Advances in natural coumaronochromones: a comprehensive review of natural occurrence, bioactivities, and chemical synthesis

1 Introduction

Coumaronochromones represent a rare class of isoflavonoid natural products characterized by a distinctive benzofuro[2,3-b]chromenone core (Scheme 1). Primarily found in leguminous plants, they exhibit a broad spectrum of significant physiological and pharmacological activities. Reported biological properties include anti-inflammatory, antibacterial, antitumor, insecticidal, and immunomodulatory effects, highlighting their considerable therapeutic and agrochemical potential [1–9]. To date, 92 natural coumaronochromones have been identified from approximately 28 species spanning 24 genera across 7 families (including one fungal source). Despite their diverse bioactivities and promising applications—ranging from pharmaceuticals to food additives and agricultural agents—a comprehensive review systematically covering their botanical origins, biological functions, synthetic methodologies, and practical applications remains unavailable. This review aims to address this gap by consolidating recent advances in the chemistry and biology of coumaronochromones. It provides a detailed overview of their natural occurrence (plant sources), documented biological activities, and reported chemical syntheses. By organizing existing knowledge and highlighting future directions, this work is intended to serve as a valuable resource for researchers in natural products chemistry, organic synthesis, and medicinal chemistry.

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Coumaronochromones are classified as a subclass of isoflavones, which are plant-derived secondary metabolites. Isoflavones represent a major group of flavonoids, structurally characterized by the migration of the B-ring from the C-2 to the C-3 position of the flavonoid core. While the complete biosynthetic pathway of coumaronochromones remains unresolved, it is hypothesized that their upstream biosynthesis aligns with that of isoflavones (Scheme 1). The biosynthesis of isoflavones in plants is well-established, initiating from malonyl-CoA and p-coumaroyl-CoA—precursors derived from carbohydrate metabolism and the phenylpropanoid pathway, respectively. The core scaffold is assembled from three malonyl-CoA molecules and one coumaroyl-CoA molecule through sequential enzymatic reactions. First, chalcone synthase (CHS) catalyzes the condensation of these substrates to form a chalcone intermediate. This chalcone is subsequently isomerized by chalcone isomerase (CHI) to yield a dihydroflavone. As documented in the literature, dihydroflavone is then converted into the corresponding isoflavone by isoflavone synthase (IFS) [10, 11].

Based on this pathway, we propose a biosynthetic hypothesis wherein isoflavones bearing a hydroxyl group at a specific position (when R=OH) may undergo further cyclization and oxidation to generate coumaronochromones and 3-hydroxycoumaronochromones. Whether this hydroxyl group originates from the initial substrate or is introduced via a later oxidative step remains to be clarified through detailed biosynthetic studies.

2 Plant sources

To date, a total of 92 coumaronochromones have been isolated and characterized from natural sources, encompassing 28 species distributed across 24 genera within 7 families (including one fungal species). The structures, botanical origins, and plant parts of these compounds are summarized in Table 1, with further contextual details provided in the accompanying text.

Table 1

The plant sources of natural coumaronochromones

Structure	Name	Plants	Parts	Bioactivity	References
	Lupinalbin A (1)	luteus L. albus A. americana	Roots/rhizomes	–	[12–14]
	Lupinalbin B (2)	luteus L. albus F. altissima	Roots/fruits	–	[12, 18, 54]
	Lupinalbin C (3)	L. albus L	Roots	–	[12]
	Lupinalbin D (4)	L. albus L	Roots	–	[12]
	Lupinalbin E (5)	L. albus L	Roots	–	[12]
	Lupinalbin G (6)	L. albus L. L. albus	Roots	–	[12, 13]
	Lupinalbin F (7)	L. luteus	Roots	–	[16]
	Lupinalbin H (8)	L. luteus	Roots	–	[17]
	Lupilutin (9)	L. luteus	Roots	–	[19]
	Lupalbin B (10)	L. luteus	Roots	–	[19]
	Euchretin A (11)	japonica E. formosana	Stems/roots	Cytotoxicity	[20, 21]
	Euchretin D (12)	E. formosana	Roots	–	[22]
	Euchretin E (13)	E. formosana	Roots	–	[22]
	Euchretin G (14)	E. japonica	Roots	–	[23]
	Euchretin J (15)	E. formosana	Roots	Cytotoxicity	[21]
	Euchretin K (16)	E. formosana	Root	–	[21]
	Euchretin L (17)	E. formosana	Roots	–	[21]
	Euchretin M (18)	E. formosana	Roots	Cytotoxicity	[21]
	Euchretin N (19)	E. formosana	Roots	–	[21]
	Formosanatin A (20)	E. formosana	Roots	–	[22]
	Formosanatin B (21)	E. formosana	Roots	–	[22]
	Formosanatin C (22)	E. formosana	Roots	–	[22]
	Formosanatin D (23)	E. formosana	Roots	–	[22]
	Euchretin B (24)	E. formosana	Stems	–	[24]
	Euchretin C (25)	E. formosana	Stems	–	[24]
	Euchretin F (26)	E. japonica	Roots	–	[23]
	Euchretin H (27)	E. japonica	Roots	–	[23]
	Euchretin I (28)	E. tubulosa	Roots	Anti-inflammatory	[25, 36]
	Desmoxyphyllin A (29)	D. oxyphyllum	Leaves	–	[26]
	Desmoxyphyllin A 7-O-β-D-glucopyranoside (30)	D. oxyphyllum	Leaves	–	[26]
	Desmoxyphyllin B (31)	D. oxyphyllum	Leaves	–	[26]
	Desmoxyphyllin B 7-O-β-D-glucopyranoside (32)	D. oxyphyllum	Leaves	–	[26]
	Lisetinone (33)	P. erythrina	Root barks	–	[28]
	Lisetm hydrate (34)	P. erythrina	Root barks	–	[28]
	Lisetin (35)	P. erythrina	Root barks	–	[28]
	8-prenyl-lisetin (36)	P. erythrina	Root barks	–	[28]
	Piscerythrol (37)	P. erythrina	Root barks	–	[28, 29]
	Obiongin (38)	D. elliptica D. oblonga	Aerial/roots	Insecticidal	[30, 32]
	Oblonginol (39)	D. oblonga	Roots	–	[30]
	Erysenegalensein J (40)	E. seneoalensis	Stem barks	–	[31]
	6,4'-dihydroxy-7,5'-dimethoxycoumaronochromone (41)	D. elliptica	Aerial parts	Insecticidal	[32]
	Erythrinasubumbrin A (42)	E. subumbrans	Twigs/leaves	Anti-inflammatory	[33]
	(+)-(2S,3R)-Erythrinasubumbrin B (43)	E. subumbrans	Twigs/leaves	Anti-inflammatory	[33]
	(−)-(2R,3S)-Erythrinasubumbrin B (44)	E. subumbrans	Twigs/leaves	Anti-inflammatory	[33]
	Lupinol C (45)	E. subumbrans	Twigs/leaves	Anti-inflammatory	[33]
	3,5,7,4'-tetrahydroxy-coumaronochromone (46)	D. styracifolium	Aerial	–	[34]
	Nor-dehydrodeguelin (47)	L. nicou	Roots	–	[35]
	(-)-nor-dehydrorotenone (48)	L. nicou	Roots	–	[35]
	Hirtellanine A (49)	C. hirtella	Roots	Immunomodulatory	[8]
	4', 5'-dihydroxy-5,7-dimethoxy-6-(3-methylbut-2-enyl)coumaronochromone (50)	C. hirtella	Roots	Immunomodulatory	[36, 37]
	3,8,9,16-tetrahydroxy-18-methoxy-2-((R)-5-methoxy-2,2-dimethyl-7,8-dihydro-2H, 6H-pyrano[3,2-g]chromen-7-yl)-17-(3-methylbut-2-en-1-yl)-11H-10b,5a-(epoxy[1,2]benzeno)benzofuro[2,3-b]chromen-11-one (51)	C. hirtella	Roots	–	[37]
	Sophorophenolone (52)	S. japonica	Pericarps	–	[38]
	Dalbergichromone (53)	D. boehmii	Leaves/heartwoods	–	[3]
	Eriocoumaronochromone (54)	E. robustum	Twigs	Antibacterial	[2]
	(2R,3S)-3,7,4'-trihydroxy-5-methoxycoumaronochromone (55)	A. americana	Rhizomes	Anti-inflammatory	[15]
	7,3'-dihydroxy-2',4'-dimethoxycoumaronochromone (56)	M. lasiantha	Roots	–	[39]
	Cajasan (57)	C. cajan L	Cell culture	Anti-inflammatory	[40]
	Ayamenin A (58)	I. pseudacorus	Leaves	–	[41]
	Ayamenin B (59)	I. pseudacorus	Leaves	–	[41]
	Ayamenin C (60)	I. pseudacorus	Leaves	–	[41]
	Ayamenin D (61)	I. pseudacorus	Leaves	–	[41]
	5,7,3'-trihydroxy-6-methoxycoumaronochromone (62)	I. pseudacorus	Leaves	–	[41]
	Irisbungin (63)	I. bungei	Leaves	–	[42]
	Urophyllumol (64)	U. chinensis	Branche/leaves	–	[43]
	Boeravinone J (65)	B. diffusa	Roots	–	[44]
	Boeravinone R (66)	B. diffusa	Roots	–	[45]
	Boeravinone Y (67)	A. nana	Cell culture	Anti-inflammatory	[7]
	Aervin A (68)	A. persica	Whole plant	Antibacterial	[46, 47]
	Aervin B (69)	A. persica	Whole plant	Antibacterial	[46, 47]
	Aervin C (70)	A. persica	Whole plant	Antibacterial	[46, 47]
	Cristatone I (71)	C. cristata	Inflorescences	–	[48, 49]
	Cristatone Ⅱ (72)	C. cristata	Inflorescences	Cytotoxicity	[6, 48, 49]
	Suaeglaucin A (73)	S. glauca	Whole plant	–	[50]
	Agrisquarin D (74)	A. squarrosum L	Whole plant	Anti-inflammatory	[51]
	Agrisquarin E (75)	A. squarrosum L	Whole plant	Anti-inflammatory	[51]
	(±)-Agrisquarin G (76)	A. squarrosum L	Whole plant	Anti-inflammatory	[51]
	Suaeglaucin C (77)	S. glauca	Rhizomes	Cytotoxicity	[52]
	Baeckein F (78)	B. frutescens L	Roots	Anti-inflammatory	[9]
	Baeckein G (79)	B. frutescens L	Roots	Anti-inflammatory	[9]
	Baeckein H (80) R = β-D-glu	B. frutescens L	Roots	Anti-inflammatory	[9]
	Baeckein I (81) R = β-D-glu	B. frutescens L	Roots	Anti-inflammatory	[9]
	Lotuschromone (82)	mycorrhiza	Cell culture	–	[15]
	Ficusaltin C (83)	F. altissima	Fruits	–	[18, 53]
	Ficusaltin D (84)	F. altissima	Fruits	Anti-inflammatory	[18, 53]
	Ficusaltin E (85)	F. altissima	Fruits	–	[53]
	Ficusaltin F (86)	F. altissima	Fruits	–	[53]
	(2R,3S)-3,5,7-trihydroxy-4'-methoxycoumaronochromone (87)	F. altissima	Fruits	–	[53]
	(2S,3R)-3,5,7-trihydroxy-4'-methoxycoumaronochromone (88)	F. altissima	Fruits	–	[53]
	(2S,3R)-6-(3-methyl-2-buten-1-yl)-3,5,7-trihydroxy-4'-methoxycoumaranochroman-4-one) (89)	F. altissima	Fruits	–	[18]
	(2R,3S)-6-(3-methyl-2-buten-1-yl)-3,5,7-trihydroxy-4'-methoxycoumaranochroman-4-one (90)	F. altissima	Fruits	–	[18]
	(2S,3R)-6-(3-methyl-2-buten-1-yl)-3,5,7,4'-tetrahydroxy-coumaranochroman-4-one (91)	F. altissima	Fruits	–	[18]
	(2R,3S)-6-(3-methyl-2-buten-1-yl)-3,5,7,4'-tetrahydroxy-coumaranochroman-4-one (92)	F. altissima	Fruits	–	[18]

Analysis of their distribution indicates that coumaronochromones occur predominantly within the Fabaceae family, from which more than half (64%) of all known derivatives have been isolated. The Moraceae family represents the second most significant source, accounting for 14% of reported compounds. Notably, approximately 20% of all coumaronochromones have been identified from plants belonging to the genus Euchresta (Fabaceae). Among these species, Euchresta japonica has a long history of use in traditional Chinese medicine (TCM), where it is employed for its heat-clearing, detoxifying, throat-soothing, and anti-inflammatory properties.

2.1 Fabaceae

Roots of Lupinus albus L.: lupinalbins A–E (1–5), and lupinalbin G (6) [12, 13].

Roots of Lupinus luteus: lupinalbins A and B (1 and 2) [12, 14, 15], lupinalbin D (4) [12], lupinalbin F (7) [12, 16], lupinalbin H (8) [17], lupilutin (9), and lupalbin B (10) [12, 18, 19].

Roots of Euchresta formosana: euchretin A (11) [20, 21], euchretins D and E (12 and 13) [22], euchretin G (14) [23], euchretins J-N (15–19), formosanatins A-D (20–23) [22].

Stems of Euchresta formosana: euchretins B and C (24 and 25) [24].

Roots of Euchresta japonica: euchretin G (14), euchretins F and H (26 and 27)[23].

Roots of Euchresta tubulosa: euchretin I (28) [25].

Leaves of Desmodium oxyphyllum: desmoxyphyllin A (29), desmoxyphyllin A 7-O-β-D-glucopyranoside (30), desmoxyphyllin B (31), desmoxyphyllin B 7-O-β-D-glucopyranoside (32) [26].

Root barks of Piscidia erythrina: lisetinone (33), lisetm hydrate (34), lisetin (35), 8-prenyl-lisetin (36), ptscerythro (37) [27, 28, 29].

Roots of Derris oblonga: obiongin (38) and oblonginol (39) [30].

Stem barks of Erythrina seneoalensis: erysenegalensein J (40) [31].

Arial parts of Derris elliptica: obiongin (38) and 6,4'-dihydroxy-7,5'-dimethoxy-coumaronochromone (41) [30, 32].

Twigs and leaves of Erythrina subumbrans: erythrinasubumbrin A (42) and (+)-erythrinasubumbrin B (43), (−)-erythrinasubumbrin B (44), and lupinol C (45)[33].

Arial parts of Desmodium styracifolium: 3,5,7,4'-tetrahydroxycoumaronochromone (46) [34].

Roots of Lonchocarpus nicou: nor-dehydrodeguelin (47) and (-)-nor-dehydrorotenone (48) [35].

Roots of Campylotropis hirtella: hirtellanine A (49) [8], 4',5'-dihydroxy-5,7-dimethoxy-6-(3-methylbut-2-enyl)coumaronochromone (50) [36] and 3,8,9,16-tetrahydroxy-18-methoxy-2-((R)-5-methoxy-2,2-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-yl)-17-(3-methylbut-2-en-1-yl)-11H-10b,5a-(epoxy[1,2]benzeno)benzofuro[2,3-b]chromen-11-one (51) [37].

Pericarps of Sophora japonica: sophorophenolone (52) [38].

Leaves and heartwood of Dalbergia boehmii: dalbergichromone (53) [3].

Twigs of Eriosema robustum: eriocoumaronochromone (54) [2].

Rhizomes of Apios americana: (2R,3S)-3,7,4'-trihydroxy-5-methoxycoumaronochromone (55) [15].

Roots of Millettia lasiantha: 7,3'-dihydroxy-2',4'-dimethoxycoumaronochromone (56) [39].

Roots of Cajanus cajan L.: cajasan (57) [40].

2.2 Iridaceae

Leaves of Iris pseudacorus: ayamenins A–D (58–61), 5,7,3'-trihydroxy-6-methoxycoumaronochromone (62) [41].

Leaves of Iris bungei Maxim.: irisbungin (63) [42].

2.3 Rubiaceae

Twigs and leaves of Urophyllum chinense Merr. & Chun: urophyllumol (64) [43].

2.4 Nyctaginaceae

Roots of Boerhaavia diffusa: boeravinone J (65) [44] and boeravinone R (66) [45].

Cell culture of Abronia nana: boeravinone Y (67) [7].

2.5 Amaranthaceae

Whole plant of Aerva persica: aervins A–C (68–70) [46, 47].

Inflorescences of Celosia cristata: cristatones Ⅰ and Ⅱ (71 and 72) [48, 49].

Whole plant of Suaeda glauca: suaeglaucin A (73) [50].

Whole plant of Agriophyllum squarrosum: agrisquarins D and E (74 and 75), and (±)-agrisquarin G (76) [51].

Rhizomes of Suaeda glauca: suaeglaucin C (77) [52].

2.6 Myrtaceae

Roots of Baeckea frutescens L.: baeckeins F–I (78–81) [9].

2.7 Arbuscular mycorrhizal fungi

Cell culture of Arbuscular mycorrhiza: lotuschromone (82) [15].

2.8 Moraceae

Fruits of Ficus altissima: lupinalbin B (2), lupinalbin D (3), ficusaltins C–F (83–86), (2R,3S)-3,5,7-trihydroxy-4'-methoxycoumaronochromone (87), (2S,3R)-3,5,7-trihydroxy-4'-methoxycoumaronochromone (88), (2S,3R)-6-(3-methyl-2-buten-1-yl)-3,5,7-trihydroxy-4'-methoxycoumaranochroman-4-one) (89), (2R,3S)-6-(3-methyl-2-buten-1-yl)-3,5,7-trihydroxy-4'-methoxycoumaranochroman-4-one (90), (2S,3R)-6-(3-methyl-2-buten-1-yl)-3,5,7,4'-tetrahydroxycoumaranochroman-4-one (91), and (2R,3S)-6-(3-methyl-2-buten-1-yl)-3,5,7,4'-tetrahydroxycoumaranochroman-4-one (92) [18, 53, 54].

3 Bioactivities

Despite no coumaronochromone-derived drugs having reached clinical development or the market, natural coumaronochromones exhibit diverse biological activities, notably including anti-inflammatory, antibacterial, cytotoxicity, insecticidal, and immunomodulatory properties (Fig. 1). These findings underscore the potential of coumaronochromones as a valuable source of bioactive leads worthy of further investigation.

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3.1 Anti-inflammatory

Euchretin F (28) demonstrated significant inhibitory activity against arachidonic acid (AA)- and collagen-induced platelet aggregation [36].

Erythrinasubumbrin A (42), (+)-erythrinasubumbrin B (43), (-)-erythrinasubumbrin B (44), and lupinol C (45) significantly suppressed NO production at 10 μM in LPS-stimulated BV-2 cells, with inhibition rates of 37.50%, 24.76%, 40.92%, and 86.17%, respectively (p < 0.05) [33].

(2R,3S)-3,7,4'-Trihydroxy-5-methoxycoumaronochromone (55) showed marked anti-inflammatory activity in vitro, effectively inhibiting LPS-induced NO production in RAW 264.7 macrophages with an IC₅₀ of 0.38 ± 0.04 μM, suggesting its potential to mitigate inflammatory responses via suppression of excessive NO generation [15].

Boeravinone Y (67) was found to effectively inhibit HMGB1-mediated septic responses induced by LPS. In a cecal ligation and puncture (CLP)-induced sepsis model, this compound enhanced macrophage phagocytic activity and promoted bacterial clearance in both peritoneal fluid and blood of septic mice [7].

The anti-inflammatory activities of baeckeins F–I (78–81) were also examined in LPS-stimulated RAW 264.7 cells. Following MTT viability testing, baeckein I (81) displayed the highest NO-inhibitory activity, with an IC₅₀ of 15.2 μM, comparable to that of the positive control indomethacin (IC₅₀ = 13.8 μM) [9].

Ficusaltin D (84) exhibited notable anti-neuroinflammatory effects. It significantly suppressed LPS-induced NO production in BV-2 cells and down-regulated the expression of iNOS, IL-6, and IL-1β. Furthermore, the compound inhibited nuclear translocation of NF-κB, indicating a multi-target mechanism underlying its anti-neuroinflammatory activity [53].

Cajasan (57), agrisquarin D (74), agrisquarin E (75), and (±)-agrisquarin G (76), exhibited certain inhibitory rates of 51.99 ± 4.26%, 5.77 ± 1.24%, 26.54 ± 1.80%, and 16.10 ± 1.04%, respectively, in inhibition of LPS-induced NO production in RAW 264.7 cells (with L-NMMA as a positive control, 52.01 ± 1.96% inhibition) [40, 51].

3.2 Antibacterial

Compound 54 exhibited weak antimicrobial activity, with minimum inhibitory concentrations (MICs) > 150 μg/mL against two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), two Gram-negative bacteria (Klebsiella pneumoniae and Escherichia coli), one fungus (Candida albicans), and one yeast (Saccharomyces cerevisiae)[2].

Imran et al. found aervins A–C (68–70) exhibited notable antibacterial activity against a panel of bacterial strains, with MIC values ranging from 60.05 to 79.21 μg/mL. In addition, compounds 68–70 showed carbonic anhydrase inhibitory activity, with IC₅₀ values of 19.01, 18.24, and 18.65 μM, respectively. These findings highlight their promising bioactivity and suggest their potential as novel pharmacophores for the treatment of conditions such as glaucoma, epilepsy, and cystic fibrosis [47].

3.3 Cytotoxicity

At a concentration of 10 μg/mL, euchretin A (11), euchretin J (15), and euchretin M (18) exhibited moderate inhibitory effects against the human hepatoma cell line 59 T, with inhibition rates of 52.0%, 86.5%, and 71.5%, respectively. In addition, compound 15 showed an inhibition rate of 53.0% against the human gastric cancer cell line SCM-1 at the same concentration [21]. In a separate study on the same plant, coumaronochromone 50 was reported to inhibit prostate-specific antigen (PSA) secretion with an IC₅₀ value of 0.28 μM, while displaying low cytotoxicity [36].

The inflorescences of Celosia cristata are used in TCM for hemostasis, as documented in Chinese Pharmacopoeia (2025) [55]. Its constituent, cristatone Ⅱ (72), exhibited significant inhibitory activity against HeLa and BGC-823 cancer cell lines with IC₅₀ values of 23.82 and 3.34 μM, respectively [6].

Suaeglaucin C (77) exhibited cytotoxicity on HCT116 cells at 30 and 50 μM, and showed marked lethality with a median lethal concentration (LC₅₀) of 9.41 μM in healthy zebrafish embryos [52].

3.4 Insecticidal

Obiongin (38) exhibited insecticidal activity against the larvae of Aedes albopictus, with a LC₅₀ value of 5.85 mg/L. In cytotoxicity evaluations, 38 demonstrated potent inhibitory effects against both Spodoptera litura (SL) cells and the insect cell lines BTI-TN-5B1-4 (Hi-five). Compound 41 similarly showed high toxicity toward these cell lines, with inhibition rates of 68.41% against SL cells and 56.11% against Hi-five cells. Notably, the cytotoxic activities of both 38 and 41 were significantly higher than those of the positive control rotenone (which exhibited inhibition rates of 20.83% and 21.53% against SL and Hi-five cells, respectively) [32].

3.5 Immunomodulatory

Campylotropis hirtella, a shrub widely distributed in subtropical regions of China, has traditionally been used in folk medicine, with its stems and roots employed for the treatment of benign prostatic hyperplasia (BPH). The plant is recognized for its rich profile of flavonoids, indicating a well-developed flavonoid biosynthetic system. Among these, the coumaronochromones hirtellanine A (49) and 4', 5'-dihydroxy-5,7-dimethoxy-6-(3-methylbut-2-enyl)coumaronochromone (50) were isolated from the roots of C. hirtella. In vitro studies revealed that compound 49 exhibits potent immunosuppressive activity with IC₅₀ values of 0.06 µM against B-lymphocyte proliferation and 0.92 µM against T-lymphocyte proliferation. Cytotoxicity assays using mouse splenic lymphocytes showed that 49 possessed low cytotoxicity, with CC₅₀ values of 3.03 µM (B-cells) and 26.32 µM (T-cells), suggesting its potential as a promising lead for novel immunosuppressive agents [8]. Similarly, compound 50 demonstrated significant immunosuppressive activity in mitogen-induced mouse splenocyte proliferation assays, with IC₅₀ values of 0.28 µM (B-cells) and 1.55 µM (T-cells), while maintaining low cytotoxicity (CC₅₀ = 1.34 µM) [36, 37].

4 Construction of the coumaronochromone core

As outlined in Scheme 2, five main strategies have been reported to construct the core scaffold of coumaronochromones. The longest linear sequence from starting materials (SM) to the coumaronochromone skeleton consists of 8 steps, while the shortest requires only 4 steps. These synthetic approaches generally proceed through one of three key intermediates (Ⅰ–Ⅲ). Although direct cross-coupling between a chromone C-3 position and an aryl halide may appear efficient [11], this route often limits the late-stage introduction of polyhydroxy and other substituents [56]. Therefore, the following strategies have been developed: Route A employs a Suzuki–Miyaura cross-coupling to afford isoflavone I, which subsequently undergoes intramolecular oxidative cyclization to form the coumaronochromone core [57, 58]. Route B involves oxidative rearrangement of a chalcone to give isoflavone I, followed by intramolecular oxidative cyclization to yield the target structure [59]. Route C proceeds via Friedel–Crafts acylation of a phenol with a benzoic acid derivative to generate the key α-aryl phenone intermediate Ⅱ. This intermediate is then condensed and cyclized to isoflavone I, and finally oxidized to the coumaronochromone [60]. Route D utilizes a Buchwald–Hartwig-Miura (BHM)-arylation between an acetophenone and a bromobenzene to produce α-aryl phenome Ⅱ, which is transformed into the coumaronochromone via a tandem condensation/oxidative cyclization sequence [61]. Route E relies on nucleophilic addition–elimination between an activated chromone (C-2 position) and a phenol to give the key 2-phenoxychromone intermediate Ⅲ. Intramolecular cross-dehydrogenative coupling (CDC) then delivers the coumaronochromone [48].

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4.1 Suzuki–Miyaura cross-coupling enabled total syntheses of lupinalbins A and H

Van Heerden et al. used resorcinol 3a and phloroglucinol 3d as the starting materials for total syntheses of lupinalbins A and H. Starting from the protection of the phenolic hydroxyl groups of 3a with MOM chloride, followed by iodination, afforded the iodobenzene 3b. This intermediate underwent lithium-iodine exchange, nucleophilic substitution with B(OiPr)₃, and subsequent hydrolysis with NH₄Cl to give phenylboronic acid 3c. Concurrently, phloroglucinol 3d was subjected to MOM protection and then condensed with DMF-DMA to furnish enamine 3e. Treatment of 3e with iodine induced cyclization and iodination, providing 3-iodochromone 3f as the major product, along with a minor amount of iodobenzene by-product 3f′ (Scheme 3) [57]. Subsequently, a Suzuki–Miyaura cross-coupling between 3c and 3f then delivered isoflavone 3g. Deprotection of the MOM protections using HCl/MeOH afforded isoflavone 3h. Subsequent oxidation with DDQ, proceeding via hydrogen atom transfer (HAT) and single-electron transfer (SET) pathways to generate key intermediates i and ii, enabled an intramolecular cross-dehydrogenative coupling (CDC) between the 2′-hydroxy group on the B-ring with the C-2 site. This key step successfully furnished the natural product lupinalbin A (1). Finally, an aldol reaction between prenal and lupinalbin A (1) yielded intermediate 3j, which spontaneously underwent an intramolecular [4 + 2] cyclization (via transition state iii) to complete the synthesis of the natural product lupinalbin H (8) [58].

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4.2 Tl(Ⅲ)-mediated oxidative rearrangement enabled the total synthesis of lupinalbin A and lupilutin

Tsukayama and co-workers reported the total syntheses of lupinalbin A and lupilutin starting from functionalized substrates 4a–c, which were first converted via aldol addition, protection (Ac₂O), and elimination sequences to furnish chalcones 4d and 4e (Scheme 4). These intermediates subsequently underwent a Tl(Ⅲ)-mediated oxidative rearrangement (via intermediates i–iii) to yield acetals 4f and 4g. Under basic conditions (10% NaOH/MeOH), 4f and 4g then underwent 1,4-addition/elimination to afford isoflavones 4h and 4i, respectively. Isoflavone 4h was subjected to debenzylation using Pd/C under a H₂ atmosphere to give 4j, which then underwent a DDQ-mediated oxidative cyclization successfully yielding the natural product lupinalbin A (1).

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In parallel, isoflavone 4i was coupled with 2-methyl-3-butyn-2-ol via a Pd-catalyzed Sonogashira cross-coupling reaction to afford 4k. Subsequent debenzylation (Pd/C, H₂) furnished isoflavone 4l. Finally, treatment of 4l with o-chloranil—an oxidant that operates through a similar mechanism to that of DDQ-enabled CDC reaction completed the synthesis of the natural product lupilutin (9) (Scheme 4) [59].

4.3 Friedel–Crafts acylation enabled total synthesis of lupinalbin A

In the total synthesis of lupinalbin A (1) reported by Miller et al., 2,4-dimethoxyphenylacetic acid (5a) was condensed with 1,3,5-trimethoxybenzene through Friedel–Crafts acylation to afford the α-aryl phenome 5b. Selective demethylation of 5b with AlCl₃ in chloroform gave the ortho-hydroxy phenome 5c, which subsequently underwent intramolecular cyclization using CH(OMe)₃ in the presence of morpholine to furnish isoflavone 5d. Treatment of 5d with BBr₃ effected the regioselective demethylation, yielding the 2′-hydroxyisoflavone 5e. Finally, oxidative cyclization with DDQ followed by global demethylation using pyridinium hydrochloride provided 1 (Scheme 5) [60].

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4.4 BHM arylation enabled total synthesis of cristatone Ⅱ

The BHM arylation represents an efficient method for aryl group introduction [62–65]. In our laboratory, a de novo synthetic route was developed starting from acetophenone 6a and bromobenzene 6b (Scheme 6). A palladium-catalyzed intermolecular BHM arylation afforded the corresponding α-aryl phenone, which after debenzylation (Pd/C, H₂) yielded α-aryl phenome 6c. Subsequently, 6c was treated with activated DMF under the conditions of DDQ/BF₃·OEt₂/MsCl to generate the reactive intermediate i. In the presence of DDQ, intermediate i underwent a tandem oxidative cyclization to furnish coumaronochromone 6d. Selective methylation of 6d (MeI, K₂CO₃) then provided 6e. Finally, application of a modified Vilsmeier–Haack reaction (TiCl₄, dichlorodimethyl ether) followed by selective reduction and methylation (NaBH₃CN/H₂SO₄/MeOH) completed the total synthesis of the natural product cristatone Ⅱ (72) [61].

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4.5 Chromone-based 1,4-addition/elimination enabled total synthesis of lupinalbin A

In the synthetic route developed by Xu and Chen et al., 2-hydroxyacetophenone 7a was converted to 2-thiochromone 7b via a three-step sequence involving nucleophilic addition to CS₂, cyclization, and elimination. Subsequent oxidation of 7b with mCPBA furnished the activated 2-mesylchromone 7c. Treatment of 7c with the phenol derivative 7d in the presence of NaH promoted a 1,4-addition/elimination process, affording the 2-phenoxychromone 7h. Notably, 7h could also be prepared from a corresponding 3-triazolochromone via an analogous transformation. Palladium-catalyzed CDC reaction of 7h then delivered the coumaronochromone scaffold 7i. Final demethylation with BBr₃ completed the synthesis of the natural product lupinalbin A (1) (Scheme 7) [48, 66, 67].

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5 Conclusion

Coumaronochromones represent a significant subclass of natural isoflavonoids. A comprehensive review summarizing their natural occurrence, botanical origins, biosynthetic pathways, pharmacological activities, and chemical synthesis strategies will provide valuable insights and facilitate further research and development of these natural products. These compounds are primarily distributed in plants of the Fabaceae and Moraceae families. Notably, some source plants, such as Euchresta formosana and Desmodium styracifolium, have a long history of use in TCM, underscoring their therapeutic relevance. Corresponding coumaronochromones exhibit a broad spectrum of bioactivities, including anti-inflammatory, antibacterial, antitumor, and immunomodulatory effects, highlighting their considerable potential in drug discovery. In addition, the chemical synthesis of coumaronochromones has been achieved through diverse strategies. Conventional approaches for constructing the core benzofuro[2,3-b]chromenone scaffold include Suzuki–Miyaura cross-coupling, Tl-mediated oxidative rearrangement, Friedel–Crafts acylation, chromone-based 1,4-addition/elimination, and subsequent DDQ-mediated cross-dehydrogenative coupling (CDC) cyclization. Recently, a novel modular strategy featuring a BHM arylation/DDQ-oxidative cyclization sequence was developed. This efficient four-step protocol offers mild reaction conditions and excellent functional-group tolerance, and has been successfully applied to the concise seven-step total synthesis of the natural product cristatone Ⅱ. With the rapid advancement of green chemistry and synthetic biology, more efficient and environmentally benign synthetic methodologies for this promising class of compounds are anticipated to emerge.

Notes

Author contributions

D. X, Q. L, and W. W were contributed equally; D. X, Q. L, and W. W carried out all references collection, data analysis, figures preparation, and wrote the manuscript. M.‑F. X and J.‑C. L assisted in the figures preparation. K. L revised the manuscript. D. L and W.‑J. W checked the manuscript. L.‑D. S supervised all work presented in this manuscript. All authors above reviewed this manuscript. All data were generated in‑house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy. The author(s) read and approved the final manuscript.

Funding

The authors are grateful to the financial support from National Natural Science Foundation of China (82260683), the Yunnan Fundamental Research Projects-Joint Special Funds of Yunnan University of Chinese Medicine (202401AZ070001-007 and 202401AZ070001-106), the Start-up Fund of Yunnan University of Chinese Medicine (2019YZG03), the Bioactive Ethnopharmacol Molecules Chemical Conversion and Application Innovation Team of Department of Education of Yunnan Province (2022), and Science Research Foundation of Department of Education of Yunnan Province (2026Y0644).

Data availability

The data availability is not applicable.

Declarations

Competing interests

The authors confirm that there are no known conflicts of interest associated with this publication.