Directed C–H Bond Functionalization: A Unified Approach to Formal

Sep 13, 2018 - Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol have been accomplished on the ba...
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Cite This: J. Org. Chem. 2018, 83, 12327−12333

Directed C−H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol, and Macrophyllol Gowri Sankar Grandhi, Jayaraman Selvakumar, Suman Dana, and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India

J. Org. Chem. 2018.83:12327-12333. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/05/18. For personal use only.

S Supporting Information *

ABSTRACT: Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol have been accomplished on the basis of successive C−H bond functionalization of ready-stock benzoic acids. This concise strategy involves transition-metal-catalyzed directed C−H olefination, C−H hydroxylation, and acid-mediated C−H prenylation as key steps.

α-Hydroxy benzoic acid decorated bibenzyls and stilbenes constitute a very rapidly developing field of research as molecules possessing such frameworks are ubiquitous in myriad natural products with diverse biological activities.1,2 Pivotal examples include prenylated compound amorfrutin A (1), which has been isolated from the two dietary legumes Glycyrrhiza fetida and Amorpha f ruticosa (Figure 1).1a It

route to these natural products. However, efficient synthetic protocols to access these molecules are limited. In general, their syntheses have been addressed through the construction of an aromatic ring with desired substitutions from prefunctionalized linear molecules4 or olefination of protected salicyclic acid derivatives.2h,5 Syntheses of macrophyllol and hydrangenol primarily rely on strategic ortho- and laterallithiation processes using salicylic acid derivatives.6 Over the past decades, transition-metal-catalyzed reactions have shaped contemporary organic synthesis by enabling direct functionalization of unreactive C−H bond and successfully been executed in the synthesis and late-stage functionalization of various natural products.7−9 We envisioned that implementation of this step- and atom-economic technology for syntheses of aforementioned molecules would be very effective. Accordingly, a retrosynthetic plan was conceived (Figure 1). A 3-fold C−H bond functionalization consisting of C−H homobenzylation (C−H styrylation/reduction or hydroarylation), hydroxylation, and prenylation of ready-stock aromatic acid would deliver the amorfrutin A (1). Cajaninstilbene acid (2) can be prepared following C−H styrylation, hydroxylation, and prenylation as key steps. Similarly, a 2-fold regioselective C−H bond functionalization such as C−H styrylation with readily available styrene derivatives and hydroxylation of benzoic acid and subsequent cyclization would result in natural products hydrangenol (3) and macrophyllol (4). Herein, we report the development of this approach for the formal syntheses of amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol. Synthesis of amorfrutin A (1) started with the installation of homobenzyl group at the ortho-position of commercially available p-anisic acid (Scheme 1a). Recently, we have developed weak coordination-directed ortho C−H styrylation of benzoic acids using Ru(II) catalyst under mild conditions.10

Figure 1. Natural products 1−4 and retrosynthetic analysis.

exhibits profound activation of PPARγ and is also a lead compound in type II diabetes drug discovery.1c The unsaturated analogue cajaninstilbene acid (2) displays antiinflammatory,2g antioxidant,2a−c and antitumor activities.2d−f Other cyclic analogues, such as hydrangenol (3) and macrophyllol (4), members of dihydroisocoumarine family of natural products, are known to suppress T-lymphocyte proliferation and inhibit histamine release.3 These extraordinary bioactivities fuel on the pursuit of synthetic strategies en © 2018 American Chemical Society

Received: August 15, 2018 Published: September 13, 2018 12327

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

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The Journal of Organic Chemistry Scheme 1. Formal Synthesis of Amorfrutin A (1) and Cajaninstilbene Acid (2)

Adaptation of this strategy in the coupling reaction of p-anisic acid (5a) with commercially available styrene 6a produced the styrylated ester 7 in 56% yield. Hydrogenation of the double bond with H2 and Pd/carbon followed by hydrolysis of the ester group quantitatively delivered the acid 8. Alternatively, the ruthenium-catalyzed C−H hydroarylation reaction of 4acetylanisole 9 with styrene 6a followed by manganesecatalyzed oxidation furnished the desired acid 8 in 76% isolated yield (in two steps).11 To execute the inexpensive copper-mediated C−H hydroxylation reaction, acid 8 was converted to the corresponding acid chloride, which was then coupled with 2-aminophenylpyrazole (2-APP, 10), a directing group independently introduced by us and the Li group for C− H bond activation strategy.12,13 Treatment of 2-APP directing group coupled amide 11 with copper acetate (1.5 equiv) and K2CO3 (1.5 equiv) in DMSO solvent at 80 °C produced the ortho C−H hydroxylated compound 12 in 84% yield. The 2APP directing group was removed via Lewis acid mediated methanolysis to obtain o-hydroxyl ester 13.12,14 To install the prenyl functionality on the aromatic ring, previously reported rearrangement of O-prenyl ether to C-prenyl aromatic alcohol was implemented.15 For that purpose, the hydroxyl group was prenylated with prenyl bromide in the presence of sodium hydride to provide compound 14. Exposure of O-prenylated ether 14 to montmorillonite K10 (1 wt equiv) offered the methyl ester of amorfrutin A (1a) in 38% yield along with

deprenylated precursor 13 in 56% yield. It is worth noting that compound 13 can be utilized in prenylation followed by Oprenyl ether rearrangement sequence, mitigating the loss of material during synthesis. Cajaninstilbene acid (2) structurally resembles amorfrutin A (1), where the homobenzyl group is replaced with a styryl group. Thus, tactically the synthesis of cajaninstilbene can be accomplished in a fashion similar to that described in the preceding section, excluding the step that was involved in the hydrogenation of alkene functionality. Accordingly, compound 7, obtained via Ru-catalyzed styrylation of p-anisic acid (5a), was hydrolyzed to afford styrylated aromatic acid 15 in 98% yield (Scheme 1b). The 2-APP directing group was installed to give stilbene-substituted benzamide 16. Satisfyingly, when compound 16 was exposed to the hydroxylation conditions described above, the desired C−H hydroxylated compound 17 was isolated in 81% yield. While direct C−H hydroxylation of various benzoic acid derivatives has been intensively investigated using transition-metal catalysts,16 utilization of challenging ortho-styrylated benzoic acid derivatives for such a purpose is elusive, signifying the importance of our findings and the effectiveness of the 2-APP directing group in C−H bond activation. The execution of the prior established sequence, removal of the directing group, formation of Oprenyl ether 19, and its rearrangement under montmorillonite K10 produced the desired methyl ester of cajaninstilbene acid 12328

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

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The Journal of Organic Chemistry 2a. Simple hydrolysis of the esters 1a and 2a to forge natural products amorfrutin A (1) and cajaninstilbene acid (2), respectively, was previously reported.5d For the synthesis of cyclic dihydroisocoumarine natural product hydrangenol (3), parent benzoic acid (5b) was reacted with 4-methoxystyrene (6b) under chelation-assisted Ru(II)catalyzed ortho-styrylation conditions to prepare key building block 20 (58% yield, Scheme 2, left).10 It was then utilized to hinge the 2-APP (10) directing group following ester hydrolysis/acid chloride formation/amidation sequences,

delivering compound 22 in high yield. Copper-mediated hydroxylation followed by removal of the 2-APP directing group via methanolysis resulted in compound 24 in excellent yield. Synthesis of natural product hydrangenol (3) from compound 24 via cyclization is known in the literature.6b,d To accomplish the formal synthesis of macrophyllol (4), C− H styrylation of benzoic acid 5b was performed with electronrich styrene 6c (Scheme 2, right). This coupling process was relatively slow, and the desired product 25 was isolated in 44% yield after prolonging the reaction time. Nevertheless, compound 25 was transformed to amide 27 in a similar manner and then subjected to C−H hydroxylation with Cu(OAc)2 to furnish compound 28. Removal of directing group delivered the hydroxylated ester 29 from which the synthesis of macrophyllol (4) is a known process.6b,c,17 In conclusion, we have devised a succinct and unified route for formal syntheses of four natural products, amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol. This strategy uses otherwise unactivated C−H bonds of benzoic acids as a pivotal synthetic handle to install styryl, hydroxyl, and prenyl functionalities. Further applications of direct activation/functionalization of ubiquitous C−H bonds toward natural products syntheses are ongoing in our laboratory.

Scheme 2. Formal Synthesis of Hydrangenol (3) and Macrophyllol (4)

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EXPERIMENTAL SECTION

General Information. All anhydrous solvents were dried by standard techniques and freshly distilled prior to use. Column chromatography was carried out using dry packed Finar silica gel 100−200 μm, and thin-layer chromatography was carried out in WhatmanPartisil K6F TLC plates (silica gel 60 Å, 0.25 mm thickness). Visualization was accomplished using ultraviolet light (366 or 254 nm) and chemical staining with basic potassium permanganate solution. 13C and 1H NMR spectra were recorded on Bruker 400 or Bruker 500 MHz spectrometers. Chemical shift values (δ) are reported in ppm and calibrated to the residual solvent peak CDCl3 δ = 7.260 ppm for 1H, δ = 77.160 for 13C or calibrated to tetramethylsilane (δ = 0.00). All NMR spectra were recorded at ambient temperature (290 K) unless otherwise noted. 1H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constant, integration). The following abbreviations are used to indicate multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublet; dt, doublet of triplet; dq, doublet of quartet; br, broad. Mass spectra were recorded by electrospray ionization (ESI) method on a Q-TOF Micro with a lock spray source. Synthesis of Compounds 7, 20, and 25 via Ru(II)-Catalyzed C−H Styrylation of Benzoic Acids. To an oven-dried 50 mL round-bottom flask were added p-anisic acid 5a (3.2 mmol, 1 equiv), styrene 6a (1.5 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), K2HPO4 (1 equiv), and CuO (2 equiv), and then 10 mL methanol solvent was added. The round-bottom flask was then sealed with a glass stopper. The reaction mixture was stirred at 85 °C for 24 h under air. After completion (monitored by TLC), the solvent was evaporated under reduced pressure. Then K2CO3 (2 equiv) and MeI (3 equiv) were added to the crude reaction mixture in the presence of acetonitrile solvent (10 mL), and the reaction mixture was stirred for 4 h at room temperature. After completion (monitored by TLC), the crude reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. Next, the solvent was evaporated under reduced pressure. In order to obtain pure 2-styrylbenzoic acid methyl ester 7, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate (2−5% ethyl acetate in hexane). Compounds 20 and 25 were synthesized following the same synthetic procedure from the benzoic acid 5b using styrene 6b and 6c, respectively. (E)-Methyl 4-methoxy-2-styrylbenzoate (7): liquid, yield 56% (465 mg); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 16.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.55−7.53 (m, 2H), 7.36−7.32 (m, 2H), 12329

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

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The Journal of Organic Chemistry

2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 159.7, 140.6, 133.2, 131.7, 131.5, 130.4, 129.6, 128.4, 127.2, 127.0, 125.5, 114.3, 55.5; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C16H14O3Na+ 277.0841, found 277.0857. (E)-2-(3,4,5-Trimethoxystyryl)benzoic acid (26): white solid, yield 94% (295 mg); mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 8.07−7.93 (m, 2H), 7.72−7.70 (m, 1H), 7.56−7.47 (m, 1H), 7.35− 7.20 (m, 1H), 6.94 (d, J = 16.1 Hz, 1H), 6.78 (s, 2H), 3.88 (s, 6H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 153.5, 140.2, 138.4, 133.3, 133.2, 131.8, 131.7, 127.42, 127.37, 126.4, 105.6, 104.2, 61.1, 56.2 (C × 2). HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C18H18O5H+ 315.1232, found 315.1262. Synthesis of Compound 8 from 4-Acetylanisole 9. To an oven-dried 15 mL Schlenk tube were added 4-acetylanisole 9 (4 mmol, 1 equiv), styrene 6a (2 equiv), [Ru(p-cymene)Cl2]2 (2.5 mol %), sodium formate (HCO2Na) (30 mol %), and PPh3 (15 mol %) under N2 atmosphere. Dry toluene (5 mL) was injected, and the reaction mixture was stirred at 140 °C for 36 h. After completion (monitored by TLC), the reaction mixture was diluted with DCM and filtered through a Celite pad. The volatiles were evaporated under reduced pressure. The resulting residue was transferred to a 25 mL round-bottom flask, and Mn(OAc)2·4H2O (1 mol %) was added. Next, acetic acid (4.0 mL) was injected in the reaction mixture, and the flask was equipped with a balloon filled with O2. The mixture was then stirred at 100 °C for 15 h. After completion, the reaction mixture was cooled to room temperature and extracted with NaHCO3 solution followed by workup with 1 N HCl to give acid 8 (778.5 mg, 76% yield). Installation of 2-APP Directing Group To Prepare Compounds 11, 16, 22, and 27. In an oven-dried 50 mL round-bottom flask (with suitable gas outlet), acid 8 (0.9 mmol, 1 equiv) was dissolved in 10 mL dichloromethane, and oxalyl chloride (2 equiv) was added under N2 atmosphere. The reaction mixture was cooled to 0 °C, and then one drop of DMF was added. The reaction mixture was stirred at 0 °C for 1 h and further stirred for 3 h at room temperature. Afterward, the volatiles were evaporated under reduced pressure. The resulting residue was dissolved in 10 mL of dichloromethane, and (2-aminophenyl)pyrazole (2-APP) 10 (1.1 equiv) and triethylamine (2 equiv) were added at 0 °C under inert atmosphere. The mixture was stirred at room temperature overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. Amides 16, 22, and 27 were also prepared following the above-mentioned procedure from acids 15, 21, and 26, respectively. N-(2-(1H-Pyrazol-1-yl)phenyl)-4-methoxy-2-phenethylbenzamide (11): liquid, yield 99% (350 mg); mp 92−94 °C; 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 8.65 (dd, J = 8.3, 1.2 Hz, 1H), 7.80 (dd, J = 2.5, 0.5 Hz, 1H), 7.73−7.72 (m, 1H), 7.45−7.38 (m, 2H), 7.35−7.32 (m, 1H), 7.21−7.18 (m, 3H), 7.16−7.08 (m, 3H), 6.77− 6.74 (m, 1H), 6.68−6.67 (m, 1H), 6.46−6.45 (m, 1H), 3.77 (s, 3H), 3.18−3.14 (m, 2H), 2.94−2.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.6, 161.0, 143.8, 141.9, 141.2, 132.2, 130.3, 129.3, 129.0, 128.8, 128.7, 128.3, 128.2, 125.9, 124.1, 123.0, 122.6, 116.5, 111.5, 107.2, 55.4, 37.9, 35.9; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C25H23N3O2H+ 398.1869, found 398.1857. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-4-methoxy-2-styrylbenzamide (16): liquid, yield 99% (350 mg); mp 93−95 °C; 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.71−8.69 (m, 1H), 7.71−7.56 (m, 4H), 7.45−7.38 (m, 3H), 7.30−7.16 (m, 6H), 7.00 (d, J = 16.7 Hz, 1H), 6.86−6.84 (m, 1H), 6.33 (s, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 161.3, 141.1, 138.9, 137.2, 132.1, 131.4, 130.0, 129.7, 129.2, 128.5, 128.1, 127.8, 126.9, 126.4, 124.0, 122.8, 122.5, 113.9, 113.0, 111.8, 107.1, 55.4; HRMS (ESI/TOF- Q) m/z [M + Na]+ calcd for C25H21N3O2Na+ 418.1531, found 418.1537. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-2-(4-methoxystyryl)benzamide (22): liquid, yield 96% (340 mg); mp 98−100 °C; 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.74 (d, J = 7.4 Hz, 1H), 7.71−7.69 (m, 2H), 7.61−7.54 (m, 2H), 7.45−7.39 (m, 3H), 7.37−7.35 (m,

7.27−7.23 (m, 1H), 7.17 (d, J = 2.6 Hz, 1H), 6.98−6.94 (m, J = 16.2 Hz, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 167.5, 162.6, 142.1, 137.5, 133.2, 131.6, 128.8, 128.1, 128.0, 127.0, 120.9, 112.8, 112.2, 55.6, 51.9. HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C17H16O3Na+ 291.0990, found 291.0997. (E)-Methyl 2-(4-methoxystyryl)benzoate (20): white solid, yield 58% (490 mg); mp 125−127 °C; 1H NMR (400 MHz, CDCl3) δ 7.91−7.83 (m, 2H), 7.70−7.68 (m, 1H), 7.49−7.46 (m, 3H), 7.27 (t, J = 7.5 Hz, 1H), 6.98−6.94 (m, 1H), 6.89−6.87 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.1, 159.6, 139.6, 132.2, 131.1, 130.8, 130.4, 128.4, 128.2, 126.88, 126.85, 125.3, 114.2, 55.5, 52.2; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C17H16O3Na+ 291.0997, found 291.0992. (E)-Methyl 2-(3,4,5-trimethoxystyryl)benzoate (25): white solid, yield 44% (460 mg); mp 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.95−7.87 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.54−7.48 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 16.2 Hz, 1H), 6.78 (s, 2H), 3.92 (s, 9H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0, 153.5, 139.4, 133.4, 132.3, 131.6, 130.9, 128.6, 127.3, 127.21, 127.15, 105.7, 104.2, 61.1, 56.3, 56.2, 52.2; HRMS (ESI/TOF-Q) m/z [M + K]+ calcd for C19H20O5K+ 367.0948, found 367.0941. Synthesis of Compound 8 from Compound 7. To an ovendried 25 mL round-bottom flask were added styrylated product 7 (1.4 mmol, 1 equiv) and 10% Pd/C (10 mol %), and then 10 mL of dry methanol was added. The reaction mixture was stirred overnight at room temperature under H2 balloon pressure. After completion (monitored by TLC), the reaction mixture was filtered through a Celite pad. Then the solvent was evaporated under reduced pressure, and the resulting residue was transferred to a 25 mL round-bottom flask and KOH (2 equiv) was added. Next, an 8 mL mixture of H2O and ethanol (5:1, v/v) was added in the flask, and the mixture was refluxed for 3 h. After completion (monitored by TLC), the ethanol was evaporated under reduced pressure. The reaction mixture was neutralized with 1 N HCl, and then crude carboxylic acid was obtained through workup with ethyl acetate. The solvent was evaporated under reduced pressure, and to obtain pure compound 8, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. (E)-4-Methoxy-2-styrylbenzoic acid (8): solid, yield 99% (250 mg); mp 116−118 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.7 Hz, 1H), 7.27−7.18 (m, 5H), 6.81−6.68 (m, 2H), 3.81 (s, 3H), 3.35- 3.31 (m, 2H), 2.96−2.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.2, 163.2, 147.9, 142.2, 134.6, 128.8, 128.5, 126.0, 120.2, 116.8, 111.7, 55.5, 38.1, 37.7; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C16H16O3H+ 257.1178, found 257.1188. Procedure for the Hydrolysis of Esters 7, 20, and 25. To an oven-dried 25 mL round-bottom flask were added ester compound 7 (1 mmol, 1 equiv) and KOH (2 equiv), and an 8 mL mixture of H2O and ethanol (5:1, v/v) was added. The reaction mixture was refluxed for 3 h. After completion (monitored by TLC), the ethanol was evaporated under reduced pressure. The reaction mixture was neutralized with 1 N HCl, and then crude carboxylic acid was obtained through workup with ethyl acetate. The solvent was evaporated under reduced pressure, and to obtain pure compound 15, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. Compounds 21 and 26 were prepared following the same procedure from the corresponding esters 20 and 25, respectively. (E)-4-Methoxy-2-styrylbenzoic acid (15): white solid, yield 98% (250 mg); mp 152−154 °C; 1H NMR (400 MHz, CDCl3) δ 8.14− 8.06 (m, 2H), 7.57−7.55 (m, 2H), 7.38−7.19 (m, 4H), 7.01−6.93 (m, 1H), 6.87 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H); 13CNMR (101 MHz, CDCl3) δ 172.9, 163.4, 143.0, 137.4, 134.4, 131.8, 128.8, 128.2, 128.1, 127.1, 119.8, 112.9, 112.6, 55.6; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C16H14O3H+ 255.1021, found 255.1025. (E)-2-(4-Methoxystyryl)benzoic acid (21): white solid, yield 95% (360 mg); mp 177−179 °C; 1H NMR (400 MHz, CDCl3) δ 8.08− 8.06 (m, 1H), 7.96−7.92 (m, 1H), 7.74−7.72 (m, 1H), 7.57−7.49 (m, 3H), 7.34 (t, J = 7.1 Hz, 1H), 7.02−6.98 (m, 1H), 6.92−6.90 (m, 12330

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

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The Journal of Organic Chemistry

126.1, 125.1, 123.7, 122.5, 119.1, 116.8, 107.2, 104.1, 60.9, 56.0 (2 × C); HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C27H25N3O5H+ 472.1872, found 472.1876. Synthesis of Compounds 13, 18, 24, and 29 via Removal of the 2-APP Directing Group. In a 30 mL pressure tube equipped with a magnetic stir bar were added compound 12 and dry methanol (8 mL). Then BF3·Et2O (6 equiv) was added dropwise to the stirred solution at room temperature. The resulting mixture was stirred at 100 °C for 36 h. After the mixture was cooled to room temperature, Et3N (10 equiv) was added dropwise to the reaction mixture. The volatile components were removed under reduced pressure, and the crude reaction mixture was directly loaded onto silica gel column and purified through gradient eluent of hexane and ethyl acetate mixture to obtain the pure product 13. The removal of directing group from compounds 17, 23, and 28 to prepare hydroxyl compounds 18, 24, and 29, respectively, was also accomplished following this procedure. Methyl 2-hydroxy-4-methoxy-6-phenethylbenzoate (13): oil, yield 95% (65 mg); 1H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 7.31−7.17 (m, 5H), 6.36−6.28 (m, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 3.18−3.14 (m, 2H), 2.85−2.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.9, 165.8, 164.2, 146.8, 142.0, 128.55, 128.46, 126.1, 111.0, 104.8, 99.3, 55.4, 52.1, 39.0, 38.4; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C17H18O4Na+ 309.1103, found 309.1124. Methyl (E)-2-hydroxy-4-methoxy-6-styrylbenzoate (18): oil, yield 95% (64 mg); 1H NMR (400 MHz, CDCl3): δ 11.67 (s, 1H), 7.70− 7.66 (m, 1H), 7.49−7.47 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.29− 7.24 (m, 1H), 6.81−6.77 (m, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 165.3, 164.3, 143.0, 137.6, 131.0, 129.9, 128.9, 127.9, 126.8, 108.1, 104.1, 100.4, 55.6, 52.4; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C17H16O4Na+ 307.0946, found 307.0964. (E)-Methyl 2-hydroxy-6-(4-methoxystyryl)benzoate (24): oil, yield 92% (60 mg); 1H NMR (400 MHz, CDCl3) δ 11.16 (s, 1H), 7.57 (d, J = 16.0 Hz, 1H), 7.45−7.43 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.09−7.07 (m, 1H), 6.92−6.90 (m, 3H), 6.80 (d, J = 16.0 Hz, 1H), 3.98 (s, 3H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.9, 162.5, 159.6, 141.6, 134.5, 130.7, 130.4, 128.0, 127.6, 119.6, 116.8, 114.3, 110.9, 55.5, 52.7; HRMS (ESI/TOF- Q) m/z [M + Na]+ calcd for C17H16O4Na+ 307.0946, found 307.0971. (E)-Methyl 2-hydroxy-6-(3,4,5-trimethoxystyryl)benzoate (29): oil, yield 92% (73 mg); 1H NMR (500 MHz, CDCl3) δ 11.16 (s, 1H), 7.62−7.58 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.08−7.06 (m, 1H), 6.95 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (s, 1H), 6.74−6.73 (m, 2H), 3.99 (s, 3H), 3.92 (s, 6H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.7, 162.5, 153.6, 141.1, 134.6, 133.4, 131.1, 131.0, 119.8, 117.2, 116.8, 106.5, 103.8, 61.1, 56.25 (2 × C), 52.66; HRMS (ESI/ TOF-Q) m/z [M + Na]+ calcd for C19H20O6Na+ 367.1158, found 367.1167. Synthesis of Compounds 14 and 19 through O-Prenylation. To a 10 mL round-bottom flask equipped with a magnetic stir bar was added 13 (0.20 mmol, 1 equiv). Then NaH (2 equiv) and prenyl bromide (3 equiv) were added in the presence of DMF (3 mL) solvent, and the reaction mixture was stirred overnight under N2 atmosphere. After completion of the reaction (monitored by TLC), the mixture was extracted with ethyl acetate and purified by column chromatography to isolated compound 14. Compound 19 was also synthesized using the same synthetic procedure as used for compound 18. Methyl 4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)-6-phenethylbenzoate (14): oil, yield 92% (65 mg); 1H NMR (400 MHz, CDCl3) δ 7.29−7.25 (m, 2H), 7.20−7.16 (m, J = 7.1 Hz, 3H), 6.33− 6.24 (m, 2H), 5.42 (s, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.86−2.85 (m, 4H), 1.76 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 161.2, 157.5, 141.8, 141.6, 137.4, 128.46, 128.37, 125.9, 119.7, 116.8, 106.1, 97.9, 65.9, 55.3, 52.0, 37.6, 36.2, 25.7, 18.2; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C22H26O4H+ 355.1909, found 355.1921. (E)-Methyl-4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)-6-styrylbenzoate (19): liquid, yield 94% (66 mg); 1H NMR (400 MHz, CDCl3) δ 7.48−7.45 (m, 2H), 7.36−7.32 (m, 2H), 7.28- 7.24 (m,

2H), 7.32−7.27 (m, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.00−6.96 (m, 1H), 6.84−6.81 (m, 2H), 6.32 (s, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 159.6, 141.2, 136.8, 135.4, 131.9, 131.0, 130.7, 130.2, 130.1, 129.2, 128.3, 128.2, 127.9, 127.2, 126.4, 124.3, 123.9, 122.9, 122.6, 114.1, 107.2, 55.4; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C25H21N3O2Na+ 418.1531, found 418.1525. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-2-(3,4,5-trimethoxystyryl)benzamide (27): yellow solid, yield 98% (380 mg); 1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 8.73 (d, J = 7.1 Hz, 1H), 7.75- 7.69 (m, 2H), 7.63 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.57−7.41 (m, 3H), 7.33 (d, J = 6.5 Hz, 2H), 7.20 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.67 (s, 2H), 6.37−6.35 (m, 1H), 3.84 (s,9H); 13C NMR (100 MHz, CDCl3) δ 167.7, 153.4, 141.3, 136.5, 135.5, 133.2, 131.9, 131.5, 130.8, 130.0, 129.2, 128.2, 127.9, 127.6, 126.7, 125.9, 124.4, 122.9, 122.5, 107.3, 104.2, 61.1, 56.2(C × 2); HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C27H25N3O4Na+ 478.1743, found 478.1740. Synthesis of Compounds 12, 17, 23, and 28 via Directed C− H Hydroxylation Using Cu(OAc)2. A mixture of amide 11 (0.75 mmol, 1.0 equiv), anhydrous copper acetate (1.5 equiv), and K2CO3 (1.5 equiv) in DMSO (6 mL) was taken in a 25 mL round-bottom flask under open-air conditions. The mixture was stirred at 80 °C for 5 h. After completion of the reaction (monitored by TLC), the crude mixture was then transferred to a 125 mL separatory funnel, and 25 mL of brine solution was added. It was extracted with ethyl acetate (3 × 20), and volatiles were removed under reduced pressure. Then the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. The same coppermediated directed C−H hydroxylation procedure was followed for the syntheses of compounds 17, 23, and 28 from 16, 22, and 27, respectively. N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-4-methoxy-6-phenethylbenzamide (12): white solid, yield 84% (250 mg); mp 130−132 °C; 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 10.28 (s, 1H), 8.43 (dd, J = 8.3, 1.2 Hz, 1H), 7.74 (dd, J = 2.5, 0.5 Hz, 1H), 7.67−7.66 (m, 1H), 7.43−7.39 (m, 1H), 7.35- 7.33 (m, 1H), 7.25−7.12 (m, 4H), 7.06−7.03 (m, 2H), 6.40−6.39 (m, 1H), 6.36 (s, 2H), 3.77 (s, 3H), 3.16−3.12 (m, 2H), 2.93−2.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.8, 162.8, 161.7, 142.0, 141.5, 141.2, 130.8, 130.1, 129.9, 128.5(2 × C), 128.1, 126.1, 125.0, 124.0, 122.9, 111.8, 109.7, 107.5, 99.7, 55.4, 37.5, 36.7; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C25H23N3O3H+ 414.1818, found 414.1802. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-4-methoxy-6-styrylbenzamide (17): solid, yield 81% (251 mg); mp 145−147 °C; 1 HNMR (400 MHz, CDCl3) δ 11.58 (s, 1H), 10.58 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.41−7.32 (m, 5H), 7.28− 7.15 (m, 5H), 7.02−6.98 (m, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.10 (t, J = 2.2 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 163.4, 163.2, 141.0, 139.6, 136.8, 133.7, 130.9, 130.1, 129.4, 128.6, 128.2, 127.7, 127.1, 126.5, 124.9, 124.2, 122.9, 109.2, 107.4, 107.2, 100.9, 55.5; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C25H21N3O3H+ 412.1661, found 412.1682. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-6-(4methoxystyryl)benzamide (23): white solid, yield 88% (250 mg); mp 126−128 °C; 1H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 10.75 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.43−7.40 (m, 1H), 7.36−7.30 (m, 4H), 7.26−7.17 (m, 3H), 7.07 (d, J = 7.7 Hz, 1H), 6.98−6.94 (m, 1H), 6.90−6.88 (m, 1H), 6.81 (d, J = 8.3 Hz, 2H), 6.13 (s, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 160.3, 159.7, 141.2, 138.1, 133.1, 132.9, 130.9, 130.1, 129.8, 129.5, 128.4, 127.9, 125.1, 124.2, 123.9, 122.9, 119.4, 116.7, 116.6, 114.1, 107.3, 55.4; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C25H21N3O3H+ 412.1661, found 412.1659. (E)-N-(2-(1H-Pyrazol-1-yl)phenyl)-2-hydroxy-6-(3,4,5trimethoxystyryl)benzamide (28): white solid, yield 85% (280 mg); mp 176−178 °C; 1H NMR (400 MHz, CDCl3) δ 10.85 (s, 1H), 10.48 (s, 1H), 8.59 (d, J = 6.3 Hz, 1H), 7.61 (s, 1H), 7.43−7.39 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.28−7.23 (m, 3H), 7.10−7.09 (m, 1H), 6.97−6.90 (m, 2H), 6.61 (s, 2H), 6.20 (s, 1H), 3.83 (s, 3H), 3.74 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6, 159.9, 153.2, 141.0, 138.2, 137.4, 132.9, 132.81, 132.78, 130.6, 129.8, 129.3, 127.8, 12331

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

Note

The Journal of Organic Chemistry 1H), 7.12−7.01 (m, 2H), 6.76 (d, J = 2.1 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 5.44−5.40 (m, 1H), 4.54 (d, J = 6.5 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.6, 161.4, 157.6, 137.7, 137.5, 136.9, 131.7, 128.8, 128.1, 126.9, 125.5, 119.6, 116.6, 101.7, 99.5, 66.0, 55.5, 52.3, 25.8, 18.4; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C22H24O4H+ 353.1753, found 353.1750. Synthesis of Amorfrutin A Methyl Ester (1a) and Cajaninstilbene Acid Methyl Ester (2a). The O-prenyl ether 14 (0.16 mmol) was taken into an oven-dried 10 mL reaction tube equipped with a magnetic stir. Then Montmorillonite K10 (1 wt equiv) was added in the presence of dichloromethane (3 mL) solvent, and the reaction mixture was stirred at room temperature for 8 h. After completion (monitored by TLC), the crude reaction mixture was diluted with ethyl acetate and filtered through a Celite pad, and the solvent was evaporated under reduced pressure. In order to obtain pure product 1a, the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. Compound 2a was prepared following the same synthetic procedure from O-prenyl ether 19. Methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6-phenethylbenzoate (1a): oil, yield 38% (23 mg); 1H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 7.32−7.28 (m, 2H), 7.22−7.18 (m, 3H), 6.21 (s, 1H), 5.22−5.17 (m, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 3.34 (d, J = 7.0 Hz, 2H), 3.19−3.15 (m, 2H), 2.86−2.82 (m, 2H), 1.78 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 162.0, 161.3, 144.2, 142.2, 131.8, 128.5 (2 × C), 126.1, 122.5, 115.3, 106.0, 105.3, 55.6, 52.2, 39.5, 38.5, 25.9, 22.1, 17.9; HRMS (ESI/TOF-Q) m/z [M + H]+ calcd for C22H26O4H+ 355.1909, found 355.1934. (E)-Methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6styrylbenzoate (2a): white solid, yield 40% (22 mg); mp 94−96 °C; 1H NMR (400 MHz, CDCl3) δ 11.69 (s, 1H), 7.72 (d, J = 15.9 Hz, 1H), 7.51−7.49 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.30−7.28 (m, 1H), 6.78 (d, J = 15.9 Hz, 1H), 6.61 (s, 1H), 5.22 (t, J = 6.8 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.38 (d, J = 7.1 Hz, 2H), 1.79 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.1, 161.6, 161.5, 140.4, 137.6, 132.0, 130.8, 130.2, 128.9, 127.9, 126.7, 122.2, 116.8, 104.6, 103.0, 55.8, 52.4, 25.9, 22.3, 17.9; HRMS (ESI/TOF-Q) m/z [M + Na]+ calcd for C22H24O4Na+ 375.1572, found 375.1591.

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Groot, J. C.; Prasad, A.; Freiwald, A.; Quedenau, C.; Kliem, M.; Witzke, A.; Kodelja, V.; Han, C. T.; Giegold, S. Amorfrutins are potent antidiabetic dietary natural products. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 7257. (c) Sauer, S. Amorfrutins: A Promising Class of Natural Products that Are Beneficial to Health. ChemBioChem 2014, 15, 1231. (d) Fuhr, L.; Rousseau, M.; Plauth, A.; Schroeder, F. C.; Sauer, S. Amorfrutins Are Natural PPARγ Agonists with Potent Antiinflammatory Properties. J. Nat. Prod. 2015, 78, 1160. (e) Weidner, C.; Rousseau, M.; Micikas, R. J.; Fischer, C.; Plauth, A.; Wowro, S. J.; Siems, K.; Hetterling, G.; Kliem, M.; Schroeder, F. C.; Sauer, S. Amorfrutin C Induces Apoptosis and Inhibits Proliferation in Colon Cancer Cells through Targeting Mitochondria. J. Nat. Prod. 2016, 79, 2. (2) (a) Wu, N.; Fu, K.; Fu, Y. J.; Zu, Y. G.; Chang, F. R.; Chen, Y. H. S.; Liu, X. L.; Kong, Y.; Liu, W.; Gu, C. B. Antioxidant activities of extracts and main components of pigeonpea [Cajanus cajan (L.) Millsp.] leaves. Molecules 2009, 14, 1032. (b) Kong, Y.; Wei, Z. F.; Fu, Y. J.; Gu, C. B.; Zhao, C. J.; Yao, X. H.; Efferth, T. Negative-pressure cavitation extraction of cajaninstilbene acid and pinostrobin from pigeon pea [Cajanus cajan (L.) Millsp.] leaves and evaluation of antioxidant activity. Food Chem. 2011, 128, 596. (c) Liang, L.; Luo, M.; Fu, Y. J.; Zu, Y. G.; Wang, W.; Gu, C. B.; Zhao, C. J.; Li, C. Y.; Efferth, T. Cajaninstilbene acid (CSA) exerts cytoprotective effects against oxidative stress through the Nrf2-dependent antioxidant pathway. Toxicol. Lett. 2013, 219, 254. (d) Jiang, B. B.; Liu, Y. M.; Le, L.; Li, Z. Y.; Si, J. Y.; Liu, X. M.; Chang, Q.; Pan, R. L. Cajaninstilbene Acid Prevents Corticosterone-Induced Apoptosis in PC12 Cells by Inhibiting the Mitochondrial Apoptotic Pathway. Cell. Physiol. Biochem. 2014, 34, 1015. (e) Liu, Y. M.; Shen, S. N.; Li, Z. Y.; Jiang, Y. M.; Si, J. Y.; Chang, Q.; Liu, X. M.; Pan, R. L. Cajaninstilbene acid protects corticosterone-induced injury in PC12 cells by inhibiting oxidative and endoplasmic reticulum stress-mediated apoptosis. Neurochem. Int. 2014, 78, 43. (f) Fu, Y. J.; Kadioglu, O.; Wiench, B.; Wei, Z. F.; Gao, C.; Luo, M.; Gu, C. B.; Zu, Y. G.; Efferth, T. Cell cycle arrest and induction of apoptosis by cajanin stilbene acid from Cajanus cajan in breast cancer cells. Phytomedicine 2015, 22, 462. (g) Huang, M. Y.; Lin, J.; Lu, K.; Xu, H. G.; Geng, Z. Z.; Sun, P. H.; Chen, W. M. Anti-Inflammatory Effects of Cajaninstilbene Acid and Its Derivatives. J. Agric. Food Chem. 2016, 64, 2893. (h) Ji, X. Y.; Chen, J. H.; Zheng, G. H.; Huang, M. H.; Zhang, L.; Jin, J.; Jiang, J. D.; Peng, Z. G.; Li, Z. R.; Yi, H. Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1. J. Med. Chem. 2016, 59, 10268. (i) Schuster, R.; Holzer, W.; Doerfler, H.; Weckwerth, W.; Viernstein, H.; Okonogi, S.; Mueller, M. Cajanus cajan - a source of PPARγ activators leading to anti-inflammatory and cytotoxic effects. Food Funct. 2016, 7, 3798. (j) Dvorakova, M.; Landa, P. Anti-inflammatory activity of natural stilbenoids: A review. Pharmacol. Res. 2017, 124, 126. (3) (a) Asahina, Y.; Asano, J. Ü ber die Konstitution von Hydrangenol und Phyllodulcin. Chem. Ber. 1929, 62B, 71. (b) Hashimoto, T.; Tori, M.; Asakawa, Y. Three dihydroisocoumarin glucosides from Hydrangea macrophylla subsp. serrata. Phytochemistry 1987, 26, 3323. (c) Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M. Immunomodulatory activity of thunberginol A and related compounds isolated from Hydrangeae Dulcis Folium on splenocyte proliferation activated by mitogens. Bioorg. Med. Chem. Lett. 1998, 8, 215. (4) Song, Y. Y.; He, H. G.; Li, Y.; Deng, Y. A facile total synthesis of amorfrutin A. Tetrahedron Lett. 2013, 54, 2658. (5) (a) Ji, X. Y.; Xue, S. T.; Zheng, G. H.; Han, Y. X.; Liu, Z. Y.; Jiang, J. D.; Li, Z. R. Total synthesis of cajanine and its antiproliferative activity against human hepatoma cells. Acta Pharm. Sin. B 2011, 1, 93. (b) Mitra, P.; Shome, B.; Ranjan De, S.; Sarkar, A.; Mal, D. Stereoselective synthesis of hydroxy stilbenoids and styrenes by atom-efficient olefination with thiophthalides. Org. Biomol. Chem. 2012, 10, 2742. (c) Laclef, S.; Anderson, K.; White, A. J. P; Barrett, A. G. M. Total synthesis of amorfrutin A via a palladium-catalyzed migratory prenylation-aromatization sequence. Tetrahedron Lett.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02116. 1 H and 13C NMR spectra of products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mahiuddin Baidya: 0000-0001-9415-7137 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge CSIR New Delhi (02(0212)/14/ EMR-II) and DST-India (EMR/2014/000225) for financial support. G.S.G. acknowledges UGC for SRF, and S.D. acknowledges IIT-Madras for an HTRA fellowship. We also thank the Department of Chemistry, IIT-Madras, for instrumental facilities.

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REFERENCES

(1) (a) Mitscher, L. A.; Park, Y. H.; Alshamma, A.; Hudson, P. B.; Haas, T. Amorfrutin A and B, bibenzyl antimicrobial agents from Amorpha fruticosa. Phytochemistry 1981, 20, 781. (b) Weidner, C.; de 12332

DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333

Note

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DOI: 10.1021/acs.joc.8b02116 J. Org. Chem. 2018, 83, 12327−12333