Challenges and opportunities in the synthesis of biologically relevant flavonoids and their glycosides

Contents

• 1. Introduction
  • 1.1. Background

• 2. Classification of flavonoids
  • 2.1. Flavanols
  • 2.2. Flavanones
  • 2.3. Flavonols
  • 2.4. Isoflavones
  • 2.5. Flavones
  • 2.6. Anthocyanidins
  • 2.7. Other flavonoid derivatives
  • 2.8. Biological activity

• 3. Total synthesis of flavonoid O-glycosides
  • 3.1. Synthesis of houttuynoid B
  • 3.2. Agalloside
  • 3.3. Houttuynoid A
  • 3.4. Apios isoflavones
  • 3.5. Leontopodioside A

• 4. Total synthesis of flavonoid C-glycosides
  • 4.1. (+)-Vicenin‐2
  • 4.2. Acicullatin
  • 4.3. 6-Tert-butyl puerarin and 6-tert-butyl-4′-methoxypuerarin
  • 4.4. Carambolaflavone A (1)
  • 4.5. Schaftoside
  • 4.6. Carambolaflavone A (2)

• 5. Total synthesis of flavonoid derivatives
  • 5.1. Sophoflavescenol
  • 5.2. I3, II8-biapigenin and idiculuflavone A
  • 5.3. Wikstrol A and wikstrol B
  • 5.4. Sophoraflavanone H
  • 5.5. Neocyclomorusin
  • 5.6. Kuwanons A and B
  • 5.7. Pongaflavone
  • 5.8. Lupinifolin
  • 5.9. Osajin and scandenone

• 6. Conclusion

• 7. Conflicts of interest

• 8. Data availability

• Acknowledgements

• References

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Abstract

Covering: 2015 to 2025

Natural product synthesis is key to unravel the roles and functions of complex biological molecules and drive innovations in drug discovery, agrochemicals, and materials sciences. Flavonoids are ubiquitous plant secondary metabolites with a C(6)–C(3)–C(6) benzo-γ-pyrone carbon skeleton, and they encompass a vast family of derivatives that play essential roles in UV protection, flower pigmentation, auxin transport, and defense against environmental stress. Flavonoid biosynthesis yields a diverse array of compounds, including flavones, anthocyanins, and proanthocyanidins, whose stability and bioactivity are often enhanced by post-translational modifications such as glycosylation and methylation. Flavonoids are known for their potent antioxidant properties and thus play a critical role in neutralizing reactive oxygen species and preserving cellular redox balance. Beyond their antioxidant activity, these phytochemicals exhibit a wide range of biological effects, including antibacterial, antiviral, anti inflammatory, and anticancer activities, highlighting their significant therapeutic potential. Due to their structural complexity and pharmacological promise, the total synthesis of flavonoids and their glycosylated analogues has garnered considerable research interest. This review aims to provide an overview of the recent advances in the total synthesis of flavonoid glycosides and their derivatives over the last decade. We selected twenty exemplary examples to illustrate key synthetic strategies while discussing their natural sources, therapeutic applications, and structure–activity relationship (SAR) studies that helped elucidate specific functional groups that are important for their pharmacological properties. We hope we can provide a current perspective on the recent advancements in flavonoid chemistry and their significance in the development of novel therapeutic agents for a range of diseases.

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Debabrata Giri

Debabrata Giri obtained his BSc degree in Chemistry from Ramakrishna Mission Vivekananda Centenary College, Rahara, in 2021. Afterward, he enrolled in the M.Sc. program in Chemistry at Banaras Hindu University, graduating in 2023 with a specialization in Organic Chemistry under the supervision of Prof. Ganesh Pandey on total synthesis. He qualified the Indian UGC-NET exam and joined the Indian Institute of Technology Hyderabad to pursue his PhD under the supervision of Dr Abhijit Sau. His research interest focuses on synthetic studies of biologically relevant flavonoids and their glycosides.

Saikat Mondal

Saikat Mondal earned his BSc degree in Chemistry from the University of Burdwan, West Bengal, in 2021. Afterward, he enrolled in the MSc. program in Chemistry at the Indian Institute of Technology Hyderabad, graduating in 2024 with a specialization in Organic Chemistry under the supervision of Dr Abhijit Sau. He subsequently worked as a Project Associate-I at CSIR-IICT. He is currently a PhD scholar at the Indian Institute of Science Education and Research, Thiruvananthapuram, working on radical-mediated organic synthesis and catalysis.

M. Carmen Galan

M. Carmen Galan is currently a Professor of Organic and Biological Chemistry in the School of Chemistry at the University of Bristol. She has held several prestigious fellowships: ERC consolidator grant (2015–2020), EPSRC Career Acceleration Fellowship (2012–2017), and Royal Society Dorothy Hodgkin Fellowship (2008–2012). Her internationally recognized research spans from carbohydrate synthesis, catalysis, and functional nanomaterials to biological applications in the areas of cancer, antimicrobials and agriculture. Her work has been recognised with several awards: 2017 RSC Dextra Carbohydrate Chemistry award; 2021 RSC Jeremy Knowles award; 2022 SRUK Merit award, 2025 ACS Melvile L. Wolfrom award and Emil L. Fisher Carbohydrate award.

Abhijit Sau

Abhijit Sau is an Assistant Professor in the Department of Chemistry at IIT Hyderabad, India. He earned his PhD from Bose Institute, Kolkata, under the supervision of Prof. Anup Kumar Misra in 2014. After a year at Åbo Akademi University, Finland, he continued his postdoctoral research at the University of Bristol, UK, with Prof. M. Carmen Galan, and later at the University of Strasbourg, France, with Prof. Joseph Moran. His contributions have been recognized through several prestigious fellowships, including the Marie Curie Postdoctoral Fellowship, Ramanujan Fellowship, and Johan Gadolin Postdoctoral Fellowship. His current research focuses on the development of sustainable synthetic methods for biologically active molecules and mechanistic investigations in organic chemistry.

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1. Introduction

1.1. Background

Flavonoids are a diverse group of polyhydroxylated phenolic compounds characterized by a benzo-γ-pyrone structure and are widely found throughout the plant kingdom, especially in the seeds, leaves, bark, and flowers of plants, and they are also linked to the production of colors.^1–3 Both flavonoid and their glycosides exhibit broad inhibitory activities against diseases like cancer, diabetes, and cardiovascular and neurological disorders, with their protective effects in biological systems attributed to their ability to transfer electrons to free radicals, chelate metal catalysts, activate antioxidant enzymes, reduce alpha-tocopherol radicals, and inhibit oxidases.^4–8 Dietary flavonoids, which feature distinct hydroxy, methoxy, and glycosidic functional groups and include A- and B-ring conjugation, predominantly exist in food as 3-O-glycosides and polymers, which undergo hydroxylation, methylation, sulfation, or glucuronidation during metabolism. Interestingly, flavonoid moieties found in wine have been shown to exert potent antioxidant activity by inhibiting the oxidation of human low-density lipoproteins in vitro and also by reducing thrombosis, which is a major cause of death from coronary disease.^9,10 During the fermentation of green tea leaves to produce black tea, flavanols oxidize and polymerize into tannins and a complex blend of polyphenolic compounds, which are responsible for the distinctive color and flavor of black tea.^11–13 One of the major components found in black tea is procyanidins, composed of (+)-catechin and (−)-epicatechin monomers, and they stand out as key dietary elements and contribute to the rich flavor of grape seeds, apples, and cocoa.^14,15

Building on the 2014 review from Yu and co-workers, which discussed glycosylation reactions in the synthesis of flavonoid glycosides,¹⁶ as well as the significant contribution of Liu in 2020 to flavonoid chemistry,¹⁷ we aim to provide an updated overview of recent synthetic advances in the total synthesis of this very important class of natural products. Key seminal examples will be discussed to highlight the key challenges in the field, emerging strategies and developments, and current limitations. In particular, twenty case studies were selected not as exemplary targets per se, but as representative platforms that expose recurring synthetic bottlenecks and decision points, including the regioselective functionalisation of the flavone A- and B-rings, strategic timing of O- vs. C-glycosylation, late-stage oxidation and dearomatisation challenges, and the chemoselective manipulation of densely functionalised phenolic systems.

2. Classification of flavonoids

Flavonoids present a C(6)–C(3)–C(6) carbon skeleton structure that consists of at least two aromatic rings, called A and B, linked by a three-carbon chain that can form a heterocyclic ring containing oxygen, called ring C, with ring A (Fig. 1). Generally, flavonoids are divided into flavones, flavonols, flavanones, flavanols, isoflavones, leucoanthocyanidins, anthocyanidins, and chalcones based on the oxidation level of the central pyran C-ring.¹⁸ The subclasses are determined by minor structural variations, including the absence of ring C, the position of the bond between ring B and ring C, the degree of unsaturation, and ring C oxidation.

Fig. 1 Classification of plant flavonoids.

2.1. Flavanols

A highly complex class of polyphenol monomers, flavanols have an extra hydroxy group in the C-3 position and lack a C2–C3 double bond; they include polymeric procyanidins, also referred to as condensed tannins, and monomeric flavan-3-ols, such as epicatechin, gallo-catechin, and catechin (Fig. 1-I). The primary sources of flavanols are fruit and their derivatives, such as fruit juices and jams. In addition, this group can be found in cereals, apples, kiwis, cocoa, red wine, and tea.^19,20 Except for broad beans and lentils, they are virtually nonexistent in vegetables and legumes. Flavanols are also present in fruit and vegetable peels and seeds, but since these components are frequently eliminated during processing or eating, their consumption is likewise restricted. Flavanols primarily exert health benefits through their metabolic products, with phase-II and microbial metabolites entering systemic circulation and promoting nitric oxide (NO) release, which supports vascular health. By promoting NO-mediated vascular repair, long-term ingestion of foods that are high in flavanols enhances endothelial function and helps avoid cardiovascular illnesses, with advantages even for smokers.^21,22

2.2. Flavanones

Dihydroflavones (Fig. 1-II) known as flavanones, are structurally different from other flavonoids due to their unique saturation of the C ring,²³ notable lack of a double bond between the C2–C3 positions²⁴ and the presence of hydroxy groups at the C5 and C7 positions, along with hydroxy or methoxy groups located at C-3′ or C-4′ positions (Fig. 1).²⁵ Flavanones are widely distributed across approximately 42 major families, with Compositae, Leguminosae, Rutaceae containing the highest amounts.²⁶ Although flavanones are present in all parts of a plant, including the bark, branches, leaves, roots, flowers, and fruits, they are most abundant in the peel of citrus fruits rather than in the meaty inside.^27–29 Because of their high occurrence and health benefits, naringenin (5,7,4′-trihydroxyflavanone) and hesperetin (4′-methoxy-5,7,3′-trihydroxyflavanone)—flavanones present in common foods including tomatoes and citrus fruits (lemon, orange, lime, and tangelo)—are of special interest. Without altering liver histology, these substances, which are found as both aglycones and glycosides, aid in thyroid function restoration.³⁰ Additionally, naringenin has been suggested to strengthen the immune system, bolster antioxidant enzymes to protect organs from oxidative damage, and control intestinal inflammation by lowering nitrate and nitrite levels and preventing the creation of pro-inflammatory cytokines.³¹

2.3. Flavonols

Distinguished by their unique substitutions on the A- and B-rings, flavonols (also referred to as 3-hydroxy flavones) are connected by a flexible three-carbon chain (Fig. 1-III).³² Predominantly observed in epidermal cells, it acts as nature's shield by protecting DNA from the harmful effects of UV radiation due to the hydroxy groups placed at the C-5 and C-7 positions on the A-ring.³³ The significance of flavonols concerning their biological activities and antioxidant properties makes them one of the most studied subgroups of flavonoids. This class of polyphenolic phytochemicals is abundant in frequently eaten fruits, like apples and grape berries, vibrant vegetables, such as red lettuce, broccoli, tomato, and onion, as well as plant-based beverages.^34,35 Drinks like red wine, black tea, and green tea are important sources of flavonols, in addition to fruits and vegetables. Among the main flavonols, myricetin, kaempferol, and quercetin can be identified. Celebrated for their antioxidant, cardioprotective, antibacterial, antiviral, and anticancer properties,³⁶ dietary flavonols have been shown to significantly reduce the risk of gastric cancer, especially in women and smokers.³⁷ They also improve enzymatic and non-enzymatic antioxidant defenses, such as those modulated by quercetin, to combat reactive oxygen species (ROS) mediated liver cancer.³⁸

2.4. Isoflavones

A unique and significant subclass of flavonoid compounds is isoflavones. The 3-phenylchromen skeleton is made up of these structures, which are chemically derived from the 2-phenylchromen skeleton through an aryl-migration mechanism (Fig. 1-IV).^39,40 The majority of isoflavones are found in legumes, particularly soy. However, their presence has also been reported in split peas, chickpeas, black beans, lima beans, clover sprouts, and sunflower seeds. Genistein and daidzein are the two main isoflavones found in the human diet, among a total of twelve soybean isoflavones.⁴¹ They are found in four related chemical structures: aglycones, 7-O-glucosides, 6′-O-acetylglucosides, and 6′-O-malonylglucosides. This type of flavonoid acts as a potential antioxidant, which can lower the risk of cancer and prevent free radical damage to DNA.⁴²

2.5. Flavones

One of the biggest and most varied groups of flavonoids, flavones are mostly found as 7-O-glycosides and are based on the 4H-chromen-4-one backbone with a phenyl group at the C-2 position (Fig. 1-V).^43,44 The two main flavones, luteolin and apigenin, are present in a wide variety of foods. While luteolin graces broccoli, celery, carrots, parsley, onion leaves, cabbages, peppers, chrysanthemum flowers, and apple skins, apigenin makes its mark in seasonings, onions, wheat sprouts, tea, oranges, and chamomile.⁴⁵ The apigenin group, which includes substances like vitexin, isovitexin, rhoifolin, schaftoside and apiin, is well known for its strong anti-inflammatory and free radical scavenging properties.^46,47 It also protects pancreatic cells and lessens the loss of antioxidant enzymes in disorders such as cancer, heart disease, and neuroinflammation.⁴⁸

2.6. Anthocyanidins

Anthocyanidins, a class of phytochemicals, are natural water-soluble plant vacuolar pigments responsible for the stunning spectrum of blue, red, purple, and orange hues that grace many fruits, flowers, vegetables, as well as various delicious food products made from them.⁴⁹ There are more than 650 distinct anthocyanidins that have been identified and documented in the literature.⁵⁰ This class of flavonoids is predominant in teas, honey, cereals, fruits, vegetables, nuts, olive oil, and cocoa.⁵¹ The structural basis of anthocyanidins is the flavylium or 2-phenylbenzopyrilium cation, which has hydroxyl and methoxy groups positioned at various points in the basic structure of flavonoids (Fig. 1-VI). Anthocyanidins have also been observed in the aglycone form of anthocyanins. The stability of anthocyanins (glycosylated anthocyanidins), which are extremely reactive and unstable substances, is affected by several variables, including pH, temperature, light, oxygen, enzymes, other flavonoids, proteins, and metal ions. As the pH rises, these compounds are converted into blue quinoidal bases (pH 2–4), colorless hemiketals, and finally pale-yellow chalcones, which can break down into phenolic acids (pH 5–6). They are most stable as red-colored flavylium cations in acidic environments (pH 1–3).^52–54

2.7. Other flavonoid derivatives

Flavonoids are undergoing rapid developments in the field of molecular science, influenced by the moieties that bind to them. These modifications cause them to transform into fascinating and biologically active new forms, such as pyranoflavones, biflavones, and prenyl flavanones.

2.7.1. Pyranoflavones. A specific category of flavonoids that have a pyran group is called pyranoflavones (Fig. 2-I). The synthesis of these compounds has been the subject of a recent study in order to investigate their potential as selective inhibitors of cytochrome P450 enzymes, specifically cytochrome P450 1A1, P450 1A2, and cytochrome P450 B1, which are implicated in the bioactivation of polycyclic aromatic hydrocarbons like procarcinogens.^55,56 The findings revealed that cytochrome P450 1A2 is strongly inhibited by the α-naphthoflavone-like derivatives 7,8-pyranoflavone (78 PF) and 5-hydroxy-7,8-pyranoflavone (5H78 PF), with IC₅₀ values of 0.059 and 0.014 µM, respectively, while P450 1A1 is weakly inhibited. However, cytochrome P450 1A1 is more strongly inhibited by the β-naphthoflavone-like derivatives 5,6-pyranoflavone (56 PF) and 6,5-pyranoflavone (65 PF) (IC₅₀ values of 0.32 and 0.15 µM) than P450 1A2 (IC₅₀ values of 1.13 and 0.76 µM).⁵⁷

Fig. 2 Structures of various flavonoid derivatives.

2.7.2. Biflavones. Angiosperms, bryophytes, ferns, and gymnosperms naturally contain biflavones, which comprise two monoflavonoid residues. Biflavones are dimeric flavonoids composed of two flavonoid units connected by a C–C or C–O–C bond, typically between the C-6 and C-8 positions (Fig. 2-II).⁵⁸ They can have free or methylated hydroxyl groups and are substituted at the 5-, 7- and 4′-positions. Flavone–flavone and flavanone–flavanone dimers make up the majority of this subclass's members.⁵⁹ Various other factors, including the kind of monomeric flavonoid (flavones, flavanones, and flavonols), the substituents on their monomers (usually hydroxy or methoxy groups), and the interflavonoid bond between the units, contribute to the structural diversity of these biflavones.^60,61 Regardless of the bioactivity associated with each monomeric unit, some of these biflavones have been shown to exhibit improved biological activities.⁶²

2.7.3. Prenyl flavanones. Prenylated flavonoids, which combine a lipophilic prenyl side chain with a flavonoid skeleton, are a significant class of polyphenolic compounds (Fig. 2-III). The most prevalent subclass of prenylated flavonoids is prenylated flavonones, whereas the rarest is prenylated flavanols. On flavonoids, C-prenylation occurs far more frequently than O-prenylation. Prenylation makes flavonoids more lipophilic, improving their interaction with target proteins and increasing their affinity for biological membranes.⁶³

2.8. Biological activity

Flavonoids are primarily known for their antioxidant properties, which are attributed to the presence of a large number of phenolic hydroxy groups that act as hydrogen-donating radical scavengers.^64,65 These compounds are also known for their health benefits as anti-inflammatory,⁶⁶ antiulcer, antiviral,⁶⁷ antifungal,⁶⁸ anticancer,⁶⁹ antiallergic,⁷⁰ and antidiabetic⁷¹ agents in addition to exhibiting some cytotoxic effects, among others.⁷² It is believed that the hydroxyl group of the B-ring on the flavan (Fig. 3) nucleus plays a critical role in the scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by donating both a hydrogen atom and an electron to hydroxyl, peroxyl, and peroxynitrite radicals. Additionally, the presence of a catechol group at the 3′- and 4′-positions on the B-ring significantly boosts the inhibition of lipid peroxidation.⁷³ The 5-OH group enhances antioxidant effects and explains the higher Trolox equivalent antioxidant capacity (TEAC) and peroxynitrite scavenging of genistein, while the 5,7-dihydroxy arrangement increases TEAC, but methylation of the 6-OH group does not alter lipid peroxidation inhibition. Furthermore, the A-ring hydroxylation's impact on antioxidant activity is less significant compared to that of the B-ring.⁷⁴ In a microsomal system, flavonoids containing a 2–3 double bond conjugated with a 4-carbonyl group exhibit lower IC₅₀ values compared to those with saturated heterocycles. The reduction of this double bond reduces the antiperoxidative phenomenon, as the resonance conjugation between the A and B rings via the unsaturated carbonyl moiety enhances the stabilization of flavonoid radicals.⁷⁵ Glycosylation on the A-ring of flavonoids reduces antioxidant activity more than glycosylation at the 3-position. Whereas the glycosylation in rat mitochondria at the 7-position has been shown to weaken antioxidant activity. However, no difference was found between 3- and 7-glucosides of quercetin in phospholipid bilayers.^76,77 The existence of the 3-OH group preserves the coplanarity and conjugation with the B-ring through intramolecular hydrogen bonding, which is essential for effective radical scavenging ability.⁷⁸ Quercetin is a highly effective peroxyl radical scavenger, with its O-methylated and O-glycosylated derivatives showing reduced potency, likely due to steric hindrance from the O-methylation that disrupts molecular planarity and diminishes antioxidant activity.⁷⁹ Prenylation of flavonoids at positions 3, 6, and 8 enhances their inhibitory effects against various enzymatic processes, including tyrosinase, melanin biosynthesis, alpha-glucosidase, and mitogen-activated protein kinase (MAPK) pathways, as seen with luteolin, apigenin, quercetin, genistein, and chalcone.^63,80–82

Fig. 3 Structure-activity relationship of flavonoids towards therapeutic applications.

3. Total synthesis of flavonoid O-glycosides

Flavonoids are characterized by a six-membered ring in the C6–C3–C6 carbon skeleton, which will be highlighted in this research. The coupling between a hydroxyl group of a flavonoid aglycone and the anomeric carbon of a sugar moiety will generate an O-linkage to form flavonoid O-glycosides.^83,84 Flavonoid O-glycosides are generally more stable than their corresponding aglycone under physiological conditions, but can be hydrolyzed under acidic environments or by the action of enzymes. This stability is attributed to the presence of the glycosidic bond, which protects the flavonoid core from oxidation and degradation. Although 5-, 8-, and 4′-O-glycosides have also been found in some exceptional cases, flavonoid glycosides are more commonly present as 3- or 7-O-glycosides.⁸⁵ Because of the steric barrier and decreased ability for electron delocalization, O-glycosylation at the C-7, C-3, and C-4′ sites reduces the radical scavenging action of flavanones.^86–88 These natural products are found in many plants, where they support interspecies communication as well as growth and development. Flavonoid O-glycosides also have a wide range of protective effects on humans, such as antibacterial, anticancer, and radical-scavenging capabilities.⁸⁹

3.1. Synthesis of houttuynoid B

3.1.1. Synthetic approach. In 2016, the Schmalz group achieved the first total synthesis of houttuynoid B,⁹⁰ an antiviral agent that suppresses the herpes simplex virus with IC₅₀ values of 57.7 µM.^91,92 This compound was isolated by the Yao group from the tree Houttuynia cordata in 2012.^93,94 The target molecule 1 was generated via the Baker–Venkataraman rearrangement⁹⁵ and cyclization from the intermediate ester, containing the appropriate sugar scaffold, which is formed by esterification with the intermediate having a furan ring 14 and an acetophenone scaffold 9. Compound 9 was obtained from chrysin 3 via retro-aldol degradation and alpha oxidation, followed by glycosylation. Similarly, compound 12 was obtained from 3,4-dihydroxybenzaldehyde 5 by Sonogashira coupling, Corey–Fuchs reaction, and domino Sonogashira coupling/5-endo-dig-cyclization. Although a normal ester is suitable for the esterification of compound 9, a stable HOBT-activated ester of compound 14 was produced for easier handling (Fig. 4).

Fig. 4 Convergent strategy for the total synthesis of houttuynoid B.

3.1.2. Synthetic route. Based on their retrosynthetic study, the group started by synthesizing aromatic scaffold 13, which serves as the building block for benzofurans. By treating 3,4-dihydroxybenzaldehyde 5 with benzyl bromide, KI, and K₂CO₃ in acetone, the known intermediate 4-benzyl-3,4-dihydroxybenzaldehyde 10 was generated, which was then treated with iodine monochloride and pyridine in DCM to yield 11. Separately, 1-undecyne 12 was prepared from decanal 4 in two steps under Corey–Fuchs conditions using CBr₄, PPh₃ in DCM at 0 °C^96,97 and n-butyllithium in THF at −78 °C, followed by the addition of water. The benzofuran 13 was produced by a domino Sonogashira coupling between iodo-phenol 11 and alkyne 12 using Pd(PPh₃)₂Cl₂, CuI, and NEt₃ in DMF at 60 °C. The Pinnick oxidation of benzofuran 13 with NaH₂PO₄, NaClO₂, and 2-methyl-2-butane in THF/H₂O produced the carboxylic acid intermediate,⁹⁸ which was then transformed into the HOBT-activated ester 14 by the reaction with HOBT and EDC HCl in DCM. Compound 9,⁹⁹ the second building block, was created from chrysin 3 by first double O-benzylation with BnBr and K₂CO₃ and then retro-aldol degradation with 18 M KOH and pyridine in ethylene glycol at 120 °C, and alpha oxidation, resulting in the hydroxylated product 7.¹⁰⁰ BF₃ OEt₂ was used to glycosylate alcohol 7 with peracetylated β-galactose 6, resulting in the galactose derivative 9.¹⁰¹ Under Steglich conditions, the ester intermediate was produced in 76% yield through the esterification of 9 and 13 in the presence of NaH using THF as solvent.¹⁰² By using in situ cyclization and Baker–Venkataraman rearrangement with K₂CO₃, TBAF, and toluene at 70 °C, this ester was transformed into the chromenone intermediate.¹⁰³ Ultimately, benzyl ethers were finally eliminated by Pd/C, H₂ in THF/EtOH, and the sugar moiety was deprotected with NaOMe in MeOH to get the natural product Houttuynoid B 1 (Scheme 1).

Scheme 1 Forward synthesis of houttuynoid B (Schmalz, 2016).⁹⁰

3.1.3. Strategies and lessons learned from the synthesis. Their approach is intriguing since they formed the glycosyl derivative 9 and then produced an intermediate ester. Their previous study revealed that metalation or halogenation could not be used to achieve regioselective functionalization of quercetin derivatives 15 at C-2′, and that the benzofuran moiety's electron-donating effect was the reason behind the failure of attempts to introduce an oxy-substituent at C-3 in the intermediate of type 17 (Fig. 5).^104–106

Fig. 5 Lessons from the total synthesis of houttuynoid B.

3.2. Agalloside

3.2.1. Synthetic strategy. In 2017, Arai and Ishibashi's group embarked on an intricate journey to synthesize Agalloside 18,¹⁰⁷ a compound that activates neural stem cell differentiation,¹⁰⁸ by leveraging the direct O-glycosylation of the corresponding flavan with a disaccharide 21 (Fig. 6). This naturally occurring substance had been isolated by the same research group in 2016 from Aquilaria agallocha.^109,110 The crucial process consisted of selectively choosing the flavan unit for the glycosylation instead of the flavonoid unit for glycosylating disaccharide 21. The sophisticated synthesis of the flavan unit began with 2,4,6-trihydroxyacetophenone 20 and proceeded via a series of methylation, chalcone production, cyclization catalyzed by NaOAc/EtOH, selective demethylation by AlCl₃, acylation, and reduction of the carbonyl moiety.

Fig. 6 Conversion strategy for the synthesis of agalloside.

3.2.2. Synthetic route. The synthesis of glycosyl donors began with the protection of glucose 23 and xylose 22, where glucose's 6-hydroxy group was protected as the trityl ether with trityl chloride and pyridine at 40 °C, followed by acetylation of the remaining hydroxyl groups with acetic anhydride and removal of the trityl group in HBr/AcOH to yield compound 29.¹¹¹ Then, the xylose donor 30 was crafted by protecting all hydroxyl groups with benzoyl groups, and selectively removing the anomeric –OBz with HBr/AcOH to unveil a perbenzoylated xylose with an anomeric bromide. Starting with chalcone 25, a Michael reaction in the presence of NaOMe in ethanol medium yielded the cyclized product 26, which was subsequently used to deprotect the 5-OMe group using AlCl_3, followed by acetylation and reduction of the carbonyl group in 27 with NaBH₄ in THF/H₂O to produce the desired flavan 28. The O-glycosylation of flavan 28 with glycosyl fluoride 32, catalyzed by BF₃ OEt₂ and 4 equiv. of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) in DCM, proceeded efficiently in just 3.5 hours, yielding 5-O-glycoside 33 in 68% yield.¹¹² Subsequently, oxidation of 33 with DDQ in DCM/H₂O medium and complete deprotection with NaOMe/MeOH afforded the target molecule, Agalloside 18 (Scheme 2).

Scheme 2 Forward synthesis of agalloside (Arai and Ishibashi, 2017).¹⁰⁷

3.2.3. Strategies and lessons learned from the synthesis. Due to strong hydrogen bonding between the 5-OH and carbonyl group, attempts to glycosylate flavone 34 with the synthesized disaccharide donors 21 under Mitsunobu,¹¹³ Lewis acid,^111,114 and S_N2 conditions¹¹⁵ did not result in the production of O-glycosides (Fig. 7). Furthermore, under BF₃·OEt₂ and DTBMP conditions, the glycosylation of flavan 28 with glycosyl fluoride produced an inseparable combination of 5-O-glycoside and 6-C-glycoside with yields of 38% and 22%, respectively. After that, the glycosyl donor to flavan ratio was increased to 2 : 1, and the amount of DTBMP was raised to 4 equiv. to enhance the formation of the desired O-glycoside with a short reaction time of 3.5 h.

Fig. 7 Lessons from the total synthesis of agalloside.

3.3. Houttuynoid A

3.3.1. Synthetic strategy. Houttuynoid A, isolated from Houttuynia cordata in 2013 by the Yao group,¹¹⁶ was synthesized in 2018 by Sun and Gao's group;¹¹⁷ the compound was shown to inhibit herpes simplex virus type 1 (HSV-1) multiplication and prevent lesions in a mouse model.^93,118,119 This compound demonstrated wide antiviral activity against α-herpesviruses such as varicella zoster and herpes simplex virus type 2 (HSV-2), and it also rendered HSV-1 inactive by preventing viral membrane fusion. With an IC₅₀ value of 23.5 µM, its effectiveness against the herpes simplex virus was associated with the aldehyde group at the C-2″ position.^93,120 The target molecule is synthesized from the corresponding flavone intermediate by means of functional group interconversions and O-glycosylation with 39 at the C-3 position (Fig. 8). The flavone is created by oxidizing chalcone and adding by oxa-Michael reaction, then protecting the C-2 hydroxycarbonyl group. In this procedure, compound 7 is subjected to a Claisen–Schmidt condensation with benzofuran aldehyde scaffold to form the corresponding chalcone, which is also synthesized from commercially available 3,4-dihydroxybenzaldehyde 5 with concomitant selective protection and intermolecular Heck reaction with 38.

Fig. 8 Conversion strategy for the total synthesis of houttuynoid A.

3.3.2. Synthetic route. According to their retrosynthetic analysis, the para-hydroxy group of 3,4-dihydrobenzaldehyde 5 was first regioselectively benzylated with BnBr, KI, and K₂CO₃ in acetone at 60 °C, resulting in the formation of compound 40 in 76% yield.¹²¹ The treatment of this benzaldehyde with iodine monochloride in 1,4-dioxne resulted in a 90% yield of the iodinated compound, after which the formyl group was protected as acetal 41 using 1,3-propanediol, p-TsOH/toluene in two consecutive steps before the conjugate addition of phenol 41 to methyl dodec-2-ynoate 38 in DMF at 110 °C to produce aryl ether 42 with 84% yield.^122–125 Using an intramolecular Heck reaction, compound 42 could be used to generate the benzofuran skeleton 43 with 79% yield,¹²⁶ and the hydrolysis of the 1,3-dioxanyl group with HCl in moist THF produced the critical intermediate 44 with a 90% yield. Through the Claisen–Schmidt condensation of compound 7 and aldehyde 44, with NaOH/EtOH, compound 44 was transformed into chalcone 45, which, in turn, was converted into 4H-chromen-4-one derivative 46 with 89% yield using I₂/DMSO cyclization at 110 °C.^127,128 Prior to oxidation at C-3, the hydroxycarboxyl group at C-2 was methylated with MeI/K₂CO₃. A 62% yield of 3-hydroxyflavone 47 was achieved by treating compound 46 with in situ-generated DMDO, followed by TsOH-mediated rearrangement and the selective deprotection of the 5-benzyloxy group via refluxing in HOAc/H₂O.^129,130 Chromenone 48 was quantitatively generated via glycosylation of 47 with compound 39 in the presence of K₂CO₃/DMF.¹³¹ The acetyl and benzyl protecting groups of compound 48 were removed using conventional hydrolysis with K₂CO₃, MeOH/THF, and hydrogenation with H₂, Pd(OH)₂ in MeOH/THF, respectively. Ultimately, a 54% reduction in the yield of target Houttuynoid A 36 was observed after exposure of the ester intermediate to DIBAL-H (Scheme 3).

Scheme 3 Forward synthesis of houttuynoid A (Gao and Sun, 2018).¹¹⁷

3.3.3. Strategies and lessons learned from this synthesis. In this synthesis, several attempts to glycosylate compound 49 with the glycosyl donor 39 were unsuccessful (Fig. 9). This was attributed to hydrogen bonding between the C-4 carbonyl group and the 3-hydroxyl group, which rendered the 3-OH group unavailable towards nucleophilic attack. Therefore, the C-5 benzyl group was first debenzylated using AcOH/H₂O at 110 °C to resolve the encountered issue.

Fig. 9 Lessons from the total synthesis of houttuynoid A.

3.4. Apios isoflavones

3.4.1. Synthetic strategy. In 2019, Nihei and co-workers embarked on the remarkable total synthesis of apios isoflavones,¹³² which are potent and hydrophilic tyrosinase inhibitors extracted from the edible tuber of A. americana by the Shindo group in 2013.^133–136 To unlock novel inhibitors, the synthesis of target molecule 51 was ingeniously designed, culminating in a global transesterification of compound 52 (Fig. 10). This key intermediate 52 was crafted via selective acylation of 2′-OH and 4′-OH positions using PvCl and pyridine, followed by precise methylation at the C-5 position of the flavone intermediate. Notably, the isoflavone intermediate was synthesized through the selective glycosylation of the isoflavone scaffold and compound 54, with the isoflavone part itself being obtained through a masterful Friedel–Crafts reaction and Bischler–Napieralski-type cyclization using compound 56 and trimethoxybenzene 53.

Fig. 10 Conversion strategy for the total synthesis of apios isoflavone.

3.4.2. Synthetic route. The forward synthesis, inspired by the retrosynthetic analysis, began with a masterful Friedel–Crafts reaction between 1,3,5-trimethoxybenzene 53 and carboxylic acid 56 at 70 °C using BF₃ OEt₂ as a Lewis acid to form phenyl ketone 57 with 79% yield.^137,138 The exquisitely methylated isoflavone 58 was obtained in 73% using a Bischler–Napieralski-type cyclization of 56 with N,N-dimethylformamide dimethylacetal (DMFDMA).¹³⁹ Then, employing BBr₃, a high-yielding ether cleavage of 58 was performed, converting it into an isoflavone intermediate in an amazing 89% yield.¹⁴⁰ In the presence of a phase transfer catalyst, the glycosyl donor 2,3,5,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide, (Pv)₄GlcBr, 54 proved essential in achieving the selective glycosylation of that intermediate because of its resilience to basic environments, resulting in compound 59 with 84% yield.^141,142 The final product 51 was obtained by the protection of 2′- and 4′-OH groups with -Pv groups in the presence of PvCl/Py using DCM as a solvent, methylation with DBU and MeI, forming compound 60, followed by transesterification with NaOMe (Scheme 4).

Scheme 4 Forward synthesis of apios isoflavone (Nihei, 2019).¹³²

3.4.3. Strategies and lessons learned from this synthesis. A crucial observation in this synthesis was that during the Friedel–Crafts reaction, fully methylated product 61 was not identified by TLC due to the preferential deprotection of the 2′-OMe group, most likely resulting from Lewis acid coordination between the carbonyl and 2′-OMe groups (Fig. 11). Furthermore, only 30% of compound 58 was produced during its synthesis, along with a number of unknown side products, suggesting problems with DMF and BF₃·OEt₂ and methanesulfonyl chloride.¹⁴³ Ultimately, the process became even more sluggish when 2,3,4,6-tetra-O-acetyl-α-D-glycosyl trichloroacetimidate 62 was used as a glucosyl donor for the Schmidt glycosylation of compound 64.^144,145

Fig. 11 Lesson from the total synthesis of apios isoflavone. (A) Abnormal Friedel–Crafts reaction; (B) unsuccessful glycosylation.

3.5. Leontopodioside A

3.5.1. Synthetic strategy. In 2020, Li's group synthesized leontopodioside A,¹⁴⁶ a potent α-glucosidase inhibitor with an IC₅₀ of 55.6 ± 1.9 µM, significantly lower than that of acarbose (IC₅₀ = 626.3 ± 25.8 µM), which had been isolated from Leontopodium leontopodioides by Xie's group in 2016.^147–149 They employed a convergent synthetic strategy, connecting the aglycone intermediate 11 with the sugar unit 67 (Fig. 12). The aglycone was synthesized via aldol condensation of protected compounds 5 and 7 using a strong base, starting from commercially available 3,4-dihydroxybenzaldehyde 5. Similarly, the introduction of the ester linkage at the primary –OH group is achieved by selectively reacting the glucose unit with benzyl-protected 4-hydroxybenzoyl chloride 68, following the formation of the glycosyl bond with the flavone unit.

Fig. 12 Conversion strategy for the total synthesis of leontopodioside A.

3.5.2. Synthetic route. The synthesis started with 3,4-dihydroxybenzaldehyde 5, which underwent benzyl chloride and NaH treatment in DMF to regioselectively create the 3-O-benzyl product 10 in 59% yield, as per the retrosynthetic analysis.¹⁵⁰ The methoxymethyl (MOM) group was used to preserve the remaining free phenolic –OH group in compound 10 using DCM and DIPEA as a base. Compound 70 was obtained via aldol condensation of compound 69 and 7 in the presence of NaH. It was then deprotected with 3 M HCl in THF under reflux for 2 h, resulting in 91% yield of the chalcone aglycone. After this, the required glycosylated compound 71 was generated in 74% yield by phase-transfer glycosylation with glycosyl donor 67 and 0.5 M K₂CO₃ at 45 °C.¹⁵¹ After employing a MeONa/MeOH system to deprotect the acyl group, glucoside 71 was O-6 acylated with benzyl-protected 4-hydroxybenzoyl chloride 68 and DIPEA/Me₂SnCl₂ to produce compound 72. Compound 65, leontodioside A, was generated in 88% yield by cyclization with I₂/DMSO¹⁵² with final deprotection using hydrogen and Pd(OH)₂/C (Scheme 5).

Scheme 5 Forward synthesis of leontopodioside A (Ding and Li, 2020).¹⁴⁶

3.5.3. Strategies and lessons learned from this synthesis. In this paper, the authors encountered significant challenges in optimizing the yield of the target molecule. Their first approach involved cyclizing the chalcone to obtain the flavone, followed by the introduction of the sugar unit 67 (Fig. 13). However, only 41% of the flavone was produced, mostly because of the elimination of the -MOM group. Therefore, they changed their synthetic strategy, concentrating on glycosylating the chalcone. The phase-transfer glycosylation procedure was hindered by the use of 1.0 M KOH as a base, even though K₂CO₃ was used to execute glycosylation between compounds 73 and 67. Furthermore, the typical MeONa/MeOH system did not deprotect the acyl groups on compound 75, and attempts to utilize (MeO)₂Mg as a moderate base in DCM/MeOH were similarly unsuccessful, underscoring the instability of the flavonoid ring.¹⁵³

Fig. 13 Lessons from the total synthesis of leontopodioside A. (A) Unexpected deprotection of the MOM group; (B) unsuccessful glycosylation of flavone; (C) unsolved deacetylation.

4. Total synthesis of flavonoid C-glycosides

C-Glycosylated flavonoids are an intriguing class of chemicals that are present in many different plants. They are oxygen-rich heterocycles that are stable compared to the flavonoid O-glycoside due to the presence of more acid, base, or enzymatic hydrolysis-resistant covalent C–C bonds,^154,155 and they are formed when the sugar moiety's anomeric carbon is joined to the carbon of the flavonoid aglycone skeleton by a C-glycosidic bond.¹⁵⁶ As siderophores, antibiotics, antioxidants, and even insect attractants or feeding deterrents, flavonoid C-glycosides found in various plants, microbes, and insects have a variety of vital functions in nature.¹⁵⁷ Flavone C-glycosides, which are abundant in major cereal crops, including maize, wheat, and rice, are noteworthy for their resistance to hydrolysis, which guarantees both their biological activity in plants and their nutritional value.¹⁵⁸ Curiously, research has demonstrated that C-glycosylation in the A-ring can lower antioxidant activity; this impact may be related to the intrinsic characteristics of the sugar rather than the removal of a hydroxyl group.⁷³ The improved enzymatic and chemical stability of these C-glycosides suggests their potential for developing small-molecule inhibitors targeting glycoside metabolism and cell-surface recognition.^159,160

4.1. (+)-Vicenin‐2

4.1.1. Synthetic strategy of (+)-vicenin-2. In 2016, Ohmori and Suzuki efficiently synthesized (+)-vicenin-2, a bis-C-glycosyl apigenin, extracted by Ferraro's group in 2011 from the Argentinean native herb Urtica circularis¹⁶¹ and used as anticancer,¹⁶² antidiabetic,¹⁶³ anti-inflammatory¹⁶⁴ and antioxidant¹⁶⁵ agents, utilizing 1,3,5-trifluorobenzenes as a starting material.¹⁶⁶ They leveraged two distinct reactions of fluorobenzenes, namely, ortho-lithiation and nucleophilic aromatic substitution (S_NAr), to modify the structure. By substituting oxygenated functional groups for fluorine atoms on the A-ring via S_NAr, the flavone C-ring was created through an intramolecular oxa-Michael addition, followed by oxidation. Aryl anion attacks on carbonyl derivatives were used to gradually add the sugar lactone units 80 and the cinnamoyl-group-containing compound 81 (Fig. 14).

Fig. 14 Conversion strategy for the total synthesis of (+)-vicenin-2.

4.1.2. Synthetic route for (+)-vicenin-2. The synthesis started with compound 79, which was lithiated with ⁿBuLi in a diethyl ether medium, and hemiketal 82 was quantitatively generated through a reaction with lactone 80.¹⁶⁷ Compound 82 was reduced with triethylsilane and BF₃·OEt₂ in DCM to give mono-β-C-glycoside 83 in 83% yield.¹⁶⁸ Similarly, lactol 84 was produced by lithiating C-glycosyl trifluorobenzene 83 with ^tBuLi and then reacting with lactone 80. Compound 84 was then reduced under similar conditions to produce bis-β-C-glycoside 85 in 82% yield. The crucial intermediate 86 was obtained in 80% yield through the deprotonation of 85 with ^tBuLi using Et₂O solvent at −78 °C and subsequent reaction with α,β-unsaturated Weinreb amide 81.¹⁶⁹ Vicenin 2 was produced in 92% yield through the last transformations, which included the substitution of a hydroxy group for fluorine of compound 86 with ^tBuOK and benzaldoxime in THF,¹⁷⁰ the production of chromanone using I₂/DMSO cyclization of compound 87,¹⁷¹ replacement of C-5 and C-7 fluorine atoms of compound 88 with BnOH/KOH in 1,4-dioxane at 88 °C (ref. 172) and hydrogenolysis in the presence of H₂/Pd(OH)₂/C (Scheme 6).

Scheme 6 Forward synthesis of (+)-vicenin-2 (Ohmori and Suzuki, 2016).¹⁶⁶

4.1.3. Strategies and lessons learned from the synthesis of (+)-vicenin-2. After compound 86 was obtained, attempts to substitute hydroxy or alkoxy groups for all fluorine atoms failed, and no trisubstituted compound 89 was produced (Fig. 15).¹⁷³ Byproducts 90 and 91 were produced as a result of the severe circumstances, causing retro-aldol condensation and/or cleavage of the C(4)–C(10) bond. Therefore, the C-5 fluorine atom was first replaced with the hydroxy group, and 90% of the phenol 87 was formed when 86 reacted with benzaldoxime in THF at room temperature. By treating flavone 88 with KOH and benzyl alcohol in 1,4-dioxane at 88 °C, the remaining fluorines were substituted with benzyl alkoxide, resulting in a fully benzoxylated compound in 89% yield.¹⁷² However, ether cleavage at C(4′), C(5′), and C(7) occurred when dipolar aprotic solvents like DMF, NMP, or DMSO were utilized in the presence of the same chemical environment, resulting in the undesirable mono- and di-phenolic compounds 92. Similarly, retro-aldol condensation of 86 occurred in the absence of benzaldoxime by reaction with KOH in THF at rt to form 90 instead of 87.

Fig. 15 Lesson from the total synthesis of (+)-vicenin-2. (A) Unsuccessful S_NAr reaction; (B) regioselective defluorination; (C) random debenzylation.

4.2. Acicullatin

4.2.1. Synthetic strategy. Acicullatin, a potent anti-inflammatory¹⁷⁴ and anti-cancer¹⁷⁵ agent isolated from Chrysopogon aciculatus by Carte's group in 1991,^175,176 was synthesized by Lee's group in 2016 based on a retrosynthetic scheme that starts with β-D-digitoxopyranosylflavone 95 and proceeds through a sequence of functional group modifications (Fig. 16).¹⁷⁷ In the beginning, using a one-pot process including protection and functional group transformations, methyl 2,3,4,6-tetra-O-trimethylsilyl-alpha-glucopyranoside 96 is converted into the crucial digitoxosyl donor intermediate. Then the β-C-digitoxosyl derivative is anticipated to be produced by glycosylation of an electron-rich phenol acceptor 7 with the digitoxyl donor through an O-to-C Fries-type rearrangement. The following stages involve the esterification of β-D-digitoxopyranosyl phenol and –OBn protected acid 97, which is then converted into the flavone through a Beker–Venkataraman rearrangement and cyclohydration reaction with CSA.

Fig. 16 Convergent strategy for the total synthesis of aciculatin.

4.2.2. Synthetic route. Starting with methyl 2,3,4,6-tetra-O-trimethylsilyl-α-D-glucopyranoside 96, thiodigitoxoside 95 was synthesized. In a one-pot reaction, methyl 4,6-O-benzylidene-2,3-di-O-tosyl-α-D-glucopyranoside 98 was produced from compound 96 with an extraordinary 71% yield.¹⁷⁸ Compound 99 (methyl 3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α-ribohexopyranoside) was produced in 94% when glucoside 98 was reduced with lithium triethylborohydride (LiBEt₃) in THF via the involvement of the α-D-allo-2,3-epoxide intermediate and selective ring opening and further benzoylation of the 3-axial hydroxy group of the intermediate formed in this reaction with BzCl in pyridine.¹⁷⁹ Fully protected digitoxoside 100 was obtained in 86% yield through the NBS-mediated fragmentation of 4,6-benzylideneacetal using the Hanessian–Hullar reaction in CCl₄ at 90 °C.^180,181 After that, reductive debromination with Bu₃SnH and AIBN in toluene at 90 °C, and subsequent p-thiocresol and SnCl₄ were used to convert compound 100 into the desired 3,4-di-O-benzoylthiodigitoxide 95, yielding 85% product.¹⁸² Then, with the help of digitoxin derivative 95 and NIS/TfOH, the electron-rich phenol 7 was glycosylated, yielding β-D-digitoxopyranoside 101 with strong regio- and stereo-selectivity (81% yield).¹⁸³ The hydroxy-C-glycosyl product was likely produced via an in situ O-to-C Fries-type rearrangement. Using EDC, β-C-digitoxoside 101 was esterified with 4-benzyloxybenzoic acid 97, resulting in 98% yield of ester 102. This ester was rearranged by the Baker and Venkataraman rearrangement using NaH as a reagent to produce a 1,3-diketone, which was subsequently cyclodehydrated by CSA to form flavone 103.^184,185 The monomethoxy C-glycosyl compound 93 was finally generated via BBr₃/DCM mediated de-O-methylation and then de-O-benzoylation of flavone 103 with NaOMe/MeOH, DCM to yield aciculatin in 88% yield (Scheme 7).¹⁸⁶

Scheme 7 Forward synthesis of aciculatin (Lee, 2016).¹⁷⁷

4.2.3. Strategies and lessons learned from this synthesis. Numerous issues with the entire synthesis were observed, including a 52% lower yield for the reductive cleavage of methyl-4,6-O-benzylidene-2,3-di-O-mesyl-α-D-glucopyranoside with lithium triethylborohydride (Fig. 17). Therefore, the synthesis was continued with the tosyl-protected compound 98. Additionally, employing the 3,4-di-O-benzoyldigitoxosyl imidate donor 95A with a catalytic quantity of TMSOTf resulted in a low yield of just 63% of compound 101, highlighting that TfOH is the optimal choice for achieving the best yield in this C-glycosylation process. Then, purification was made more difficult by the development of two significant byproducts when ^tBuOK or KOH was used as a base in the 1,3-diketone formation reaction using the Beker–Venkataraman rearrangement. However, the utilization of NaH as a base in this process provides satisfactory results. In this particular case, the selective demethylation of flavone 103, using the BBr₃·SMe₂ complex, produces the desired compound with an unsatisfactory yield of 42%, which inspires us to pursue this process with BBr₃ in DCM medium.

Fig. 17 Lesson from the total synthesis of aciculatin. (A) Unsuccessful reductive cleavage; (B) low-yielding C-glycosylation; (C) re-optimisation for B–V rearrangement.

4.3. 6-Tert-butyl puerarin and 6-tert-butyl-4′-methoxypuerarin

4.3.1. Synthetic strategy. The isoflavone C-glycosides from Pueraria radix¹⁸⁷ show strong anti-myocardial ischemic action¹⁸⁸ and are more resistant to hydrolysis in acidic gastric juices than O-glycosides and aglycones; they exhibit various biological activities like radio-protectivity,¹⁸⁹ colony-stimulating¹⁹⁰ and antidiabetic effect, and derivatives such as 6-tert-butylpurrarin and 6-tert-butyl-4′-methoxy-puerarin have been synthesized to enhance the efficacy and concentration of puerarin by preventing its metabolism in the liver.¹⁹¹ Therefore, in 2017, Peng, Gao, and Wang pioneered a green synthesis of 6-tert-butylpuerarin and 6-tert-butyl-4′-methoxypuerarin via a streamlined deoxybenzoin route.¹⁹² Starting with compound 108, they employed an O- to C-glycoside rearrangement, followed by de-tert-butylation to create 2-C-β-D-glucopyranoside 114 (Fig. 18). This compound was reacted with thionyl chloride, producing a deoxyenzoin intermediate, which was then cyclized in DMF using POCl₃/DMF to form the desired flavone structure. Finally, debenzylation and demethylation were performed to yield the target compounds.

Fig. 18 Convergent strategy for the total synthesis of 6-tert-butyl-4′-methoxypuerarin and 6-tert-butyl puerarin.

4.3.2. Synthetic route. They began the synthesis with compound 108, which was reacted with 2,3,4,6-tetra-O-benzylglucopyranosyl trifluoroacetamide 109 to form 2-C-β-D-glucopyranoside 113 via O- to C-glycoside rearrangement with TMSOTf in DCM medium.^193,194 The tert-butyl group was then removed in the presence of trifluoroacetic acid at room temperature for 1.5 h,¹⁹⁵ and the intermediate was reacted with 4-methoxyphenylacetyl chloride 111, synthesized from the corresponding acid with thionyl chloride 110 at room temperature,¹⁹⁶ to yield deoxybenzoin 114 with 63.6% isolated product. Treatment of 114 with POCl₃/DMF gave glucosylisoflavone in 68.3% yield,¹⁹⁷ and subsequent temperature-controlled debenzylation (at −78 °C) and demethylation (−10 °C) with BBr₃/DCM yielded the final compound 6-tert-butyl-4′-methoxy-puerarin and 6-tert-butylpurrarin in 95.5% and 98.6% yield, respectively (Scheme 8).^198–200

Scheme 8 Forward synthesis of 6-tert-butyl-4′-methoxypuerarin and 6-tert-butyl puerarin (Peng, Gao, and Wang, 2017).¹⁹²

4.3.3. Strategies and lessons learned from the synthesis. Their attempt to react 1-(5-tert-butyl-2,4-dihydroxyphenyl)-2-(4-methoxypenyl)-ethenone 115 with 2,3,4,6-tetra-O-benzyl-glucopyranosyl trifluoroacetimidate 109 was unsuccessful because the phenol acceptor's electron-withdrawing acyl group decreased the reactivity and prevented the production of C-glycoside (Fig. 19). Several attempts to de-tert-butylate β-C-glycoside 113 with solutions such as HBr,²⁰¹ TfOH,²⁰² AlCl₃/toluene,²⁰³ AlCl₃/DCM,²⁰⁴ AlCl₃/toluene and nitromethane,²⁰⁵ and sulfuric acid/toluene were unsuccessful. Furthermore, subsequent attempts to cyclize deoxybenzoin 114 using DMF, morpholine, and triethyl orthoformate at 140 °C destroyed the sugar ring, and debenzylation of 119 using 10% Pd–C also failed due to olefin reduction and produced compound 120.²⁰⁶

Fig. 19 Lessons from the synthesis of 6-tert-butyl-4′-methoxypuerarin and 6-tert-butyl puerarin. (A) Unsuccessful C-glycosylation; (B) failed de-tert-butylation; (C) issue with cyclization reaction; (D) uncontrolled reduction.

4.4. Carambolaflavone A (1)

4.4.1. Synthetic strategy. In 2018, the Du and Sun group achieved a remarkable enantioselective total synthesis of the hypoglycemic drug carambolaflavone A, which was extracted from the leaves of Averrhoa carambola in 2005 by Chou's group.^207–209 Carambolaflavone A is used to treat diabetes mellitus, which is synthesized using a masterfully designed convergent strategy (Fig. 20).²¹⁰ Central to their approach was the construction of a crucial C-glycosidic linkage, seamlessly connecting a flavone subunit derived from monobenzyl-protected 2,4,6-trihydroxyacetophenone 123, derived from dimethoxymethylated 2,4,6-trihydroxyacetophenone 124. By leveraging the thermodynamically favored Suzuki O → C glycoside rearrangement²¹¹ with a perbenzylated L-fucopyranosyl acetate donor 126, derived from 1,2:3,4-di-O-isopropyllidine-α-fucopyranose 127, they elegantly assembled the flavone scaffold through a sophisticated sequence of esterification with 4-(benzyloxy) benzoic acid 125, Baker–Venkataraman rearrangement, and acid-catalyzed cyclization.

Fig. 20 Convergent strategy for the total synthesis of carambolaflavone A.

4.4.2. Synthetic route. The synthesis began with the protection of the 6-OH group of dimethoxymethylated 2,4,6-trihydroxyacetophenone 124 using a 2-naphthylmethyl group (Nap) in the presence of K₂CO₃/DMF, yielding the mononaphthylated compound 128 in 94%. Subsequent selective removal of the methoxymethyl groups with 3 M HCl in MeOH afforded a diol intermediate, which, after regioselective benzylation under mild conditions with K₂CO₃ and BnCl in DMF and controlled hydrogenolysis removing the Nap group selectively, provided the desired monobenzylated acetophenone 123 in 62% yield.²¹² Using Sc(OTf)₃ in dry toluene at 70 °C, the critical C-glycosidic linkage was formed after obtaining the main acceptor 126, yielding C-glycoside 130 with great effectiveness.^213–215 They synthesized perbenzylated fucosyl intermediate 126 starting from fucose diacetone 127. First, they carried out a glycosylation reaction between fucose diacetone and allyl alcohol in the presence of a catalytic amount of acyl chloride. The product was then benzylated using BnBr and NaH in DMF, yielding the allyl-protected perbenzylated D-fucosyl donor 128. Subsequent deallylation using PdCl₂/MeOH, followed by acylation with acetic acid in pyridine, gave the desired intermediate 126.^216,217 Based on NMR spectroscopic analysis, atropisomer formation of the reported compound was caused by the inclusion of a tert-butyldiphenylsilyl (TBDPS) group in intermediate 130. The flavone scaffold was eventually produced by tetrabutylammonium fluoride (TBAF)-mediated TBDPS removal to obtain compound 131 in 92% yield after Mitsunobu protection of compound 130 with BnOH, DEAD, and PPh₃ in THF (95%), followed by dehydrative esterification of the intermediate with EDCl, DMAP in DMF,²¹⁸ Baker–Venkataraman rearrangement in the presence of NaH in THF medium, and CSA mediated cyclization (2 steps, 61%). Hydrogenolysis by Pd/C and H₂ in EtOH/EtOAc of perbenzylated intermediate 132 was used to achieve universal deprotection and produce carambolaflavone A 121 (Scheme 9).

Scheme 9 Forward synthesis of carambolaflavone A (Du and Sun, 2018).²⁰⁷

4.4.3. Strategies and lessons learned from this synthesis. While synthesizing the target molecule 121, when the same procedure was followed for the synthesis of carambolaflavone A with perbenzylated L-fucosyl acetate donor 133, a product with identical NMR spectra but an opposite optical rotation value was obtained, indicating that the enantiomer of authentic 121 was produced and that the originally proposed structure of 121 was misassigned (Fig. 21). Additionally, the coupling of monobenzylated acetophenone 123 with perbenzylated L-fucosyl acetate under Suzuki's conditions²¹⁹ (0.2 equiv. Sc(OTf)₃) in dry DCM yielded only 25% of the desired β-C-glycoside, alongside 30% α-C-glycoside and 22% α-O-glycoside. Although switching to toluene provided a broader tunable temperature range, the yield was not improved under these conditions. Increasing the reaction temperature proved effective in suppressing O-glycoside formation, and raising the Sc(OTf)₃ amount from 0.2 to 0.5 equiv. increased the β-C-glycoside yield to 78%. Further optimization, including the removal of 4 Å MS, led to a clean conversion to the desired product with a high yield of 94% under the final optimal conditions of 0.2 equiv. of Sc(OTf)₃ in dry toluene at 70 °C.²²⁰

Fig. 21 Lessons from the total synthesis of carambolaflavone A.

4.5. Schaftoside

4.5.1. Synthetic strategy. The total synthesis of schaftoside, found in the leaves of sugarcane,²²¹ was started in 2021 by Liu and Du's group²²² to investigate its anti-obesity, anti-diabetic, hepatoprotective, and antiallergenic effects.^223–225 Although the synthesis strategy comprised severing the apigenin A-ring at the 6-C-β-D-glucopyranoside and 8-C-α-L-arabinopyranoside linkages, they strategically selected (±)-naringenin as the starting material due to its electron-rich aromatic ring, which facilitated C-glycosylation at the C-6 position of the flavone moiety. After introducing the sugar units onto the naringenin derivative 138, they converted it to apigenin derivatives through a two-step process (Fig. 22). This process involved the two consecutive oxidations of C-glycosylflavan. Lewis acid-promoted O-to-C fries-type rearrangement was used to achieve regio- and stereo-selective C-glycosylation between flavan, which is strategically derived from flavanone 138, and the peracetylglycosyl trichloroacetimidates 137 and 139, which were actually synthesized from D-glucose and L-arabinose.

Fig. 22 Convergent strategy for the total synthesis of schaftoside.

4.5.2. Synthetic route. According to the retrosynthetic analysis, the synthesis of key C-glycosyl flavan 142 started with (±)-naringenin. Before acetylating the 5-OH and 4″-OH groups with acyl chloride in the presence of pyridine to produce the diacetate flavone intermediate with a 70% yield, regioselective silyl protection of (±)-naringenin 138 with TBSCl in the presence of triethylamine/THF occurred at the 7-OH group due to its higher acidity. After removing the carbonyl group at C-4 by reduction with sodium borohydride in THF-H₂O to obtain compound electron-rich flavan 140.²²⁶ Compound 6-C-β-D-glucopyranosyl flavan 141 was produced by C-glycosylation of flavan 140 with glucosyl donor 137 and a catalytic amount of TMSOTf at −15 °C. The TBS group was then selectively removed to yield a phenolic intermediate by the reaction of 141 with HF Py. Following a second glycosylation with donor 139 and TMSOTf to yield 6-C-β-D-glucopyranosyl-8-C-α-L-arabinopyranosyl flavan 142, the latter was then bis-benzylated in the presence of benzyl bromide and K₂CO₃ base in DMF medium and oxidized twice, first with CAN and then with PDC, to form di-C-glycosylflavanone 143.^227,228 Finally, hydrogenolysis of 143 with 10% Pd/C and H₂, followed by acetylation, produced compound 144, which, in turn, cyclized with I₂/DMSO for the synthesis of the required flavone.²²⁹ Global deacetylation of the intermediate flavone with MeOH/MeONa yielded the target compound, schaftoside 135, in 89% yield (Scheme 10).

Scheme 10 Forward synthesis of schaftoside (Liu, 2021).²²²

4.5.3. Strategies and lessons learned from this synthesis. Their strategy is unique as they first synthesized the target molecule by modifying the core structure, recognizing that the apigenin derivative is less susceptible to C-glycosylation due to the electron-withdrawing effect of the C-4 carbonyl group and strong hydrogen bonding between the 5-OH and C-4, prompting a shift towards the forward synthesis. The oxidative dehydrogenation of C-glycosylflavan 142 proved challenging, with direct oxidation attempts failing and producing undesired benzoquinone byproducts (Fig. 23).²³⁰ Protecting the phenolic hydroxyl groups with benzyl groups using K₂CO₃ allowed the reaction to proceed. However, one-pot oxidation method with cerium(IV) ammonium nitrate and peracetylated C-glycosylflavan 145 yielded the product 146 in less than 30% yield, likely due to reduced reactivity from electron-withdrawing acyl groups.

Fig. 23 Lessons from the total synthesis of schaftoside.

4.6. Carambolaflavone A (2)

4.6.1. Synthetic strategy. The Simpson group initiated stereoselective C-aryl glycosylation with bismuth triflate in 2022 to synthesize carambolaflavone A,²³¹ a possible lead for antihyperglycemic medications, which was extracted from leaves of Averrhoa carambola in 2005 by Chou's group.^209,232 They wanted to build (+)-carambolaflavone A by C-glycosylating the protected flavan derivative 149 and D-fucose derivative 148 because breakdown occurs when flavones are directly C-glycosylated (Fig. 24). Flavan derivative 149 was produced from (±)-naringenin, and compound 148 was made from commercially available D-galactose 147 via a couple of concomitant protection–deprotection reactions.

Fig. 24 Convergent strategy for the total synthesis of (+)-carambolaflavone A.

4.6.2. Synthetic route. According to the retrosynthetic strategy, compound 149, reacting with anhydrous K₂CO₃ and benzyl bromide in acetone at 23 °C to 56 °C for 12 hours, produced the monobenzylated intermediate, which was acylated with acetyl chloride in pyridine to produce diacetate intermediate 150 in two steps with a 69% yield. In dioxane and H₂O, diacetate 150 was reduced with NaBH₄ to obtain protected flavan derivative 151 as a racemic mixture in 91% yield. Diisopropylidene derivative 152 was formed in 93% yield by reacting D-(+)-galactose 147 with ZnCl₂, acetone, and a catalytic amount of H₂SO₄. In two processes, the main alcohol of 152 was transformed into an iodide intermediate with the reaction of I₂, imidazole/PPh₃ in toluene, and then the fucose derivative 153 was produced by hydrogenolysis with H₂, Pd(OH)₂, and Et₃N in MeOH with 93% yield. After heating the glucose derivative 153 in AcOH to produce the tetraol, it was then benzylated with BnBr and NaH in DMF, to yield the tetrabenzyl derivative 154 in 75% yield.²³³ After compound 154 was treated with H₂SO₄ and AcOH to create a hemiacetal, benzoyl chloride was added, and over the course of two stages, compound 154 produced fucose derivative 148 in a 63% yield. Bismuth triflate catalyzed C-aryl glycosylation of racemic flavan derivative 151 and glycosyl donor 148 in the presence of DCM solvent, resulting in a 76% yield of compound 155.²³⁴ In two phases, compound 155 underwent acetylation with Ac₂O/Py and oxidation with ceric ammonium nitrate in MeCN to give flavanone derivative 156 in 38% yield.¹¹² Protected flavone 157 was produced in 52% yield by brominating and dehydrogenating flavanone 156 in the presence of PPh₃·HBr in DMSO for 10 hours at 80 °C. Ultimately, flavone 157 was deprotected by saponification with LiOH in MeOH and hydrogenolysis with H₂/Pd–C in EtOAc-EtOH, producing synthetic (+)-carambolaflavone A in 50% yield (Scheme 11).²³⁵

Scheme 11 Forward synthesis of carambolaflavone A (Simpson, 2022).²³¹

4.6.3. Strategies and lessons learned from this synthesis. Direct C-glycosylation of flavone derivatives frequently results in degradation of the starting material; Oyama and Kondo already tackled this issue using 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and BF₃ OEt₂. Although Sc(OTf)₃ has been utilized for this purpose in the past, Bi(OTf)₃, a nontoxic and affordable Lewis acid, was used in this study for the first time as an effective catalyst for the C-glycosylation of flavan derivatives 151, utilizing acetate or benzoate derivatives to achieve a higher yield (Fig. 25). Also, using a racemic flavan derivative and a small excess of acetate glycosyl donor, different metal triflates were used to study the C-aryl glycosylation processes in DCM at 23 °C. In the case of Sc(OTf)₃, 39% of β-C-aryl glycoside 155 was formed, but Fe(OTf)₃ yielded significantly smaller amounts of the desired product. Other catalysts, such as Dy(OTf)₃, Cu(OTf)₂, and Zn(OTf)₂, on the other hand, did not yield any product and instead recovered the starting material. Using benzoate derivatives as the glycosyl donor and Bi(OTf)₃ as a catalyst produced the highest yield of the flavan derivative 151 (76%). Electron-donating or electron-withdrawing groups on the phenyl ring of the benzoate glycosyl donor 148, however, reduced the reactivity.

Fig. 25 Lessons from the total synthesis of carambolaflavone A (2).

5. Total synthesis of flavonoid derivatives

Pyranoflavones, biflavones, and prenylated flavones are three fascinating families into which flavonoid derivatives are intriguingly divided. Flavonoid derivatives with a pyran group are called pyranoflavonoids, whereas bioflavonoids are dimeric substances made up of two monoflavonoid residues joined by C–C or C–O–C bonds. Flavone–flavone and flavanone–flavanone dimers are examples of these molecules, which may have free or methylated hydroxyl groups and frequently have substitutions at the 5-, 7-, and 4′-positions. Prenylated flavonones are the most prevalent subclass of prenylated flavonoids, which are also significant due to their lipophilic prenyl side chain. These types of flavonoids are praised for their many physiological functions, including their potent anti-inflammatory and anti-cancer properties, antioxidant protection, and prevention of atherosclerosis.^236,237

5.1. Sophoflavescenol

5.1.1. Synthetic strategy. Sophoflavescenol, a prenylated flavonoid with strong inhibitory activity against HL-60, LLC, and A549 tumor cells,²³⁸ was synthesized by the Wang group in 2015, after being extracted from Sophora flavescens by the Lee group in 2002.^239–241 It is the most selective CGMP phosphodiesterase 5 inhibitor (IC₅₀: 0.013 µM), making it a promising therapeutic option for erectile dysfunction.²⁴¹ To convert a 5-O-prenylflavonoid into the required 8-prenylated structure, their synthesis involved a regioselective, microwave-assisted Claisen rearrangement, beginning with commercially available 2,4,6-trihydroxyacetophenone 20 and MOM-protected 4-hydroxybenzaldehyde 163 (Fig. 26).

Fig. 26 Convergent strategy for the total synthesis of sophoflavescenol.

5.1.2. Synthetic route. Starting from commercially available 2,4,6-trihydroxyacetophenone 20, the base-stable and acid-labile MOM-protected 2-hydroxyacetophenone compound 124 was produced by reaction with MOM-Cl and K₂CO₃ using acetone as solvent. Then, a base-catalyzed aldol condensation reaction of compound 124 with MOM-protected 4-hydroxybenzaldehyde 163 using KOH in ethanol was performed to produce chalcone 164. The I₂/DMSO catalyzed cyclization of chalcone 164 was performed to obtain a flavone intermediate, on which the 3-OH group was installed by treatment with DMDO/acetone, generated in situ from oxone and acetone, followed by the opening of the resulting epoxide with catalytic p-TsOH to yield the flavanol 165.²⁴² Selective deprotection and prenylation of 5-MOM with dilute HCl and prenyl bromide/K₂CO₃ in acetone were consecutively performed to obtain the O-prenylated compound 166. Microwave-assisted Claisen rearrangement was performed to obtain the C-prenylated product 167 from 166 with 82% yield. The target natural sophoflavscenol 160 was synthesized by introducing methyl functionality at the 5-OH position, followed by the deprotection of all MOM groups with HCl and EtOH in 96% yield (Scheme 12).

Scheme 12 Forward synthesis of sophoflavescenol (Wang, 2015).²³⁹

5.1.3. Strategies and lessons learned from this synthesis. A major regioselectivity issue was highlighted by the fact that the ortho-rearranged product was obtained in 70% yield, with just 15% of the targeted para rearrangement product, when the usual heating approach was used for the Claisen-rearrangement of O-prenylated precursor 166 in N,N-diethylaniline at 190 °C (Fig. 27). This restriction was successfully overcome by microwave-assisted synthesis by preferentially producing the para rearrangement product with an astounding 82% yield under the same conditions.

Fig. 27 Lessons from the total synthesis of sophoflavescenol.

5.2. I3, II8-biapigenin and idiculuflavone A

5.2.1. Synthetic strategy. In 2017, the group of Lu and Yu initiated the first total synthesis of two naturally occurring unsymmetrical bioflavonoids: I3, II8-biapigenin, which was extracted from Hypericum perforatum L. by the Holzl group in 2006,^243,244 and ridiculuflavone A, whose biological studies remain unpublished. I3, II8-biapigenin exhibits various biological activities, including antidepressant,²⁴⁵ α-estrogen and benzodiazepine receptor inhibitor,²⁴⁶ as well as anti-cancer,²⁴⁷ anti-inflammatory,²⁴⁸ and neuroprotective properties.²⁴⁹ The synthesis involved a rhodium-catalyzed oxidative coupling between the corresponding alkyne intermediates and aldehyde 173 as a key step (Fig. 28).²³⁶ In this synthesis, the key alkyne intermediates were elegantly crafted through a Sonogashira reaction, coupling the iodo-derivative of corresponding flavone components with 1-ethynyl-4-methoxybenzene 171. By selectively inserting iodine at the C-8 or C-6 position using NIS in DMF, they produced the required iodo-intermediates. The corresponding flavones can then be synthesized through the standard I₂/DMSO cyclization of the chalcone products.

Fig. 28 Convergent strategy for the total synthesis of I3, II8-biapigenin.

5.2.2. Synthetic route. According to retrosynthesis analysis, the key intermediate 175 was derived from 1,3,5-trimethoxybenzene 53, which was converted into compound 7 through acetylation with BF₃·OEt₂ and acetic anhydride in an ethyl acetate medium, followed by selective demethylation using BCl₃ in DCM with 87% yield. Then the synthesis proceeded with an aldol condensation between 7 and 172 under basic conditions (KOH, EtOH/H₂O), forming chalcone, which underwent I₂/DMSO-mediated cyclization to form the required flavone 174. Subsequent regioselective iodination with NIS in DMF yielded 175 in 89% yield,²⁵⁰ followed by a high-yielding Sonogashira coupling reaction between 175 and 1-ethynyl-4-methoxybenzene 171 in the presence of PdCl₂(PPh₃)₂, CuI, CH₃CN and Et₃N, resulting in 176 with a 90% yield. After successfully synthesizing compound 176, a rhodium-catalyzed oxidative coupling with 173 produced the desired product in 70% yield,²⁵¹ which, upon complete deprotection with BBr₃ at 100 °C, afforded the target biflavonoid 169. Employing a comparable method, compound 179 was adeptly produced. They again started the synthesis from luteolin 177, which involved methylation with MeI and K₂CO₃, regioselective iodination using NIS of the alkyne compound and again methylation using MeI, followed by Sonogashira coupling with compound 171 and rhodium-catalyzed oxidative coupling with the previously utilized reagents, resulting in an intermediate, which, upon demethylation with BBr₃, yielded 179 in an impressive 90% yield (Scheme 13).

Scheme 13 Forward synthesis of I3, II8-biapigenin.

5.2.3. Strategies and lessons learned from this synthesis. Their previous work showed that apigenin with isopropyl-protecting groups has high solubility in organic solvents, which is important in any organic process.²⁵² This resulted in the cyclization alkyne precursor being synthesized from 1,3,5-trimethoxybenzene 53 after an isopropoxy group was purposefully kept at the 4′-position.^253,254 The failure of the Suzuki coupling attempts to create compound 181 with triflate 180 and borate 179 was probably caused by the ortho-substituents’ steric hindrance, which prevented transmetallation and reductive elimination (Fig. 29). The M+H peak in mass spectrometry showed that Satoh and Miura's rhodium-catalyzed oxidative coupling²⁵⁵ produced the intended product, but the yield was too low to pursue the pathway for the forward synthesis. However, by substituting a methyl group for the isopropyl group, these problems were fixed in this process.

Fig. 29 Lesson from the total synthesis of I3, II8-biapigenin.

5.3. Wikstrol A and wikstrol B

5.3.1. Synthetic strategy. Wikstrol A and B, two diastereomers with interflavonyl linkages, were first isolated from the root of Wikstroemia sikokiana by the Baba group in 1994,²⁵⁶ and later found in Wikstroemia indica.²⁵⁷ Their first total synthesis was achieved by the Yu group in 2019.²⁵⁸ Wikstrol A demonstrated inhibitory activity against aldose reductase²⁵⁹ and NO production,²⁶⁰ but the bioactivity of wikstrol B has not yet been reported. The retro-synthesis of the target compounds was masterfully executed using a conversion strategy, featuring a rhodium-catalyzed cyclization²⁵⁵ and deprotection of salicylaldehyde derivative 173 and the corresponding flavane (Fig. 30). The synthesis of flavane involved a sophisticated Sonogashira coupling between compound 185 and the corresponding iodo derivative. Remarkably, the iodo derivative was produced by cyclization and regioselective iodination of an intermediate diol, which was created via aldol condensation, reduction, and Sharpless asymmetric dihydroxylation using compounds 7 and 187.

Fig. 30 Convergent strategy for the total synthesis of wikstrol A and wikstrol B.

5.3.2. Synthetic route. The forward synthesis was initiated by converting 2,4,6-trihydroxyacetophenone 20 into its dimethyl ether 7 using CF₃SO₂Me and K₂CO₃ in an acetone medium at 70 °C, which then underwent aldol condensation with 4-methoxybenzaldehyde 185 in 60% KOH, EtOH/H₂O to produce chalcone 186 in an impressive 81% yield. Using ClCOOEt and TEA in THF, the hydroxy group of compound 186 was first protected. It was then reduced and deprotected in a single step using NaBH₄ and CeCl₃·7H₂O in EtOH at −5 °C. Finally, a reaction with TBDMSCl and imidazole produced the protected intermediate 187. Compound 188 was expertly created by Sharpless asymmetric dihydroxylation using AD-Mix-α and CH₃SO₂NH₂ in 1 : 1 ^tBuOH : H₂O, and, consecutively, the -TBDMS group was removed with TBAF/THF. The catechin derivative 189 was produced in 74% yield by hydrolyzing and cyclizing the product under the influence of acid, PPTS, and CH(OEt)₃ in DCE medium.^261,262 Compound 200 was obtained by regioselective iodination of 189 with NIS in DMF and protection with TBDMSCl in imidazole. This compound then underwent Sonogashira coupling with 1-ethynyl-4-methoxybenzene 162 in the presence of PdCl₂(PPh₃)₂, CuI, DIEA, and THF, yielding the crucial intermediate 201 in an impressive 90% yield. Ultimately, compounds 182 and 183 in 50% and 48% yields, respectively, were produced by the oxidative coupling of 201 with 173 mediated by RhCl(cod)₂ catalyst and Cu(OAc)₂·H₂O in o-xylene medium, followed by removal of the silyl group with TBAF and dealkylation with BBr₃ (Scheme 14).²⁵¹

Scheme 14 Forward synthesis of wikstral A and wikstral B (Zhang and Yu, 2019).²⁵⁸

5.3.3. Strategies and lessons learned from this synthesis. The synthesis proceeded smoothly overall, but complications arose when attempting to synthesize protected target compounds with isopropyl-protected hydroxyl groups. By using diisopropyl ether 164 as a cyclization precursor with compound 183, no intended product was produced, likely because the free hydroxyl group of compound 184 coordinated with the rhodium catalyst, impeding the reaction (Fig. 31). Therefore, they protected the hydroxy group and the TBDMS group to solve the problem.

Fig. 31 Lessons from the total synthesis of wikstral A and wikstral B.

5.4. Sophoraflavanone H

5.4.1. Synthetic strategy. In 2020, the Kan group succeeded for the first time in synthesizing sophoraflavanone H, which had been isolated in 1991 by the Komatsu group from Sophora moorcroftiana.^263,264 This type of polyphenol compound, which combines prenyl flavanone and 2,3-dihydrobenzofuran lignin moieties, is lethal to human oral carcinoma cells and has antibacterial action against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).²⁶⁵ Their synthesis approach to the target compound comprised the formation of flavanone molecules by a crucial oxy-Michael reaction of the corresponding chalcone synthesized from compound 124 and the formation of the 2,3-diaryl-2,3-dihydrobenzofuran ring via C–H insertion mediated by a rhodium carbenoid (Fig. 32).²⁶⁶ Strategically, compound 208 is used as the key starting material to gradually introduce the flavanone ring.

Fig. 32 Convergent strategy for the total synthesis of sophoraflavanone H.

5.4.2. Synthetic route. According to their retrosynthesis analysis, they synthesized the dihydrobenzofuran moiety by first selectively protecting the three hydroxyl groups in 5-bromo-2,4-dihydroxybenzoic acid 208 as a methyl ester and then selectively incorporating a MOM group at OH-4, leaving OH-2 unprotected because of its hydrogen bonding with the ester carbonyl group. After that, K₂CO₃ in DMF was used to benzylate the residual OH-2, resulting in compound 209.²⁶⁷ By using magnesium amide to facilitate ester exchange to a Weinreb amide and then reacting with aryl Grignard reagent 206, diaryl ketone 210 was created from 209.^169,268 Treatment of 210 with anhydrous hydrazine in acetic acid/ethanol at 50 °C for 5 h and subsequent MnO₂ oxidation in DCM produced unstable diaryl diazomethane 211, which underwent a smooth Rh-catalysed C–H insertion at −55 °C without purification, yielding cis-dihydrobenzofuran 213.^269,270 Following halogen–lithium exchange and DMF treatment, the benzaldehyde derivative of 213 was utilized for aldol condensation reaction with acetophenone 124 to form chalcone 214,¹⁵⁰ which then underwent reverse prenylation in the reaction with compound 215 in the presence of Pd(PPh₃)₄/THF and Claisen rearrangement in presence of N,N-diethylaniline solvent at 160 °C,²⁷¹ cyclization with (DHQ)₂Pyr catalyst,²⁷² and deprotection with BBr₃ in DCM at −78 °C to yield the desired product 203 (Scheme 15).

Scheme 15 Forward synthesis of sophoraflavanone H (Kan, 2020).²⁶⁴

5.4.3. Strategies and lessons learned from this synthesis. During the synthesis of the methylated cis-dihydrobenzofuran 220, they found considerable difficulties in removing the methyl ether. As a result, they boldly substituted tert-butyl ether 216, which maintained the exceptional enantioselectivity they had previously discovered (Fig. 33).²⁷³ Furthermore, efforts to reduce the flavone ring via a β-diketone intermediate failed because different reduction techniques, such as hydrogenolysis, one-electron reduction, and hydride reduction, had undesirable results, and the Sajiki's protocol²⁷⁴ caused unwanted cleavage of the benzyl O-7 bond in dihydrobenzofuran, yielding 219 instead.²⁷⁵

Fig. 33 Lessons from the total synthesis of sophoraflavanone H. (A) Unsuccessful chemoselective reduction; (B) unwanted hydrogenolysis; (C) functional group-dependent deprotection.

5.5. Neocyclomorusin

5.5.1. Synthetic strategy. In 2022, Shi synthesised neocyclomorusin 221, originally extracted from plants of the Moraceae family by the Fukai group in 2005,^276,277 a potent antimicrobial agent²⁷⁸ with cytotoxicity,²⁷⁹ β-secretase²⁸⁰ and cholinesterase-inhibiting effect,²⁸¹ along with anti-inflammatory activity.²⁸² Their synthesis begins with the formation of compound 222 via a base-catalyzed intramolecular S_N2 reaction on an epoxide, which is synthesized from the epoxidation of prenylated flavone 223 (Fig. 34). Flavone 223 is derived from the alkylation of β-diketone, obtained from protected hydroxybenzoic acid 224 and hydroxyacetophenone 20, utilizing the BK–VK rearrangement reaction, with 1-bromo-3-methyl-2-butene, followed by cyclization. In this particular case, the intermediate 20 originates from m-trihydroxybenzene through a Friedel–Crafts reaction with acetyl chloride.

Fig. 34 Convergent strategy for the total synthesis of neocyclomorusin.

5.5.2. Synthetic route. The Shi group's total synthesis of neocyclomorusin 221 commenced with the selective methylation and Friedel–Crafts reaction of the starting material m-trihydroxybenzene 227, first with MeOH in H₂SO₄ and then with AcCl/AlCl₃ in DCM, consecutively.²⁸³ The product formed in the reaction sequence was then protected with methoxymethyl bromide (MOMBr) in the presence of DIPEA, producing 124 in an excellent 80% yield, and when 2,4-dihydroxybenzoic acid 224 was benzylated with BnBr in the presence of K₂CO₃/acetone at 65 °C and hydrolyzed with 5 mol L⁻¹ NaOMe/MeOH, 2,4-bis(benzyloxy)benzoic acid 226 was produced in 96% yield.²⁸⁴ Carboxylic acid 226 and compound 124 were coupled in the presence of EDCI/DMAP in DCM to form an ester, which then underwent a BK-VK rearrangement in the presence of NaH/DMSO to provide β-diketone 227.^285–287 It was then further alkylated with 3,3-dimethylallyl bromide using acetone as a solvent and K₂CO₃ as a base to make compound 228, and, lastly, it underwent a sophisticated NaOAc/AcOH-mediated cyclization to yield 229 in 90% yield. In the end, the benzyl group of the flavone 229 was removed by a debenzylation reaction using Pd(OH)₂–C in 1,4-cyclohexadiene/EtOH, and the free hydroxy group was again protected with a benzoyl moiety.²⁸⁸ This resulted in compound 230 being deprotected with dilute HCl, forming a crucial intermediate in 78% yield, which, with 1,1-diethoxy-3-methyl-2-butene, produced compound 231 in a selective aldol-type condensation.²⁸⁹ Finally, a simple epoxidation of compound 231 with m-CPBA in DCM and a facile treatment with 60% KOH of the intermediate were conducted to obtain neocyclomorusin 221 in 41% yield (Scheme 16).

Scheme 16 Forward synthesis of neocyclomorusin (Shi, 2022).²⁷⁶

5.5.3. Strategies and lessons learned from this synthesis. While synthesizing the target compound, they also followed the synthetic path, having the methyl protection in place of the –MOM group. However, the removal of the methyl group from compound 235 is highly difficult using BBr₃, AlCl₃, HBr, or pyridinium hydrohalide. The instability of the isopentenyl double bond, however, prevented attempts to deprotect compound 232 with HCl/CH₃COOH and other acids, such as AlCl₃ and trifluoroacetic acid, from succeeding (Fig. 35).^290,291 During the synthesis, the deprotection of the benzyl group from compound 229 was required. However, significant side-chain alkene reduction occurred even under mild hydrogenolysis conditions (Pd–C/H₂, Pd-(OH)₂/H₂, Pd–C/HCOONH₄), complicating the synthesis. Hence, the issue was resolved by using 20% Pd(OH)₂–C with 1,4-cyclohexadiene in EtOH medium.

Fig. 35 Lessons from the total synthesis of neocyclomorusin. (A) Unsuccessful debenzylation; (B) regio-selective reduction; (C) chemo-selective de-etherification.

5.6. Kuwanons A and B

5.6.1. Synthetic strategy. In 2023, Xu, Liao, and Lu synthesized Kuwanons A and B,²⁹² two prenylated flavone isomers with antimicrobial properties, which had been extracted from the root bark of the Morus alba L. tree in 1997 by the Katayanagi group.^293–300 These substances are made from a common prenylated flavone core containing model substrate 239 (Fig. 36). The synthesis of compound 239, as usual, commenced with a β-diketone, obtained via the Baker–Venkataraman rearrangement, which was itself derived from a selective protection and esterification of commercially available 2,4-dihydroxybenzoic acid 240 and 1-(2,4,6-trihydroxyphenyl)-ethan-1-one 20, followed by a strategic acid-catalyzed cyclization to complete the transformation.

Fig. 36 Convergent strategy for the total synthesis of kuwanon A and kuwanon B.

5.6.2. Synthetic route. The synthesis started with the esterification of compound 224 using MeOH and concentrated H₂SO₄ to afford the methyl ester,³⁰¹ which was selectively alkylated with 3-chloro-3-methylbut-1-yne 240 to form compound 241. Subsequent heating in DMF at 175 °C provided cyclized compound 242 in 85% yield, followed by benzyl protection of the C-2 phenol and hydrolysis to yield intermediate 243 in 95% yield. After synthesizing MOM-protected acetophenone 124 from 1-(2,4,6-trihydroxyphenyl)-ethan-1-one by reacting with MOMBr in DCM using DIPEA, esterification with compound 243 in the presence of EDCl/DMAP in DCM led to the formation of an ester, which underwent a NaH-promoted Baker–Venkataraman (Bk–Vk) rearrangement to produce 1,3-diketone 244. Subsequent alkylation produced compound 245, and cyclization with AcONa/AcOH at 100 °C resulted in the desired product 246 in 71% yield, with the concomitant removal of the C-5 MOM group during the final cyclization step.^302,303 Following the formation of compound 246, the benzyl group was removed using excess 1-dodecantiol and NaOMe in DMF at 120 °C, giving the target compounds 247 and 248 in 35% and 55% yield, respectively.³⁰⁴ Compounds 247 and 248 were then refluxed with 3 N HCl/EtOH to produce kuwanon B and kuwanon A in the final step (Scheme 17).

Scheme 17 Forward synthesis of kuwanon A and kuwanon B (Xu, Liao and Lu, 2023).²⁹²

5.6.3. Strategies and lessons learned from this synthesis. Cyclization attempts with compound 245 using various reported conditions, including H₂SO₄/AcOH,^291,305 H₂SO₄/EtOH,³⁰⁶ CuCl₂/TMSCl,²⁸⁴ and CSA,²⁰⁷ led only to complex mixtures without yielding the desired cyclic product, likely due to the instability of MOM and isopentenyl groups under strong acidic conditions (Fig. 37). Therefore, the weak acidic mixture of AcOH/AcONa was successfully employed for the cyclization.³⁰⁷ Additionally, compound 246 was decomposed when attempts were made to remove both the benzyl and MOM groups in a single step using BBr₃, AlCl₃, 48% HBr(aq.), and CF₃COOH. Subsequent attempts to debenzylate 246 with Pd–C/HCOONH₄, Pd–C/HCOOH, or Pd(OH)₂–C/cyclohexadiene resulted in a significant alkene reduction. Hence, highly nucleophilic dodecane-1-thiol in the presence of freshly prepared NaOMe was used for the debenzylation.

Fig. 37 Lessons from the total synthesis of kuwanon A and kuwanon B. (A) Deprotection cyclization; (B) regioselective deprotection; (C) mild debenzylation.

5.7. Pongaflavone

5.7.1. Synthetic strategy. Pongaflavone, a secondary metabolite isolated from the root of the tree Pongamia pinnata L.,^308,309 was synthesized by He and the Dong group in 2023.³¹⁰ It exhibits notable cytotoxicity against M156 and HepG2 cell lines (IC₅₀ values of 0.5 ± 0.08 µM),³¹¹ antimycobacterial activity against Mycobacterium tuberculosis H37Ra (MIC: 15 µg mL⁻¹),³¹² and significant inhibition of LPS-induced NO release in BV-2 microglial cells (IC50; 15.2 ± 5.4 µM).^313,314 The compound was successfully synthesized in 2023 by the Dong group with an impressive yield under considerably mild conditions.³¹⁰ The key pyran ring structural components are easily integrated through a Claisen rearrangement and cyclization with 3-chloro-3-methylbut-1-yne 240 (Fig. 38). Through a base-catalyzed aldol condensation between compound 252 and benzaldehyde 253, the target molecule's flavone part was elegantly constructed, paving the way for chalcone cyclization under AFO reaction conditions.

Fig. 38 Convergent strategy for the total synthesis of pongaflavone.

5.7.2. Synthetic route. The total synthesis of pongaflavone started with the synthesis of compound 250, starting with the selective protection of the 4-hydroxyl group of compound 252 with the methoxymethyl (-MOM) group in the presence of DIPEA using DCM as solvent at 0 °C,²³⁷ followed by KOH-catalyzed aldol condensation with benzaldehyde to give chalcone 254.³¹⁵ AFO reaction was used to perform the oxidative cyclization of chalcone 254 with NaOH and H₂O₂ in MeOH. The resultant flavone intermediate 255 was methylated with methyl iodide in the presence of K₂CO₃, and the –MOM group was deprotected with aq. HCl at 60 °C to yield compound 256. Alkylation of compound 256 was done with 3-chloro-3-methylbut-1-yne 240 in the presence of KI with K₂CO₃ and CuI catalyst to produce compound 257,³¹⁶ which was then subjected to Claisen rearrangement/cyclization in DMF at 175 °C to successfully synthesize pongaflavone 250 (Scheme 18).

Scheme 18 Forward synthesis of pongaflavone (Dong, 2023).³¹⁰

5.7.3. Strategies and lessons learned from this synthesis. After the successful synthesis of intermediate 258 via the Bk–Vk reaction, followed by cyclization,³¹⁷ the DMDO-mediated oxidation step failed to afford compound 259 (Fig. 39). This is probably because of the instability of the olefin between C-3″ and C-4″ of compound 258 under strong oxidants (DMDO).³¹⁸ The attempt to synthesize compound 259 by the AFO route also failed, most likely because the olefin's electron cloud density at C-3″/4″ was higher than that at the C-alpha/beta double bond. This made the olefin more susceptible to oxidation by peroxide (H₂O₂), which produced a variety of byproducts. Based on these results, it was concluded that to obtain the target compound, the flavonol framework in pongaflavone 250 must be constructed before the dihydropyran ring is installed at C-7/C-8 positions.

Fig. 39 Lessons from the total synthesis of pongaflavone. (A) Chemoselective oxidation of flavone olefin; (B) oxidative cyclization of chalcone.

5.8. Lupinifolin

5.8.1. Synthetic strategy. In 2024, the synthesis of lupinifolin, extracted from a plant belonging to the family of Fabaceae by the Sutthivaiyakit group in 2009,^319,320 was initiated by Xu's group from compound 262 (Fig. 40).²³⁷ It exhibits remarkable potential as an antibacterial agent^321–323 and demonstrates strong inhibition of biofilm formation in multidrug-resistant (MDR) enterococcal bacteria.³²⁴ The construction of compound 262, having a prenylated flavanone core, was achieved through Mitsunobu reaction, followed by a para-Claisen/Cope rearrangement, and an electrocyclization (to make the pyrane ring) starting from compound 263. By using a chalcone, which is prepared using aldol condensation with commercially available 2,4,6-trihydroxy acetophenone monohydrate 20 and benzaldehyde 163, in an oxy-Michael reaction, compound 263 was synthesized.

Fig. 40 Convergent strategy for the total synthesis of lupinifolin.

5.8.2. Synthetic route. The synthesis began with 2,4,6-trihydroacetophenone 20, which was protected using methoxymethyl bromide (MOM-Br) and DIPEA in dry DCM to yield the 2,4-di-MOM protected intermediate in 84% yield, which then undergoes a base-catalyzed aldol condensation with MOM-protected p-hydroxybenzaldehyde 163, resulting in a 95% yield of chalcone 121.^302,325 Through careful optimization, chalcone 164 was cyclized using sodium acetate, yielding a 67% equilibrium of product, which, after removing the –MOM groups with diluted HCl, transformed into compound 264 with an impressive 88% yield.^{237,326–328} Treating 264 with 3-methyl-2-butenal and Ca(OH)₂/MeOH, 6,7-pyran, adduct 265 was synthesized in 45% yield. Finally, under Mitsunobu conditions using DEAD and PPh₃ in THF, compound 266 was formed by coupling 265 with 3-methylbut-2-en-1-ol. In the presence of Eu(fod)₃, compound 266 underwent a para-rearrangement and concomitant hydrolysis using KOH/MeOH, yielding lupinifolin 261 with an impressive yield (Scheme 19).³²⁹

Scheme 19 Forward synthesis of lupinifolin (Xu, 2024).²³⁷

5.8.3. Strategies and lessons learned from this synthesis. The 6,7-pyrane adduct 265 was the only product obtained by treating molecule 264 with 3-methyl-2-butenal and Ca(OH)₂/MeOH in this synthesis, demonstrating remarkable selectivity (Fig. 41). Interestingly, despite the apparent structural similarities between these sites in flavanone 264, no 7,8-cyclized product appeared, demonstrating a remarkable degree of reaction specificity.^330–332

Fig. 41 Lessons from the total synthesis of lupinifolin. (A) Regioselective pyrane adduct formation.

5.9. Osajin and scandenone

5.9.1. Synthetic strategy. In 2024, Zhao and Jin achieved the synthesis of two remarkable natural flavonoid compounds, osajin and scandenone,³¹⁵ which are known for their potent abilities to inhibit the proliferation of various cancer cells and exhibit significant anti-inflammatory properties.^333,334 The compounds were isolated from the tree, Derris scandens, by Babu in 2010.³³⁵ Targeting the C-7 hydroxy group of molecules 270, which acts as a common intermediary for both natural products, the compounds were produced by chemoselective propargylation (Fig. 42). Compound 270's sequential reactions resulted from an intramolecular cyclization and nucleophilic substitution reaction concomitant with aromatic Claisen rearrangement at 250 °C, which led to the formation of the desired natural products. The intermediate 270 was produced by Suzuki cross-coupling reactions, aldol condensation, intramolecular iodoetherification, and elimination using 1-(2,4,6-trihydroxyphenyl)-ethan-1-one 20, 1,1-dimethoxy-N,N-dimethylmethanamine 272, and 4-hydroxyphenyl boronic acid 271.

Fig. 42 Convergent strategy for the total synthesis of osajin and scandenone.

5.9.2. Synthetic route. In order to create the compounds, the free hydroxyl group of 20 was protected with a methyl group using acetone, dimethyl sulfate, and K₂CO₃, and the intermediate was subsequently reacted with 272 in DMF at 80 °C to produce compound 273 in 88% yield. Compound 273 and I₂, pyridine, and MeOH underwent an addition reaction to produce the iodo-derivative of the cyclized flavone intermediate. Then, using PdCl₂(dppf) as a catalyst in 1,4-dioxane/H₂O at 50 °C, with an 86% yield, this intermediate underwent a Suzuki cross-coupling reaction with (4-hydroxyphenyl)boronic acid 271 to form the main tricyclic core containing compound 274.³³⁶ Treatment of compound 274 with 40% aqueous HBr in refluxing water, followed by chemoselective propargylation of the C-7 hydroxy group, produced compound 275 in 72% yield. With yields of 52% and 41%, respectively, compounds 276 and 277 were produced by cyclization of 275 in the presence of diethylaniline at 250 °C for 1 h.³³⁷ In the two processes, compound 278 was produced with 64% yield by reacting compound 276 with TBSCl and imidazole in DCM medium to protect its more reactive C4′-hydroxy group with the TBS group and subsequent nucleophilic substitution reaction with 3,3-dimethylallyl bromide in DMF in the presence of NaH as a base. Compound 278 underwent Claisen rearrangement when it was treated with montmorillonite K₁₀ in DCM, and further deprotection of the intermediate with TBAF in THF gave the target compound 268 in an excellent 90% yield. TBS-protected compound 277 was prenylated with 225 and NaH in DMF to produce compound 279 in 74% yield. The rearrangement product was then produced in 76% yield by reacting with Eu(fod)₃ in CHCl₃ at 60 °C for 8 h. Natural product 269 was obtained in 93% yield after the 4-OH group of the rearrangement intermediate was deprotected with TBAF in THF (Scheme 20).

Scheme 20 Forward synthesis of osajin and scandenone (Zhao and Jin, 2024).³¹⁵

5.9.3. Strategies and lessons learned from this synthesis. Initially, the reaction yielded only 20% to 36% of the cyclized flavone intermediate's iodo derivative. However, the yield increased after the addition of one equivalent of pyridine. The Suzuki cross-coupling reaction between the same iodo intermediate and 271 under normal conditions Pd(OAc)₂/MeOH/NaCO₃, yielded only 40% of product 274, with minimal improvement from changes in solvents and bases like Pd(OAc)₂/DMF/K₂CO₃ and Pd(PPh₃)₄/DMF/K₂CO₃ at different temperatures; however, increasing the temperature to 50 °C improved the yield to 60%.^338,339

6. Conclusion

On account of the diverse biological activities and therapeutic potential of flavonoids, much effort has been devoted to their total synthesis within the last few decades. Here, we have highlighted synthetic efforts for twenty distinct flavonoid analogues of high biomedical importance (Fig. 43). We have described the synthetic routes to access them, including the challenges and limitations of current approaches. In this exceptionally elegant synthesis of flavonoid molecules, the pivotal benzo-γ-pyrone ring core was exquisitely constructed via an aldol condensation between an acetophenone moiety and an aldehyde scaffold, yielding the chalcone intermediate, which then cyclized efficiently in the presence of iodine to produce the flavone. Alternatively, the benzo-γ-pyrone ring core was ingeniously synthesized from a 1,3-diketone intermediate, itself derived through a Baker–Venkataraman rearrangement of a 2-hydroxy-protected acetophenone ester, followed by cyclization in the presence of acid. For highly intricate structures, an extraordinary Rh-catalyzed cyclization of alkynes with protected aldehydes was masterfully employed. The creation of O- or C-glycosyl derivatives of these flavone frameworks unfolds through an enchanting coupling between the flavone core and a meticulously selected glycosyl acceptor, orchestrated under the influence of a masterfully chosen catalyst.

Fig. 43 Summary of flavonoids and their glycosides.

During the synthesis of flavonoid-type natural products, several significant challenges remain to be addressed:

1. Regioselective functionalization of the B-ring of the quercetin nucleus, particularly for the construction of benzofuran moieties, continues to be a formidable challenge (from the synthesis of houttuynoid B).

2. The development of efficient glycosyl donors and suitable activated catalysts remains necessary for the synthesis of phenolic glycosides in the presence of a flavone enone moiety (from the synthesis of agalloside, houttuynoid A, etc).

3. Functionalization of the chalcone scaffold to access flavone cores bearing electron-withdrawing groups is particularly challenging due to the predominance of retro-aldol pathways under such conditions (from the synthesis of vicenin-2).

4. Achieving regioselective oxidation of the benzopyran core from the synthesis of flavone-type molecules from the flavan core, while retaining free phenolic hydroxyl groups, remains difficult (from the synthesis of schaftoside).

5. Rhodium-catalysed cross-coupling reactions involving unprotected hydroxy flavones are still inefficient, limiting the development of more atom-economical methodologies, as the synthesis of biflavones faces severe obstacles in other Pd-catalysed conventional cross-coupling reactions (from the synthesis of wikstral A and B).

6. Chemoselective reduction of the flavone enone moiety remains insufficiently developed. Moreover, the stereoselective synthesis of the flavanone core from chalcone precursors using modern synthetic approaches is highly desirable to overcome the current limitations (from the synthesis of sophoraflavanone H).

7. The synthesis of flavanol cores from flavones predominantly relies on oxone-mediated oxidation; however, this approach is highly functional-group dependent. Alternatively, the AFO reaction of chalcones to flavanols often leads to the undesired formation of the aurone framework (from the synthesis of pongaflavone).

The total synthesis of flavonoid-type natural compounds represents a fascinating frontier, offering vast potential for groundbreaking innovations, despite its numerous challenges, with the diversity of yet unidentified molecules. The synthesis of these complex flavanol molecules has led to the development of new catalysts, reagents, and reactions with the potential to transform the field of natural product synthesis. We hope this review will encourage synthetic chemists to further develop innovative methodologies that will advance the frontiers of natural product synthesis and address its intrinsic challenges.

7. Conflicts of interest

There are no conflicts to declare.

8. Data availability

The data that support the findings of this study are available in the published research articles.

9. Acknowledgements

The authors appreciate the financial support from the SERB and MoE-STARS, India, (SRG/2023/000034 & MoE-STARS/STARS-2/2023–0126) and the Indian Institute of Technology Hyderabad (SG-132). D.G thanks the UGC (University Grants Commission) India for his PhD fellowship.

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