Next Article in Journal
Photocatalytic and Antibacterial Potency of Titanium Dioxide Nanoparticles: A Cost-Effective and Environmentally Friendly Media for Treatment of Air and Wastewater
Next Article in Special Issue
Propylene Polymerization and Deactivation Processes with Isoselective {Cp/Flu} Zirconocene Catalysts
Previous Article in Journal
Pragmatic Approach toward Catalytic CO Emission Mitigation in Fluid Catalytic Cracking (FCC) Units
Previous Article in Special Issue
Design of Iridium N-Heterocyclic Carbene Amino Acid Catalysts for Asymmetric Transfer Hydrogenation of Aryl Ketones
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Cross-Coupling as a Key Step in the Synthesis and Structure Revision of the Natural Products Selagibenzophenones A and B

1
Department of Organic Chemistry, Faculty of Science, Charles University, Albertov 6, 128 00 Prague 2, Czech Republic
2
Department of Organic Chemistry, Center for Physical Sciences and Technology (FTMC), Akademijos g. 7, LT-08412 Vilnius, Lithuania
*
Author to whom correspondence should be addressed.
Catalysts 2021, 11(6), 708; https://doi.org/10.3390/catal11060708
Received: 25 May 2021 / Revised: 1 June 2021 / Accepted: 1 June 2021 / Published: 4 June 2021
(This article belongs to the Special Issue 10th Anniversary of Catalysts: Molecular Catalysis)

Abstract

:
Selagibenzophenone A (1) and its isomer selagibenzophenone B (2) were recently described as natural products from Selaginella genus plants with PDE4 inhibitory activity. Herein, we report the first total syntheses of both compounds. By comparing spectroscopic data of the synthetic compounds with reported data for the isolated material, we demonstrate that the structure of one of the two natural products was incorrectly assigned, and that in fact isolated selagibenzophenone A and selagibenzophenone B are identical compounds. The synthetic strategy for both 1 and 2 is based on a cross-coupling reaction and on the addition of organometallic species to assemble the framework of the molecules. Identifying a suitable starting material with the correct substitution pattern is crucial because its pattern is reflected in that of the targeted compounds. These syntheses are finalized via global deprotection. Protecting the phenols as methoxy groups provides the possibility for partial control over the selectivity in the demethylation thanks to differences in the reactivity of the various methoxy groups. Our findings may help in future syntheses of derivatives of the biologically active natural product and in understanding the structure–activity relationship.

Graphical Abstract

1. Introduction

Plants from the genus Selaginella (Selaginellaceae) are used in traditional medicine in China, India, and Colombia to treat various ailments such as asthma, dysmenorrhea, or traumatic injuries [1,2]. Species from this genus are sources of structurally diverse natural products, including various bioflavonoids and alkaloids, which can be isolated from different sources as well. Several polyphenolic compounds have been isolated exclusively from species of the Selaginella genus, including selagibenzophenones A (1) [2] and B [3] (2; also referred to as selaphenin A [4] in the literature); selaginpulvilin (3) [5,6], which contains a rather rare bisaryl fluorene motif; and selaginellin (4) [7] (Figure 1). These compounds have shown various biological activities, including antimicrobial [8], cytotoxic [9], antidiabetic [10], anticancer [4], and phosphodiesterase-4 (PDE4) inhibitory properties [2,11].
Several approaches have been developed to synthesize selaginpulvilins, including our formal syntheses of selaginpulvilins C and D [12,13,14,15,16,17], as well as other unnatural derivatives containing the characteristic diaryl acetylene motif [18]. Syntheses of polyarylated benzophenone containing natural products have not been described yet.
Selagibenzphenone A (1) is a naturally occurring benzophenone derivative, which was recently isolated from Selaginella pulvinata [2]. The determination of the structure revealed that the natural product contains three 4′-hydroxyphenyl rings in positions 2, 4, and 6 of one of the benzophenone rings, the aromatic ring B (Figure 1, 1). The compound has demonstrated inhibitory activity against PDE4, with a promising EC50 value of 1.04 μM. Enzyme PDE4 is involved in the regulation of cyclic adenosine monophosphate (cAMP), and therefore in the modulation of cellular processes [18]. As such, PDE4 is a key target in various indications, including inflammation or memory enhancement (cognitive function stimulation) [19]. Nevertheless, little is known about the other biological properties of selagibenzophenone A (1).
Liang and Wang [4] in 2018, and later Xu and Tan [3] in 2020, reported the isolation of a novel benzophenone analogue, selagibenzophenone B (2) (referred to as selaphenin A by Liang and Wang), with potential anticancer activity. The authors proposed that compound 2 differed from selagibenzophenone A (1) in the position of the substitution of the benzophenone core. Benzophenone 1 contains three 4′-hydroxyphenyl rings in positions 2, 4, and 6 of aromatic ring B, whereas selagibenzophenone B (2) has 4′-hydroxyphenyl rings in positions 3, 4, and 5 (Figure 1, 2).
A closer analysis of the reported 1H and 13C NMR spectra of isolated selagibenzophenone A (1) and selagibenzophenone B (2) showed their striking similarity. We put forth two explanations for this similarity: (a) their origin is coincidental, and both compounds actually display similar spectral characteristics; or more likely, (b) only one natural product exists in nature and the structure of the other one was assigned incorrectly. It is not uncommon for the structure of a natural product to be incorrectly solved, as shown by the numerous examples of synthetic work published in the literature that have resulted in subsequent corrections to previously proposed structures of isolated compounds [20,21]. Therefore, we decided to synthesize both molecules. Based on the comparison of spectroscopic data of synthetic and isolated materials, we shed light on this discrepancy in this study. The synthesis and our findings are summarized in the following discussion.

2. Results and Discussion

Our synthetic strategy relied on the formation of a benzophenone moiety in both cases via an addition of organometallic species to an aldehyde, followed by re-oxidation to a ketone and a cross-coupling reaction with a suitably substituted starting material. The substitution pattern of the starting aromatic synthon is crucial because it will be reflected in the final substitution pattern of compounds 1 and 2. We identified commercially available 2,4,6-tribromobenzaldehyde (6) and methyl gallate (8) as suitable starting materials for compounds 1 and 2, respectively (Scheme 1).
The synthesis of selagibenzophenone A (1) commenced with the Suzuki cross-coupling reaction of 2,4,6-tribromobenzaldehyde (6) with a three-fold excess of boronic acid 9 (Scheme 2). In the presence of tetrakis(triphenylphosphine)palladium (0) and potassium carbonate, this reaction provided benzaldehyde 10 in 79% yield. In the next step, aldehyde 10 was subjected to the Grignard reaction with 4-methoxyphenylmagnesium bromide (11) to furnish secondary alcohol 12 in 91% yield. Further oxidation of the alcohol led to the formation of ketone 13 in 74% yield.
Our attempts to demethylate anisole moieties led to an unexpected outcome. Using conditions commonly applied for demethylation of methylphenyl ethers and employing boron tribromide [22,23] in CH2Cl2 at 0 °C, a new product was formed in 53% yield and with a significantly higher polarity, indicating the formation of free phenols. However, NMR analysis revealed the presence of one remaining methoxy group at the aromatic ring A, as depicted in the structure of compound 14 (Scheme 2). The resistance of this methoxy group to demethylation can be explained by the decrease in the Lewis basicity of this particular methoxy group, which was caused by the electron-withdrawing effect of the carbonyl moiety in the para position, thus decreasing the reactivity towards boron tribromide. Such a reactivity has already been described in the literature for similar systems [24]. Despite the fact that such a selectivity in the deprotection step can be beneficial in the synthesis of derivatives of this natural product for medicinal chemistry purposes and for understanding the structure–activity relationship, this approach is not applicable for the synthesis of the natural product. Increasing the reaction temperature to 25 °C or to a refluxing temperature did not change the outcome of the reaction either. In addition, applying harsh conditions, as described in the synthesis of related selaginpulvilins C and D, namely using neat MeMgI at 160 °C [12,15], led to the decomposition of the material and to the formation of a complex mixture of products.
Considering the above, we hypothesized that the remaining methoxy group could also be cleaved using nucleophilic instead of electrophilic conditions. Indeed, when applying sodium ethanethiolate in DMF at 100 °C [24], the remaining methoxy group was cleaved and tetraphenol 1 was formed in 42% yield. Moreover, subjecting the fully protected compound 13 to the same reaction conditions resulted in the cleavage of all methoxy groups and in the formation of the desired product 1 in 44% yield (Scheme 2). However, we found that this demethylation was not reproducible despite extensive research. The reasons for the lack of reproducibility of this protocol remain elusive.
These unsatisfactory results, combined with the unpractical use of a large excess of sodium ethylthiolate, which has an unpleasant odor, prompted us to develop a more reliable route to compound 1, employing an alternative and easily removable tert-butyldimethyl silyl (TBS) protective group. Therefore, the second-generation synthesis began with the synthesis of boronic acid 17 from 4-bromophenol (15), which was achieved in two steps, namely protection of the phenol moiety, yielding 91% of bromide 16; and introduction of boronic acid via lithium-halogen exchange, reaction with isopropyl borate, and in situ hydrolysis. Suzuki coupling of aldehyde 6 and boronic acid 17 under similar conditions to those applied in the previous synthesis provided aldehyde 18 in 79% yield. In the next step, aryl bromide 16 was treated with t-butyl lithium and the resulting organolithium species reacted with aldehyde 18. The immediate oxidation of the crude reaction mixture provided ketone 19 in 57% yield over two steps. Global deprotection of TBS groups employing HF–pyridine resulted in the formation of the natural product (1) in 82% yield (Scheme 3).
In the synthesis of selagibenzophenone B (2), the hydroxy groups of gallate 8 were converted into triflates in a reaction with triflic anhydride in the presence of triethylamine (Scheme 4). This reaction provided the desired triflate 20 in 96% yield. Suzuki cross-coupling of compound 20 and 3.15 equivalents of 4-methoxyphenyl boronic acid (9) proceeded smoothly and furnished the trisarylated aromatic ester 21 in 71% yield. Reduction of the ester moiety in compound 21 was pursued next. When using DIBAL-H at −78 °C, this reaction resulted in the formation of the desired aldehyde, albeit with partial overreduction to alcohol. Therefore, the crude reaction mixture was subjected to re-oxidation with pyridinium chlorochromate (PCC) to provide aldehyde 22 in 83% yield. Alternatively, LiAlH4 can be used for a complete reduction of the ester to primary alcohol, and after re-oxidation with PCC, aldehyde 22 was obtained in 72% overall yield. The aromatic ring D was introduced into the structure via Grignard reaction with 4-methoxyphenylmagnesium bromide. The resulting alcohol was subjected to the PCC-mediated oxidation without further purification and yielded the desired ketone 23 in 61% yield (over two steps). To our delight, subjecting compound 23 to BBr3 in CH2Cl2 at room temperature resulted in the formation of the desired polyphenol 2 in 36% yield along with monomethoxy derivative 24 in 48% yield (Scheme 4).
Having both desired compounds 1 and 2 in hand, we compared their analytical data. The spectra of the synthetic compounds 1 and 2 are clearly different (Figure 2). In fact, the change in the chemical shifts of corresponding protons of these molecules in the 1H NMR spectra are more significant than it appears at first glance. The chemical shift in the signals of aromatic rings A and D in both compounds are strongly influenced by the anisotropic effect of aromatic rings C and E. In compound 1, protons HA and HB (ring A) are shielded by aromatic rings C and E and shifted upfield relative to protons HA and HB in compound 2 (1: HA = 7.42 ppm and HB = 6.60 ppm; 2 HA = 7.78 ppm and HB = 6.76 ppm). Conversely, in compound 2, the shielding zone of rings C and E affects the protons of the aromatic ring D, meaning the signals HC and HD are shifted upfield in compound 2 relative to those in compound 1 (1: HC = 7.58 ppm and HD = 6.90 ppm; 2 HC = 6.66 ppm and HD = 6.48 ppm). The effect is most significant on proton HC, for which the difference in chemical shift is nearly one ppm. Similarly, in both compounds, protons HE and HF from rings C and E are affected by the anisotropic shielding of either conjugated system of the carbonyl group together with ring A in compound 1 or by aromatic ring D in compound 2. The chemical shifts of protons HE (1: 7.11 ppm; 2 6.90 ppm) clearly show that the shielding of the aromatic ring D in 2 is stronger than that of the conjugated carbonyl–aromatic ring A system in 1.
Based on the findings described above, the coincidental similarity for the spectra of isolated selagibenzophenones A and B was ruled out. Consequently, the structure of one of the isolated compounds was incorrectly assigned. For this reason, we compared the spectra of both synthetic compounds 1 and 2 with the spectra of the isolated selagibenzophenones reported in the literature. The chemical shift in the signals observed in 1H and 13C NMR spectra are summarized in Table S1 (see supplementary information). The reported spectra of both isolated compounds correspond to the spectra of synthetic compound 1. As such, the structure of the isolated selagibenzophenone B was assigned incorrectly and the compound previously reported as selagibenzophenone B was in fact selagibenzophenone A.

3. Materials and Methods

3.1. General

All of the chemicals were purchased from the common sources, namely Merck KGaA (Darmstadt, Germany), Acros Organics (part of Thermo Fisher, Geel, Belgium), Alfa Aesar (part of Thermo Fisher, Kandel, Germany), Strem Chemicals (Kehl, Germany), PENTA Chemicals (Prague, Czech Republic), Fluorochem (Headfield, UK), and Cambridge Isotope Laboratories (Tewksbury, MA, USA), Inc. All of the reagents were used without further purification unless otherwise noted. Solvents used in the reactions were distilled and dried prior the use. The reactions were monitored by TLC using Merck TLC (Merck KGaA, Darmstadt, Germany) silica gel 60 F254 plates, using UV lamp (254 nm) detection and Hanessian’s stain (CAM). NMR spectra were recorded on a Bruker Avance III spectrometer (Bruker, Billerica, MA, United States, 400 MHz and 600 MHz for 1H NMR and 100 MHz and 150 MHz for 13C NMR, respectively) and Varian NMR Solutions 300 (Varian, Inc., Palo Alto, CA, USA, 300 MHz for 1H NMR and 75 MHz for 13C NMR). All chemical shifts δ are reported in ppm with a reference to a residual solvent. Mass spectrometry was performed on a VG-Analytical ZAB SEQ (VG Analytical, Manchester, UK). Infrared spectrum were measured in KBr with a Thermo Nicolet AVATAR 370 FT-IR spectrometer (Thermo Fisher Scientific Inc., Waltham, MA, USA). Melting points were determined using a MXBAOHENG Melting Point Apparatus with Microscope X-4 (MRC laboratory-instruments, Harlow, UK). Unless otherwise stated, for reactions that required heating, these were carried out using the oil bath as the heat source. Copies of the NMR spectra are available in supplementary information.

3.2. Synthesis

3.2.1. Synthesis of 4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-2′-carbaldehyde (10)

2,4,6-Tribromobenzaldehyde 6 (0.73 mmol, 250 mg), Pd(PPh3)4 (0.037 mmol, 5 mol%, 42 mg), K2CO3 (2.56 mmol, 353 mg), and (4-methoxyphenyl)boronic acid 9 (2.3 mmol, 355 mg) were dissolved in a degassed mixture of benzene and H2O (5:1, 6 mL). The reaction was heated in a closed vial at 90 °C for 16 h. Then, the reaction mixture was concentrated and the product was purified with column chromatography (EA:Hex 1:6 to 1:4). The reaction yielded 574 mg (93%) of product in the form of a yellow glassy oil. Rf = 0.3 [EA:Hex (1:4)]; IR (KBr) 3033, 2999, 2954, 2933, 2906, 2835, 2754, 1693, 1608 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.70–7.59 (m, 2H), 7.54 (s, 2H), 7.41–7.32 (m, 4H), 7.10–6.91 (m, 6H), 3.88 (s, 6H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.4, 160.2, 159.4 (2C), 145.1 (2C), 143.9, 132.3 (2C), 132.0, 131.3, 131.0 (4C), 128.6 (2C), 128.4 (2C), 114.6 (2C), 113.8 (4C), 55.5 (3C); HRMS (ESI) calculated for C28H25O4 (MS + H+): 425.1747; found 425.1746.

3.2.2. Synthesis of (4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanol (12)

A solution of (4-methoxyphenyl)magnesium bromide 11 (1 M in THF, 0.1 mmol, 0.1 mL) was added in a dropwise manner to a solution of 4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-2′-carbaldehyde 10 (0.071 mmol, 34 mg) in THF (1 mL) at 0 °C. After stirring the reaction in the ice bath for 40 min, it was quenched with saturated NH4Cl solution (3 mL). The product was extracted with EA (3 × 5 mL). Combined organic phases were dried over Na2SO4, then filtered and concentrated. The product was purified by column chromatography (gradient eluent EA:Hex 1:6 to 1:4). The reaction yielded 30 mg (79%) of product in the form of a colorless glassy oil. Rf = 0.2 [EA:Hex (1:4)]; IR (KBr) 3556, 3033, 2999, 2952, 2933, 2906, 2835, 2044, 1888, 1736, 1608 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62–7.56 (m, 2H), 7.43 (s, 2H), 7.13 (d, J = 7.9 Hz, 4H), 6.99–6.93 (m, 2H), 6.91–6.85 (m, 2H), 6.84–6.78 (m, 4H), 6.73–6.67 (m, 2H), 5.95 (d, J = 9.2 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 6H), 3.77 (s, 3H), 2.14 (d, J = 10.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.5, 158.9 (2C), 158.1, 142.8 (2C), 139.1, 138.0 (2C), 134.0 (2C), 132.7, 130.8 (4C), 128.8 (2C), 128.2 (2C), 126.7 (2C), 114.4 (2C), 113.5 (4C), 113.2 (2C), 72.3, 55.5, 55.4 (3C); HRMS (ESI) calculated for C35H31O4: 515.2217; found 515.2219.

3.2.3. Synthesis of (4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone (13)

PCC (0.483 mmol, 104 mg), (4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanol 12 (0.4 mmol, 214 mg), and Celite® (214 mg) were suspended in DCM (15 mL) and refluxed for 24 hours. Then reaction mixture was filtered through a plug of Celite® and concentrated. On TLC, the conversion was visible only when the plate was stained with Hanessian’s stain (CAM). The product was purified by column chromatography (EA:Hex 1:6 to 1:4). Reaction yielded 156 mg (74%) of product in the form of a colorless glassy oil. Rf = 0.2 [EA:Hex (1:4)]; mp = 180–182 °C (DCM:MeOH), lit. 173–174 °C [25] (AcOH); IR (KBr) 3033, 3001, 2956, 2933, 2908, 2835, 2048, 1660, 1606, 1597 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 2H), 7.58–7.53 (m, 4H), 7.26–7.22 (m, 4H), 7.03–6.98 (m, 2H), 6.79–6.73 (m, 4H), 6.70–6.64 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 197.9, 163.2, 159.7, 158.9 (2C), 141.2, 140.9, 136.9 (2C), 133.1 (2C), 132.8, 131.9, 131.7 (2C), 130.4 (4C), 128.4 (2C), 127.2 (2C), 114.5 (2C), 113.7 (4C), 113.4 (2C), 55.5, 55.4, 55.3 (2C); HRMS (ESI) calculated for C35H31O5 (M + H): 531.2166; found 531.2167.

3.2.4. Synthesis of (4,4′-dihydroxy-5′-(4-hydroxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone (14)

BBr3 solution (1 M in heptane, 0.415 mmol, 0.415 mL) was added into a solution of (4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone (0.094 mmol, 50 mg) in DCM (2 mL) in a dropwise manner at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with a solution of NaHSO3 (50%, 5 mL), then extracted with EA (3 × 7 mL). Organic phases were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (EA:Hex 1:4 to 1:1). The reaction yielded 24 mg (53%) of product in the form of a colorless glassy oil. Rf = 0.2 [EA:Hex (1:1)]; IR (KBr) 3323, 3070, 3033, 3014, 2964, 2935, 2839, 2044, 1894, 1643, 1610, 1591 cm−1; 1H NMR (600 MHz, MeOD-d4) δ 7.59–7.56 (m, 2H), 7.51–7.48 (m, 4H), 7.12–7.08 (m, 4H), 6.92–6.88 (m, 2H), 6.78–6.74 (m, 2H), 6.64–6.60 (m, 4H), 3.77 (s, 3H); 13C NMR (150 MHz, MeOD-d4) δ 200.7, 165.2 (2C), 158.8, 157.9 (2C), 143.1, 142.4 (2C), 137.5, 133.2 (2C), 133.1, 132.7, 132.6, 131.5 (4C), 129.3 (2C), 127.6 (2C), 116.8 (2C), 115.9 (4C), 114.5 (2C), 56.0; HRMS (ESI) calculated for C32H25O5 (M + H): 489.1697; found 489.1697.

3.2.5. Synthesis of (4,4′-dihydroxy-5′-(4-hydroxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-hydroxyphenyl)methanone—selagibenzophenone A (1)

Procedure A: A solution of (4,4′-dihydroxy-5′-(4-hydroxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone 13 (0.01 mmol, 5 mg) and NaSEt (0.24 mmol, 20 mmol) in DMF (0.8 mL, anhydrous) was heated in a vial at 100 °C. After 10 h, the reaction mixture was cooled down and diluted with an aqueous HCl (1 M, 8 mL). The product was extracted with EA (3 × 10 mL). Combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced vacuum. The product was purified by preparative TLC with EA:Hex (1:2 × 3). The reaction yielded 2 mg (42%) of product in the form of an off-white glassy oil.
Procedure B: A solution of (4,4′-dimethoxy-5′-(4-methoxyphenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone 14 (0.038 mmol, 20 mg) and NaSEt (0.667 mmol, 56 mg) in DMF was loaded into a vial, closed, and heated at 100 °C. After 18 h, the reaction mixture was cooled down and diluted with HCl solution (1 M, 15 mL). The product was extracted with EA (3 × 20 mL). Organic phases were washed with brine (1 × 4 mL), dried over Na2SO4, filtered, and concentrated. The product was purified using column chromatography (EA:Hex, 1:4 to 2:1). The reaction yielded 8 mg (44%) of product in the form of an off-white glassy oil.
Procedure C: Olah’s reagent (HF·pyridine, 12 mmol, 0.3 mL) was added to a solution of (4,4′-bis((tert-butyldimethylsilyl)oxy)-5′-(4-((tert-butyldimethylsilyl)oxy)phenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-((tert-butyldimethylsilyl)oxy)phenyl)methanone (19) (0.02 mmol, 20 mg) in THF (5 mL) in a plastic flask and stirred at 22 °C for 2 h. Then, the reaction mixture was quenched with saturated solution NaHCO3 (5 mL) and extracted with EA (3 × 10 mL). Combined organic layers were washed with HCl (1M, 1 × 20 mL), dried over Na2SO4, filtrated, and concentrated under reduced pressure. The selagibenzophenone A (1) was purified with column chromatography (DCM:MeOH 20:1). The reaction yielded 8.4 mg (82%) of product in the form of a slightly yellow solid. Rf = 0.1 [1:1 (EA:Hex)]; 1H NMR (600 MHz, MeOD-d4) δ 7.60–7.56 (m, 2H), 7.50 (s, 2H), 7.43–7.39 (m, 2H), 7.12–7.09 (m, 4H), 6.92–6.88 (m, 2H), 6.65–6.62 (m, 4H), 6.61–6.58 (m, 2H); 13C NMR (150 MHz, MeOD-d4) δ 200.7, 163.8, 158.8, 157.9 (2C), 143.0, 142.4 (2C), 137.6, 133.5 (2C), 133.2 (2C), 132.8, 131.6, 131.5 (4C), 129.3 (2C), 127.6 (2C), 116.8 (2C), 116.0 (2C), 115.8 (4C). The recorded values are in a good agreement with the published data [2].

3.2.6. Synthesis of (4-bromophenoxy)(tert-butyl)dimethylsilane (16)

Tert-butyl dimethyl silyl chloride (104 mmol, 16 g) and imidazole (104 mmol, 7.5 g) were added to a solution of a 4-bromophenol 15 (87 mmol, 15.5 g) in DCM (80 mL) at 0 °C. After 16 hours of stirring at 22 °C, the reaction mixture was filtered through a short pad of silica gel and washed with hexanes (200 mL). The product was used in the next reaction without additional purification. The reaction yielded 22.5 g (91%) of product in the form of a transparent oil. Rf = 0.4 [Hex]; 1H NMR (400 MHz, CDCl3) δ 7.37–7.34 (m, 2H), 6.77–6.74 (m, 2H), 1.03 (s, 9H), 0.23 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 155.0, 132.4 (2C), 122.0 (2C), 113.8, 25.8 (3C), 18.3, −4.4 (2C). The recorded values are in good agreement with the published data [26].

3.2.7. Synthesis of (4-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (17)

A solution of n-BuLi (1.6 M in hexane, 3.8 mmol, 2.4 mL) was slowly added to a solution of (4-bromophenoxy)(tert-butyl)dimethylsilane (16) (3.5 mmol, 1 g) in THF (10 mL) at −78 °C. After 30 min, triisopropyl borate (10.5 mmol, 2.3 mL) was added in a dropwise manner at −78 °C and the reaction was then allowed to warm to 22 °C and stirred for 16 h. The reaction mixture was acidified with HCl (1 M, 3 mL). Then, the organic layer was washed with brine (1 × 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified with column chromatography (DCM to DCM:MeOH 20:1). The reaction yielded 700 mg (80%) of product in the form of an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.13–8.11 (m, 2H), 6.97–6.95 (m, 2H), 1.02 (s, 9H), 0.26 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 159.9, 137.6 (2C), 123.1, 119.9 (2C), 25.9 (3C), 18.5, −4.2 (2C). The recorded values are in good agreement with the published data [26].

3.2.8. Synthesis of 4,4′-bis((tert-butyldimethylsilyl)oxy)-5′-(4-((tert-butyldimethylsilyl)oxy)phenyl)-[1,1′:3′,1′-terphenyl]-2′-carbaldehyde (18)

2,4,6-Tribromobenzaldehyde 6 (0.29 mmol, 100 mg), Pd(PPh3)4 (0.029 mmol, 10 mol%, 34 mg), K2CO3 (1.02 mmol, 140 mg), and (4-methoxyphenyl)boronic acid 9 (0.92 mmol, 140 mg) were dissolved in a degassed mixture of benzene and H2O (5:1, 2.2 mL). The reaction was heated in a closed vial at 90 °C for 16 h. Then, the reaction mixture was concentrated and the product was purified with column chromatography (EA:Hex 1:20 to 1:4). The reaction yielded 166 mg (79%) of product in the form of a yellow glassy oil. Rf = 0.14 [EA:Hex (1:30)]; IR (KBr) 3033, 2956, 2858, 2540, 1699, 1604, 1508, 1263, 914, 837, 781 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.52 (s, 2H), 7.30–7.22 (m, 4H), 6.96–6.86 (m, 6H), 1.02 (s, 18H), 1.00 (s, 9H), 0.25 (s, 12H), 0.23 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 193.5, 156.4, 155.6 (2C), 145.1 (2C), 143.8, 132.9 (2C), 132.7, 131.3, 130.9 (4C), 128.6 (2C), 128.4 (2C), 120.7 (2C), 119.8 (4C), 25.8 (9C), 18.4 (3C), −4.2 (6C); HRMS (ESI) calculated for C43H61O4Si3 (MS + H+): 725.3872; found 725.3895.

3.2.9. Synthesis of (4,4′-bis((tert-butyldimethylsilyl)oxy)-5′-(4-((tert-butyldimethylsilyl)oxy)phenyl)-[1,1′:3′,1′-terphenyl]-4′-yl)(4-((tert-butyldimethylsilyl)oxy)phenyl)methanone (19)

A solution of t-BuLi (1.7 M in heptane, 0.25 mmol, 0.16 mL) was added in a dropwise manner to a solution of (4-bromophenoxy)(tert-butyl)dimethylsilane (16, 0.25 mmol, 70 mg) in THF (3 mL) at −78 °C. After 20 min, a solution of 4,4′-bis((tert-butyldimethylsilyl)oxy)-5′-(4-((tert-butyldimethylsilyl)oxy)phenyl)-[1,1′:3′,1′-terphenyl]-2′-carbaldehyde (18, 0.18 mmol, 130 mg) in THF (3 mL) was added and the reaction was stirred at −78 °C for 1 h. The reaction mixture was warmed up to room temperature, quenched with water (10 mL), and extracted with EA (3 × 20 mL). Combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting crude product was redissolved in DCM (10 mL) and Celite® (200 mg) and PCC (0.4 mmol, 90 mg) was added to it. After 16 h, the reaction mixture was filtered through a pad of Celite®. The product was purified with column chromatography (DCM:Hex, 1:3 to 1:1). The reaction yielded 96 mg (57%) of product in the form of a yellow oil. Rf = 0.2 [DCM:Hex (1:2)]; IR (KBr) 2966, 2929, 2887, 2858, 1666, 1597, 1508, 1263 cm−1; 1H NMR (400 MHz, CD3OD) 7.59–7.57 (m, 2H), 7.55 (s, 2H), 7.44–7.42 (m, 2H), 7.17–7.15 (m, 4H), 6.94–6.92 (m, 2H), 6.68–6.66 (m, 4H), 6.59–6.57 (m, 2H), 1.01 (s, 9H), 0.94 (s, 27H), 0.24 (s, 6H), 0.16 (s, 6H), 0.13 (s, 12H). 13C NMR (100 MHz, CD3OD) δ 197.9, 159.8, 155.9, 155.1 (2C), 141.3, 141.1 (2C), 136.9, 133.8 (2C), 133.5, 132.4, 131.7 (2C), 130.5 (4C), 128.4 (2C), 127.2 (2C), 120.6 (2C), 119.8 (4C), 119.4 (2C), 25.9 (3C), 25.8 (6C), 25.7 (3C), 18.4, 18.3 (3C), −4.2 (2C), −4.3 (2C), −4.3 (4C); HRMS (ESI) calculated for C55H78O5Si4 (MS + H+): 931.4999; found 931.5030.

3.2.10. Synthesis of Methyl 3,4,5-tris(((trifluoromethyl)sulfonyl)oxy)benzoate (20)

In a flame-dried flask, methyl gallate (7.6 mmol, 1.5 g) was dissolved in CH2Cl2 (20 mL) under an inert atmosphere. Triethyl amine (24.2 mmol, 3.4 mL) was added, whereupon the suspension dissolved. The mixture was cooled to 0 °C and Tf2O (24.2 mmol, 4.07 mL) was added. The mixture was heated to the room temperature and stirred for 5 minutes. After this, the reaction was quenched via the addition of 5% HCl (20 mL). The organic phase was separated and washed with NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried with MgSO4 and concentrated under reduced pressure. The mixture was used without further purification for the next step. Rf = 0.3 [EA:Hex (1:10)]; mp = 49–51 °C (DCM); IR (KBr) 3116, 2968, 2682, 2355, 1728, 1597, 1435, 1321 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 2H), 4.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 142.4, 132.1, 125.1, 124.1, 120.8, 120.7, 116.6, 116.4, 112.3, 53.8; HRMS (ESI) calculated for C11H9F9NO11S3 (MS + NH4+): 597.9198; found 597.9192.

3.2.11. Synthesis of Methyl 4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-carboxylate (21)

Aldehyde 20 (2.60 mmol, 1.49 mg), Pd(PPh3)4 (0.26 mmol, 10 mol%, 300 mg), K2CO3 (9.1 mmol, 1.25 mg), and (4-methoxyphenyl)boronic acid 9 (8.20 mmol, 1.24 mg) were dissolved in a degassed mixture of benzene and H2O (5:1, 20 mL). The reaction was heated in a closed vial at 90 °C for 16 h. Then, the reaction mixture was concentrated and the product was purified with column chromatography (EA:Hex 1:99 to 1:10). The reaction yielded 865 mg (71%) of product in the form of a yellow glassy oil. Rf = 0.15 [EA:Hex (1:4)]; mp = 133–136 °C (DCM); IR (KBr) 3066, 3005, 2993, 2935, 2839, 2065, 1716, 1608, 1514, 1435 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 2H), 7.03–6.96 (m, 4H), 6.80–6.68 (m, 6H), 6.61–6.54 (m, 2H), 3.94 (s, 3H), 3.76 (s, 6H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 158.3 (2C), 158.0, 143.4, 142.2, 133.8, 132.5 (2C), 131.4, 131.0 (4C), 130.4 (2C), 128.8, 113.3 (4C), 113.1 (2C), 55.3, 55.1, 52.3; HRMS (ESI) calculated for C29H27O5 (MS + H+): 455.1853; found 455.1853.

3.2.12. Synthesis of 4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-carbaldehyde (22)

A solution of LiAlH4 (1M in THF, 1.6 mmol, 1.6 mL) was added dropwise into a solution of methyl 4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-carboxylate (21) (0.82 mmol, 400 mg) in THF (10 mL) at 0 °C. After 1 h, the reaction mixture was quenched with Na2SO4 (300 mg), filtered through a pad of Celite®, then the filtrate was concentrated under reduced pressure. The crude mixture was then dissolved in DCM (10 mL). After adding Celite® (400 mg) and PCC (1.6 mmol, 356 mg), the reaction mixture was left to stir for 16 h. Then, it was filtered through a plug of Celite®, the filtrate was concentrated, and the product was purified with column chromatography (EA:Hex 1:5). The reaction yielded 270 mg (72%) of product in the form of a yellow glassy oil. Rf = 0.2 [EA:Hex (1:4)]; IR (KBr) 3032, 2999, 2956, 2933, 2835, 2729, 2536, 2044, 1888, 1695, 1512, 1441cm−1; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.86 (s, 2H), 7.00–6.98 (m, 4H), 6.74–6.72 (m, 6H) 6.59–6.57 (m, 2H), 3.77 (s, 6H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.3, 158.5 (2C), 158.2, 145.1, 142.9 (2C), 135.2, 133.5 (2C), 132.4 (2C), 131.2, 130.9 (4C), 130.6 (2C), 113.4 (4C), 113.2 (2C), 55.3 (2C), 55.2; HRMS (ESI) calculated for C28H25O4 (MS + H+): 425.1747; found 425.1749.

3.2.13. Synthesis of (4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone) (23)

A solution of (4-methoxyphenyl)magnesium bromide (1M in THF, 1 mL, 1 mmol) was added in a dropwise manner to a solution of 4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-carbaldehyde (22, 0.64 mmol, 270 mg) in THF (10 mL) at 0 °C. After 16 h, the reaction was quenched with a saturated solution of NH4Cl (20 mL) and extracted with EA (3 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, and evaporated. The crude mixture was then dissolved in DCM (20 mL) and Celite® (240 mg) and PCC (0.9 mmol, 196 mg) was added to it. After 16 h, the reaction mixture was filtered over a Celite® pad and the filtrate was concentrated. The product was purified with column chromatography (EA:Hex 1:10 to 4:1). The reaction yielded 141 mg (70%) of product in the form of a slightly yellow solid. Rf = 0.2 [EA:Hex (1:5)]; mp = 77–78 °C (DCM); IR (KBr) 3032, 3001, 2956, 2931, 2908, 2835, 1510, 1250, 1034, 831 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.95–7.93 (m, 2H), 7.75 (s, 2H), 7.01–6.97 (m, 6H), 6.77–6.70 (m, 2H), 6.72–6.70 (m, 4H), 6.60–6.57 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.4, 163.4, 158.3 (2C), 158.1, 142.4, 141.9 (2C), 137.1, 133.9 (2C), 132.7 (2C), 132.6 (2C), 131.5, 131.1 (4C), 130.7 (2C), 130.4, 113.8 (2C), 113.3 (4C), 113.1 (2C), 55.6, 55.3(2C), 55.2; HRMS (ESI) calculated for C35H31O5 (MS + H+): 531.2166; found 531.2161.

3.2.14. Synthesis of (4,4′-dihydroxy-6′-(4-hydroxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-yl)(4-hydroxyphenyl)methanone—selagibenzophenone B (2)

A solution of a BBr3 (1M in heptane, 0.2 mmol, 0.2 ml) was added in a dropwise manner to a solution of the (4,4′-dimethoxy-6′-(4-methoxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone (23, 0.026 mmol, 14 mg) in DCM (2 mL) at room temperature. After 16 h, the reaction was quenched with a saturated solution of NH4Cl (5 mL) and extracted with EA (3 × 10 mL). Combined organic phases were dried over Na2SO4, filtered, and evaporated. The product was purified with preparative TLC (DCM:MeOH, 20:1). The reaction yielded 6 mg of the monomethoxy derivative (4,4′-dihydroxy-6′-(4-hydroxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone (48% yield) and 6 mg of the selagibenzophenone B (2) in the form yellow solids (36% yield). Selagibenzophenone B (2): Rf = 0.2 [DCM:MeOH 20:1]; mp = 250 °C (decomp.); IR (KBr) 3459, 2927, 2792, 1587, 1342 cm−1; 1H NMR (600 MHz, MeOD-d4) δ 7.79–7.55 (m, 2H), 7.58 (s, 2H), 6.93–6.88 (m, 4H), 6.77–6.74 (m, 2H), 6.77–6.74 (m, 2H), 6.61–6.58 (m, 4H), 6.50–6.46 (m, 2H); 13C NMR (150 MHz, MeOD-d4) δ 197.5, 170.5, 157.2 (2C), 156.9, 143.7, 143.4 (2C), 138.8, 134.6 (2C), 134.2, 133.7 (2C), 132.1 (4C), 131.9, 131.0 (2C), 126.5, 118.2 (2C), 115.6 (4C), 115.4 (2C). HRMS (ESI) calculated for C31H23O5 (MS + H+): 475.1540, found 475.1545.

3.2.15. Synthesis of (4,4′-dihydroxy-6′-(4-hydroxyphenyl)-[1,1′:2′,1′-terphenyl]-4′-yl)(4-methoxyphenyl)methanone—(monomethoxy-selagibenzophenone B) (24)

Rf = 0.4 [DCM:MeOH 20:1]; mp = 253–254 °C (DCM); IR (KBr) 3302, 3032, 2958, 2841, 1888, 1699, 1595, 1512, 1419, 1342, 1257 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.90–7.88 (m, 2H), 7.62 (s, 2H), 7.07–7.05 (m, 2H), 6.90–6.88 (m, 4H), 6.66–6.64 (m, 2H), 6.60–6.58 (m, 4H), 6.49–6.47 (m, 2H,), 3.89 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 197.5, 165.2, 157.2 (2C), 156.9, 144.4, 143.7 (2C), 137.8, 134.0, 133.7 (3C), 133.7 (2C), 132.0 (4C), 131.7, 131.3 (2C), 131.2, 115.6 (4C), 115.4 (2C), 114.9 (2C), 56.1; HRMS (ESI) calculated for C32H25O5 (MS + H+): 489.1697 found 489.1691.

4. Conclusions

In conclusion, we accomplished the total synthesis of the natural product selagibenzophenone A (1), comprising a Suzuki coupling and an addition of an organometallic aromatic compound to a carbonyl moiety to assemble the backbone of the natural product. Further adjustment of the oxidation state and liberation of the phenols led to the synthesis of selagibenzophenone A (1) and to confirmation of the proposed structure. The synthesis was performed using two different protecting group strategies. In the first, the phenols were protected as methoxy groups and partial control over the selectivity of the deprotection was gained, depending on the deprotection method used. This will be useful in the future synthesis of derivatives of the natural product and determination of the structure–activity relationship. However, the protocol leading to the formation of the desired natural product lacked reproducibility, which prompted us to develop a second-generation synthesis procedure, using easily removable TBS protecting groups. This approach allowed us to achieve the first reliable total synthesis of selagibenzophenone A (1).
In addition, we achieved the total synthesis of compound 2, which had been described as a natural product known as selagibenzophenone B by Xu and Tan [3] and by Liang and Wang [4]. Our synthetic studies and comparison of our data with previously reported data revealed that the structure of the isolated material, described as selagibenzophenone B, is in fact misassigned and that the isolated compound is selagibenzophenone A. This finding is important not only for natural product chemists but also for the medicinal chemistry community because several biological activities have been reported for selagibenzophenone B (2) when they should be instead ascribed to selagibenzophenone A (1).
Currently, follow-up studies are being conducted in our laboratory and in the laboratories of our collaborators, where natural and unnatural selagibenzophenones are being prepared and assessed for their biological effects.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/catal11060708/s1: Figure S1: Numbering of selagibenzophenones A and B and key HMBC correlations for selagibenzophenone B; Table S1: Comparison of NMR shifts of synthetic and isolated selagibenzophenones A and B; Figure S2: 1H NMR spectra of compound 10 in CDCl3 (400 MHz); Figure S3: 13C NMR spectra of compound 10 in CDCl3 (100 MHz); Figure S4: 1H NMR spectra of compound 12 in CDCl3 (400 MHz); Figure S5: 13C NMR spectra of compound 12 in CDCl3 (100 MHz); Figure S6: 1H NMR spectra of compound 13 in CDCl3 (400 MHz); Figure S7: 13C NMR spectra of compound 13 in CDCl3 (100 MHz); Figure S8: 1H NMR spectra of compound 14 in MeOD-d4 (600 MHz); Figure S9: 13C NMR spectra of compound 14 in MeOD-d4 (150 MHz); Figure S10: 1H NMR spectra of selagibenzophenone A (1) in MeOD-d4 (400 MHz); Figure S11: 13C NMR spectra of selagibenzophenone A (1) in MeOD-d4 (100 MHz); Figure S12: COSY spectra of selagibenzophenone A (1) in MeOD-d4; Figure S13: HSQC spectra of selagibenzophenone A (1) in MeOD-d4; Figure S 14: HSQC spectra of selagibenzophenone A (1) in MeOD-d4; Figure S15: 1H NMR spectra of compound 18 in CDCl3 (400 MHz); Figure S17: 1H NMR spectra of compound 19 in CDCl3 (400 MHz); Figure S18: 13C NMR spectra of compound 19 in CDCl3 (100 MHz); Figure S19: 1H NMR spectra of compound 20 in CDCl3 (300 MHz); Figure S20: 13C NMR spectra of compound 20 in CDCl3 (75 MHz); Figure S21: 1H NMR spectra of compound 21 in CDCl3 (400 MHz); Figure S22: 13C NMR spectra of compound 21 in CDCl3 (100 MHz); Figure S23: 1H NMR spectra of compound 22 in CDCl3 (400 MHz); Figure S24: 13C NMR spectra of compound 22 in CDCl3 (100 MHz); Figure S25: 1H NMR spectra of compound 23 in CDCl3 (400 MHz); Figure S27: 1H NMR spectra of selagibenzophenone B (2) in MeOD-d4 (400 MHz); Figure S28: 13C NMR spectra of selagibenzophenone B (2) in MeOD-d4 (100 MHz); Figure S29: COSY spectra of selagibenzophenone B (2) in MeOD-d4; Figure S30: HSQC spectra of selagibenzophenone B (2) in MeOD-d4; Figure S31: HMBC spectra of selagibenzophenone B (2) in MeOD-d4; Figure S32: 1H NMR spectra of monomethoxy-selagibenzophenone B 24 in MeOD-d4 (400 MHz); Figure S33: 13C NMR spectra of monomethoxy-selagibenzophenone B 24 in MeOD-d4 (100 MHz); Figure S34: COSY spectra of monomethoxy-selagibenzophenone B 24 in MeOD-d4 (100 MHz).

Author Contributions

Conceptualization, L.R.; methodology, R.L., Š.M., M.M.; resources, L.R.; writing—original draft preparation, L.R.; writing—review and editing, R.L.; supervision, L.R.; project administration, L.R.; funding acquisition, L.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Charles University Primus program grant number PRIMUS/20/SCI/017 and Charles University Research Center program grant number UNCE/SCI/014.

Data Availability Statement

The following data are available: primary NMR FID files for compounds: 1, 2, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Banks, J.A. Selaginella and 400 Million Years of Separation. Annu. Rev. Plant. Biol. 2009, 60, 223–238. [Google Scholar] [CrossRef] [PubMed]
  2. Liu, X.; Tang, G.-H.; Weng, H.-Z.; Zhang, J.-Z.; Xu, Y.-K.; Yin, S. A new selaginellin derivative and a new triarylbenzophenone analog from the whole plant of Selaginella pulvinata. J. Asian Nat. Prod. Res. 2018, 20, 1123–1128. [Google Scholar] [CrossRef]
  3. Liu, R.; Zou, H.; Zou, Y.-X.; Cheng, F.; Yu, X.; Xu, P.S.; Li, X.M.; Li, D.; Xu, K.-P.; Tan, G.-S. Two new anthraquinone derivatives and one new triarylbenzophenone analog from Selaginella tamariscina. Nat. Prod. Res. 2020, 34, 2709–2714. [Google Scholar] [CrossRef] [PubMed]
  4. Wang, C.-G.; Yao, W.-N.; Zhang, B.; Hua, J.; Liang, D.; Wang, H.-S. Lung cancer and matrix metalloproteinases inhibitors of polyphenols from Selaginella tamariscina with suppression activity of migration. Bioorg. Med. Chem. Lett. 2018, 28, 2413–2417. [Google Scholar] [CrossRef] [PubMed]
  5. Liu, X.; Luo, H.-B.; Huang, Y.-Y.; Bao, J.-M.; Tang, G.-H.; Chen, Y.-Y.; Wang, J.; Yin, S. Selaginpulvilins A–D, New Phosphodiesterase-4 Inhibitors with an Unprecedented Skeleton from Selaginella pulvinata. Org. Lett. 2014, 16, 282–285. [Google Scholar] [CrossRef]
  6. Woo, S.; Kang, K.B.; Kim, J.; Sung, S.H. Molecular Networking Reveals the Chemical Diversity of Selaginellin Derivatives, Natural Phosphodiesterase-4 Inhibitors from Selaginella tamariscina. J. Nat. Prod. 2019, 82, 1820–1830. [Google Scholar] [CrossRef]
  7. Li, W.; Tang, G.-H.; Yin, S. Selaginellins from the genus Selaginella: Isolation, structure, biological activity, and synthesis. Nat. Prod. Rep. 2020. [Google Scholar] [CrossRef]
  8. Cao, Y.; Chen, J.-J.; Tan, N.-H.; Oberer, L.; Wagner, T.; Wu, J.-P.; Zeng, G.-Z.; Yan, H.; Wang, Q. Antimicrobial selaginellin derivatives from Selaginella pulvinata. Bioorg. Med. Chem. Lett. 2010, 20, 2456–2460. [Google Scholar] [CrossRef]
  9. Zhang, G.-G.; Jing, Y.; Zhang, H.-M.; Ma, E.-I.; Guan, J.; Xue, F.-N.; Liu, H.-X.; Sun, X.-Y. Isolation and Cytotoxic Activity of Selaginellin Derivatives and Biflavonoids from Selaginella tamariscina. Planta Med. 2012, 78, 390–392. [Google Scholar] [CrossRef][Green Version]
  10. Nguyen, P.-H.; Zhao, B.-T.; Ali, M.Y.; Choi, J.-S.; Rhyu, D.-Y.; Min, B.-S.; Woo, M.-H. Insulin-Mimetic Selaginellins from Selaginella tamariscina with Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Activity. J. Nat. Prod. 2015, 78, 34–42. [Google Scholar] [CrossRef]
  11. Sengupta, S.; Mehta, G. Natural products as modulators of the cyclic-AMP pathway: Evaluation and synthesis of lead compounds. Org. Biomol. Chem. 2018, 16, 6372–6390. [Google Scholar] [CrossRef] [PubMed]
  12. Karmakar, R.; Lee, D. Total Synthesis of Selaginpulvilin C and D Relying on in Situ Formation of Arynes and Their Hydrogenation. Org. Lett. 2016, 18, 6105–6107. [Google Scholar] [CrossRef]
  13. Chinta, B.S.; Baire, B. Formal total synthesis of selaginpulvilin D. Org. Biomol. Chem. 2017, 15, 5908–5911. [Google Scholar] [CrossRef] [PubMed]
  14. Chinta, B.S.; Baire, B. Total synthesis of selaginpulvilins A and C. Org. Biomol. Chem. 2018, 16, 262–265. [Google Scholar] [CrossRef]
  15. Sowden, M.J.; Sherburn, M.S. Four-Step Total Synthesis of Selaginpulvilin D. Org. Lett. 2012, 19, 636–637. [Google Scholar] [CrossRef]
  16. Zhang, J.-S.; Liu, X.; Weng, J.; Guo, Y.-Q.; Li, Q.-J.; Ahmed, A.; Tang, G.-H.; Yin, S. Natural diarylfluorene derivatives: Isolation, total synthesis, and phosphodiesterase-4 inhibition. Org. Chem. Front. 2017, 4, 170–177. [Google Scholar] [CrossRef]
  17. Rycek, L.; Mateus, M.; Beytlerová, N.; Kotora, M. Catalytic Cyclotrimerization Pathway for Synthesis of Selaginpulvilins C and D: Scope and Limitations. Org. Lett. 2021. Ahead of Print. [Google Scholar] [CrossRef]
  18. Press, N.J.; Banner, K.H. PDE4 Inhibitors—A Review of the Current Field. In Progress in Medicinal Chemistry; Lawton, G., Witty, D.R., Eds.; Elsevier B.V.: Amsterdam, The Netherlands, 2009; Volume 47, pp. 37–74. [Google Scholar]
  19. Zhang, K.Z.J.; Ibrahim, P.N.; Gillette, S.; Bollag, G. Phosphodiesterase-4 as a potential drug target. Expert Opin. Ther. Targets 2005, 9, 1283–1305. [Google Scholar] [CrossRef]
  20. Nicolaou, K.C.; Snyder, S.A. Chasing Molecules That Were Never There: Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Elucidation. Angew. Chem. Int. Ed. 2005, 44, 1012–1044. [Google Scholar] [CrossRef]
  21. Carroll, A.W.; Willis, A.C.; Hoshino, M.; Kato, A.; Pyne, S.G. Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis. J. Nat. Prod. 2019, 82, 358–367. [Google Scholar] [CrossRef]
  22. McOmie, J.F.W.; Watts, M.L.; West, D.E. Demethylation of aryl methyl ethers by boron tribromide. Tetrahedron 1968, 24, 2289–2292. [Google Scholar] [CrossRef]
  23. Weissman, S.A.; Zewge, D. Recent advances in ether dealkylation. Tetrahedron 2005, 61, 7833–7863. [Google Scholar] [CrossRef]
  24. Dodge, J.A.; Stocksdale, M.G.; Fahey, K.J.; Jones, C.D. Regioselectivity in the Alkaline Thiolate Deprotection of Aryl Methyl Ethers. J. Org. Chem. 1995, 60, 739–741. [Google Scholar] [CrossRef]
  25. Vshivkov, A.A.; Gertman, G.A. Preparation of 2,4,6-substituted benzophenones. Zhurnal Vsesoyuznogo Khimicheskogo Obs. D. I. Mendeleeva 1984, 29, 105–106. [Google Scholar]
  26. Kapdi, A.R.; Fairlamb, I.J.S. Synthesis of Macrocyclic Ketones Exploiting Palladium-Catalyzed Activation of Carboxylic Acids as an Enabling Step. New J. Chem. 2013, 37, 961–964. [Google Scholar] [CrossRef]
Figure 1. Examples of natural products isolated from Selaginella plants.
Figure 1. Examples of natural products isolated from Selaginella plants.
Catalysts 11 00708 g001
Scheme 1. Retrosynthetic analysis and identification of suitable starting materials (6 and 8).
Scheme 1. Retrosynthetic analysis and identification of suitable starting materials (6 and 8).
Catalysts 11 00708 sch001
Scheme 2. Synthesis of selagibenzophenone A (1).
Scheme 2. Synthesis of selagibenzophenone A (1).
Catalysts 11 00708 sch002
Scheme 3. Improved synthesis of selagibenzophenone A (1).
Scheme 3. Improved synthesis of selagibenzophenone A (1).
Catalysts 11 00708 sch003
Scheme 4. Synthesis of selagibenzophenone B (2).
Scheme 4. Synthesis of selagibenzophenone B (2).
Catalysts 11 00708 sch004
Figure 2. Comparison of the 1H NMR spectra of synthetic compounds 1 and 2.
Figure 2. Comparison of the 1H NMR spectra of synthetic compounds 1 and 2.
Catalysts 11 00708 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lapinskaite, R.; Malatinec, Š.; Mateus, M.; Rycek, L. Cross-Coupling as a Key Step in the Synthesis and Structure Revision of the Natural Products Selagibenzophenones A and B. Catalysts 2021, 11, 708. https://doi.org/10.3390/catal11060708

AMA Style

Lapinskaite R, Malatinec Š, Mateus M, Rycek L. Cross-Coupling as a Key Step in the Synthesis and Structure Revision of the Natural Products Selagibenzophenones A and B. Catalysts. 2021; 11(6):708. https://doi.org/10.3390/catal11060708

Chicago/Turabian Style

Lapinskaite, Ringaile, Štefan Malatinec, Miguel Mateus, and Lukas Rycek. 2021. "Cross-Coupling as a Key Step in the Synthesis and Structure Revision of the Natural Products Selagibenzophenones A and B" Catalysts 11, no. 6: 708. https://doi.org/10.3390/catal11060708

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop