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Jan 25, 2018 - An improved procedure is described for the preparation of pyranoflavylium cations from the reaction of 5,7-dihydroxy-4-methylflavylium ...
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Article Cite This: ACS Omega 2018, 3, 954−960

Improved Synthesis of Analogues of Red Wine Pyranoanthocyanin Pigments Cassio Pacheco da Silva,† Renan Moraes Pioli,† Liu Liu,†,‡ Shasha Zheng,†,‡ Mengjiao Zhang,†,‡,∥ Gustavo Thalmer de Medeiros Silva,† Vânia Maria Teixeira Carneiro,§ and Frank H. Quina*,† †

Instituto de Química, Universidade de São Paulo, Av. Lineu Prestes 748, Cidade Universitária, São Paulo 05508-000, Brazil School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072 China § Departamento de Química, Universidade Federal de Viçosa, Av. Peter Henry Rolfs s/n, Campus Universitário, 36570-900 Viçosa, Minas Gerais, Brazil ‡

S Supporting Information *

ABSTRACT: An improved procedure is described for the preparation of pyranoflavylium cations from the reaction of 5,7-dihydroxy-4-methylflavylium cation with aromatic aldehydes. Modifications of the procedure of Chassaing et al. (Tetrahedron Lett. 2008, 49, 6999−7004; Tetrahedron 2015, 71, 3066−3078) circumvent the reported restriction to electronrich benzaldehydes and provide access to a wide variety of substituted pyranoflavylium cations, including those with electron-withdrawing substituents or an attached heterocyclic or polycyclic aromatic ring. This opens the way for studies of substituent and structural effects on the ground and excited states of these pyranoanthocyanin analogues, the behavior of which should mirror fundamental aspects of the chemistry and photophysics of the pyranoanthocyanin chromophores present in mature red wines. group at the 4-position of the flavylium chromophore to block ring-opening tautomerization.8−10 During the maturation of red wine, the content of free anthocyanins decreases because of chemical reactions with yeast metabolic products, with colorless copigment molecules derived from grapes or with the intervention of other additives present in the wine.19−26 These reactions slowly transform the anthocyanins into complex molecules that impart a more burgundy coloration to the wine. Among the products that are formed, pyranoanthocyanins (Scheme 1) are particularly interesting because of their overall contribution to the color of aged red wines,19,24 the much greater stability of their color,19,27,28 their potential contributions to the taste (e.g., astringency),29,30 their antioxidant capacity,31,32 and the health benefits33 of moderate consumption of red wines. Over the last several years, various synthetic approaches have been developed to prepare pyranoflavylium cation analogues of the naturally occurring pyranoanthocyanin pigments of wine.19,33−40 As in the case of anthocyanins, for which the synthetic analogues containing the 7-hydroxyflavylium cation chromophore successfully mimic the ground- and excited-state chemistry of naturally occurring anthocyanin pigments,7−9,41 synthetic analogues with the pyranoflavylium cation chromo-

1. INTRODUCTION Anthocyanin malvidin-3-O-glucoside (oenin), the principal redpurple pigment of Vitis vinifera grapes, is primarily responsible for the initial color of red wines produced from them.1−3 Although large quantities of grape-derived anthocyanin pigments are available as a byproduct of wine making, the range of potential applications of these pigments as safe coloring agents in foods or consumer products4−6 is limited by the relatively facile hydration reaction.4−9 Thus, attack of water at the 2position of the flavylium cation chromophore group of anthocyanins to form the corresponding hemiketal, followed by ring-opening tautomerism to the Z-chalcone and subsequent isomerization and equilibration with the E-chalcone, results in loss of the color of these pigments above about pH 3.6−10 In nature, this pH-dependent loss of color can be shifted to a slightly higher pH by copigmentation,11 that is, charge-transfermediated complexation of anthocyanins with colorless electronrich molecules11,12 such as hydroxybenzoic or hydroxycinnamic acids or, somewhat more efficiently, by complexation with metal cations such as Al3+ or formation of stoichiometric supramolecular metal−organic complexes.13−16 Several studies have also shown that the hydration reaction can be inhibited by avoiding contact of the pigment with water,6 as in inclusion complexes,17 by selectively stabilizing the cationic flavylium cation form at negatively charged interfaces such as in anionic micelles,18 or by introducing a methyl or other substituent © 2018 American Chemical Society

Received: December 7, 2017 Accepted: January 16, 2018 Published: January 25, 2018 954

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ACS Omega Scheme 1. Formation of Pyranoanthocyanins during the Maturation of Red Wine

phore can also be expected to reproduce the reactivity patterns of their natural counterparts.42 Moreover, they could eventually serve as a novel source of synthetic cationic dyes with tunable colors43 or as chromophores in dye-sensitized solar cells.44 The principal synthetic routes reported to date in the literature include43 (a) the reaction of a 5,7-dihydroxyflavylium cation or, as presumably occurs in red wine, of a natural anthocyanin with a substrate containing an enolizable keto group (Scheme 1) or a vinylbenzene derivative;20,28,35,37 (b) reaction of either of these with hydroxy- or dimethylamino-substituted cinnamic acids;35,36,43 (c) reaction of methyl or carboxy pyranoanthocyanins (analogues of vitisin A or B) with a substituted cinnamaldehyde or cinnamic acid, respectively;38,39 or (d) reaction of 5,7-dihydroxy-4-methylflavylium (DHMF) cations with electron-rich benzaldehydes26,34,40 (Scheme 2).

difference were attributable to a role of the chloride counterion acting, for example, as a weak base catalyst, the addition of a small amount of sodium bicarbonate should potentially improve the reaction. However, the addition of 1.5 mmol (3 equiv) of sodium bicarbonate to the reaction mixture inhibited almost completely the reaction of DHMF with p-cyanobenzaldehyde. This suggested the possibility that the important factor might be the presence of residual acidity (as HCl) in the chloride salt of DHMF. Indeed, the DHMF employed by us is routinely prepared by the condensation of phloroglucinol (1,3,5-benzenetriol) with benzoylacetone in acetic acid saturated with dry gaseous HCl and isolated by precipitation with ethyl ether. Scheme 3 outlines a plausible reaction sequence, initiated by the deprotonation of the methyl group at the 4-carbon of

Scheme 2. Overall Reaction of DHMF with Electron-Rich Benzaldehydes (R = p-Methoxybenzaldehyde or pDimethylaminobenzaldehyde) Reported by Roehri-Stoeckel et al.40 and Chassaing et al26,34

Scheme 3. Outline of the Proposed Mechanism of Reaction of DHMF with Aromatic Aldehydes

Of these synthetic routes, the last would potentially represent the most attractive and perhaps the most general route to substituted pyranoflavylium ions if the reported limitation of the reaction only to benzaldehydes bearing electron-rich substituents26,34 could be overcome. In the present work, we report several modifications of the reaction conditions, along with several improvements in the product purification procedure, which now make this synthetic route viable for the more general preparation of pyranoflavylium cations, including those prepared from benzaldehydes with strong electron-withdrawing substituents.

DHMF. This is consistent with the facile hydrogen−deuterium exchange of the methyl group in acidified perdeuteromethanol.40 Because the attack of the resultant methylene on the aldehyde should form a hemiacetal, the first modifications of the reaction conditions reported by Chassaing et al.26,34 was the deliberate addition of 1 mM trifluoroacetic acid (TFA) to ensure the presence of an acid catalyst to favor the cyclization of the hemiacetal. In ethanol, TFA should be a much weaker acid than in water,45−48 by about 5 pK units, whereas the pKa of the methyl group of the cationic flavylium of DHMF should be increased by perhaps only about one pK unit.48 This should attenuate the effect of TFA on the initial deprotonation equilibrium of DHMF, while still allows it to act as an efficient acid catalyst in the subsequent dehydration−cyclization steps. The second modification was to employ a fourfold molar excess

2. RESULTS AND DISCUSSION As reported by Chassaing et al.,26,34,40 the reaction of the DHMF cation with electron-rich benzaldehydes such as pmethoxybenzaldehyde or p-dimethylaminobenzaldehyde proceeded smoothly in ethanol to produce the corresponding substituted pyranoflavylium ions in good overall yield and in an essentially pure form. However, in contrast to the results of Chassaing et al.26,34 for the hexafluorophosphate salt of DHMF, in our hands the chloride salt of DHMF also reacted quite well with benzaldehyde, 2-naphthaldehyde, and even with benzaldehydes containing electron-withdrawing substituents such as pcyanobenzaldehyde or p-nitrobenzaldehyde to yield the corresponding substituted pyranoflavylium cations. If this 955

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ACS Omega of the aldehyde to shift the second equilibrium in favor of the hemiacetal. The third modification was to conduct the reaction under an inert atmosphere during the first two hours of the reaction to delay the onset of the autoxidative aromatization of the dihydropyran intermediate to give the final pyranoflavylium ion. The addition of TFA solved two of the problems initially encountered in the reactions between DHMF and benzaldehydes with electron-withdrawing substituents such as 4nitrobenzaldehyde or 4-cyanobenzaldehyde, viz., somewhat erratic yields of the products and the incomplete reaction even after 24 h. Implementation of the other two modifications largely prevented the formation of the two principal side products produced in the reactions with aldehydes bearing electron-withdrawing substituents in the presence of TFA alone. One of these side products, with two additional hydrogen atoms in its structure (as detected by unit resolution mass spectrometry), was a presumably residual dihydropyran intermediate that had not yet undergone autoxidative aromatization. Because aromatic aldehydes are known to be excellent mediators of autoxidation upon exposure to air,49,50 this constituted an additional rationale for employing excess aldehyde in the reaction mixture. The other side product, which apparently conserved the flavylium chromophore, had four additional hydrogen atoms. Four of its hydrogen atoms were exchanged for deuterium in perdeuteromethanol, including two OH groups and two acidic methylene hydrogens adjacent to the flavylium chromophore. These observations suggested that this side product resulted from the reduction of the 4-arylvinyl intermediate (on the left in the brackets in Scheme 3) by adventitious radical species49,50 generated concurrently during the autoxidative aromatization step. Indeed, conducting the initial two hours of the reaction under an inert atmosphere to delay the onset of autoxidation until after cyclization to the dihydropyran intermediate had occurred nicely eliminated the significant formation of this second side product. In the product workup, excess aldehyde could be recovered by washing the product with ethyl ether after the removal of the solvent (ethanol) under vacuum. Because DHMF is highly soluble in aqueous solutions and all of the pyranoflavylium ions prepared thus far are only modestly soluble in water at best, the product purification was further improved by washing the final product with ice-cold dilute aqueous HCl to remove any residual DHMF. Although Chassaing et al.40 originally proposed a reaction pathway equivalent to that outlined in Scheme 3, they subsequently postulated26,34 the involvement of a specific charge-transfer interaction between DHMF and electron-rich benzaldehydes to rationalize the apparent lack of reaction with electron-poor benzaldehydes. Nonetheless, by implementing three modifications of their reaction conditions that are compatible with the mechanism in Scheme 3, we were able to extend the scope of the reaction to a wide range of substituted benzaldehydes, as well as to other types of aromatic aldehydes (Table 1). Consequently, the results of the present work suggest that such a charge-transfer interaction, though not necessarily excluded for electron-rich benzaldehydes, is clearly not the dominant factor controlling reactivity.

Table 1. Structures of the Starting Aldehydes and of the Corresponding Pyranoflavylium Cations and the Isolated Product Yields

a

Reference 34.

polycyclic aromatic rings, opening the way for studies of substituent and structural effects on the ground-state and excited-state acidities and other relevant properties such as redox potentials of these pyranoanthocyanin analogues. Because the substituted 7-hydroxyflavylium cations exhibit virtually all of the salient features of the chemistry and photochemistry of naturally occurring anthocyanin pigments, the behavior of these pyranoflavylium cations should mirror fundamental aspects of the chemistry and photophysics of the pyranoanthocyanin chromophores present in mature red wines.

4. EXPERIMENTAL SECTION 4.1. Materials and Methods. Product purity was confirmed by high-performance liquid chromatography photodiode array on a Promosil C18 column (4.6 mm × 150 mm, 5 μm) at 30 °C, eluting at 0.8 mL/min with a gradient of solvent A, 0.05% formic acid (Merck) in H2O, and solvent B, 0.05% formic acid (Fluka) in acetonitrile (Merck HPLC grade). The gradient employed was 15−100% solvent B from 0 to 20 min and 100% solvent B from 20 to 30 min. All compounds were characterized on the basis of 1H and 13C NMR spectra recorded at 500 and 128 MHz, respectively, and reported in parts per

3. CONCLUSIONS The procedure described here permits the relatively facile preparation of a wide variety of substituted pyranoflavylium cations, including those with attached heterocyclic and 956

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4.4. 5-[4-(Dimethylamino)phenyl]-8-hydroxy-2phenylpyrano[4,3,2-de]chromenium Chloride (1). Purple solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S2): δ 7.96 (d, J = 9 Hz, 2H), 7.74 (d, J = 9.3 Hz, 2H), 7.61 (m, 1H), 7.54 (m, 2H), 7.26 (s, 1H), 7.19 (s, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 9.3 Hz, 2H), 2.98 (s, 6H). HRMS (ESI-TOF in methanol, positive mode) m/z: [M − Cl−]+ calcd for C25H20NO3, 382.1443; found, 382.1437. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 352 (12 000), 552 nm(33 900). Lit. (as the hexafluorophosphate salt):26 1H NMR (300 MHz, MeCN/1% TFA-d1): δ 8.25−8.29 (m, 2H), 8.17−8.21 (m, 2H), 7.74−7.80 (m, 1H), 7.67−7.71 (m, 2H), 7.56−7.61 (m, 2H), 7.52 (s, 1H), 7.51 (s, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 3.28 (s, 6H). UV−vis (MeOH/5% 1 M HCl) λmax (ε, L mol−1 cm−1) 552 nm (44 200). 4.5. 8-Hydroxy-5-(4-methoxyphenyl)-2phenylpyrano[4,3,2-de]chromenium Chloride (2). Reddish-brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S3): δ 8.21 (m, 4H), 7.22 (s, 2H), 7.66 (m, 4H), 7.73 (m, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 3.95 (s, 3H). HRMS (ESI-TOF in methanol, positive mode) m/z: [M − Cl−]+ calcd for C24H17O4, 369.1127; found, 369.1125. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm −1 ) 372 (15 300), 478 nm (26 500). Lit. (as the hexafluorophosphate salt):26 1H NMR (300 MHz, MeCN/1% TFA-d1): δ 8.11−8.15 (m, 4H), 7.29 (s, 2H), 7.61−7.73 (m, 3H), 7.41 (s, 1H), 7.44 (s, 1H), 7.13−7.16 (m, 2H), 3.92 (s, 3H). UV−vis (MeOH/5% 1 M HCl) λmax (ε, L mol−1 cm−1) 372 (22 400), 478 nm (10 500). (Note: the λmax values coincide, but the ε values are reversed relative to ours). 4.6. 8-Hydroxy-5-(4-methylphenyl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (3). Yellow-brown solid. 1 H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S4): δ 8.22 (d, J = 7.7 Hz, 2H), 8.13 (d, J = 8.1 Hz, 2H), 7.71 (m, 5H), 7.49 (d, J = 8.1 Hz, 2H), 7.26 (br s, 2H), 2.49 (s, 3H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S4): δ 170.07, 169.53, 168.45, 155.42, 153.80, 147.56, 135.48, 131.69, 130.94, 129.05, 128.89, 117.33, 111.01, 110.11, 104.10, 103.66, 101.95, 21.98. HRMS (ESI-TOF, in methanol, positive mode) m/z: [M − Cl−]+ calcd for C24H17O3, 353.1178; found, 353.1166. UV− vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 362 (18 800), 446 (19 400), 466 nm (19 200). 4.7. 8-Hydroxy-2,5-diphenylpyrano[4,3,2-de]chromenium Chloride (4). Brown solid. 1 H NMR (MeOD/1% TFA-d1, 500 MHz): δ 8.23 (dd, J = 8.5, 1.3 Hz, 4H; Figure S5), 7.74 (s, 2H), 7.67 (m, 6H), 7.26 (br s, 2H). 13 C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S5): δ 169.81, 169.71, 155.05, 154.05, 135.58, 131.51, 130.97, 129.79, 128.97, 104.27, 102.03. HRMS (ESI-TOF in methanol, positive mode) m/z: [M − Cl−]+ calcd for C23H15O3, 339.1021; found, 339.1028. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 356 (16 200), 402 (12 400), 444 nm (15 200). 4.8. 8-Hydroxy-5-(4-fluorophenyl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (5). Brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S6): δ 8.32 (m, 2H), 8.25 (dd, J = 7.25, 1.3 Hz 2H), 7.78 (s, 1H), 7.75 (s, 1H), 7.69 (m, 3H), 7.43 (t, J = 8.7 Hz, 2H), 7.30 (d, J = 1.9 Hz, 1H), 7.29 (t, J = 1.9 Hz, 1H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S6): δ 169.88, 169.73, 168.75, 155.57, 155.47, 154.05, 135.61, 131.94, 131.86, 131.51, 131.20, 130.98, 128.98, 118.27, 118.09, 110.30, 104.27, 104.08, 102.06. HRMS (ESITOF, in methanol, positive mode) m/z: [M − Cl−]+ calcd for

million (ppm) downfield from the solvent methanol-d4 (MeOD; δ 3.31 for 1H NMR and δ 49.15 for 13C NMR; Sigma-Aldrich) containing 1% deutero TFA-d1 (SigmaAldrich). The signal of the residual water in methanol (δ 4.70 in the 1H NMR) was suppressed using the ZGPR pulse sequence. Multiplicities are indicated as s (singlet), br s (broad singlet), d (doublet), t (triplet), m (multiplet), and dd (double of doublets). After an initial check of purity by unit resolution mass spectrometry (Bruker amaZon SL ion trap), highresolution mass spectra (HRMS) were determined by electrospray ionization time of flight (ESI-TOF) at the Central ́ Analytical Facility of the Instituto de Quimica, USP (CA-IQUSP). UV−visible spectra were recorded on a HP8452A diode array spectrometer in spectroquality acetonitrile (Merck) containing 0.1 mM TFA as a function of solute concentration to ensure linearity of the Lambert−Beer relationship. 4.2. Preparation of DHMF Chloride. The flavylium salt, an orange solid, was prepared in 85% yield from the reaction of equimolar amounts of phloroglucinol and benzoylacetone in acetic acid at room temperature, as described by Chassaing et al.,26 modified by saturating the solution with gaseous HCl rather than employing HPF6 as the acid catalyst. After precipitation of the product by adding ethyl ether, subsequent washing with ethyl ether, and drying in vacuum, the identity of the crystalline product was confirmed by comparing the NMR spectra with those reported by Roehri-Stoeckel et al.40 in perdeuteromethanol and Chassaing et al.26 in acetonitrile-d3 and by HRMS (ESI-TOF, in methanol, positive ion mode) m/ z: [M − Cl−]+ calcd for C16H13O3, 253.0870; found, 253.0858. 1 H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S1): δ 8.36 (dd, J = 8.4, 1.1 Hz, 2H), 8.12 (s, 1H), 7.79 (m, 1H), 7.70 (m, 3H), 7.01 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H); 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S1): δ 172.80, 172.07, 169.26, 163.38, 160.61, 136.41, 131.18, 130.48, 129.77, 115.39, 114.60, 104.42, 96.83, (25.63?). The peaks due to the methyl group at C-4 are absent in the 1H NMR, as has been reported in the literature,40 and very weak (tentatively identified as the small peak at δ 25.62) in the 13C NMR because of the rapid exchange of the methyl hydrogens for deuterium in MeOH-d4. 4.3. General Procedure for the Condensation of DHMF Chloride with Aromatic Aldehydes (Scheme 3 and Table 1). The aromatic aldehyde (2 mmol or 4 equiv) was added to a solution of DHMF (0.144 g, 0.5 mmol) in 100 mL of ethanol (EtOH, Merck) containing 1 mM TFA (SigmaAldrich). Benzaldehyde and 4-dimethylaminobenzaldehyde were obtained from Merck; the remaining aromatic aldehydes were obtained from Sigma-Aldrich. The solution was heated at reflux under a nitrogen atmosphere for 2 h before opening to the atmosphere to initiate the autoxidative aromatization of the pyran ring. The progress of the reaction was monitored periodically by thin-layer chromatography (Sigma precoated silica gel plates with a 254 nm fluorescent indicator; developed with 2:5 or 4:5 ethyl acetate/heptane). When complete conversion was observed (generally 24 h heating was employed), the reaction mixture was cooled to room temperature and EtOH was removed under vacuum. The resulting residue was washed with diethyl ether (Synth, Brazil) to remove excess aromatic aldehyde, followed by ice-cold 0.001 M aqueous HCl to remove any traces of unreacted or partially reacted flavylium salt, to give the expected pyranoflavylium ions as chloride salts in a pure form. 957

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ACS Omega

154.70, 154.03, 149.39, 136.91, 135.84, 131.03, 129.13, 128.46, 126.02, 117.34, 115.08, 110.81, 105.15, 104.54, 102.30, 102.21. HRMS (ESI-TOF, in methanol, positive mode) m/z: [M − Cl−]+ calcd for C22H14NO3, 340.0974; found, 340.0974. UV− vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 360 (21 700), 452 nm (17 500). 4.14. 8-Hydroxy-5-(naphthalen-2-yl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (11). Red solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S12): δ 8.87 (br s, 1H), 8.25 (d, J = 7.5 Hz, 1H), 8.19 (dd, J = 8.9, 1.2 Hz, 1H), 8.12 (t, J = 9.3 Hz, 1H), 7.99 (m, 1H), 7.87 (s, 1H), 7.76 (m, 3H), 7.68 (m, 4H), 7.34 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S12): δ 180.39, 169.72, 169.69, 169.64, 159.61, 159.28, 158.95, 137.46, 135.55, 134.49, 131.55, 130.98, 130.88, 129.25, 129.00, 128.96, 128.59, 123.83, 119.60, 117.34, 115.08, 112.81, 104.56, 104.26, 102.08, 102.02. HRMS (ESI-TOF, in methanol, positive mode) m/z: [M − Cl−]+ calcd for C27H17O3, 389.1177; found, 389.1163. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 360 (10 600), 392 (10 400), 464 (14 200), 476 nm (14 500).

C23H14FO3, 357.0927; found, 357.0925. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 358 (15 900), 402 (12 800), 444 nm (15 500). 4.9. 8-Hydroxy-5-(4-cyanophenyl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (6). Brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S7): δ 8.40 (d, J = 8.5 Hz, 2H), 8.28 (d, J = 7.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.87 (s, 1H), 7.84 (s, 1H), 7.78 (m, 1H), 7.70 (m, 3H), 7.35 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S7): δ 170.58, 170.27, 167.02, 159.38, 158.83, 155.78, 155.47, 154.09, 135.87, 135.51, 134.53, 131.40, 131.04, 129.43, 129.15, 121.85, 118.83, 118.08, 114.32, 110.93, 110.55, 105.83, 104.66, 102.27. HRMS (ESITOF in methanol, positive mode) m/z: [M − Cl−]+ calcd for C24H14NO3, 364.0974; found, 364.0964. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 356 (20 700), 452 nm (16 000). 4.10. 8-Hydroxy-5-[(4-trifluoromethyl)phenyl]-2phenylpyrano[4,3,2-de]chromenium Chloride (7). Brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S8): δ 8.41 (d, J = 7.8 Hz, 2H), 8.26 (d, J = 7.6 Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H), 7.78 (m, 3H), 7.69 (m, 2H), 7.29 (br s, 2H); 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S8): δ 159.11, 158.77, 135.39, 135.04, 135.04, 131.30, 130.89, 130.78, 130.33, 129.21, 128.77, 127.50, 119.43, 117.17, 114.91, 112.65, 110.44, 104.93, 103.96. HRMS (ESI-TOF in methanol, positive mode) m/z: [M − Cl−]+ calcd for C24H14F3O3, 407.0900; found, 407.0876. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 354 (19 600), 402 (12 400), 446 nm (17 300). 4.11. 8-Hydroxy-5-(4-nitrophenyl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (8). Brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S9): δ 8.50 (d, J = 9.0 Hz, 2H), 8.46 (d, J = 9.0 Hz, 2H), 8.28 (d, J = 1.4 Hz, 2H), 7.88 (s, 1H), 7.84 (s, 1H), 7.78 (m, 1H), 7.70 (m, 2H), 7.34 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S9): δ 170.65, 170.47, 166.58, 160.25, 155.81, 155.48, 154.01, 153.82, 152.15, 135.91, 131.17, 131.05, 130.08, 129.74, 129.17, 125.69, 110.96, 106.14, 104.69, 102.34. HRMS (ESI-TOF, in methanol, positive mode) m/z: [M − Cl−]+ calcd for C23H14NO5, 384.0872; found, 384.0873. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 356 (20 600), 456 nm (16 000). 4.12. 8-Hydroxy-5-(3,4,5-trimethoxyphenyl)-2phenylpyrano[4,3,2-de]chromenium Chloride (9). Red solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S10): δ 8.23 (dd, J = 7.2, 1.6 Hz, 2H), 7.81 (s, 1H), 7.78 (m, 1H), 7.73 (m, 2H), 7.69 (br s, 1H), 7.65 (m, 1H), 7.52 (br s, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 4.01 (s, 6H), 3.93 (s, 3H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S10): δ 159.28, 158.95, 158.61, 155.43, 135.26, 131.65, 130.91, 128.72, 126.51, 119.60, 117.34, 115.08, 112.81, 106.67, 103.68, 103.66, 102.55, 61.59, 57.25, 56.79. HRMS (ESI-TOF, in methanol, positive mode) m/z: [M − Cl]+ calcd for C26H21O6, 429.1338; found, 429.1317. UV−vis (MeCN/0.1 mM TFA) λmax (ε, L mol−1 cm−1) 380 (12 900), 480 nm (23 200). 4.13. 8-Hydroxy-5-(pyridine-3-yl)-2-phenylpyrano[4,3,2-de]chromenium Chloride (10). Brown solid. 1H NMR (MeOD/1% TFA-d1, 500 MHz; Figure S11): δ 9.38 (dd, J = 2.3, 0.7 Hz, 1H), 8.87 (dd, J = 4.9, 1.5 Hz, 1H), 8.64 (ddd, J = 8.1, 2.3, 1.6 Hz, 1H), 8.28 (d, J = 0.9 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.73 (m, 5H), 7.33 (br s, 2H). 13C NMR (MeOD/1% TFA-d1, 125 MHz; Figure S11): δ 170.49, 170.14, 167.01, 159.28, 155.73, 155.48,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b01955. NMR spectra (1H and 13C) of all the compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: ++55-11-3091-2162 (F.H.Q.). ORCID

Renan Moraes Pioli: 0000-0002-8017-7417 Frank H. Quina: 0000-0003-2981-3390 Present Address ∥

National Institute of Biological Sciences, #7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China (M.Z.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the CNPq (F.H.Q. Universal grant 408181/ 2016-3), INCT-Catálise, and NAP-PhotoTech for the support, the CNPq for a research productivity fellowship (F.H.Q.), and CAPES for graduate fellowships (R.M.P., G.T.d.M.S., and C.P.d.S.). The Chinese undergraduate exchange students (L.L., S.Z., and M.Z.) from the Department of Pharmaceutical Science and Technology, Tianjin University, acknowledge fellowships from the Chinese Scholarship Council (CSC) under the auspices of the international cooperation agreement between Tianjin University and IQ-USP. Unit resolution mass spectrometrograms were graciously provided by the IQ-USP multiuser mass spectroscopy facility coordinated by Dr. Thiago C. Correra (FAPESP Process 2015/08539-1). The authors thank Dr. Erick L. Bastos, IQ-USP, for a critical reading of the manuscript.

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