Recent advances in the construction of quaternary pseudoanomeric centers in gem-C,C-glycosides: from zaragozic acids to remdesivir

Abstract

Gem-C,C-glycosides—C-glycosides characterized by two carbon substituents at the pseudo-anomeric position—constitute a structurally distinctive class of glycomimetics with growing relevance in natural products and drug discovery. These motifs appear in diverse bioactive compounds such as maitotoxin, nogalamycins, zaragozic acids and remdesivir, displaying antimicrobial, anti-inflammatory, and anticancer properties. The unique architectures of gem-C,C-glycosides expand the glycochemical space and hold promise for therapeutic development. In contrast to classical C-glycosyl compounds, which benefit from a well-developed synthetic toolbox, the construction of gem-C,C-glycosides remains particularly demanding. This is primarily due to the dual requirement of forming a quaternary center while achieving stereocontrol at a highly congested site. The present review surveys current strategies for constructing quaternary pseudoanomeric centers in gem-C,C-glycosides, highlighting key advances, challenges, and opportunities in this evolving field. Particular attention is given to innovative methodologies that enable direct transformation from carbohydrate precursors, including novel approaches such as metal-hydride hydrogen atom transfer (MHAT) and C–H activation processes.

---

Damien Hazelard

Dr Damien Hazelard obtained his PhD in 2005 under the supervision of Dr A. Fadel (Paris-Sud University). In 2006, he received post-doctoral training in the field of organocatalysis in the group of Prof. Y. Hayashi at the Tokyo University of Science. Then he joined the group of Prof. F. Colobert to work on total synthesis at the University of Strasbourg. He was appointed in 2010 as an assistant professor at the same university in the group of Prof. P. Compain. His current research interests deal with the development of new synthetic methodologies for the synthesis of original nitrogen heterocycles related to glycomimetics.

Mathieu Pascaretti

Dr Mathieu Pascaretti earned a first Master's in Organic Chemistry from University of Grenoble Alpes (2018) and a second Master's in preparation for the national chemistry teaching exam (agrégation) at University of Strasbourg (2019). After successfully passing the competitive agrégation national exam in 2021, he completed his PhD in 2024 under the supervision of Profs P. Pale (University of Strasbourg) and V. Dalla (University of Le Havre), focusing on gold(I)-catalyzed alkynylation of glycosides. He is currently a teaching and research assistant (ATER) at ECPM and a member of the SYBIO team (LIMA), where he investigates novel cascade reactions involving exo-glycals.

Damien Tardieu

Dr Damien Tardieu obtained his Master's degree in 2017 from the University of Montpellier, where he conducted research on the total synthesis of natural isoprostanes. He then moved to Strasbourg to pursue a PhD under the supervision of Prof. P. Compain and Dr N. Kern, where he developed novel synthetic methods for gem-C,C-glycosides via metal-catalyzed hydrogen atom transfer (MHAT) strategies. In 2021, he joined SpiroChem AG, a Swiss contract research organization, as a research chemist. His current work focuses on route scouting and early process development to support drug discovery. His research interests include synthetic strategy design and the development of scalable routes to structurally complex molecules.

Nicolas Kern

Dr Nicolas Kern obtained his PhD in 2014 under the supervision of Dr A. Blanc and Prof. P. Pale, studying the reactivity of strained aza-heterocycles in homogenous gold catalysis. He undertook postdoctoral studies at the University of Manchester with Prof. D. J. Procter, developing asymmetric samarium(II) radical chemistry, then with Prof. P. Compain, working on diverse aspects of carbohydrate chemistry. In 2018 he was appointed as a Chargé de Recherche at CNRS, developing new methodologies towards original carbohydrate mimetics. His current interests focus on reactivity-driven research in radical and organometallic chemistry, targeting bioactive compounds and analogs via atom-economic approaches.

Philippe Compain

Pr Philippe Compain has been Professor of Molecular Chemistry at the University of Strasbourg since 2008. His research ranges from synthetic methodology to the design of biologically relevant glycomimetics. In 1998, he was awarded the Dina Surdin Prize by the French Chemical Society for his PhD research on alkaloid synthesis (UCBL, Lyon). After a postdoctoral stay at Montreal with Prof. S. Hanessian, he was appointed as a Chargé de Recherche at CNRS (ICOA, Orléans). Prof. Compain is an honorary member of the Institut Universitaire de France. He recently served as the 25th President of the Groupe Français des Glycosciences (GFG, the French network in Glycosciences).

---

1. Introduction

Carbohydrates are among the most structurally diverse natural products, playing key roles in various biological processes, from immune defence to protein folding.¹ Despite recent advancements,² translating carbohydrates’ therapeutic potential into tangible patient benefits remains a significant challenge. One promising approach towards this end is the use of glycomimetics,³ which mimic Nature's most effective molecules while overcoming their common drawbacks as credible drugs such as poor oral bioavailability. In addition, structurally modified analogues of carbohydrates may also serve as stable mechanistic probes and have thus the potential to drive groundbreaking advances in glycobiology.^3a As chiral, densely functionalized molecules, glycomimetics present significant synthetic challenges, inspiring the development of innovative strategies for their synthesis.³ C-Glycosides⁴ stand among the most significant and extensively researched classes of glycomimetics.^5,6 The substitution of the exocyclic anomeric oxygen atom by a carbon atom enhances resistance to both chemical and enzymatic hydrolysis, thereby rendering these compounds stable analogues of O-glycosides. Within the family of C-glycosides, gem-C,C-glycosides are characterized by the presence of two carbon substituents at the pseudo-anomeric position, forming a (stereodefined) quaternary center⁷ (Fig. 1a). Over the years, several names have been proposed for this class of compounds. Wilcox first described them as bis-alkylated C-glycosides in the early 1980s.^8,9 In the 1990′s, Schmidt employed the term C-ketosides,¹⁰ while Paquette referred to this class of compounds as bis-C,C-glycosides.¹¹

Fig. 1 (a) General structures of O-, C- and gem-C,C-glycosides. (b) Representative molecular structures of a C-ketoside and a bis-C-glycoside. (c) General approaches for the synthesis of gem-C,C-glycosides (FG = Functional Group).

Recently, the term bis-C-glycoside has gained broader usage,^12,13 although it is also applied in a different context to describe structures with two distinct C-glycosylation sites, as seen, for example, in C-glycosyl flavonoids like 6,8-di-C-D-glucosylgenistein (Fig. 1b).^14,15 Indeed, according to IUPAC nomenclature, the prefixes “di” and “bis” do not necessarily imply that the two substituents are attached to the same atom.

Choosing an unambiguous trivial name for a class of compounds is challenging, as it requires a delicate balance between precision and conciseness. Although the prefix “gem” conventionally denotes two identical substituents—a limitation shared with “di” and “bis”—we will, for the remainder of this review, use gem-C,C-glycosides to describe glycomimetics with two carbon substituents at the anomeric position, whether or not the groups are identical, as it clearly highlights the presence of two C–C bonds at the pseudo-anomeric position.¹⁶ The term C-ketoside appears more appropriate when the parent sugar is clearly identifiable, as exemplified in the C-aryl fructopyranoside structure shown in Fig. 1b. Glycomimetic research is predominantly focused on three main classes of compounds, namely iminosugars, carbasugars and C-glycosides.³ Drawing a parallel with D. Trauner's quote on polyketides, one could say that glycomimetics, like any large family, “have prominent members” but also “poor cousins, i.e. molecules that have been overlooked because of their […] unattractive name, unusual shape, or simply because synthetic chemistry was not ready for them”.¹⁷ This has certainly been true for carbohydrate mimics featuring a pseudoanomeric center bearing two exocyclic C-substituents. From the standpoint of a classical glycochemist, addressing pseudo sugars that lack both glycosidic and anomeric C–H bonds is far from straightforward. By comparison with the parent C-glycosyl compounds, gem-C,C-glycosides indeed prove to be underrepresented in chemistry publications. While a wide range of methods have been developed to access C-glycosides,^6,7 only a relatively limited number of strategies have been reported for constructing stereodefined quaternary pseudoanomeric carbon in gem-C,C-glycosides (Fig. 1c). The efficient and stereocontrolled introduction of two C–C bonds at the anomeric carbon center of carbohydrates, which contain multiple functional groups and asymmetric centers, remains indeed a significant challenge.

Gem-C,C-glycosides, with their distinctive structures and notable biological activities, have increasingly captured the interest of synthetic and medicinal chemists over the past decade. These structural motifs are found in a wide range of natural products, from relatively simple molecules like sphydrofuran¹⁸ to more complex compounds such as arenicolide C¹⁹ and maitotoxin,²⁰ a “molecular Everest” (Fig. 2). A diverse array of naturally occurring compounds and structurally related analogues also feature the gem-C,C-glycosyl moiety. The list includes nogalamycins,^6d,21,22 cinatrins,²³ aurovertins,²⁴ botcinins,²⁵ syringolides,²⁶ zaragozic acids,^27–29 and structurally related compounds (Fig. 2a). The structural diversity of these natural products is matched by a broad array of biological activities, underscoring their therapeutic potential as anti-inflammatory, antimicrobial, and anticancer agents. The distinctive gem-C,C-glycoside structures, featuring a quaternary pseudoanomeric center, open up new avenues for exploring glycochemical and patentable spaces, with the potential to significantly enrich drug discovery pipelines in the years ahead. Among emblematic examples, menogaril, a semisynthetic derivative of nogalamycin (Fig. 2b), was selected for clinical trials on different tumor types due to its reduced cardiotoxicity and improved antitumor activity, compared to the parent compound.^22c However, challenges such as drug resistance and limited intestinal absorption in non-Hodgkin's lymphoma patients, continue to emphasize the urgent need for more effective analogues. The gem-C,C-glycoside scaffolds are also critical components in analogues of synthetic drugs, such as mimics of the antidiabetic Steglatro™ (ertugliflozin).³⁰ In 2020, the pro-drug Veklury™ (remdesivir), a modified nucleotide, was approved by the FDA as an anti-COVID-19 agent.³¹ The unique structural feature of gem-C,C-glycosides also offer exciting opportunities for development of stable molecular probes, particularly as selective enzyme inhibitors. As demonstrated by Schmidt et al.,³² the ternary nature of the transition state of glycosyltransferases can be effectively mimicked by bisubstrate inhibitors³³ which combine elements of both substrates – the sugar donor and the acceptor – C-linked at the anomeric position (Fig. 2c). Anomeric spirocyclopropyl sugars have been also designed as stable, conformationally constrained glycomimetics displaying inhibitory activities towards glycosidases.³⁴ In this context, the present review provides an overview of recent developments in the synthesis of gem-C,C-glycosides, primarily focusing on the past decade (since 2015).^35,36 The goal is not to be exhaustive, but to offer a critical summary of key synthetic studies. Structures discussed were selected based on the following criterion: when a position within a glycomimetic can be intuitively recognized as corresponding to the anomeric center of a related carbohydrate, the compound is classified as a gem-C,C-glycoside if two carbon substituents occupy this site, thereby mimicking the structural role of the anomeric carbon. For example, in the Steglatro™ analog depicted in Fig. 2b, the pseudo-anomeric center is inferred based on the position of the characteristic hydroxymethyl group, which serves as a structural marker commonly found in D-hexopyranoses, such as D-glucose (highlighted in red for clarity). In contrast, in Steglatro™ itself,³⁰ the anomeric center is unambiguously defined by the ketosidic linkage and the position of the hydroxymethyl group. Here, two carbon substituents are now positioned at C-5 rather than at the anomeric C-1 position – based on the structure of the parent D-glucoside derivative (Fig. 2b) – placing Steglatro™ outside the scope of gem-C,C-glycosides as defined in this review.

Fig. 2 Selected natural and synthetic bioactive products containing the gem-C,C-glycosyl moiety.

The appeal of gem-C,C-glycosides has been further amplified by the potential to develop new synthetic methods and strategies, which can be applied to the construction of relevant analogues for drug discovery. By showcasing a selection of key examples, we aim to inspire further research in this underexplored, yet highly promising class of carbohydrate mimics. The review will be structured into two main parts. The first one will focus on the total synthesis of bioactive natural products and their analogues, highlighting the strategies used to construct the pivotal quaternary pseudoanomeric center within the gem-C,C-glycoside motif (sections 2 and 3).³⁷ The second part will discuss innovative synthetic methods developed specifically for the direct construction of this center from carbohydrate starting materials (sections 4 to 7). To achieve this, synthetic chemists must innovate and move beyond traditional C-glycosylation methods, developing processes that enable the stereocontrolled introduction of not one, but two exocyclic C-substituents at the pseudoanomeric center. A variety of synthetic approaches have been adopted from the organic chemists’ arsenal to achieve this goal, ranging from cationic rearrangements to metal-catalyzed hydrogen atom transfer (MHAT) reactions (Fig. 1c). The final section of this review will focus on specific classes of gem-C,C-glycosides of biological interest, namely strained anomeric spirocyclic C-glycosides (section 8).

2. Natural gem-C,C-glycosides and closely related analogues

The synthetic strategies described in this section involve the formation of the quaternary pseudoanomeric center either directly through gem-C,C-glycosylation or via a stepwise synthesis of the carbohydrate motif.

This section will also include compounds derived from natural products and closely related to them structurally.

2.1. Nogalamycins

Nogalamycin, an anthracycline antibiotic produced by Streptomyces nogalater, was discovered in the 1960s at The Upjohn Company (Scheme 1).^22a,b This natural product is a prototypical example of anthracycline subclass V (Fig. 2a), which includes potent antitumor natural products, such as arugomycin and decilorubicin.^6d As a member of the anthracycline class with promising therapeutic potential, nogalamycin has been the focus of extensive research.^22,38,39 However, clinical trials were never initiated due to severe toxicity.^22b Menogaril (7-con-O-methylnogarol), a semisynthetic derivative of nogalamycin (Fig. 2b), was advanced to clinical trials for various tumor types, owing to its reduced cardiotoxicity and improved antitumor activity compared to the parent compound.^22b–d,38 However, challenges such as limited intestinal absorption in non-Hodgkin's lymphoma patients, underscore the ongoing need for more effective analogues. Nogalamycin and its congeners are synthetically compelling due to their unique and intricate structures, where the aglycone aromatic moiety is connected to the sugar residue through both O- and C-glycosidic bonds, resulting in the formation of a distinctive epoxybenzoxocin ring system (Fig. 2a and Scheme 1). The difficulty in stereocontrolling the formation of the densely functionalized, carbohydrate-bridged DEF-ring system of nogalamycin partly explains why its total synthesis has remained an elusive goal for so many years. Despite numerous attempts by synthetic teams worldwide, including those of Hauser, Terashima, Thomson, VanNieuwenhze or Weinreb, a total synthesis of nogalamycin has yet to be achieved.^39,40–43 Recent studies on the biosynthesis of nogalamycin have revealed that the formation of the crucial C-aryl glycoside linkage proceeds through a glycosyl radical intermediate, with the key carbocyclization step being catalyzed by the α-ketoglutarate and nonheme iron-dependent enzyme SnoK (Scheme 1a).^44–46 Both past and recent approaches to the DEF-ring system of nogalamycin have primarily focused on anionic reactions.^39,40–43 In the late 2010s, VanNieuwenhze's group reported three different strategies for the total synthesis of nogalamycin.^47,48 One approach building on Terashima's work on menogaril,^40a involved the addition of an aryl lithium reagent to a methyl ketone derived from D-arabinose, taking advantage of the chirality within its structure (Scheme 1b).^47b

Scheme 1 Formation of the DEF-ring system of nogalamycin via biosynthetic and synthetic approaches.

A chelate-controlled addition with the α-benzyloxy group was expected to yield the desired tertiary alcohol diastereomer with high stereocontrol. However, the reaction exhibited low selectivity, likely due to the electron-withdrawing β-azido substituent, which, according to Evans’ nonchelated model, preferentially stabilized the formation of the undesired diastereomer. A second approach from D-arabinose was developed by the same group by way of a Suzuki–Miyaura reaction as the key step, which coupled the EF-ring segment with the D-ring to give a 1,1-disubstituted alkene (Scheme 1c).^47a After further manipulation, the coupling product was treated with mCPBA to afford the desired epoxide as a single diastereoisomer, although the absolute configuration of the new stereocenter was not determined. Regioselective ring opening by LAH afforded the corresponding tertiary alcohol with concomitant loss of the TBS group. Interestingly, the absence of TBS-deprotection and reductive ring opening with DIBAL and superhydride, showed clearly that lower steric hindrance of the reagent played a key role in this process. Subsequent treatment under acidic conditions afforded the expected DEF-ring fragment of nogalamycin. ¹H NMR coupling constants indicated that the F-ring adopts a chair conformation, consistent with the stereochemical preferences imposed by the anomeric effect. In a third strategy developed by VanNieuwenhze's group,⁴⁸ the carbohydrate-bridged DEF-ring system is constructed by way of a reductive intramolecular Heck reaction from a bifunctional exo-glycal intermediate (Scheme 2). Previous attempts to achieve the desired cyclization on related substrates by activating the exocyclic double bond, either under Friedel–Crafts conditions or through an intramolecular radical approach, led to undesired side products and failed to produce the targeted epoxybenzoxocin skeleton.⁴⁹ In contrast to most approaches towards nogalamycin and its analogues,^{39,40–43,47} these strategies first established the O-glycosidic bond, followed by the introduction of the C-glycosidic bond to complete the DEF-ring system of nogalamycin. The objective was to exploit the stereoelectronic preference induced by the anomeric effect to construct the quaternary pseudoanomeric center with the desired stereochemistry. Building on optimized Heck conditions identified in a previous model study using synthetically more accessible bifunctional exo-glucals,^48b VanNieuwenhze's group obtained the desired tricyclic product in 65% yield along with a small amount of the protodebrominated product.

Scheme 2 Construction of the DEF-ring system via reductive Heck cyclization.

2.2. Meayamycins

FR901464, a natural antitumor antibiotic first reported in 1996,⁵⁰ was isolated by Fujisawa Pharmaceutical Company from Pseudomonas sp. no. 2663 (Fig. 3). Notably, Koide's group later discovered that replacing the anomeric hydroxyl group with a methyl group, forming a gem-C,C-glycoside motif, not only prevented rapid degradation but also enhanced biological potency by up to 100-fold.^51–53 Among these synthetic analogues, known as meayamycins, meayamycin B stands out as the most potent splicing modulator reported to date.⁵²

Fig. 3 FR901464 and representative examples of meayamycins.

The synthesis of meayamycin B by the group of Koide reported in the late 2000s suffered from different drawbacks that limited its availability for biological studies.⁵³ Notably, the formation of the gem-C,C-glycoside motif through an oxymercuration-demercuration sequence required stoichiometric amounts of Hg(OAc)₂ (Scheme 3). In an effort to develop a more concise and environmentally friendly synthesis, Koide et al. designed in 2020 a strategy from a tertiary alcohol starting material in which the gem-dimethyl motif is already present. The pivotal tetrahydropyran ring was formed under acidic conditions from the corresponding γ-hydroxy epoxide via a 6-endo-tet cyclization.⁵⁴ In the two de novo syntheses of meayamycin B reported by Koide, the formation of enantiopure key intermediates relies on the use of enantioselective reactions, such as Sharpless epoxidation (Scheme 3). The same year, the group of Boger⁵⁵ reported the synthesis of meayamycin from D-ribose which provides two stereogenic centers of the key gem-C,C-glycoside intermediate. This intermediate was obtained in 76% yield following a sequence that included acid-catalyzed acetonide deprotection, alkene isomerization, and 6-endo-trig cyclization of the distal alcohol. Initial optimization revealed that treatment of the acetonide with pyridinium p-toluenesulfonate (PPTS) at 60 °C predominantly yielded the corresponding diol. Subsequent addition of aqueous 1 M HCl at 60 °C completed the isomerization of the double bond. Treatment with Amberlyst-15 completed the oxa-Michael-type reaction. A spirocyclopropyl carbohydrate analogue of meayamicin was synthesized by the group of Ghosh in 2018 from tri-O-acetyl-D-glucal (Scheme 3).^34,56 The cyclopropyl moiety was introduced by first treating the corresponding lactone with Petasis reagent, yielding the corresponding enol-ether in 90% yield. Simmons–Smith cyclopropanation of the resulting exo-glycal intermediate with methylene diiodide and diethylzinc provided the desired spirocyclopropyl carbohydrate derivative in a modest 42% yield. The spirocyclopropyl analogue of meayamycin showed significant biological activity in human cells as an RNA splicing inhibitor, with efficacy comparable to that of spliceostatin A.⁵⁶

Scheme 3 Construction of the gem-C,C-glycoside fragment of meayamycins.

2.3. Biomimetic synthesis of the furan ring in arenicolide C

Arenicolides A–C¹⁹ are 26-membered ring macrolides first isolated in 2007 from the marine actinomycete Salinispora arenicola (Fig. 4). At that time, arenicolide C was the only known member of the family featuring a furan ring in place of the epoxy group. Initial biological evaluation revealed that arenicolide A exhibits moderate cytotoxicity against the human colon adenocarcinoma cell line.^19b In the ongoing search for novel anti-tuberculosis agents, a new series of arenicolides bearing a gem-C,C-furanoside motif were identified in 2025 from black oil beetle gut bacterium Micromonospora sp. GR10, along with arenicolide A and related derivatives resulting from macrolactone ester bond cleavage.⁵⁷ Antimicrobial studies revealed that arenicolide A exhibited the most potent in vitro activity, underscoring how the absence of an epoxide group, as well as linear modifications of the macrocycle, can influence anti-tuberculosis efficacy.⁵⁷ Synthetic efforts directed towards the synthesis of arenicolide C were reported by Nagumo's group in 2015, using a biomimetic epoxide-to-tetrahydrofuran transformation (Scheme 4).^19a This cyclization process has been observed in the biosynthetic pathways of related natural products, such as lasalocid A.⁵⁸ Recent studies have proposed similar pathways for the biosynthesis of arenicolides C, F, G, I and K.⁵⁷

Fig. 4 Selected representative examples of arenicolides, highlighting key structural features.

Scheme 4 Construction of the gem-C,C-furanoside fragment of arenicolide C.

Recalling Koide's synthetic approach to meayamycin B (Scheme 3),⁵⁴ the tetrahydrofuran ring was formed under acidic conditions from the corresponding y-hydroxy unsaturated epoxide via a Nicolaou-type cyclization.^19a Treatment with PPTS resulted in efficient 5-endo-tet cyclization, yielding the desired gem-C,C-furanoside intermediate in excellent yield (Scheme 4). Subsequent synthetic elaboration enabled the successful construction of an advanced fragment of arenicolide C.

2.4. Zaragozic acid C

Zaragozic acids,²⁹ also known as squalestatins, were independently discovered in the early 1990s by researchers from Merck,⁵⁹ Glaxo⁶⁰ and Mitsubishi Chemical.⁶¹ Zaragozic acid C is a representative member of this family of structurally related fungal metabolites. Their potent inhibitory activity against mammalian squalene synthase makes then promising lead structures for the development of cholesterol-lowering drugs.²⁷ Zaragozic acid C features a densely oxygenated 2,8-dioxabicyclo[3.2.1]octane acid core adorned with six stereogenic centers. Despite the complexity of this structure, the organic chemist's trained eye can readily pinpoint the embedded gem-C,C-furanoside fragment. Moreover, the three fully substituted carbons at C1, C4, and C5 pose an additional, compelling challenge for its chemical synthesis. Not surprisingly, zaragozic acid C has captured the imagination of many synthetic chemistry groups, resulting in the development of numerous innovative synthetic strategies.^{27,28,62–66} The first total synthesis was reported in 1994 by Du Bois and Carreira, shortly followed by the synthesis from Evans’ group.⁶⁴ Significant contributions to the synthesis of zaragozic acids have also been made by the research groups of Armstrong, De Riccardis, Johnson, Hashimoto, Heathcock, Metz, Nakai and Nicolaou.^27,28 The key steps of these strategies were directed towards the stereocontrolled construction of the hindered tetrasubstituted C4 and C5 centers. Many approaches were employed including osmylation of tri- or tetrasubstituted alkenes, pericyclic reactions or asymmetric aldolizations.^{27,28,62–66} in 2017, the group of Inoue proposed an exciting approach based on a Norrish–Yang reaction to generate the precursor of the tetrasubstituted C4 carbon of zaragozic acid C (Scheme 5).⁶² The densely functionalized 1,2-diketone precursor for the photoinduced process was synthesized in 10 steps from a D-gluconolactone derivative. Irradiation with purple light (405 nm LED) delivered the desired fused bicyclic ketone in high yield with excellent regio- and stereoselectivity. 1,5-Hydrogen abstraction following ketone sensitization furnished the key 1,4-biradical pair. Regioselectivity of the y-hydrogen abstraction was directed by the strategic protection of both other hydroxyl moieties with electron-withdrawing benzoyl groups, biasing the reaction toward polarity-matched HAT at the electron-rich pseudo-anomeric site. The cyclization is favored by the radical anomeric effect,⁶⁷ which stabilizes the reactive α-radical intermediate. The second key step of the synthesis is a remarkable acid-promoted cascade reaction that transforms a bicyclic lactone precursor into the 2,8-dioxabicyclo[3.2.1]octane skeleton of zaragozic acid C (Scheme 5). While various Lewis and both weaker and stronger Brønsted acids proved unsuccessful, treatment with MeSO₃H in MeOH at 100 °C provided the desired bicyclic acetal advanced intermediate in 40% yield with deprotection of the hydroxyl group at C7.⁶² This impressive, complex cascade sequence involves methanolysis of the lactone, departure of the anomeric methoxy group and formation of the new acetal motif through the successive nucleophilic additions of the hydroxyl groups at C3 and C5 to the electrophilic carbon center at C1.

Scheme 5 Total synthesis of zaragozic acid by Inoue et al.

2.5. Natural glycoconjugate analogues

Ganglioside GM3 is a key glycosphingolipid that plays a critical role in regulating diverse biological processes within membrane microdomains (Fig. 5).⁶⁸ However, its metabolic instability – particularly its susceptibility to sialidase-mediated cleavage – has impeded both the investigation of its biological functions and its development as a therapeutic agent. To overcome this limitation, sialidase-resistant analogues of ganglioside GM3 have been designed and synthesized over the past decades. Substitution of the cleavable O-sialoside linkage has resulted in the development of S-sialoside and C-sialoside analogues, leading to minimal structural modifications of the parent natural product.⁶⁹

Fig. 5 Structures of ganglioside GM3 and C-sialoside analogues.

In order to mimic the conformational behaviour of the native GM3 more closely, the group of Sodeoka recently reported the synthesis of analogues incorporating a monofluoromethylene-linked sialoside (Fig. 5).⁷⁰ The stereocontrolled construction of the CHF-sialoside unit was achieved via an Ireland-Claisen rearrangement, enabling formation of the quaternary pseudoanomeric center (Scheme 6). In the same study, GM3 analogues featuring CF₂- and CH₂- linkage were also synthesized, using SiaGal building blocks prepared through the same rearrangement.^70,71 Proliferation assays in Had-1 cells, combined with NMR-based conformational analysis, revealed that the (S)-CHF-linked GM3 analogue with an exo-gauche conformation was the most potent. Had-1 cells, a murine mammary tumor cell line with a glycosylation defect, serve as a sensitive model for evaluating the biological activity of synthetic GM3 analogues. These findings therefore not only highlight the enhanced stability of C-sialoside analogues but also emphasize the crucial role of the exo-anomeric conformation in modulating GM3's biological activity.⁷⁰

Scheme 6 Synthesis of key CHF-sialoside intermediates via Ireland-Claisen rearrangement.

2.6. DEF-ring system of maitotoxin

Maitotoxin is the largest and most potent secondary metabolite identified to date. Its ladder-like polyether framework, comprising over 30 cyclic ether rings, illustrates the exceptional structural complexity characteristic of marine secondary metabolites. This unique architecture, coupled with its potent biological activity, has established maitotoxin as both a formidable synthetic target and a valuable molecular probe in chemical and biological research.²⁰ The group of Oishi has recently proposed a furan-based strategy for the synthesis of the DEF-ring system of maitotoxin (Scheme 7).⁷² The coupling of the furan-based D-ring precursor with a C-vinyl pyranoside, serving as the F-ring precursor, was accomplished via a Fujiwara–Moritani reaction in the presence of Pd(OAc)₂ and 1,4-benzoquinone. The next steps involved D-ring construction from the furan derivatives via the Achmatowicz reaction. Construction of the E ring was then pursued. Treatment of the key δ-ketol with EtSH and triflic acid furnished the corresponding cyclic S,O-acetal in 83% yield. Subsequent installation of the axial methyl group was achieved via mCPBA-mediated oxidation of the sulfur atom to the sulfoxide, followed by Me₃Al-promoted methylation,⁷³ affording the DEF fragment of maitotoxin in 63% yield as a single stereoisomer.

Scheme 7 Synthesis of the DEF-fragment of maitotoxin.

2.7. Recently isolated gem-C,C-glycosides

Over the past decade, several novel natural products bearing the gem-C,C-glycosyl moiety have been isolated, yet their total syntheses remain unreported. The majority of these compounds belongs to the aurovertins family.²⁴ The list includes aurovertin T (Fig. 2) and aurovertin U (Fig. 6) isolated from Calcarisporium arbuscula.

Fig. 6 Recently isolated members of the aurovertin family.

Evaluation of the cytotoxic activities of these compounds against triple-negative breast cancer cell line revealed that aurivertin U exhibits activity comparable to the positive control, Taxol.⁷⁸ Interestingly, the ineffectiveness of aurovertin T underscores the critical role of the 2,6-dioxabicyclo[3.2.1]octane system for anti-cancer activity.⁷⁴ In contrast, two other previously undescribed polyketides, namely aurovertins V and W (Fig. 6), isolated from the fungus Aspergillus aureoterreus, show no cytotoxicity against various human cancer cell lines, including HL-60 and U266.⁷⁵ Very recently, the marine-derived Penicillium sp. OUCMDZ-5930 was identified as prolific source of aurovertins, resulting in the isolation of seven new members of this family including 12-iso-neocitreoviridin.⁷⁶ Unfortunately, no antimicrobial or cytotoxicity activity was observed with these compounds to date. The biosynthetic formation of the gem-C,C-glycosyl moiety in aurovertins is proposed to proceed via regioselective oxidation of a polyene precursor, followed by sequential bis-epoxide ring openings.^24a For example, in the biosynthesis of aurovertin E, a flavin-dependent mono-oxygenase (AurC) and an epoxide hydrolase (AurD) are thought to act iteratively on the terminal triene segment of the precursor, converting it into the characteristic 2,6-dioxabicyclo[3.2.1]octane core of aurovertins via the corresponding dihydroxylated tetrahydrofuran ring (Scheme 8).^77,78

Scheme 8 Proposed biosynthetic pathway for the construction of the 2,6-dioxabicyclo[3.2.1]octane core of aurovertin E.

In 2023, the group of Cheng reported the isolation of four gem-C,C-glycoside-containing bisabolane-type sesquiterpenoids from the deep-sea-derived fungus Aspergillus versicolor YPH93 (Fig. 7).⁷⁹ None of the compounds displayed cytotoxic or inhibitory activity against ferroptosis.⁷⁹

Fig. 7 Structures of newly discovered phenolic bisabolane-type sesquiterpenoids.

3. Synthetic gem-C,C-glycosides of biological interest

3.1. Sugar amino acids

Sugar amino acids (SAAs) are carbohydrate-derived building blocks bearing amino and carboxylic acid functionalities, widely used in the synthesis of peptidomimetics, enzyme inhibitors, and non-natural folded polymers known as foldamers.⁸⁰ Notably, when incorporated into cyclic peptidomimetics, SAAs can influence molecular conformation in distinct and predictable ways. Recently, Pellegrini-Moïse et al. expanded the foldamer monomer repertoire by introducing geminally β,β-disubstituted γ-amino acids, in which the β-carbon corresponds to the pseudoanomeric center of the sugar ring.⁸¹ The key gem-C,C-furanoside intermediates were synthesized from the corresponding exo-glycals via a stereoselective Henry-Michael-type reaction of nitromethane in the presence of DBU (Scheme 9).

Scheme 9 Synthesis of gem-C,C-furanoside building blocks.

In the major diastereomer, the nitro group occupies the less hindered face of the sugar, likely due to thermodynamically driven equilibration involving reversible ring opening and closure. The target Boc-protected γ-amino acid building block was obtained through subsequent reduction of the nitro group.

3.2. Ertugliflozin analogues

Ertugliflozin (MK8835) is an orally active inhibitor of sodium–glucose co-transporter 2 (SGLT2), approved for the treatment of type 2 diabetes (Scheme 10).^82,83 It received FDA approval in December 2017 and EU approval in 2018. Initially discovered by Pfizer and later developed in collaboration with Merck, it is marketed under the names Segluromet, Steglatro, and Steglujan. In 2016, a series of novel C-aryl glucoside analogues of ertugliflozin were synthesized and evaluated for their inhibitory activity against human SGLT2.³⁰

Scheme 10 Synthesis of ertugliflozin analogs.

The synthesis of gem-C,C-glycoside analogues of Steglatro involved the construction of two (pseudo) anomeric centers positioned on either side of the endocyclic oxygen atom. The aromatic aglycon part was introduced via nucleophilic addition of the corresponding aryllithium reagent to TMS-protected D-gluconolactone.³⁰ The quaternary anomeric center thus formed was converted into the key gem-C,C-glycoside intermediate with high diastereoselectivity upon treatment with allylsilane in the presence of BF₃·Et₂O. The absolute configuration of the newly generated asymmetric center is consistent with the conformational model proposed by Woerpel.⁸⁴ The two exo-glycal precursors of the [3.2.1] and [3.3.1] bicyclic skeletons were synthesized from the allylated intermediate in respectively five or four steps, including a Pd-catalyzed double bond migration in the case of the former. Subsequent Sharpless dihydroxylation, followed by acid-promoted one-pot MOM deprotection and stereoselective intramolecular trapping of the putative oxocarbenium ion intermediate, furnished both the desired [3.2.1] and [3.3.1] bicyclic frameworks. Further functionalization and deprotection yielded the four targeted ertugliflozin analogues. Among these analogues, the compound most structurally related to ertugliflozin exhibited moderate SGLT2 inhibitory activity, with an IC₅₀ value of 700 nM.

3.3. Remdesivir analogues

Remdesivir, a phosphoramidate prodrug nucleotide developed by Gilead Sciences as GS-5734 in 2009, was initially aimed at treating hepatitis C (Fig. 2).^31,85,86 It was later found to be effective against a range of viruses, including Ebola, SARS, and MERS, blocking viral infection at low micromolar concentrations with a high selectivity index.³¹ Supported by these favorable bioactivity data and existing safety profiles, it was granted FDA approval as a repurposed treatment for severe COVID-19 infections, becoming the first approved therapy that specifically targets the virus. 1′-Substituted C-nucleosides are uncommon among nucleoside analogues. In remdesivir, the 1′-cyano (1′-CN) group, attached to a quaternary pseudo-anomeric carbon, plays a critical role in its antiviral action.⁸⁵ Once metabolized to its active triphosphate, remdesivir mimics ATP and is efficiently incorporated into SARS-CoV-2 RNA. The 1′-CN group induces polymerase stalling and also reduces the efficiency of incorporation as a GTP analogue. While 1-CN doesn't protect remdesivir from being excised by viral proofreading enzymes, its presence in RNA may disrupt downstream viral processes like transcription and translation. As several synthetic strategies toward remdesivir and analogues have already been thoroughly reviewed in the recent literature⁸⁶ only the most recent developments and advancements in the field are presented here. In most synthetic approaches, a protected D-ribono-1,4-lactone derivative is subjected to C-glycosylation with a heteroaryl-lithium or -magnesium reagent.^86,87 A notable example of this strategy was reported in 2022 by the group of Chandrasekhar (Scheme 11a).⁸⁸ The cyanation of the resulting lactol was performed under standard conditions (TfOH, TMSOTf)⁸⁶ to afford the gem-C,C-glycoside motif. The stereochemical outcome of this transformation was rationalized by invoking a nonbonding interaction of the allyl ether oxygen in the oxocarbenium cation intermediate with the silicon atom in TMSCN, thereby directing preferential delivery of the cyanide ion from the α-face.⁸⁹ The use of a silyl/allyl protected D-ribono-1,4-lactone as the starting material streamlined protecting group manipulations compared to the original synthetic route developed by Gilead Sciences.^86,87 In 2022, List et al. reported a novel, practical approach to remdesivir (Scheme 11b).⁹⁰ The first step involved direct addition of pyrrolo[2,1-f][1,2,4]triazin-4-amine to free D-ribose in the presence of catalytic amount of TMSOTf, which is regenerated upon protodesilylation of the innocuitous silyl cation source N,O-bis(trimethylsilyl)trifluoro acetamide (BSTFA). Remarkably, during the transformation, the dynamic mixture of isomers converged to a single TMS-protected C-glycosylation product. Acidic treatment at 25 °C afforded the α-nucleoside with high diastereoselectivity, whereas heating to 50 °C led to formation of the thermodynamically favored β-anomer. The key lactol intermediate was obtained in 37–45% yield via Mn-catalyzed benzylic C–H oxidation. Owing to the presence of acetate protecting groups, standard cyanation conditions were modified: the TfOH/TMSOTf mixture was replaced with the stronger Brønsted acid HNTf₂ to generate TMSNTf₂ in situ.

Scheme 11 . Total syntheses of remdesivir nucleoside.

The remdesivir nucleoside (GS-441524) precipitated as a single diastereoisomer during the subsequent methanolysis step. Activation of the anomeric position for cyanation has also been applied for the synthesis of remdesivir nucleoside analogues. For example, an acetyl-protected riboside was employed in the preparation of a hybrid molecule combining structural features of remdesivir and favipiravir, an antiviral agent approved for influenza treatment in Japan (Scheme 12).⁹¹

Scheme 12 Synthesis of a remdesivir nucleoside analogue.

In the continuous effort toward the discovery of broad-spectrum antiviral agents, Lubin-Germain et al. synthesized 1′-CN-triazolyl-C-ribosides.⁹² The presence of the triazole ring at the anomeric center was found to hinder cyanation, whereas introducing the cyano group prior to triazole installation via the Huisgen reaction proved to be effective (Scheme 13). Additionally, the choice of protecting groups on the ribose was found to influence the stereochemical outcome, with the isopropylidene acetal favoring β-selectivity. This observation aligns with the conformational model proposed by Woerpel.^84,92 According to this model, formation of the 1,3-cis products can be rationalized by a stereoelectronically controlled inside attack of the cyanide on the lowest-energy conformer of the oxocarbenium ion intermediate—specifically, the ³E conformation, in which the C-3 alkoxy group adopts a pseudoaxial orientation to maximize favorable electrostatic interactions. With the isopropylidene acetal hindering inside attack, outside attack is favoured, leading to preferential formation of the β-anomer (Scheme 13).

Scheme 13 Synthesis of 1′-CN-triazolyl-C-riboside.

A related study was independently reported by the Lebreton group during the same period.⁹³ The presence of terminal alkynes was detrimental to the efficiency of the cyanation reaction (Scheme 14). Activation of the alkynyl ketose derivatives towards propargylic substitution with dicobalt-octacarbonyl substantially improved the yield of the desired gem-C,C-furanoside. To circumvent the use of toxic cobalt reagents, an improved route featured cyanation after installation of the triazole moiety. Azido-methyl pivalate (POMN₃) was selected for the Huisgen reaction, anticipating orthogonal deprotection of the POM group with a methanolic ammonia solution in the presence of the anomeric cyano group. In contrast with the findings of Lubin-Germain et al. (Scheme 13),⁹² the triazole moiety at the anomeric center had no impact on the efficiency of the cyanation reaction. However, a pronounced difference of reactivity was noted between the 1,5- and 1,4-adducts derived from alkynyl ester derivatives, likely due to increased steric hindrance at the anomeric center in the 1,4-regioisomer (Scheme 14). Late stage modifications of remdesivir and GS-441524 derivatives have been also conducted to develop more potent anti-viral agents.⁹⁴

Scheme 14 Synthesis of 1′-CN-triazolyl-C-ribosides.

The biological activity of nucleosides can be fine-tuned by modifying the sugar conformation. The spirocyclic scaffold is a crucial modification for influencing the sugar conformation and enhancing the properties of nucleosides.⁹⁵ In 2018, Cobb et al. employed a cyanation reaction to access spirocyclic analogues of ribavirin⁹⁶ featuring an azetidine scaffold.⁹⁷ The desired gem-C,C-furanoside product was obtained in 58% yield from the corresponding β-D-psicofuranoside derivative using TMSCN and TMSOTf (Scheme 15).

Scheme 15 Synthesis of 1′-CN-triazolyl-C-ribosides.

The spirocyclic N-sulfonyl azetidines were subsequently obtained through functional group transformations, cyclization and deprotection. Owing to its similarity with ribavirin,⁹⁶ a well-known agent for the treatment of chronic hepatitis C, the antiviral properties of the N-tosyl derivative were evaluated using Murine Hepatitis Virus (MHV) as a model; however, no significant activity was observed.

4. Specific methods for the synthesis of gem-C,C-glycosides through glycosyl electrophilic species

C-Glycosylation via the generation of oxocarbenium cation intermediates has been extensively investigated as a key strategy for the synthesis of C-glycosides.^5a,b This approach has also proven effective in the construction of gem-C,C-glycosides (Scheme 16). For instance, in 1986 Nicolaou et al. reported the synthesis of 1,1-dialkyl glycosides using a Ferrier rearrangement (Scheme 16a).⁹⁸ Another notable early example was reported by Wilcox et al., involving the activation of a pseudo-anomeric acetate in a furanoside scaffold using ZnBr₂ as the Lewis acid.⁸ Following these seminal contributions, a wide array of C-glycosylation protocols have emerged, utilizing diverse nucleophiles, Lewis acids, and anomeric leaving groups (Scheme 16b).^86,99,100 Key challenges in these methodologies include achieving anomeric stereocontrol and suppressing competing elimination pathways that lead to glycal formation. This strategy has been applied to the synthesis of gem-C,C-glycosides of biological interest as discussed in section 3 (Schemes 10–15).

Scheme 16 Strategies for the synthesis of gem-C,C-glycosides via an oxocarbenium intermediate.

More recently, the groups of Crich, Xing and Li reported the synthesis of 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) C-glycosides via C-glycosylation of dibutylphosphate precursors or thioglycosides (Scheme 17).^101–103 Diastereoselectivity varied with reaction conditions, but complete α-selectivity was achieved upon introduction of a p-tolyl sulfide at C3, consistent with the involvement of an episulfonium intermediate.¹⁰⁴

Scheme 17 Synthesis of KDO derivatives.

Ando et al. introduced a distinct approach to stereocontrol, reporting that C-glycosylation of conformationally restricted sialic acid donors afforded exclusively the α-isomer—an otherwise challenging selectivity for this substrate class (Scheme 18).¹⁰⁵

Scheme 18 Selective α-glycosidation using macrobicyclic sialic acid donors.

As part of our ongoing efforts to develop new strategies for constructing the DEF system of nogalamycin (see Fig. 2),^46,106 we recently reported the synthesis of C-naphthyl ketosides via a Fries-type rearrangement (Scheme 19).¹⁰⁷ In this approach, O-aryl ketosides⁴⁶ were activated with a Lewis acid, generating the corresponding oxocarbenium and naphtholate derivative. These intermediates subsequently underwent a regioselective Friedel–Crafts-type coupling, leading to the desired products.^106a,107 High β-selectivity was achieved in the D-hexopyranose and L-threo series, whereas low to modest diastereoselectivity was observed for 5-membered O-ketosides. Although this methodology is currently limited to C-naphthyl ketosides, it represents the first example of constructing a quaternary pseudoanomeric center via a Fries-type rearrangement.^106a

Scheme 19 Synthesis C-naphthyl ketosides via Fries type rearrangement.

Another example involving an intramolecular Friedel–Crafts reaction was reported by Lin et al.¹⁰⁸ In this approach spiro[pyran-4-quinolines] were synthesized in a two-step sequence from exo-glycals using InCl₃ as the Lewis acid (Scheme 20). The first step involved an “exo-Ferrier”-type rearrangement generating a vinyloxonium undergoing facile 1,4 addition of anilines, resulting in a formal substitution of the acetate followed by N-glycosylation affording the corresponding C,N-glycosides. The resulting intermediates were subsequently converted into the spirosugar through treatment with InCl₃ and 4,4′-dimethoxybenzophenone, which facilitated the departure of the N-aryl group as a benzophenone imine to form the oxocarbenium intermediate.¹⁰⁸ Interestingly, in the exo-galactal series the reaction directly leads to spiro compounds in the presence of InCl₃ by increasing the temperature to 75 °C without requiring further treatment with the ketone.

Scheme 20 Synthesis of spiro[pyro-4-quinolines].

Recently, the group of Z.-T. He described the gem-C,B-glycosylation of furanose and pyranose derivatives through 1,2 boronate migration (Scheme 21a).^16a In this methodology, 2-methoxy glycosides were initially converted into the corresponding glycosylphosphoniums, which were then deprotonated to generate phosphonium ylides. Reaction with various boronic esters afforded boro-ketosides in moderate to high yields and excellent diastereoselectivity. These compounds can be further transformed into gem-C,C-glycosides^16a using Zweifel olefination conditions, which involve treatment of the boronic esters with a vinyl Grignard reagent, followed by the addition of iodine and sodium methoxide.¹⁰⁹ This approach is exemplified by the ring-closing metathesis-based synthesis of a spirofuranose derivative,¹¹⁰ whose core structure is related to that of natural gem-C,C-glycosides derived from caryose. It is worth noting that the methodology developed by Z.-T. He is limited to 2-deoxy precursors, likely due to the susceptibility of 2-oxygenated derivatives towards elimination under strongly basic conditions (see section 5). Boro-ketosides can also be obtained from glycosylidene diazirines through the generation of carbenes, which then insert into the C–B bond of boronic ester reagents (Scheme 21b).^111,112 According to G. He et al., a 1,2 migration from a zwitterionic intermediate generated from the glycosylidene carbene is also involved in this sequence.¹¹¹ Remarkably, these conditions tolerate the presence of O-substituents at C-2. The resulting C,B-anomeric products can also be transformed into gem-C,C-glycosides via vinylation.¹¹¹

Scheme 21 Synthesis of boro-ketosides and application to the formation of gem-C,C-glycosides.

The addition of anionic species to carbonyl precursors followed by cyclization is another strategy for constructing gem-C,C-glycosides. This method has been successfully applied to the synthesis of complex structures, such as the DEF core of nogalamycin (see Scheme 1b)^40a,47b and the antidiabetic drug Steglatro™.¹¹³ Aldrich et al. have recently developed a method to introduce diverse substituents at the 1′ position of C-nucleosides related to remdesivir (Scheme 22).¹¹⁴ Their methodology is based on the observation that the hemiketal formed upon the addition of the appropriate heteroaryllithium reagent to the corresponding ribolactone (see Scheme 11a) exists in equilibrium with the hydroxyketone tautomer, depending on the reaction conditions. In the presence of Lewis acids, the hemiketal is the predominant tautomer and may participate in electrophilic activation (see section 3 and Scheme 17). In contrast, under neutral or basic conditions, the hydroxyketone tautomer is favored. When exposed to a Grignard reagent, the hydroxyketone form yields a mixture of diastereoisomers, which cyclize into C-nucleosides upon treatment with methanesulfonic acid. At this point, the isomers can be separated and deprotected.¹¹⁴ The same strategy has also been applied to introduce difluoromethyl and fluoromethyl substituents.¹¹⁴

Scheme 22 Synthesis of remdesivir analogs.

5. Specific methods for the synthesis of gem-C,C-glycosides through glycosyl anionic species

Glycosyl anions have been employed as intermediates in the synthesis of C-glycosides; however, this strategy remains significantly less explored than approaches relying on electrophilic glycosyl intermediates.^5,115 The main strategies for generating glycosyl anions involve halogen–lithium exchange from chloro- or bromo-glycosides, as well as lithiation of endo-glycals.^5,115 However, these methods are not well suited for the synthesis of gem-C,C-glycosides, due, for example, to the limited accessibility of tertiary anomeric halides. An alternative strategy involves the generation of an anomeric exocyclic enolate from an ester functional group at the C1 position (Scheme 23).^{69c,120–122} Enolates derived from lithium or sodium have been reacted with a variety of electrophiles,¹¹⁶ although samarium enolates remain the most widely used for such transformations.^69c,116,117 However, these methodologies are generally limited to 2-deoxy substrates, as β-elimination may readily occur in the presence of C2 hydroxyl groups. This strategy has been applied to the synthesis of neuraminic and ulosonic acid derivatives, as well as KDO C-glycosides, as recently demonstrated by Li et al.¹¹⁸

Scheme 23 Synthesis of gem-C,C-glycosides via an enolate intermediate.

6. Specific methods for the synthesis of gem-C,C-glycosides through glycosyl radical species

Given the limitations associated with the synthesis of gem-C,C-glycosides via anionic or oxocarbenium-based strategies—such as substrate incompatibility under strongly acidic or basic conditions, and the restriction of anionic approaches to 2-deoxy precursors—the generation of anomeric radicals and their subsequent trapping with various electrophiles has emerged as a promising alternative.^5c,119 Since the pioneering work of Giese et al., several methods for generating tertiary pseudo anomeric radicals have been reported (Scheme 24).^120–125 In Giese's original report, electron transfer from a stannyl radical to a nitro group at the anomeric position generates a tertiary radical, which subsequently reacts with acrylonitrile.¹²⁰ A similar strategy has been applied to anomeric selenide precursors.¹²¹ More recently, generation of tertiary radicals via Metal-hydride-induced Hydrogen Atom Transfer (MHAT)^122,123 or photocatalyzed hydrogen atom abstraction and subsequent addition to Michael acceptors has been reported.¹²⁴

Scheme 24 General approaches to gem-C,C-glycosides via the generation of tertiary pseudo anomeric radicals (FG = Functional Group).

Recently MHAT has emerged as a powerful tool for the hydrofunctionalisation of electron rich alkenes.¹²⁶ Building on the iron-mediated Michael–Giese hydroalkylation of olefins reported by Baran,¹²⁷ our group has recently developed a method for the synthesis of gem-C,C-glycosides (Scheme 25).¹²² We demonstrated that exo-glycals can be converted into tertiary pseudo-anomeric radicals, which then undergo addition to various Michael acceptors in good yields. The reaction proceeds with high α-selectivity in the D-gluco, D-manno and D-galacto series (see also Scheme 5 for another example illustrating the concept of radical anomeric effect).⁶⁷ This methodology was successfully applied to trisubstituted exo-glycals, whose conversion however required increased catalyst and silane loading to achieve satisfactory yields. Such trend may be due to slower hydrogen atom transfer from the reactive iron(III) hydride to the more sterically demanding olefin (a step typically considered to be fast), thus resulting in catalyst deactivation and (indirect) silane consumption through H₂ evolution.

Scheme 25 Synthesis of gem-C,C-glycosides from exo-glycals by MHAT.

Our group extended this methodology to the synthesis of C,C-glycosyl amino acids using N-phthalimido-dehydroalanine derivatives as Michael acceptors (Scheme 26a).¹²³ High levels of dual stereocontrol were achieved through the coupling of exo-glycals with an enantiopure dehydroalanine derivative bearing an Evans-type oxazolidinone. Complete stereocontrol could observed at the pseudo-anomeric center, affording exclusively the α-anomer as previously discussed, along with excellent diastereoselectivity at the amino acid stereocenter when a sterically nondemanding methoxymethyl (MOM) protecting group was installed at the 2-position. Direct removal of the auxiliary proceeded conveniently without epimerization nor phthalimide opening using carefully controlled amounts of LiOH and H₂O₂. Quinones were also investigated as potentially demanding Michael acceptors considering their redox properties (Scheme 26b).⁴⁶ Under MHAT conditions, O-aryl ketosides were obtained instead of the corresponding C-aryl derivatives. Mechanistic studies indicated that the tertiary pseudoanomeric radical first generated from the exo-glycal and iron hydride undergoes subsequent oxidation by the quinone to form an oxocarbenium cation.⁴⁶ The latter and the resulting semiquinone radical then combine to give the C–O coupling product following reduction. As seen above, O-naphthyl ketosides can be converted into the corresponding gem-C,C-glycosides upon treatment with a Lewis acid (see Scheme 19).^106a

Scheme 26 Coupling of exo-glycals with challenging acceptors via MHAT process.

Recently, Rovis et al. developed a methodology for directed hydrogen atom abstraction using photoredox catalysis (Scheme 27).¹²⁴ The reaction is initiated by deprotonation of a benzoyl imide, followed by oxidation of the resulting anion to the corresponding nitrogen-centered radical by an excited iridium(III) photocatalyst.

Scheme 27 Synthesis of a gem-C,C-glycoside via directed C-H abstraction.

In a representative example involving a 2-deoxy D-glucose derivative, the pseudo-anomeric hydrogen atom is then abstracted via a [1,5-HAT] process, generating the corresponding C-radical which then undergoes addition to diethylvinylphosphonate.

7. Specific methods for the synthesis of gem-C,C-glycosides through organopalladium intermediates

Synthesis of gem-C,C-glucosides via C–H bond functionalization approach have been reported by several groups using rhodium or palladium complexes.^128–130 For example, Messaoudi et al. described the intramolecular Pd-catalyzed anomeric C–H activation of glycosyl carboxamides (Scheme 28).¹²⁹ Notably, depending on the substituent at the C2 position, either fused glycosylquinolin-2-ones or glycosylspirooxindoles were obtained. The authors proposed a mechanistic rationale to explain the pathway divergence: intramolecular C–H activation generates an axially oriented palladium C-enolate that exists in equilibrium with its diastereoisomeric equatorial counterpart. When X = H, reductive elimination leads to a diastereomeric mixture of glycosylspirooxindoles, whereas a 1,2-palladium migration occurs when X = OAc, leading to tricyclic fused products.¹²⁹

Scheme 28 Anomeric C–H activation of glycosyl carboxamides.

Lin et al. described the coupling of arylboronic acids with a trisubstituted exo-glycal via a palladium-catalyzed Heck-type reaction (Scheme 29).¹³⁰ The C-arylation products were obtained with exclusive α-selectivity and excellent yields, except when 2- methoxyphenylboronic acid was used, in which case no reaction occurred. A related Heck reaction, leading to the DEF core of nogalamycin, was described by VanNieuwenhze's group (see Scheme 2).⁴⁸

Scheme 29 Heck-type arylation of exo-glycals.

8. Anomeric spirocyclopropyl-C-glycosides and analogues

This section will focus on anomeric spirocyclopropyl-C-glycosides, a conformationally constrained sub-class of gem-C,C-glycosides, which have demonstrated inhibitory activity against biologically relevant enzymes.³⁴ The structural features underlying their bioactivity are indeed closely associated with the introduction of a spirocyclopropyl group at the anomeric position, which significantly limits molecular flexibility and reinforces the overall rigidity of the sugar framework. Two principal approaches for their synthesis have been documented in the literature.^34,131 In the first approach (Scheme 30, path A), a glycosylidene carbene is generated and then undergoes cyclopropanation with an activated carbon–carbon double bond. The second approach (path B) relies on the use of exo-glycal methylene groups, accessible from the corresponding lactones. These derivatives react with functionalized carbenes or their equivalents, also leading to the formation of the spirocyclopropane motif. A major limitation shared by both synthetic routes is the lack of stereochemical control, which often results in a mixture of the four possible isomers. These isomers are classified based on their configurations: α or β, and cis or trans.

Scheme 30 General strategies for the synthesis of spirocyclopropyl-C-glycosides.

Descotes’ group described the first example of the use of anomeric glycosylidene carbene precursors to generate anomeric spirocyclopropyl sugars (path A),¹³² which took advantage of the reactivity of C-1 gem-diazido sugars under photolytic conditions (Scheme 31a). This route was subsequently developed further by Vasella and colleagues, who published several studies on the use of diazirines as precursors for 1-spirocyclopropanes.^112d,133 Additionally, this group was the first to synthesize monosaccharide cyclopropanes by metal-catalyzed cyclopropanation of diazo esters of exo-glycals (path B) (Scheme 31b).¹³⁴ In particular, the copper-catalyzed cycloaddition of ethyl diazoacetate with exo-glycal led to the formation of spirocyclopropyl-C-glycosides in the D-glucose and D-mannose series in high yields, but low diastereoselectivity.

Scheme 31 Early examples of the synthesis of spiro-C-glycosides via the two main pathways.

Since these initial reports, the two strategies for synthesizing anomeric spirocyclopropyl-C-glycosides have been reviewed and analyzed in depth by S. Vincent's group in 2022, following their work on the development of the first controlled and selective synthesis of spirocyclic cyclopropyl glycosyl-1-phosphate analogues via a Simmons–Smith reaction (Scheme 32a).^34,135 Consequently, only the latest advances and contributions in this field are discussed here. In 2023, Cossy's group post-functionalized 5-membered exo-glycals, also via a Simmons–Smith cyclopropanation, to obtain spirocyclopropyl-C-glycosides in good yields.¹³⁶ More recently in 2024, our group described the first alkenyl cyclopropanation of exo-glycals,¹³⁷ taking advantage of the gold(I)-catalyzed 1,2-ester migration of propargyl acetates. The reaction proceeded with high yields and excellent chemoselectivity, as well as moderate to high diastereomeric control, typically towards β-cis products in the pyranoside series, along with complete (Z)-selectivity regarding the alkene moiety. The preferential activation of the propargyl fragments and the concerted [2 + 1] insertion are both facilitated by the selection of ligands and electron-enrichment of the arene in the propargyl esters (Scheme 32b). Of note, Nagib's group has very recently reported the synthesis of two spirocyclopropyl-C-glycosides from the corresponding exo-glycals via innovative Fe-catalyzed cyclopropanation reactions involving in situ generated iron carbenes.¹³⁸

Scheme 32 Gold(I)-catalyzed reactions of exo-glycals with propargyl esters.

Spirocyclobutyl-C-glycoside analogues remain largely underrepresented in the literature, with only one recent example of their synthesis since Suárez's 2008 work on photo-induced Norrish type II–Yang cyclization.^125b,139 Recently, in 2023, L. Juhász and his colleagues studied the previously unexplored [2 + 2] cycloaddition reactions of several methylene exo-glycals with dichloroketene.¹⁴⁰ The reaction conditions led to excellent regioselectivity, but the in situ dehalogenation of some cycloadducts failed. The diastereomeric mixtures obtained from monohalogenated spiro-cyclobutanones could be dehalogenated in an additional step (Scheme 33).

Scheme 33 Synthesis of cyclobutanones by [2 + 2] cycloadditions of exo-glycals.

Notably, spirocyclopropyl-C-glycosides have also been described within the iminosugar series, further expanding the structural diversity of this class of glycomimetics.^110b

9. Conclusion

Gem-C,C-glycosides represent a uniquely challenging and underexplored subclass of glycomimetics that offer compelling structural and functional diversity for chemical biology and drug discovery. Their presence in complex natural products and bioactive compounds underscores their biological relevance, yet their synthesis continues to pose significant hurdles, particularly in the formation of quaternary pseudoanomeric centers with defined stereochemistry. Recent advances—including catalytic approaches such as metal-hydride hydrogen atom transfer (MHAT), C–H activation, and metal-catalyzed cyclopropanation — have successfully addressed key challenges in the construction of gem-C,C-glycosyl frameworks. These innovative methodologies enable more direct and modular access to these densely functionalized motifs, substantially expanding the synthetic toolbox. Beyond enhancing synthetic efficiency, they also open new avenues for the design of structurally novel glycomimetics of therapeutic interest. As the field continues to mature, the integration of advanced stereoselective strategies, mechanistic insight, and biologically driven design will be critical to fully realizing the synthetic and biomedical potential of gem-C,C-glycosides.

Author contributions

Conceptualization, P. C.; methodology, P. C. and D. H.; literature review, D. H., P. C., N. K., M. P. and D. T.; writing – original draft preparation, P. C., D. H. and M. P.; writing – review and editing, P. C., D. H., N. K., M. P. and D. T. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included, and no new data were generated or analysed as part of this review.

Acknowledgements

Financial support from the CNRS and the University of Strasbourg (LIMA-UMR 7042) is gratefully acknowledged. D. T. thanks the French Ministry of Research for a PhD fellowship. The authors also wish to express their sincere gratitude to Profs O. R. Martin and P. Pale for generously sharing their expertise on carbohydrate nomenclature and for their insightful discussions regarding the term “gem-C,C-glycoside”.

References

1. (a) G. W. Hart, Structural and functional diversity of glycoconjugates: a formidable challenge to the glycoanalyst, Methods Mol. Biol., 2003, 213, 3; (b) A. Hölemann and P. H. Seeberger, Carbohydrate diversity: synthesis of glycoconjugates and complex carbohydrates, Curr. Opin. Biotechnol., 2004, 15, 615.
2. (a) S. Lalhmangaihzuala, K. Vanlaldinpuia, V. Khiangte, Z. Laldinpuii, T. Liana, C. Lalhriatpuia and Z. Pachuau, Therapeutic applications of carbohydrate-based compounds, Mol. Divers., 2024, 28, 4553; (b) X. Cao, X. Du, H. Jiao, Q. An, H. Chen, P. Fang, J. Wang and B. Yu, Carbohydrate-based drugs launched during 2000–2021, Acta Pharm. Sin. B, 2022, 12, 3783.
3. (a) P. Sears and C.-H. Wong, Carbohydrate mimetics: a new strategy for tackling the problem of carbohydrate-mediated biological recognition, Angew. Chem., Int. Ed., 1999, 38, 2300; (b) B. Hevey, Strategies for the development of glycomimetic drug candidates, Pharmaceuticals, 2019, 12, 55; (c) T. M. Gloster and D. J. Vocadlo, Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology, Nat. Chem. Biol., 2012, 8, 683; (d) S. Leusmann, P. Ménová, E. Shanin, A. Titz and C. Rademacher, Glycomimetics for the inhibition and modulation of lectins, Chem. Soc. Rev., 2023, 52, 3663; (e) P. Compain, Glycomimetics: Design, Synthesis, and Therapeutic Applications, Molecules, 2018, 23, 1658; (f) P. Compain, From sweet molecular giants to square sugars and vice versa, Synlett, 2023, 1866.
4. The term “C-glycoside”, widely cited in the literature, is however inexact from a strict chemical perspective because these compounds are not acetals. IUPAC suggests using terms like “C-glycosyl compounds” or their analogs for greater accuracy (see also ref. 6a). The primary advantage of this common term lies in its conciseness, effectively emphasizing the structural differences from the parent glycoside.
5. For recent reviews on the synthesis of C-glycosides, see: (a) Y. Yang and B. Yu, Recent Advances in the chemical synthesis of C-glycosides, Chem. Rev., 2017, 117, 12281; (b) H. Liao, J. Ma, H. Yao and X.-W. Liu, Recent progress of C-glycosylation methods in the total synthesis of natural products and pharmaceuticals, Org. Biomol. Chem., 2018, 16, 1791; (c) L.-Y. Xu, N.-L. Fan and X.-G. Hu, Recent development in the synthesis of C-glycosides involving glycosyl radicals, Org. Biomol. Chem., 2020, 18, 5095; (d) X. Wu, X. Yan and D. Qian, Stereoselective construction of glycosides enabled by glycosyl/glycal metal species, Synthesis, 2025, 1893; (e) W. Tong, J.-P. Wan and J. Liu, Synthesis of C-glycosides enabled by palladium-catalyzed glycosylation reactions, Org. Chem. Front., 2024, 11, 6918.
6. For selected reviews on C-aryl glycosides, see: (a) E. Bokor, S. Kun, D. Goyard, M. Toth, J.-P. Praly, S. Vidal and L. Somsák, C-glycopyranosyl arenes and hetarenes: synthetic methods and bioactivity focused on antidiabetic potential, Chem. Rev., 2017, 117, 1687; (b) K. Kitamura, Y. Ando, T. Matsumoto and K. Suzuki, Total synthesis of aryl C-glycoside natural products: strategies and tactics, Chem. Rev., 2018, 118, 1495; (c) T. Bililign, B. R. Griffith and J. S. Thorson, Structure, activity, synthesis and biosynthesis of aryl-C-glycosides, Nat. Prod. Rep., 2005, 22, 742; (d) S. I. Elshahawi, K. A. Shaaban, M. K. Kharel and J. S. Thorson, A comprehensive review of glycosylated bacterial natural products, Chem. Soc. Rev., 2015, 44, 7591; (e) X.-Y. Gou, X.-Y. Zhu, B.-S. Zhang and Y.-M. Liang, Synthesis of C-aryl glycosides by C-H functionalization, Chem. – Eur. J., 2023, e202203351; (f) J. Li and X. Jiang, Advances on the synthesis of C-aryl-glycosides since 2019, Synlett, 2025, 1165.
7. The term “quaternary center” is frequently misused in the literature. According to the IUPAC definition, a quaternary carbon is one that is specifically bonded to four other carbon atoms. However, this term is often incorrectly applied, for example, to tertiary alcohols and tertiary centers bonded to heteroatoms. For the sake of conciseness, the term “quaternary” will be used in this article to refer to the pseudoanomeric carbon in gem-C,C-glycosyl compounds.
8. C. S. Wilcox, G. W. Long and H. T. Suh, A new approach to C-glycoside congeners: Metal carbene mediated methylenation of aldonolactones, Tetrahedron Lett., 1984, 25, 395.
9. In 1980, Fraser-Reid and Tam did not specifically name the gem-C,C-glycosyl intermediates synthesized in their work on the total synthesis of germacranolide sesquiterpenes: T. F. Tam and B. Fraser-Reid, Chiral models of the furenone moiety of germacranolide sesquiterpene, J. Org. Chem., 1980, 45, 1344.
10. H. Streicher, A. Geyer and R. R. Schmidt, C-disaccharides of ketoses, Chem. – Eur. J., 1996, 2, 502.
11. L. A. Paquette, M. J. Kinney and U. J. Dullweber, Practical Synthesis of spirocyclic bis-C,C-glycosides. mechanistic models in explanation of rearrangement stereoselectivity and the bifurcation of reaction pathways, J. Org. Chem., 1997, 62, 1713.
12. C. Taillefumier and Y. Chapleur, Synthesis and uses of exo-glycals, Chem. Rev., 2004, 104, 263.
13. J.-M. Beau and T. Gallagher, Nucleophilic C-glycosyl donors for C-glycoside synthesis, in Glycoscience Synthesis of Substrate Analogs and Mimetics, Topics in Current Chemistry, ed. J. Thiem and H. Driguez, Springer, 1997, vol. 187, pp. 1–54.
14. S. Sato and H. Ishikawa, Total synthesis of two isoflavone bis-C-glycosides: genistein and orobol 6,8-di-C-β-D-glucopyranosides, Synthesis, 2010, 3126.
15. For other examples of the use of the term bis-C-glycoside for structures containing two distinct C-glycosidic bonds see: (a) K. Kitamura, Y. Ando, T. Matsumoto and K. Suzuki, Synthesis of the pluramycins 1: Two designed anthrones as enabling platforms for flexible bis-C-glycosylation, Angew. Chem., Int. Ed., 2014, 53, 1258; (b) K. K. Ponnapalli, A. K. Adak, A. Das, J.-S. Song, S.-H. Wu, C.-M. Sun and C.-C. Lin, Trans-Stilbene C-glycosides: Synthesis by a microwave-assisted Heck reaction and evaluation of the SGLT-2 inhibitory activity, Asian J. Org. Chem., 2017, 6, 1308.
16. (a) Recently, He et al. introduced the term gem-C,B-glycosylation to describe a process that enables the simultaneous formation of C–C and C–B bonds at the pseudoanomeric centers of gem-C,C-glycoside precursors: W.-C. Zhao, R.-P. Li, C. Ma, Q.-Y. Liao, M. Wang and Z.-T. He, Stereoselective gem-C,B-glycosylation via 1,2-Boronate Migration, J. Am. Chem. Soc., 2022, 144, 2460; (b) To our knowledge, IUPAC nomenclature does not provide a specific prefix for two different substituents on a single carbon, and “gem-” remains a concise and structurally evocative descriptor in this context.
17. A. K. Miller and D. Trauner, Mapping the chemistry of highly unsaturated pyrone polyketides, Chem. Commun., 2006, 2295.
18. (a) B. P. Maliakel and W. Schmid, Chemo-enzymatic synthesis of natural products: Synthesis of sphydrofuran, Tetrahedron Lett., 1992, 33, 3297; (b) T. Usui, S. Umezawa, T. Tsuchiya, H. Naganawa and T. Takeuchi, A new microbial metabolite, sphydrofuran. II. The structure of sphydrofuran, J. Antibiot., 1971, 24, 93.
19. (a) S. Sunagawa, H. Yamada, M. Naito, E. Yasui, M. Mizukami, M. Miyashita and S. Nagumo, Synthetic study of arenicolide C: stereoselective synthesis of the C19–C36 segment, Tetrahedron Lett., 2015, 56, 669; (b) G. Williams, E. D. Miller, R. N. Asolkar, P. R. Jensen, W. Fenical and A.-C. Arenicolides, 26-membered ring macrolides from the marine actinomycete Salinispora arenicola, J. Org. Chem., 2007, 72, 5025.
20. K. C. Nicolaou and R. J. Aversa, Maitotoxin: An Inspiration for Synthesis, Isr. J. Chem., 2011, 51, 359.
21. It is important to note that nogalamycin and its derivatives are not strictly gem-C,C-glycosides. Rather, they can be considered C-arylated hexoses featuring a quaternary carbon at the C-5 position.
22. (a) P. F. Wiley, F. A. MacKellar, E. L. Caron and R. B. Kelly, Isolation, characterization and degradation of nogalamycin, Tetrahedron Lett., 1968, 9, 663; (b) L. H. Li and W. C. Krueger, The biochemical pharmacology of nogalamycin and its derivatives, Pharmacol. Ther., 1991, 51, 239; (c) D. F. Moore Jr, T. D. Brown, M. LeBlanc, S. Dahlberg, T. P. Miller, S. McClure and R. I. Fisher, Phase II Trial of Menogaril in Non-Hodgkin's Lymphomas, Invest. New Drugs, 1999, 17, 169; (d) P. F. Wiley, D. W. Elrod, D. J. Houser and F. A. Richard, Structure-activity relationships of nogalamycin analogs, J. Med. Chem., 1982, 25, 560.
23. M. A. Rizzacasa and D. Sturgess, Total synthesis of alkyl citrate natural products, Org. Biomol. Chem., 2014, 12, 1367.
24. (a) W. Li, Z. Ma, L. Chen and W.-B. Yin, Synthesis and production of the antitumor polyketide aurovertins and structurally related compounds, Appl. Microbiol. Biotechnol., 2018, 102, 6373; (b) B. A. Patel, T. L. D'Amico and B. S. J. Blagg, Natural products and other inhibitors of F₁F₀ ATP Synthase, Eur. J. Med. Chem., 2020, 207, 112779.
25. G. Franco dos Santos, J. Moraga, J. A. Takahashi, M. Viaud, J. R. Hanson, R. Hernández Galán and I. G. Collado, The formation of sesquiterpenoid presilphiperfolane and cameroonane metabolites in the Bcbot4 null mutant of Botrytis cinerea, Org. Biomol. Chem., 2017, 15, 5357 and references cited.
26. (a) M. J. Smith, E. P. Mazzola, J. J. Sims, S. L. Midland, N. T. Keen, V. Burton and M. M. Stayton, The syringolides: Bacterial C-glycosyl lipids that trigger plant disease resistance, Tetrahedron Lett., 1993, 34, 223; (b) For a review on total syntheses of 1,7-dioxaspiro[4.4]nonane natural products, see: H. N. C. Wong, Total syntheses of naturally occurring molecules possessing 1,7-dioxaspiro[4.4]nonane skeletons, Eur. J. Org. Chem., 1999, 1757.
27. A. Nadin and K. C. Nicolaou, Chemistry and biology of the zaragozic acids (squalestatins), Angew. Chem., Int. Ed., 1996, 35, 1623.
28. For reviews on the synthesis of zaragozic acids see: (a) S. Nakamura, Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C, Chem. Pharm. Bull., 2005, 53, 1; (b) A. Armstrong and T. J. Blench, Recent Synthetic Studies on the Zaragozic Acids (Squalestatins), Tetrahedron, 2002, 58, 9321; (c) N. Jotterand and P. Vogel, Recent Progress in the Synthesis of Zaragozic Acids and Analogs, Curr. Org. Chem., 2001, 5, 637.
29. J. D. Bergstrom, C. Dufresne, G. F. Bills, M. Nallinomstead and K. Byrne, Discovery, biosynthesis, and mechanism of action of the zarogozic acids - potent inhibitors of squalene synthase, Annu. Rev. Microbiol., 1995, 49, 607.
30. Q. Yan, N. Ding and Y. Li, Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitors, Carbohydr. Res., 2016, 421, 1.
31. R. T. Eastman, J. S. Roth, K. R. Brimacombe, A. Simeonov, M. Shen, S. Patnaik and M. D. Hall, Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19, ACS Cent. Sci., 2020, 6, 672.
32. B. Waldscheck, M. Streiff, W. Notz, W. Kinzy and R. R. Schmidt, α(1–3)-Galactosyltransferase inhibition based on a new type of disubstrate analogue, Angew. Chem., Int. Ed., 2001, 40, 4007.
33. (a) P. Compain and O. R. Martin, Carbohydrate mimetics-based glycosyltransferase inhibitors, Bioorg. Med. Chem., 2001, 9, 3077; (b) M. Izumi, H. Yuasa and H. Hashimoto, Bisubstrate Analogues as Glycosyltransferase Inhibitors, Curr. Top. Med. Chem., 2009, 9, 87.
34. J. Cao and S. P. Vincent, Spirocyclopropyl carbohydrates: synthesis and applications, Tetrahedron, 2023, 140, 133465.
35. In 2016, Bera et al. published a review focusing on the installation of quaternary stereocentres in the carbohydrate unit of bioactive compounds: S. Bera, B. Chatterjee and D. Mondal, Construction of Quaternary stereocentres on carbohydrate scaffolds, RSC Adv., 2016, 6, 77212.
36. T. Yamanoi and S. Matsuda, Reactions and uses of artificial ketoses, Heterocycles, 2009, 79, 163.
37. Natural glycoconjugates containing a deoxysugar moiety with a 5,5-gem-dimethyl substituent will not be discussed in this review, as they do not strictly qualified as gem-C,C-glycosides. For recent syntheses see: (a) S. Norsikian, C. Tresse, M. François-Eude, L. Jeanne-Julien, G. Masson, V. Servajean, G. Genta-Jouve, J.-M. Beau and E. Roulland, Total synthesis of tiacumicin B: Implementing hydrogen bond directed acceptor delivery for highly Selective β-glycosylations, Angew. Chem., Int. Ed., 2020, 59, 661; (b) C. Heinz and N. Cramer, Synthesis of fijiolide A via an atropselective paracyclophane formation, J. Am. Chem. Soc., 2015, 137, 11278; (c) A. Dorst, R. Berg, C. G. W. Gertzen, D. Schäfle, K. Zerbe, M. Gwerder, S. D. Schnell, P. Sander, H. Gohlke and K. Gademann, Semisynthetic analogs of the antibiotic fidaxomicin—Design, synthesis, and biological evaluation, ACS Med. Chem. Lett., 2020, 11, 2414; (d) A. Dorst and K. Gademann, Chemistry and biology of the clinically used macrolactone antibiotic fidaxomicin, Helv. Chim. Acta, 2020, 103, e2000038; (e) C. Heinz and N. Cramer, Total synthesis of fijiolide A, Chimia, 2016, 70, 258; (f) H. Hattori, E. Kaufmann, H. Miyatake-Ondozabal, R. Berg and K. Gademann, Total synthesis, relay synthesis, and degradation studies of fidaxomicin (tiacumicin B, lipiarmycin A3), J. Org. Chem., 2018, 83, 7180.
38. G. Pratesi and S. V. Monestiroli, Preclinical evaluation of new anthracyclines, Curr. Med. Chem., 2001, 8, 9.
39. For a review see: F. Matsuda and S. Terashima, Total synthesis of nogalamycin congeners, J. Synth. Org. Chem., Jpn., 1990, 48, 738.
40. For examples of synthetic approaches before 2015 see: (a) F. Matsuda, M. Kawasaki and S. Terashima, Synthetic studies on nogalamycin congeners. Total syntheses of (+)-nogarene, (+)-7-con-O-methyl-nogarol, and their related compounds, Pure Appl. Chem., 1989, 61, 38; (b) M. A. Bates, P. G. Sammes and G. A. Thomson, Synthesis of the C-glycoside fragment of nogalamycin and some nogalamycin precursors, J. Chem. Soc., Perkin Trans. 1, 1988, 3037; (c) F. M. Hauser and D. Ganguly, Synthetic studies on nogarol anthracyclines. Enantioselective total synthesis of an aminohydroxy epoxybenzoxocin, J. Org. Chem., 2000, 65, 1842; (d) R. P. Joyce, M. Parvez and S. M. Weinreb, An approach to the aryl-C-glycoside DEF-ring system of nogalamycin, Tetrahedron Lett., 1986, 27, 4885.
41. Terashima has reported the first total synthesis of menogaril. The key step involved a convergent annulation between a naphthoquinone and racemic diene, which yielded the anthraquinone core structure, albeit in low yields see ref. 40a.
42. For details on the hemisynthesis of menogaril see: P. F. Wiley, D. W. Elrod, D. J. Houser, J. L. Johnson, L. M. Pschigoda and W. C. Krueger, Nogalamycin. Stereochemistry and chemical modification, J. Org. Chem., 1979, 44, 4030.
43. For a modular approach to nogalamycin see: H. J. Dequina, L. E. Vine, J. T. Robey, W. T. Raskopf and J. M. Schomaker, Progress toward the Total synthesis of nogalamycin using a benzyne cycloaddition strategy, J. Org. Chem., 2024, 89, 3491.
44. V. Siitonen, B. Selvaraj, L. Niiranen, Y. Lindqvist, G. Schneider and M. Metsä-Ketelä, Divergent non-heme iron enzymes in the nogalamycin biosynthetic pathway, Proc. Natl. Acad. Sci. U. S. A., 2016, 113, 5251.
45. For an enzymatic synthesis of nogalamycin R see: V. Siitonen, B. N. Wandi, A.-P. Törmänen and M. Metsä-Ketelä, Enzymatic synthesis of the C-glycosidic moiety of nogalamycin R, ACS Chem. Biol., 2018, 13, 2433.
46. For synthetic efforts toward constructing the DEF-ring system of nogalamycin via HAT-mediated formation of glycosyl radical intermediates see: H. Liu, A. G. Laporte, D. Tardieu, D. Hazelard and P. Compain, Formal glycosylation of quinones with exo-glycals enabled by iron-mediated oxidative radical-polar crossover, J. Org. Chem., 2022, 87, 13178.
47. (a) R. Peng and M. S. VanNieuwenhze, Construction of the DEF-ring system of nogalamycin and menogaril via an efficient Suzuki-Miyaura reaction, Tetrahedron Lett., 2017, 58, 2236; (b) R. Peng and M. S. VanNieuwenhze, Studies toward the total synthesis of nogalamycin: Construction of the complete ABCDEF-ring system via a convergent Hauser annulation, J. Org. Chem., 2019, 84, 760.
48. (a) R. Peng and M. S. VanNieuwenhze, Construction of the DEF-benzoxocin ring system of nogalamycin and menogaril via a reductive Heck cyclization, J. Org. Chem., 2019, 84, 173; (b) R. Peng and M. S. VanNieuwenhze, A model study for constructing the DEF-benzoxocin ring system of menogaril and nogalamycin via a reductive Heck cyclization, Org. Lett., 2012, 14, 1962.
49. (a) T. H. Smith and H. Y. Wu, Synthetic approaches to nogalamycin-related anthracyclines – an approach to a western synthon, J. Org. Chem., 1987, 52, 3566; (b) S. M. Meschwitz, Studies directed toward the synthesis of nogalamycin, Ph. D Thesis, Brown University, 1989.
50. H. Nakajima, B. Sato, T. Fujita, S. Takase, H. Terano and M. Okuhara, New antitumor substances, FR901463, FR901464, and FR901465. 1. Taxonomy, fermentation, isolation, physicochemical properties, and biological activities, J. Antibiot., 1996, 49, 1196.
51. B. J. Albert, A. Sivaramakrishnan, T. Naka and K. Koide, Total synthesis of FR901464, an antitumor agent that regulates the transcription of oncogenes and tumor suppressor genes, J. Am. Chem. Soc., 2006, 128, 2792.
52. Y. Gao, A. Vogt, C. J. Forsyth and K. Koide, Comparison of splicing factor 3b inhibitors in human cells, ChemBioChem, 2013, 14, 49.
53. B. J. Albert, A. Sivaramakrishnan, T. Naka, N. L. Czaicki and K. Koide, Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue, J. Am. Chem. Soc., 2007, 129, 2648.
54. R. K. Bressin, S. Osman, I. Pohorilets, U. Basu and K. Koide, Total synthesis of meayamycin B, J. Org. Chem., 2020, 85, 4637.
55. C. Gartshore, S. Tadano, P. B. Chanda, A. Sarkar, N. S. Chowdari, S. Gangwar, Q. Zhang, G. D. Vite, J. Momirov and D. L. Boger, Total synthesis of Meayamycin and O-acyl analogues, Org. Lett., 2020, 22, 8714.
56. A. K. Ghosh, G. C. Reddy, S. Kovela, N. Relitti, V. K. Urabe, B. E. Prichard and M. S. Jurica, Enantioselective synthesis of a cyclopropane derivative of spliceostatin A and evaluation of bioactivity, Org. Lett., 2018, 20, 7293.
57. S. Hwang, B. E. Heo, T. Q. Nguyen, Y. J. Kim, S.-G. Lee, T.-H. Huynh, E. Kim, S.-I. Jo, M.-J. Baek, E.-K. Shin, J. Oh, C. Park, Y. J. Yoon, E.-J. Park, K. T. Kim, S. Ryoo, D.-G. Lee, C. Wood, M. Woo, D.-D. Kim, S. Paik, E.-K. Jo, J. Jang and D.-C. Oh, Arenicolide family macrolides provide a new therapeutic lead combating multidrug-resistant tuberculosis, Angew. Chem., Int. Ed., 2025, 64, e202412994.
58. A. Minami, A. Migita, D. Inada, K. Hotta, K. Watanabe, H. Oguri and H. Oikawa, Enzymatic epoxide-opening cascades catalyzed by a pair of epoxide hydrolases in the ionophore polyether biosynthesis, Org. Lett., 2011, 13, 1638.
59. J. D. Bergstrom, M. M. Kurtz, D. J. Rew, A. M. Amend, J. D. Karkas, R. G. Bostedor, V. S. Bansal, C. Dufresne, F. L. Vanmiddlesworth, O. D. Hensens, J. M. Liesch, D. L. Zink, K. E. Wilson, J. Onishi, J. A. Milligan, G. Bills, L. Kaplan, M. Nallin Omstead, R. G. Jenkins, L. Huang, M. S. Meinz, L. Quinn, R. W. Burg, Y. L. Kong, S. Mochales, M. Mojena, I. Martin, F. Pelaez, M. T. Diez and A. W. Alberts, Zaragozic acids: A family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase (cholesterol synthesis inhibitors/fungal metabolites), Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 80.
60. M. J. Dawson, J. E. Farthing, P. S. Marshall, R. F. Middleton, M. J. O'Neill, A. Shuttleworth, C. Stylli, R. M. Tait, P. M. Taylor, H. G. Wildman, A. D. Buss, D. Langley and M. V. Hayes, The squalestatins, novel inhibitors of squalene synthase produced by a species of phoma, J. Antibiot., 1992, 45, 639.
61. K. Hasumi, K. Tachikawa, K. Sakai, S. Murakawa, N. Yoshikawa, S. Kumazawa and A. Endo, Competitive Inhibition of Squalene Synthase by Squalestatin 1, J. Antibiot., 1993, 46, 689.
62. T. Kawamata, M. Nagatomo and M. Inoue, Total synthesis of zaragozic acid C: Implementation of photochemical C(sp³)-H acylation, J. Am. Chem. Soc., 2017, 139, 1814.
63. Y. Hirata, S. Nakamura, N. Watanabe, O. Kataoka, T. Kurosaki, M. Anada, S. Kitagaki, M. Shiro and S. Hashimoto, Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy, Chem. – Eur. J., 2006, 12, 8898.
64. (a) E. M. Carreira and J. D. Bois, Synthesis of (+)-zaragozic acid C, J. Am. Chem. Soc., 1994, 116, 10825; (b) D. A. Evans, J. C. Barrow, J. L. Leighton, A. J. Robichaud and M. J. Sefkow, Asymmetric-synthesis of the squalene synthase inhibitor zaragozic acid-C, J. Am. Chem. Soc., 1994, 116, 12111.
65. (a) S. Nakamura, H. Sato, Y. Hirata, N. Watanabe and S. Hashimoto, Total synthesis of zaragozic acid C by an aldol-based strategy, Tetrahedron, 2005, 61, 11078; (b) D. A. Nicewicz, A. D. Satterfield, D. C. Schmitt and J. S. Johnson, Self-consistent synthesis of the squalene synthase inhibitor zaragozic acid C via controlled oligomerization, J. Am. Chem. Soc., 2008, 130, 17281; (c) Y. Wang and P. Metz, A general access to zaragozic acids: total synthesis and structure elucidation of zaragozic acid D and formal syntheses of zaragozic acids A and C, Chem. – Eur. J., 2011, 17, 3335.
66. For a recent formal synthesis of zaragozic acids C, see: J. O. Bunte, A. N. Cuzzupe, A. M. Daly and M. A. Rizzacasa, Formal total synthesis of (+)-zaragozic acid C through an Ireland-Claisen rearrangement, Angew. Chem., Int. Ed., 2006, 45, 6376.
67. (a) B. Giese and J. Dupuis, Diastereoselective Syntheses of C-Glycopyranosides, Angew. Chem., Int. Ed. Engl., 1983, 22, 622; (b) B. Giese, The stereoselectivity of intermolecular free radical reactions, Angew. Chem., Int. Ed. Engl., 1989, 28, 969.
68. (a) N. V. Prokazova, N. N. Samovilova, E. V. Gracheva and N. K. Golovanova, Ganglioside GM3 and its biological functions, Biochemistry (Moscow), 2009, 74, 235; (b) S. Sonnino and A. Prinetti, Gangliosides as regulators of cell membrane organization and functions, Adv. Exp. Med. Biol., 2010, 688, 165.
69. For selected recent examples see: (a) Y. He, Y. Yang and S. S. Iyer, Neuraminidase resistant sialosides for the detection of influenza viruses, Bioconjugate Chem., 2016, 27, 1509; (b) W. Notz, C. Hartel, B. Waldscheck and R. R. Schmidt, De novo synthesis of a methylenebridged Neu5Ac-α-(2,3)-Gal C-disaccharide, J. Org. Chem., 2001, 66, 4250; (c) Z. Abdallah, G. Doi and J.-M. Beau, Synthesis of a carbon-linked mimic of the disaccharide component of the tumor-related sialylTn antigen, Angew. Chem., Int. Ed., 2003, 42, 5209.
70. G. Hirai, M. Kato, H. Koshino, E. Nishizawa, K. Oonuma, E. Ota, T. Watanabe, D. Hashizume, Y. Tamura, M. Okada, T. Miyagi and M. Sodeoka, Ganglioside GM3 analogues containing monofluoromethylene-linked sialoside: synthesis, stereochemical effects, conformational behavior, and biological activities, JACS Au, 2021, 1, 137 and references cited.
71. G. Hirai, T. Watanabe, K. Yamaguchi, T. Miyagi and M. Sodeoka, Stereocontrolled and convergent entry to CF₂-sialosides: synthesis of CF₂-linked ganglioside GM4, J. Am. Chem. Soc., 2007, 129, 15420.
72. (a) T. Yasudomi, H. Yakushiji, K. Torikai, M. Ebine and T. Oishi, Unified synthesis of the DEF and GHI ring system of maitotoxin, Chem. Lett., 2019, 48, 1156; (b) T. Teshigawara, Y. Suzuki, Y. Yasuno, M. Satake and T. Oishi, Convergent synthesis of the BCDEF ring system of maitotoxin, Chem. Lett., 2025, 48, upaf074.
73. K. C. Nicolaou, R. J. Aversa, J. Jin and F. Rivas, Synthesis of the ABCDEFG Ring System of Maitotoxin, J. Am. Chem. Soc., 2010, 132, 6855.
74. H. Zhao, R. Wu, L.-F. Ma, L.-K. Wo, Y.-Y. Hu, C. Chen and Z.-J. Zhan, Aurovertin-Type Polyketides from Calcarisporium arbuscula with Potent Cytotoxic Activities against Triple-Negative Breast Cancer, Helv. Chim. Acta, 2016, 99, 543.
75. B. Zhou, Q. Tong, Y. Zang and H. Honghui, Two new a-pyrone-containing polyketides isolated from the fungus Aspergillus aureoterreus, Nat. Prod. Res., 2023, 37, 3207.
76. S. Cheng, Y. Xu, M. Kang, W. Zhu, L. Wang and P. Fu, Aurovertins from a Marine-derived Penicillium species and nonenzymatic reactions in their formation, J. Nat. Prod., 2025, 88, 554.
77. X.-M. Mao, Z.-J. Zhan, M. N. Grayson, M.-C. Tang, W. Xu, Y.-Q. Li, W.-B. Yin, H.-C. Lin, Y.-H. Chooi, K. N. Houk and Y. Tang, Efficient biosynthesis of fungal polyketides containing the dioxabicyclo-octane ring system, J. Am. Chem. Soc., 2015, 137, 11904.
78. For examples of pioneering biomimetic approaches toward aurovertins see: J. E. Forbes and G. Pattenden, Total synthesis of preaurovertin, putative biogenetic precursor of aurovertin. Biosynthetic interrelationships between the aurovertins, citreoviridinols and asteltoxin, J. Chem. Soc., Perkin Trans. 1, 1991, 1959.
79. Y. Li, J. Shi, R. Liu, Y. Liu, R. Liu, Z. Wu, W. Xu, H. Ma, H.-B. Luo and Z. Cheng, Structure revisions of phenolic bisabolane sesquiterpenes and a ferroptosis inhibitor from the marine-derived fungus Aspergillus versicolor YPH93, J. Nat. Prod., 2023, 86, 830.
80. (a) J. Xie and N. Bogliotti, Synthesis and applications of carbohydrate-derived macrocyclic compounds, Chem. Rev., 2014, 114, 7678; (b) R. Jwad, D. Weissberger and L. Hunter, Strategies for fine-tuning the conformations of cyclic peptides, Chem. Rev., 2020, 120, 9743; (c) S. A. W. Gruner, E. Locardi, E. Lohof and H. Kessler, Carbohydrate-based mimetics in drug design: sugar amino acids and carbohydrate scaffolds, Chem. Rev., 2002, 102, 491.
81. (a) M. Richard, A.-S. Felten, F. Chretien, M.-C. Averlant-Petit and N. Pellegrini-Moïse, Synthesis and conformational studies of short mixed γ/α-glycopeptides based on sugar γ3,3-amino acids, Tetrahedron, 2017, 73, 6795; (b) M. Richard, J. Ariztia, S. Lamandé-Langle and N. Pellegrini-Moïse, Sugar γ-amino acids as building blocks for the synthesis of cyclic neoglycopeptides, ChemistrySelect, 2018, 3, 9121.
82. (a) J. B. Hu, A. P. Deng and Y. Zhao, Ertugliflozin as a monotherapy for the treatment of type 2 diabetes, Expert Opin. Pharmacother., 2018, 19, 1841; (b) A. Markham, Ertugliflozin: First Global Approval, Drugs, 2018, 78, 513; (c) B. Tiwari, R. P. Pandey and N. Hussain, Recent advances in the synthesis of SGLT2 inhibitors and natural products from carbohydrates, Carbohydr. Res., 2025, 552, 109477.
83. C. V. A. Sasikala, P. D. Nahide, M. Beesu, S. Biswas, D. Basu, S. Achanta, R. Annapragada and R. Bandichhor, Synthetic approaches to gliflozins: a comprehensive overview, Synthesis, 2024, 906.
84. (a) J. A. C. Romero, S. A. Tabacco and K. A. Woerpel, Stereochemical reversal of nucleophilic substitution reactions depending upon substituent: reactions of heteroatom-substituted six-membered-ring oxocarbenium ions through pseudoaxial conformers, J. Am. Chem. Soc., 2000, 122, 168; (b) C. G. Lucero and K. A. Woerpel, Stereoselective C-glycosylation reactions of pyranoses: the conformational preference and reactions of the mannosyl cation, J. Org. Chem., 2006, 71, 2641.
85. B. Sama, B. Selisko, C. Falcou, V. Fattorini, G. Piorkowski, F. Touret, K. Donckers, J. Neyts, D. Jochmans, A. Shannon, B. Coutard and B. Canard, The effects of remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase, Antiviral Res., 2024, 232, 106034.
86. (a) D. F. Vargas, E. L. Larghi and T. S. Kaufman, Evolution of the synthesis of remdesivir: classical approaches and most recent advances, ACS Omega, 2021, 6, 19356; (b) N. Al Bujuq, Methods of synthesis of remdesivir, favipiravir, hydroxychloroquine, and chloroquine: four small molecules repurposed for clinical trials during the COVID-19 pandemic, Synthesis, 2020, 373; (c) D. G. Rajapaksha, S. Mondal and J. W. Wang, A guide for the synthesis of key nucleoside scaffolds in drug discovery, Med. Chem. Res., 2023, 32, 1315; (d) S. Kundu and D. Sarkar, Synthetic attempts towards eminent anti-viral candidates of SARS-CoV, Mini-Rev. Med. Chem., 2022, 22, 232.
87. For recent synthesis of remdesivir nucleoside and analogues: (a) J. Bouton, L. Maes, I. Karalic, G. Caljon and S. Van Calenbergh, Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents, Eur. J. Med. Chem., 2021, 212, 113101; (b) C. Xu, Y.-H. Hu, Y. He, Z. Hu, S. Li, H. Zhang, F. Huang, F.-L. Zhang and Y.-L. Chen, Synthesis of remdesivir by direct lithiation of pyrrolo[2,1-f][1,2,4]triazine derivatives enabled C-glycosylation, Eur. J. Org. Chem., 2023, e202300197; (c) P. Nie, E. Groaz, D. Daelemans and P. Herdewijn, Xylo-C-nucleosides with a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base: synthesis and antiproliferative properties, Bioorg. Med. Chem. Lett., 2019, 29, 1450.
88. K. K. Palli, P. Ghosh, S. K. Avula, B. S. S. Rao, A. D. Patil, S. Ghosh, G. Sudhakar, C. R. Reddy, P. S. Mainkar and S. Chandrasekhar, Total synthesis of remdesivir, Tetrahedron Lett., 2022, 88, 153590.
89. S. E. Metobo, J. Xu, O. L. Saunders, T. Butler, E. Aktoudianakis, A. Cho and C. U. Kim, Practical synthesis of 10-substituted tubercidin C-nucleoside analogs, Tetrahedron Lett., 2012, 53, 484.
90. C. Obradors, B. Mitschke, M. H. Aukland, M. Leutzsch, O. Grossmann, S. Brunen, S. A. Schwengers and B. List, Direct and catalytic C-glycosylation of arenes: expeditious synthesis of the remdesivir nucleoside, Angew. Chem., Int. Ed., 2022, 61, e202114619.
91. R. Majima, T. C. Edwards, C. D. Dreis, R. J. Geraghty and L. F. Bonnac, Enhanced remdesivir analogues to target SARS-CoV-2, Molecules, 2023, 28, 2616.
92. N. Bozinovic, V. M. de Aguiar, A. Ferry, F. Gallier, N. Lubin-Germain, J. Uziel and L. S. M. Miranda, Studies on the synthesis of 1′-CN-triazolyl-C-ribosides, Org. Biomol. Chem., 2022, 20, 7261.
93. P. Sierocki, K. Gaillard, R. A. A. Reyes, C. Donnart, E. Lambert, S. Grosse, L. Arzel, A. Tessier, J. Guillemont, M. Mathé-Allainmat and J. Lebreton, Synthesis of novel C-nucleoside analogues bearing an anomeric cyano and a 1,2,3-triazole nucleobase as potential antiviral agents, Org. Biomol. Chem., 2022, 20, 2715.
94. (a) N. S. El-Sayed, A. S. Jureka, M. R. Edwards, S. Lohan, C. G. Williams, P. T. Keiser, R. A. Davey, J. Totonchy, R. K. Tiwari, C. F. Basler and K. Parang, Synthesis and antiviral activity of fatty acyl conjugates of remdesivir against severe acute respiratory syndrome coronavirus 2 and Ebola virus, Eur. J. Med. Chem., 2021, 226, 113862; (b) R. T. Schooley, A. F. Carlin, J. R. Beadle, N. Valiaeva, X.-Q. Zhang, A. E. Clark, R. E. McMillan, S. L. Leibel, R. N. McVicar, J. Xie, A. F. Garretson, V. I. Smith, J. Murphy and K. Y. Hostetler, Rethinking remdesivir: synthesis, antiviral activity, and pharmacokinetics of oral lipid prodrugs, Antimicrob. Agents Chemother., 2021, 65, e01155–e01121; (c) Q. Zhou, Y. Luo, Y. Zhu, Q. Chen, J. Qiu, F. Cong, Y. Li and X. Zhang, Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses, Eur. J. Med. Chem., 2023, 249, 115113; (d) D. Wei, T. Hu, Y. Zhang, W. Zheng, H. Xue, J. Shen, Y. Xie and H. A. Aisa, Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2, Bioorg. Med. Chem., 2021, 46, 116364; (e) C. Sun, B. Liu, F. Zhou, Q. Zheng, C. Dai, W. Wei, G. Liao and Y. Sun, Assessment of Purity, Stability, and Pharmacokinetics of NGP-1, a Novel Prodrug of GS441254 with Potential Anti-SARS-CoV-2 Activity, Using Liquid Chromatography, Molecules, 2023, 28, 5634; (f) A. F. Carlin, J. R. Beadle, A. E. Clark, K. L. Gully, F. R. Moreira, R. S. Baric, R. L. Graham, N. Valiaeva, S. L. Leibel, W. Bray, R. E. McMillan, J. E. Freshman, A. F. Garretson, R. N. McVicar, T. Rana, X.-Q. Zhang, J. A. Murphy, R. T. Schooley and K. Y. Hostetler, 1-O-Octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-GS-4415 (V2043). Evaluation of oral V2043 in a mouse model of SARS-CoV-2 infection and synthesis and antiviral evaluation of additional phospholipid esters with enhanced anti-SARS-CoV-2 activity, J. Med. Chem., 2023, 66, 5802; (g) S. Cardoza, M. K. Shrivash, L. Riva, A. K. Chatterjee, A. Mandal and V. Tandon, Multistep synthesis of analogues of remdesivir: incorporating heterocycles at the C-1′ position, J. Org. Chem., 2023, 88, 9105; (h) R. L. Mackman, R. V. Kalla, D. Babusis, J. Pitts, K. T. Barrett, K. Chun, V. Du Pont, L. Rodriguez, J. Moshiri, Y. Xu, M. Lee, G. Lee, B. Bleier, A.-Q. Nguyen, B. M. O'Keefe, A. Ambrosi, M. Cook, J. Yu, K. E. Dempah, E. Bunyan, N. C. Riola, X. Lu, R. Liu, A. Davie, T.-Y. Hsiang, J. Dearing, M. Vermillion, M. Gale Jr, A. Niedziela-Majka, J. Y. Feng, C. Hedskog, J. P. Bilello, R. Subramanian and T. Cihlar, Discovery of GS-5245 (Obeldesivir), an oral prodrug of nucleoside GS-441524 that exhibits antiviral efficacy in SARS-CoV-2-infected African green monkeys, J. Med. Chem., 2023, 66, 11701; (i) T. N. Poudel, S. Panda, M. Orimoloye, P. Hegde and C. C. Aldrich, 1′-Cyano intermediate enables rapid and stereoretentive access to 1′-modified remdesivir nucleosides, J. Org. Chem., 2022, 87, 14452.
95. S. Kumar, Y. Khan, A. Arora, M. Kumar, P. Rungta, B. K. Singh, V. K. Sharma and S. K. Singh, Advances in the synthesis of spirocyclic nucleosides, Synthesis, 2024, 1097.
96. J. Feld and J. Hoofnagle, Mechanism of action of interferon and ribavirin in treatment of hepatitis C, Nature, 2005, 436, 967.
97. A. J. A. Cobb, A. Dell'Isola, B. O. Abdulsattar, M. M. W. McLachlan, B. W. Neuman, C. Müller, K. Shankland, H. M. N. Al-Mulla, A. W. D. Binks and W. Elvidge, Synthesis and antiviral activity of novel spirocyclic nucleosides, New J. Chem., 2018, 42, 18363.
98. K. C. Nicolaou, C.-K. Hwang and M. E. Duggan, Stereospecific Synthesis of 1,1-dialkylglycosides, J. Chem. Soc., Chem. Commun., 1986, 925.
99. See for examples: (a) F. Nicotra, L. Panza and G. Russo, Stereoselective Access to α - and β-D-fructofuranosyl C-glycosides, J. Org. Chem., 1987, 52, 5627; (b) A. M. Gómez, C. Uriel, S. Jarosz, S. Valverde and J. C. López, Stereoselective synthesis of C- and N-ketosides by Lewis acid-catalyzed C- and N-Glycosidation of Alkynyl, Phenyl, and Methyl Ketoses, Eur. J. Org. Chem., 2003, 4830; (c) A. M. Gómez, C. Uriel, S. Valverde and J. C. López, Formation and reactivity of novel pyranosidic Nicholas oxocarbenium Ions: access to C-ketosides and branched-chain C-ketosides, Org. Lett., 2006, 8, 3187; (d) B. Lv, Y. Feng, J. Dong, M. Xu, B. Xu, W. Zhang, Z. Sheng, A. Welihinda, B. Seed and Y. Chen, Conformationally constrained spiro C-arylglucosides as potent and selective renal sodium-dependent glucose Co-transporter 2 (SGLT2) inhibitor, ChemMedChem, 2010, 5, 827; (e) Y. Oda and T. Yamanoi, Trimethylsilyl trifluoromethanesulfonate catalyzed nucleophilic substitution to give C- and N-glucopyranosides derived from D-glucopyranose, Synthesis, 2007, 3021.
100. For others approaches of generation of oxocarbenium from endo or exo-glycals see: (a) S. W. Roberts and J. D. Rainier, Substitution and remote protecting group influence on the oxidation/addition of α-substituted 1,2-anhydroglycosides: a novel entry into C-ketosides, Org. Lett., 2005, 7, 1141; (b) H.-C. Lin, W.-P. Du, C.-C. Chang and C.-H. Lin, Different reaction routes found in acid-catalyzed glycosylation of endo- and exo-glycals: competition between Ferrier rearrangement and protonation, Tetrahedron Lett., 2005, 46, 5071; (c) See ref. 11.
101. E. Onobun and D. Crich, Synthesis of 3-deoxy-D-manno-oct-2-ulosonic Acid (KDO) and pseudaminic acid C-glycosides, J. Org. Chem., 2020, 85, 16035.
102. J. Zhang, G. Liu and G. Xing, β-Stereoselective KDO C-glycosylation by a (p-Tol)₂SO/Tf₂O preactivation strategy, Chem. Commun., 2025, 61, 1677.
103. For a recent study on C-glycosylation with neuraminyl and ulosonyl dibutylphosphates, see: R. Ogasahara, S. Abdullayev, V. A. Sarpe, A. R. Mandhapati and D. Crich, Influence of protecting groups on O- and C-glycosylation with neuraminyl and ulosonyl dibutylphosphates, Carbohydr. Res., 2020, 496, 108100.
104. A. Sun, Z. Li, S. Li, X. Meng, Z. Li and Z. Li, Stereoselective synthesis of α-3-deoxy-D-manno–oct-2-ulosonic acid (α-Kdo) derivatives using a C3-p-tolylthio-substituted KDO fluoride donor, Chin. Chem. Lett., 2025, 36, 109972.
105. N. Komura, K. Kato, T. Udagawa, S. Asano, H. N. Tanaka, A. Imamura, H. Ishida, M. Kiso and H. Ando, Constrained sialic acid donors enable selective synthesis of α-glycosides, Science, 2019, 364, 677.
106. (a) H. Liu, M. Lang, D. Hazelard and P. Compain, A Fries-type rearrangement strategy for the construction of stereodefined quaternary pseudoanomeric centers: an entry into C-naphthyl ketosides, J. Org. Chem., 2023, 88, 13847; (b) H. Liu, A. G. Laporte, D. G. Pinardo, I. Fernández, D. Hazelard and P. Compain, An Unexpected Lewis acid-catalyzed cascade during the synthesis of the DEF-benzoxocin ring system of nogalamycin and Menogaril: mechanistic elucidation by intermediate trapping experiments and density functional theory studies, J. Org. Chem., 2024, 89, 5634.
107. For a review on Fries-type rearrangement in carbohydrate chemistry see: R. G. dos Santos, A. R. X. Jesus, J. M. Caio and A. P. Rauter, Fries-type reactions for the C-glycosylation of phenols, Curr. Org. Chem., 2011, 15, 128.
108. P.-Y. Chen, Y.-T. Chiang, M.-T. Hsieh, Y.-C.; Hseu, C.-H. Lin and H.-C. Lin, Expeditious and stereoselective synthesis of (1S)- spiro[pyran-4-quinolines], Eur. J. Org. Chem., 2022, e202201116.
109. R. P. Sonawane, V. Jheengut, C. Rabalakos, C. R. Larouche-Gauthier, H. K. Scott and V. K. Aggarwal, Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications, Angew. Chem., Int. Ed., 2011, 50, 3760.
110. For selected reviews on the synthesis of spirosugars, see: (a) R. G. Soengas, G. da Silva and J. C. Estévez, Synthesis of spironucleosides: Past and future perspectives, Molecules, 2017, 22, 2028; (b) D. Hazelard, R. Hensienne, J.-B. Behr and P. Compain, Spiro iminosugars: structural diversity and synthetic strategies, in Carbohydrate-spiro-heterocycles, Topics in Heterocyclic Chemistry, ed. L. Somsák, Springer, 2019, vol. 57, pp. 262–290; (c) R. Kumar, M. Kumar, V. Kumar, A. Kumar, N. Haque, R. Kumar and A. K. Prasad, Nucleosides Recent progress in the synthesis of C-4′-spironucleosides and its future perspectives, Synth. Commun., 2020, 22, 3369.
111. Q. Zhu, X. Tian and G. He, Glycosylidene-carbene-mediated homologation of boronic esters for the synthesis of boro-ketosides, Chem Catal., 2024, 4, 100946.
112. For other examples of synthesis of gem-C,C-glycosides from glycosylidene carbenes, see: (a) S. E. Mangholz and A. Vasella, Glycosylidene carbenes part 21. Synthesis of N-tosylglycono-1,4-lactone hydrazones as precursors of glycofuranosylidene carbenes, Helv. Chim. Acta, 1995, 78, 1020; (b) P. Uhlmann, E. Harth, A. B. Naughton and A. Vasella, Glycosylidene carbenes part 20. Synthesis of deprotected, spiro-linked C-Glycosides of C₆₀, Helv. Chim. Acta, 1994, 77, 2335; (c) C. Waldraff, B. Bernet; and A. Vasella, Glycosylidene carbenes part 24. reactivity modulation by protecting groups of the addition of glycosylidene carbenes to electron-rich alkenes, Helv. Chim. Acta, 1997, 80, 1882; (d) A. Vasella and C. A. A. Waldraff, Glycosylidene carbenes part 3. Synthesis of Spirocyclopropanes, Helv. Chim. Acta, 1991, 74, 585; (e) S. E. Mangholz and A. Vasella, Glycosylidene carbenes part 5. Synthesis of Glycono-1,5-lactone Tosylhydrazones as Precursors of Glycosylidene Carbenes, Helv. Chim. Acta, 1991, 74, 2100.
113. P. Bowles, S. J. Brenek, S. Caron, N. M. Do, M. T. Drexler, S. Duan, P. Dubé, E. C. Hansen, B. P. Jones, K. N. Jones, T. A. Ljubicic, T. W. Makowski, J. Mistakis, J. D. Nelson, M. Olivier, Z. Peng, H. H. Perfect, D. W. Place, J. A. Ragan, J. J. Salisbury, C. L. Stanchina, B. C. Vanderplas, M. E. Webster and R. M. Weekly, Reactions commercial route research and development for SGLT2 inhibitor candidate Ertugliflozin, Org. Process Res. Dev., 2014, 18, 66.
114. S. Panda, T. N. Poudel, P. Hegde and C. C. Aldrich, Innovative Strategies for the construction of diverse 1′-modified C-nucleoside derivatives, J. Org. Chem., 2021, 86, 16625.
115. (a) L. Somsák, Carbanionic Reactivity of the anomeric center in carbohydrates, Chem. Rev., 2001, 101, 81; (b) S. Jarros and A. Zamojski, Carbohydrate derivatives containing the carbon-lithium and carbon-tin bonds, Curr. Org. Chem., 2003, 7, 13.
116. For selected examples, see: (a) D. W. Norbeck, J. B. Kramer and P. A. Lartey, Synthesis of an isosteric phosphonate analogue of cytidine 5′-monophospho-S-deoxy-D-manno-2-octulosonic Acid, J. Org. Chem., 1987, 52, 2174; (b) K. Luthman, M. Orbe, T. Waglund and A. Claesson, Synthesis of C-glycosides of S-deoxy-D-manno-2-octulosonic acid. Stereoselectivity in an enolate reaction, J. Org. Chem., 1987, 52, 3777; (c) D. Crich and D. L. B. Lim, Synthesis of 2-deoxy-β-C-pyranosides by diastereoselective hydrogen atom transfer, Tetrahedron Lett., 1990, 31, 1897; (d) N. J. Barnes, M. A. Probert and R. H. Wightman, Synthesis of 2-deoxy-α- and -β-D-arabino-hexopyranosyl phosphonic acids and related compounds; analogues of early intermediates in the shikimate pathway, J. Chem. Soc., Perkin Trans. 1, 1996, 431.
117. For selected examples, see: (a) J. Pezzotta, D. Urban, R. Guillot, G. Doisneau and J.-M. Beau, Synthesis of spirolactonic C-sialosides induced by samarium diiodide, Synlett, 2014, 375; (b) J.-H. Kim, F. Huang, M. Ly and R. J. Linhardt, Synthesis of a C-linked neuraminic acid disaccharide: potential building block for the synthesis of C-Analogues of polysialic acids, J. Org. Chem., 2008, 73, 9497; (c) T. Polat, D. Du and R. J. Linhardt, A General method for the stereospecific synthesis of C-glycosides of ulosonic acids by samarium-mediated reductive dechlorination, Synlett, 1998, 1195; (d) A. Malapelle, A. Coslovi, G. Doisneau and J.-M. Beau, An expeditious synthesis of N-acetylneuraminic acid α-C-glycosyl derivatives (“α-C-Glycosides”) from the Anomeric Acetates, Eur. J. Org. Chem., 2007, 3145.
118. Z. Zhang, Z. Xu, X. Liu, S. Luo and T. Li, Stereoselective synthesis of β-C-glycosides of 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) via SmI₂-mediated Reformatsky reactions, Org. Lett., 2021, 23, 6090.
119. (a) T. Ghosh and T. Nokami, Recent development of stereoselective C-glycosylation via generation of glycosyl radical, Carbohydr. Res., 2022, 522, 108677; (b) A. Chen, L. Xu, Z. Zhou, S. Zhao, T. Yang and F. Zhu, Recent advances in glycosylation involving novel anomeric radical precursors, J. Carbohydr. Chem., 2022, 40, 361; (c) D. J. Gorelik, S. P. Desai, S. Jdanova, J. A. Turner and M. S. Taylor, Transformations of carbohydrate derivatives enabled by photocatalysis and visible light photochemistry, Chem. Sci., 2024, 15, 1204; (d) W. Tian, B. Wan, Q. Yuan, G. Wang, S. Fan, J. Feng, Y. Zhu and D. Du, Progress on glycosidation via radical strategy, Asian J. Org. Chem., 2025, 14, e00218.
120. J. Dupuis, B. Giese, J. Hartung and M. Leising, Electron transfer from trialkyltin radicals to nitrosugars: the synthesis of C-glycosides with tertiary anomeric carbon atoms, J. Am. Chem. Soc., 1985, 107, 4332.
121. (a) Y. Liu and T. Gallagher, C-glycosides of 2-amino-2-deoxy sugars. β-C-glycosides and 1,1-disubstituted variants, Org. Lett., 2004, 6, 2445; (b) H. Woodward, N. Smith and T. Gallagher, exo-Glycals: intermediates in the synthesis of 1,1-disubstituted C-glycosides, Synlett, 2010, 869.
122. D. Tardieu, M. Desnoyers, C. Laye, D. Hazelard, N. Kern and P. Compain, Stereoselective synthesis of C,C-glycosides from exo-glycals enabled by iron-mediated hydrogen atom transfer, Org. Lett., 2019, 21, 7262.
123. M. Lang, D. Tardieu, B. Pousse, P. Compain and N. Kern, Stereoselective synthesis of C,C-glycosides from exo-glycals enabled by iron-mediated hydrogen atom transfer, Chem. Commun., 2024, 60, 3154.
124. D.-F. Chen, J. C. K. Chu and T. Rovis, Directed γ-C(sp3)−H alkylation of carboxylic acid derivatives through visible light photoredox catalysis, J. Am. Chem. Soc., 2017, 139, 14897.
125. For other examples of synthesis of gem-C,C-glycosides via the generation of tertiary pseudo anomeric radicals, see: (a) H. Paulsen and P. Matschulat, Synthese von C-glycosiden der N-acetylneuraminsaure und weiteren Derivaten, Liebigs Ann. Chem., 1991, 487; (b) A. J. Herrera, M. Rondon and E. Suárez, Stereocontrolled photocyclization of 1,2-diketones applied to carbohydrate models: a new entry to C-ketosides, Synlett, 2007, 1851; (c) A. M. Gomez, M. Casillas, S. Valverde and J. C. Lopez, Stereocontrolled entry to β-C-glycosides and bis-C,C-glycosides from C-glycals: preparation of a highly functionalized triene from D-mannose, Tetrahedron: Asymmetry, 2001, 12, 2175; (d) S. Mazzotta, J. Gori, G. Cavazzoli, S. Sattin, G. Macetti and A. Bernardi, Expanding the chemical space of sugar frameworks by quaternization of the anomeric carbon atom, Eur. J. Org. Chem., 2025, e202500599.
126. For selected reviews: (a) S. A. Green, S. W. M. Crossley, J. L. M. Matos, S. Vasquez-Cespedes, S. L. Shevick and R. A. Shenvi, The high chemofidelity of metal-catalyzed hydrogen atom transfer, Acc. Chem. Res., 2018, 51, 2628; (b) H. Shen, X. Zeng and Z. Wang, Recent advances in radical hydrofunctionalization of alkenes and dienes via reductive metal-hydride hydrogen atom transfer (MHAT), Eur. J. Org. Chem., 2025, e202401103; (c) J. Wu and Z. Ma, Metal-hydride hydrogen atom transfer (MHAT) reactions in natural product synthesis, Org. Chem. Front., 2021, 8, 7050; (d) S. W. M. Crossley, C. Obradors, R. M. Martinez and R. A. Shenvi, Mn-, Fe-, and Co-catalyzed radical hydrofunctionalizations of olefins, Chem. Rev., 2016, 116, 8912.
127. (a) J. C. Lo, D. Kim, C.-M. Pan, J. T. Edwards, Y. Yabe, J. Gui, T. Qin, S. Gutiérrez, J. Giacoboni, M. W. Smith, P. L. Holland and P. S. Baran, Fe-Catalyzed C–C bond construction from olefins via radicals, J. Am. Chem. Soc., 2017, 139, 2484; (b) J. C. Lo, J. Gui, Y. Yabe, C.-M. Pan and P. S. Baran, Functionalized olefin cross-coupling to construct carbon–carbon bonds, Nature, 2014, 516, 343.
128. (a) M. N. Villalobos and J. L. Wood, Spirolactone syntheses through a rhodium-catalyzed intramolecular C–H insertion reaction: model studies towards the synthesis of syringolides, Tetrahedron Lett., 2009, 50, 6450; (b) J. Hammoud, A. Joosten and T. Lecourt, Functionalization of glucopyranosides at position 5 by 1,5 C–H insertion of Rh(II)-carbenes: dramatic influence of the anomeric configuration, Carbohydr. Res., 2019, 486, 107834.
129. N. Probst, G. Grelier, N. Ghermani, V. Gandon, M. Alami and S. Messaoudi, Intramolecular Pd-catalyzed anomeric C(sp³)−H activation of glycosyl carboxamides, Org. Lett., 2017, 19, 5038.
130. Y.-B. Chen, S.-H. Liu, M.-T. Hsieh, C.-S. Chang, C.-H. Lin, C.-Y. Chen, P.-Y. Chen and H.-C. Lin, Stereoselective synthesis of spiro bis-C,C-α-arylglycosides by tandem Heck type C-glycosylation and Friedel−Crafts cyclization, J. Org. Chem., 2016, 81, 3007.
131. M. Pommier and S. Vidal, Anomeric spiro-annulated glycopyranosides: an overview of synthetic methodologies and biological applications, in Carbohydrate-spiro-heterocycles, Topics in Heterocyclic Chemistry, ed. L. Somsák, Springer, 2019, vol. 57, pp. 1–26.
132. (a) J.-P. Praly, Z. El Kharraf and G. Descotes, Synthesis of C-1 spirocyclopropyl sugars from anomeric diazides, Tetrahedron Lett., 1990, 31, 4441; (b) G. Descotes, Z. El Kharraf, R. Faure, B. Fenet and J.-P. Praly, Structural identification of substituted C-1 spiro cyclopropyl sugars, J. Carbohydr. Chem., 1991, 10, 959.
133. (a) A. Vasella, C. Witzig and R. Husi, Glycosylidene carbenes, Part 4. Synthesis of spirocyclopropanes from acetamidoglycosylidene-derived diazirines, Helv. Chim. Acta, 1991, 74, 1362; (b) A. Vasella, B. Bernet, M. Weber and W. Wenger, Glycosylidene Diazirines, in Carbohydrates in Chemistry and Biology, 2000, pp. 155–175.
134. C. Bluechel, C. V. Ramana and A. Vasella, Synthesis of monosaccharide-derived spirocyclic cyclopropylamines and their evaluation as glycosidase inhibitors, Helv. Chim. Acta, 2003, 86, 2998.
135. J. Cao and S. P. Vincent, Synthesis of spirocyclic cyclopropyl glycosyl-1-phosphate analogues, Org. Lett., 2022, 24, 4165.
136. P. C. Ruer, Y. Nassar, P. Polák and J. Cossy, Synthesis of five-membered exo-Glycals from six-membered 2-iodo-endo-glycals, J. Org. Chem., 2023, 88, 7228.
137. M. Lang, S. Walter, D. Hatey, A. Blanc, P. Compain and N. Kern, Gold(I)-catalyzed reactions of exo-glycals with propargyl esters toward C-1 alkenyl spirocyclopropyl carbohydrates, Org. Lett., 2024, 26, 8017.
138. (a) K. N. M. Nguyen, X. Mo, B. M. DeMuynck, M. Elsayed, J. J. A. Garwood, D. T. Ngo, I. K. Rana and D. A. Nagib, Harnessing carbene polarity: Unified catalytic access to donor, neutral, and acceptor carbenes, Science, 2025, 389, 183; (b) B. M. DeMuynck, L. Zhang, E. K. Ralph and D. A. Nagib, Cyclopropanation of unactivated alkenes with non-stabilized iron carbenes, Chem, 2024, 60, 1015.
139. A. J. Herrera, M. Rondón and E. Suárez, Stereocontrolled photocyclization of 1,2-diketones: application of a 1,3-acetyl group transfer methodology to carbohydrates, J. Org. Chem., 2008, 73, 3384.
140. J. József, L. Somsák, M. Tóth and L. Juhász, [2+2] cycloadditions of methylene exo-glycals: synthesis of glycopyranosylidene-spiro-azetidine-2-ones (β-Lactams) and cyclobutanones, Eur. J. Org. Chem., 2023, e202201488.

---