Perplexing Polyphenolics: The Isolations, Syntheses, Reappraisals, and Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids from 2016 to 2022

Flavonoids, isoflavonoids, neoflavonoids, and their various subcategories are polyphenolics–an extensive class of natural products. These compounds are bioactive and display multiple activities, including anticancer, antibacterial, antiviral, antioxidant, and neuroprotective activities. Thus, these compounds can serve as leads for therapeutic agents or targets for complex synthesis; they are coveted and routinely isolated, characterized, biologically evaluated, and synthesized. However, data regarding the compounds’ sources, isolation procedures, structural novelties, bioactivities, and synthetic schemes are often dispersed and complex, a dilemma this review aims to address. To serve as an easily accessible guide for researchers wanting to apprise themselves of the latest advancements in this subfield, this review summarizes seventy-six (76) articles published between 2016 and 2022 that detail the isolation and characterization of two hundred and forty-nine (249) novel compounds, the total and semisyntheses of thirteen (13) compounds, and reappraisals of the structures of twenty (20) previously reported compounds and their bioactivities. This article also discusses new synthetic methods and enzymes capable of producing or modifying flavonoids, isoflavonoids, or neoflavonoids.


Introduction
Natural products-compounds isolated from natural sources-and their derivatives represent an immense segment of modern medicine: approximately 25% of all Food and Drug Administration (FDA) and European Medical Agency (EMA) approved drugs are plant-based [1]. Additionally, a third of FDA-approved drugs between 1990 and 2010 were either natural products or a derivative of them [2]. Furthermore, the World Health Organization's list of essential medicines features more than twenty-two (22) compounds sourced exclusively from angiosperms [3]. Another estimate lists 40% of all available medicines as either natural products or derivatives [4,5].
Plants carry a massive reservoir of secondary metabolites that are potent and bioactive molecules. Millions of years of evolutionary pressures have fine-tuned these molecules to serve as effective defenses against both endogenous and exogenous threats, boosting their host's survivability and explaining their potencies as antiviral, antibacterial, and anticancer agents [6][7][8]. Apart from their biological activities, natural products, under their structural complexity, are coveted targets in synthesis. Their novel structures help

Isolation Methods
In this review, articles were selected from 2016 to 2022, and no novel method of isolating flavonoids, isoflavonoids, or neoflavonoids from mixtures extracted from natural sources was discussed, as apparent in Table 1. Conventional procedures involve extracting the source, often dried plant material, with a polar solvent, usually ethanol, ethyl acetate, or methanol. Next, the mixture is filtered, and the filtrate (crude extract) is concentrated and partitioned with organic solvents. Nonpolar solvents such as petroleum ether or n-hexane remove fatty acids. Finally, column chromatography separates and purifies polar phases to yield pure compounds.

Isolation Methods
In this review, articles were selected from 2016 to 2022, and no novel method of isolating flavonoids, isoflavonoids, or neoflavonoids from mixtures extracted from natural sources was discussed, as apparent in Table 1. Conventional procedures involve extracting the source, often dried plant material, with a polar solvent, usually ethanol, ethyl acetate, or methanol. Next, the mixture is filtered, and the filtrate (crude extract) is concentrated and partitioned with organic solvents. Nonpolar solvents such as petroleum ether or n-hexane remove fatty acids. Finally, column chromatography separates and purifies polar phases to yield pure compounds. Wulfenia amherstiana Extracted with ethanol [24] 10 Lonicera hypoglauca Extracted thrice with 85% ethanol; concentrated and extracted with petroleum ether and ethyl acetate [25]

38-44 Tephrosia linearis
Extracted thrice with dichloromethane and methanol; concentrated and partitioned with water and n-hexane; aqueous layer was further partitioned with ethyl acetate [33]

Onopordum alexandrinum
Extracted thrice with methanol, concentrated, and partitioned with ethyl acetate and water; the aqueous phase was further partitioned with butanol [38]
Extracted five times with methanol; concentrated and resuspended in water; extracted with dichloromethane and ethyl acetate [41] 82

Tetraena mongolica
Extracted thrice with methanol; concentrated and resuspended in water; partitioned with ethyl acetate and n-butanol [48]

182-184 Berchemia berchemiifolia
Extracted with methanol; concentrated and resuspended in water; partitioned with chloroform, ethyl acetate, and n-butanol [66] 185 Arcytophyllum thymifolium Extracted with n-hexane, chloroform, and methanol [67] 186-189 Althaea officinalis Extracted with methanol and water (1:1) and centrifuged; the resulting pellet was again extracted with methanol and water (1:1); concentrated and high molecular weight compounds were precipitated by adding the extract into cold ethanol; the suspension was centrifuged, and ethanol was removed from the supernatant [68]

Carthamus tinctorius
Extracted with 95% and 70% ethanol; concentrated and resuspended in water; partitioned with petroleum ether and ethyl acetate [71]

Structural Novelties
The presence of various subclasses in the isolated compounds is listed in Figure 2. As shown, flavonoid subunits were the most common, followed by isoflavonoid subunits. Only one example of a neoflavonoid (a neoflavanol) was found.  Compound 1 was isolated from the roots, stem, leaves, and flowers of Strobilanthes kunthianus and is a flavone glycoside (Figure 3.) [19]. Similarly, compound 2 is also a flavone and was isolated from the aerial parts of Adenosma bracteosum [20]. Compounds 3 and 4 were isolated from the aerial parts and roots of Glandularia selloi and are glycosylated derivatives of chrysoeriol. They are acylated disaccharides and are the first acylated flavone O-glycosides to be isolated from the Verbenaceae family [21]. Compounds 5 and 6 were isolated from the gametophytes of Ceratodon purpureus and were fully characterized for the first time. Both compounds are dimers, with compound 5 containing two flavone subunits and compound 6 containing one flavone and one flavanone subunit [22]. The flavone C-glycosides, compounds 7 and 8, were isolated from the leaves of Afrocarpus gracilior [23]. A trimethylated flavone, compound 9, was extracted by analyzing the entire Wulfenia amherstiana plant [24]. Compound 10, a methoxylated flavone, contains a 2′,4′,5′trisubstituted B ring, a motif rarely encountered in nature. It was isolated from the stems and leaves of Lonicera hypoglauca [25]. Compounds 11-14 were isolated from Fuzhuan brick tea, produced from the leaves of Camellia sinensis. Compounds 11 and 12 represent quercetin acyl glycosides, while 13 and 14 are kaempferol acyl glycosides [26]. Compounds 15-16 were isolated from the twigs of Artocarpus nigrifolius and are prenylated flavones [27]. Compound 17 is a tetramethoxylated flavone isolated from the leaves and twigs of Murraya tetramera [28]. Compounds 18-25 are flavone glucoside cyclodimers and were isolated by analyzing the whole Palhinhaea cernua herb; they are the first flavonoid glucoside cyclodimers to be isolated from the Lycopodiaceae family. They also possess a unique cyclobutane ring and are truxinate esters: compounds 18, 19, 21, and 23 are βtruxinates, while compounds 20, 22, 24, and 25 are μ-truxinates. Furthermore, compounds 19 and 20, 21 and 22, and 23 and 24 represent three pairs of stereoisomers [29]. Compound 1 was isolated from the roots, stem, leaves, and flowers of Strobilanthes kunthianus and is a flavone glycoside ( Figure 3) [19]. Similarly, compound 2 is also a flavone and was isolated from the aerial parts of Adenosma bracteosum [20]. Compounds 3 and 4 were isolated from the aerial parts and roots of Glandularia selloi and are glycosylated derivatives of chrysoeriol. They are acylated disaccharides and are the first acylated flavone O-glycosides to be isolated from the Verbenaceae family [21]. Compounds 5 and 6 were isolated from the gametophytes of Ceratodon purpureus and were fully characterized for the first time. Both compounds are dimers, with compound 5 containing two flavone subunits and compound 6 containing one flavone and one flavanone subunit [22]. The flavone C-glycosides, compounds 7 and 8, were isolated from the leaves of Afrocarpus gracilior [23]. A trimethylated flavone, compound 9, was extracted by analyzing the entire Wulfenia amherstiana plant [24]. Compound 10, a methoxylated flavone, contains a 2 ,4 ,5trisubstituted B ring, a motif rarely encountered in nature. It was isolated from the stems and leaves of Lonicera hypoglauca [25]. Compounds 11-14 were isolated from Fuzhuan brick tea, produced from the leaves of Camellia sinensis. Compounds 11 and 12 represent quercetin acyl glycosides, while 13 and 14 are kaempferol acyl glycosides [26]. Compounds 15-16 were isolated from the twigs of Artocarpus nigrifolius and are prenylated flavones [27]. Compound 17 is a tetramethoxylated flavone isolated from the leaves and twigs of Murraya tetramera [28]. Compounds 18-25 are flavone glucoside cyclodimers and were isolated by analyzing the whole Palhinhaea cernua herb; they are the first flavonoid glucoside cyclodimers to be isolated from the Lycopodiaceae family. They also possess a unique cyclobutane ring and are truxinate esters: compounds 18, 19, 21, and 23 are β-truxinates, while compounds 20, 22, 24, and 25 are µ-truxinates. Furthermore, compounds 19 and 20, 21 and 22, and 23 and 24 represent three pairs of stereoisomers [29].
Compound 26, a flavone glucoside, was isolated from the aerial parts of Agastache rugosa (Figure 4.) [30]. Compounds 27-34 are flavones that were isolated from the leaves of Celmisia viscosa. Their O-acylations are noteworthy as flavonoids with acylated core phenols are rare. Additionally, compound 31 contains a naturally occurring 3-methylbutanoate moiety, an unprecedented discovery. Similarly, flavonoids with 2-methylbutanoate and 2-methylpropanoate substituents are rare, giving compounds 30, 27, and 32 particular importance [31]. Compounds 35-37 are acetylated flavone glycosides isolated from the aerial parts of Elsholtzia ciliata [32]. Compounds 38-44 were isolated from the aerial parts of Tephrosia linearis. Compounds 38-41 contain a fused pyran-flavone core, and compounds 43 and 44 are flavanones [33]. Compounds 45-48, all prenylated flavones, were isolated from the twigs of Morus nigra [34]. Compounds 49 and 50, a flavanone and flavone, respectively, are chamanetin derivatives and feature C-benzylation. They were isolated from the leaves, stem, and root bark of Sphaerocoryne gracilis [35]. Compounds 51 and 52 are prenylated flavones isolated from the aerial parts of Epimedium brevicornum. The latter also contains a fused furan ring [36]. Compounds 53 and 54, a furanoflavanone and a furanoflavone, respectively, were isolated from the vine stems of Millettia velutina [37]. Compound 55 is an acylated flavonoid glucoside that was isolated from the aerial parts of Onopordum alexandrinum [38]. Compound 26, a flavone glucoside, was isolated from the aerial parts of Agastache rugosa (Figure 4.) [30]. Compounds 27-34 are flavones that were isolated from the leaves of Celmisia viscosa. Their O-acylations are noteworthy as flavonoids with acylated core phenols are rare. Additionally, compound 31 contains a naturally occurring 3-methylbutanoate moiety, an unprecedented discovery. Similarly, flavonoids with 2-methylbutanoate and 2-methylpropanoate substituents are rare, giving compounds 30, 27, and 32 particular importance [31]. Compounds 35-37 are acetylated flavone glycosides isolated from the aerial parts of Elsholtzia ciliata [32]. Compounds 38-44 were isolated from the aerial parts of Tephrosia linearis. Compounds 38-41 contain a fused pyran-flavone core, and compounds 43 and 44 are flavanones [33]. Compounds 45-48, all prenylated flavones, were isolated from the twigs of Morus nigra [34]. Compounds 49 and 50, a flavanone and flavone, respectively, are chamanetin derivatives and feature C-benzylation. They were isolated from the leaves, stem, and root bark of Sphaerocoryne gracilis [35]. Compounds 51 and 52 are prenylated flavones isolated from the aerial parts of Epimedium brevicornum. The latter also contains a fused furan ring [36]. Compounds 53 and 54, a furanoflavanone and a furanoflavone, respectively, were isolated from the vine stems of Millettia velutina [37]. Compound 55 is an acylated flavonoid glucoside that was isolated from the aerial Compounds 56-59 are (3,3 )-linked biflavanone O-methyl ethers and were isolated from the bark of Ouratea spectabilis. Compounds 57, 58, and 59 are mono-, bi-, and trimethoxylated, respectively ( Figure 5) [39]. Compounds 60-75 are biisoflavones that were isolated from Streptomyces sp. HDN154127, a Takla Makan desert-derived strain. Their dimeric and chlorinated forms are rare, and an actinomycete producing both features in an isoflavone has not been reported earlier. Compounds 60-65 are the first biisoflavone atropisomers isolated from a bacterial culture [40]. Compounds 76-81 are isoflavones isolated from the leaves of Vatairea guianenis. They all feature C8 prenylation, with compounds 76-78 displaying chain prenylation and compounds 79-81 displaying ring-closed prenylation [41]. Compound 82 is a flavanonol isolated from Dietes bicolor's leaves. It features tetrasubstitution and has a fully oxygenated A-ring with an unsubstituted B-ring, rare motifs [42]. Compounds 83-91 are prenylated isoflavonoids isolated from the aerial parts Compounds 56-59 are (3,3″)-linked biflavanone O-methyl ethers and were isolated from the bark of Ouratea spectabilis. Compounds 57, 58, and 59 are mono-, bi-, and trimethoxylated, respectively ( Figure 5) [39]. Compounds 60-75 are biisoflavones that were isolated from Streptomyces sp. HDN154127, a Takla Makan desert-derived strain. Their dimeric and chlorinated forms are rare, and an actinomycete producing both features in an isoflavone has not been reported earlier. Compounds 60-65 are the first biisoflavone atropisomers isolated from a bacterial culture [40]. Compounds 76-81 are isoflavones isolated from the leaves of Vatairea guianenis. They all feature C8 prenylation, with compounds 76-78 displaying chain prenylation and compounds 79-81 displaying ring-closed prenylation [41]. Compound 82 is a flavanonol isolated from Dietes bicolor's leaves. It features tetrasubstitution and has a fully oxygenated A-ring with an unsubstituted B-ring, rare motifs [42]. Compounds 83-91 are prenylated isoflavonoids isolated from the aerial parts of Glycyrrhiza uralensis. Compounds 83-87 are isoflavanones, while compounds 88-91 are isoflavans. Additionally, compound 90 contains a formyl group at C-6, a rarity among flavonoids and isoflavonoids [43]. Compound 92 was isolated from the leaves of Sabia limoniacea. It is a flavone disaccharide and a quercetin derivative ( Figure 6) [44]. Compound 93 is a flavone glucoside derivative isolated from the aerial parts of Atriplex tatarica [45]. Compounds 94 and 95 are biflavanones isolated from the stem bark of Ochna holstii. Compound 95 is a methoxy derivative of 94, consistent with the O-methylation present in flavonoids [46]. Compound 96 was isolated from the shoots of Myrsine africana and is a flavone featuring five hydroxyl substitutions on its core [47]. Compound 97 is a glycosylated quercetin derivative and was isolated from the leaves of Tetraena mongolica [48]. Compounds 98-101 were isolated from the leaves of Drosera magna. Compounds 98-100 are flavone diglycosides, while compound 101 is a flavan glycoside [49]. Compounds 102-104 were isolated from the roots of Phyllanthus acidus. Compounds 102 and 103 are the first sulfonic acid-containing flavanone and isoflavone to be reported, respectively. Additionally, compound 104 is a sulfonic acid-containing flavonol [50]. Compounds 105-109 are flavones that were isolated from the leaves of Mimosa caesalpiniifolia. They are apigenin derivatives [51]. Compounds 110 and 111 were isolated from the leaves of Ormosia arborea. They are A-type proanthocyanidins-containing two flavan subunits-linked to a p-coumaroyl unit [52]. Compound 112 is a biflavone that was isolated from the aerial parts of Salvia circinate [53]. Compound 92 was isolated from the leaves of Sabia limoniacea. It is a flavone disaccharide and a quercetin derivative ( Figure 6) [44]. Compound 93 is a flavone glucoside derivative isolated from the aerial parts of Atriplex tatarica [45]. Compounds 94 and 95 are biflavanones isolated from the stem bark of Ochna holstii. Compound 95 is a methoxy derivative of 94, consistent with the O-methylation present in flavonoids [46]. Compound 96 was isolated from the shoots of Myrsine africana and is a flavone featuring five hydroxyl substitutions on its core [47]. Compound 97 is a glycosylated quercetin derivative and was isolated from the leaves of Tetraena mongolica [48]. Compounds 98-101 were isolated from the leaves of Drosera magna. Compounds 98-100 are flavone diglycosides, while compound 101 is a flavan glycoside [49]. Compounds 102-104 were isolated from the roots of Phyllanthus acidus. Compounds 102 and 103 are the first sulfonic acid-containing flavanone and isoflavone to be reported, respectively. Additionally, compound 104 is a sulfonic acid-containing flavonol [50]. Compounds 105-109 are flavones that were isolated from the leaves of Mimosa caesalpiniifolia. They are apigenin derivatives [51]. Compounds 110 and 111 were isolated from the leaves of Ormosia arborea. They are A-type proanthocyanidins-containing two flavan subunits-linked to a p-coumaroyl unit [52]. Compound 112 is a biflavone that was isolated from the aerial parts of Salvia circinate [53].   (Figure 7). Additionally, patulein glycosides previously isolated from the Amaranthaceae family only featured 3-O-glucosides, not 3-O-galactosides. This rarer substitution is present in compound 113 [54]. Compounds 122-129 are isoflavans isolated from the Brazilian Red Propolis; bees that produce the propolis feed on Dalbergia ecastophyllum. They all contain a benzofuran moiety [55]. Compounds 130-138 are complex flavanones and were isolated from the leaves and twigs of Cryptocarya  This rarer substitution is present in compound 113 [54]. Compounds 122-129 are isoflavans isolated from the Brazilian Red Propolis; bees that produce the propolis feed on Dalbergia ecastophyllum. They all contain a benzofuran moiety [55]. Compounds 130-138 are complex flavanones and were isolated from the leaves and twigs of Cryptocarya metcalfiana [56]. Compounds 139 and 140 were isolated from the leaves of Woodfordia uniflora. Compound 139 is a mixture of two enantiomeric flavans, while compound 140 is a flavone and a quercetin derivative [57]. Compounds 141 and 142 were isolated from the shoots of Cyclopia genistoides and were completely characterized. They are flavanones and represent a pair of diastereomeric naringenin derivatives [58]. Compound 143 is a flavanone isolated from the fruits and leaves of Melodorum siamensis [59]. Compounds 144-148 are flavans isolated from the inner bark of Pinus massoniana. Compounds 144-147 are seco B-type procyanidin dimers, with compounds 144 and 145 optical antipodes of gambiriin A1 and A2, respectively. Similarly, compounds 146 and 147 are a pair of optical antipodes, while compound 148 is the first seco B-type procyanidin trimer [60]. Compounds 149-155 are prenylated flavanones isolated from the roots and rhizomes of Sophora tonkinensis [61]. Compounds 156-168 are C-methylated flavanone glycosides isolated from the rhizomes of Pentarhizidium orientale ( Figure 8). Compounds 156-163 are matteuorienates A-C analogs and contain a characteristic 3-hydroxy-3-methylglutaryl (HMG) moiety [62]. Compound 169 is a flavone isolated from the aerial parts of Houttuynia cordata. It is the first houttuynoid containing a bis-houttuynin chain connected to a flavonoid core to be reported [63]. Compounds 170-177 are flavonoid-based 3′-O-β-D-glucopyranosides with an acylated glucopyranosyl moiety. They were isolated from  teuorienates A-C analogs and contain a characteristic 3-hydroxy-3-methylglutaryl (HMG) moiety [62]. Compound 169 is a flavone isolated from the aerial parts of Houttuynia cordata. It is the first houttuynoid containing a bis-houttuynin chain connected to a flavonoid core to be reported [63]. Compounds 170-177 are flavonoid-based 3 -O-β-D-glucopyranosides with an acylated glucopyranosyl moiety. They were isolated from the aerial parts of Saxifraga spinulosa. Additionally, compounds 170-173 and 177 are flavanones, compounds 174 and 175 are flavanonols, and compound 176 is a flavonol [64]. Compounds 178-181 contain glucosylated flavanones containing 1,3-diaryl propane C6-C3-C6 units ( Figure 9). They were isolated from the fruits of Mansoa hirsute. Additionally, compound 178 is diglucosylated, while compounds 179-181 are triglucosylated and are isomeric with mansoin A [65]. Compounds 182-184 are flavanone 5-O-diglycosides that were isolated from the unripe fruits of Berchemia berchemiifolia. Compounds 182 and 183 are diastereomers and eriodictyol derivatives, while 184 is a naringenin derivative [66]. Compound 185 is prenylated flavanone and was isolated from the aerial parts of Arcytophyllum thymifolium. It is also an eriodictyol derivative [67]. Compounds 186-189 are flavones isolated from the roots of Althaea officinalis. They are hypolaetin-O-sulfoglycosides [68]. Compounds 190-194 were isolated from the roots and rhizomes of Glycyrrhiza uralensis. Compounds 190-192 are isoflavans; compound 193 is a neoflavanol, and compound 194 is an isoflavone [69]. Compounds 195-198 were isolated from the white petals of Impatiens balsamina. They are biflavonoid glycosides containing an isoflavanone and flavone subunit [70]. However, the initially reported epoxide motif was reappraised and replaced with a fused dihydrofuran motif (compounds 438-441) [79]. Compound 199 is a quinochalcone C-glycoside containing a flavone linked by a methylene bridge. It was isolated from the florets of Carthamus tinctorius, which is the only known source of the extremely rare C-glycosylated quinochalcones [71]. Compounds 178-181 contain glucosylated flavanones containing 1,3-diaryl propane C6-C3-C6 units ( Figure 9). They were isolated from the fruits of Mansoa hirsute. Additionally, compound 178 is diglucosylated, while compounds 179-181 are triglucosylated and are isomeric with mansoin A [65]. Compounds 182-184 are flavanone 5-O-diglycosides that were isolated from the unripe fruits of Berchemia berchemiifolia. Compounds 182 and 183 are diastereomers and eriodictyol derivatives, while 184 is a naringenin derivative [66]. Compound 185 is prenylated flavanone and was isolated from the aerial parts of Arcytophyllum thymifolium. It is also an eriodictyol derivative [67]. Compounds 186-189 are flavones isolated from the roots of Althaea officinalis. They are hypolaetin-O-sulfoglycosides [68]. Compounds 190-194 were isolated from the roots and rhizomes of Glycyrrhiza uralensis. Compounds 190-192 are isoflavans; compound 193 is a neoflavanol, and compound 194 is an isoflavone [69]. Compounds 195-198 were isolated from the white petals of Impatiens balsamina. They are biflavonoid glycosides containing an isoflavanone and flavone subunit [70]. However, the initially reported epoxide motif was reappraised and replaced with a fused dihydrofuran motif (compounds 438-441) [79]. Compound 199 is a quinochalcone C-glycoside containing a flavone linked by a methylene bridge. It was isolated from the florets of Carthamus tinctorius, which is the only known source of the extremely rare C-glycosylated quinochalcones [71]. Compounds 200-203 are A-type flavanol-dihydroretrochalcone dimers isolated from the resin of Daemonorops draco ( Figure 10) [72]. Compounds 204-214 were isolated from the fruits of Amorpha fruticosa. Compound 204 is a geranylated flavanonol, while compounds 205 to 207 are geranylated isoflavones. Additionally, compounds 208-212 are rotenoids and contain an isoflavanone core. Furthermore, compound 213 is a flavone glycoside, while compound 214 is an isoflavone glycoside [73]. Compounds 215 and 216 are geranylated flavanones and were isolated from the fruits of Paulownia tomentosa [74]. Compounds 200-203 are A-type flavanol-dihydroretrochalcone dimers isolated from the resin of Daemonorops draco ( Figure 10) [72]. Compounds 204-214 were isolated from the fruits of Amorpha fruticosa. Compound 204 is a geranylated flavanonol, while compounds 205 to 207 are geranylated isoflavones. Additionally, compounds 208-212 are rotenoids and contain an isoflavanone core. Furthermore, compound 213 is a flavone glycoside, while compound 214 is an isoflavone glycoside [73]. Compounds 215 and 216 are geranylated flavanones and were isolated from the fruits of Paulownia tomentosa [74]. Compounds 217-225 are flavone-containing glycoside cyclodimers isolated from the leaves of Ginkgo biloba. Compounds 217-223 are truxinates-resembling compounds 18-25-while compounds 224 and 225 are truxillates ( Figure 11). Additionally, these compounds also contain a cyclobutane ring [75]. Compounds 226-228 are flavanol-containing compounds isolated from the roots of Zizyphus jujuba. Additionally, they are ceanothanetype triterpenoids bonded to a catechin moiety via carbon-carbon bonds; the first reported natural products to have a carbon-carbon bond between a triterpene and a flavonoid. Furthermore, the C2 carbonyl in compound 226 is characteristic of ceanothane-type triterpenoids, and likely directed the formation of the unique carbon-carbon bonds between the triterpene and flavonoid moieties [76]. Compounds 229-234 were isolated from the aerial parts of Atraphaxis frutescens. Compounds 229-234 are 7-methoxyflavonols containing a pyrogallol B-ring, with 230 and 232 being 8-O-acetyl derivatives of 231 and 233, respectively. Additionally, compound 234 is a fisetinidol glucoside and has a flavanol core [77]. Compounds 235-247 were isolated from Actinomadura sp. RB99, which itself was extracted from the fungus-farming termites, Macrotermes natalensis. The isoflavones either display polychlorination, as in compounds 235-240, or polybromination, as in compounds 241-247 [78]. Compounds 248 and 249 are biflavonoid glycosides and contain a flavanone and flavone unit. They have fused dihydrofuran rings akin to the reappraised structures of compounds 195-198 and were also isolated from the same source (white petals of Impatiens balsamina) [79]. Compounds 217-225 are flavone-containing glycoside cyclodimers isolated from the leaves of Ginkgo biloba. Compounds 217-223 are truxinates-resembling compounds 18-25-while compounds 224 and 225 are truxillates ( Figure 11). Additionally, these compounds also contain a cyclobutane ring [75]. Compounds 226-228 are flavanol-containing compounds isolated from the roots of Zizyphus jujuba. Additionally, they are ceanothanetype triterpenoids bonded to a catechin moiety via carbon-carbon bonds; the first reported natural products to have a carbon-carbon bond between a triterpene and a flavonoid. Furthermore, the C2 carbonyl in compound 226 is characteristic of ceanothane-type triterpenoids, and likely directed the formation of the unique carbon-carbon bonds between the triterpene and flavonoid moieties [76]. Compounds 229-234 were isolated from the aerial parts of Atraphaxis frutescens. Compounds 229-234 are 7-methoxyflavonols containing a pyrogallol B-ring, with 230 and 232 being 8-O-acetyl derivatives of 231 and 233, respectively. Additionally, compound 234 is a fisetinidol glucoside and has a flavanol core [77]. Compounds 235-247 were isolated from Actinomadura sp. RB99, which itself was extracted from the fungus-farming termites, Macrotermes natalensis. The isoflavones either display polychlorination, as in compounds 235-240, or polybromination, as in compounds 241-247 [78]. Compounds 248 and 249 are biflavonoid glycosides and contain a flavanone and flavone unit. They have fused dihydrofuran rings akin to the reappraised structures of compounds 195-198 and were also isolated from the same source (white petals of Impatiens balsamina) [79].

Total Synthesis
The first total synthesis of neocyclomorusin (278) was completed in 2022. Compound 278 is a bioactive pyranoflavone, exhibiting cytotoxic, antioxidant, anti-inflammatory, and cholinesterase-inhibiting properties, and is mainly isolated from plants in the Moraceae family. In addition, other structurally related flavones, such as oxyisocyclointegrin (264), morusin (276), and cudraflavone B (277), were also synthesized. The synthetic route yields these flavones utilizing a Friedel-Crafts reaction, a Baker-Venkataraman (BK-VK) rearrangement, a selective epoxidation, and a novel SN2-type cyclization.
To synthesize oxyisocyclointegrin (264), m-trihydroxy benzene (250) was selectively methylated and acylated, forming 252 ( Figure 12). Its 2-hydroxy group was selectively protected by treating it with methoxymethyl bromide and DIPEA, affording 253. Separately, compound 254 was protected with benzyl bromide and hydrolyzed in basic conditions to afford 256. Subsequently, it was combined with compound 253 in the presence of EDC, producing 257. Its base-catalyzed BK-VK rearrangement provided 258, which was alkylated using prenyl bromide to give 259. Its acid-mediated intramolecular cyclization gave 260. Subsequently, it was deprotected using Pd (OH)2/C-catalyzed hydrogenation in the presence of 1,4-cyclohexadiene (which left the double bond intact), furnishing compound 261, which was protected again using benzoic anhydride and DIPEA, giving 262. Its epoxidation using mCPBA produced 263, whose protecting groups were removed via hydrolysis using a 60% KOH solution. The basic conditions also allowed the formation of oxyisocyclointegrin (264).

Total Synthesis
The first total synthesis of neocyclomorusin (278) was completed in 2022. Compound 278 is a bioactive pyranoflavone, exhibiting cytotoxic, antioxidant, anti-inflammatory, and cholinesterase-inhibiting properties, and is mainly isolated from plants in the Moraceae family. In addition, other structurally related flavones, such as oxyisocyclointegrin (264), morusin (276), and cudraflavone B (277), were also synthesized. The synthetic route yields these flavones utilizing a Friedel-Crafts reaction, a Baker-Venkataraman (BK-VK) rearrangement, a selective epoxidation, and a novel S N 2-type cyclization.
To synthesize oxyisocyclointegrin (264), m-trihydroxy benzene (250) was selectively methylated and acylated, forming 252 ( Figure 12). Its 2-hydroxy group was selectively protected by treating it with methoxymethyl bromide and DIPEA, affording 253. Separately, compound 254 was protected with benzyl bromide and hydrolyzed in basic conditions to afford 256. Subsequently, it was combined with compound 253 in the presence of EDC, producing 257. Its base-catalyzed BK-VK rearrangement provided 258, which was alkylated using prenyl bromide to give 259. Its acid-mediated intramolecular cyclization gave 260. Subsequently, it was deprotected using Pd (OH) 2 /C-catalyzed hydrogenation in the presence of 1,4-cyclohexadiene (which left the double bond intact), furnishing compound 261, which was protected again using benzoic anhydride and DIPEA, giving 262. Its epoxidation using mCPBA produced 263, whose protecting groups were removed via hydrolysis using a 60% KOH solution. The basic conditions also allowed the formation of oxyisocyclointegrin (264). To synthesize morusin (276), cudraflavone B (277), and neocyclomorusin (278), compound 250 was treated with acetyl chloride in the presence of AlCl3 to deliver compound 265 ( Figure 13). Subsequently, by following the same procedure, which transformed compound 252 into compound 260, compound 265 was transformed into compound 270, with an overall yield of 14.7%. Similarly, compound 270 was deprotected to furnish compound 271, which was protected with benzoyl groups to compound 272 with a 95% yield. Additionally, its methoxymethyl group was removed by dilute hydrochloric acid, furnishing compound 273 in 78% yield. An aldol-type condensation utilizing 1,1-diethoxy-3-methyl-2-butene transformed compound 273 into the isomers 274 and 275, isolated in 68% and 6% yields, respectively. Their 60% KOH solution treatment afforded compounds 276 and 277, respectively. Finally, the selective epoxidation of compound 274 by mCPBA in the presence of K2CO3 at 0-5 °C and subsequent hydrolysis using KOH produced morusin (276) with a yield of 45% over two steps [80]. To synthesize morusin (276), cudraflavone B (277), and neocyclomorusin (278), compound 250 was treated with acetyl chloride in the presence of AlCl 3 to deliver compound 265 ( Figure 13). Subsequently, by following the same procedure, which transformed compound 252 into compound 260, compound 265 was transformed into compound 270, with an overall yield of 14.7%. Similarly, compound 270 was deprotected to furnish compound 271, which was protected with benzoyl groups to compound 272 with a 95% yield. Additionally, its methoxymethyl group was removed by dilute hydrochloric acid, furnishing compound 273 in 78% yield. An aldol-type condensation utilizing 1,1-diethoxy-3-methyl-2butene transformed compound 273 into the isomers 274 and 275, isolated in 68% and 6% yields, respectively. Their 60% KOH solution treatment afforded compounds 276 and 277, respectively. Finally, the selective epoxidation of compound 274 by mCPBA in the presence of K 2 CO 3 at 0-5 • C and subsequent hydrolysis using KOH produced morusin (276) with a yield of 45% over two steps [80]. The prenylated isoflavones, 5-deoxy-3′-prenylbiochanin A (289) and erysubin F (299), and the latter's novel regioisomer 301, were synthesized for the first time. Compound 289 has been obtained by hydrolyzing its naturally occurring glucoside or isolating it from E. sacleuxii [81,82]. It displays moderate antiviral and antiplasmodial activity [82,83]. Compound 299 has been isolated from many sources, including E. sacleuxii [81]. It exhibits moderate antiplasmodial, antibacterial, and PTP1B-inhibitory activity [82,83]. Their synthetic routes use flavanones as key intermediates by treating them with hypervalent iodine-produced isoflavones.
To synthesize 5-deoxyprenylbiochanin (289), compound 279 was allylated and subsequently irradiated with microwaves at 250 °C to yield 281 via Claisen rearrangement ( Figure 14). Next, compound 281 was methylated. Then, the product was treated with compound 283-produced by a regioselective methoxymethyl (MOM)-etherification of 2,4-dihydroxyacetophenone-to give a chalcone, compound 284, which underwent a base-catalyzed cyclization to afford 285. Next, compound 285 was converted to 288, and the other byproducts using a one-pot oxidative rearrangement and deprotection sequence. The byproducts, compounds 286 and 287, were minimized using a combination of trimethylorthoformate and compound 290. Finally, compound 288 was converted to 289 using a second-generation Grubbs catalyst (291). The final conversion displayed 100% regioselectivity and used tetrahydrofuran (THF) as a solvent due to the insolubility of compound 288 in dichloromethane, the usual choice of solvent for metathesis reactions. The prenylated isoflavones, 5-deoxy-3 -prenylbiochanin A (289) and erysubin F (299), and the latter's novel regioisomer 301, were synthesized for the first time. Compound 289 has been obtained by hydrolyzing its naturally occurring glucoside or isolating it from E. sacleuxii [81,82]. It displays moderate antiviral and antiplasmodial activity [82,83]. Compound 299 has been isolated from many sources, including E. sacleuxii [81]. It exhibits moderate antiplasmodial, antibacterial, and PTP1B-inhibitory activity [82,83]. Their synthetic routes use flavanones as key intermediates by treating them with hypervalent iodineproduced isoflavones.
To synthesize 5-deoxyprenylbiochanin (289), compound 279 was allylated and subsequently irradiated with microwaves at 250 • C to yield 281 via Claisen rearrangement ( Figure 14). Next, compound 281 was methylated. Then, the product was treated with compound 283-produced by a regioselective methoxymethyl (MOM)-etherification of 2,4-dihydroxyacetophenone-to give a chalcone, compound 284, which underwent a basecatalyzed cyclization to afford 285. Next, compound 285 was converted to 288, and the other byproducts using a one-pot oxidative rearrangement and deprotection sequence. The byproducts, compounds 286 and 287, were minimized using a combination of trimethylorthoformate and compound 290. Finally, compound 288 was converted to 289 using a second-generation Grubbs catalyst (291). The final conversion displayed 100% regioselectivity and used tetrahydrofuran (THF) as a solvent due to the insolubility of compound 288 in dichloromethane, the usual choice of solvent for metathesis reactions. To synthesize erysubin F (299), compound 281 was protected and condensed with compound 293 to yield another chalcone 294 ( Figure 15). A microwave-promoted one-pot Claisen rearrangement of compound 294 gave 295, whose oxidative rearrangement formed regio-isomers, compounds 296 and 297. Both compounds reacted with 2-methyl-2-butene in dichloromethane to form 298 and 300, respectively. Finally, both compounds were deprotected to give compounds 299 and 301, respectively [84]. To synthesize erysubin F (299), compound 281 was protected and condensed with compound 293 to yield another chalcone 294 ( Figure 15). A microwave-promoted one-pot Claisen rearrangement of compound 294 gave 295, whose oxidative rearrangement formed regio-isomers, compounds 296 and 297. Both compounds reacted with 2-methyl-2-butene in dichloromethane to form 298 and 300, respectively. Finally, both compounds were deprotected to give compounds 299 and 301, respectively [84]. The natural furanoflavonoid glucosides, pongamosides A (314), B (326), and C (338), were synthesized for the first time, with overall yields ranging from 2.9% to 29%. The compounds were isolated from the fruits of Pongamia pinnata (L.) Pierre [85]. Other isolates from the same plant exhibited potent anti-inflammatory and analgesic effects, indicating that compounds 314, 326, and 338 are also bioactive [86,87]. The synthetic route featured a sodium hydride-promoted BK-VK rearrangement and an acid-catalyzed intramolecular cyclization as key steps. In addition, a phase-transfer-catalyzed glycosylation and Schmidt's trichloroacetimidate procedure were employed to create the O-glycosidic linkage.
To synthesize pongamoside A (314), compound 302 was treated with chloroacetalde-  The natural furanoflavonoid glucosides, pongamosides A (314), B (326), and C (338), were synthesized for the first time, with overall yields ranging from 2.9% to 29%. The compounds were isolated from the fruits of Pongamia pinnata (L.) Pierre [85]. Other isolates from the same plant exhibited potent anti-inflammatory and analgesic effects, indicating that compounds 314, 326, and 338 are also bioactive [86,87]. The synthetic route featured a sodium hydride-promoted BK-VK rearrangement and an acid-catalyzed intramolecular cyclization as key steps. In addition, a phase-transfer-catalyzed glycosylation and Schmidt's trichloroacetimidate procedure were employed to create the O-glycosidic linkage.
To synthesize pongamoside A (314), compound 302 was treated with chloroacetaldehyde to give compound 303, which was converted into its enolate form using excess sodium hydride and subsequently reacted with ethyl acetate to produce compound 304 ( Figure 16). Finally, it was oxidized by DDQ to compound 305. Separately, compound 306 was protected and converted into acyl chloride, compound 308, which was treated with compound 305 to its ester 309. A BK-VK rearrangement using sodium hydride in DMSO produced 310, which was converted into 311 using concentrated hydrochloric acid and acetic acid. Similarly, 311 gave 312 by treating with a mixture of hydrochloric acid and acetic acid; 312 was glucosylated using 2,3,4,6-tetracetyl-α-D-glucopyranosyl trichloroacetimidate in the presence of BF 3 and diethyl ether to yield 313. Subsequently, it was deprotected using sodium methoxide and methanol and produced pongamoside A (314). For the synthesis of pongamoside B (326), the formyl group of 315 was converted into a formate using Baeyer-Villiger oxidation; subsequent hydrolysis furnished phenol 317 ( Figure 17). When it reacted with zinc chloride in acetic acid, it transformed into 318. Its carbonyl group and C2 phenolic hydrogen formed an intramolecular hydrogen bond, deactivating the C2 phenol and enabling the C4 phenol to react selectively with 2-bromo- For the synthesis of pongamoside B (326), the formyl group of 315 was converted into a formate using Baeyer-Villiger oxidation; subsequent hydrolysis furnished phenol 317 ( Figure 17). When it reacted with zinc chloride in acetic acid, it transformed into 318. Its carbonyl group and C2 phenolic hydrogen formed an intramolecular hydrogen bond, deactivating the C2 phenol and enabling the C4 phenol to react selectively with 2bromo-1,1-diethoxyethane, affording 319. The strong acid ion exchange resin Amberlyst-15 promoted the cyclization of 319 and yielded 320. The transformation of 320 into the final product, 326, used the same synthetic procedure to convert compound 304 into 314. To synthesize pongamoside C (338), 320 was demethylated using BBr3 to avoid selectivity issues later ( Figure 18). Subsequently, the C7 phenol was protected using a benzyl group, yielding 328. The unprotected phenol was protected using a benzoyl group, generating 329. It was treated with PTT, forming 330, reacting with potassium benzoate in acetonitrile to yield 331. A BK-VK rearrangement using sodium hydride in DMSO converted 331 into β-diketone, 332, which was cyclized utilizing a mixture of sodium acetate and acetic acid, giving 333. Subsequently, it was treated with sodium hydroxide to form 334, which was alkylated using dimethyl sulfate to afford 335. Deprotection of 335 was achieved using hydrochloric acid and acetic acid, yielding the aglycone 336. The same conditions were used to glycosylate compounds 312 and 314 to transform 336 into 337. Similarly, the acetyl groups were hydrolyzed using sodium methoxide, producing pongamoside C (338) [88]. To synthesize pongamoside C (338), 320 was demethylated using BBr 3 to avoid selectivity issues later ( Figure 18). Subsequently, the C7 phenol was protected using a benzyl group, yielding 328. The unprotected phenol was protected using a benzoyl group, generating 329. It was treated with PTT, forming 330, reacting with potassium benzoate in acetonitrile to yield 331. A BK-VK rearrangement using sodium hydride in DMSO converted 331 into β-diketone, 332, which was cyclized utilizing a mixture of sodium acetate and acetic acid, giving 333. Subsequently, it was treated with sodium hydroxide to form 334, which was alkylated using dimethyl sulfate to afford 335. Deprotection of 335 was achieved using hydrochloric acid and acetic acid, yielding the aglycone 336. The same conditions were used to glycosylate compounds 312 and 314 to transform 336 into 337. Similarly, the acetyl groups were hydrolyzed using sodium methoxide, producing pongamoside C (338) [88]. Houttuynoid A (354), an antiviral flavone, was synthesized for the first time. The compound was isolated from Houttuynia cordata and displayed the most potent inhibitory activity against HSV-1 in the houttuynoid class [89]. Its synthetic route features an I2-catalyzed oxa-Michael addition of a chalcone intermediate, thus forming the C6-C3-C6 structure.
To synthesize houttuynoid A (354), 339 was selectively protected to 340 (Figure 19). It was treated with iodine monochloride to 341, whose formyl group was protected to 342. Subsequently, it was reacted with methyl dodec-2-ynoate, giving 343, which was transformed to 344 using an intramolecular Heck reaction. Hydrolysis of 344 deprotected its formyl group, and a subsequent Claisen-Schmidt condensation with 1-[2,4-bis(benzyloxy)-6-hydroxyphenyl]ethanone yielded 346. It was converted into 347 using iodine in DMSO, which was methylated at C-2″ using methyl iodide, forming 348. In situ generated DMDO followed by acid-induced rearrangement oxidized compound 348 to 349, which was selectively deprotected with acetic acid and water to give 350. Compound 350 was glucosylated using 351 and gave 352. It was deacylated and debenzylated via hydrolysis to give 353, which was reduced using DIBAL-H to afford the final product, houttuynoid A (354) [90]. Houttuynoid A (354), an antiviral flavone, was synthesized for the first time. The compound was isolated from Houttuynia cordata and displayed the most potent inhibitory activity against HSV-1 in the houttuynoid class [89]. Its synthetic route features an I 2 -catalyzed oxa-Michael addition of a chalcone intermediate, thus forming the C6-C3-C6 structure.
To synthesize houttuynoid A (354), 339 was selectively protected to 340 (Figure 19). It was treated with iodine monochloride to 341, whose formyl group was protected to 342. Subsequently, it was reacted with methyl dodec-2-ynoate, giving 343, which was transformed to 344 using an intramolecular Heck reaction. Hydrolysis of 344 deprotected its formyl group, and a subsequent Claisen-Schmidt condensation with 1-[2,4-bis(benzyloxy)-6-hydroxyphenyl]ethanone yielded 346. It was converted into 347 using iodine in DMSO, which was methylated at C-2" using methyl iodide, forming 348. In situ generated DMDO followed by acid-induced rearrangement oxidized compound 348 to 349, which was selectively deprotected with acetic acid and water to give 350. Compound 350 was glucosylated using 351 and gave 352. It was deacylated and debenzylated via hydrolysis to give 353, which was reduced using DIBAL-H to afford the final product, houttuynoid A (354) [90]. Sericetin (361), a prenylated flavonol isolated from the root bark of Mundulea sericea, can inhibit the growth of various cancer cell lines [91]. It was synthesized in four steps, featuring an electrocyclization to produce the tricyclic core and an aromatic Claisen/Cope rearrangement to incorporate the C8 prenyl group.
To synthesize sericetin (361), compound 355, produced from phloroglucinol using a Friedel-Crafts reaction followed by a pyrone annulation, was cyclized using 3,3-dimethylacrylaldehyde to furnish compound 356 ( Figure 20). Subsequently, it was prenylated to 357, which was treated with diethylaniline in a Claisen rearrangement to give compound 360 via the two intermediate isomers, 358 and 359. Compound 360 was deprotected to yield the final product, sericetin (361) [92]. Sericetin (361), a prenylated flavonol isolated from the root bark of Mundulea sericea, can inhibit the growth of various cancer cell lines [91]. It was synthesized in four steps, featuring an electrocyclization to produce the tricyclic core and an aromatic Claisen/Cope rearrangement to incorporate the C8 prenyl group.
To synthesize glaziovianin A (374), 362 was transformed into compound 363 using Dakin oxidation ( Figure 21). It was then methylated to 364 using methyl iodide and selectively demethylated with aluminum chloride to yield 365. Subsequently, it was converted into an acetal using methylene iodide to give 366, which was demethylated using TMSI, furnishing 367. The oxidation of 367 with DDQ gave 368. Separately, 369 was condensed with DMF-DMA to 370, coupled with 368, which resulted in compound 371. It was demethylated using excess TMSI, and an intramolecular cyclization gave 372 and its reduced form, 373. The latter was methylated to glaziovianin A (374) [95].  Glaziovianin A (374) was first isolated from the leaves of Ateleia glazioviana [93]. It exhibited cytotoxicity against various cancer cell lines; its O-benzylated derivative inhibited microtubule polymerization more than 374 and colchicine, demonstrating the scaffold's biological potential [94].

Semisynthesis
To synthesize glaziovianin A (374), 362 was transformed into compound 363 using Dakin oxidation ( Figure 21). It was then methylated to 364 using methyl iodide and selectively demethylated with aluminum chloride to yield 365. Subsequently, it was converted into an acetal using methylene iodide to give 366, which was demethylated using TMSI, furnishing 367. The oxidation of 367 with DDQ gave 368. Separately, 369 was condensed with DMF-DMA to 370, coupled with 368, which resulted in compound 371. It was demethylated using excess TMSI, and an intramolecular cyclization gave 372 and its reduced form, 373. The latter was methylated to glaziovianin A (374) [95]. Glaziovianin A (374) was first isolated from the leaves of Ateleia glazioviana [93]. It exhibited cytotoxicity against various cancer cell lines; its O-benzylated derivative inhibited microtubule polymerization more than 374 and colchicine, demonstrating the scaffold's biological potential [94].
To synthesize glaziovianin A (374), 362 was transformed into compound 363 using Dakin oxidation ( Figure 21). It was then methylated to 364 using methyl iodide and selectively demethylated with aluminum chloride to yield 365. Subsequently, it was converted into an acetal using methylene iodide to give 366, which was demethylated using TMSI, furnishing 367. The oxidation of 367 with DDQ gave 368. Separately, 369 was condensed with DMF-DMA to 370, coupled with 368, which resulted in compound 371. It was demethylated using excess TMSI, and an intramolecular cyclization gave 372 and its reduced form, 373. The latter was methylated to glaziovianin A (374) [95].

Semisynthesis
Analyzing the constituents of the roots of Derris laxiflora yielded the potent insecticide isolaxifolin (380) [96]. It is also an excellent insect antifeedant as it is not toxic to humans [97]. Apigenin, chosen for its natural abundance, was transformed into 380 with an overall yield of 17%.

Synthesis of Derivatives
1-Deoxynojirimycin is an α-glucosidase inhibitor that exhibits anticancer and antidiabetic activities [99,100]. However, its use has been limited due to its poor lipophilicity and susceptibility to degradation. Thus, to improve its pharmacokinetics and antitumor activity, 1-deoxynojirimycin was coupled with kaempferol, affording compounds 387-389. The derivatives differed in the length of the carbon chain that connected both subunits.
To synthesize the derivatives 387-389 of 1-deoxynojirimycin, compound 381 was methylated using dimethyl sulfate and potassium carbonate in acetone, yielding 382. It was selectively demethylated using aluminum bromide, giving compound 383, which was treated with three linear dibromoalkanes, affording 384 to 386 (Figure 23). Subsequently, treating them with 1-deoxynojirimycin in the presence of potassium carbonate furnished the final derivatives 387 to 389 [101].

Synthesis of Derivatives
1-Deoxynojirimycin is an α-glucosidase inhibitor that exhibits anticancer and antidiabetic activities [99,100]. However, its use has been limited due to its poor lipophilicity and susceptibility to degradation. Thus, to improve its pharmacokinetics and antitumor activity, 1-deoxynojirimycin was coupled with kaempferol, affording compounds 387-389. The derivatives differed in the length of the carbon chain that connected both subunits.
To synthesize the derivatives 387-389 of 1-deoxynojirimycin, compound 381 was methylated using dimethyl sulfate and potassium carbonate in acetone, yielding 382. It was selectively demethylated using aluminum bromide, giving compound 383, which was treated with three linear dibromoalkanes, affording 384 to 386 ( Figure 23). Subsequently, treating them with 1-deoxynojirimycin in the presence of potassium carbonate furnished the final derivatives 387 to 389 [101]. Analyzing the constituents of the roots of Derris laxiflora yielded the potent insecticide isolaxifolin (380) [96]. It is also an excellent insect antifeedant as it is not toxic to humans [97]. Apigenin, chosen for its natural abundance, was transformed into 380 with an overall yield of 17%.

Synthesis of Derivatives
1-Deoxynojirimycin is an α-glucosidase inhibitor that exhibits anticancer and antidiabetic activities [99,100]. However, its use has been limited due to its poor lipophilicity and susceptibility to degradation. Thus, to improve its pharmacokinetics and antitumor activity, 1-deoxynojirimycin was coupled with kaempferol, affording compounds 387-389. The derivatives differed in the length of the carbon chain that connected both subunits.

Synthetic Methods
In addition to target-oriented and diversity-oriented synthesis, which are covered in the earlier sections, new tools for efficiently preparing or modifying flavonoids or isoflavonoids are also discussed. These tools vary from promiscuous enzymes to synthetic routes/methods of creating novel flavonoids/isoflavonoids.

Enzymes
A new glucuronosyltransferase (UGT), UGT71BD1, was extracted from Cistanche tubulosa, a desert herb plant abundant with phenylethanoid glycosides. However, the aglycone analogs were not substrates for the enzyme, which catalyzed the multiglycosylation of phenylethanoid glycosides.

Synthetic Methods
In addition to target-oriented and diversity-oriented synthesis, which are covered in the earlier sections, new tools for efficiently preparing or modifying flavonoids or isoflavonoids are also discussed. These tools vary from promiscuous enzymes to synthetic routes/methods of creating novel flavonoids/isoflavonoids.

Enzymes
A new glucuronosyltransferase (UGT), UGT71BD1, was extracted from Cistanche tubulosa, a desert herb plant abundant with phenylethanoid glycosides. However, the aglycone analogs were not substrates for the enzyme, which catalyzed the multiglycosylation of phenylethanoid glycosides.

Synthetic Methods
In addition to target-oriented and diversity-oriented synthesis, which are covered in the earlier sections, new tools for efficiently preparing or modifying flavonoids or isoflavonoids are also discussed. These tools vary from promiscuous enzymes to synthetic routes/methods of creating novel flavonoids/isoflavonoids.

Enzymes
A new glucuronosyltransferase (UGT), UGT71BD1, was extracted from Cistanche tubulosa, a desert herb plant abundant with phenylethanoid glycosides. However, the aglycone analogs were not substrates for the enzyme, which catalyzed the multiglycosylation of phenylethanoid glycosides.
Notably, the enzyme could also accept flavone (405, 407-409, and 412), flavonol (406), flavanones (410 and 411), and isoflavone (413) glycosides as substrates ( Figure 28). UGTs capable of transforming glycoside compounds are rare, but those with such substrate promiscuity are remarkable discoveries. Additionally, the enzyme could also utilize UDP-GlcA as a sugar donor and transfer glucuronic acid to 406 [109]. promiscuity are remarkable discoveries. Additionally, the enzyme could also utilize UDP-GlcA as a sugar donor and transfer glucuronic acid to 406 [109].  Using various flavonoids (flavans and their subclasses), the enzymatic activity of FOMT and its constituent enzymes, SlOMT3 and OsNOMT, were tested. SlOMT3 methylated all flavonoids containing a hydroxyl group at C3′ but showed no activity towards isoflavonoids. Furthermore, OsNOMT's ability to methylate diverse flavonoids was validated. Finally, FOMT was determined to display comparable catalytic activity to its constituting enzymes and could sequentially generate polymethoxyflavonoids [110]. promiscuity are remarkable discoveries. Additionally, the enzyme could also utilize UDP-GlcA as a sugar donor and transfer glucuronic acid to 406 [109]. A new enzyme to generate di-O-methylflavonoids in one step was bioengineered; flavonoid O-methyltransferase (FOMT) was generated by fusing two O-methyltransferases (OMTs), a 3′-OMT (SlOMT3), and a 7-OMT (OsNOMT) (Figure 29). Using various flavonoids (flavans and their subclasses), the enzymatic activity of FOMT and its constituent enzymes, SlOMT3 and OsNOMT, were tested. SlOMT3 methylated all flavonoids containing a hydroxyl group at C3′ but showed no activity towards isoflavonoids. Furthermore, OsNOMT's ability to methylate diverse flavonoids was validated. Finally, FOMT was determined to display comparable catalytic activity to its constituting enzymes and could sequentially generate polymethoxyflavonoids [110]. Using various flavonoids (flavans and their subclasses), the enzymatic activity of FOMT and its constituent enzymes, SlOMT3 and OsNOMT, were tested. SlOMT3 methylated all flavonoids containing a hydroxyl group at C3 but showed no activity towards isoflavonoids. Furthermore, OsNOMT's ability to methylate diverse flavonoids was validated. Finally, FOMT was determined to display comparable catalytic activity to its constituting enzymes and could sequentially generate polymethoxyflavonoids [110].
A separately prepared aromatic bromide, compound 418, and aldehyde, compound 419, were reacted together, affording compound 420 as a diastereomeric mixture ( Figure  31). This mixture was deprotected in acidic media, prompting its cyclization and producing another mixture, compound 421. Protecting the mixture using methoxymethyl chloride yielded only the trans-isomer 422, which was converted into a lithiate and treated with DMF to introduce a formyl group to form 423. Subsequently, it was condensed with a protected aldehyde, compound 424, producing 425. Epoxidation, deprotection, and subsequent cyclization of 425 yielded diastereomers 426 and 427. Additionally, first deprotecting compound 425 in acidic conditions and then inducing intramolecular cyclization using basic conditions afforded the diastereomers 428 and 429 [111]. A previously developed method for synthesizing 1,4-benzodioxane neolignans produced 1,4-benzodioxane flavonolignans and flavanolignans. To prove the method's efficacy and provide sufficient amounts of compounds for biological evaluations, silybin A and B (426 and 427), a pair of diastereomeric 1,4-benzodioxane flavonolignans, were synthesized. Additionally, their flavanolignan analogs, isosilandrin A and B (428 and 429), were also produced.
A separately prepared aromatic bromide, compound 418, and aldehyde, compound 419, were reacted together, affording compound 420 as a diastereomeric mixture ( Figure 31). This mixture was deprotected in acidic media, prompting its cyclization and producing another mixture, compound 421. Protecting the mixture using methoxymethyl chloride yielded only the trans-isomer 422, which was converted into a lithiate and treated with DMF to introduce a formyl group to form 423. Subsequently, it was condensed with a protected aldehyde, compound 424, producing 425. Epoxidation, deprotection, and subsequent cyclization of 425 yielded diastereomers 426 and 427. Additionally, first deprotecting compound 425 in acidic conditions and then inducing intramolecular cyclization using basic conditions afforded the diastereomers 428 and 429 [111]. A novel method of brominating flavonoids was developed. It employed α,β-dibromohydrocinnamic acid to slowly release bromine at relatively low temperatures, enabling the regioselective bromination of compounds susceptible to oxidation. The method can also be used to brominate flavonolignans, an otherwise arduous task. The equivalents of base (Cs2CO3 or K2CO3) used did not exceed 0.5 equivalents, as higher concentrations re- A novel method of brominating flavonoids was developed. It employed α,β-dibromohydrocinnamic acid to slowly release bromine at relatively low temperatures, enabling the regioselective bromination of compounds susceptible to oxidation. The method can also be used to brominate flavonolignans, an otherwise arduous task. The equivalents of base (Cs 2 CO 3 or K 2 CO 3 ) used did not exceed 0.5 equivalents, as higher concentrations resulted in the production of hydrogen bromide.
Generally, flavonols containing hydroxy substituents at C5 and C7 were monobrominated at C6, while flavanonols containing both hydroxy groups were monobrominated at C8 only ( Figure 32). Changing the base and heating the mixture more strongly usually resulted in dibrominations at C6 and C8. Modifying one of the hydroxyl groups also destroyed regioselectivity, with monobromination occurring at C6 and C8. Interestingly, modifying both hydroxyl substituents restored selectivity (based on the general rule stated above), and removing the C5 hydroxy group entirely (tested with 3,7-dihydroxyflavone) resulted in monobromination at C8 only [112].
A novel method of brominating flavonoids was developed. It employ mohydrocinnamic acid to slowly release bromine at relatively low temperat the regioselective bromination of compounds susceptible to oxidation. Th also be used to brominate flavonolignans, an otherwise arduous task. The base (Cs2CO3 or K2CO3) used did not exceed 0.5 equivalents, as higher conc sulted in the production of hydrogen bromide.
Generally, flavonols containing hydroxy substituents at C5 and C7 w minated at C6, while flavanonols containing both hydroxy groups were mo at C8 only ( Figure 32). Changing the base and heating the mixture more str resulted in dibrominations at C6 and C8. Modifying one of the hydroxyl g stroyed regioselectivity, with monobromination occurring at C6 and C8. modifying both hydroxyl substituents restored selectivity (based on the stated above), and removing the C5 hydroxy group entirely (tested with 3,7vone) resulted in monobromination at C8 only [112].

Reappraisals
The structural complexity of natural products necessitates using different spectroscopic analyses to determine their structure accurately. Unfortunately, due to insufficient data or technical oversights, spectra can be misinterpreted to produce erroneous isolates structures. Revisions of these spectra, prompted by new synthetic discoveries or discrepancies, using contemporary analytical tools yield reappraised structures, rectifying the initial inaccuracies.
Elucidating the structures of complex flavanones containing a heteroatomic bicyclononane ring (compounds 130-136) provided important spectroscopic information, enabling the reappraisal of other compounds having the same motif. The modified compounds were oboflavanone A and B and cryptoflavanones C and D, initially reported as compounds 430, 432, 434, and 435, respectively ( Figure 33). The structure of compound 430 was reappraised as compound 431. Only the absolute configurations of the other three compounds were modified, producing compounds 433, 436, and 437, respectively [56].

Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids
Tables 2-4 summarize the bioactivities of the novel compounds discovered or synthesized from 2016 to 2022. However, they do not list all bioactivities exhibited, as some were not expressed using EC50s or similar metrics. Instead, they were expressed as percentages at various concentrations or compared to controls and left as is. In addition, it may be due to some compounds' relative inactivity, which did not merit further extrapolations, calculations, or tests. Thus, additional bioactivities are detailed in the text, along with brief structure-activity relationship studies wherever possible.

Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids
Tables 2-4 summarize the bioactivities of the novel compounds discovered or synthesized from 2016 to 2022. However, they do not list all bioactivities exhibited, as some were not expressed using EC 50 s or similar metrics. Instead, they were expressed as percentages at various concentrations or compared to controls and left as is. In addition, it may be due to some compounds' relative inactivity, which did not merit further extrapolations, calculations, or tests. Thus, additional bioactivities are detailed in the text, along with brief structure-activity relationship studies wherever possible.     [19,25,31,38,41,60,76,79]. Additionally, compound 82 was not tested due to the putative inactivity of flavanonols in the antigen-induced degranulation assay in RBL-2H3 cells [42]. Similarly, compounds 85, 87, 89, and 90 were not evaluated for their ability to increase glucose uptake [43]. Finally, compounds 103, 104, 122, 124,  125, 127 to 129, 143, 160, 161, 165, and 178-180 were not tested due to the scarce amounts isolated [50,55,59,62,65].
Compounds 11-14 were only evaluated in silico; their inhibition of α-glucosidase and HMG-CoA reductase was evaluated using docking models. All four compounds scored better on α-glucosidase than acarbose, a positive control. Compounds 11, 12, and 14 also displayed a better docking score than mevastatin, another positive control, on HMG-CoA reductase. The results indicated that a more significant number of glucosyl moieties decreased bioactivity. For both targets, compound 12 exhibited better scores than compound 11, and compound 14 displayed better scores than compound 13 [26]. Compounds 15 and 16 showed weak to moderate cytotoxic activities against SiHa and SGC-7901 cells [27].
The protective effects of compounds 18-25 against damage induced by L-glutamate on HT-22 cells were evaluated. Compounds 21 and 22 displayed better activity than trolox, the positive control, between 1.3 to 15 µM. Additionally, compounds 23 and 24 displayed protective activity similar to trolox. Furthermore, the inhibition of ROS generation by compound 21 was evaluated; it decreased ROS generation in a dose-dependent manner. Compounds with more than two sugar groups, such as 19, 20, and 25, were inactive. In contrast, the most potent compounds, 21 and 22, only contained one sugar group, indicating the group's deactivating effects, possibly due to steric hindrance. The marginally better protective effects of compound 21 than compound 22 suggest that chirality is not a significant determinant of bioactivity in this scenario [29].
The anti-inflammatory activity of compound 26 was evaluated by measuring its inhibition of prostaglandin E2 (PGE2) in LPS-treated RAW 264.7 macrophages [30].
Compounds 35-37 were assayed for neuroprotective effects by a cell viability assay on HT22 cells. Compounds 36 and 37 were inactive despite all three compounds differing only by the position and number of acetyl groups on their sugar moieties, suggesting that one of the hydroxyl groups on the saccharides is a major determinant of bioactivity [32].
Compounds 45-48 were evaluated for inhibition of PTP1B; compound 48 was inactive, indicating that an unmodified prenyl moiety (present in compounds 45-47) was necessary for activity. Additionally, the number and length of prenyl chains were also determinants of bioactivity as compounds 46 and 47 inhibited PTP1B more strongly than compound 45 [34].
Compounds 53 and 54 were both moderately active inhibitors of NLRP3 inflammasome, demonstrated by the decrease in IL-1β in the presence of these compounds-0.62 and 0.58 µg/mL, respectively, of IL-1β at 10 µM. In contrast, the positive control, curcumin, inhibited IL-1B levels to 0.28 ug/mL at 50 µM [37].
Compounds 56-59 did not inhibit the release of TNF or IL-1β. However, compound 59 strongly inhibited CCL2 secretion by THP-1 cells, demonstrating its usefulness as a selective inhibitor. Additionally, compound 59 contained more methylated hydroxyl groups than the other isolates (although it still contained three unmodified hydroxyl groups), indicating its activating effect. [39].
Compounds 76 to 78 and 80 were assessed against multiple bacteria, fungi, and cancer cell lines. However, compound 80 showed no activity, while the active compounds, compounds 76 to 78, did not inhibit C. albicans, C. neoformans, or T. rubrum, nor did they show any activity towards A-375, HCT-116, and MB-231. Notably, all active compounds showed chain-open prenylation, while none of the compounds with ring-closed isoprene moieties were effective. Additionally, the marginally better antibacterial activity of compound 76 against MRSA indicated that the C3 and C4 hydroxyl groups are minor determinants of bioactivity [41].
Compounds 83-91 were tested for their inhibitory activity of PTP1B, with compounds 84 and 88 showing the most potency and compound 91 being the most inactive. As IC 50 data for the other compounds were not determined, inhibitory rates (at 10 µM) were used to quantify and compare activity. Compound 83 displayed slightly lower activity than compound 84, while compounds 85 and 87 showed considerably weaker activity than compound 84. Similarly, compounds 86, 89, and 90 were slightly weaker PTP1B inhibitors than compound 88. Additionally, the isolates were also tested for their inhibition of α-glucosidase. All compounds except compound 84 displayed little to no activity. Furthermore, their ability to increase glucose uptake was also evaluated. However, only compound 86 expressed significant activity [43].
Compound 93 displayed stronger antibacterial activity than streptomycin against M. flavus and P. aeruginosa (MIC: 344.2 µM for both). It also had lower MIC values than ampicillin against all four bacterial strains. Since compound 93 showed promise as a potent antibacterial, its inhibition of biofilm formation by P. aeruginosa was also evaluated. At a concentration of 0.5 MIC, it inhibited 43% of the biofilm formation. Additionally, it also showed weak inhibition (1.8%) at a concentration of 0.125 MIC [45].
Compounds 94 and 95 showed no substantial inhibitory activity towards E. coli or MCF-7. Compound 95 was also inactive against B. subtilis, implying that its C7 and C4 methoxy groups were deactivating; compound 94 had hydroxy substituents on both positions [46].
Compound 96 was inactive when tested for inhibition of tyrosinase. It was evaluated with molecular docking and compared with kojic acid, which had a high docking score Life 2023, 13, 736 38 of 46 despite its two H-bonds. It was attributed to the small distance between the acid and the cupric ion, leading to stronger polar interactions. Compound 96 did not share this trait and had marginally longer polar interactions, which, despite its multiple H-bond interactions with active site residues, led to a lower docking score [47].
Compound 97 did not show any protective effects on HEK 293 t-cells damaged by CdCl 2 [48]. Compounds 98-101 were assessed against five bacteria (MRSA, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa) and two fungi (C. albicans and C. neoformans). However, compounds 99-101 were inactive, while compound 98 displayed weak activity against S. aureus, A. baumanni, and C. neoformans. Compounds 98 and 99 showed no anthelmintic activity against exsheathed third-stage larvae and fourth-stage larvae of H. contortus. The results indicated that the acetyl groups in compounds 99-101 were deactivating [49].
Compound 102 was inactive against HepG2 and MCF-7 cells [50]. A bioassay preceded the testing of compounds 105-109. Consequently, only compounds 105 and 107 were evaluated. Compound 105 was inactive against the fungi C. krusei and C. glabrata. However, compound 107 showed selectivity for C. krusei as it did not inhibit the growth of C. glabrata while being more potent than the positive control, fluconazole (IC 50 : 16 µg/mL), at inhibiting C. krusei. Furthermore, another isolate, trans-coumaric acid, was also tested against the fungi but showed no activity, demonstrating that the combination of a carboxyethenyl moiety and a flavone core is necessary for activity [51].
Compounds 110-111 were screened for their inhibition of Leishmaniasis donovani nucleoside hydrolase inhibitors (LdNH). Both were active and were identified as non-competitive inhibitors. Compound 110 was a slightly worse inhibitor; its C5 hydroxyl group was slightly deactivating [52].
Compound 112 was tested against mammalian α-glucosidase and was 2.5 times more active than acarbose (IC 50 : 100 µM), which was used as the positive control [53].
Compounds 113-121 were evaluated for inhibiting ROS generation, TNF-α, and IL-8 secretion. Compounds 115, 117, and 118 most potently inhibited TNF-α, ROS generation, and IL-8 production. Interestingly, increasing the number of sugar groups did not inhibit bioactivity as compound 119, containing the least sugar motifs, was also a weaker inhibitor than the other isolates. Furthermore, the C3 hydroxy group in compound 120 was a better-activating group than the methoxy group in compound 121 [54].
Compounds 123 and 126 displayed moderate cytotoxicity, even for the NCI-ADR/RES cell line, which expresses the multidrug-resistant (MDR) phenotype, suggesting that the compounds are not substrates for the Pgp-efflux pump [55].
Compounds 130-138 were evaluated for cytotoxicity against HCT-116 cells. However, compounds 130, 131, 135, and 136 were inactive. The unsaturated C20 bond in compound 132 is slightly deactivating compared to 133, likely due to the restricted movement of the phenyl group [56].
Compounds 139 and 140 were evaluated for their antifungal activity. Enantiomerically pure samples of 139 were separately tested, with both isomers possessing identical antifungal potencies. Both compounds inhibited C. neoformans more strongly than the positive control, fluconazole (MIC: 25.5 µM) [57].
C. genistoides is used to prepare green, bitter herbal tea. The tea's analysis revealed compound 141, which epimerizes to compound 142 on prolonged heating. Additionally, the bitterness of naringin and compound 141 were tested using descriptive sensory analysis. At the same concentrations, compound 141 was only slightly bitter (7 on a 100-point scale), while naringin was considerably more bitter (26 on the same scale). Since both compound 141 and naringin are structural isomers, the results highlight the importance of sugar positions on the bitterness of the compound [58].
Due to the unavailability of enantiopure samples, compounds 144 and 145 were evaluated with their respective enantiomers, gambiriin A1 and A2. Similarly, compounds 146 and 147 were evaluated together. The racemic mixtures were tested for their dental activities, and all three significantly increased the complex modulus of dentin by 3.3-Compound 361 and synthetic intermediate compounds 357 and 360 were tested for their protective effects against cisplatin-induced cytotoxicity in NRK-52E cells at a concentration of 20 µM. Compound 361 decreased cell viability, while compound 360 only showed a marginal increase. Compound 357 significantly increased cell viability, inhibiting ROS generation and reducing cleaved caspase-3 levels [92].
Compounds 387-389 were assayed for their α-glucosidase inhibitory activity; only compound 387 was less active than 1-deoxynojirimycin (IC 50 : 8.03 µM). However, its lipophilicity (experimentally determined as log P) was more significant than the lipophilicity of 1-deoxynojirimycin (0.49 compared to −0.68). Additionally, the lipophilicity of the more active derivatives, compounds 388 and 389, was also greater (1.65 and 2.92, respectively), indicating that a longer alkyl chain between the two moieties increased lipophilicity and bioactivity. The compounds were also evaluated for their anticancer activity, but only 388 and 389 showed any activity. Using a wound-healing assay, the ability of compound 389 to effectively inhibit the migration of MCF-7 cells at only 5 and 10 µM was proven. It was also implicated in disrupting DNA synthesis and regulating cell cycle progression. Furthermore, compound 389 could induce MMP collapse and increase intracellular ROS levels, implying that it induced apoptosis through the mitochondrial pathway [101].
Compounds 393, 396, 399, and 404 were tested against HUVEC-a model to evaluate antiangiogenic activity-and their cytotoxicity and inhibition of proliferation and migration were measured. Only compound 393 displayed weaker activities than 2,3-dehydrosilybin (IC 50 : 12 µM), indicating that the galloyl group has an activating effect subject to its position [108].
While compounds 426-429 were not tested, the more potent bioactivities of synthesized 1,4-benzodioxane lignans than previously reported bioactivities of silybin against Huh7.5.1 cells or HCV demonstrated that the chromanone motif was not necessary for anticancer and antiviral activity [111].

Conclusions
A total of two hundred and forty-nine (249) flavonoids, isoflavonoids, and neoflavonoids were isolated during 2016-2022, along with the flavonoids and isoflavonoids synthesized during those years, representing only a small number of known flavonoids, isoflavonoids, and neoflavonoids. Given their ubiquity in plants and the vast number of plant species yet to be analyzed for their chemical contents, it is plausible to consider the number of undiscovered flavonoids, isoflavonoids, and neoflavonoids as dwarfing their known counterparts. To facilitate the discovery of more potent and structurally diverse analogs, this review collected and summarized relevant information regarding flavonoids, isoflavonoids, and neoflavonoids discovered in the past 7 years to provide interested researchers an accessible guide into the recent developments of the field. It also highlights potent isolates or synthetic derivatives that can serve as lead compounds for future therapeutics. The utility of contemporary computational and spectroscopic methods is demonstrated with the inclusion of reappraisals. Additionally, new methods of synthesizing or modifying flavonoids and isoflavonoids are also discussed to highlight the second aspect of drug development: optimizing the lead.