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Article

Total Synthesis of Lineaflavones A, C, D, and Analogues

by
Rui Wang
1,
Yu Fu
1,2,
Ran Ma
1,2,
Hongzhen Jin
1,* and
Wei Zhao
1,*
1
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
2
Tianjin International Joint Academy of Biomedicine, Tianjin 300457, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(5), 2373; https://doi.org/10.3390/molecules28052373
Submission received: 14 February 2023 / Revised: 27 February 2023 / Accepted: 1 March 2023 / Published: 4 March 2023
(This article belongs to the Special Issue Chemical Synthesis of Natural Products)
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Abstract

The first total synthesis of lineaflavones A, C, D, and their analogues has been accomplished. The key synthetic steps include aldol/oxa-Michael/dehydration sequence reactions to assemble the tricyclic core, Claisen rearrangement and Schenck ene reaction to construct the key intermediate, and selective substitution or elimination of tertiary allylic alcohol to obtain natural compounds. In addition, we also explored five new routes to synthesize fifty-three natural product analogues, which can contribute to a systematic structure–activity relationship during biological evaluation.

Graphical Abstract

1. Introduction

Flavonoids are a class of compounds that are produced by plants as secondary metabolites and exhibit important functions in reproduction; these compounds can be classified as flavanones, flavanols, isoflavones, flavones, and flavonols [1,2]. Modern pharmacological research has revealed that flavonoids have a wide range of bioactivities, such as antitumor, antioxidant, anti-inflammatory, and antivirus [1,3,4]. Flavonoids can affect the behavior of cellular systems by modulating the activity of enzymes, exerting beneficial effects on the organism [5]. A large variety of flavonoids have been isolated and characterized [6,7], but lead compounds with new biological activities remain to be discovered. The synthesis and identification of bioactive derivatives are crucial for intensive studies to discover lead compounds with novel structures.
Lineaflavones A, C, and D are natural flavonoids isolated from the aerial parts of Tephrosialinearis by Spiteller and co-workers in 2020 (Figure 1) [8]. The structures of the compounds were elucidated on the basis of their NMR and HRMSn data. The anti-inflammatory effects of the isolated compounds were evaluated by measuring the levels of IL-6 and TNF-α and the tested compounds inhibited the production of IL-6 and TNF-α. Further study of these natural products and their analogues may provide new guidance for drug discovery. Due to their intriguing biological activity and unique structure; herein, the first total synthesis of lineaflavone A, lineaflavone C, and lineaflavone D was described. In addition, we also synthesized fifty-three flavonoid derivatives. Newly synthesized derivatives could be suitable for evaluating anti-inflammatory activity.

2. Results and Discussion

The isolated compounds with a 2″,2″-dimethylpyran ring and a linear side chain contain a C6-C3-C6 skeleton structure [9]. The protocol used to synthesize target molecules is depicted in the retrosynthetic analysis in Scheme 1. Lineaflavones A and D could be synthesized from intermediate 4 through substitution or elimination. Construction of the key intermediate 4 by photooxygenation of prenylphenol followed by a reduction formed the structure of 3-hydroxy-3-methylbut-enyl based on the Schenck ene reaction and compound 5 as the reaction substrate [10]. Compound 5 could be derived from 5,7-dihydroxy-2-phenyl-4H-chromen-4-one (6), 3,3-dimethylallyl bromide (7), 3-chloro-3-methylbut-1-yne (8) and iodomethane (9) by the sequential chemical reactions. Compound 6 could be synthesized from the commercially available materials 1-(2,4,6-trihydroxyphenyl)ethan-1-one (10) and benzaldehyde (11) through aldol/oxa-Michael/dehydration sequence reactions [11,12].
The coupling of compounds 10 and 11 affords compound 6 via the aldol reaction, I2-catalyzed oxa-Michael addition reaction, and dehydration reaction, which may suffer from poor functional group tolerance to exposed hydroxyl groups and thus lead to the production of some other unknown side-products [12,13]. Accordingly, the free hydroxyl groups of substance 10 were protected using the protecting groups with satisfactory yields. Our initial strategy was to use methoxymethyl (MOM) to protect the C2′, C4′-hydroxy groups of 10 selectively in 92% yield, and the MOM-protected compound 10 was reacted with benzaldehyde 11 to afford the intermediate (78% yield), which was further reacted to obtain 6 by intramolecular addition reaction, but we only detected the yield of intermediate 6 from 10% to 18% by screening different temperatures and solvents. The possible reason for the low yield comes from the fact that the condition of the I2-catalyzed oxa-Michael addition reaction necessitates elevated temperatures, which can result in the removal of the MOM group. Therefore, we selected methyl with higher chemical stability as the protecting group, and compound 10 was converted to intermediate 14 by the sequential chemical reactions, resulting in a 68% overall yield (Scheme 2). The deprotection of methyl groups of 14 was smoothly accomplished using HBr in AcOH to obtain compound 6 (78% yield) [14].
Chemoselective propargylation of the C7-hydroxyl of compound 6 provided 15 in 70% yield, which underwent an aromatic Claisen rearrangement to furnish cyclization products 16 (52% yield) and 17 (41% yield) under high-temperature conditions of 250 °C [15,16]. Then the cyclization product 17 was prenylated with 3,3-dimethylallyl bromide 7 to afford 18 (80% yield) (Scheme 2). Compound 18 was subjected to the Claisen rearrangement reaction to establish the structure of 19, and we did not detect any products using montmorillonite K10 or Bi(OTf)3·4H2O as the catalyst at the beginning [17]. Finally, we selected Eu(fod)3 as the catalyst in refluxing chloroform to obtain the intermediate 19 (76% yield). Methylation of the free hydroxy group of 19 with iodomethane using NaH gave the corresponding compound 20 in an 82% yield. Compound 20 was converted to 21 via photooxygenation of prenylphenol followed by reduction at room temperature, which can yield tertiary allylic alcohol and secondary allylic alcohol based on the Schenck ene reaction [10], therefore we also obtained the byproduct 22. After a systematic investigation of catalysts and solvents, we determined to use Rose Bengal as a photosensitizer and MeOH as a solvent to give 21 and 22 in a 73% overall yield [18]. We turned to perform the Schenck ene reaction of 19 by using Rose Bengal, which only gave secondary allylic alcohol 23 as the main product (54% yield). An oxygen atom was introduced into compound 20 by alkene epoxidation with 3-chloroperoxybenzoic acid to produce compound 24 in 87% yield [19].
Having prepared tertiary allylic alcohol 21 successfully, we sought to construct the natural flavonoids 1 and 3. We first attempted to convert 21 to 1 by nucleophilic substitution reaction. We used iodomethane and dimethyl sulfate as methylation agents. Even though various alkalis, including K2CO3, KOH, NaOH, and NaH, of this reaction were screened, we failed to detect the transformation of 21 into the desired compound 1. One possible reason is that the tertiary alcohol has a strong steric hindrance effect. Given the fact that the tertiary alcohol is a typical substrate for dehydration, we then tried to use inorganic acid as a catalyst to achieve an elimination or substitution reaction. We only obtained the natural compound 3 with a 60% yield under the conditions of H2SO4 and MeOH in a 1:10 ratio (Table 1, entry 1). Changing the acid to HCl improved the yield (78% yield); however, we still detected compound 3 as the sole product (entry 2). After the systematic study of the reaction conditions, we found that decreasing the concentration of acid markedly improved the ratio of 1 (entries 3 and 4). When the concentration of HCl was further reduced, the proportion of 1 decreased, and the overall yield was also diminished (entries 5–7). The tertiary alcohol underwent transformation to give 1 as the major product by using the condition of entry 4. Based on the above research, we successfully synthesized the natural products lineaflavone A (1) (1.67% overall yield) and lineaflavone D (3) (2.50% overall yield). The spectroscopic data for synthetic 1 and 3 were well matched with those reported in the literature (Supplementary Tables S2A,B and S4A,B) [8].
The synthesis of natural product 2 from intermediate 19 is summarized in Scheme 3. Initially, we attempted to remove the methyl group of 21, followed by elimination, leading to compound 2. To liberate the hydroxyl group of compound 21, numerous attempts were made using different methods, including strong acids (HI and HBr), Lewis acids (AlCl3, BBr3, and BCl3), and inorganic base (NaNH2) [20,21]. None of these approaches provided the desired product. Thus, we selected the acetyl group to protect the C5-hydroxy group of 19. Acetylation of intermediate 19 provided Ac-protected compound 25 (88% yield) and the Schenck ene reaction of the latter with the photosensitizer Rose Bengal yielded secondary allylic alcohol 26 (36% yield) and tertiary allylic alcohol 27 (41% yield), whose conversion to 28 was achieved by selective elimination (76% yield). Deacetylation of 28 was smoothly accomplished with LiOH in tetrahydrofuran from 0 °C to 60 °C to afford compound 2 in a 97% yield [22]. The spectroscopic data for synthetic 2 were consistent with those reported for the natural product (Supplementary Tables S3A and S3B) (3.51 % overall yield) [8].
The byproduct 22 has a unique hydroxyisoprenyl group, and flavonoids containing this structure usually exhibit biological activities according to the literature [23,24,25,26]. Thus, we synthesized a series of novel derivatives. Esterification of the hydroxyl group of 22 with various acyl chlorides by using 4-Dimethylaminopyridine (DMAP) gave the corresponding ester compounds 29a–29i (yield from 65% to 83%) (Scheme 4A). Beyond that, we introduced different side chains at the 8-position of compound 17 to increase the structural diversity. Compound 30 was prepared from 17 by treatment with allyl bromide in the presence of NaH in DMF at room temperature. The resultant 30 underwent rearrangement reactions to give 31 in a 51% yield in two steps. Compound 31 was coupled with commercially available reagents under typical alkene metathesis reaction conditions to give 32a–32c (yield from 75% to 87%) (Scheme 4B) [27].
Compound 15 was subjected to an aromatic Claisen rearrangement to give the byproduct 16. After rationally screening different temperatures of the reaction, we found that the yield was enhanced from 52% to 95% at 120 °C, and compound 16 was the only product. Compound 16 was prenylated with 3,3-dimethylallyl bromide 7 to afford 33 (83% yield), which was further reacted in the presence of montmorillonite K10 to give the desired rearrangement product 34 (65% yield). Compounds 35a and 35b were synthesized from the methylation or esterification reaction of compound 34. The Schenck ene reaction was carried out to obtain 36a, 36c, 37a, and 37b. Next, the secondary allylic alcohol 36c was esterified and generated 40a–40e via a substitution reaction with various acyl chlorides. Compounds 38 and 41 were prepared through an elimination or substitution reaction using inorganic acid as a catalyst. Removal of the Ac protecting group from 36a and 38 with LiOH led to the final products 36b and 39 (Scheme 5A). Compound 33 was also converted to 42 in the presence of Eu(fod)3 as a catalyst by the [3, 3] sigmatropic rearrangement reaction, and we synthesized a new series of analogues 43a–43f by esterification or etherification of the free hydroxy group (yield from 65% to 89%) (Scheme 5B) [28].
We also designed and synthesized a series of chalcone derivatives with new chemical structures. Compound 44 was selectively substituted with 3-chloro-3-methylbut-1-yne in DMF to produce 45 (78% yield), which was converted to 46 via an intramolecular cyclization (93% yield). Subsequent protection of the 5-OH of 46 with NaH and 3,3-dimethylallyl bromide afforded 47 in an 86% yield. Compound 47 was subjected to Claisen rearrangement, methylation, and aldol reactions to establish the structures of 50a–50c (yield from 58% to 75%, three steps). Oxidation of 50a–50c with tetraphenylporphyin (Tpp) and subsequent treatment of the resulting peroxide with PPh3 in one-pot afforded the corresponding compounds 51a–51c and 52a–52c (yield from 35% to 49%). Interestingly, the tertiary allylic alcohol underwent a further transformation to give the diene under Schenck ene reaction conditions (Scheme 6). Beyond that, we removed the 2″,2″-dimethylpyran ring structure from compound 49 and synthesized the chalcone derivative 58 from the commercially available material 44 through the sequential chemical reactions in a 38% overall yield (Scheme 7).

3. Experimental Section

3.1. General Information

Unless otherwise stated, all reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions. Dimethylformamide (DMF) and dichloromethane (CH2Cl2) were distilled from calcium hydride and stored under argon. All other reagents were purchased at the highest commercial quality and used without further purification. Flash chromatography was performed using 200–400 mesh silica gel. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 aluminum sheets. TLC was visualized by one of the following methods: use of UV light (254 nm), exposure to iodine vapor, or treatment of acidic anisaldehyde.
NMR spectra were recorded on Bruker 400 MHz instruments and calibrated using residual solvent as an internal reference (1H NMR: CDCl3 = 7.26, DMSO-d6 = 2.50, Acetone-d6 = 2.05 and 13C NMR: CDCl3 = 77.16, DMSO-d6 = 39.52, Acetone-d6 = 29.84, 206.26). The coupling constant was reported in Hertz units (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. High-resolution mass spectra (HRMS) were obtained on an IonSpec QFT mass spectrometer with ESI ionization.

3.2. Materials

All solvents and commercially available chemicals were used as received without further purification unless otherwise stated.

3.3. Procedure for the Synthesis of Lineaflavones A, C, D

To a solution of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (2.00 g, 11.89 mmol) in anhydrous acetone (50 mL) was added K2CO3 (3.62 g, 26.17 mmol) and dimethyl sulfate (2.32 mL, 24.38 mmol). The reaction mixture was stirred at 60 °C for 4 h. The resulting mixture was cooled to room temperature, filtered, and washed with acetone. The filtrate was extracted with EtOAc (250 mL). The organic layer was washed three times with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 20:1) to afford 12 (2.10 g, 90% yield) as a white solid.
1H NMR (400 MHz, Acetone-d6) δ 13.97 (s, 1H), 6.07 (d, J = 2.7 Hz, 1H), 6.03 (d, J = 2.7 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), and 2.56 (s, 3H).
13C NMR (100 MHz, Acetone-d6) δ 203.88, 168.43, 167.41, 164.21, 106.52, 94.44, 91.40, 56.08, and 33.05.
To a solution of compound 12 (5.00 g, 25.50 mmol) and benzaldehyde (9.02 mL, 76.50 mmol) in EtOH (250 mL) was added NaOH (2.01 g, 50.10 mmol) at 0 °C. After stirring for 0.5 h, the resulting solution was stirred at 50 °C for 24 h before the addition of water and EtOAc. The aqueous phase was extracted three times with EtOAc (200 mL × 3), and the organic layers were successively washed three times with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1) to afford 13 (6.45 g, 89% yield) as a yellow solid.
1H NMR (400 MHz, Acetone-d6) δ 14.23 (s, 1H), 8.04 (d, J = 15.6 Hz, 1H), 7.82–7.73 (m, 3H), 7.54–7.39 (m, 3H), 6.14 (d, J = 2.1 Hz, 1H), 6.12 (s, 1H), 4.02 (s, 3H), and 3.89 (s, 3H).
13C NMR (100 MHz, Acetone-d6) δ 192.53, 168.29, 166.74, 162.91, 142.13, 135.51, 130.22, 129.00, 128.42, 127.46, 105.95, 93.79, 91.00, 55.68, and 55.24.
Compound 13 (0.3 g, 1.06 mmol) and iodine (26.90 mg, 0.11 mmol) were stirred in DMSO (25 mL) at 170 °C for 3 h. Then, the mixture was poured into an 80 mL solution of 10% Na2S2O3 and stirred. The precipitate was collected by filtration and washed with hexane. The crude product was recrystallized from ethanol and water (1:1) to yield the pure product 14 (0.25 g, 85%). Compound 14 was stirred in hydrobromic acid (33 wt.% solution in acetic acid) at 120 °C for 24 h. H2O and EtOAc were added to the reaction mixture, then the aqueous phase was extracted three times with EtOAc (150 mL × 3), and the organic layers were washed three times with brine (80 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 3:1) to afford 6 (0.21 g, 78% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.90 (s, 1H), 8.18–7.92 (m, 2H), 7.72–7.47 (m, 3H), 6.93 (s, 1H), 6.51 (s, 1H), and 6.22 (s, 1H).
13C NMR (100 MHz, DMSO-d6) δ 182.32, 164.91, 163.61, 161.95, 157.92, 132.44, 131.18, 129.52, 126.81, 105.63, 104.44, 99.49, and 94.58.
To a suspension of compound 6 (0.50 g, 1.97 mmol) in DMF (50 mL) was added K2CO3 (0.54 mg, 3.93 mmol), KI (0.49 mg, 2.95 mmol), CuI (18.75 mg, 0.09 mmol), and 3-chloro-3-methylbut-1-yne (0.42 mL, 3.74 mmol) at room temperature for 2 h. The resulting mixture was a light red solution. The reaction mixture was quenched by saturated aqueous NH4Cl (20 mL). The layers were separated, and the aqueous layer was extracted three times with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1) to afford 15 (0.44 g, 70% yield) as a yellow solid.
1H NMR (400 MHz, Acetone-d6) δ 12.80 (s, 1H), 8.11–8.05 (m, 2H), 7.66–7.53 (m, 3H), 7.00 (d, J = 2.2 Hz, 1H), 6.83 (s, 1H), 6.62 (d, J = 2.2 Hz, 1H), 3.39 (s, 1H), and 1.75 (s, 6H).
13C NMR (100 MHz, Acetone-d6) δ 182.50, 164.21, 162.12, 161.64, 157.22, 131.98, 131.28, 129.15, 126.47, 105.95, 105.49, 102.29, 97.47, 84.68, 76.39, 72.88, and 29.36.
A solution of 15 (280.40 mg, 0.88 mmol) in diethylaniline (20 mL) was stirred at 250 °C for 1 h. The resulting mixture was cooled to room temperature, and EtOAc was added to the reaction mixture. The organic layers were extracted three times with 1N HCl solution (100 mL × 3), and the organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 20:1) to afford 17 (114.96 mg, 41% yield) and 16 (145.81 mg, 52% yield) as a yellow solid.
17: 1H NMR (400 MHz, Chloroform-d) δ 13.03 (s, 1H), 7.98–7.78 (m, 2H), 7.58–7.45 (m, 3H), 6.72 (d, J = 9.6 Hz, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 5.62 (d, J = 9.6 Hz, 1H), and 1.48 (s, 6H).
13C NMR (100 MHz, Chloroform-d) δ 182.56, 163.75, 159.61, 157.15, 156.45, 131.78, 131.37, 129.09, 128.18, 126.26, 115.50, 105.73, 105.67, 105.60, 95.12, 78.05, and 28.32.
16:1H NMR (400 MHz, Chloroform-d) δ 12.79 (s, 1H), 8.10–7.75 (m, 2H), 7.62–7.48 (m, 3H), 6.79 (dd, J = 9.9, 1.5 Hz, 1H), 6.64 (s, 1H), 6.27 (s, 1H), 5.62 (dd, J = 9.9, 1.5 Hz, 1H), and 1.49 (s, 6H).
13C NMR (100 MHz, Chloroform-d) δ 182.69, 163.49, 161.79, 159.68, 151.98, 131.87, 131.45, 129.17, 127.60, 126.21, 114.83, 105.87, 105.52, 101.39, 100.40, 78.10, and 28.22.
To a solution of 17 (1.70 g, 5.31 mmol) in anhydrous DMF (50 mL) was added NaH (0.64 g, 15.92 mmol) and 3,3-dimethylallyl bromide (1.14 mL, 10.61 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with brine (50 mL). The aqueous layer was extracted three times with EtOAc (50 mL × 3). The combined organic layers were washed three times with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 8:1) to afford 18 (1.65 g, 80% yield) as a yellow solid.
1H NMR (400 MHz, Acetone-d6) δ 8.10–7.95 (m, 2H), 7.69–7.46 (m, 3H), 6.80 (s, 1H), 6.73 (d, J = 10.3 Hz, 1H), 6.66 (s, 1H), 5.86 (d, J = 10.3 Hz, 1H), 5.59 (m, 1H), 4.60 (d, J = 7.3 Hz, 2H), 1.75 (s, 3H), 1.67 (s, 3H), and 1.47 (s, 6H).
13C NMR (100 MHz, Acetone-d6) δ 175.74, 160.46, 158.67, 157.93, 154.01, 137.63, 131.58, 131.30, 130.59, 129.05, 125.99, 120.70, 116.47, 113.69, 112.83, 108.04, 100.54, 77.53, 71.47, 27.48, 25.09, and 17.19.
To a solution of 18 (0.10 g, 0.26 mmol) in anhydrous chloroform (20 mL) was added Eu(fod)3 (14 mg, 0.01 mmol). The resulting orange solution was stirred at 60 °C for 8 h and then the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1) to afford 19 (76 mg, 76% yield) as a white solid.
1H NMR (400 MHz, Acetone-d6) δ 13.21 (s, 1H), 8.16–7.95 (m, 2H), 7.72–7.50 (m, 3H), 6.79 (s, 1H), 6.66 (d, J = 10.0 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 5.24 (m, 1H), 3.53 (d, J = 7.1 Hz, 2H), 1.84 (s, 3H), 1.66 (s, 3H), and 1.48 (s, 6H).
13C NMR (100 MHz, Acetone-d6) δ 182.78, 163.74, 156.80, 154.47, 154.42, 131.88, 131.58, 131.28, 129.19, 128.40, 126.38, 122.30, 115.23, 107.59, 105.23, 105.20, 105.02, 77.91, 27.46, 24.99, 21.32, and 17.37.
IR (thin film): 2361, 2338, 1651, 1458, 1344, 1308, 873, 722, and 652 cm−1
m.p.: 485.8 °C
To a solution of 19 (0.60 g, 1.54 mmol) in anhydrous DMF (50 mL) was added NaH (0.86 g, 6.16 mmol) and CH3I (0.19 mL, 3.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with brine (50 mL). The aqueous layer was extracted three times with EtOAc (250 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1) to afford 20 (0.51 g, 82% yield) as a yellow solid.
1H NMR (400 MHz, Acetone-d6) δ 8.14–7.92 (m, 2H), 7.70–7.46 (m, 3H), 6.74 (d, J = 10.1 Hz, 1H), 6.66 (s, 1H), 5.89 (d, J = 10.1 Hz, 1H), 5.32–5.22 (m,1H), 3.84 (s, 3H), 3.61 (d, J = 7.0 Hz, 2H), 1.85 (s, 3H), 1.67 (s, 3H), and 1.49 (s, 6H).
13C NMR (100 MHz, Acetone-d6) δ 175.94, 160.49, 156.05, 155.11, 153.14, 131.94, 131.65, 131.28, 130.91, 129.11, 126.02, 121.98, 116.04, 113.43, 112.75, 112.45, 107.94, 77.54, 61.91, 27.44, 25.01, 21.88, and 17.45.
IR (thin film): 3068, 2921, 1699, 1654, 1242, 1165, 1121, 1099, 1027, 872, 689, and 650 cm−1
m.p.: 420.2 °C
Dried air was continuously bubbled through a MeOH (60 mL) solution of 20 (0.20 g, 0.49 mmol) and Rose Bengal (25.20 mg, 0.03 mmol) as the photosensitizer. A 500 W halogen lamp was used as the light source. The reaction mixture was irradiated and stirred at room temperature for 10 h. The crude residue was directly used without further purification. Triphenylphosphine (0.19 g, 0.74 mmol) was added, and the solution was stirred at room temperature for 16 h before being concentrated in vacuo. The crude residue was purified by flash chromatography (hexane:EtOAc = 4:1) to afford 21 (72.78 mg, 35%) and 22 (78.83 mg, 38%) as a white solid.
21: 1H NMR (400 MHz, Acetone-d6) δ 8.10–8.04 (m, 2H), 7.61–7.53 (m, 3H), 7.03 (d, J = 16.4 Hz, 1H), 6.90 (d, J = 16.4 Hz, 1H), 6.76 (d, J = 10.1 Hz, 1H), 6.68 (s, 1H), 5.92 (d, J = 10.1 Hz, 1H), 3.86 (s, 3H), 1.52 (s, 6H), and 1.44 (s, 6H).
13C NMR (100 MHz, Acetone-d6) δ 175.88, 160.60, 155.53, 155.24, 153.49, 144.58, 131.86, 131.29, 130.79, 129.05, 126.23, 116.02, 113.90, 112.80, 112.49, 110.89, 108.00, 77.82, 70.17, 61.95, 29.74, and 27.49.
IR (thin film): 1735, 1716, 1471, 1434, 1420, 1396, 1315, 1023, 773, and 651 cm−1
m.p.: 497.4 °C
22:1H NMR (400 MHz, Chloroform-d) δ 7.96–7.85 (m, 2H), 7.58–7.40 (m,3H), 6.84–6.69 (m, 2H), 5.74 (d, J = 10.1 Hz, 1H), 5.02 (s, 1H), 4.88 (s, 1H), 4.42 (dd, J = 8.0, 5.2 Hz, 1H), 3.91 (s, 3H), 3.17 (m, 2H), 2.46 (s, 1H), 1.90 (s, 3H), 1.52 (s, 3H), and 1.50 (s, 3H).
13C NMR (100 MHz, Chloroform-d) δ 177.45, 161.22, 156.73, 156.17, 153.81, 147.53, 131.71, 131.44, 130.37, 129.08, 126.17, 116.34, 112.87, 112.29, 110.93, 110.64, 108.06, 78.23, 75.59, 62.87, 30.01, 28.55, 28.39, and 17.88.
IR (thin film): 1621, 1522, 1405, 1329, 1244, 1064, 829, 702, and 539 cm−1.
m.p.: 492.8 °C
To a solution of 27 (100 mg, 0.22 mmol) in anhydrous MeOH (5 mL) was added HCl (0.3 mL). The reaction mixture was stirred at room temperature for 0.1 h. EtOAc was added to the reaction mixture. The organic layer was extracted three times with saturated sodium bicarbonate solution (100 mL × 3) and the organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 20:1) to afford 28 (72.93 mg, 76% yield) as a yellow solid.
1H NMR (400 MHz, Chloroform-d) δ 7.94–7.82 (m, 2H), 7.59–7.47 (m, 3H), 7.41 (d, J = 16.5 Hz, 1H), 6.88 (d, J = 16.5 Hz, 1H), 6.64 (s, 1H), 6.54 (d, J = 10.1 Hz, 1H), 5.81 (d, J = 10.1 Hz, 1H), 5.17 (s, 1H), 5.14 (s, 1H), 2.48 (s, 3H), 2.08 (s, 3H), and 1.54 (s, 6H).
13C NMR (100 MHz, Chloroform-d) δ 177.10, 169.53, 161.81, 156.43, 155.29, 155.14, 142.85, 137.72, 131.73, 131.68, 131.50, 129.13, 126.25, 118.03, 117.18, 115.53, 112.72, 112.53, 111.02, 108.18, 78.47, 28.46, 21.12, and 18.18.
IR (thin film): 3589, 1991, 1770, 1735, 1540, 1472, 1457, 1420, 1362, 1288, 670, and 577cm−1
m.p.: 414.2 °C
To a solution of 28 (0.10 g, 0.23 mmol) in anhydrous THF (20 mL) was added 3M LiOH (2 mL). The reaction mixture was stirred at 60 °C for 3 h. EtOAc was added to the reaction mixture. The organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1) to afford 2 (87.49 mg, 97% yield) as a yellow solid.
The 1H NMR and 13C NMR spectra of 2 are summarized in Tables S2A,B.
Compound 3 and 1 was synthesized by following a similar procedure as that of 28.
The 1H NMR and 13C NMR spectra of 3 and 1 are summarized in Tables S3A,B and 4A,B.
Other experimental procedures and characterization data (1 H NMR,13 C NMR, and HRMS) can be found in the Supplementary Materials.

4. Conclusions

In conclusion, we have accomplished the first total synthesis of lineaflavones A, C, and D and their analogues starting from commercially available raw materials. The key methods for the preparation of these compounds involve I2-catalyzed oxa-Michael addition, aldol reaction, Claisen rearrangement, and Schenck ene reaction. Besides this, we have developed five new routes to synthesize fifty-three natural product analogues, which provided the groundwork to explore structure–activity relationship studies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052373/s1. Table S2A: Comparison of 1H NMR Spectral Data.; Table S2B: Comparison of 13C NMR Spectral Data.; Table S3A: Comparison of 1H NMR Spectral Data.; Table S3B: Comparison of 13C NMR Spectral Data.; Table S4A: Comparison of 1H NMR Spectral Data.; Table S4B: Comparison of 13C NMR Spectral Data. Experimental procedures, and characterization data (1 H NMR,13 C NMR, and HRMS) can be found in Supplementary Materials. References [29,30,31] are cited in the supplementary materials.

Author Contributions

R.W. conceptualization, methodology, software, formal analysis, investigation, data curation, writing—original draft, writing—review and editing; Y.F. investigation, visualization, conceptualization, writing—review and editing; R.M. offered much help in the process of experiments; H.J. supervision, writing—review and editing; W.Z. funding acquisition, conceptualization, supervision, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Key R&D Program of China (2018YFA0507204), the National Natural Science Foundation of China (22077068).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article and supplementary material.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Sample Availability

Samples have generally been consumed during the course of research.

References

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Molecules 28 02373 g001
Figure 1. The structure of lineaflavone A, lineaflavone C and lineaflavone D.
Figure 1. The structure of lineaflavone A, lineaflavone C and lineaflavone D.
Molecules 28 02373 g001
Molecules 28 02373 sch001
Scheme 1. Retrosynthetic analysis of lineaflavone A (1) and lineaflavone D (3).
Scheme 1. Retrosynthetic analysis of lineaflavone A (1) and lineaflavone D (3).
Molecules 28 02373 sch001
Molecules 28 02373 sch002
Scheme 2. Synthesis of the intermediate 21–24. Regents and conditions: (a) dimethyl sulfate, K2CO3, acetone, 60 °C, 4 h, 90%; (b) benzaldehyde, NaOH, EtOH, 50 °C, 24 h, 89%; (c) I2, DMSO, 170 °C, 3 h, 85%; (d) HBr, AcOH, 120 °C, 24 h, 78%; (e) 3-chloro-3-methylbut-1-yne, CuI, K2CO3, KI, DMF, rt, 2 h, 70%; (f) diethylaniline, 250 °C, 1 h, 16 (52%), 17 (41%); (g) 3,3-dimethylallyl bromide, NaH, DMF, rt, 6 h, 80%; (h) Eu(fod)3, chloroform, 60 °C, 8 h, 76%; (i) CH3I, NaH, DMF, rt, 3 h, 82%; (j) 1. Rose Bengal, MeOH, hv, O2, rt, 10 h; 2. PPh3, rt, 16 h, 21 (35%), 22 (38%), 23 (54%); (k) 3-chloroperoxybenzoic acid, DCM, rt, 3 h, 87%.
Scheme 2. Synthesis of the intermediate 21–24. Regents and conditions: (a) dimethyl sulfate, K2CO3, acetone, 60 °C, 4 h, 90%; (b) benzaldehyde, NaOH, EtOH, 50 °C, 24 h, 89%; (c) I2, DMSO, 170 °C, 3 h, 85%; (d) HBr, AcOH, 120 °C, 24 h, 78%; (e) 3-chloro-3-methylbut-1-yne, CuI, K2CO3, KI, DMF, rt, 2 h, 70%; (f) diethylaniline, 250 °C, 1 h, 16 (52%), 17 (41%); (g) 3,3-dimethylallyl bromide, NaH, DMF, rt, 6 h, 80%; (h) Eu(fod)3, chloroform, 60 °C, 8 h, 76%; (i) CH3I, NaH, DMF, rt, 3 h, 82%; (j) 1. Rose Bengal, MeOH, hv, O2, rt, 10 h; 2. PPh3, rt, 16 h, 21 (35%), 22 (38%), 23 (54%); (k) 3-chloroperoxybenzoic acid, DCM, rt, 3 h, 87%.
Molecules 28 02373 sch002
Molecules 28 02373 sch003
Scheme 3. Synthesis of lineaflavone C (2). Regents and conditions: (a) DMAP, TEA, acetic anhydride, DCM, rt, 2 h, 88%; (b) 1. Rose Bengal, MeOH, hv, O2, rt, 6 h; 2. PPh3, rt, 19 h, 26 (36%), 27 (41%); (c) HCl, MeOH, rt, 0.1 h, 76%; (d) 3M LiOH, THF, 60 °C, 0.5 h, 97%.
Scheme 3. Synthesis of lineaflavone C (2). Regents and conditions: (a) DMAP, TEA, acetic anhydride, DCM, rt, 2 h, 88%; (b) 1. Rose Bengal, MeOH, hv, O2, rt, 6 h; 2. PPh3, rt, 19 h, 26 (36%), 27 (41%); (c) HCl, MeOH, rt, 0.1 h, 76%; (d) 3M LiOH, THF, 60 °C, 0.5 h, 97%.
Molecules 28 02373 sch003
Molecules 28 02373 sch004
Scheme 4. (A) Synthesis of compounds 29a–29i. (B) Synthesis of compounds 32a–32c. Regents and conditions: (a) allyl bromide, NaH, DMF, rt, 3 h, 71%; (b) diethylaniline, 220 °C, 0.5 h, 72%; (c) Grubbs catalyst 2nd generation, DCM, rt, 5 h, yield from 75% to 87%.
Scheme 4. (A) Synthesis of compounds 29a–29i. (B) Synthesis of compounds 32a–32c. Regents and conditions: (a) allyl bromide, NaH, DMF, rt, 3 h, 71%; (b) diethylaniline, 220 °C, 0.5 h, 72%; (c) Grubbs catalyst 2nd generation, DCM, rt, 5 h, yield from 75% to 87%.
Molecules 28 02373 sch004
Molecules 28 02373 sch005
Scheme 5. (A) Synthesis of compounds 36a–36c, 37a–37b, 40a–40e, and 38–41. Regents and conditions: (a) 3,3-dimethylallyl bromide, NaH, DMF, rt, 6 h, 83%; (b) montmorillonite K10, DCM, rt, 18 h, 65%; (c) CH3I, NaH, DMF, rt, 3 h or DMAP, TEA, acetic anhydride, rt, 1 h, 35a (88%), 35b (85%); (d) 1. Rose Bengal, MeOH, hv, O2, rt, 24 h; 2. PPh3, rt, 4 h, yield from 35% to 56%; (e) HCl, MeOH, rt, 0.2 h, 38 (76%), 41 (77%); (f) 3M LiOH, THF, 60 °C, 1.5 h, 36b (83%), 39 (89%); (g) DMAP, TEA, acyl chloride, DCM, rt, 2 h, yield from 77% to 98%. (B) Synthesis of compounds 43a–43f. Regents and conditions: (h) Eu(fod)3, chloroform, 60 °C, 8 h, 86%; (i) DMAP, TEA, acyl chloride, rt, 1 h or NaH, DMF, rt, 3 h, yield from 65% to 89%.
Scheme 5. (A) Synthesis of compounds 36a–36c, 37a–37b, 40a–40e, and 38–41. Regents and conditions: (a) 3,3-dimethylallyl bromide, NaH, DMF, rt, 6 h, 83%; (b) montmorillonite K10, DCM, rt, 18 h, 65%; (c) CH3I, NaH, DMF, rt, 3 h or DMAP, TEA, acetic anhydride, rt, 1 h, 35a (88%), 35b (85%); (d) 1. Rose Bengal, MeOH, hv, O2, rt, 24 h; 2. PPh3, rt, 4 h, yield from 35% to 56%; (e) HCl, MeOH, rt, 0.2 h, 38 (76%), 41 (77%); (f) 3M LiOH, THF, 60 °C, 1.5 h, 36b (83%), 39 (89%); (g) DMAP, TEA, acyl chloride, DCM, rt, 2 h, yield from 77% to 98%. (B) Synthesis of compounds 43a–43f. Regents and conditions: (h) Eu(fod)3, chloroform, 60 °C, 8 h, 86%; (i) DMAP, TEA, acyl chloride, rt, 1 h or NaH, DMF, rt, 3 h, yield from 65% to 89%.
Molecules 28 02373 sch005
Molecules 28 02373 sch006
Scheme 6. Synthesis of compounds 50a–50c, 51a–51c, and 52a–52c. Regents and conditions: (a) 3-chloro-3-methylbut-1-yne, CuI, K2CO3, KI, DMF, rt, 2 h, 78%; (b) diethylaniline, 250 °C, 0.5 h, 93%; (c) 3,3-dimethylallyl bromide, NaH, DMF, rt, 3 h, 86%; (d) Eu(fod)3, chloroform, 60 °C, 5 h, 89%; (e) CH3I, K2CO3, DMF, rt, 2 h, 93%; (f) aromatic aldehydes, NaOH, EtOH, 50 °C, 24 h, yield from 70% to 91%; (g) 1.Tpp, DCM, hv, O2, rt, 9 h; 2. PPh3, rt, 15 h (51a–51c: yield from 35% to 47%; 52a–52c: yield from 37% to 49%).
Scheme 6. Synthesis of compounds 50a–50c, 51a–51c, and 52a–52c. Regents and conditions: (a) 3-chloro-3-methylbut-1-yne, CuI, K2CO3, KI, DMF, rt, 2 h, 78%; (b) diethylaniline, 250 °C, 0.5 h, 93%; (c) 3,3-dimethylallyl bromide, NaH, DMF, rt, 3 h, 86%; (d) Eu(fod)3, chloroform, 60 °C, 5 h, 89%; (e) CH3I, K2CO3, DMF, rt, 2 h, 93%; (f) aromatic aldehydes, NaOH, EtOH, 50 °C, 24 h, yield from 70% to 91%; (g) 1.Tpp, DCM, hv, O2, rt, 9 h; 2. PPh3, rt, 15 h (51a–51c: yield from 35% to 47%; 52a–52c: yield from 37% to 49%).
Molecules 28 02373 sch006
Molecules 28 02373 sch007
Scheme 7. Synthesis of compound 58. Regents and conditions: (a) CH3I, K2CO3, DMF, rt, 2 h, 96%; (b) 3,3-dimethylallyl bromide, NaH, DMF, rt, 3 h, 94%; (c) diethylaniline, 250 °C, 0.5 h, 91%; (d) CH3I, NaH, DMF, rt, 2 h, 93%; (e) benzaldehyde, NaOH, EtOH, 50 °C, 24 h, 90%; (f) 1. Tpp, DCM, hv, O2, rt, 9 h; 2. PPh3, rt, 15 h, 56%.
Scheme 7. Synthesis of compound 58. Regents and conditions: (a) CH3I, K2CO3, DMF, rt, 2 h, 96%; (b) 3,3-dimethylallyl bromide, NaH, DMF, rt, 3 h, 94%; (c) diethylaniline, 250 °C, 0.5 h, 91%; (d) CH3I, NaH, DMF, rt, 2 h, 93%; (e) benzaldehyde, NaOH, EtOH, 50 °C, 24 h, 90%; (f) 1. Tpp, DCM, hv, O2, rt, 9 h; 2. PPh3, rt, 15 h, 56%.
Molecules 28 02373 sch007
Table 1. Screening reaction conditions for the reaction.
Table 1. Screening reaction conditions for the reaction.
Molecules 28 02373 i001
EntryConditionsYield(%) a1/3 b
1H2SO4:MeOH = 1:10600:1
2HCl:MeOH = 1:10780:1
33N HCl:MeOH = 1:5761:1
43N HCl:MeOH = 1:10852.2:1
53N HCl:MeOH = 1:15771.8:1
62N HCl:MeOH = 1:15 701.5:1
71N HCl:MeOH = 1:15621:3
a Yield of isolated product. b Based on 1H NMR integration.
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Wang, R.; Fu, Y.; Ma, R.; Jin, H.; Zhao, W. Total Synthesis of Lineaflavones A, C, D, and Analogues. Molecules 2023, 28, 2373. https://doi.org/10.3390/molecules28052373

AMA Style

Wang R, Fu Y, Ma R, Jin H, Zhao W. Total Synthesis of Lineaflavones A, C, D, and Analogues. Molecules. 2023; 28(5):2373. https://doi.org/10.3390/molecules28052373

Chicago/Turabian Style

Wang, Rui, Yu Fu, Ran Ma, Hongzhen Jin, and Wei Zhao. 2023. "Total Synthesis of Lineaflavones A, C, D, and Analogues" Molecules 28, no. 5: 2373. https://doi.org/10.3390/molecules28052373

APA Style

Wang, R., Fu, Y., Ma, R., Jin, H., & Zhao, W. (2023). Total Synthesis of Lineaflavones A, C, D, and Analogues. Molecules, 28(5), 2373. https://doi.org/10.3390/molecules28052373

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