section describes the reactions of aryl anions with glycosyl halides. As described before, early attempts at the use of Grignard reagents on glycosyl chlorides met with many problems, often producing undesired products. Hurd and Bonner, for example, had to protect the hydroxy groups of the sugar moiety after coupling with phenyl magnesium bromide (Scheme 40).50 The example by Eade et al. in 1975 (Scheme 41)139,140 was not an exception, resulting in the problem of low yield of the desired product, 95. For the Cglycosyl flavonoid synthesis, the α/β-anomers were converged to the desired β-anomer by acid treatment. The ways to circumvent the problems with the use of aryl anion species for aryl C-glycoside synthesis include (a) use of aryl

Scheme 63. Dienone−Phenol-Type Rearrangement of Glycal/Quinone Mono-acetal Adduct (1995, Parker)209

reaction promoters. Scheme 37 shows a pioneering contribution of Sato and co-workers.114−116 The reaction of trihydroxyacetophenone 87 and glucose in water−EtOH gave mono- and bisC-glucosides, proving the robustness of the Sc(OTf)3 catalysis, which enables aryl C-glycosylation of nonprotected reaction partners in protic solvents. Rauter and co-workers reported the glycosylation of naringenin, a flavonoid compound. Among various rare-earth metal triflates, Pr(OTf)3 proved most effective (Scheme 38), and 1520


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Scheme 66. Transition-Metal-Mediated Coupling Approach to Aryl C-Glycosides

Scheme 70. Heck-Type C(1) Arylation

Scheme 71. Pd-Mediated C-Arylation of Glycal (1983, Czernecki)229

Scheme 72. Cross-coupling Approaches to the Gilvocarcin Skeletons (1987, 1991, Daves Jr.)230,231

Scheme 67. Arylation of the C(1) Position via π-Allyl Transition-Metal Complex

Scheme 68. Pd-Catalyzed Arylation of Glycal Acetate (1982, Dunkerton)215

Scheme 73. Use of Phenyl Grignard Reagent in Heck-Type Arylation (1999, Tingoli)234

Scheme 69. Stereochemically Divergent Arylation of Glycal Derivative (1995, Sinou)217

metal species other than aryl Grignard reagents and (b) use of other electrophilic sugar partners, as discussed in the following section. Use of transition-metal catalysis, which has been extensively investigated, will be discussed later in section 2.2.3. 1521


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Scheme 79. Synthesis of Stannyl Glycal (2) (1991, Friesen)205

Scheme 74. Heck-Type Arylation of Glycal with Arenediazonium Salt (2000, Schmidt)235

Scheme 80. Synthesis of Stannyl Glycal (3) (1986, Beau)204 Scheme 75. Use of Arylboronic Acid in Heck-Type Arylation (2001, Maddaford)238,239

Scheme 81. Pd-Catalyzed Cross-coupling of Stannyl Glycal with Aryl Halides (1990, Beau)244

Scheme 76. Use of Benzoic Acid (A) and Aryl Hydrazine (B) in Heck-Type Approach to Aryl C-Glycoside (2013, Liu)240,242

Scheme 77. Cross-coupling of Glycal Derivatives

Scheme 82. Pd-Catalyzed Cross-coupling of Stannyl Glycal with Aryl Halides (1990, Friesen)245

Scheme 78. Synthesis of Stannyl Glycal (1) (1986, Hanessian)203

2.2.1.3.1. Use of Aryl Metal Species Other than Aryl Grignard Reagents. The use of Ar2Cd or Ar2Zn species, for example, in place of ArMgX, enabled substitution reactions of 2deoxyribosyl chloride 96, giving the corresponding C-glycosides 97 with various aryl groups in good yields as reported by Kool and co-workers in 1995 (Scheme 42).141−143 Cuprates further improved the yields, as reported by Seitz and co-workers in 2003 1522


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Scheme 83. Syntheses of the Papulacandin Core by Dubois and Beau246,247 (Left) and Friesen and Sturnio248 (Right) in 1990

Scheme 85. Tius’ Protocol for Reducing 1-Aryl Glycals (1990, 1991, Tius)249,250

Scheme 86. Synthesis of Derhodinosylurdamycin A (2015, Zhu)255 Scheme 84. Negishi Coupling of Zincated Glycal with Anthracenyl Iodide (1990, 1991, Tius)249,250

Scheme 87. Pd-Catalyzed Coupling of Glycal Indium with Aryl Iodide (2003, Minehan)256

(Scheme 43).144,145 In both cases the reactions were α-selective, but acid-catalyzed anomerization gave the β-anomers, which were used as polyarene C-nucleoside mimics for biological studies. The above-described examples were only applicable to sugars of the 2-deoxy series but not to the sugars with a 2-hydroxy group. However, this restriction was overcome by Lemaire, Knochel, and co-workers with their reports in 2012 (Scheme 44).146,147 By exploiting an aryl zinc species, generated from 99, direct substitution of glycosyl bromide 100 became possible in high yield. The use of a pivaloyl protecting group was indispensable, avoiding the trapping of the extended cationic species generated by the neighboring group participation, which

was observed when benzoyl protecting groups were employed instead. 1523


Chemical Reviews

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Scheme 88. Arenesulfonyl Chlorides in Pd-Catalyzed Coupling with Stannyl Glycal (2004, Vogel)258

Scheme 91. Glycal Silanol in Cross-coupling Approach to Papulacandin D (2007, Denmark)265

Scheme 89. Synthesis of Glycal Boronate (2005, Mitsubishi− Tanabe Pharma260,261) and the Structure of Canagliflozin

Scheme 92. 1-Iodoglycal for Cross-coupling (1991, Tius)250

Scheme 90. Glycal Boronates for Cros- Coupling: Synthesis of 8,10-Di-O-methylbergenin (2005, Mitsubishi−Tanabe Pharma260,261) Scheme 93. 1-Iodoglycal for Cross-coupling (1991, Friesen)269

2.2.1.3.2. Use of Other Electrophilic Sugar Partners. The use of other electrophilic sugar partners indeed generated viable methodologies, as shown in the following section. 3-Ketoglycals (Sugar-Derived Enones). Although not having been employed in the synthesis of natural aryl C-glycosides, 3ketoglycals are reported as a viable Michael acceptor. Reaction of 102 with higher-order phenylcuprate in the presence of acetic anhydride as trapping agent gave phenyl C-glycoside 103 in high yield (Scheme 45).148−150 In the absence of acetic anhydride,

side reactions occurred, including epimerization at the C4position and/or opening of the pyran ring. 1524


Chemical Reviews

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Scheme 94. Use of Glycal Phosphates in Cross-coupling (2013, Pongdee)270

Scheme 98. Cross-coupling of Glycosyl Stannane with Aryl Halides (2016, Walczak)275

Scheme 95. Cross-coupling Reaction at sp3-Hybridized Anomeric Carbon Center

Scheme 96. Ni-Catalyzed Reaction of Arylzinc Halides with Glycosyl Bromides (2008, Gagné)271

Sugar-Derived Lactones.159−174 One of the key methods frequently used in natural product synthesis is the nucleophilic addition to sugar-derived lactones followed by the hydride reduction of the resulting ketol derivatives initiated by Kishi and co-workers (Scheme 49).159 Because of the high stereoselectivity of this reaction sequence, hydride is delivered stereoselectively from the α-side (axial attack) due to the anomeric effect from the ring oxygen (see A). In the context of aryl C-glycoside synthesis, Kraus and Molina exploited this two-step approach in 1988 (Scheme 50).160,161The total synthesis of medermycin by Tatsuta et al. in 1990 exemplifies an application of this protocol in natural aryl Cglycoside synthesis (Scheme 51).162 In 2016, Ohmori, Suzuki, and co-workers reported an approach to vicenin-2, a bis-C-glycosyl flavone, by exploiting 1,3,5-trifluorobenzene as a surrogate of phloroglucinol (Scheme 52).171 The fluorine atoms were replaced by oxygen functions in late stages of the synthesis. The synthesis used two times the 1,2addition of lithiated trifluorobenzene derivatives to D-gluconolactone 114 followed by the silane reduction. For the total synthesis, see Scheme 177. 1,2-Anhydro Sugars. In relation to the palytoxin total synthesis, Kishi and co-workers reported the nucleophilic addition to 1,2-anhydro sugars in 1982 (Scheme 53).175 Since then, sugar-derived epoxides started to be used in the reactions with various nucleophiles, including aryl anionic species. In 1989, Bellosta and Czernecki reported the reaction of phenylcuprate (Scheme 54a).176 β-Epoxide 124 smoothly underwent the nucleophilic attack, as it leads to the diaxial ring-opening (Fürst−Plattener’s rule). By contrast, the corresponding reaction of α-epoxide 127 was initially quite low yielding. Subsequent studies have improved the yield, while prediction of the stereochemical outcome remained difficult, depending on the nucleophile (Scheme 54b).177,178 In the Ito synthesis of α-C-mannosyltryptophan (Scheme 55),179,180 the key C-glycoside bond formation was achieved by

Scheme 97. Cocatalyzed Reaction of Aryl Grignard Reagent with Glycosyl Bromide (2013, Cossy)274

Acyclic Sugars. Frick and Schmidt reported, in their synthesis of 5,7,4′-tri-O-methylvitexin, that acyclic sugar aldehyde 104 could be combined with aryl nucleophile 105, and the primary adduct 106 cyclized into aryl C-glycoside structure (Scheme 46).151 Although the C-glycoside structure was completed at a much later stage of the synthesis, this strategy of coupling an acyclic sugar derivative with an anionic aryl species was employed in the total syntheses of griseusin (Scheme 47)152 and 7-con-Omethylnogarol (Scheme 48).153−158 For details, see section 3. 1525


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Figure 18. Accomplished total syntheses via the formation of C-glycoside linkage by using transition-metal-catalyzed coupling reactions.

arylzinc reagents. The chemoselectivity is also notable by the absence of halogen−metal exchange for the bromo-substituted arylboronic acid. Use of Phenolate (Casiraghi Reaction). Although not a carbanionic species, use of phenolate as the nucleophilic aromatic reaction partner provided interesting possibilities (Scheme 57). Reaction of glycal 11 and magnesium phenolate 133 gave the anti-SN2′ product 134 with α-stereochemistry.182 Reaction of magnesium phenolate 136 with sugar lactol 135 gave β-137 as the sole product.183 To close this section, Figure 17 summarizes accomplished total syntheses of aryl C-glycoside natural products by the use of glycosyl anions.

Scheme 99. De Novo Construction of the Sugar Moiety

the reaction of lithio indole 129 and glycosyl epoxide 124 to give adduct 130. Choice of the N-protecting group affected the stereoselectivity, and high α-selectivity was attained by using a benzenesulfonyl group. Scheme 56 shows a recent example.181 The arylzinc reagent, generated in situ by the B → Zn exchange of 131, reacted with epoxide 127 to give C-glycoside 132 in high yield, manifesting promising utility in view of the broad availability of various 1526


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Scheme 100. Hetero-Diels−Alder Reaction for De Novo Construction of Sugar Moiety (1983, Danishefsky)276

Scheme 103. 1,3-Dipolar Cycloaddition for De Novo Construction of Sugar Moiety (2002, Hauser)283

Scheme 104. Metathesis Reaction for De Novo Construction of Sugar Moiety (2000, Schmidt)284 Scheme 101. Hetero-Diels−Alder Reaction for De Novo Construction of Sugar Moiety (1987, Schmidt)281

Scheme 105. De Novo Construction of Aromatic Moiety

Scheme 102. Hetero-Diels−Alder Reaction for De Novo Construction of Sugar Moiety (2009, Dujardin)282

Scheme 106. C5 Platform for De Novo Construction of Aromatic Moiety (1992, Yamaguchi)285

2.2.2. Methods Using Glycosyl Anions. Use of glycosyl anions A corresponds to a “reversed polarity” or “umpolung” approach in aryl C-glycoside synthesis (Scheme 58).185,186 Because synthetic equivalents to the electrophilic aromatic units B are also necessary, the scope of this approach is rather limited accordingly. However, aid of the transition-metal catalysis offers effective solutions to this polarity problem, as will be discussed in section 2.2.3. This section will show a small collection of examples that

exploits glycosyl anion equivalents without aid of the transitionmetal catalysis. Glycosyl anion can be generated from the sugar derivatives having an electron-withdrawing group at the anomeric position 1527


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Scheme 107. Installation of Furyl Group by Ferrier-Type Reaction [Isobe−Goto (BF3)287; Venkateswarlu (ZrCl4)288; Yadav (InCl3)289]

Scheme 111. Use of Furyl Group for De Novo Construction of Aromatic Moiety in the Synthesis of Isokidamycin (2010, Martin)110

Scheme 108. Installation of Furyl Group by Friedel−CraftsType Reaction (1984, Grynkiewicz−BeMiller)290 Scheme 112. C3-Platform for De Novo Construction of Aromatic Moiety (2013, Tripathi)292

Scheme 109. Installation of Furyl Group by Furyllithium Addition to Sugar Lactone (1989, Czernecki)161

Scheme 110. Martin’s Syntheses of Galtamycinone (2003) and Vineomycinone B2 (2006) by Using Furyl Group for De Novo Construction of the Aromatic Moieties

Scheme 113. Installation of Alkynyl Group (1) ((A) 1986, Nicolaou294; (B) 1987, Isobe−Goto287)

Scheme 114. Installation of Alkynyl Group (2)295

to enhance the acidity. For example, nitro sugar 138 could be deprotonated with a weak base, such as n-Bu4NF (Scheme 59).187 Other electron-withdrawing groups used for this purpose include −CO2R,188,189 −SPh,190,191 and −SO2Ph.192−194 On the other hand, the glycosyl anions without anion-stabilizing groups can be generated either by reduction of the C1-heteroatom functionality (Scheme 60)192,195−199 or by the metal-exchange 1528


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Scheme 115. Use of Alkynyl Sugars for De Novo Construction of Aromatic Moiety (1): Total Synthesis of Vineomycinone B2 (1991, Mioskowski−Falck)296

Scheme 118. Use of Alkynyl Group for De Novo Construction of Aromatic Moiety (4) (1995, McDonald)300

Scheme 116. Use of Alkynyl Group for De Novo Construction of Aromatic Moiety (2) (2007, Kaliappan)298

Scheme 119. Use of Alkynyl Group for De Novo Construction of Aromatic Moiety (5) (2004, Yamamoto)301

Scheme 117. Use of Alkynyl Group for De Novo Construction of Aromatic Moiety (3) (1999, Serra)299 Scheme 120. Use of Alkynyl Group for De Novo Construction of Aromatic Moiety (6) (1999, Döts)303

reactions of glycosyl stannane (Scheme 61)200 or tellurium.201,202 In the context of aryl C-glycoside synthesis, however, these species have remained virtually unexploited. By contrast, the glycal anions have found synthetic utilities, which could be generated by deprotonation with t-BuLi or the Schlosser−Lochmann base (n-BuLi−t-BuOK) and could be directly used as nucleophile.203−205 Alternatively, trapping with Bu3SnCl gives the 1-stannyl glycal as a stable surrogate, which undergoes tin−lithium exchange by reaction with n-BuLi.

Stannyl glycal is also useful for the transition-metal-mediated coupling for aryl C-glycoside synthesis (see section 2.2.3). In the following section, two examples are shown on the use of glycal anions in the context of aryl C-glycoside synthesis. Parker reported the reactions of glycal anion and quinone derivatives for constructing the bisaryl C-glycoside structures 1529


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Scheme 121. Use of Nitromethyl Glycoside in Aryl CGlycoside Synthesis (1987, Kozikowski)305

68). Use of PhZnCl gave phenyl C-glycoside 162 in excellent yield.215 In 1995, Sinou and co-workers reported the allylic substitution of p-tert-butylphenyl glycoside 163 by phenyl Grignard reagent, giving phenyl C-pyranoside 164. The stereochemistry of the product was different depending on the catalyst (Scheme 69).217−219 2.2.3.2. Heck-Type Reactions. This subsection describes the Heck-type arylation at the C(1) position of glycal derivative C (Scheme 70).220 The overall process includes (1) formation of aryl metal species B from the precursor A via transmetalation (if X = metal) or oxidative addition (if X = halogen) or direct metalation in some cases; (2) π-complexation and syn-insertion to form σ-adduct D; (3) conversion of D to Heck-type product E via the syn-β-hydride elimination or to Ferrier-type product F via the anti-β-oxygen elimination. After the extensive study of the Heck-type reactions of glycals in the C-nucleoside synthesis by Daves Jr. toward the end of the 1970s,221−228 application to the aryl C-glycoside synthesis was reported by Czernecki and Dechavanne in 1983 (Scheme 71).229 Direct palladation of benzene with stoichiometric Pd(OAc)2 and the syn addition to the CC bond of glycal 11 gave enol acetate 165 by syn-β-hydride elimination accompanied by 2,3-enopyranoside 166 by the anti-β-oxygen elimination. Reactions of pyrano- and furanoglycals were reported by Daves Jr., using tetracyclic arylstannane 167228,230 or aryl iodide 170228,231−233 under palladium catalysis in the synthetic study of the gilvocarcin-class antibiotics (Scheme 72). Tingoli et al. reported Ni-catalyzed coupling of glycal with phenyl Grignard reagent to give 2,3-unsaturated aryl Cfuranoside 174 (Scheme 73).234 As a limited substrate scope, pyranoid glycal 175 gave acyclic product 176 due to the accompanying reductive ring-opening. Schmidt and Biernat used arenediazonium salt 178 as an aromatic source, as exemplified by the reaction of 3-deoxyglycal 177 catalyzed by Pd2(dba)3·CHCl3, giving C-aryl pyranoside 179 (Scheme 74).235−237 Maddaford and co-workers used arylboronic acid in this context (Scheme 75).238 The Rh-catalyzed conjugate addition of arylboronic acid to glycal-derived enone 102 was also reported.239 In 2011, Liu and co-workers applied the Pd-catalyzed decarboxylative Heck coupling of benzoic acid derivatives (Scheme 76A).240,241 In the presence of Ag2CO3 as an oxidant, C-glycoside 183 was obtained as the α-anomer. The presence of strong electron-donating groups at the 2,6-positions (or 2,4positions) of the benzoic acid was necessary. Furthermore, arylhydrazine 184 was used for the reaction with glycal 11 in the presence of Pd(OAc)2 (1 atm O2, room temperature), giving aryl C-glycoside 185 via the anti-β-elimination (Scheme 76 B).242,243 2.2.3.3. Cross-coupling of Glycal Derivatives. This section will describe the transition-metal-catalyzed couplings of glycals (Scheme 77). Section 2.2.3.3.1 will describe the use of metalated glycals in a chronological order. Section 2.2.3.3.2 will describe the charge-inverted approach, using glycal halides with metalated arenes as substrates. 2.2.3.3.1. Cross-coupling of Metalated Glycals with Aryl Halides. As metalated glycals, 1-stannyl glycals have been most often used for the transition-metal-catalyzed coupling approach to aryl C-glycosides. For the preparation, Hanessian et al. reported a protocol by deprotonation of the silyl-protected glycal 186 with strong bases and trapping with Bu3SnCl (Scheme 78).203 Use of the tri-O-benzyl counterpart failed. It was reported

related to the pluramycin-class antibiotics (Schemes 62−64).206−211 Glycal 146 was lithiated with t-BuLi (THF, − 78 °C), which was combined with quinone monoacetal 147 to give 1,2-adduct 148. Treatment of 148 with DIBAL effected “reductive aromatization”, giving initially a 2:1 mixture of the reduced product 149 and the aromatized product 150, which converged into 150 by dehydration of 149 (Scheme 62).207,208,210 Treatment of 148 with ZnCl2 induced a dienone−phenol rearrangement to give phenyl glycal 152 in excellent yield (Scheme 63).209 The latter protocol was applied to naphthoquinone 154, suggesting an interesting approach to install two C-glycosyl units to a naphthalene scaffold (Scheme 64).211 Lithiated glycal was used for the 1,2-addition reaction to isoxazole-fused ketone 158, an anthraquinone surrogate, to give cis-diol 159, which was used in the total synthesis of cassialoin, a natural anthorone C-glycoside (Scheme 65).212 2.2.3. Transition-Metal-Mediated Coupling Reactions. This section deals with the approaches based on the transitionmetal-catalyzed cross-coupling to make C-glycoside linkages, which are subdivided into four categories (Scheme 66): (a) the reactions of sugar-derived π-allyl metal complex II with aryl nucleophile III [section 2.2.3.1], (b) the Heck-type reactions of glycal derivatives V [section 2.2.3.2], (c) the cross-coupling reactions by metalloglycal IX and aromatic halide (or pseudohalide) X or its reverse variants [section 2.2.3.3], and (d) transition-metal-catalyzed coupling at the sp3-hybridized anomeric carbon center [section 2.2.3.4]. 2.2.3.1. Reactions via π-Allyl Complex. Along with the progress of transition-metal catalysis in organic synthesis, application of π-allyl palladium chemistry initiated by Tsuji213,214 was introduced to the carbohydrate field (Scheme 67).215,216 Work by Dunkerton and Serino in 1982 represents the reaction of glycosyl acetate 160 with a Pd(0) complex and sodium malonate derivative, giving C-glycoside 161 (Scheme 1530


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synthesis of papulacandin D (Scheme 91).265−268 Glycal silanol 232 was prepared by the Ru(II)-catalyzed oxidative hydrolysis of silane 231, which in turn was obtained by lithiation of glycal 226 followed by trapping with chlorodimethylsilane. 2.2.3.3.2. Cross-coupling of Glycal Iodide or Phosphate with Aryl Metals. Although much less studied, “reverse-polarity approaches” have also been reported. The initial report was the one by Tius et al. during his total synthesis study toward vineomycinone B2 (Scheme 92).250,251 In 1991, Friesen and Loo reported the cross-coupling of iodoglycal 236 with phenylzinc chloride. Also reported was the use of arylboronic acid 238 as the aromatic unit (Scheme 93).269 Importantly, reactions of electron-rich aromatics occurred in high yields under both Negishi and Suzuki−Miyaura conditions as exemplified by the synthesis of anisyl glycal 240, which was obtained only in low yield by the Stille reaction of stannyl glycals and 4-haloanisole (cf. Scheme 82).245 As a surrogate of glycal iodides, glycal phosphate 241 appeared, readily prepared from the corresponding 2-deoxy sugar lactone by enolization−phosphorylation (LiN(SiMe3)2, (PhO)2P(O)Cl), which was used for the cross-coupling with aryl boronate esters (Scheme 94).270 2.2.3.4. Cross-coupling at sp3-Hybridized Anomeric Carbon Center. Recent progress of the transition-metal catalysis coupled with stoichiometric organozinc reagents has solved the previously difficult issues of the substitution reactions of glycosyl halides with aryl metal reagents, reinforcing the practicality in synthesis (Scheme 95). Reaction of glycosyl bromide 244 and arylzinc reagent 245 catalyzed by Ni(cod)2 in the presence of terpyridyl ligand (t-BuTerpy) gave C-glycoside 246 in high yield (Scheme 96).271,272 Scheme 97 shows the reaction of glycosyl bromide 247 and arylmagnesium reagent 248 in the presence of Co(acac)3 catalyst and TMEDA.273,274 Walczak and co-workers reported the cross-coupling at the sp3-hybridized anomeric carbon by using glycosyl stannanes and aryl halides (Scheme 98).275 Glycosyl stannanes are configurationally stable, and both anomers are available in a stereoselective manner. Under carefully set conditions, retentive reactions occurred for both anomers, not only fully protected glycosyl stannanes but also partly or fully unprotected glycosyl stannanes and 2-deoxyglycosyl stannanes. To close this section, Figure 18 summarizes the accomplished total syntheses of aryl C-glycoside natural products via the formation of C-glycoside linkage by using transition-metalcatalyzed coupling reactions.

later by Friesen et al. that even the TBS group was problematic by competing deprotonation of the Si-methyls, giving 187 only in low yields.205 A solution was to use TIPS (or TBDPS) protection, which is less prone to the α-silyl carbanion formation (Scheme 79). An alternative approach exploited a radicalmediated conversion of phenylsulfonyl glycal 192, which in turn was available from thioglycoside 191 by the oxidation−βelimination (Scheme 80).204 In 1990, three groups (Dubois and Beau, Friesen and Sturino, and Tius et al.) reported the use of stannyl glycals in the transition-metal-mediated coupling with aryl halides. Dubois and Beau reported that glycals 188 and 194 were efficiently coupled with aryl bromides in the presence of Pd(PPh3)4 (Scheme 81).244 The reaction of 194 with an excess of 1,3-dibromobenzene gave monocoupled product 195, and further coupling with stannane 194 gave 1,3-di-C-glycoside, showing the possibility of selective formation of bis-C-glycosides. Friesen and Sturino studied similar reactions of silyl-protected glycal 187 (Scheme 82).245 Scheme 83 shows synthesis of the core structure of the papulacandin-class antibiotics by Dubois and Beau (left)246,247 and by Friesen and Sturino (right).248 The homocoupling of stannyl glycal was a common issue. In the Dubois and Beau synthesis, a sizable amount of dimer 205 was formed, while Friesen and Sturino used an excess of aryl bromide 202 to suppress it. In 1990, Tius et al. reported the Negishi-type coupling of zincated glycal 207 and iodoanthracene 208 in the context of the total synthesis of vineomycinone B2 (Scheme 84; see also Scheme 123).249−251 In this relation, the reactions of the corresponding stannyl or magnesium glycals, 210 and 211, were examined. Also examined were the reactions of the chargeinverted combinations, i.e., glycal iodide 212 and metalloanthracenes. See the second part of this section. For completing the sugar moiety, an effective protocol was developed by Tius et al. (Scheme 85).249,250 By careful alternate addition of HCl and NaBH3CN, keeping the pH around 4.5, the enol ether moiety in 213 was reduced to give pyran 214. This protocol was devised for circumventing the difficulty in reducing the lactol derivatives of 2-deoxy sugars, for which Kishi conditions (Et3SiH, BF3·OEt2) only produce glycal.159,160 The Tius protocol has been applied in many related instances,252−255 including the recent synthesis of derhodinosylurdamycin A by Zhu and co-workers (Scheme 86).255 Minehan and co-workers exploited glycal derivatives of indium for cross-coupling with aryl halide (Scheme 87).256 According to the literature procedure,257 the indium species were generated in situ by treating glycal 189 with t-BuLi followed by InCl3, giving mono- and/or diglycal indium species, 221 and 222, which were coupled with aryl iodide 219 under the Pd catalysis. Reactions with both electron-rich and -deficient aryl iodides were viable. Arenesulfonyl chlorides are used as coupling partners in the Pd-catalyzed coupling with stannyl glycals (Scheme 88).258,259 The reactivity order is I− > ClSO2− > Cl−. Use of glycal boronates appeared in a patent by the Mitsubishi−Tanabe research group during the SAR study in search of drug candidates, culminating in the development of canagliflozin (Scheme 89).260−262 Boronate 228 served as an effective coupling partner in the Suzuki−Miyaura reaction, as exemplified by the synthesis of 8,10-di-O-methylbergenin (Scheme 90).263 A similar synthesis of bergenin was reported by Kotora and co-workers in 2014.264 See Scheme 191. In 2007, Denmark et al. used glycal silanol for the crosscoupling in aryl C-glycoside synthesis and achieved the total

2.3. De Novo Construction of the Sugar Moiety

This section outlines the approaches based on the de novo construction of the sugar moiety (Scheme 99). Methods for the sugar construction will include (a) hetero-Diels−Alder reaction (section 2.3.1), (b) 1,3-dipolar cycloaddition of nitrile oxides (section 2.3.2), and (c) ring-closing olefin metathesis (section 2.3.3). 2.3.1. Hetero-Diels−Alder Reaction. Bednarski and Danishefsky employed mild lanthanide catalysis for the heteroDiels−Alder reaction to access aryl C-glycosides (Scheme 100).276 Siloxydiene 255 reacted with aldehyde 256 in the presence of Eu(fod)3 to give cycloadduct 257 as a single isomer. Hydroboration of 257 followed by oxidation gave C-glycoside 258. The method was applied to the total synthesis of vineomycinone B2 methyl ester (see Scheme 122).277,278 1531


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(Scheme 108)290 and the Kishi-type protocol from sugar lactone (Scheme 109).159,161 Martin exploited furyl C-glycosides as versatile starting materials for the total syntheses of aryl C-glycoside antibiotics (see section 3).291 Here are shown the initial installation of the furyl moiety to the sugars, as well as where the four-carbon units of the furan are incorporated in the final products. In the syntheses of galtamycinone and vineomycinone B2 (Scheme 110),252−254 the starting furyl C-glycosides were prepared by the Kishi-type protocol (see Scheme 85).159,250 On the other hand, the synthesis of isokidamycin started with the Friedel−Craftstype reaction for preparing the starting C-glycosyl furan (Scheme 111).110,111 The furan moiety is incorporated to the D-ring of the final product by exploiting benzyne−furan [4 + 2] cycloaddition reaction. 2.4.3. Use of Acetonyl Glycosides. Tripathi and coworkers reported a Diels−Alder approach to anthraquinone Cglycoside (Scheme 112).292 The starting point was the preparation of acetonyl C-glycoside 292,293 which was converted to glycosyl diene 293. In the presence of a catalytic amount of InCl3, diene 293 and naphthoquinone underwent Diels−Alder reaction, and oxidative workup gave anthraquinone 294. 2.4.4. Use of Alkynyl Glycosides. 1-Alkynyl C-glycosides serve as a class of useful two-carbon platform toward various glycoconjugates, including aryl C-glycosides. This section outlines several approaches to prepare 1-alkynyl C-glycosides and their use in the context of aryl C-glycoside synthesis. Two major protocols for preparing 1-alkynyl sugars are frequently used, (1) the Friedel−Crafts-type reaction using alkynylsilanes or -stannanes with glycals (Scheme 113)287,294 or glycosyl halides (Scheme 114)295 and (2) Kishi-type two-step protocol using sugar lactone (Scheme 115). Mioskowski, Falck, and co-workers reported the total synthesis of vineomycinone B2 methyl ester via dual Bradsher cycloadditions as the key steps (Scheme 115).296 Alkynyl Cglycoside 301 was prepared by Kishi-type protocol by installing a silylated ethynyl group to sugar lactone 300 followed by silane reduction of the resulting lactol in the presence of BF3·OEt2. Desilylation of 301 gave 302, which was converted to Cglycoside 303 by oxymercuration and demercuration.297 The enol ether moiety in 303 served as the electron-rich dienophile in the [4 + 2] cycloaddition with an isoquinolinium salt (see Schemes 125 and 207). Kaliappan and Subrahmanyam used alkynyl C-glycoside 304 as the starting material for the Diels−Alder approach to aryl Cglycoside synthesis (Scheme 116).298 C-Glycosyl diene 305 was prepared by the enyne metathesis of C-alkynyl glycoside 304, which was treated with naphthoquinone to undergo [4 + 2] cycloaddition. Treatment of the cycloadduct with triethylamine and silica gel gave C-glycosyl anthraquinone 306. Alkynyl C-glycoside was also used as the precursor to aryl Cglycoside via electrocyclization (Scheme 117).299 Hexadienoic acid 308, prepared from alkynyl C-glycoside 307, was treated with ClCO2Et followed by addition of triethyl amine to give phenol 309.

Yamamoto and co-workers reported the asymmetric version of this reaction catalyzed by chiral organoaluminum reagent.279,280 Schmidt et al. used an inverse electron-demand hetero-Diels− Alder reaction for the de novo construction of aryl C-glycoside (Scheme 101).281 α,β-Unsaturated ketone 259 reacted as the heterodiene with styrene 260 under high pressure to give cycloadduct 261. After deprotection and desulfurization, hydroboration and oxidative workup gave aryl C-glycoside 262. These hetero-Diels−Alder reactions were used in combination for the synthesis of fluoro-substituted naphthyl C-glycoside 266, a compound of medicinal interest (Scheme 102).282 Reaction of enone 263 and vinylnaphthalene 264 in the presence of Eu(fod)3 under high pressure gave cycloadduct 265 in moderate yield. Subsequent conversions including hydroboration−oxidation furnished C-glycoside 266. 2.3.2. 1,3-Dipolar Cycloaddition. Hauser and Hu exploited a 1,3-dipolar cycloaddition for the de novo construction of the sugar moiety in aryl C-glycosides (Scheme 103).283 The nitrile oxide, generated from oxime 267 by treatment with NCS, underwent cycloaddition with alkyne 268 to give isoxazole 269. Fission of the N−O bond in 269 and acid-catalyzed cyclization of the diketone intermediate gave pyranone 270. Acetoxylation of 270 with Mn(OAc)3 gave enone 271, which was hydrogenated to give C-glycoside 272. 2.3.3. Metathesis. Schmidt used ring-closing olefin metathesis for aryl C-glycoside synthesis (Scheme 104).284 Enantiopure allylic−homoallylic ether 273, prepared via enzymatic resolution, was subjected to metathesis reaction with Grubbs catalyst, giving dihydropyran 274. Epoxidation and transdiaxial opening of the epoxide gave C-glycoside 275. 2.4. De Novo Construction of the Aromatic Moiety

Discussion here is limited to the approaches based on installation of small (C1−C5) nonaromatic units that serve as progenitors to the aromatic moiety in the aryl C-glycoside structures. Although some of these methods have not yet been exploited in total synthesis, they may provide unique future opportunities (Scheme 105). 2.4.1. Biomimetic Polyketide Condensation Approach. Yamaguchi et al. developed a biomimetic approach to aryl Cglycosides via repeated Claisen condensations (Scheme 106).285 The first stage was the reaction of sugar lactol 276 with ketodiester 277 as a “triketide unit” under Knoevenagel conditions to give C-glycoside 278 in 47% yield. The five-carbon unit was subsequently manufactured by Ca(OAc)2-mediated biomimetic polycyclization en route to the total synthesis of urdamycicinone B,286 which will be discussed in section 3 (see Scheme 129). 2.4.2. Use of Furyl Glycosides. Furyl C-glycosides have been used as versatile synthetic intermediates for C-nucleosides through various conversions of furan into other heterocyclic systems. They have found utilities also as useful platforms for the aryl C-glycoside synthesis by de novo construction of the aromatic moiety from the furyl group. The initial availability of the furyl C-glycosides is summarized as follows. As furan is a heteroaromatic, similar methods described for the aryl C-glycoside synthesis could be basically applicable to furyl C-glycosides as well. Reaction of glycals and furan in the presence of BF3·OEt2 was not regioselective, giving a mixture of C1 and C3-furyl products (Scheme 107).287 However, it was reported that use of ZrCl4288 or InCl3289 as the Lewis acidic promoter led to C1-selective reactions. Other methods for preparing furyl C-glycosides include Friedel−Crafts reaction

Figure 19. Vineomycinone B2 methyl ester.

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Scheme 122. Danishefsky Synthesis of Vineomycinone B2 Methyl Ester (1984)277

Scheme 123. Tius Synthesis of Vineomycinone B2 Methyl Ester (1990)249

McDonald et al. reported a rhodium-catalyzed approach to an aryl C-glycoside (Scheme 118).300 Reaction of C-alkynyl glycal 310 with diketodiyne 311 in the presence of Wilkinson’s catalyst led to alkyne cyclotrimerization to give anthraquinone Cglycoside 312. Cyclotrimerization of diyne 313 with saturated ethanolic solution of acetylene gave spirocyclic C-glycoside 314.

Yamamoto and co-workers reported that this alkyne trimerization procceds under milder conditions by using a Ru(II) catalyst (Scheme 119).301,302 Paetsch and Dötz reported a chromium-mediated benzannulation with an ethynyl sugar (Scheme 120).303 The glucosederived alkyne 319 was treated with electrophilic chromium 1533


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Scheme 124. Suzuki−Matsumoto Synthesis of Vineomycinone B2 Methyl Ester (1991)43

Scheme 125. Mioskowski−Falck Synthesis of Vineomycinone B2 Methyl Ester (1991)296

subdivision by the biosynthetic origin of polycyclic moieties, that is, polyketides (section 3.1), flavonoids (section 3.2), and miscellaneous (section 3.3).

diphenylcarbene 320 followed by decomplexation upon exposure to air, giving β-naphthyl C-glycoside 321. 2.4.5. Use of Nitromethyl Glycosides. Nitromethyl glycoside, first reported by Sowden and Fischer,304 was used by Kozikowski and Cheng for aryl C-glycoside synthesis (Scheme 121).305 Nitromethyl glycoside 322, prepared by Sudoh’s method,306 was used for generating a nitrile oxide by the Mukaiyama method,307 and the 1,3-dipolar cycloaddition to olefin 323 gave isoxazoline 324. The N−O bond fission followed by the Lewis acid-mediated annulation gave naphthyl Cglycoside 326.

3.1. Polyketides

3.1.1. Vineomycins. The vineomycins constitute a class of antitumor antibiotics isolated from the culture broth of Streptomyces matensis by Omura and co-workers. (Figure 19).308,309 Some members are active against Gram-positive bacteria and sarcoma 180 solid tumors in mice. Vineomycinone B2 methyl ester is a chemical degradation product. The structure features a characteristic 1,5-hydroxy-9,10-anthraquinone chromophore possessing a β-linked D-olivoside and at the opposite side a (R)-hydroxyisovaleryl side chain. This particular compound attracted considerable attention of the synthetic

3. NATURAL PRODUCT SYNTHESES This section will almost comprehensively cover the total syntheses of natural products in the order of the following 1534


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Scheme 126. Martin Synthesis of Vineomycinone B2 Methyl Ester (2006)252

Scheme 127. O’Doherty Synthesis of Vineomycinone B2 Methyl Ester (2013)321

community, serving as a cornerstone to test various synthetic strategies to install aryl C-glycoside structure and also introducing the characteristic side-chain moiety. To date, seven total syntheses have been reported, which will be outlined in the following sections. Danishefsky Synthesis.277,278 In 1984, Danishefsky et al. reported the first total synthesis of vineomycinone B2 methyl ester using 3-fold Diels−Alder reactions of siloxy dienes (Scheme 122).310 The first cycloaddition was the reaction of ketene acetal 328 with 2,5-dichloroquinone 329. Methylation afforded

naphthoquinone 330. After isomerization of the terminal olefin in 330, the second cycloaddition of quinone 331 was carried out with siloxy diene 332, and methylation gave anthraquinone 333. Ozonolysis of 333 provided keto-aldehyde 334, ready for the de novo construction of the carbohydrate moiety.276 Reaction of 334 with diene 335 in the presence of Eu(fod)3 gave dihydropyran 336 in excellent yield. This mild lanthanide catalysis for hetero-Diels−Alder reaction furnished the endo cycloadduct 336.311 Hydroboration of the enol silyl ether moiety in 336 led to C-glycoside 337 in a stereoselective manner. 1535


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Scheme 128. Toshima Synthesis of Vineomycin B2 (2013)121

Reformatsky reaction using a chiral auxiliary allowed an access to the side chain. Separation of the stereoisomers and the final methanolysis gave vineomycinone B2 methyl ester. Tius Synthesis.249,250 Tius et al. reported a convergent approach to vineomycinone B2 methyl ester to enable threecomponent coupling (Scheme 123). For enabling the metalation at both sides of the anthraquinone core, the oxidation level of this building block was reduced to the anthracene level, removing the

Figure 20. Urdamycinone B.

Scheme 129. Yamaguchi Synthesis of Urdamycinone B (1992)286

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Scheme 130. Sulikowski Synthesis of Urdamycinone B (1995)138

Scheme 131. Toshima Synthesis of Urdamycinone B (1996)119

groups in a single operation furnished the target, vineomycinone B2 methyl ester. Suzuki−Matsumoto Synthesis.42,43 In 1991, Suzuki, Matsumoto, and co-workers reported a convergent total synthesis of vineomycinone B2 methyl ester (Scheme 124). As for the building block of the central tricyclic core, anthrol derivative 52 was used, in which the free phenol served as a pivot for the regioselective construction of the C-glycoside bond via the O → C-glycoside rearrangement.86 The hafnocene-mediated reaction with D-olivosyl fluoride 42 cleanly gave β-C-glycoside 53 as a single regio- and stereoisomer (see Scheme 25). Anthrol 53 was converted into C-glycosylated stannyl anthracene 345. As the building block for the side-chain moiety, chiral, nonracemic aldehyde 346 was prepared via enzyme-mediated kinetic resolution.314 The tin−lithium exchange of 345 using MeLi in toluene followed by the reaction with aldehyde 346 gave adduct 347. After conversion into quinone benzoate 348, selective removal of the benzylic hydroxy group was achieved by the Marschalk reaction.315 Oxidative cleavage of the double bond to give the corresponding methyl ester followed by deprotection gave vineomycinone B2 methyl ester. Mioskowski and Falck Synthesis.296 In 1991, Mioskowski, Falck, and co-workers reported a unique approach via dual Bradsher cycloadditions of electron-rich dienophiles and isoquinolinium salts (Scheme 125). The first cycloaddition was conducted between enol ether 351 and isoquinolinium salt 350 in the presence of CaCO3 as an acid scavenger,316 and concomitant intramolecular interception of the resultant

Figure 21. Antibiotic C104.

9,10-oxygen functionalities. First, the aryl C-glycoside bond was formed in the presence of a Pd(0) catalyst, generated in situ from Pd(PPh3)2Cl2 and DIBAL. Glycal 206 was lithiated and transmetalated to give the corresponding zinc reagent, which was coupled with iodoanthracene 208 to give C-glycoside 209 in high yield. The double bond in glycal 209 was reduced under carefully controlled conditions by treatment with methanolic HCl and NaBH3CN, giving β-C-glycoside 339 stereoselectively in high yield.249 This protocol has been applied in many related instances (see Scheme 85). To introduce the five-carbon side chain, chiral, nonracemic dioxinone 341 by Seebach et al. was used.312 The anthracene unit was converted to aryl stannane 340 by the ortho-lithiation of 339 and stannylation. Coupling of stannyl anthracene 340 and bromide 341 in the presence of palladium catalyst gave the coupling product 342. Addition of lithium dimethylcuprate to dioxinone 342 proceeded in a stereoselective manner to establish the stereogenic center at the side chain to give 343. Oxidation of the anthracene moiety in 343 produced anthraquinone 344,313 and removal of all protecting 1537


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Scheme 132. Total Synthesis of C104 (1995, Suzuki−Matsumoto)100,101

diastereomers. Under basic conditions, the bonds between the silicon atoms and the bridgehead carbon in 364 were cleaved.320 Acid-catalyzed ring-opening of bisepoxide proceeded in a regioselective manner, and air oxidation gave anthrarufin 365. Further elaboration of the side chain and deprotection completed the total synthesis of vineomycinone B2 methyl ester. O’Doherty Synthesis.321 In 2013, O’Doherty and co-workers reported a convergent synthesis of vineomycinone B2 methyl ester (Scheme 127). The approach is stereodivergent, allowing access to unnatural congeners as well. The carbohydrate moiety was synthesized from furyl ketone 371:322 Noyori asymmetric reduction of 371 gave furyl alcohol 372 with high enantiomeric purity. Achmatowicz reaction of 372 afforded enone 373, which was further converted to olivosyl acetate 55. Anthrarufin (366) was elaborated to enantiomerically enriched epoxide 367 via Sharpless asymmetric dihydroxylation,323 which was then converted to β-lactone 368 by Coates carbonylation.324 Further conversion gave phenol 369 as a glycosyl acceptor. The Cglycosylation of phenol 369 with glycosyl donor 55 was realized by O → C-glycoside rearrangement using typical Suzuki conditions (Cp2HfCl2 and AgClO4).86 Finally, a single-step deprotection−oxidation with BBr3 gave the desired product, vineomycinone B2 methyl ester. Toshima Synthesis.121 In 2013, Toshima and co-workers reported the synthesis of vineomycin B2 by installing two disaccharide moieties as O-glycosides (Scheme 128). Glycosyl acceptor 378 was prepared essentially along the same route reported by Suzuki, Matsumoto, and co-workers.42,43 The difference was the C-glycosylation of anthrol 52 was carried out using unprotected sugar 374 in the presence of TMSOTf, which was then protected to give stannyl anthracene 345, the Suzuki−Matsumoto intermediate, which was combined with aldehyde 376 to give adduct 377.

Figure 22. Aquayamycin.

iminium ion by the N-tethered alcohol gave cycloadduct 352 as a diastereomeric mixture. Selective von Braun cleavage of the mixed azaacetal using methanolic cyanogen bromide,317 acidic hydrolysis, and in situ aromatization afforded aldehyde 354. The second Bradsher cycloaddition of the 2,4-dinitrophenyl salt derived from 354 with the C-glycoside precursor 303 (see Scheme 115) provided cycloadduct 356. Acid hydrolysis and aromatization by the same procedure as above smoothly gave anthracene 357 possessing the complete carbon framework of the target. Oxidative processes converted 357 into anthraquinone 358,318 which was finally converted to vineomycinone B2 methyl ester. Martin Synthesis.252,253 In 2006, Martin and co-workers reported the synthesis of vineomycinone B2 methyl ester, featuring tandem intramolecular benzyne−furan cycloadditions using silicon tethers as disposable linkers to control the regiochemistry (Scheme 126). The cycloaddition precursor 363 was prepared by iterative Mitsunobu reactions. First, the reaction of hydroquinone 359 and alcohol 360 by employing DIAD and PPh3 provided aryl ether 361. After removal of the silyl protecting group by HF·py, the resulting phenol was coupled with glycosyl furan 362 (see Scheme 110) by the second Mitsunobu reaction to deliver 363 in high yield. The pivotal tandem benzyne−furan cycloaddition was performed by the addition of n-BuLi to tetrabromide 363 (Et2O, −20 °C),319 giving bis-cycloadduct 364 in 85% yield as a mixture of 1538


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Scheme 133. Suzuki−Matsumoto Total Synthesis of Aquayamycin (2000)133−135

Scheme 134. Toshima Synthesis of Aquayamycin (2016)112

3.1.2. Angucyclines. The angucyclines constitute a large

decaketide biosynthesis. In this section, total syntheses of the angucyclines will be outlined.34,35 3.1.2.1. Urdamycinone B. The urdamycins constitute a class of angucycline antibiotics, isolated from Streptomyces f radie

class of antibiotics sharing a characteristic curved tetracyclic aglycon framework (benz[a]anthracene) derived from the 1539


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Scheme 135. Total Synthesis of Derhodinosylurdamycin A (2015, Zhu)255

Figure 24. Mayamycin. Figure 23. Benzanthrin B.

106).285 The anomeric stereochemistry was β, reflecting the thermodynamic stability. Reduction of the carbonyl group in 278 gave alcohol 380. For elaboration of the polyaromatic ring system, Claisen condensation of β-hydroxyglutarate 380 with dianion 381 derived from methyl acetoacetate in HMPA and THF (1:1) followed by Ca(OAc)2-promoted aromatization gave naphthalenediol 383 in 40% yield.326 After conversion of 383 into ketoaldehyde 384, via selective elaboration of the two ester functionalities, the aldol reaction with the lithium enolate derived from acetylacetone monothioacetal 385 followed by the K2CO3promoted aromatic ring formation gave C-glycosyl anthracene 387 in 60% yield. Deprotection, oxidation, and dethioacetaliza-

(Figure 20).325 Urdamycinone B was obtained by careful acid hydrolysis of an O-glycosidic bond, which also showed antitumor activities (Figure 20). Yamaguchi Synthesis.286 In 1992, Yamaguchi et al. reported the first total synthesis of urdamycinone B, featuring a biomimetic polycyclization related to the polyketide biosynthesis (Scheme 129). The C-glycoside linkage was constructed at the stage of acyclic polyketide, β-oxoglutarate 277, which was condensed with L-rhamnal-derived sugar 276 under Knoevenagel conditions to give C-glycoside 278 in 47% yield (see Scheme

Scheme 136. Synthesis of Benzanthrin Pseudoaglycon (2000, Parker)337

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tion converted 387 into anthraquinone 388. The final ringclosure of diketone 388 was achieved by the intramolecular aldol reaction (NaOH, MeOH) at low temperature, giving urdamycinone B and its diastereomer, which were separated by chromatography. Sulikowski Synthesis.123,138 In 1995, Boyd and Sulikowski reported a convergent total synthesis of urdamycinone B by exploiting Diels−Alder reaction of C-glycosyl juglone 392 to diene 393 to assemble the whole carbon framework (Scheme 130). The C-glycosylation of naphthol 389 was carried out by O → C-glycoside rearrangement by using methyl glycoside 390 promoted by BF3·OEt2, which smoothly gave naphthyl Cglycoside 391 as single β-anomer in 90% yield. Oxidation of the naphthol moiety afforded bromonaphthoquinone 392, which was ready for the cycloaddition. Heating of bromoquinone 392 and enantioenriched diene 393 gave cycloadduct 394 in 72% yield. Oxidation of 394 with Dess−Martin periodinane gave anthraquinone 395, and saponification and hydrogenation gave urdamycinone B. Toshima Synthesis.119,120 In 1996, Toshima and co-workers reported the third synthesis of urdamycinone B, also using a Diels−Alder reaction of C-glycosyl juglone 398 (Scheme 131). For the aryl C-glycosidation, unprotected D-olivose 374 was used as reported by this group, and the reaction with naphthol 396 promoted by TMSOTf gave β-C-glycoside 397 in 27% yield. Hydrogenolysis gave the unprotected C-olivosyl juglone 398, which was used as a dienophile for the Diels−Alder reaction with diene 399 using B(OAc)3 as a promoter (see Schemes 203 and 204). Subsequent treatment of the primary cycloadduct with DBU gave 400 in 58% overall yield. The silyl group in 400 was converted into tert-hydroxy group by the Fleming method, giving diastereomeric alcohols 401 (see Scheme 205). Krohn photooxidation (see Scheme 206) of 401 gave a 1:1 mixture of urdamycinone B and its C3 epimer,327 which were separated by reversed-phase preparative thin-layer chromatography (TLC).

Scheme 137. O → C-Glycoside Rearrangement Approach to Mayamycin Analogue (2013, Mal)339

Figure 25. Gilvocarcins.

Scheme 138. Total Synthesis of Gilvocarcin M (1992, Suzuki−Matsumoto)98

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Scheme 139. Total Synthesis of Gilvocarcin V (1994, Suzuki−Matsumoto)99

Scheme 140. Total Synthesis of ent-Ravidomycin (2000, Suzuki−Matsumoto−Hosoya)88

3.1.2.2. Antibiotic C104. Antibiotic C104 is one of the Cglycosyl angucyclines and was isolated by Arnone et al. (Figure 21).328 The essential problems in the synthesis were the selective construction of the benz[a]anthraquinone framework and the regio- and stereochemical control in the C-glycosylation. In 1995, Suzuki and co-workers reported the first total synthesis of C104 by the assembly of three building blocks: the tetracyclic skeleton, the sugar, and the E,E-dienoic acid (Scheme 132).100,101 The synthesis commenced with the construction of the angular tetracyclic core via benzyne−furan cycloaddition. Butenolide 403, easily derived from known tetralone 402,329 was converted to α-siloxyfuran 404 by treatment with NaH and TBSCl. Choice of the base was crucial to avoid the undesired Csilylation. Because of the high moisture sensitivity, siloxyfuran 404 was directly used for the next cycloaddition reaction. Upon addition of n-BuLi to a mixture of siloxyfuran 404 and iodotriflate 405 at −50 °C, the generated benzyne underwent [4 + 2]

cycloaddition in a regioselective manner as in A to give unstable cycloadduct 406, and oxidative workup with CAN gave the corresponding naphthoquinone (not shown). After conversion to phenol 407, the C-glycoside formation by the reaction with Dolivosyl acetate 55 promoted by Cp2HfCl2 and AgClO4 cleanly gave C-glycoside 408 in regio- and stereoselective manner. As for the aromatization of the B ring, double enolization of quinone 409 followed by exposure to air gave quinone 410. For the regioselective installation of the dienoyl moiety at the 4-Oposition, the less-hindered C3-hydroxy group was selectively silylated to give TBS ether 411, and Yamaguchi esterification with acid 412 proceeded without side reactions,330 such as the silyl migration or double-bond isomerization. Removal of all protecting groups gave the desired antibiotic C104. 3.1.2.3. Aquayamycin. Among the angucycline antibiotics sharing an angular tetracyclic structure, aquayamycin (Figure 22) was isolated in 1967 by Umezawa and co-workers from the 1542


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Scheme 141. Total Synthesis of ent-Deacetylravidomycin M (2011, Suzuki−Matsumoto)106

Scheme 142. Total Synthesis of Polycarcin V (2014, Minehan)84

culture broth of Streptomyces misawanensis.331 It is active against Gram-positive bacteria, Ehrlich ascites carcinoma, and Yoshida rat sarcoma cells. The structure elucidated by Ohno et al. in 197024 features a C-glycosylated benz[a]anthraquinone skeleton and two hydroxy groups at the junction of the A and B rings. The AB ring system is unstable due to the conjugated diene (C5−

C6−C6a−C12a) and the trihydroxycyclohexanone structure (A ring), and it is prone to rearrange or aromatize under acidic and basic conditions and also photoirradiation (see Figure 8 for the biosynthesis). Suzuki−Matsumoto Synthesis.133−135 In 2000, Suzuki, Matsumoto, and co-workers achieved the first total synthesis of 1543


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pinacol cyclization was performed by using VCl3·(THF)3 and Zn to construct the AB-ring junction with cis stereochemistry.334 The tetracycle 420 was then converted to quinone mesylate 421 in six steps, including oxidation at the C1 position, removal of the acetonide under acid, selective mesylation of the C5-hydroxy group, hydrogenolysis of benzyl groups, and CAN-promoted oxidation of the C-ring to the quinone. Because the C6 position is adjacent to the quinone moiety and susceptible to deprotonation, elimination of a mesylate from 421 was effected under mild basic conditions with i-Pr2NEt to construct the unstable AB ring system, allowing access to the target, aquayamycin. Toshima Synthesis.112 Toshima and co-workers employed a similar synthetic route to aquayamycin (Scheme 134), featuring diastereoselective 1,2-addition of C-glycosyl naphthyllithium to functionalized cyclohexanone 427. Sc(OTf)3-catalyzed Cglycosylation of D-olivosyl acetate 55 and naphthol 423 gave C-glycoside 424 with β-stereoselectivity, which was converted to bromonaphthalene 426. Cyclic ketone 427 was prepared from Dquinic acid. The naphthyllithium species, generated by bromine−lithium exchange of bromonaphthalene 426 with nBuLi, underwent addition to cyclic ketone 427, giving alcohol 428 in diastereoselective manner. Calculations suggested that the α-face of 427 was more hindered by the TBS group. Indiummediated site-selective allylation−rearrangement sequence of naphthoquinone 429 gave ketoaldehyde 430.335 For construction of the B-ring, intramolecular pinacol coupling of 430 was performed using low-valent vanadium to give diol 431 as a single diastereomer. Diol 431 was converted to the Suzuki− Matsumoto intermediate 421.135

Figure 26. Medermycin.

aquayamycin by an approach featured by the construction of the unstable AB ring by introducing the C5−C6 unsaturation at the last stage of the synthesis (Scheme 133). The strategy involved the Hauser annulation of C-glycosyl phthalide 416 and highly functionalized cyclohexenone 417 to construct the linear BCDring system, as well as an intramolecular pinacol cyclization of a ketoaldehyde to form the A-ring with an angular cis-diol. CGlycosyl phthalide 416 was prepared in the following manner: The benzyne, generated from iodotriflate 413, reacted with ketene silyl acetal 414. The [2 + 2] cycloaddition proceeded regioselectively to give, after selective cleavage of the silyl acetal moiety with KF, benzocyclobutendione monoacetal 415 in 73% yield,332 which was selectively elaborated into phthalide sulfone 416 via the Baeyer−Villiger oxidation. It is notable that the isomeric phthalide 416′ is also selectively accessible by the same approach, providing a potential approach to the isomeric congeners as well. On the other hand, highly functionalized cyclohexenone 417 was prepared in an enantio- and diastereoselective manner via enzymatic hydrolysis of a meso-substrate 422a.134 The Hauser annulation of lithio anion of phthalide 416 and enone 417 gave the unstable hydroquinone,333 which was protected to give dimethyl ether 418 in 73% yield. Intramolecular Scheme 143. Total Synthesis of Medermycin (1990, Tatsuta)162

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Scheme 144. Synthetic Study of Medermycin (2002, Brimble)356

disaccharide donor 435 gave the whole carbon framework, leading to derhodinosylurdamycin A. 3.1.2.4. Benzanthrins. Benzanthrins are isolated from Nocardia lurida and are diglycosides of a trihydroxy benz[a]anthraquinone chromophore, where one of the sugars is linked as a C-glycoside, while the other is linked as an O-glycoside; for both of these, the absolute stereochemistries (D or L) have not been clarified (Figure 23).336 In 2000, Parker and Ding reported the C-glycosylation of dehydrorabelomycin dimethyl ether 436 with various glycosyl acetates 437a−d, which proceeded in moderate to good yields using SnCl4 (Scheme 136).337 Azido glycoside 438d enabled access to the benzanthrin pseudoaglycon 439. 3.1.2.5. Mayamycin. Mayamycin, isolated from the cultures of marine Streptomyces sp. strain HB202 in 2010, exhibits potent cytotoxic activities. A structural feature is the amino C-glycoside attached at the C5 position of the angucycline framework (Figure 24).338 In 2013, Mal and co-workers reported the synthesis of a mayamycin analogue by using the O → C-glycoside rearrangement of glycoside 440 and β-naphthol, giving C-glycoside 441

Figure 27. Galtamycinone.

Zhu Synthesis.255 Zhu and co-workers reported the synthesis of a related antitumor antibiotic, derhodinosylurdamycin A, featuring the late-stage introduction of the sugar moiety to the aglycon (Scheme 135). Glycosyl acceptor 216 was prepared via the Hauser annulation of cyanophthalide 432 and cyclohexenone 417, the Suzuki−Matsumoto intermediate (see Scheme 133), in the presence of t-BuOLi followed by intramolecular pinacol cyclization for the angular ring-closure. The C-glycoside bond was formed by the Stille coupling of stannyl glycal 215 and aryl iodide 216. The cyclic enol ether in C-glycal 217 was stereoselectively reduced using the Tius protocol, NaBH3CN and HCl under careful control of pH, to give β-C-glycoside 434 (see Scheme 86).249 For installation of the oligosaccharide, Lewis acid-catalyzed stereoselective glycosylation of acceptor 434 with

Scheme 145. Total Synthesis of Galtamycinone (1997, Suzuki−Matsumoto)104

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Scheme 146. Formal Synthesis of Galtamycinone (2003, Martin)254

biological properties, including antibacterial and significant antitumor activity. For example, gilvocarcin V is a DNAintercalating agent that induces single-strand cleavage of DNA upon activation with low-energy UV or visible light. 3.1.3.1. Gilvocarcin M and Gilvocarcin V.98,99 The first total synthesis of gilvocarcin M was reported by Suzuki, Matsumoto, and Hosoya in 1992, establishing the absolute configuration (Scheme 138). A major synthetic challenge was the unfavorable disposition of the aryl C-glycoside linkage, 1,2-cis and 1,4-cis. For the O → C-glycoside rearrangement, glycosyl acetate 50 and iodophenol 48 were treated with Cp2HfCl2−AgClO4 to obtain C-glycoside 51 in high yield with high stereoselectivity (α/β = 8/ 1). Note that the anomer shown in the figure is α-anomer, as the L-series sugar is concerned. After extensive screening, further improvement of the stereoselectivity was achieved by employing a Lewis acid based on norbonylsilyl chloride and AgClO4 (α/β = 26/1). Phenol 51 was converted to triflate 64 for the benzyne generation.342 Upon treatment of 64 with n-BuLi (THF, −78 °C), sequential benzyne formation, regioselective [4 + 2] cycloaddition with 2-methoxyfuran, and aromatization of the primary adduct occurred to give naphthol 445 in high yield. For construction of the teracycle, a Pd-catalyzed cyclization approach was used: Acylation of 445 with acid chloride 446 gave ester 447, which was cyclized by intramolecular biaryl coupling catalyzed by (PPh3)2PdCl2 in the presence of NaOAc (see section 4.8),343 giving tetracycle 448 in 90% yield. Removal of all four benzyl groups by catalytic hydrogenolysis gave gilvocarcin M. In a similar manner, gilvocarcin V having a vinyl group essential to antitumor activity was also synthesized (Scheme 139).99 Note that the natural enantiomer was synthesized

Figure 28. Pluramycins.

(Scheme 137).339 Oxidative dearomatization of 441 gave enone 442, and the Hauser annulation with cyanophthalide 443 enabled access to the C5-glycosyl angucycline structure 444. 3.1.3. Gilvocarcins. The gilvocarcin family of antibiotics was isolated from several strains of Streptomyces (Figure 25).340,341 Structurally, they share a common benzonaphthopyranone system, to which a sugar is attached at the C4 position through a C-glycoside linkage. These compounds exhibit impressive 1546


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Scheme 147. Total Synthesis of Isokidamycin (2010, 2011, Martin)110,111

anticipating the nonobvious preference of the conformation of the sugar. However, starting from D-glucurono-δ-lactone, several steps of conversion gave glycosyl donor 47 having tbutyldiphenylsilyl group as a stereocontrolling factor by enhancing the Gauche interaction of the 3-O and 4-O substituents to bias the ring-flipping mode (see Schemes 22 and 23).44 Indeed, the Hf-promoted C-glycoside formation of 47 proceeded stereoselectively to give C-glycoside 49 as a sole product in 83% yield. Subsequent conversions included the regioselective [4 + 2] cycloaddition of benzyne derived from iodotriflate 453 and 2-methoxyfuran to give naphthalene 454,342 after MOM protection. Introduction of the amino group was achieved by removing the TBDPS group with CsF followed by

starting from D-series fucofuranose as a starting material. Condensation of naphthol 445 and carboxylic acid 449 by water-soluble carbodiimide gave ester 450, which was cyclized in the presence of a Pd catalyst and sodium pivalate as a base to give tetracycle 451 in 65% yield. Conversion of 451 into alcohol 452 followed by application of the Grieco−Nishizawa method344 allowed access to the natural enantiomer of gilvocarcin V. 3.1.3.2. Ravidomycin and Deacetylravidomycin M. The first total synthesis of ravidomycin,345−348 an amino sugar congener of the gilvocarcin-class antibiotics, was reported by Suzuki and co-workers (Scheme 140).88 To install the nitrogen functionality to the sugar moiety at a late stage, one needed the L-β-Cglycoside 49 with the 3-O functionality axially disposed, while 1547


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Scheme 148. Total Synthesis of Saptomycin B (2014, Suzuki−Kitamura−Ando)79,80

Scheme 149. Synthetic Study of Kidamycin (2007, McDonald)77

Figure 29. Pluraflavin A.

product was antipodal to the natural ravidomycin, thereby establishing the relative and absolute stereochemistry of the naturally occurring compound. Total synthesis of the unnatural enantiomer of deacetylravidomycin M was achieved by Suzuki, Matsumoto, and co-workers (Scheme 141).106 The synthesis started with the C-glycosylation of iodophenol 48 with the azido-bearing glycosyl acetate 73 by employing Sc(OTf)3 in the presence of Drierite, which gave β-Cglycoside 71 in 80% yield. After conversion of phenol 71 to the corresponding triflate 459, the [2 + 2] cycloaddition of benzyne to ketene silyl acetal 460 (n-BuLi, THF, −98 °C) proceeded in a regioselective manner as in A, which gave cycloadduct 461. Construction of the tetracyclic aromatic nucleus was achieved by a [2 + 2 + 2] approach (see Figure 48 and Scheme 211 in section 4),351 starting with the nucleophilic addition of the styryllithium, generated from styryl bromide 463 and t-BuLi, to benzocyclo-

conversion to imidazolylsufonate 455,349 which underwent an SN2 reaction with NaN3 and the reductive methylation to give dimethylamino C-glycoside 456. Formation of the tetracyclic structure 458 via the Pd-catalyzed cyclization was not straightforward by the presence of the dimethylamino function but was realized under the Harayama conditions.350 The final 1548


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Scheme 150. Synthetic Study of Pluraflavin A (2014, Danishefsky)371

tetracyclic aglycon core with gilvocarcin V but possesses an αlinked L-rhamnopyranosyl moiety (Figure 25). Minehan and co-workers reported the synthesis of polycarcin V, starting with the Friedel−Crafts-type C-glycosylation for constructing the C-glycosidic linkage (Scheme 142).84 Reaction of dibenzyloxynaphthalene 469 with rhamnosyl donor 470 in the presence of TMSOTf proceeded regioselectively to give Cglycoside 471 in 70% yield with high α/β selectivity (>95/5), which was rationalized by the neighboring group participation of the C2-ester group on the sugar, shielding the β-face of the resulting oxocarbenium ion. Introduction of an additional phenol function to naphthalene 471 was achieved in two steps, (1) Vilsmeier formylation and (2) Baeyer−Villiger oxidation, to give naphthol 472, which was further converted to dihydroquinone 473 by CAN-oxidation followed by dithionite reduction. Selective and successive protection of the two phenols in 473 was achieved in three steps: (1) ethoxymethylation, (2) methylation, and (3) removal of the ethoxymethyl group to give naphthol 474. The synthetic scheme of the Suzuki− Matsumoto synthesis of gilvocarcin V was followed; condensa-

Figure 30. Griseusins.

butenone 462, giving alcohol 464. The ring-expansion reaction of alcohol 464 was realized by heating in degassed toluene at 110 °C, and workup by acetylation gave naphthalene 465 in 86% yield. The synthesis revealed that the natural product is not the proposed amine 467 but the corresponding N-oxide 468. 3.1.3.3. Polycarcin V. Polycarcin V, a gilvocarcin-type natural product, was isolated from a culture extract of Streptomyces polyformus sp. nov. in 2008.352 It shows significant cytotoxicity selective to nonsmall-cell lung cancer, breast cancer, and melanoma cells. Structurally, this compound shares a common

Scheme 151. Total Synthesis of Griseusin A and B (1983, Yoshii)152

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Scheme 152. Total Synthesis of Griseusin A (2015, Thorson)376

Scheme 153. Total Synthesis of Granaticin (1987, 1989, Yoshii)379,380

Figure 31. Granaticin and related compounds.

tion of naphthol 474 with carboxylic acid 475 to give ester 476 in 98% yield followed by Pd-catalyzed cyclization gave lactone 477 in 64% yield, which was converted to polycarcin V. 3.1.4. Medermycin. Medermycin was isolated from a strain of Streptomyces K73 in 1976, showing strong activity against Gram-positive bacteria (Figure 26).353 It possesses a pyranonaphthoquinone skeleton with an amino sugar, D-angolosamine, attached through a C-glycoside linkage. The first total synthesis of medermycin was reported by Tatsuta et al. in 1990 (Scheme 143).162 The dimethylamino group of the sugar moiety was introduced at a late stage. The Cglycoside bond was constructed by 1,2-addition of aryllithium species, generated from aryl bromide 478 (n-BuLi, −78 °C), to D-rhamnal-derived lactone 117, and oxidation of the dimethyl acetal gave carboxylic acid 120. Stereoselective reduction of lactol 120 with Et3SiH in the presence of TFA gave β-C-glycoside 121.159 After debromination, diethylamide 479 was converted to phthalide sulfone 482, which was used for the Hauser annulation with enantiopure enone 483 (n-BuLi, t-BuOH).354 O-Methylation of the resulting hydroquinone and stereoselective reduction by NaBH4 gave pyranonaphthalene 484. After acidic hydrolysis, the corresponding hemiacetal was subjected to Wittig reaction to give lactone by oxa-Michael addition.354 The lesshindered C3′-hydroxy group in the sugar part was selectively silylated to give lactone 485. At this stage, the undesired diastereomer 486 was separated by silica-gel column chromatography. After installation of the amino group to give 487, reductive

Figure 32. Nogalamycin and 7-con-O-methylnogarol. 1550


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Scheme 154. Total Synthesis of 7-Con-O-methylnogarol (1988, Terashima)154

N,N-dimethylation and oxidative demethylation gave the labile quinone, which was deprotected with AlCl3 to complete the synthesis of medermycin. The synthesis and biological evaluation of the enantiomer were also reported.355 Synthetic Study. Brimble et al. reported a synthetic study of medermycin (Scheme 144).356 The O → C-glycoside rearrangement of azido-bearing methyl glycoside 488 with naphthol 489 promoted by BF3·OEt2 gave C-glycoside 490, which was converted to bromoquinone 491. Introduction of an acetyl group to the naphthalene ring in 491 gave hydroquinone 492, which was oxidized to the corresponding quinone, and the reaction with siloxyfuran afforded pyranonaphthalene 494 as a 1:1 diastereomer mixture. Oxidation of naphthalene 494 was followed by spontaneous acetal formation to give C-glycosyl pyranonaphthoquinone 495. Unfortunately, conversion to the target, medermycin, failed by the lability of the pyranonaphthoquinone under the reductive conditions. 3.1.5. Galtamycinone. Galtamycinone is a naphthacenequinone having a C-glycoside (Figure 27).357,358 Although displaying a linear tetracyclic structure, it is also categorized as the angucyclines from the biogenetic standpoint, attracting biological interests in structural relation to the anthracyclines, a clinically important class of antitumor agents. Suzuki−Matsumoto Synthesis.104 Total synthesis of galtamycinone was achieved by Suzuki, Matsumoto, and Yamaguchi in 1997 (Scheme 145). C-Glycosyl juglone 499 can be used as a general intermediate for synthesizing both classes of the angucyclines, angular and linear. Iodotriflate 66 was subjected to the O → C-glycoside rearrangement with glycosyl acetate 55, which gave β-C-glycoside 67 as a sole product. The aromatic ring in 67 was elaborated, giving iodotriflate 496, which upon treatment with n-BuLi (−78 °C) generated a benzyne species that underwent regioselective cycloaddition to chlorofuran 497 as in A, and spontaneous aromatization of the cycloadduct cleanly gave naphthol derivative 498,342 which was then oxidized by CAN to chlorojuglone 499. For the construction of the

naphthacenequinone framework, Kita−Tamura’s chemistry (see Figure 50 and Scheme 212 in section 4) was exploited:359 Treatment of homophthalic anhydride 500 with NaH at 0 °C generated the corresponding anion, to which was added chlorojuglone 499 at −78 °C. Upon warming to 0 °C, regioselective cycloaddition and spontaneous decarboxylation occurred to give naphthacenequinone 501 in high yield. All protecting groups in 501 were removed by BBr3 and completed the synthesis of galtamycinone. Martin Synthesis (Formal).254 Martin and co-workers reported a formal synthesis of galtamycinone (Scheme 146). The bottom line was the Diels−Alder reaction of C-glycosyl furan to benzyne to give a juglone derivative, which can be converted to the natural product by Suzuki’s procedure. Nucleophilic addition of 3-furyllithium to lactone 286 followed by reduction of the resulting lactol by Tius’ protocol gave Cglycosyl furan 287. Subsequent reaction with the benzyne generated from chlorobenzene 502 and sec-BuLi gave a diastereomeric mixture of the Diels−Alder cycloadduct 503. Epoxynaphthalene 503 was aromatized upon treatment with TFA to give naphthol 504. O-Methylation and CAN oxidation of 504 gave quinone 505, which was converted in two steps [(1) Cl2, AcOH, (2) EtOH, 75 °C] to chloronaphthoquinone 499, the penultimate intermediate of the Suzuki−Matsumoto synthesis (see Scheme 145), therefore completing a formal synthesis of galtamycinone. In pursuit of an alternative annulation strategy, Martin and coworkers examined the direct use of quinone 505 without chlorination, which was not straightforward. The reaction with isobenzofuran 507 gave an uncharacterized mixture of general structures 508/509, whose composition was simplified by treatment with NCS and NaH to introduce a double bond at the central quinone ring. Subsequent treatment with TMSOTf gave a separable mixture (ca. 1.1:1) of regioisomers 501 and 510, among which the former coincided with the final intermediate in the Suzuki−Matsumoto synthesis of galtamycinone.104 1551


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Scheme 155. Total Synthesis of 7-Con-O-methylnogarol (1991, Hauser)383

and (2) selective construction of the highly oxygenated tetracycle. 3.1.6.1. Isokidamycin. The total synthesis of isokidamycin was reported by Martin, exploiting silicon tether for the regiocontrol in an intramolecular Diels−Alder reaction of benzyne and furan and a Sc(OTf)3-promoted O → C-glycoside rearrangement (Scheme 147).110,111 The first C-glycosylation was realized by the Friedel−Crafts reaction of furan with azido sugar 288, corresponding to the angolosamine subunit. Glycosyl furan 289 was converted to furyl C-glycoside 511, to which a βhydroxyethylsilyl tether was introduced and combined with naphthol 513 via the Mitsunobu reaction to give the intermediate 514 in 92% yield, thereby setting the stage for intramolecular Diels−Alder reaction. Treatment of 514 with n-BuLi at −25 °C delivered, via A, oxabicycle 515 as a diastereomer mixture in 92% yield.365 Removal of the silicon tether and opening of the oxabicyclic ring in 515 gave the corresponding C-glycosyl anthracene 516. After regioselective bromination, anthracene 517 was combined with alkynal 518 via halogen−lithium exchange to give ynone 519. Pyranone formation was realized by Lewis acid-promoted cyclization of the intermediary vinylogous diethylamide to provide tetracycle 82. For introducing the vancosamine unit via acetate 81 to anthrol 82, the O → Cglycoside rearrangement was used, where extensive screening of

Figure 33. Anthrone C-glycosides.

3.1.6. Pluramycins. The pluramycins constitute a family of antibiotics sharing a unique structural feature of two amino Cglycosides attached to the polyketide-derived anthra[1,2-b]pyrantrione chromophore (Figure 28).360,361 Since the discovery of pluramycin A as the first member of this family in 1956 by Umezawa and Kondo,25,27 a large number of congeners have appeared, including kidamycin,362,363 hedamycin, and the saptomycins.364 The potent antitumor activities of these compounds are attributed to the intercalation into the DNA, where two amino sugars play a key role for the sequence selectivity. As for the synthetic point of view, two key challenges are (1) regioselective installation of two C-glycosides, Dangolosamine at C8 and N,N-dimethyl-L-vancosamine at C10, 1552


Chemical Reviews

Review

Scheme 156. Total Synthesis of Cassialoin (2008, Suzuki−Koyama)212

Scheme 157. Synthetic Study of 5-Hydroxyaloin A (2010, Martin)386

Lewis acid revealed that Sc(OTf)3 and Drierite allowed the highyield formation of β-C-glycoside 83. Further manipulation including removal of protecting groups on the amino sugars and oxidative demethylation of the central ring of the anthracene core gave the final product. 3.1.6.2. Saptomycin B. Saptomycin B was isolated from Streptomyces sp. HP530, which shows antitumor activity against human and murine tumor cell lines. Structurally, it shares a common anthrapyranone chromophore containing two amino C-glycosides and a six-carbon side chain. In 2014, Suzuki, Matsumoto, and co-workers reported a convergent total synthesis and the structure assignment of saptomycin B (Scheme

Figure 34. Xanthone C-glycosides.

1553


Chemical Reviews

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Scheme 158. Total Synthesis of Mangiferin (1967, Nott)389

Scheme 159. Total Synthesis of Mangiferin (2010, Yu)74

was carefully oxidized by PhI(OCOCF3)2 in aqueous MeCN to the corresponding naphthoquinone, which was directly treated with DBU and then exposed to air to give anthraquinone 527 in 67% overall yield. Finally, conversion of two azide groups into N,N-dimethylamino groups369 and removal of all protecting groups gave the final product, saptomycin B. Following this synthetic route, the enantiomer of alkynal 523 was also incorporated in the final product in similar overall yield. Careful comparison of the two synthetic samples revealed that the configuration of the stereogenic center at C14 of the natural product is R. 3.1.6.3. Synthetic Studies. Fei and McDonald reported a synthetic study toward kidamycin, featuring an attempt at the late-stage introduction of two amino sugars onto anthrapyran aglycon 528, having an additional free hydroxy group at C9, in the hope of facilitating the dual C-glycosylation (Scheme 149).77 The first C-glycosylation of tetracycle 528 with D-angolosamine donor 529 was cleanly achieved by using SnCl4, forming the Cglycosidic bond at the C8 position, to give C-glycoside 530 in 70% yield. However, the second C-glycosylation of 530 was hampered by the severe steric hindrance. The reaction of 530 with L-vancosamine donor 531 under similar conditions gave bisC-glycoside 532 unfortunately only in low yield. The preparation of the starting material 528 will be described in section 4 (Scheme 218). Pluraflavin A, belonging to the pluramycin family, was isolated in 2001 from the cultures of Saccharothrix sp. DSM 12931, featuring an anthrapyranone chromophore with a C-linked disaccharide at C10 and a hydroxymethyl group at C5, bearing a β-3-epi-vancosamine residue (Figure 29).370 Danishefsky and co-workers reported a synthetic study toward pluraflavin A based on a late-stage installation of the carbohydrates (Scheme 150).371 Enantioenriched bromoanthrapyran 534 was prepared by an approach previously described by the same group.372 The key steps were the [3 + 2] cycloaddition of a naphthonitrile oxide to form a functionalized isoxazoline and regioselective Diels−Alder reaction of a siloxy diene to construct the tetracyclic core structure. Stannyl glycal 533 was combined with bromoquinone 534 by Stille coupling, giving glycal Cglycoside 535 in 80% yield. The next challenge was stereoselective hydrogenation of the glycal CC bond, for which heterogeneous conditions in less-polar solvent were effective. CGlycal 535 was converted to quinone monoacetal 536, which was hydrogenated (Pd/C, toluene) to give C-glycoside 537, favoring the desired α isomer. The dimethyl acetal in 536 conferred the stability during reduction of the glycal double bond. Further steps including the O-glycosylation gave the advanced intermediate 538. 3.1.7. Griseusins. Griseusins, isolated from Streptomyces griseus, constitute a class of pyranonaphthoquinone antibiotics sharing a unique 1,7-dioxaspiro[5.5]undecane ring system fused to a juglone moiety (Figure 30).373,374 Although the intriguing structure attracted considerable synthetic interest, only two completed total syntheses have been reported so far. In 1983, Yoshii and co-workers reported the first total synthesis of (+)-griseusins A and B (Scheme 151).152 The

148).79,80 The target compound was assembled from four building blocks, a tricyclic platform, two amino sugars, and an alkynal, through 10 synthetic operations. Use of tricycle 85 allowed the stepwise and regiocontrolled installation of two amino sugars. The reaction of L-vancosaminyl acetate 84366 with 85 in the presence of Sc(OTf)3 and Drierite gave the mono-C-glycoside 86 in 82% yield. The D angolosaminyl acetate 33 was combined with C-glycoside 86 under similar conditions to give bis-C-glycoside 35 in 96% yield. The anomeric configurations of the C-glycoside moieties were both β. For elaboration of the tetracyclic aglycon structure, tricycle 522 was enolized by LDA and allowed to react with chiral, enantiopure aldehyde 523, giving aldol 524 in 89% yield as a diastereomeric mixture. Alkynal 523 was prepared in both enantiomeric forms via asymmetric alkylation by using Seebach’s auxiliary.367 The alcohol in 524 was then oxidized with IBX to give 1,3-diketone 525. The A-ring closure was realized by treating 525 with K2CO3 in MeOH to provide pyranone 526 via the 6-endo cyclization.368 Further steps toward the final product were performed under light shielding, for avoiding the potential photoinduced degradation of the pluramycins. Tetracycle 526 1554


Chemical Reviews

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Scheme 160. Total Synthesis of Neomangiferin (2016, Li)76

Scheme 161. General Synthetic Methods of C-Glycosyl Flavones

Figure 35. C-Glycosyl flavones.

aryllithium species, generated from bromonaphthalene 539, was added to chiral, nonracemic aldehyde 540, an L-dideoxygulose derivative,375 and subsequent oxidation gave naphthyl ketone 541. Bromohydration of the terminal olefin in 541 in the presence of perchloric acid followed by selective removal of the isopropylidene group on the sugar moiety by treatment with HCl gave a 1:2 ratio of diastereomeric bromospiroacetals 542. This intramolecular spiroacetalization failed when the peri-phenol was protected as methyl ether rather than as an acetonide, due to steric reasons. After the bromide in 542 was replaced by a cyano group, epimerization at the C3 position and hydrolysis under basic conditions gave carboxylic acid 543. Finally, oxidation to (+)-griseusin B and the γ-lactone formation gave (+)-griseusin A. Thorson and co-workers reported the synthesis of griseusins via a C−H functionalization strategy (Scheme 152).376 Enantioenriched alcohol 546 was prepared by the Sharpless enantioselective dihydroxylation of olefin 545.377 The key hydroxy-directed C−H olefination of naphthalene 546 was achieved by the reaction with enone 547 in the presence of Pd(OAc)2 and Ag2CO3,378 giving pyran 548 and methylene

isochroman 549. Further oxidation and the spiroacetal formation of 549 allowed the synthesis of (−)-griseusin A. This group also synthesized related natural products by a similar approach. 3.1.8. Granaticin. Granaticin was isolated in 1957 from the culture of Streptomyces olivaceus (Figure 31).37 Since then, this antibiotic and various congeners have been found from the cultures of various other Actinomycetes. Granaticin is highly active against Gram-positive bacteria and protozoa and also active against P-388 lymphocytic leukemia in mice and cytotoxic against KB cells. The structure features a 2-oxabicyclo[2.2.2]oct5-ene system derived from a doubly connected C-glycoside, 1555


Chemical Reviews

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Scheme 162. Syntheses of Cytisoside and Isocytisoside (1966, Chopin)393

Scheme 164. Synthesis of 5,7,4′-Tri-O-methylvitexin (1964, Eade)81

Scheme 163. Synthesis of 7,4′-Di-O-methylbayin (1975, Eade)139 Scheme 165. Synthesis of 7,4′-Di-O-methylisobayin (1982, Tschesche)394

conversion of 553 into phthalide 554, the Hauser reaction with enone 555 gave pyrone 556. Finally, the γ-lactone formation and oxidation of the naphthalene ring afforded (−)-granaticin. This protocol was previously utilized in the synthesis of sarubicin A.381 3.1.9. Nogalamycin. Nogalamycin, an anthracycline antibiotic, was isolated from Streptomyces nogalator by Wiley et al. in 1968 (Figure 32).38−41 It is active against Gram-positive bacteria and also shows prominent cytotoxicity against L1210 and KB cell lines in vitro. A semisynthetic derivative, 7-con-O-methyl nogarol, exhibited enhanced anticancer activity. Structurally, these compounds possess the characteristic C-glycoside moiety (DEF-ring), in which an amino sugar is fused to the anthracycline D-ring to form the E-ring. In 1988, Terashima, Matsuda, and Kawasaki reported the first total synthesis of 7-con-O-methylnogarol by exploiting a regioselective Diels−Alder reaction of a naphthoquinone with a highly functionalized diene (Scheme 154).154 For the selective construction of dienophile 565, D-arabinose was converted to methyl ketone 558,382 which was combined with the aryllithium, generated from naphthalene 559 and n-BuLi, to give tert-alcohol 560 in high stereoselectivity (14:1). After conversion to naphthalene 561, oxidation with CAN gave naphthoquinone 562 in 72% yield in regioselective manner. The regioisomeric quinone 563 was obtained in 21% yield. After reduction of 562 with sodium dithionite, brief exposure of the unstable

which is the same structure found in sarubicin A. The other side of the molecule resembles nanaomycin D and other pyrano-γlactones. Yoshii and co-workers reported the total synthesis of granaticin (Scheme 153).379,380 Tetralone 550 was converted into ketol 551, which was further converted to alcohol 552. After optical resolution, alcohol 552 was subjected to stereoselective dihydroxylation to give the corresponding triol. Benzylic bromination followed by an intramolecular etherification gave oxacycle 553 with a 2-oxabicyclo[2.2.2]oct-5-ene system. After 1556


Chemical Reviews

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Scheme 166. Synthesis of Tetra-acetate of 5,7,4′-Tri-Omethylvitexin (1989, Schmidt)151

Scheme 168. Syntheses of Vitexin and Isovitexin (1995, Schmidt)82

Scheme 167. Synthesis of Isoembigenin (1995, Schmidt)82

Scheme 169. Synthesis of Aciculatin (2016, Lee)124

dihydroxynaphthoquinone to Me3SiBr effected simultaneous cleavage of three methoxymethyl groups and intramolecular acetal formation, giving, after acetylation, bicyclic acetal 564 corresponding to the CDEF-ring system.153 After conversion of 564 to naphthoquinone 565, the Diels−Alder reaction with racemic ketene silyl acetal 566 proceeded regioselectively, and subsequent air oxidation of the cycloadduct during mild acidic 1557


Chemical Reviews

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Scheme 170. Synthesis of Isoorientin via O → C-Glycoside Rearrangement (2000, Kumazawa−Sato)90

Scheme 171. Synthesis of Orientin, Isoswertiajaponin, and Parkinsonins A and B (2001, Kumazawa−Sato)91

workup gave the whole carbon framework. The final steps were introduction of the C7-methoxy group and deacetylation to give 7-con-O-methylnogarol. Hauser et al. reported a racemic synthesis of 7-con-Omethylnogarol by using an isobenzofuranone annulation as the key step (Scheme 155).383 C-Glycosyl cyanophthalide 575, corresponding to the DEF ring system, was prepared in a highly stereoselective manner: Regioselective conversion of 2,5dimethoxyacetophenone (567) into amide 568 followed by addition of furyllithium gave furyl alcohol 569, which was subjected to Achmatowicz oxidation and acid treatment in methanol, giving methyl glycoside 571. After conversion to amino C-glycoside 572, acid treatment produced the corresponding bicyclic acetal 573, which was subjected to the formylation at the aromatic ring with DMF to give benzaldehyde 574. For the annulation, aldehyde 574 was converted to cyanophthalide 575 by using the protocol reported by Yoshii and co-workers.379 The anion derived from cyanophthalide 575 was combined with enone 576 and oxidation of the resulting hydroquinone gave hexacyclic compound 577. The C9-hydroxy

group was introduced via oxidation of the A-ring and ring opening of the epoxide, and the C7-hydroxy group was installed via radical bromination and solvolysis. 3.1.10. Anthrone C-Glycosides. Anthrone C-glycosides constitute a class of natural products in which sugars are connected to an anthrone skeleton at the C10 position through a C−C bond (Figure 33). Cassialoin was isolated from the plant extracts traditionally used in Ayurvedic and Asian folk medicine, namely, a heartwood of Cassia garrettinana CRAIB or the roots of Rheum emodi WALL.384,385 Such unique structures present challenges for the stereocontrolled synthesis as well as for the structure elucidation. In 2008, Suzuki and co-workers reported the first total synthesis of cassialoin, utilizing the chiral, nonracemic ketol 158 as a selectively protected stereogenic surrogate of anthraquinone (Scheme 156).212 The cyclocondensation of nitrile oxide 582 and diketone 583 in the presence of MS 4A gave isoxazole 584. After removal of the menthyloxycarbonyl moiety and hydrolysis of acetal, ketoaldehyde 585, thus obtained, was subjected to intramolecular benzoin reaction using thiazolium salt 586 and 1558


Chemical Reviews

Review

Scheme 172. Synthesis of Flavocommelin (2004, Kondo)395

butoxide, inducing an intramolecular redox reaction via cleavage of the isoxazole ring and the aromatization of the right ring to give imine 588. Hydrolysis of the imine required the protection of the phenol with a nosyl group as in 589. Stereoselective oxidation of the glycal moiety in 589 by dimethyldioxirane followed by borane reduction and deprotection gave the targeted product. This synthesis established the stereochemistry of cassialoin and also revealed that the epimer is present as a minor component in the natural material. Martin and co-workers reported a synthetic study toward 5hydroxyaloin A (Scheme 157).386 The benzyne−furan [4 + 2] cycloaddition was used for constructing the anthrone skeleton. A benzyne species, generated from chlorobenzene 591 and sbutyllithium, reacted with C-glycosyl furan 285 to give cycloadduct 592. After conversion of 592 into C-glycosyl naphthalene 595 having a tethered furan, the intramolecular [4 + 2] cycloaddition afforded cycloadduct 596. Cleavage of the silicon tether and removal of the protective groups under acidic conditions gave anthrone 597 with the C10 stereochemistry unassigned. The final desulfurization was unsuccessful, despite various trials. 3.1.11. Xanthone C-Glycosides. Mangiferin and isomangiferin represent xanthone C-glycosides, which were isolated from mango tree, Mangiferin indica L., possessing a wide spectrum of pharmacological activities (Figure 34).387,388 The first total synthesis of mangiferin was achieved by Nott and Roberts (Scheme 158),389 using Chopin’s direct C-glycoside formation (see Scheme 162) between α-glycosyl bromide 244 and aglycon 598 under basic conditions, which resulted in extremely low yield (0.1%). In 2010, Yu and co-workers reported the total syntheses of mangiferins based on the Friedel−Crafts-type C-glycosylation (Scheme 159).74 C-Glycosylation of xanthene 24 with D-glucosyl N-phenyltrifluoroacetimidate 23 gave a mixture of regioisomers 25 and 26. When benzyl or methoxymethyl groups were used for protecting the xanthene acceptor, the glycosylation failed. DDQ oxidation of the C9 position of 25 gave glucosyl xanthone 599, and deprotection gave mangiferin. Isomangiferin was also synthesized from isomer 26. In 2016, Li and co-workers reported the total synthesis of neomangiferin, 7-O-glucosyl mangiferin, via a strategy of constructing the xanthone skeleton after the C-glycosylation (Scheme 160).76 C-Glucosylated phloroglucinol derivative 603 was prepared by using the Friedel−Crafts reaction. The Vilsmeier formylation, 1,2-addition of aryllithium 605, and oxidation gave benzophenone derivative 606. After transformation into phenol 607, the intramolecular SNAr reaction under basic conditions furnished the xanthone structure. 7-OGlycoside 609 was obtained by the reaction of α-glucosyl bromide 244 with phenol 608, and deprotection gave neomangiferin.

Scheme 173. Synthesis of 6-C-7-O-Di-β-D-glucosylapigenin and Flavocommelin (2013, Sato)396,397

3.2. Flavonoid/Isoflavonoid/Chalcone

3.2.1. C-Glycosyl Flavones. Among the flavonoids, widely distributed in plants, with antioxidant activities, the Cglycosylated derivatives are found as represented by vitexin and vicenin-2 (Figure 35).390−392 The C-glycosides are generally linked at the C-6 and/or C-8 positions on the A-ring of the flavonoid nucleus. For their chemical synthesis, various combinations of glycosyl donors and acceptors have been used for constructing the aryl Cglycoside bond. Scheme 161 outlines general synthetic routes to C-glycosyl flavones. A classical, standard route starts with the

Figure 36. Chafurosides.

DBU to afford ketol 158. 1,2-Addition of the glycal anion, derived from 226, gave adduct 159 in stereoselective manner. After conversion to methylene acetal 587, formation of the anthrone structure was achieved by treatment with potassium t1559


Chemical Reviews

Review

Scheme 174. Synthesis of Chafuroside A via O → C-Glycoside Rearrangement (2004, Nakatsuka)93

Scheme 175. Synthesis of Chafurosides via O → C-Glycoside Rearrangement (2009, Kan)128

derivative C, giving C-glycoside D. More recently, Rauter and coworkers showed a possibility of protection-free C-glycosylation, suggesting a potential way to C-glycosyl flavones (see section 2, Scheme 38).117 In 1966, Chopin et al. reported the syntheses of cytisoside and isocytisoside by the nucleophilic substitution of glucosyl bromide 244 by acacetin. However, the yields were

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