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. Author manuscript; available in PMC: 2017 Mar 17.
Published in final edited form as: ChemMedChem. 2016 Feb 17;11(6):600–611. doi: 10.1002/cmdc.201600008

Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases

Mykhaylo S Frasinyuk [a,b,c], Galyna P Mrug [c], Svitlana P Bondarenko [d], Volodymyr P Khilya [d], Vitaliy M Sviripa [a,b], Oleksandr A Syrotchuk [e], Wen Zhang [a,f], Xianfeng Cai [a,f], Michael V Fiandalo [g], James L Mohler [g], Chunming Liu [a,f], David S Watt [a,b,f]
PMCID: PMC4818953  NIHMSID: NIHMS768972  PMID: 26889756

Abstract

The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6 substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μM concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.

Keywords: isoflavonoid, Mannich reaction, ortho-quinone methides, inverse electron-demand Diels-Alder reaction, prostate cancer PC-3 cell line

graphic file with name nihms-768972-f0001.jpg

Introduction

Androgen-deprivation therapy produces temporary palliation but fails to cure advanced prostate cancer in which tissue levels of testosterone and 5α-dihydrotestosterone are sufficient to activate the androgen receptor.[1] Although the steroidal drug, abiraterone, interferes with the metabolism of adrenal androgens to testosterone and 5α-dihydrotestosterone by inhibiting cytochrome 17A1 (CYP17A1),[2] its effects are only short-lived when used after the failure of androgen-deprivation therapy.[3] Prostate cancer remains the second leading cause of cancer-related mortality in men,[4] and new therapies focused on the selective inhibition of enzymes participating in the backdoor pathway[5] to dihydrotestosterone from 4-androstene-3,17-dione remain a worthy goal for enhancing the extent or duration of response to androgen-deprivation therapy.

Isoflavones, particularly daidzein (1a) and genistein (1b) (Figure 1), attracted interest as potential agents for the treatment of prostate cancer,[6] but these natural products and their metabolites have a spectrum biological effects, including those that act on androgen receptor expression and enzymes associated with androgen metabolism.[7] We selected 7-hydroxyisoflavones as candidates as part of a program to develop antineoplastic agents against selective biological targets. Prior work in our laboratories demonstrated that the removal or transformation of hydroxyl groups from natural products and replacement of these groups with functional groups capable of hydrogen bonding and van der Waals interactions led to new agents with singular and important biological targets.[8]

Figure 1.

Figure 1

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Naturally occurring isoflavones daidzein (1a) and genistein (1b), and synthetic isoflavonoids 2 and 3.

Results and Discussion

The removal of hydroxyl groups found frequently in naturally occurring isoflavones limited competitive redox processes as well as phase II metabolism (e.g., sulfation or glucuronidation) and provided an opportunity to acquire a pharmacophore with a singular mechanism of action. For example, the elimination of hydroxyl groups in resveratrol, a hackneyed natural product with a multiplicity of biological effects, led to the fluorinated stilbenes.[8a, 9] These antineoplastic agents act as epigenetic regulators of a single molecular target, the catalytic subunit of methionine adenosyltransferase-2. Additional modifications of the stilbene pharmacophore led to the fluorinated 3-arylquinolines[8b] as antineoplastic agents that bind uniquely to the intermediate filament protein, vimentin, and promote the secretion of the natural tumor suppressor, Prostate apoptosis response-4 protein (Par-4). In the same fashion, we initiated a structure-activity study on semisynthetic isoflavones using an in vitro proliferation assay based on the PC-3 human prostate cancer cell line to interrogate structures, identify potent analogs and provide a framework for biotinylation and target identification. This decision distanced us from the debate surrounding the naturally occurring isoflavone and allowed us to focus on developing synthetic isoflavonoids with substituent patterns not seen in natural products. As part of this effort to identify enzyme inhibitors within new, heterocyclic platforms, we explored Diels-Alder cycloadditions involving the chromone core, which appears in isoflavones. Although chromones were used previously in Diels-Alder reactions with various dienes, invariably successful Diels-Alder reactions required the presence of electron-withdrawing carbonyl- or cyano- group in position 3 of chromone ring.[10]

This limitation would appear to exclude the use of semisynthetic flavonoids or isoflavonoids in Diels-Alder reactions because they possess electron-donating phenyl substituent at positions 2 or 3, respectively. The in situ generation of ortho-quinone methides from phenolic Mannich bases,[11] hydroxybenzyl alcohol derivatives,[12] and oxygen-contain heterocycles[13] provided chromane derivatives in hetero-Diels-Alder reaction but the generation of ortho-quinone methides in a chromone platform was without precedent. It was unclear at the outset of this work if the reactive 1,4-benzopyrone functionality in isoflavonoids would accommodate a transitory ortho-quinone methides and trap dieneophiles without competitive, interfering reactions. Specifically, we wanted to synthesize substituted 3-aryl-9,10-dihydropyrano[2,3-f]chromen-4(8H)-ones 2 and 3-aryl-3,4-dihydro-2H,6H-pyrano[3,2-g]chromen-6-ones 3 (Figure 1).[14] To accomplish this aim, aminomethyl-, hydroxymethyl-, and methoxymethyl derivatives of 7-hydroxyflavones were tested as precursors to ortho-quinone methides and as dienes in an inverse electron-demand Diels Alder addition. Synthesis of these precursors involved the application of the Mannich reaction to 7-hydroxyisoflavonoids 4 with bis(N,N-dimethylamino)methane in isopropanol at reflux to provide regioselectively the C-8 substituted N,N-dimethylaminomethyl analogs 5 (Scheme 1) in good yields.[15] The 7-hydroxy-8-methyisoflavonoids 6 gave, as expected, the isomeric C-6 analogs 7.

Scheme 1.

Scheme 1

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Regioselective modification of 7-hydroxyisoflavones 4 and 7-hydroxy-8-methylisoflavones 6. Reagents and conditions: a) CH2(NMe)2, i-PrOH, 80°C, 2-4 h, 68-91% yields; b) CH2(NMe)2, dioxane, 100°C, 16 h, 72-99% yields

Heating the N,N-dimethylaminomethyl-substituted isoflavonoids 5 generated the intermediate ortho-quinone methides 8 (Scheme 2) that trapped various electron-rich dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholino–cyclopentene, and 1-morpholinocyclohexene. These reactions led to Diels-Alder adducts 11-15 (Scheme 2) in yields that varied with dienophile reactivity (Table 1). Table 1 summarizes representative combinations of dienophiles and N,N-dimethylamino-substituted isoflavonoids that led to biologically active adducts. Among the various dienophiles, dihydrofuran and dihydropyran produced the most biologically active compounds, and consequently, these dienophiles were explored in the most detail. The few adducts synthesized from other dienophiles, such as the enamines, had low activity, or in the case of 3-(N-N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, produced very insoluble adducts that could not be evaluated in a biological assay.

Scheme 2.

Scheme 2

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Diels-Alder reaction of N,N-dimethylaminoisoflavones 5 and 7 with dienophiles Reagents and conditions: a) 2,3-dihydrofuran, DMF, reflux; 24-40 h; b) 3,4-dihydro-2H-pyran, DMF, reflux; 36-40 h; c) 3-(dimethylamino)-5,5-dimethylcyclohex-2-en-1-one, DMF, reflux; 4 h; d) 4-cyclopent-1-en-1-yl morpholine, DMF, reflux; 4 h; e) 4-cyclohex-1-en-1-yl morpholine, DMF, reflux; 4 h

Table 1.

Isolated yields of Diels-Alder adducts 11-17 from the reaction of dienophiles and ortho-quinone methides derived from 5 and 7

Subst-
rate		 Dienophile Solvent, Tempera–
ture and Time		 Diels-Alder
Adduct		 Isolated
Yield (%)
5a 2,3-dihydro–
furan		 DMF, 154°C, 24 h 11a 70
5a 3,4-dihydro-
2H-pyran		 DMF, 154°C, 36 h 12a 30
5a graphic file with name nihms-768972-t0007.jpg 1,4-dioxane,
100°C, 12 h		 13a [a] 81
5a graphic file with name nihms-768972-t0008.jpg toluene, 110°C
12h		 13a [a] 68
5a graphic file with name nihms-768972-t0009.jpg 2-methoxyethanol,
124°C, 8 h		 13a [a] 69
5a graphic file with name nihms-768972-t0010.jpg DMSO, 160°C, 4 h 13a [a] 71
5a graphic file with name nihms-768972-t0011.jpg DMF, 154°C, 4 h 13a [a] 92
5a graphic file with name nihms-768972-t0012.jpg DMF, 154°C, 16 h 15a [b] 91
5b 2,3-dihydro–
furan		 DMF, 154°C, 40 h 11b 29
5b 3,4-dihydro-
2H-pyran		 DMF, 154°C, 40 h 12b 55
5b graphic file with name nihms-768972-t0013.jpg DMF, 154°C, 4 h 13b [a] 75
5b graphic file with name nihms-768972-t0014.jpg DMF, 154°C, 4 h 15b [b] 85
6c 2,3-dihydro–
furan		 DMF, 154°C, 36 h 11c 64
5c 3,4-dihydro-
2H-pyran		 DMF, 154°C, 40 h 12c 25
5c graphic file with name nihms-768972-t0015.jpg DMF, 154°C, 4 h 13c [a] 81
5c graphic file with name nihms-768972-t0016.jpg DMF, 154°C, 4 h 15c [b] 76
6d 2,3-dihydro–
furan		 DMF, 154°C, 36 h 11d 75
5d 3,4-dihydro-
2H-pyran		 DMF, 154°C, 40 h 12d 36
6e 2,3-dihydro–
furan		 DMF, 154°C, 24 h 11e 55
5e 3,4-dihydro-
2H-pyran		 DMF, 154°C, 36 h 12e 19
5f 2,3-dihydro–
furan		 DMF, 154°C, 40 h 11f 73
5f 3,4-dihydro-
2H-pyran		 DMF, 154°C, 38 h 12f 33
5f graphic file with name nihms-768972-t0017.jpg DMF, 154°C, 4 h 13f [a] 84
5g 2,3-dihydro–
furan		 DMF, 154°C, 24 h 11g 62
5g 3,4-dihydro-
2H-pyran		 DMF, 154°C, 40 h 12g 34
5g graphic file with name nihms-768972-t0018.jpg DMF, 154°C, 4 h 13g [a] 81
5g graphic file with name nihms-768972-t0019.jpg DMF, 154°C, 4 h 14g [b] 58
5g graphic file with name nihms-768972-t0020.jpg DMF, 154°C, 4 h 15g [b] 69
5h 2,3-dihydro–
furan		 DMF, 154°C, 30 h 11h 56
5h 3,4-dihydro-
2H-pyran		 DMF, 154°C, 36 h 12h 15
5h graphic file with name nihms-768972-t0021.jpg DMF, 154°C, 4 h 14h [b] 53
5h graphic file with name nihms-768972-t0022.jpg DMF, 154°C, 4 h 15h [b] 51
5i 2,3-dihydro–
furan		 DMF, 154°C, 40 h 11i 60
5i 3,4-dihydro-
2H-pyran		 DMF, 154°C, 40 h 12i 15
7a 2,3-dihydro–
furan		 DMF, 154°C, 16 h 16a 27
7a graphic file with name nihms-768972-t0023.jpg DMF, 154°C, 4 h 17a 80
7g 2,3-dihydro–
furan		 DMF, 154°C, 16 h 16g 46
7g graphic file with name nihms-768972-t0024.jpg DMF, 154°C, 4 h 17g 72
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[a]

Product of elimination of dimethylamine;

[b]

Product of hydrolysis of hemi-aminals

The further transformation of hemi-aminals 10 that were intermediates in some cases depended on substituents. The presence of an electron-withdrawing carbonyl group led to dimethylamine elimination (path A) with formation of 13. In cases of 1-morpholinocyclopentene or 1-morpholinocyclohexene, the hydrolysis of hemi-aminals 10 (path B) led to 2-substituted ketones or tautomeric hemi-ketals 14 or 15. The yields were low (<50%) using either 2,3-dihydrofuran or 3,4-dihydro-2H-pyran due to dimerization and polymerization reactions but were acceptable using other dienophiles. Similar reactions with dienophiles were observed for the intermediate ortho-quinone methides 9 derived from 6-dimethylaminomethyl isoflavones 7. In these cases, linear 6a,7,8,9a-tetrahydro-4H,6H-furo[2,3-b]pyrano[3,2-g]chromen-4-ones 16 and 6,8,9,10-tetrahydro-4H,7H-pyrano[3,2-b]xanthene-4,7-dione 17 were formed. Attempts to employ common electron-deficient dienophiles were unsuccessful.

The Diels-Alder reactions of 5 with either 2,3-dihydrofuran or 3,4-dihydro-2H-pyran led to a 1:1 ratio of enantiomeric, cis-fused adducts 11 or 12, respectively, which was confirmed by the coupling constants 3J between the acetal proton at C-7a and bridgehead proton at C-10a and by chiral phase HPLC. The structures of the cis-fused adducts 11 and 12 were also confirmed by 2D NOESY spectra. The Diels-Alder reaction of the isomeric isoflavonoids 7 with 2,3-dihydrofuran led to the corresponding cis-fused adduct 16. The 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene skeleton within adducts 11 and 16 appears in bioactive xyloketals isolated from fungi.[14] The Diels-Alder reactions of 5 and 7 with 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one led to initial adducts that suffered concomitant thermal eliminations of dimethylamine to give the isolated adducts 13 and 17, respectively, in excellent yield. A study of the reaction of 5a with the 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one in various solvents led to the selection of refluxing N,N-dimethylformamide (DMF) as the optimal conditions for these reactions (Table 1). Finally, Diels-Alder reactions with 1-morpholinocyclopentene and 1-morpholinocyclohexene led to the adducts 14 and 15, respectively. The mechanism leading to each of these adducts involved an initial cycloaddition and the subsequent hydrolysis of intermediate hemi-aminals. The adducts adopted either the open-chain tautomer 14 in the case of 1-morpholinocyclopentene or the cyclic hemiacetal 15 in the case of 1-morpholinocyclohexene.

In place of the Mannich bases as precursors to the ortho-quinone methides, we also investigated 8-hydroxymethyl- and 8-methoxymethyl substituted 7-hydroxyisoflavones 18a, 18g, 19a, and 19g and diacetates 20a and 20g[15] as intermediates for generation of ortho-quinone methides in model reaction with 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one in DMF (Scheme 3). Although 8-methoxymethyl-7-hydroxyisoflavonoids gave only marginally improved yields of pyranoxanthones 13a and 13g than the 8-dimethylaminomethylisoflavonoids 5a and 5g (Table 2), the use of the Mannich bases was preferred given their ready availability. These findings suggest that other naturally ocurring hydroxymethyl- or methoxymethyl hydroxychromones could be deployed in inverse electron-demand Diels-Alder reactions.

Scheme 3.

Scheme 3

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Regioselective modification of 7-hydroxyisoflavones 5 and 7-hydroxy-8-methylisoflavones 7. Reagents and conditions: a) CH2(NMe)2, i-PrOH, 80°C, 2-4 h; b) CH2(NMe)2, dioxane, 100°C, 16 h

Table 2.

Isolated yields of Diels-Alder adducts 13a,g from the reaction of 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one and precursors of ortho-quinone methides in DMF at 154°C, 4 h

Subst-
rate		 Substituents on Isoflavonoid Diels-Alder
Adduct		 Isolated
Yield (%)
X Y
5a H NMe2 13a 92
5g H NMe2 13g 81
18a H OH 13a 96
18g H OH 13g 88
19a H OMe 13a 84
19g H OMe 13g 78
20a Ac OAc 13a 87
20g Ac OAc 13g 74
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Proliferation studies using PC-3 cells revealed that Diels-Alder adducts formed from 2,3-dihydrofuran or 3,4-dihydro-2H-pyran with the ortho-quinone methide derived from C-8 N,N-dimethylaminomethyl-substituted isoflavonoids 6 produced the most active adducts 11 and 12 (Table 3). Adduct 12 was more active than other adducts, with a few exceptions. Among the exceptions, adducts 11a and 11e were comparable in activity to 12a and 12e, and adduct 15g was slightly superior in activity to 12g. With respect to substituents on the isoflavonoid framework, those adducts bearing 3-(4′-methoxyphenyl), 3-(3′,4′-dimethoxyphenyl), 3-(3′,4′-methylenedioxyphenyl), or 3-(4′-chlorophenyl) substituents were most active. In a promising outcome, the adduct 13b, which was generated using 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, displayed 86% inhibition at 10 μM and 31% inhibition at 1 μM.

Table 3.

Percent inhibition of PC-3 proliferation by some isoflavonoid-based Diels-Alder adducts

Isoflavonoid
Diels-Alder
Adduct		 Substituents on
Isoflavonoid		 Inhibition[a]
at 10 μM
(%)		 Cell Diameter
(microns) [a,b]
C-2 C-3
Genistein
(1b) 		H C6H4OH-4 46 ± 4.5 17.41 ± 0.46
11a H C6H4OMe-4 62 ± 7 16.43 ± 0.19
11c H C6H3(OCH2O)-3,4 47 ± 4 16.37 ± 0.34
11e H C6H4Cl-4 63 ± 10 16.50 ± 0.19
12a H C6H4OMe-4 73 ± 6 17.08 ± 0.34
12b H C6H3(OMe)2-3,4 35 ± 10 16.56 ± 0.17
12c H C6H3(OCH2O)-3,4 68 ± 0.5 16.39 ± 0.11
12d H C6H3(OCH2CH2O)
-3,4		 48 ± 3 16.50 ± 0.29
12e H C6H4Cl-4 44 ± 4 16.53 ± 0.08
12g Me C6H4OMe-4 62 ± 0.4 17.08 ± 0.27
12h Me C6H3(OMe)2-3,4 44 ± 3 16.55 ± 0.18
12i Me C6H4Cl-4 74 ± 3 16.30 ± 0.35
13b H C6H3(OMe)2-3,4 86 ± 1 13.68 ± 0.74
15a H C6H4OMe-4 30 ± 15 17.25 ± 1.03
15b H C6H3(OMe)2-3,4 56 ± 5 17.11 ± 0.17
15g Me C6H4OMe-4 78 ± 1 17.11 ± 0.45
16a H C6H4OMe-4 78 ± 3 15.89 ± 0.10
16g Me C6H4OMe-4 61 ± 2 16.77 ± 0.59
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[a]

mean ± SD for at least three experiments;

[b]

16.24 ± 0.34 for DMSO alone

In a preliminary study of cell toxicity, the treated cells were analyzed by Vi-Cell XR viability analyzer that took 50 images per sample and permitted the determination of cell concentrations, viability and size. The viability of each sample was greater than 95%; however, the cell numbers were significantly reduced by active compounds. The cell sizes were similar (Table 3) except for cells treated with 13b, which was the most potent compound. Isoflavonoid 13b significantly reduced the size of PC-3 cells, suggesting that it may inhibit PC-3 cell proliferation by inhibiting the cell cycle as well as inducing apoptosis. Additional studies will be needed to clarify this point.

Conclusions

A regioselective condensation of 7-hydroxyisoflavonoids 4 or 7-hydroxy-8-methylisoflavonoids 6 with bis(N,N-dimethylamino)methane in isopropanol at reflux provided 5 or 7, respectively. Thermal eliminations of dimethylamine from these Mannich bases as well as elimination of methanol or water from corresponding 8-methoxymethyl- or 8-hydroxymethyl 7-hydroxyisoflavones generated ortho-quinone methide intermediates that trapped a variety of dienophiles to give various Diels-Alder adducts 11-17 in good yields. Some of these adducts, particularly those derived from 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, or 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, displayed good activity in a proliferation assay using PC-3 cells. Subsequent studies will focus on identifying the biological target of these isoflavonoids.

Experimental Section

Chemicals and instruments. 1H and 13C NMR spectra were recorded on a Varian 500 spectrometer (at 500 MHz or at 125 MHz, respectively) or on a Varian 400 spectrometer (at 400 MHz or at 100 MHz, respectively) in deuteriochloroform (CDCl3) or deuterated dimethylsulfoxide (DMSO-d6). 13C NMR Chemical shifts for minor isomers compounds 15 are given in brackets. IR spectra were recorded on a Bruker Vertex 70 FT/IR spectrometer. Melting points were determined in open capillarity tubes with a Buchi B-535 apparatus and were uncorrected. Mass spectra were obtained with an Agilent 1100 spectrometer under chemical ionization conditions. Column chromatography was performed using Macherey-Nagel Silica 60, 0.04-0.063 mm silica gel.

General procedure for synthesis of Mannich bases 5a-5i

To a stirred suspension of isoflavonoids 4a-4i (2 mmol) in 10 mL of isopropanol was added 0.3 mL (2.2 mmol, 1.1 eq) of bis(N,N-dimethylamino)methane at 70°C. The mixture was heated at 80°C for 2 h and cooled to to afford a precipitate that was collected by gravity fitration. In the absence of crystallization, the residue was triturated with hexane to induce crystallization. The Mannich bases 5 were re-crystallized from isopropanol-hexane.

8-[(N,N-Dimethylamino)methyl]-7-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one (5a)

Pale yellow solid (83% yield); mp 174-176°C; IR (KBr) vmax 3448, 2951, 1626, 1427, 1246, 1178, 1028 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 6H, N(CH3)2), 3.85 (s, 3H, 4′-OCH3), 3.99 (s, 2H, 8-CH2), 6.90 (d, 1H, 3J = 8.8 Hz, 6-H), 6.97 (d, 2H, 3J = 8.8 Hz, 3′, 5′-H), 7.50 (d, 2H, 3J = 8.8 Hz, 2′, 6′-H), 7.89 (s, 1H, 2-H), 8.14 (d, 1H, 3J = 8.8 Hz, 5-H), 10.21 ppm (br s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 44.41, 54.87, 55.20, 107.27, 113.80, 115.44, 116.89, 124.22, 124.32, 126.67, 130.00, 151.25, 154.96, 159.41, 163.97, 175.74 ppm; MS (CI): m/z 326.1 (MH+, 100). Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.88; H, 5.97; N, 4.39.

3-(3,4-Dimethoxyphenyl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-4H-chromen-4-one (5b)

Pale yellow solid (77% yield); mp 154-155°C; IR (KBr) vmax 2948, 1636, 1602, 1517, 1266, 1145, 1024 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 6H, N(CH3)2), 3.91, 3.93 (2s, 6H, 3′, 4′-OCH3), 3.99 (s, 2H, 8-CH2), 6.86-6.96 (m, 2H, 6, 6′-H), 7.00-7.07 (m, 1H, 5′-H), 7.18–7.23 (m, 1H, 2′-H), 7.92 (s, 1H, 2-H), 8.13 (d, 1H, 3J = 8.8 Hz, 5-H), 9.79 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 44.52, 55.04, 55.88, 55.89, 107.40, 111.04, 112.46, 115.58, 116.93, 120.90, 124.45, 124.70, 126.68, 148.64, 148.95, 151.44, 154.93, 164.05, 175.86 ppm; MS (CI): m/z 356.2 (MH+, 100). Anal. Calcd for C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.88; H, 5.97; N, 4.39.

3-(1,3-Benzodioxol-5-yl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-4H-chromen-4-one (5c)

Pale yellow solid (73% yield); mp 160-161°C; IR (KBr) v max 2960, 2987, 1639, 1488, 1425, 1246, 1017 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 6H, N(CH3)2), 3.98 (s, 2H, 8-CH2), 5.98 (s, 2H, 3′,4′-OCH2O), 6.80–7.00 (m, 3H, 6, 5′, 6′-H), 7.06-7.13 (m, 1H, 2′-H), 7.86 (s, 1H, 2-H), 8.11 (d, 1H, 3J = 8.8 Hz, 5-H), 9.95 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 44.60, 55.15, 101.13, 107.49, 108.34, 109.78, 115.62, 116.94, 122.34, 124.61, 125.78, 126.78, 147.56, 147.62, 151.46, 154.97, 164.12, 175.73 ppm; MS (CI): m/z 340.3 (MH+, 100). Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.48; H, 4.97; N, 4.39.

3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-4H-chromen-4-one (5d)

Pale yellow solid (68% yield); mp 179-180°C; IR (KBr); vmax 3072, 2955, 1643, 1602, 1509, 1289, 1060, 1027 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 6H, N(CH3)2), 3.97 (s, 2H, 8-CH2), 4.27 (s, 4H, 3′,4′-OCH2 CH2O), 6.88 (d, 1H, 3J = 8.7 Hz, 6-H), 6.91 (d, 1H, 3J = 8.4 Hz, 8′-H), 7.02 (dd, 1H, 3J = 8.7 Hz, 4J = 2.0 Hz, 7′-H), 7.09 (d, 1H, 4J = 2.0 Hz, 5′-H), 7.86 (s, 1H, 2-H), 8.11 (d, 1H, 3J = 8.7 Hz, 5-H), 10.04 ppm(s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 44.39, 54.63, 64.24, 64.38, 107.04, 115.54, 116.87, 117.16, 117.88, 122.08, 124.27, 125.10, 126.94, 143.32, 143.57, 151.46, 155.02, 164.03, 175.67 ppm; MS (CI): m/z 354.2 (MH+, 100). Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C, 68.10; H, 5.67; N, 4.79.

3-(4-Chlorophenyl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-4H-chromen-4-one (5e)

Pale yellow solid (78% yield); mp 174-176°C; IR (KBr) vmax 3061, 2958, 2838, 1881, 1632, 1590, 1466, 1378, 1257, 1204, 1176, 1011, 824 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 6H, N(CH3)2), 3.97 (s, 2H, 8-CH2), 6.90 (d, 1H, 3J = 8.8 Hz, 6-H), 7.36-7.41 (m, 2H, 3′, 5′-H), 7.46 – 7.52 (m, 2H, 2′, 6′-H), 7.89 (s, 1H, H-2), 8.11 (d, 1H, 3J = 8.8 Hz, 5-H), 12.48 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, CDCl3) δ 44.59, 55.14, 107.55, 115.79, 116.89, 123.84, 126.75, 128.60, 130.21, 130.51, 134.01, 151.79, 155.00, 164.32, 175.37 ppm; MS (CI): m/z 330.2 (MH+, 100), 332.2 (MH+, 28). Anal. Calcd for C18H16CINO3: C, 65.56; H, 4.89; N, 4.25. Found: C, 65.81; H, 5.07; N, 4.47.

8-[(N,N-Dimethylamino)methyl]-7-hydroxy-2-methyl-3-phenyl-4H-chromen-4-one (5f)

Pale yellow solid (81% yield); mp 168-170°C; IR (KBr) vmax 3052, 2952, 1633, 1599, 1399, 1287, 1258, 1018 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H, 2-CH3), 2.44 (s, 6H, N(CH3)2), 3.98 (s, 2H, 8-CH2), 6.84 (d, 1H, 3J = 8.8 Hz, 6-H), 7.24-7.47 (m, 5H, 3-Ph), 8.05 (d, 1H, 3J = 8.8 Hz, 5-H), 11.79 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 19.32, 44.41, 54.67, 106.69, 115.12, 115.83, 122.95, 126.83, 127.58, 128.24, 130.38, 133.17, 154.73, 161.90, 163.78, 176.29 ppm; MS (CI): m/z 310 (MH+, 100). Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.92; H, 5.99; N, 4.43.

8-[(N,N-Dimethylamino)methyl]-7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one (5g)

Pale yellow solid (91% yield); mp 185-187°C decomp; IR (KBr) vmax 3450, 2958, 1626, 1603, 1255, 1176, 1016 cm−1; 1H NMR (400 MHz, CDCL3): δ 2.30 (s, 3H, 2-CH3), 2.44 (s, 6H, N(CH3)2), 3.84 (s, 3H, 4′-OCH3), 3.98 (s, 2H, 8-CH2), 6.85 (d, 1H, 3J = 8.8 Hz, 6-H), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.20 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 8.04 (d, 1H, 3J = 8.8 Hz, 5-H), 11.30 ppm (br s, 1H); 13C NMR (125 MHz, CDCl3): δ 19.28, 44.44, 54.85, 55.21, 106.83, 113.78, 115.03, 115.89, 122.51, 125.33, 126.74, 131.51, 154.68, 158.99, 161.76, 163.69, 176.47 ppm; MS (CI): m/z 340.1 (MH+, 100). Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.91; H, 5.95; N, 4.33.

3-(3,4-dimethoxyphenyl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-2-methyl-4H-chromen-4-one (5h)

Pale yellow solid (87% yield); mp 150-152°C; IR (KBr) vmax 2995, 2841, 1635, 1516, 1393, 1262, 1020 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H, 2-CH3), 2.45 (s, 6H, N(CH3)2), 3.87, 3.91 (2s, 6H, 3′, 4′-OCH3), 3.99 (s, 2H, 8-CH2), 6.78-6.83 (m, 2H, 2′, 6′-H), 6.85 (d, 1H, 3J = 8.8 Hz, 6-H), 6.92 (d, 1H, 3J = 8.7 Hz, 5′-H), 8.05 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 19.39, 44.62, 55.24, 55.88, 55.89, 107.14, 111.11, 113.67, 115.11, 115.94, 122.76, 122.80, 125.84, 126.64, 148.50, 148.70, 154.61, 161.89, 163.78, 176.50 ppm; MS (CI): m/z 370.3 (MH+, 100). Anal. Calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 67.97; H, 6.14; N, 4.56.

3-(4-Chlorophenyl)-8-[(N,N-dimethylamino)methyl]-7-hydroxy-2-methyl-4H-chromen-4-one (5i)

Pale yellow solid (86% yield); mp 174-175°C; IR (KBr) vmax 2974, 2835, 1631, 1407, 1371, 1285, 1258, 1014 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H, 2-CH3), 2.44 (s, 6H, N(CH3)2), 3.98 (s, 2H, 8-CH2), 6.86 (d, 1H, 3J = 8.8 Hz, 6-H), 7.19-7.25 (m, 2H, 3′, 5′-H), 7.36-7.42 (m, 2H, 2′, 6′-H), 8.03 (d, 1H, 3J = 8.8 Hz, 5-H), 12.14 ppm (s, 7-OH); 13C NMR (100 MHz, CDCl3) δ 19.32, 44.63, 55.24, 107.18, 115.29, 115.80, 121.99, 126.65, 128.54, 131.76, 131.88, 133.61, 154.63, 161.76, 163.99, 176.03 ppm; MS (CI): m/z 344.3 (MH+, 100), 346.3 (MH+, 29). Anal. Calcd for C19H18CINO3: C, 66.38; H, 5.28; N, 4.07. Found: C, 66.10; H, 4.99; N, 3.85.

6-[(N,N-Dimethylamino)methyl]-7-hydroxy-3-(4-methoxyphenyl)-8-methyl-4H-chromen-4-one (7a)

To a suspension of 2 mmol of 6a in 10 mL of 1,4-dioxane was added 1 mL (7.4 mmol) of bis(N,N-dimethylamino)methane at 70°C. The mixture was heated at 100°C for 16 h, cooled, and diluted with hexane. The precipitate was collected to afford 672 mg (99 %) of 7a as a yellow solid: mp 182-183°C; IR (KBr) vmax 3069, 2954, 2831, 1627, 1512, 1461, 1369, 1290, 1223, 1176, 830 cm-1; 1H NMR (400 MHz, CDCL3) δ 2.32 (s, 3H, 8-CH3), 2.37 (s, 6H, N(CH3)2), 3.78 (s, 2H, 6-CH2), 3.84 (s, 3H, 4′-OCH3), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.50 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.81 (s, 1H, 5-H), 7.97 (s, 1H, 2-H), 9.81 ppm (br s, 1H, 7-OH); 13C NMR (125 MHz, CDCl3) δ 7.81, 44.21, 55.30, 62.37, 111.80, 113.88, 116.63, 120.31, 122.69, 124.02, 124.60, 130.07, 152.01, 155.76, 159.38, 161.30, 176.30 ppm; MS (CI): m/z 340.3 (MH+, 100). Anal. Calcd for C20H21NO4: C, 70.87; H, 6.24; N, 4.13. Found: C, 70.62; H, 6.43; N, 4.11.

6-[(N,N-Dimethylamino)methyl]-7-hydroxy-3-(4-methoxyphenyl)-2,8-dimethyl-4H-chromen-4-one (7g)

The procedure described for 6a was repeated to afford 509 mg of 7g as white solid (72% yield); mp 176-177°C; IR (KBr) v max 3039, 2952, 2834, 1643, 1606, 1511, 1397, 1239, 1158 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 6H, 2, 8-CH3), 2.36 (s, 6H, N(CH3)2), 3.76 (s, 2H, 6-CH2), 3.85 (s, 3H, 4′-OCH3), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.74 ppm (s, 1H, 5-H); 13C NMR (125 MHz, CDCl3) δ 7.83, 19.43, 44.20, 55.23, 62.34, 111.39, 113.77, 115.55, 119.84, 122.14, 122.62, 125.67, 131.55, 155.31, 158.87, 161.02, 162.34, 176.92 ppm; MS (CI): m/z 354.2 (MH+, 100). Anal. Calcd.for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.46; H, 6.31; N, 4.17.

General procedure for synthesis of Diels-Alder adducts 11 and 16

To a solution of 2 mmol of 5 or 7 in 10 mL of DMF was added 2 mL (26 mmol, 13 eq) of 2,3-dihydrofuran. The use of 13 equivalents of 2,3-dihydrofuran per mmole of 5 or 7 was chosen arbitrarily and does not represent an optimized ratio. Increased equivalents, however, lowered the reflux temperature, slowed the generation of the ortho-quinone methide and reduced product yield. The solution was refluxed for 24-40 h. The solvent and excess 2,3-dihydrofuran were evaporated in vacuo, and the residue was purified by chromatography using 1:50 methanol-dichloromethane to afford adducts 11 or 16.

3-(4-Methoxyphenyl)-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11a)

Pale yellow solid (70% yield); mp 201-202°C; IR (KBr) vmax 2903, 2844, 1643, 1610, 1510, 1435, 1295, 1242, 1205, 1052 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.69 – 1.82 (m, 1H, 10α-CH), 2.10-2.20 (m, 1H, 10β-CH), 2.75-2.86 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.5 Hz, 3J = 6.2 Hz, 11α-CH), 3.19 (dd, 1H, 2J = 17.5 Hz, 3J = 2.0 Hz, 11β-CH), 3.85 (s, 3H, 4′-OMe), 4.01-4.10 (m, 1H, 9α-CH), 4.16-4.24 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.94 (d, 1H, 3J = 8.8 Hz, 6-H), 6.96-7.00 (m, 2H, 3′, H-5′-H), 7.48-7.54 (m, 2H, 2′, H-6′-H), 7.96 (s, 1H, 2-H), 8.10 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.46, 27.72, 36.27, 55.34, 68.45, 100.86, 107.02, 113.95, 115.55, 118.49, 124.19, 124.79, 125.49, 130.11, 151.74, 155.39, 157.14, 159.57, 175.95 ppm; MS (CI): m/z 351.2 (MH+, 100). Anal. Calcd. for C21H18O5: C, 71.99; H, 5.18. Found: C, 72.17; H, 4.92.

3-(3,4-Dimethoxyphenyl)-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11b)

Pale yellow solid (29% yield); mp 193-195°C; IR (KBr) vmax 2900, 2843, 1637, 1607, 1510, 1437, 1398, 1290, 1244, 1057, 1025, 840 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.681.82 (m, 1H, 10α-CH), 2.10-2.21 (m, 1H, 10β-CH), 2.75-2.86 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.5, 3J = 6.0 Hz, 11α-CH), 3.14-3.24 (m, 1H, 11β-CH), 3.92 (s, 3H, 3′-OMe), 3.93 (s, 3H, 4′-OMe), 4.01-4.12 (m, 1H, 9α-CH), 4.15-4.24 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.1 Hz, 7a-CH), 6.91-6.98 (m, 2H, 6, 5′-H), 7.03-7.09 (m, 1H, 6′-H), 7.22 (d, 1H, 4J = 1.8 Hz, 2′-H), 7.99 (s, 1H, 2-H), 8.10 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.47, 27.71, 36.26, 55.96, 55.99, 68.46, 100.87, 107.03, 111.15, 112.52, 115.65, 118.47, 121.01, 124.62, 124.85, 125.47, 148.76, 149.10, 151.94, 155.38, 157.21, 176.00 ppm; MS (CI): m/z 381.2 (MH+, 100). Anal. Calcd for C22H20O6: C, 69.46; H, 5.30. Found: C 69.21; H, 5.01.

3-(1,3-Benzodioxol-5-yl)-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11c)

Pale yellow solid (64% yield); mp 203-205°C; IR (KBr) vmax 2986, 2903, 1641, 1600, 1490, 1435, 1245, 1226, 1056, 1032 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.67-1.81 (m, 1H, 10α-CH), 2.10-2.20 (m, 1H, 10β-CH), 2.75-2.86 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.6, 3J = 6.2 Hz, 11α-CH), 3.19 (dd, 1H, 2J = 17.6, 3J = 2.0 Hz, 11β-CH), 4.00-4.11 (m, 1H, 9α-CH), 4.14-4.24 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.00 (s, 2H, OCH2O), 6.87 (d, 1H, 3J = 8.0 Hz, 7′-H), 6.94 (d, 1H, 3J = 8.8 Hz, 6-H), 6.98 (dd, 1H, 3J = 8.0, 4J = 1.7 Hz, 6′-H), 7.10 (d, 1H, 3J = 1.7 Hz, 4′-H), 7.95 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.46, 27.71, 36.26, 68.46, 100.87, 101.16, 107.04, 108.36, 109.75, 115.63, 118.41, 122.35, 124.93, 125.50, 125.64, 147.63, 147.66, 151.91, 155.37, 157.21, 175.79 ppm; MS (CI): m/z 365.1 (MH+, 100). Anal. Calcd. for C21H16O6: C, 69.23; H, 4.43. Found: C 69.52; H, 4.18.

3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11d)

Pale yellow solid (75% yield); mp 188-189°C; IR (KBr) vmax 2936, 2862, 1656, 1611, 1512, 1437, 1281, 1219, 1198, 1138 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.68-1.82 (m, 1H, 10α-CH), 2.09-2.20 (m, 1H, 10β-CH), 2.75-2.86 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.4, 3J = 6.4 Hz, 11α-CH), 3.19 (dd, 1H, 2J = 17.4, 3J = 2.0 Hz, 11β-CH), 3.99-4.09 (m, 1H, 9α-CH), 4.14-4.23 (m, 1H, 9β-CH), 4.25-4.32 (m, 4H, OCH2CH2O), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.90-6.96 (m, 2H, 6, 8′-H), 7.04 (dd, 1H, 3J = 8.3, 4J = 2.0 Hz, 7′-H), 7.11 (d, 1H, 3J = 2.0 Hz, 2′-H), 7.94 (s, 1H, 7-H), 8.09 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.45, 27.70, 36.25, 64.32, 64.46, 68.45, 100.87, 107.05, 115.55, 117.25, 117.94, 118.46, 122.13, 124.63, 125.09, 125.48, 143.42, 143.69, 151.92, 155.35, 157.15, 175.79 ppm; MS (CI): m/z 379.2 (MH+, 100). Anal. Calcd. for C22H18O6: C, 69.84; H, 4.79. Found: C, 70.07; H, 4.95.

3-(4-Chlorophenyl)-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11e)

Pale yellow solid (55% yield); mp 194-195°C; IR (KBr) vmax 2961, 2899, 1637, 1598, 1492, 1438, 1377, 1244, 1092, 1064, 1012, 819 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.70-1.82 (m, 1H, 10α-CH), 2.12-2.21 (m, 1H, 10β-CH), 2.77-2.86 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.5, 3J = 6.3 Hz, 11α-CH), 3.19 (dd, 1H, 2J = 17.5, 3J = 2.0 Hz, 11β-CH), 4.02-4.11 (m, 1H, 9α-CH), 4.16-4.25 (m, 1H, 9β-CH), 5.69 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.96 (d, 1H, 3J = 8.9 Hz, 6-H), 7.39-7.44 (m, 2H, 3′, 5′-H), 7.49-7.55 (m, 2H, 2′, 6′-H), 7.99 (s, 1H, 2-H), 8.10 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.46, 27.70, 36.22, 68.48, 100.90, 107.10, 115.83, 118.38, 124.19, 125.50, 128.65, 130.22, 130.36, 134.15, 152.27, 155.42, 157.40, 175.50 ppm; MS (CI): m/z 355.2 (MH+, 100), 357.1 (MH+, 30). Anal. Calcd for C20H15ClO4: C, 67.71; H, 4.26. Found: C, 67.55; H, 4.43.

2-Methyl-3-phenyl-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11 f)

Pale yellow solid (73% yield); mp 181-182°C; IR (KBr) vmax 2966, 2900, 1634, 1607, 1579, 1510, 1437, 1398, 1244, 1057, 840 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.70-1.83 (m, 1H, 10α-CH), 2.11-2.21 (m, 1H, 10β-CH), 2.32 (s, 3H, 2-CH3), 2.75-2.85 (m, 1H, 10a-CH), 3.10 (dd, 1H, 2J = 17.4, 3J = 6.1 Hz, 11α-CH), 3.21 (dd, 1H, 2J = 17.4, 3J = 2.0 Hz, 11β-CH), 4.01-4.10 (m, 1H, 9α-CH), 4.16-4.23 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.91 (d, 1H, 3J = 8.8 Hz, 6-H), 7.27-7.30 (m, 2H, 2′, 6′-H), 7. 46-7.34 (m, 3H, 3′, 4′, 5′, H), 8.02 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.39, 19.52, 27.76, 36.31, 68.44, 100.84, 106.71, 115.15, 117.44, 123.38, 125.40, 127.68, 128.33, 130.42, 133.20, 155.01, 157.00, 162.28, 176.34 ppm; MS (CI): m/z 335.2 (MH+, 100). Anal. Calcd for C21H18O4: C, 75.43; H, 5.43. Found: C 75.85; H, 5.72.

3-(4-Methoxyphenyl)-2-methyl-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11g)

Pale yellow solid (62% yield); mp 227-229°C; IR (KBr) vmax 2900, 2825, 1634, 1607, 1510, 1437, 1398, 1290, 1244, 1057, 1025 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.68-1.82 (m, 1H, 10α-CH), 2.09-2.20 (m, 1H, 10β-CH), 2.33 (s, 3H, 2-CH3), 2.74-2.85 (m, 1H, 10a-CH), 3.09 (dd, 1H, 2J = 17.4, 3J = 6.2 Hz, 11α-CH), 3.19 (dd, 1H, 2J = 17.4, 3J = 1.6 Hz, 11β-CH), 3.85 (s, 3H, 4′-OMe), 4.00-4.09 (m, 1H, 9α-CH), 4.15-4.22 (m, 1H, 9β-CH), 5.67 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.90 (d, 1H, 3J = 8.8 Hz, 6-H), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.41, 19.53, 27.78, 36.33, 55.29, 68.43, 100.84, 106.69, 113.87, 115.08, 117.43, 122.92, 125.31, 125.42, 131.55, 154.98, 156.94, 159.07, 162.22, 176.55 ppm; MS (CI): m/z 365.1 (MH+, 100). Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.80; H, 5.82.

3-(3,4-Dimethoxyphenyl)-2-methyl-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11h)

Pale yellow solid (56% yield); mp 217-219°C; IR (KBr) vmax 2936, 2859, 1634, 1602, 1578, 1506, 1436, 1386, 1242, 1216, 1067 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.69-1.82 (m, 1H, 10α-CH), 2.10-2.19 (m, 1H, 10β-CH), 2.33 (s, 3H, 2-CH3), 2.75-2.84 (m, 1H, 10a-CH), 3.10 (dd, 1H, 2J = 17.5, 3J = 6.1 Hz, 11α-CH), 3.20 (dd, 1H, 2J = 17.5, 2J = 2.0 Hz, 11β-CH), 3.88 (s, 3H, 3′-OMe), 3.92 (s, 3H, 4′-OMe), 4.02-4.10 (m, 1H, 9α-CH), 4.15-4.23 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.80-6.83 (m, 2H, 2′, 6′-H), 6.90 (d, 1H, 3J = 8.8 Hz, 6-H), 6.93 (d, 1H, 3J = 8.6 Hz, 5′-H), 8.02 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.45, 19.53, 27.77, 36.32, 55.90, 55.92, 68.43, 100.85, 106.68, 111.18, 113.68, 115.16, 117.42, 122.80, 123.14, 125.41, 125.73, 148.60, 148.77, 154.99, 156.99, 162.44, 176.57 ppm; MS (CI): m/z 395.3 (MH+, 100). Anal. Calcd for C23H22O6: C, 70.04; H, 5.62. Found: C, 69.85; H, 5.90.

3-(4-Chlorophenyl)-2-methyl-9,10,10a,11-tetrahydro-4H,7aH-furo[2,3-b]pyrano[2,3-f]chromen-4-one (11i)

Pale yellow solid (60% yield); mp 266-268°C; IR (KBr) vmax 2971, 2903, 1641, 1605, 1582, 1491, 1438, 1399, 1251, 1088, 1068 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.69-1.83 (m, 1H, 10α-CH), 2.11-2.20 (m, 1H, 10β-CH), 2.32 (s, 3H, 2-CH3), 2.75-2.85 (m, 1H, 10a-CH), 3.10 (dd, 1H, 2J = 17.4, 3J = 6.3 Hz, 11α-CH), 3.20 (dd, 1H, 2J = 17.4, 2J = 2.1 Hz, 11β-CH), 4.02-4.11 (m, 1H, 9α-CH), 4.16-4.23 (m, 1H, 9β-CH), 5.68 (d, 1H, 3J = 4.2 Hz, 7a-CH), 6.91 (d, 1H, 3J = 8.8 Hz, 6-H), 7.19-7.25 (m, 2H, 3′, 5′-H), 7.38-7.44 (m, -2′, 6′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCl3) δ 19.38, 19.52, 27.74, 36.28, 68.45, 100.87, 106.75, 115.32, 117.27, 122.34, 125.38, 128.59, 131.65, 131.86, 133.71, 155.01, 157.16, 162.32, 176.10 ppm; MS (CI): m/z 369.1 (MH+, 100)., 371.1 (MH+, 29). Anal. Calcd for C21H17CIO4: C, 68.39; H, 4.65. Found: C, 68.70; H, 4.87.

3-(4-Methoxyphenyl)-11-methyl-6a,7,8,9a-tetrahydro-4H,6H-furo[2,3-b]pyrano[3,2-g]chromen-4-one (16a)

Pale yellow solid (27% yield); mp 155-157°C; IR (KBr) vmax 2963, 2907, 1640, 1606, 1512, 1462, 1289, 1219, 1176, 1056 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.53-1.67 (m, 1H, 7α-CH), 2.00-2.14 (m, 1H, 7β-CH), 2.33 (s, 3H, 11-CH3), 2.79-2.93 (m, 2H, 6a-CH, 6α-CH), 3.10 (dd, 2J = 16.4, 3J = 5.9 Hz, 1H, 6β-CH), 3.83 (s, 3H, 4′-OCH3), 3.88-3.98 (m, 2H, 8-CH2), 5.83 (d, 1H, 3J = 5.1 Hz, 9a-CH), 6.98 (d, 2H, 3J = 8.8 Hz, 3′, 5′-H), 7.51 (d, 2H, 3J = 8.8 Hz, 2′, 6′-H), 7.91 (s, 1H, 5-H), 8.00 ppm (s, 1H, 2-H); 13C NMR (100 MHz, CDCI3) δ 8.20, 26.53, 27.97, 37.67, 55.34, 68.33, 102.87, 113.96, 118.62, 120.49, 123.20, 124.19, 124.49, 130.11, 152.27, 154.78, 155.98, 159.49, 176.33 ppm; MS (CI): m/z 365.3 (MH+, 100). Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.80; H, 5.35.

3-(4-Methoxyphenyl)-2,11-methyl-6a,7,8,9a-tetrahydro-4H,6H-furo[2,3-b]pyrano[3,2-g]chromen-4-one (16g)

Pale yellow solid (24% yield); mp 155 -157°C; IR (KBr) vmax 2933, 2837, 1635, 1608, 1513, 1462, 1238, 1932 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.52-1.62 (m, 1H, 7α-CH), 2.02-2.12 (m, 1H, 7β-CH), 2.33, 2.35 (2s, 3H, 3H, 2, 11-CH3), 2.80-2.91 (m, 2H, 6α-CH, 6a-CH), 3.09 (dd, 2J = 16.0, 3J = 5.7 Hz, 1H, 6β-CH), 3.84 (s, 3H, 4′-OCH3), 3.88-3.99 (m, 2H, 8-CH2), 5.83 (d, 1H, 3J = 5.3 Hz, 9a-CH), 6.97 (d, 2H, 3J = 8.6 Hz, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.6 Hz, 2′, 6′-H), 7.82 ppm (s, 1H, 5-H); 13C NMR (100 MHz, CDCI3) δ 8.24, 19.50, 26.54, 28.03, 37.76, 55.29, 68.32, 102.91, 113.60, 113.88, 117.58, 120.15, 122.38, 123.09, 125.59, 131.59, 154.37, 155.79, 159.00, 162.77, 176.94 ppm; MS (CI): m/z 365.3 (MH+, 100). Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.80; H, 5.35.

General procedure for synthesis of Diels-Alder adducts 12

To a solution of 2 mmol of 5 in 10 mL of DMF was added 2 mL (22 mmol, 11 eq) of 2H,3,4-dihydropyran. The solution was refluxed for 36-40 h. The solvent and excess 2H,3,4-dihydropyran were evaporated in vacuo, and the residue was purified by chromatography with1:50 methanol-dichloromethane to afford 12.

3-(4-Methoxyphenyl)-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12a)

Pale yellow solid (30% yield); mp 182-183°C; IR (KBr) vmax 2966, 2933, 1636, 1598, 1511, 1437, 1248, 1205, 1178, 1090, 1029 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.47-1.92 (m, 4H, 10, 11-CH2), 2.24-2.40 (m, 1H, 11a-CH), 2.90 (dd, 1H, 2J = 17.4 Hz, 3J = 4.2 Hz, 12α-CH), 3.01 (dd, 1H, 2J = 17.4, 3J = 6.1 Hz, 12β-CH), 3.75-3.82 (m, 1H, 9α-CH), 3.85 (s, 3H, 4′-OMe), 3.95-4.09 (m, 1H, 9β-CH), 5.44 (d, 1H, 3J = 2.0 Hz, 7a-CH), 6.93-7.02 (m, 3H, 6, 3′, 5′-H), 7.50 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.96 (s, 1H, 2-H), 8.10 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 23.17, 23.57, 24.02, 30.62, 55.33, 62.58, 96.94, 107.86, 113.94, 115.27, 118.45, 124.19, 124.79, 125.29, 130.13, 151.79, 155.37, 157.15, 159.55, 176.07 ppm; MS (CI): m/z 365.1 (MH+, 100). Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.38; H, 5.67.

3-(3,4-Dimethoxyphenyl)-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12b)

Pale yellow solid (54% yield); mp 177-178°C; IR (KBr) vmax 3076, 2925, 1642, 1600, 1515, 1436, 1267, 1249, 1139, 1090, 1023 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.61-1.82 (m, 4H, 10, 11-CH2), 2.27-2.37 (m, 1H, 11a-CH), 2.91 (dd, 1H, 2J = 17.3, 3J = 4.1 Hz, 12α-CH), 2.99 (dd, 1H, 2J = 17.3, 3J = 6.1 Hz, 12β-CH), 3.76-3.83 (m, 1H, 9α-CH), 3.92 (s, 3H, 3′-OMe), 3.93 (s, 3H, 4′-OMe), 4.00-4.08 (m, 1H, 9β-CH), 5.45 (d, 1H, 3J = 2.0 Hz, 7a-CH), 6.93 (d, 1H, 3J = 8.3 Hz, 5′-H), 6.98 (d, 1H, 3J = 8.9 Hz, 6-H), 7.04 (dd, 1H, 3J = 8.3, 4J = 2.0 Hz, 6′-H), 7.22 (d, 1H, 4J = 2.0 Hz, 2′-H), 7.99 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 23.15, 23.56, 24.05, 30.64, 55.96, 55.98, 62.61, 96.97, 107.89, 111.16, 112.55, 115.34, 118.46, 121.02, 124.67, 124.83, 125.26, 148.76, 149.10, 151.96, 155.35, 157.22, 176.06 ppm; MS (CI): m/z 395.3 (MH+, 100). Anal. Calcd for C23H22O6: C, 70.04; H, 5.62. Found: C, 70.27; H, 5.90.

3-(1,3-Benzodioxol-5-yl)-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12c)

Pale yellow solid (25% yield); mp 179-181°C; IR (KBr) vmax 2925, 1637, 1599, 1434, 1247, 1142, 1033 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.68-1.84 (m, 4H, 10, 11-CH2), 2.25-2.37 (m, 1H, 11a-CH), 2.83-3.08 (m, 2H, 12α, 12β-CH), 3.75-3.85 (m, 1H, 9α-CH), 4.00-4.09 (m, 1H, 9β-CH), 5.44 (d, 1H, 3J = 2.4 Hz, 7a-CH), 6.00 (s, 2H, OCH2O), 6.88 (d, 1H, 3J = 8.0 Hz, 7′-H), 6.95-7.01 (m, 2H, 6, 6′-H), 7.10 (d, 1H, 3J = 1.7 Hz, 4′-H), 7.95 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 23.19, 23.58, 24.05, 30.63, 62.58, 96.91, 101.11, 107.82, 108.31, 109.71, 115.29, 118.30, 122.31, 124.86, 125.23, 125.56, 147.53, 147.55, 151.88, 155.25, 157.13, 175.82 ppm; MS (CI): m/z 379.2 (MH+, 100). Anal. Calcd for C22H18O6: C, 69.84; H, 4.79. Found: C, 70.07; H, 4.61.

3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12d)

Pale yellow solid (36% yield); mp 160-162°C; IR (KBr) vmax 2943, 2924, 2860, 1635, 1599, 1507, 1436, 1303, 1287, 1249, 1091 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.67-1.82 (m, 4H, 10, 11-CH2), 2.27-2.35 (m, 1H, 11a-CH), 2.91 (dd, 1H, 2J = 17.3, 3J = 4.1 Hz, 12α-CH), 2.99 (dd, 1H, 2J = 17.3, 3J = 6.1 Hz, 12β-CH), 3.75-3.83 (m, 1H, 9α-CH), 4.00-4.09 (m, 1H, 9β-CH), 4.27-4.31 (m, 4H, OCH2CH2O), 5.44 (d, 1H, 3J = 2.4 Hz, 7a-CH), 6.93 (d, 1H, 3J = 8.3 Hz, 8′-H), 6.97 (d, 1H, 3J = 8.9 Hz, 6-H), 7.03 (dd, 1H, 3J = 8.3, 4J = 2.1 Hz, 7′-H), 7.10 (d, 1H, 4J = 2.1 Hz, 5′-H), 7.94 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 23.19, 23.58, 24.01, 30.63, 62.56, 64.32, 64.46, 96.94, 107.85, 115.27, 117.28, 117.96, 118.45, 122.18, 124.67, 125.12, 125.32, 143.42, 143.68, 151.93, 155.33, 157.17, 175.90 ppm; MS (CI): m/z 393.2 (MH+, 100). Anal. Calcd for C23H20O6: C, 70.40; H, 5.14. Found: C, 70.15; H, 5.40.

3-(4-Chlorophenyl)-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12e)

Pale yellow solid (19% yield); mp 195-197°C; IR (KBr) vmax 2930, 1643, 1597, 1437, 1256, 1206, 1094, 826 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.67-1.84 (m, 4H, 10, 11-CH2), 2.28-2.38 (m, 1H, 11a-CH), 2.85-3.07 (m, 2H, 12α, 12β-CH), 3.76-3.85 (m, 1H, 9α-CH), 3.99-4.11 (m, 1H, 9β-CH), 5.45 (d, 1H, 3J = 2.4 Hz, 7a-CH), 6.99 (d, 1H, 3J = 8.8 Hz, 6-H), 7.42 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.52 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.99 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 23.20, 23.59, 24.05, 30.61, 62.60, 96.93, 107.89, 115.47, 118.33, 124.13, 125.25, 128.60, 130.16, 130.32, 134.06, 152.16, 155.28, 157.28, 175.27 ppm; MS (CI): m/z 369.2 (MH+, 100), 371.2 (MH+, 25). Anal. Calcd for C21H17CIO4: C, 68.39; H, 4.65. Found: C, 68.17; H, 4.43.

2-Methyl-3-phenyl-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12f)

Pale yellow solid (33% yield); mp 165-167°C; IR (KBr) vmax 2927, 1626, 1600, 1440, 1400, 1255, 1139, 1090 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.66-1.81 (m, 4H, 10, 11-CH2), 2.32 (s, 4H, 2-CH3, 11a-CH), 2.86-3.08 (m, 2H, 12α, 12β-CH), 3.75-3.86 (m, 1H, 9α-CH), 4.01-4.11 (m, 1H, 9β-CH), 5.45 (d, 1H, 3J = 2.4 Hz, 7a-CH), 6.94 (d, 1H, 3J = 8.8 Hz, 6-H), 7.28-7.32 (m, 2H, 2′, 6′-H), 7.36 (t, 1H, 3J = 7.3 Hz, 4′-H), 7.44 (t, 2H, 3J = 7.3 Hz, 3′, 5′-H), 8.02 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 19.43, 23.24, 23.62, 24.09, 30.72, 62.58, 96.86, 107.44, 114.77, 117.37, 123.30, 125.15, 127.59, 128.25, 130.36, 133.16, 154.87, 156.87, 162.15, 176.26 ppm; MS (CI): m/z 349.2 (MH+, 100). Anal. Calcd for C22H20O4: C, 75.84; H, 5.79. Found: C, 76.01; H, 5.95.

3-(4-Methoxyphenyl)-2-methyl-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12g)

Pale yellow solid (34% yield); mp 199-200°C; IR (KBr) vmax 2931, 2901, 1637, 1606, 1510, 1440, 1397, 1255, 1243, 1136, 1091, 1030 cm−1; 1H NMR (400 MHz, CDCI3) δ I.61-1.82 (m, 4H, 10, 11-CH2), 2.28-2.35 (m, 4H, 2-CH3, 11a-CH), 2.92 (dd, 1H, 2J = 17.3, 3J = 4.2 Hz, 12α-CH), 3.00 (dd, 1H, 2J = 17.3, 3J = 6.3 Hz, 12β-CH), 3.76-3.83 (m, 1H, 9α-CH), 3.85 (s, 3H, 4′-OMe), 4.00-4.10 (m, 1H, 9β-CH), 5.44 (d, 1H, 3J = 2.2 Hz, 7a-CH), 6.93 (d, 1H, 3J = 8.8 Hz, 6-H), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 19.41, 23.18, 23.58, 24.06, 30.69, 55.28, 62.59, 96.90, 107.48, 113.84, 114.76, 117.38, 122.88, 125.19, 125.32, 131.55, 154.94, 156.91, 159.02, 162.25, 176.63 ppm; MS (CI): m/z 379.3 (MH+, 100). Anal. Calcd for C23H22O5: C, 73.00; H, 5.86. Found: C, 73.18; H, 6.02.

3-(3,4-Dimethoxyphenyl)-2-methyl-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12h)

Pale yellow solid (15% yield); mp 209-210°C; IR (KBr) vmax 2934, 1636, 1581, 1513, 1438, 1394, 1258, 1138 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.56-1.82 (m, 4H, 10, 11-CH2), 2.27-2.35 (m, 4H, 2-CH3, 11a-CH), 2.98 (dd, 1H, 2J = 17.2, 3J = 4.4 Hz, 12α-CH), 3.00 (dd, 1H, 2J = 17.2, 3J = 6.3 Hz, 12β-CH), 3.75 – 3.83 (m, 1H, 9α-CH), 3.88 (s, 3H, 3′-OMe), 3.92 (s, 3H, 4′-OMe), 4.00-4.10 (m, 1H, 9β-CH), 5.44 (d, 1H, 3J = 2.4 Hz, 7a-CH), 6.79-6.83 (m, 2H, 2′, 6′-H), 6.91-6.95 (m, 2H, 6, 5′-H), 8.02 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 19.45, 23.17, 23.57, 24.08, 30.69, 55.90, 55.91, 62.61, 96.93, 107.51, 111.17, 113.68, 114.86, 117.37, 122.81, 123.12, 125.19, 125.76, 148.58, 148.76, 154.97, 156.99, 162.51, 176.68 ppm; MS (CI): m/z 409.2 (MH+, 100). Anal. Calcd for C24H24O6: C, 70.58; H, 5.92. Found: C, 70.69; H, 6.17.

3-(4-Chlorophenyl)-2-methyl-10,11,11a,12-tetrahydro-4H,7aH,9H-dipyrano[2,3-b:2′,3′-f]chromen-4-one (12i)

Pale yellow solid (15% yield); mp 205-206°C; IR (KBr) vmax 2927, 1635, 1605, 1439, 1398, 1257, 1139, 1094, 895 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.82-1.64 (m, 4H, 10, 11-CH2), 2.28-2.37 (m, 4H, 2-CH3, 11a-CH), 2.84-3.07 (m, 2H, 12α, 12β-CH), 3.75 – 3.84 (m, 1H, 9α-CH), 4.00-4.10 (m, 1H, 9β-CH), 5.44 (d, 1H, 3J = 2.5 Hz, 7a-CH), 6.95 (d, 1H, 3J = 8.8 Hz, 6-H), 7.20-7.25 (m, 2H, 2′, 6′-H), 7.38-7.43 (m, 2H, 3′, 5′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 19.38, 23.12, 23.51, 24.03, 30.60, 62.59, 96.90, 107.55, 115.03, 117.15, 122.27, 125.16, 128.57, 131.59, 131.83, 133.67, 154.96, 157.15, 162.44, 176.20 ppm; MS (CI): m/z 383.2 (MH+, 100), 385.2 (MH+, 25). Anal. Calcd for C22H19ClO3: C, 72.03; H, 5.22. Found: C, 72.31; H, 5.43.

General procedure for synthesis of pyranoxanthenediones 13 and 17

To a solution of 1 mmol of 5 or 7 was added 1.25 mmol (1.25 eq) of 3-(N,N-dimethylamino)-5,5-dimethylcyclohex-2-en-1-one in 10 mL of DMF. The solution was refluxed for 4 h. The mixture was diluted with 20 mL of methanol, and the precipitate was collected by filtration and re-crystallized from DMF-methanol to afford 13 or 17.

3-(4-Methoxyphenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (13a)

Beige solid (92% yield); mp 223-225°C; IR (KBr) vmax 2949, 1647, 1606, 1511, 1438, 1237, 1032 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.10 (s, 6H, 9-CH3), 2.33 (s, 2H, 10-CH2), 2.53 (2, 2H, 8-CH2), 3.52 (s, 2H, 12-CH2), 3.81 (s, 3H, 4′-OCH3), 7.01 (d, 2H, 3J = 8.6, 3′, 5′-H), 7.18 (d, 1H, д, 3J = 8.8, 6-H), 7.54 (d, 2H, 3J = 8.6, 2′, 6′-H), 8.00 (d, 2H, 3J = 8.8, 5-H), 8.50 ppm (s, 1H, 2-H); 13C NMR (125 MHz, CDCI3 and DMSO-d6 1:1) δ 16.01, 27.89, 31.67, 40.57, 50.07, 54.80, 107.61, 109.39, 113.36, 113.84, 120.34, 123.22, 124.36, 124.84, 129.51, 151.86, 152.47, 153.99, 159.01, 163.63, 174.96, 196.87 ppm; MS (CI): m/z 403.2 (MH+, 100). Anal. Calcd for C25H22O5: C, 74.61; H, 5.51. Found: C, 74.47; H, 5.27.

3-(3,4-Dimethoxyphenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (13b)

Beige solid (75% yield); mp 196-198°C; IR (KBr) vmax 2955, 1654, 1640, 1516, 1440, 1261, 1237, 1195 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.17 (s, 6H, 9-CH3), 2.39 (s, 2H, 10-CH2), 2.50 (s, 2H, 8-CH2), 3.65 (s, 2H, 12-CH2), 3.93, 3.94 (2s, 6H, 3′, 4′-OCH3), 6.94 (d, 1H, 3J = 8.3 Hz, 5′-H), 7.02-7.10 (m, 2H, 6, 6′-H), 7.21 (d, 1H, 4J = 1.8 Hz, 2′-H), 8.04 (s, 1H, 2-H), 8.15 ppm (d, 1H, 3J = 8.3 Hz, 5-H); 13C NMR (400 MHz, CDCI3) δ 16.51, 28.42, 32.20, 41.17, 50.60, 55.94, 55.96, 108.31, 109.99, 111.18, 112.39, 114.45, 121.02, 121.07, 124.17, 125.20, 125.60, 148.80, 149.24, 152.51, 153.12, 154.62, 164.28, 175.76, 197.69 ppm; MS (CI): m/z 433.3 (MH+, 100). Anal. Calcd for C26H24O6: C, 72.21; H, 5.59. Found: C, 72.49; H, 5.22.

3-(1,3-Benzodioxol-5-yl)-9,9-dimethyl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (13c)

Beige solid (80% yield); mp 258-260°C; IR (KBr) vmax 2950, 2897, 1649, 1599, 1429, 1240, 1194, 1037cm−1; 1H NMR (400 MHz, CDCI3) δ 1.17 (s, 6H, 9-CH3), 2.39 (s, 2H, 10-CH2), 2.50 (s, 2H, 8-CH2), 3.64 (s, 2H, c, 12-CH2), 6.00 (s, 2H, OCH2O), 6.88 (d, 1H, 3J = 8.0 Hz, 5′-H), 6.99 (dd, 1H, 4J = 1.7 Hz, 3J = 8.0 Hz, 6′-H), 7.05 (d, 1H, 3J = 8.8 Hz, 6-H), 7.10 (d, 1H, 4J = 1.7 Hz, 2′-H), 8.00 (s, 1H, 2-H), 8.15 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (100 MHz, CDCI3) δ 16.52, 28.43, 32.21, 41.19, 50.61, 101.22, 108.33, 108.45, 109.71, 110.01, 114.46, 120.99, 122.42, 125.23, 125.32, 125.69, 147.74, 147.81, 152.49, 153.15, 154.65, 164.28, 175.62, 197.69 ppm; MS (CI): m/z 417.3 (MH+, 100). Anal. Calcd for C25H20O6: C, 72.11; H, 4.84. Found: C, 72.29; H, 5.11.

2,9,9-trimethyl-3-phenyl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (13f)

Beige solid (84% yield); mp 265-266°C; IR (KBr) vmax 3047, 2947, 2885, 1646, 1590, 1390, 1235, 1215, 700 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.17 (s, 6H, 9-CH3), 2.35 (s, 3H, 2-CH3), 2.40 (s, 2H, 10-CH2), 2.51 (s, 2H, 8-CH2), 3.66 (s, 2H, 12-CH2), 7.01 (d, 1H, 3J = 8.8 Hz, 6-H), 7.26-7.30 (m, 2H, 2′, 6′-H), 7.35-7.40 (m, 1H, 4′-H), 7.41-7.47 (m, 2H, 3′, 5′-H), 8.08 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (100 MHz, CDCI3) δ 16.48, 19.55, 28.42, 32.20, 41.22, 50.64, 108.34, 109.56, 113.99, 120.04, 123.73, 125.56, 127.85, 128.41, 130.34, 132.82, 152.94, 154.29, 163.30, 164.46, 176.08, 197.89 ppm; MS (CI): m/z 387.3 (MH+, 100). Anal. Calcd for C25H22O4: C, 77.70; H, 5.74. Found: C, 77.92; H, 5.88.

3-(4-Methoxyphenyl)-2,9,9-trimethyl-8,9,10,12-tetrahydro 4H,11H-pyrano[2,3--a]xanthene-4,11-dione (13g)

Beige solid (90% yield); mp 236-237°C; IR (KBr) vmax 2958, 2890, 1653, 1586, 1515, 1440, 1393, 1239, 1174, 1026 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.14 (s, 6H, 9-CH3), 2.32 (s, 3H, 2-CH3), 2.36 (s,2H, 10-CH2), 2.47 (s, 2H, 8-CH2), 3.62 (s, 2H, 12-CH2), 3.82 (s, 3H, 4′-OCH3), 6.92-6.99 (m, 3H, 6, 3′, 5′-H), 7.15-7.21 (m, 2H, 2′, 6′-H), 8.04 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (100 MHz, CDCI3) δ 16.47, 19.56, 28.42, 32.19, 41.23, 50.65, 55.28, 108.36, 109.52, 113.92, 113.93, 120.02, 123.28, 124.91, 125.56, 131.50, 152.90, 154.26, 159.17, 163.25, 164.46, 176.30, 197.86 ppm; MS (CI): m/z 417.3 (MH+, 100). Anal. Calcd for C26H24O5: C, 74.98; H, 5.81. Found: C, 74.70; H, 6.10.

3-(4-Methoxyphenyl)-9,9,12-trimethyl-6,8,9,10-tetrahydro-4H,7H-pyrano[3,2-b]xanthene-4,7-dione (17a)

Beige solid (80% yield); mp 230-232°C; IR (KBr) vmax 3079, 2958, 2835, 1645, 1612, 1514, 1463, 1391, 1296, 1220, 1179 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.16 (s, 6H, 9-CH3), 2.35 (s, 2H, 8-CH2), 2.39 (s, 3H, 12-CH3), 2.52 (s, 2H, 10-CH2), 3.62 (s, 2H, 6-CH2), 3.84 (s, 3H, 4′-OCH3), 6.97 (d, 2H, 3J = 8.8 Hz, 3′, 5′-H), 7.50 (d, 2H, 3J = 8.8 Hz, 2′, 6′-H), 7.96 (s, 1H, 5-H), 8.00 ppm (s, 1H, 2-H); 13C NMR (100 MHz, CDCI3) δ 8.32, 20.97, 28.45, 32.20, 41.29, 50.62, 55.34, 109.16, 113.99, 114.18, 118.85, 120.88, 124.05, 124.16, 124.49, 130.05 , 151.43, 152.48, 153.96, 159.62, 163.91, 175.92, 197.56 ppm; MS (CI): m/z 417.3 (MH+, 100). Anal. Calcd for C26H14O5: C, 74.98; H, 5.81. Found: C, 75.22; H, 5.64.

3-(4-Methoxyphenyl)-2,9,9,12-tetramethyl-6,8,9,10-tetrahydro-4H,7H-pyrano[3,2-b]xanthene-4,7-dione (17g)

Beige solid (72% yield); mp 270-272°C; IR (KBr) vmax 2954, 2878, 1642, 1609, 1395, 1238, 1220, 1142 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.16 (s, 6H, 9-CH3), 2.34 (s, 3H, 2-CH3), 2.36 (s, 2H, 8-CH2), 2.40 (s, 3H, 12-CH3), 2.52 (2H, 10-CH2), 3.61 (s, 2H, 6-CH2), 3.85 (s, 3H, 4′-OCH3), 6.97 (d, 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.20 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.89 ppm (s, 1H, 5-H); 13C NMR (100 MHz, CDCI3) δ 8.33, 19.54, 20.95, 28.47, 32.20, 41.33, 50.63, 55.29, 109.19, 113.70, 113.91, 118.35, 119.84, 122.75, 124.08, 125.16, 131.54, 151.26, 153.58, 159.11, 163.11, 163.96, 176.53, 197.61 ppm; MS (CI): m/z 431.1 (MH+, 100). Anal. Calcd for C27H26O5: C, 75.33; H, 6.09. Found: C, 75.52; H, 5.87.

General procedure for synthesis of Diels-Alder adducts 14 and 15

To a solution of 2 mmol of 5 in 10 mL of DMF was added 2.2 mmol (1.1 eq) of 1-morpholinocyclopentene or 1-morpholinocyclohexene. The mixture was heated at 154°C for 4 h. The solvent was evaporated in vacuo, and residue was chromatographed using 1:50 methanol-dichloromethane to afford 14 or 15.

7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-8-[(2-oxocyclopentyl)methyl]-4H-chromen-4-one (14g)

Pale yellow solid (58% yield); mp 210-211°C; IR (KBr) vmax 2960, 1735, 1631, 1580, 1512, 1436, 1291, 1244 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.62-2.25 (m, 4H, 4″, 5″-CH2), 2.33 (s, 3H, 2-CH3), 2.38-2.63 (m, 2H, 3″-CH2), 3.01-3.17 (m, 2H, 8-CH2), 3.37-3.74 (m, 1H, 1″-H), 3.84 (s, 3H, 4′-OCH3), 6.91-7.00 (m, 3H, 6, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.6 Hz, 2′, 6′-H), 7.99 ppm (d, 1H, 3J = 8.7 Hz, 5-H); 13C NMR (125 MHz, DMSO-d6) δ 19.15, 20.05, 22.40, 28.91, 37.40, 48.03, 55.04, 113.25, 113.43, 113.69, 115.56, 121.25, 124.27, 125.31, 131.67, 155.07, 158.46, 159.94, 162.29, 175.36, 219.25 ppm; MS (CI): m/z 379.1 (MH+, 100). Anal. Calcd for C23H22O5: C, 73.00; H, 5.86. Found: C, 73.26; H, 5.62.

3-(3,4-Dimethoxyphenyl)-7-hydroxy-2-methyl-8-[(2-oxocyclopentyl)methyl]-4H-chromen-4-one (14h)

Pale yellow solid (53% yield); mp 88-90°C; IR (KBr) vmax 2924, 1736, 1633, 1515, 1440, 1265 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.51-2.07 (m, 4H, 4″, 5″-CH2), 2.27 (s, 3H, 2-CH3), 2.66-3.16 (m, 4H, 8, 3″-CH2), 3.36-3.60 (m, 1H, 1″-H), 3.74, 3.79 (2s, 6H, 3′, 4′- OCH3), 6.74-6.88 (m, 2H, 2′, 6′-H), 6.93-7.03 (m, 2H, 6, 5′-H), 7.76 (d, 1H, 3J = 8.7 Hz, 5-H), 10.64 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, DMSO-d6) δ 19.63, 20.47, 29.33, 37.83, 48.43, 55.93, 55.97, 111.89, 113.68, 114.12, 114.80, 116.05, 122.01, 123.24, 124.70, 126.17, 148.54, 148.68, 155.50, 160.34, 162.85, 175.75, 219.65 ppm; MS (CI): m/z 409.2 (MH+, 100). Anal. Calcd for C24H24O6: C, 70.58; H, 5.92. Found: C, 70.28; H, 6.18.

7a-Hydroxy-3-(4-methoxyphenyl)-8,9,10,11,11a,12-hexahydro-4H,7aH-pyrano[2,3-a]xanthen-4-one (15a)

Pale yellow solid (91% yield); mp 222-223°C; IR (KBr) vmax 2987, 1613, 1513, 1439, 1251, 1030 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.30-2.18 (m, 9H, 8, 9, 10, 11-CH2, 11a-CH), 2.35-3.26 (m, 2H, 12-CH2), 3.85 (s, 3H, 4′-OCH3), 6.81-6.89 (m, 1H, 6-H), 6.98 (d, 2H, 3J = 8.6 Hz, 3′, 5′-H), 7.51 (d, 2H, 3J = 8.6 Hz, 2′, 6′-H), 7.96 (s, 1H, 2-H), 8.02-8.09 ppm (m, 1H, 5-H); 13C NMR (125 MHz, DMSO-d6) δ 21.82 (21.73), 22.82 (23.00), 24.93 (24.30), 29.11 (28.59), 36.33 (35.45), 37.51 (37.28), 55.13, 98.10 (97.70), 111.20 (108.97), 113.58, 115.63 (115.65), 117.11 (117.33), 123.13 (123.18), 123.84, 124.16, 130.06 (130.08), 153.15, 154.26 (154.95), 156.84 (156.37), 158.96, 174.88 (174.86) ppm; MS (CI): m/z 349.2 (MH+, 100). Anal. Calcd for C23H22O5: C, 73.00; H, 5.86. Found: C, 72.71; H, 5.98.

3-(3,4-Dimethoxyphenyl)-7a-hydroxy-8,9,10,11,11a,12-hexahydro-4H,7aH-pyrano[2,3-a]xanthen-4-one (15b)

Pale yellow solid (85% yield); mp 214-216°C; IR (KBr) vmax 2930, 1629, 1612, 1516, 1439, 1263, 1143, 1027 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.40-2.62 (m, 9H, 8, 9, 10, 11-CH2, 11a-CH), 2.70-3.60 (m, 2H, 12-CH2), 3.75 (s, 6H, 3′, 4′-OCH3), 6.84-6.99, 7.07–7.19 (2m, 4H, 6, 2′, 5′, 6′-H), 7.81-7.87 (m, 1H, 5-H), 8.42, 8.43 ppm (2s, 1H, 2-H); 13C NMR (125 MHz, DMSO-d6) δ 22.22 (22.13), 23.25 (23.42), 25.35 (24.73), 29.54 (29.02), 36.76 (35.87), 37.94 (37.71), 55.96, 55.96, 98.54 (98.13), 109.39 (109.30), 111.95 (111.62), 113.17, 116.10 (116.07), 117.56 (117.78), 121.63 (121.66), 123.63 (123.63), 124.28, 124.90 (124.91), 148.68, 149.03, 153.79, 154.63 (155.32), 157.27 (156.79), 175.28 (175.26) ppm; MS (CI): m/z 409.2 (MH+, 100). Anal. Calcd for C24H4O6: C, 70.58; H, 5.92. Found: C, 70.31; H, 6.21.

3-(1,3-Benzodioxol-5-yl)-7a-hydroxy-8,9,10,11,11a,12-hexahydro-4H,7aH-pyrano[2,3-a]xanthen-4-one (15c)

Pale yellow solid (76% yield); mp 197-197°C; IR (KBr) vmax 2937, 1630, 1587, 1435, 1251, 1027 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.23-2.62 (m, 9H, 8, 9, 10, 11-CH2, 11a-CH), 2.70-3.60 (m, 2H, 12-CH2), 6.05 (s, 2H, OCH2O), 6.88-7.18 (2m, 4H, 6, 2′, 5′, 6′-H), 7.81-7.99 (m, 1H, 5-H), 8.41, 8.45 ppm (2s, 1H, 2-H); 13C NMR (125 MHz, DMSO-d6) δ 22.24 (22.14), 23.24 (23.42), 25.35 (24.72), 29.53 (29.02), 36.76 (35.88), 37.95 (37.70), 98.56 (98.15), 101.45, 108.51, 109.83 (109.86), 111.65, 116.13 (116.10), 117.49 (117.72), 122.81 (122.84), 123.58 (123.63), 124.29, 126.11 (126.13), 147.34, 147.41, 153.86 (153.64), 154.64 (155.33), 157.32 (156.86), 175.16 (175.15) ppm; MS (CI): m/z 393.2 (MH+, 100). Anal. Calcd for C23H20O6: C, 70.40; H, 5.14. Found: C, 70.14; H, 4.85.

7a-Hydroxy-3-(4-methoxyphenyl)-2-methyl-8,9,10,11,11a,12-hexahydro-4H,7aH-pyrano[2,3-a]xanthen-4-one (15g)

Pale yellow solid (69% yield); mp 212-213°C; IR (KBr) vmax 2924, 1632, 1608, 1514, 1435, 1251, 1177 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.57-2.17 (m, 9H, 8, 9, 10, 11-CH2, 11a-CH), 2.33 (s, 3H, 2-CH3), 2.54- 3.27 (m, 2H, 12-CH2), 3.85 (s, 3H, 4′-OCH3), 6.70-6.81 (m, 1H, 6-H), 6.97 (d, 2H, 3J = 8.5 Hz, 3′, 5′-H), 7.21 (d, 2H, 3J = 8.5 Hz, 2′, 6′-H), 7.87-7.97 ppm (m, 1H, 5-H); 13C NMR (400 MHz, CDCI3) δ 19.43 (19.44), 22.12 (21.97), 23.09 (23.34), 25.51 (24.92), 29.44 (29.13), 36.64 (38.54), 37.80 (37.85), 55.29, 97.93 (97.76), 110.68 (108.50), 113.85, 115.24 (115.21), 116.93 (117.14), 122.74 (122.77), 124.61 (124.70), 125.50 (125.51), 131.61, 154.48 (155.18), 155.81 (156.39), 159.02, 162.51 (162.51), 177.10 (177.07) ppm; MS (CI): m/z 393.2 (MH+, 100). Anal. Calcd for C24H24O5: C, 73.45; H, 6.16. Found: C, 73.18; H, 6.42.

3-(3,4-Dimethoxyphenyl)-7a-hydroxy-2-methyl-8,9,10,11,11a,12-hexahydro-4H,7aH-pyrano[2,3-a]xanthen-4-one (15h)

Pale yellow solid (51% yield); mp 193-194°C; IR (KBr) vmax 2938, 1631, 1610, 1577, 1514, 1437, 1264, 1028 cm−1; 1H NMR (400 MHz, CDCI3) δ 1.30-2.16 (m, 9H, 8, 9, 10, 11-CH2, 11a-CH), 2.34 (s, 3H, 2-CH3), 2.53-3.28 (m, 2H, 12-CH2), 3.88, 3.92 (2s, 6H, 3′, 4′-OCH3), 6.62-6.99 (m, 1H, 6-H), 6.78-6.86, 6.90-6.96 (2m, 3H, 2′, 5′, 6′-H), 7.84-7.92 ppm (m, 1H, 5-H); 13C NMR (125 MHz, DMSO-d6) δ 19.19 (19.21), 21.76 (21.69), 22.80 (22.99), 24.96 (24.32), 29.10 (28.59), 36.36 (35.46), 37.57 (37.31), 55.47, 55.50, 97.97 (97.58), 110.87 (108.64), 111.41, 114.31, 115.20 (115.17), 116.05 (116.27), 122.02 (122.08), 122.80, 123.64, 125.65 (125.67), 148.13, 148.22, 153.81 (154.50), 156.65 (156.16), 162.53, 175.20 (175.17) ppm; MS (CI): m/z 423.2 (MH+, 100). Anal. Calcd for C25H26O6: C, 71.07; H, 6.20. Found: C, 71.33; H, 6.07.

Cell Proliferation Assay

PC-3 human prostate cancer cells were grown in Dulbecco's Modified Eagle Medium Nutrient Mixture F-12 (DMEM/F-12 HAM) (Sigma D8437) with 10% Fetal Bovine Serum (Atlanta Biological S11150). For cell proliferation assays, 3.5×104 cells per well were placed into 12-well plates. After 1 d, 10μM of each compound was added to each well. DMSO was used as a control. The experiments were performed in triplicate. Cell viability and number were analyzed using Vi-Cell XR Cell Viability Analyzer (Beckman Coulter) as previously described.[8a] Inhibition data represents the mean±SD for at least three experiments.

Supplementary Material

Supporting Information

Figure 2.

Figure 2

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Diels-Alder adducts 11-17 derived from thermal reactions of Mannich bases 5 or 7 with various dienophiles

Acknowledgements

DSW and CL were supported by R21 CA139359 and CA172379 from the NIH, by the Office of the Dean of the College of Medicine, and by NIH Grant Number P30 GM110787 (L. Hersh, PI. JLM and MVF were supported by P01 CA77739 from the NIH. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

Footnotes

Supporting information for this article is given via a link at the end of the document.

References

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