Article Cite This: J. Nat. Prod. 2018, 81, 98−105
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Concise Synthesis of Natural Phenylphenalenone Phytoalexins and a Regioisomer Ming-Zhong Wang,*,†,‡ Chuen-Fai Ku,‡ Tong-Xu Si,† Siu-Wai Tsang,‡ Xiao-Meng Lv,† Xiao-Wan Li,† Zheng-Ming Li,§ Hong-Jie Zhang,*,‡ and Albert S. C. Chan*,† †
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, People’s Republic of China § State Key Laboratory of Elemento-organic Chemistry, Research Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China ‡
S Supporting Information *
ABSTRACT: Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1), 2hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are accomplished in 11 or 12 steps. The synthetic strategy features a Friedel−Crafts acylation to construct the 1H-phenalen-1one tricyclic core followed by a Suzuki cross-coupling to obtain the target compounds. yield was less than 1.5%, and the final product needed purification by repeated preparative TLC. This limits the potential applications of 8-phenylphenalenones in agricultural or clinical use. In order to provide sufficient amounts of phenylphenalenones for pharmacological studies as well as for further structure−activity relationship (SAR) assessments, the 8-phenylphenalenones 1 and 2 with unusual substituted positions, the 5-phenylphenalenone (3),7 and a 9-phenylphenalenone (4) were selected to develop an efficient synthetic strategy for phenylphenalenone-type phytoalexins. Herein, we describe concise and efficient syntheses of 2-hydroxy-8-(4hydroxyphenyl)phenalen-1-one (1) and hydroxyanigorufone (4), the first total synthesis of 2-hydroxy-8-(3,4dihydroxyphenyl)phenalen-1-one (2), and a synthesis of the originally proposed structure of emenolone (3).
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hytoalexins are natural antibiotics, and some of them are used as fungicides or templates for the production of new pesticides involving unique modes of action.1 Phenylphenalenones are a class of phytoalexins mainly produced by plants of the Hemodoraceae, Pontederiaceae, Strelitziaceae, and Musaceae families in response to chemical, physical, or microbial stress factors.2 Phenylphenalenones are mainly composed of 4-, 6-, 7-, and 9-phenylphenalenones,3 but two 8-phenylphenalenones, 1 and 2 (Figure 1), have been isolated from Eichhornia crassipes by Holscher and Schneider.4 Research by others has led to the synthesis of 4- and 9phenylphenalenones2a,5 and 2-hydroxy-8-(4-hydroxyphenyl)1H-phenalen-1-one (1).6 The latter synthesis was achieved in 11 steps by Otålvaro and co-workers in 2015,6 but the overall
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RESULTS AND DISCUSSION 2-Hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1) and 2hydroxy-8-(3, 4-dihydroxyphenyl)phenalen-1-one (2) were synthesized from 8-bromo-2-hydroxy-1H-phenalen-1-one (5) by Suzuki cross-coupling with their corresponding aryl boronic acids, while the proposed structure of emenolone (3) was Received: August 19, 2017 Published: December 27, 2017
Figure 1. Selected phenylphenalenone compounds of 1−4. © 2017 American Chemical Society and American Society of Pharmacognosy
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DOI: 10.1021/acs.jnatprod.7b00709 J. Nat. Prod. 2018, 81, 98−105
Journal of Natural Products
Article
by oxidation with Dess-Martin periodinane to afford 13 in 79% yield (33% overall yield from 13a). Compound 13 was converted to the key intermediate 10 by reaction with carbethoxymethyl-triphenylphosphonium bromide, followed by hydrolysis and acidification. With a sufficient amount of 10, the focus was turned to the key Friedel−Crafts acylation reaction to construct the phenalenone tricyclic core of 8-bromo-1H-phenalen-1-one (7). Successive treatment of 10 with oxalyl chloride/DMF/CH2Cl2 and AlCl3/CH2Cl2 gave 7 in 61% yield, which underwent a Δ2(3) Yang−Finnegan epoxidation/ring-opening/proton migration reaction to afford 8-bromo-2-hydroxy-1H-phenalen-1-one (5, Scheme 2). Finally, the reaction of 5 with potassium 4-hydroxyphenyltrifluoroborate10 through a Suzuki cross-coupling reaction afforded 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1) in 78% yield (Scheme 3). Using the same procedure, 2-hydroxy8-(3,4-dihydroxyphenyl)phenalen-1-one (2) was synthesized in 70% yield (two steps) via reaction of 5 with (3,4dimethoxyphenyl)boronic acid followed by deprotection of the methoxy groups (Scheme 3). The physical and spectroscopic data of the synthesized compounds 1 and 2 were identical to the reported data.4 The synthesis of 3 was carried out using benzo[de]isochromene-1,3-dione11 as starting material. The tricyclic core of 5-bromo-1H-phenalen-1-one (8) was synthesized via the Friedel−Crafts acylation of 11 in a one-pot reaction (Scheme 4). Unsurprisingly, the 1H NMR spectroscopic data of 3 in CDCl3 were different from those of hydroxyanigorufone (4). Hydroxyanigorufone (4), the structure of emenolone established by Luis and co-worker, was also synthesized.7b Although hydroxyanigorufone (4) was first obtained via a synthetic study in 1978,12 the total yield was low and a 60 h refluxing under nitrogen protection was required in the final step. Here, compound 4 was conveniently synthesized starting from 15 (Scheme 4) or 9 (Scheme 5) by adopting the same reaction procedure that was used for the synthesis of 3. Intermediate 17 was synthesized according to a literature procedure.2a The deprotection step of the methoxy group of 18 was carried out under mild conditions, and a 23.8% overall yield of hydroxyanigorufone (4) was achieved (from 15, Schemes 4 and 5). The physical and spectroscopic data (1H NMR, methanold4; 1H NMR, acetone-d6) of synthesized hydroxyanigorufone (4) are identical to the reported data of hydroxyanigorufone.3e,13 Furthermore, the 1H NMR spectroscopic data (CDCl3) of synthesized hydroxyanigorufone (4) were identical to those reported for emenolone (1H NMR, CDCl3; see Supporting Information).7a This confirms that emenolone and hydroxyanigorufone are the same compound. The synthesized phenylphenalenones were evaluated for their biological activities against five phytofungal strains, namely, Alternaria solani, Cercospora arachidicola, Fusarium omysporum, Gibberella zeae, and Physalospora piricola, and tobacco mosaic virus (TMV, Nicotiana tabacum L.), and four human cancer cell lines (HCT-116, HT-29, PANC-1, and PC3). Compounds 1−4 and 16−18 did not show significant antifungal activity. However, compounds 1 and 3 exhibited more potent antiviral activity than the commercial virucidal agent ribavirin (Table 1). Analogue 16 was cytotoxic to the p53-wild-type HCT-116 colon cancer cells (IC50, 5.3 μM) and PC-3 prostate cancer cells (IC50, 7.8 μM), but not the p53mutated HT-29 colon cancer cells or PANC-1 pancreatic
synthesized from cross-coupling of 5-bromo-2-hydroxy-1Hphenalen-1-one (6) with an arylboronic acid. The intermediates 5 and 6 were derived from enones 7 and 8 via a Yang− Finnegan epoxidation/ring-opening/proton migration process between C-2 and C-3. Inspired by Echeverri’s work on the syntheses of perinaphthenone,2a compounds 7−9 were prepared directly from 10−12 in one pot using the Friedel−Crafts acylation reaction. The (E)-3-(naphthalen-1-yl)acrylic acid derivatives 10−12 were synthesized by reaction of naphthaldehydes 13− 15 with carbethoxymethyl-triphenylphosphonium bromide in a Wittig reaction, followed by hydrolysis and acidification (Figure 2). Although 6-bromo-1-naphthaldehyde (13) is a
Figure 2. Retro-synthetic protocol toward 1−3.
known compound, no synthetic method has been reported. We thus used ethyl 2-(4-bromophenyl)acetate (13a) as the starting material to synthesize 13. Compound 13a could be converted to 13b by reacting with tert-butyl acrylate via a Michael annulation (35 g scale, Scheme 1). Deprotection of the tert-butyl group of 13b gave the free acid 13c, which was treated with oxalyl chloride/dimethylformamide (DMF)/CH2Cl2 and AlCl3/CH2Cl2 to produce tetrahydronaphthalene 13d in 75% yield. Compound 13d was subsequently reduced to 13e followed by dehydration to give 13f and 13g as byproducts (p-Toluenesulfonic acid (PTSA), catalysis). As previously reported by Tagat,8 several PTSA conditions were screened for the best yield of 13f. However, the yields under all tested conditions were less than 13% (a). The Burgess reagent was then utilized, and 13e was fully consumed to form 13f and a complex mixture (b, no 13g produced). However, the yields were still low (
