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Article

High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach

by
Marco A. Obregón-Mendoza
1,
William Meza-Morales
1,
Yair Alvarez-Ricardo
1,
M. Mirian Estévez-Carmona
2 and
Raúl G. Enríquez
1,*,†
1
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Ciudad de México 04510, Mexico
2
Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu SN, U. A. Zacatenco, Ciudad de México 07738, Mexico
*
Author to whom correspondence should be addressed.
†
In fond memory of our colleague Dr. Xavier Lozoya-Legorreta, d. 9 November 2022.
Molecules 2023, 28(1), 289; https://doi.org/10.3390/molecules28010289
Submission received: 7 December 2022 / Revised: 23 December 2022 / Accepted: 27 December 2022 / Published: 30 December 2022
(This article belongs to the Special Issue Isolation, Identification and Application of Biologically Active Natural Products)
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Abstract

:
The worldwide known and employed spice of Asian origin, turmeric, receives significant attention due to its numerous purported medicinal properties. Herein, we report an optimized synthesis of curcumin and symmetric curcuminoids of aromatic (bisdemethoxycurcumin) and heterocyclic type, with yields going from good to excellent using the cyclic difluoro-boronate derivative of acetylacetone prepared by reaction of 2,4-pentanedione with boron trifluoride in THF (ca. 95%). The subsequent cleavage of the BF2 group is of significant importance for achieving a high overall yield in this two-step procedure. Such cleavage occurs by treatment with hydrated alumina (Al2O3) or silica (SiO2) oxides, thus allowing the target heptanoids obtained in high yields as an amorphous powder to be filtered off directly from the reaction media. Furthermore, crystallization instead of chromatographic procedures provides a straightforward purification step. The ease and efficiency with which the present methodology can be applied to synthesizing the title compounds earns the terms “click” and “unclick” applied to describe particularly straightforward, efficient reactions. Furthermore, the methodology offers a simple, versatile, fast, and economical synthetic alternative for the obtention of curcumin (85% yield), bis-demethoxycurcumin (78% yield), and the symmetrical heterocyclic curcuminoids (80–92% yield), in pure form and excellent yields.

Graphical Abstract

1. Introduction

Curcumin [(1,7-bis-(4-hydroxy-3-methoxy-phenyl)-1,6-heptadien-3,5-dione] [1,2], also known as diferuloylmethane, is a bioactive molecule found in the rhizome of the Curcuma longa Asian spice from Zingiberaceae family [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20] Chemically, curcumin is described as a typical Michael-type acceptor [21,22,23,24]. The worldwide scientific interest in this molecule is due to its broad therapeutic activities, which include its purported properties as an anticancer [25,26,27,28,29,30,31], antiangiogenic disease [32], antimetastatic [33], antioxidant [34,35,36], free radical scavenger [37], anti-inflammatory [38,39], antidepressant [40] and anti-Alzheimer’s disease agent [41,42,43,44,45].
The importance of having curcumin as a pure metabolite lies in expanding its complementary studies on its pharmacokinetics, pharmacodynamics, and toxicological studies [46], which help to understand the effects of this fascinating bioactive molecule in living systems. The research in chemical synthesis has been mainly directed to the preparation of derivatives [47,48] that help overcome its physicochemical properties [49] and rapid metabolism [27,42,50] and to increase its bioavailability [11,51].
Curcumin has a long historical pathway as a natural colorant [49,52,53,54] (E100), and curcumin’s chemistry began early in the 19th century. Curcumin was isolated in 1815 [9], and its crystallized form was known in 1870 [54]. Until early in the 20th century, the molecular formula of curcumin (C21H20O6) could be assessed by Miłobȩdzka, J. et al. in 1910 [55]. In the following years, Lampe [56] (1918), Pavolini [54] (1950), and Pabon [57] (1964) carried out a total synthesis of this molecule. The chemical structure was confirmed in 1973 [58], while studies of the keto-enol equilibrium [3,41,59,60,61], stability [62], and metabolic pathway [63,64,65] in vivo stand out as relatively recent findings.
Although separations of curcumin are reported in various investigations [8,10,13,66,67], its purification is a difficult task due to the presence of two closely related curcuminoids (i.e., demethoxycurcumin and bis-demethoxycurcumin [25,26,53,68,69]) due to co-crystallization phenomena. Furthermore, obtaining high-purity curcumin from natural sources is difficult since it involves repeated chromatographic and crystallization procedures.
In the methodologies developed for synthesizing curcumin, it was early recognized that protecting the α-diketone functionality is a critical step for the subsequent condensation of two vanillin molecules at the sidechain methyl groups. Thus, the well-known secondary Knoevenagel reaction on carbon C-1 is avoided [54]. In addition, adequate protection of the b-diketone function can be achieved through boron complexes using reagents such as boron trioxide [47,57,70], boric acid [58], and, more recently, boron trifluoride [71]. The approach named “click chemistry” is applied in the obtention of compounds following simple steps of joining small modular units [72]. In the present case, the protective reaction on the b-diketo function to give the BF2 derivative occurs with a high degree of efficiency, i.e., in a “click” fashion. Furthermore, the removal of the BF2 group occurs under equally simple conditions and high efficiency, allowing us to propose the term “unclick” for this reaction step.
The synthetic approach used in our work is adequate for obtaining the natural symmetric curcuminoids curcumin and bisdemethoxycurcumin, with a significant reduction of expensive chromatographic and crystallization steps. However, the other essential natural asymmetric demethoxycurcumin requires a somewhat different synthetic route, which is under investigation. Nevertheless, the method demonstrated robustness for synthesizing symmetric heterocyclic curcuminoids using the corresponding aldehydes. A convenient feature altogether is the economy of reagents and laboratory steps needed.

2. Results

Although the protection reaction of acetylacetone is commonly carried out with boron trifluoride etherate [73,74,75], its manipulation requires extreme caution [2]. A much safer alternative is found using boron trifluoride complex in THF (Scheme 1). Five advantages at least are introduced, i.e., (I) minimum release of toxic vapors from the container, (II) both high density (1.268 g/mL) and boiling point (180 °C) allows easier manipulation when measuring the required volumes; (III) the addition of the reagent to the reaction flask is carried out at room temperature; (IV): no violent reaction is observed upon addition of reagents and (V): the use of inert atmosphere does not seem critical for the reaction to proceed.
The synthesis of curcuminoids-BF2 has been previously reported in a one-pot reaction [76]. In our scaled-up approach (98 mmol), it was found convenient a stepwise procedure to overcome the bulk generation of HF, which promotes the formation of quaternary ammonium salts from n-butylamine. The isolation of a powdered product renders a rather convenient material for further workup. Thus, the BF2 derivatives can be advantageously manipulated and purified as solid starting materials, favoring cleaner and higher overall yields (see Table 1).
The high yields obtained in the aldol condensation reaction (Scheme 2) are explained by the following two reasons: (1) the precipitation of the condensed compound consequently produces a continuous consumption of the reactants in solution [76] and (2) the protection of acac through the use of BF3 is an approach that affords much better yields [77].
The crude product of the aldol condensation reaction to obtain curcumin-BF2 contains residues (see Figure 1) of n-butylamine and tributyl borate, which are easily removed after washing with a mixture of distilled water and acetone (10–20% acetone), see Figure 2.
One of the critical steps in the synthesis of curcuminoids (heptanoids) is the cleavage of the BF2 group to obtain 1,3-diketone form (or enol). Yields greater than 80% are reported when the BF2 group is hydrolyzed in several media (organics: MeOH/DMSO [76,78] and MeOH/DMSO/triethylamine or inorganics: diluted NaOH [73] and sodium oxalate [79]). However, the efficiency and reproducibility of reported procedures have been considered limited [73].
The removal of boron reaction by-products has been reported using inorganic salts [80] (e.g., aluminum sulfates and sodium aluminates) or silica, but efficient removal has been reported using amorphous Al2O3 [81]. This feedback has served to assay additional means that can catalyze the hydrolysis of the BF2 group through the use of three different metal-hydrated oxides (Scheme 3): SiO2 (silica) or Na12[(AlO2)12(SiO2)12]·xH2O (molecular sieves) or Al2O3 xH2O (alumina).
Initially, it was chosen to carry out the opening reactions catalyzed in silica using two different alcoholic solvents (ethanol and methanol). However, ethanol is more eco-friendly, and curcumin was obtained 72 h later in low yield (possibly due to the adsorption of curcumin to silica). Therefore, methanol was found more appropriate for removing the boron-difluoride moiety (Table 2).

3. Discussion

The synthesis of curcumin and curcuminoids has been carried out with three simple reaction steps: (1) protection of keto-enol functionality of acetylacetone (acac) by BF3·THF; (2) condensation of the corresponding aromatic aldehyde catalyzing with n-butylamine; (3) cleavage of the BF2 group by means of hydrated metal oxides. Curcumin, bis-demethoxycurcumin itself, and two heterocyclic curcuminoids were obtained with very good yields and were fully characterized by spectroscopic techniques.
In a general description, this procedure consists of three basic yet simple general steps: (a) a protective step (reaction of the 2,4-pentanedione with boron trifluoride avoiding the Knoevenagel secondary reaction) while activating the methyl groups promoting (b) the efficient aldol condensation and (c) the deprotecting reaction step removing the BF2 group and allowing the recovery of the original b-diketone function.
It suggested that the mechanism for the removal of the BF2 group is due to an anion exchange phenomenon involving the reaction of boron and the basic OH—group or water in agreement with previous mechanistic proposals [81,82], which are specifically adsorbed and are present at the surfaces of hydrated metal oxides [83,84,85]. A possible reaction mechanism is depicted in Scheme 4.
The proposal mechanism in step I is supported by Venkata [71], and steps II, III, and IV are supported by Weiss [73]. Adsorption and removal of the B(OH−)4 species are supported by previous references [80,81,82,83,84].
The integrity of the free curcuminoid on the aluminum oxides or under the reaction medium does not lead to decomposition since it is known that the breakdown of the BF2 generates HF [73], and the curcuminoids are relatively unaffected by pH from 2 to 7 [8]. Furthermore, greater boron adsorption by alumina occurs between pH 6 and 7 [81,86].
Our best yields in the obtention of curcumin were achieved using MeOH/Al2O3, probably associated with the more significant boron adsorption in acidic pH, though other authors associate boron adsorption with the presence of hydroxide ions present in alumina [86].
The 1H-NMR spectrum of curcumin (Figure 3) confirms the assigned structure, and characteristic signals of the vinyl protons (α,β-unsaturated, system AB) are present in the form of two doublets at 7.54 and 6.75 with coupling constants ca. 16 Hz (trans). Evidence for the keto-enol tautomerism is given by the signal observed at 16.47 ppm (enol) and the signal corresponding to the methine proton (CH) at 6.06 ppm. Additionally, the DEPT-135 spectrum (see Supplementary Material) shows no (CH2) methylene carbons; methines (CH) and methyl groups (CH3) are observed as positive signals and fit satisfactorily with data reported in the literature [59]. Similarly, the 1H-NMR spectra of all other symmetric curcuminoids show a consistent correlation between structure and spectral features (see Supplementary Material).
The mass spectrum (MS) of curcumin shows a characteristic peak at m/z = 368, which corresponds adequately to the molecular ion of curcumin and is consistent with the chemical formula C21H20O6. In addition, the spectrum shows a base peak with m/z = 177 representing the expected molecular fragment. Mass spectra of bis-demethoxycurcumin (6) m/z = 308, furan-curcumin (7) m/z = 256, and thiophene-curcumin (8) m/z = 288 show a consistent peak with the chemical formulas C19H16O4, C15H12O4, and C15H12O2S2, respectively (see Supplementary Material).
The present synthetic route was successfully extended for the obtention of other symmetrical curcuminoids (compounds 6–8) with 4-hidroxybenzaldehyde, furfural, and thiophenecarboxaldehyde. Thus, when 4-hidroxybenzaldehyde and furfural were used in the corresponding curcuminoid synthesis using a modified Pabon´s approach, the yields decreased significantly to a reported 33 and 8%, respectively [77,87].
Interestingly, the heterocyclic curcuminoid resulting from 2-thiophene carboxaldehyde (compound 4) afforded excellent yields (95%) in the aldol condensation reaction, while the cleavage of the BF2 group on MeOH/alumina afforded (compound 8) in 92% yield. This overall high yield is even higher than the corresponding one observed for curcumin.
The term “Click Chemistry” [88] has been adopted for curcumin synthesis based on three simple concepts: (I) reactions are broad in scope and give high yields; (II) starting reagents are readily available, and simple reaction conditions are needed, and (III) no chromatographic methods are required to purify curcumin and other symmetric curcuminoids. The term “Unclick” refers to the efficient removal of the protecting/activator group, namely BF2, which was also achieved in high yield.

4. Materials and Methods

Boron trifluoride.THF complex (CAS 462-34-0), silica gel high-purity grade, average pore size 60 Å (52–73 Å), 70–230 mesh, 63–200 μm, for column chromatography (CAS 112926-00-8), molecular sieves 4Å beads, 8–12 mesh (CAS 70955-01-0) and Alumina Brockmann III (1344-28-1) were purchased from Sigma-Aldrich and were used without prior activation or purification.
All chemicals were available commercially, and the solvents were purified with conventional methods before use [89].
Melting points were determined on an Electrothermal Engineering IA9100 digital melting point apparatus in open capillary tubes and were uncorrected [1,2].
1H and 13C NMR spectra were obtained in a Bruker Fourier 400 MHz spectrometer using TMS as an internal reference and CDCl3 or Acetone-d6, or DMSO-d6 as solvents. NMR spectra were processed with MestreNova software 12.0.0 [90] and are found in the Supplementary Materials.
Spectroscopic measurements. IR absorption spectra were recorded using an FT-IR Bruker Tensor 27 spectrophotometer in the range of 4000–400 cm−1 as KBr pellets [1,2] (see Supplementary Materials).
Mass Spectra were recorded using The MStation JMS-700 JEOL equipment (Electron Ionization, 70 eV, 250 °C, Impact positive mode and calibration standard with perfluorokerosene) and the AccuTOF JMS-T100LC JEOL equipment (DART+, 350 °C, positive ion mode and calibration standard with PEG 600) [1,2]. All mass spectra are shown in Supplementary Materials.
HPLC chromatograms were obtained using an Agilent 1260 infinity II with diode -UV detector at 425 nm, column Eclipse Plus C18(2) 100 × 2.0 mm 3 μm; eluting with a solvent gradient (previously described with minor modifications [70,91]) from acetonitrile/water (acetic acid 2%) 40:60 to acetonitrile/water (acetic acid 2%) 50:50 and are included in the Supplementary Materials.

4.1. Synthon Preparation

In a 250 mL round flask, 10 mL of 2,4-pentanodione (acac, 98 mmol) was dissolved in 30 mL of dichloromethane; subsequently, 11 mL of boron trifluoride tetrahydrofuran complex (BF3·THF, 98 mmol) was added to the solution, and the reaction was left overnight with magnetic stirring at room temperature. After, the organic phase was concentrated in vacuo affording the resulting product, which can be directly used for the following reaction step.
2,2-difluoro-4,6-dimethyl-2H-1,3,2-dioxaborinin-1-ium-2-uide (Synthon): yield 95%, solid amber, melting point 40 °C, 1H NMR (400 MHz, CDCl3, TMS): δ 5.96 (s, 1H, Methine-H), 2.27 (s, 6H, Methyl-H); 13C NMR (100 MHz, CDCl3, TMS): δ 192.63 (C=O), 102.12 (Cmethine-H), 24.32 (-CH3). IR (KBr) 1556 v(C=O, C=C), 1148 v(B-F, B-O), 1086 v(B-F, B-O)cm−1, DART+-MS: m/z (%) = 129 (148–19), m/z calc. = 148.

4.2. Condensation of Aldehydes with the Synthon

The curcuminoid-BF2 symmetric structure is obtained by an aldol condensation reaction under similar experimental conditions previously reported [71,73,74,75,76,77].

4.3. General Methodology

Mixture 1. In a 100 mL Erlenmeyer flask, 7.5 g of vanillin (49 mmol) was dissolved in 25 mL of EtOAc, 6.3 mL of tributyl borate (24.5 mmol) was added, and this mixture was heated until homogenization was achieved.
Mixture 2. In a 250 mL round flask, 4 g of synthon (1.1 eq, 27 mmol) was dissolved in 25 mL of EtOAc, and then the homogenous product 1 was added to the solution; then, 2.7 mL of N-butylamine (27 mmol, in 10 mL of EtOAc) was added dropwise. The reaction was left overnight with magnetic stirring at room temperature. Finally, a solid red precipitate was filtered-off and washed with a mixture of 50 mL water/acetone 90::10. This same methodology (same molar amounts) was carried out to synthesize the symmetrical curcuminoids-BF2.
Spectral data of Curcumin-BF2 (1): 2,2-difluoro-4,6-bis((E)-4-hydroxy-3-methoxystyryl)-2H-1,3,2-dioxaborinin-1-ium-2-uide, yield 90%, red solid, melting point 230 °C, 1H NMR (400 MHz, DMSO-d6, TMS): δ 10.10 (s, 2H,-OH), 7.92 (d, J = 15.6 Hz, 2H, Vinyl-H), 7.47 (d, J = 1.8 Hz, 2H, Aryl-H), 7.34 (dd, J = 8.3 Hz, 2H, Aryl-H), 7.02 (d, J = 15.6 Hz, 2H, Vinyl-H), 6.88 (d, J = 8.2 Hz, 2H, Aryl-H), 6.45 (s, 1H, Methine-H), 3.85 (s, 6H, -OCH3); 13C NMR (100 MHz, DMSO-d6, TMS): δ 178.72 (C=O), 151.34 (C-OH), 148.17 (Caryl), 146.97 (Cvinyl-H), 125.99 (Caryl), 125.26 (Caryl-H), 117.86 (Cvinyl-H), 115.95 (Caryl-H), 112.39 (Caryl-H), 101.12 (Cmethine-H), 55.76 (-OCH3). IR (KBr) 3482 v(-OH), 1615 v(C=O), 1586 v(C=C), 1509 v(C=O, C=C), 1146 v(B-F, B-O) cm−1, DART+-MS: m/z = 397 (416–19), m/z calc. = 416.
4-hydroxy-curcuminoid-BF2 (2) 2,2-difluoro-4,6-bis((E)-4-hydroxystyryl)-2H-1,3,2-dioxaborinin-1-ium-2-uide, yield 85%, red powder, melting point 225 °C, 1H NMR (400 MHz, Acetone-d6, TMS): δ 9.29 (br, 2H, -OH), 7.96 (d, J = 15.6 Hz, 2H, Vinyl-H), 7.73 (m, 4H, Aryl-H), 6.97 (m, 4H, Aryl-H), 6.90 (d, J = 15.6 Hz, 2H, Vinyl-H), 6.39 (s, 1H, Methine-H ); 13C NMR (100 MHz, Acetone-d6, TMS): δ 180.81 (C=O), 162.16 (C-OH), 147.35 (Cvinyl-H), 132.67 (Caryl-H), 127.27 (Caryl), 118.96 (Cvinyl-H), 117.15 (Caryl-H), 102.20 (Cmethine-H). IR (KBr) 3422 v(-OH), 1598 v(C=O), 1579 v(C=C), 1518 v(C=O, C=C), 1147 v(B-F, B-O) cm−1, EI-MS: m/z = no observed, m/z calc. = 356.
Furan-curcuminoid-BF2 (3) 2,2-difluoro-4,6-bis((E)-2-(furan-2-yl)vinyl)-2H-1,3,2-dioxaborinin-1-ium-2-uide, yield 80%, red powder, melting point 200 °C, 1H NMR (400 MHz, CDCl3, TMS): δ 7.64 (d, J = 15.15, 2H, Vinyl-H), 7.51 (d, J = 1.74, 2H, Aryl-H), 6.75 (d, J = 3.49, 2H, Aryl-H), 6.51 (d, J = 15.22, 2H, Vinyl-H), 6.47 (dd, J = 3.51, 1.77, 2H, Aryl-H), 5.96 (s, 1H, Methine-H); 13C NMR (100 MHz, CDCl3, TMS): δ 178.98 (C=O), 151.01 (Caryl), 146.78 (Caryl-H), 131.91 (Cvinyl-H), 119.04 (Caryl-H), 117.95 (Cvinyl-H), 113.37 (Caryl-H),102.34 (Cmethine-H). IR (KBr) 1619 v(C=O), 1569 v(C=O, C=C), 1455 v(C-H), 1385 v(C-H), 1276 v(C-O), 1067 v(B-F, B-O) cm−1, DART+-MS: m/z = 305 (304 + 1), m/z calc. = 304.
Thiophene-curcuminoid-BF2 (4) 2,2-difluoro-4,6-bis((E)-2-(thiophen-2-yl)vinyl)-2H-1,3,2-dioxaborinin-1-ium-2-uide, yield 95%, violet powder, melting point 270 °C, 1H NMR (400 MHz, Acetone-d6, TMS): δ 8.20 (d, J = 15.38, 2H, Vinyl-H), 7.84 (d, J = 5.10, 2H, Aryl-H), 7.73 (d, J = 3.70, 2H, Aryl-H), 7.26 (dd, J = 5.05; 3.69, 2H, Aryl-H), 6.79 (d, J = 15.38, 2H, Vinyl-H), 6.51 (s, 1H, Methine-H); 13C NMR (100 MHz, Acetone-d6, TMS): δ 180.71 (C=O), 140.92 (Caryl), 139.92 (Cvinyl-H), 135.63 (Caryl-H), 133.32 (Caryl-H), 130.14 (Caryl-H), 120.67 (Cvinyl-H), 102.81(Cmethine-H). IR (KBr) 1594 v(C=O), 1541 v(C=O), 1494 (C=C), 1411(-C=Cring), 1291 v(C-O), 1152 v(B-F, B-O) cm−1, DART+-MS: m/z = 317 (336–19), m/z calc. = 336.

4.4. Reaction Conditions for “Unclick” Removal of the BF2 Group

In a 500 mL round flask, 10 g of curcuminoid-BF2 was dissolved in 400 mL of methanol (MeOH), 20% weight of metal oxide (catalyst) was added to the solution, and the mixture was left overnight under magnetic stirring at reflux. The reaction was quenched by filtration using a sintered glass funnel packed with celite. MeOH was evaporated in vacuo, and reaction crude was extracted with 150 mL of EtOAc (ethyl acetate) and water (3 × 100 mL). The organic phase was dried with Na2SO4 and concentrated in vacuo to afford the curcuminoid product, which was purified by recrystallization using EtOAc and hexane. The yields obtained for the synthesis of curcumin with several catalyzers were as follows: silica (70%), molecular sieves (80%) and alumina (85%). This same methodology (same amounts) was carried out for the synthesis of symmetrical curcuminoids (compounds 6–8).
Curcumin (5) 1,7-bis-(4-hydroxy-3-methoxy-phenyl)-1,6-heptadien-3,5-dione, yellow-orange powder, purified by recrystallization using EtOAc and hexane, purity by HPLC 99.48%, melting point 180 °C, 1H NMR (400 MHz, DMSO-d6, TMS): δ 16.47 (br, 1H, Enol-H), 9.66 (br, 2H, -OH), 7.55 (d, J = 15.8 Hz, 2H, Vinyl-H), 7.32 (d, J = 1.89 Hz, 2H, Aryl-H), 7.15 (dd, J = 8.2; 1.93 Hz, 2H, Aryl-H), 6.82 (d, J = 8.13 Hz, 2H, Aryl-H), 6.75 (d, J = 15.81 Hz, 2H, Vinyl-H), 6.06 (s, 1H, Methine-H), 3.84 (s, 6H, -OCH3); 13C NMR (100 MHz, DMSO-d6, TMS): δ 183.22 (C=O), 149.36 (C-OH), 148.00 (Caryl), 140.72 (Cvinyl-H), 126.34 (Caryl), 123.14 (Caryl-H), 121.10 (Cvinyl-H), 115.70 (Caryl-H), 111.33 (Caryl-H), 100.85 (Cmethine-H), 55.69 (-OCH3). IR (KBr) 3506 v(OH), 1628 v(C=O), 1602 v(C=Cring), 1509 v(C=O, C=C), 1428 v(C-Ophenol), 1281 v(C-Oenol), 1154 v(C-O), 1028 v(=C-O-CH3) cm−1, EI-MS: m/z = 368, m/z calc. = 368.
Bis-demethoxycurcumin (6) 1,7-bis(4-hydroxyphenyl)-1,6-heptadien-3,5-dione, red-orange powder, purified by recrystallization using CH2Cl2 and MeOH, purity by HPLC 99.45%, melting point 215 °C, 1H NMR (400 MHz, Acetone-d6, TMS): δ 9.24 (br, 2H,-OH), 7.60 (d, J = 15.8 Hz, 2H, Vinyl-H), 7.55 (m, 4H, Aryl-H), 6.90 (m, 4H, Aryl-H), 6.66 (d, J = 15.8 Hz, 2H, Vinyl-H), 5.99 (s, 1H, Methine-H); 13C NMR (100 MHz, Acetone-d6, TMS): δ 184.57 (C=O), 160.77 (C-OH), 141.19 (Cvinyl-H), 131.03 (Caryl-H), 127.58 (Caryl), 121.98 (Cvinyl-H), 116.86 (Caryl-H), 101.78 (Cmethine-H). IR (KBr) 3232 v(OH), 1622 v(C=O), 1599 v( C=O), 1513 v(C=O, C=C), 1444 v(OH), 1276 v(C-Oenol), 1140 v(C-O)cm−1, EI-MS: m/z = 308, m/z calc. = 308.
Furan-curcuminoid (7) 1,7-di(furan-2-yl)-5-hydroxyhepta-1,4,6-trien-3-one, brown powder, purified by recrystallization using EtOAc and hexane, purity by HPLC 99.33%, melting point 130 °C, 1H NMR (400 MHz, DMSO-d6, TMS): δ 16.06 (br, 1H, Enol-H), 7.87 (d, J = 1.70, 2H, Aryl-H), 7.45 (d, J = 15.71, 2H, Vinyl-H), 6.96 (d, J = 3.37, 2H, Aryl-H), 6.66 (dd, J = 3.43; 1.68, 2H, Aryl-H), 6.57 (d, J = 15.71, 2H, Vinyl-H), 6.19 (s, 1H, Methine-H); 13C NMR (100 MHz, DMSO-d6, TMS): δ 182.48 (C=O), 151.02 (Caryl), 146.12 (Caryl-H), 126.94 (Cvinyl-H), 121.18 (Cvinyl-H), 116.15 (Caryl-H), 113.03 (Caryl-H), 101.98 (Cmethine-H). IR (KBr) 3124 v(C=Cring), 1628 v(C=O), 1563 v(C=O, C=C), 1468 v(C=Cring), 1262 v(C-Oenol), 1139 v(C-O), 962 v(C-C=C) cm−1, EI-MS: m/z = 256, m/z calc. = 256.
Thiophene-curcuminoid (8) 1,7-di(thiophen-2-yl)-5-hydroxyhepta-1,4,6-trien-3-one, yellow powder, purified by recrystallization using acetone and hexane, purity by HPLC 98.68%, melting point 184 °C, 1H NMR (400 MHz, DMSO-d6, TMS): δ 16.07 (br, 1H, Enol-H), 7.81 (d, J = 15.71, 1H, Vinyl-H), 7.75 (d, J = 5.04, 2H, Aryl-H), 7.54 (d, J = 3.31, 2H, Aryl-H), 7.17 (dd, J = 5.04; 3.60, 2H, Aryl-H), 6.56 (d, J = 15.64, 2H, Vinyl-H), 6.19 (s, 1H, Methine-H); 13C NMR (100 MHz, DMSO-d6, TMS): δ 182.52 (C=O), 139.83 (Caryl), 133.23 (Cvinyl-H), 132.06 (Caryl-H), 130.06 (Caryl-H), 128.76 (Caryl-H), 122.70 (Cvinyl-H), 101.52 (Cmethine-H). IR (KBr) 3102 v(C=Cring), 1619 v(C=O), 1565 (C=O, C=C), 1505 v(C-O), 1418 v(C-OH), 964 (C-C=C) cm−1, EI-MS: m/z = 288, m/z calc. = 288.

5. Conclusions

Using simple high-yield steps, we contribute with a laboratory-scale strategy to obtain curcumin and symmetric curcuminoids. As a result, it can provide significant quantities of these compounds for physicochemical, analytical, and biological assay studies. This synthetic route is appropriate for using different aldehydes to obtain the corresponding symmetric curcuminoids. Due to the accessibility of this simple three-step synthetic approach, the method offers excellent potential for making available curcumin and symmetric curcuminoids on a large scale. The benefits of the present synthesis widen the perspectives for expanding the scientific studies concerning the fascinating molecular structures of curcuminoids and their widely recognized biological effects.

6. Patents

An application for a patent is underway in the country of the authors.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28010289/s1, Figures S1–S71: High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach.

Author Contributions

Conceptualization, R.G.E. and M.A.O.-M.; methodology, R.G.E. and. M.A.O.-M.; validation, R.G.E.; formal analysis, M.A.O.-M., W.M.-M., Y.A.-R., M.M.E.-C. and R.G.E.; investigation, M.A.O.-M., W.M.-M., Y.A.-R. and M.M.E.-C.; resources, R.G.E.; data curation, R.G.E., M.A.O.-M.; writing—original draft preparation, M.A.O.-M. and R.G.E.; writing—review and editing M.A.O.-M. and R.G.E.; supervision R.G.E.; project administration, R.G.E.; funding acquisition, R.G.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by CONACyT FOINS-PRONACES, grant number 307152, and DGAPA, PAPIIT, UNAM, grant number IT200720.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Raúl G. Enríquez acknowledges support from CONACyT (FOINS-PRONACES-307152) and DGAPA-UNAM (IT200720). Marco A. Obregón-Mendoza, William Meza-Moprales, and Yair Alvarez-Ricardo acknowledge honorary payment from CONACyT (FOINS-PRONACES-307152). Acknowledgments are extended to MSc. Elizabeth Huerta (NMR), Dra. Adriana Romo (IR), and Dra. María del Carmen García (MS), MSc. Eréndira García Ríos (HPLC) and MSc. Lucero Ríos (HPLC).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of compounds 1–8 are available from the authors.

References

  1. Meza-Morales, W.; Machado-Rodriguez, J.C.; Alvarez-Ricardo, Y.; Obregón-Mendoza, M.A.; Nieto-Camacho, A.; Toscano, R.A.; Soriano-García, M.; Cassani, J.; Enríquez, R.G. A new family of homoleptic copper complexes of curcuminoids: Synthesis, characterization and biological properties. Molecules 2019, 24, 910. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Obregón-Mendoza, M.A.; Arias-Olguín, I.I.; Estévez-Carmona, M.M.; Meza-Morales, W.; Alvarez-Ricardo, Y.; Toscano, R.A.; Arenas-Huertero, F.; Cassani, J.; Enríquez, R.G. Non-Cytotoxic Dibenzyl and Difluoroborate Curcuminoid Fluorophores Allow Visualization of Nucleus or Cytoplasm in Bioimaging. Molecules 2020, 25, 3205. [Google Scholar] [CrossRef] [PubMed]
  3. Srivastava, S.; Gupta, P.; Singh, R.P.; Jafri, A.; Arshad, M.; Banerjee, M. Synthesis, spectroscopic characterization, theoretical study and anti-hepatic cancer activity study of 4-(1E,3Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-1,3,6-trien-1-yl)-2-methoxyphenyl 4-nitrobenzoate, a novel curcumin congener. J. Mol. Struct. 2017, 1141, 678–686. [Google Scholar] [CrossRef]
  4. Mapoung, S.; Mapoung, S.; Suzuki, S.; Fuji, S.; Naiki-Ito, A.; Kato, H.; Yodkeeree, S.; Yodkeeree, S.; Sakorn, N.; Sakorn, N.; et al. Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo. Molecules 2020, 25, 2737. [Google Scholar] [CrossRef]
  5. Chignell, C.F.; Bilski, P.; Reszka, K.J.; Motten, A.G.; Sik, R.H.; Dahl, T.A. Spectral and Photochemical Properties of Curcumin. Photochem. Photobiol. 1994, 59, 295–302. [Google Scholar] [CrossRef]
  6. Sumanont, Y.; Murakami, Y.; Tohda, M.; Vajragupta, O.; Watanabe, H.; Matsumoto, K. Effects of manganese complexes of curcumin and diacetylcurcumin on kainic acid-induced neurotoxic responses in the rat hippocampus. Biol. Pharm. Bull. 2007, 30, 1732–1739. [Google Scholar] [CrossRef] [Green Version]
  7. Parameswari, A.R.; Devipriya, B.; Jenniefer, S.J.; Muthiah, P.T.; Kumaradhas, P. Low temperature crystal structure of 5-hydroxy-1,7-bis-(4-hydroxy-3-Methoxy-phenyl)-hepta-1,6-dien-3-one. J. Chem. Crystallogr. 2012, 42, 227–231. [Google Scholar] [CrossRef]
  8. Price, L.C.; Buescher, R.W. Kinetics of alkaline degradation of the food pigments curcumin and curcuminoids. J. Food Sci. 1997, 62, 267–269. [Google Scholar] [CrossRef]
  9. Shehzad, A.; Lee, Y.S. Curcumin: Multiple molecular targets mediate multiple pharmacological actions—A review. Drugs Future 2010, 35, 113–119. [Google Scholar] [CrossRef]
  10. Feng, L.; Li, Y.; Song, Z.F.; Li, H.J.; Huai, Q.Y. Synthesis and biological evaluation of curcuminoid derivatives. Chem. Pharm. Bull. 2015, 63, 873–881. [Google Scholar] [CrossRef]
  11. Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: Problems and promises. Mol. Pharm. 2007, 4, 807–818. [Google Scholar] [CrossRef] [PubMed]
  12. Kumar, B.; Singh, V.; Shankar, R.; Kumar, K.; Rawal, R. Synthetic and medicinal prospective of structurally modified curcumins. Curr. Top. Med. Chem. 2016, 16, 1–14. [Google Scholar] [CrossRef]
  13. Ramirez-Ahumada, M.d.C.; Timmermann, B.N.; Gang, D.R. Biosynthesis of curcuminoids and gingerols in turmeric (Curcuma longa) and ginger (Zingiber officinale): Identification of curcuminoid synthase and hydroxycinnamoyl-CoA thioesterases. Phytochemistry 2006, 67, 2017–2029. [Google Scholar] [CrossRef] [PubMed]
  14. Zamrus, S.N.H.; Akhtar, M.N.; Yeap, S.K.; Quah, C.K.; Loh, W.S.; Alitheen, N.B.; Zareen, S.; Tajuddin, S.N.; Hussin, Y.; Shah, S.A.A. Design, synthesis and cytotoxic effects of curcuminoids on HeLa, K562, MCF-7 and MDA-MB-231 cancer cell lines. Chem. Cent. J. 2018, 12, 31. [Google Scholar] [CrossRef]
  15. Jacob, J.N. Comparative studies in relation to the structure and biochemical properties of the active compounds in the volatile and nonvolatile fractions of turmeric (C. longa) and ginger (Z. officinale). Stud. Nat. Prod. Chem. 2016, 48, 101–135. [Google Scholar]
  16. Lin, L.; Lee, K.H. Structure-activity relationships of curcumin and its analogs with different biological activities. Stud. Nat. Prod. Chem. 2006, 33, 785–812. [Google Scholar]
  17. Banuppriya, G.; Sribalan, R.; Padmini, V. Synthesis and characterization of curcumin-sulfonamide hybrids: Biological evaluation and molecular docking studies. J. Mol. Struct. 2018, 1155, 90–100. [Google Scholar] [CrossRef]
  18. Medigue, N.E.H.; Bouakouk-Chitti, Z.; Bechohra, L.L.; Kellou-Taïri, S. Theoretical study of the impact of metal complexation on the reactivity properties of Curcumin and its diacetylated derivative as antioxidant agents. J. Mol. Model. 2021, 27, 192. [Google Scholar] [CrossRef]
  19. Banerjee, S.; Chakravarty, A.R. Metal complexes of curcumin for cellular imaging, targeting, and photoinduced anticancer activity. Acc. Chem. Res. 2015, 48, 2075–2083. [Google Scholar] [CrossRef]
  20. Obregón-Mendoza, M.A.; Estévez-Carmona, M.M.; Hernández-Ortega, S.; Soriano-García, M.; Ramírez-Apan, M.T.; Orea, L.; Pilotzi, H.; Gnecco, D.; Cassani, J.; Enríquez, R.G. Retro-curcuminoids as mimics of dehydrozingerone and curcumin: Synthesis, NMR, X-ray, and cytotoxic activity. Molecules 2017, 22, 33. [Google Scholar] [CrossRef] [Green Version]
  21. Gupta, S.C.; Prasad, S.; Kim, J.H.; Patchva, S.; Webb, L.J.; Priyadarsini, I.K.; Aggarwal, B.B. Multitargeting by curcumin as revealed by molecular interaction studies. Nat. Prod. Rep. 2011, 28, 1937–1955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Li, W.; Wu, W.; Yu, F.; Huang, H.; Liang, X.; Ye, J. Catalytic asymmetric Michael addition with curcumin derivative. Org. Biomol. Chem. 2011, 9, 2505–2511. [Google Scholar] [CrossRef] [PubMed]
  23. Ayyagari, N.; Jose, D.; Mobin, S.M.; Namboothiri, I.N.N. Stereoselective construction of carbocycles and heterocycles via cascade reactions involving curcumins and nitroalkenes. Tetrahedron Lett. 2011, 52, 258–262. [Google Scholar] [CrossRef]
  24. Ayyagari, N.; Namboothiri, I.N.N. Diastereo- and enantioselective synthesis of densely functionalized cyclohexanones via double Michael addition of curcumins with nitroalkenes. Tetrahedron Asymmetry 2012, 23, 605–610. [Google Scholar] [CrossRef]
  25. Urošević, M.; Nikolić, L.; Gajić, I.; Nikolić, V.; Dinić, A.; Miljković, V. Curcumin: Biological activities and modern pharmaceutical forms. Antibiotics 2022, 11, 135. [Google Scholar] [CrossRef] [PubMed]
  26. Ravindran, J.; Prasad, S.; Aggarwal, B.B. Curcumin and cancer cells: How many ways can curry kill tumor cells selectively? AAPS J. 2009, 11, 495–510. [Google Scholar] [CrossRef] [PubMed]
  27. Devassy, J.G.; Nwachukwu, I.D.; Jones, P.J.H. Curcumin and cancer: Barriers to obtaining a health claim. Nutr. Rev. 2015, 73, 155–165. [Google Scholar] [CrossRef]
  28. Jalili-Nik, M.; Soltani, A.; Moussavi, S.; Ghayour-Mobarhan, M.; Ferns, G.A.; Hassanian, S.M.; Avan, A. Current status and future prospective of Curcumin as a potential therapeutic agent in the treatment of colorectal cancer. J. Cell. Physiol. 2018, 233, 6337–6345. [Google Scholar] [CrossRef]
  29. Zoi, V.; Galani, V.; Lianos, G.D.; Voulgaris, S.; Kyritsis, A.P.; Alexiou, G.A. The role of curcumin in cancer treatment. Biomedicines 2021, 9, 1086. [Google Scholar] [CrossRef]
  30. Kong, W.Y.; Ngai, S.C.; Goh, B.H.; Lee, L.H.; Htar, T.T.; Chuah, L.H. Is curcumin the answer to future chemotherapy cocktail? Molecules 2021, 26, 4329. [Google Scholar] [CrossRef]
  31. Badreldin, H.; Marrif, H.; Noreldayem, S.A.; Bakheit, A.O.; Blunden, G. Some biological properties of curcumin: A review. Nat. Prod. Commun. 2006, 1, 509–521. [Google Scholar]
  32. Sanphui, P.; Bolla, G. Curcumin, a Biological Wonder Molecule: A Crystal Engineering Point of View. Cryst. Growth Des. 2018, 18, 5690–5711. [Google Scholar] [CrossRef]
  33. Bandyopadhyay, D. Farmer to pharmacist: Curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer. Front. Chem. 2014, 2, 113. [Google Scholar] [CrossRef]
  34. Mishra, S.; Palanivelu, K. The effect of curcumin (turmeric) on Alzheimer’s disease: An overview. Ann. Indian Acad. Neurol. 2008, 11, 13–19. [Google Scholar] [CrossRef]
  35. Boarescu, P.M.; Boarescu, I.; Bocșan, I.C.; Gheban, D.; Bulboacă, A.E.; Nicula, C.; Pop, R.M.; Râjnoveanu, R.M.; Bolboacă, S.D. Antioxidant and anti-inflammatory effects of curcumin nanoparticles on drug-induced acute myocardial infarction in diabetic rats. Antioxidants 2019, 8, 504. [Google Scholar] [CrossRef] [Green Version]
  36. Hussain, H.; Ahmad, S.; Shah, S.W.A.; Ullah, A.; Rahman, S.U.; Ahmad, M.; Almehmadi, M.; Abdulaziz, O.; Allahyani, M.; Alsaiari, A.A.; et al. Synthetic mono-carbonyl curcumin analogues attenuate oxidative stress in mouse models. Biomedicines 2022, 10, 2597. [Google Scholar] [CrossRef]
  37. Ak, T.; Gülçin, I. Antioxidant and radical scavenging properties of curcumin. Chem. Biol. Interact. 2008, 174, 27–37. [Google Scholar] [CrossRef]
  38. Ghosh, S.; Banerjee, S.; Sil, P.C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem. Toxicol. 2015, 83, 111–124. [Google Scholar] [CrossRef]
  39. Witika, B.A.; Makoni, P.A.; Matafwali, S.K.; Mweetwa, L.L.; Shandele, G.C.; Walker, R.B. Enhancement of biological and pharmacological properties of an encapsulated polyphenol: Curcumin. Molecules 2021, 26, 4244. [Google Scholar] [CrossRef]
  40. Hussain, H.; Ahmad, S.; Shah, S.W.A.; Ullah, A.; Almehmadi, M.; Abdulaziz, O.; Allahyani, M.; Alsaiari, A.A.; Halawi, M.; Alamer, E. Investigation of antistress and antidepressant activities of synthetic curcumin analogues: Behavioral and biomarker approach. Biomedicines 2022, 10, 2385. [Google Scholar] [CrossRef]
  41. Hussain, H.; Ahmad, S.; Shah, S.W.A.; Ullah, A.; Ali, N.; Almehmadi, M.; Ahmad, M.; Khalil, A.A.K.; Jamal, S.B.; Ahmad, H.; et al. Attenuation of scopolamine-induced amnesia via cholinergic modulation in mice by synthetic curcumin analogs. Molecules 2022, 27, 2468. [Google Scholar] [CrossRef]
  42. Ahmed, T.; Gilani, A.H. Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia may explain medicinal use of turmeric in Alzheimer’s disease. Pharmacol. Biochem. Behav. 2009, 91, 554–559. [Google Scholar] [CrossRef] [PubMed]
  43. Sato, T.; Hotsumi, M.; Makabe, K.; Konno, H. Design, synthesis and evaluation of curcumin-based fluorescent probes to detect Aβ fibrils. Bioorganic Med. Chem. Lett. 2018, 28, 3520–3525. [Google Scholar] [CrossRef] [PubMed]
  44. Chainoglou, E.; Hadjipavlou-Litina, D. Curcumin in health and diseases: Alzheimer’s disease and curcumin analogues, derivatives, and hybrids. Int. J. Mol. Sci. 2020, 21, 1975. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Amalraj, A.; Pius, A.; Gopi, S.; Gopi, S. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives: A review. J. Tradit. Complement. Med. 2017, 7, 205–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Soleimani, V.; Sahebkar, A.; Hosseinzadeh, H. Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review. Phyther. Res. 2018, 32, 985–995. [Google Scholar] [CrossRef]
  47. Basile, V.; Ferrari, E.; Lazzari, S.; Belluti, S.; Pignedoli, F.; Imbriano, C. Curcumin derivatives: Molecular basis of their anti-cancer activity. Biochem. Pharmacol. 2009, 78, 1305–1315. [Google Scholar] [CrossRef] [Green Version]
  48. Rodrigues, F.C.; Anil Kumar, N.V.; Thakur, G. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review. Eur. J. Med. Chem. 2019, 177, 76–104. [Google Scholar] [CrossRef]
  49. Jha, N.N.; Ghosh, D.; Das, S.; Anoop, A.; Jacob, R.S.; Singh, P.K.; Ayyagari, N.; Namboothiri, I.N.N.; Maji, S.K. Effect of curcumin analogs on α-synuclein aggregation and cytotoxicity. Sci. Rep. 2016, 6, 28511. [Google Scholar] [CrossRef] [Green Version]
  50. Sohn, S.; Priya, A.; Balasubramaniam, B.; Muthuramalingam, P. Biomedical Applications and Bioavailability of Curcumin—An Updated Overview. Pharmaceutics 2021, 13, 2102. [Google Scholar] [CrossRef]
  51. Linder, B.; Köhler, L.H.F.; Reisbeck, L.; Menger, D.; Subramaniam, D.; Herold-Mende, C.; Anant, S.; Schobert, R.; Biersack, B.; Kögel, D. A new pentafluorothio-substituted curcuminoid with superior antitumor activity. Biomolecules 2021, 11, 947. [Google Scholar] [CrossRef] [PubMed]
  52. Wanninger, S.; Lorenz, V.; Subhan, A.; Edelmann, F.T. Metal complexes of curcumin—Synthetic strategies, structures and medicinal applications. Chem. Soc. Rev. 2015, 44, 4986–5002. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Scotter, M.J. Synthesis and chemical characterisation of curcuminoid colouring principles for their potential use as HPLC standards for the determination of curcumin colour in foods. LWT—Food Sci. Technol. 2009, 42, 1345–1351. [Google Scholar] [CrossRef]
  54. Esatbeyoglu, T.; Huebbe, P.; Ernst, I.M.A.; Chin, D.; Wagner, A.E.; Rimbach, G. Curcumin-from molecule to biological function. Angew. Chem. Int. Ed. 2012, 51, 5308–5332. [Google Scholar] [CrossRef] [PubMed]
  55. Miłobȩdzka, J.V.; Kostanecki, S.; Lampe, V. Zur Kenntnis des Curcumins. Ber. Dtsch. Chem. Ges. 1910, 43, 2163–2170. [Google Scholar] [CrossRef] [Green Version]
  56. Lampe, V. Synthese von Curcumin. Ber. Dtsch. Chem. Ges. 1918, 51, 1347–1355. [Google Scholar] [CrossRef] [Green Version]
  57. Pabon, H.J.J. A synthesis of curcumin and related compounds. Recl. Trav. Chim. Pays-Bas 1964, 83, 379–386. [Google Scholar] [CrossRef]
  58. Roughley, P.J.; Whiting, D.A. Experiments in the biosynhtesis of curcumin. J. Chem. Soc. Perkin Trans. 1973, 2379–2388. [Google Scholar] [CrossRef]
  59. Payton, F.; Sandusky, P.; Alworth, W.L. NMR study of the solution structure of curcumin. J. Nat. Prod. 2007, 70, 143–146. [Google Scholar] [CrossRef]
  60. Cooksey, C.J. Turmeric: Old spice, new spice. Biotech. Histochem. 2017, 92, 309–314. [Google Scholar] [CrossRef]
  61. Anjomshoa, S.; Namazian, M.; Noorbala, M.R. The Effect of Solvent on Tautomerism, Acidity and Radical Stability of Curcumin and Its Derivatives Based on Thermodynamic Quantities. J. Solut. Chem. 2016, 45, 1021–1030. [Google Scholar] [CrossRef]
  62. Wang, Y.J.; Pan, M.H.; Cheng, A.L.; Lin, L.I.; Ho, Y.S.; Hsieh, C.Y.; Lin, J.K. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal. 1997, 15, 1867–1876. [Google Scholar] [CrossRef] [PubMed]
  63. Hassaninasab, A.; Hashimoto, Y.; Tomita-Yokotani, K.; Kobayashi, M. Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. Proc. Natl. Acad. Sci. USA 2011, 108, 6615–6620. [Google Scholar] [CrossRef] [PubMed]
  64. Schneider, C.; Gordon, O.N.; Edwards, R.L.; Luis, P.B. Degradation of curcumin: From mechanism to biological implications. J. Agric. Food Chem. 2015, 63, 7606–7614. [Google Scholar] [CrossRef] [Green Version]
  65. Cao, Y.; Xu, R.X.; Liu, Z. A high-throughput quantification method of curcuminoids and curcumin metabolites in human plasma via high-performance liquid chromatography/tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2014, 949–950, 70–78. [Google Scholar] [CrossRef] [Green Version]
  66. Péret-Almeida, L.; Cherubino, A.P.F.; Alves, R.J.; Dufossé, L.; Glória, M.B.A. Separation and determination of the physico-chemical characteristics of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Res. Int. 2005, 38, 1039–1044. [Google Scholar] [CrossRef]
  67. Priyadarsini, K.I. The chemistry of curcumin: From extraction to therapeutic agent. Molecules 2014, 19, 20091–20112. [Google Scholar] [CrossRef] [Green Version]
  68. Pfeiffer, E.; Hoehle, S.I.; Walch, S.G.; Riess, A.; Sólyom, A.M.; Metzler, M. Curcuminoids form reactive glucuronides in vitro. J. Agric. Food Chem. 2007, 55, 538–544. [Google Scholar] [CrossRef]
  69. Di Meo, F.; Filosa, S.; Madonna, M.; Giello, G.; Di Pardo, A.; Maglione, V.; Baldi, A.; Crispi, S. Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: An in vitro and in vivo analysis. J. Exp. Clin. Cancer Res. 2019, 38, 360. [Google Scholar] [CrossRef]
  70. Wichitnithad, W.; Nimmannit, U.; Wacharasindhu, S.; Rojsitthisak, P. Synthesis, characterization and biological evaluation of succinate prodrugs of curcuminoids for colon cancer treatment. Molecules 2011, 16, 1888–1900. [Google Scholar] [CrossRef] [Green Version]
  71. Venkata Rao, E.; Sudheer, P. Revisiting curcumin chemistry part I: A new strategy for the synthesis of curcuminoids. Indian J. Pharm. Sci. 2011, 73, 262–270. [Google Scholar]
  72. Titekar, R.V.; Hernández, M.; Land, D.P.; Nitin, N. “Click chemistry” based conjugation of lipophilic curcumin to hydrophilic ε-polylysine for enhanced functionality. Food Res. Int. 2013, 54, 44–47. [Google Scholar] [CrossRef]
  73. Weiss, H.; Reichel, J.; Görls, H.; Schneider, K.R.A.; Micheel, M.; Pröhl, M.; Gottschaldt, M.; Dietzek, B.; Weigand, W. Curcuminoid-BF2 complexes: Synthesis, fluorescence and optimization of BF2 group cleavage. Beilstein J. Org. Chem. 2017, 13, 2264–2272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Polishchuk, V.; Stanko, M.; Kulinich, A.; Shandura, M. D–π–A–π–D Dyes with a 1,3,2-Dioxaborine Cycle in the Polymethine Chain: Efficient Long-Wavelength Fluorophores. Eur. J. Org. Chem. 2018, 2018, 240–246. [Google Scholar] [CrossRef]
  75. Bellinger, S.; Hatamimoslehabadi, M.; Bag, S.; Mithila, F.; La, J.; Frenette, M.; Laoui, S.; Szalda, D.J.; Yelleswarapu, C.; Rochford, J. Photophysical and Photoacoustic Properties of Quadrupolar Borondifluoride Curcuminoid Dyes. Chem.—A Eur. J. 2018, 24, 906–917. [Google Scholar] [CrossRef] [PubMed]
  76. Liu, K.; Chen, J.; Chojnacki, J.; Zhang, S. BF3·OEt2-promoted concise synthesis of difluoroboron-derivatized curcumins from aldehydes and 2,4-pentanedione. Tetrahedron Lett. 2013, 54, 2070–2073. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Gál, E.; Csaba Nagy, L. Photophysical Properties and Electronic Structure of Symmetrical Curcumin Analogues and Their BF2 Complexes, Including a Phenothiazine Substituted Derivative. Symmetry 2021, 13, 2299. [Google Scholar] [CrossRef]
  78. Insuasty, D.; Cabrera, L.; Ortiz, A.; Insuasty, B.; Quiroga, J.; Abonia, R. Synthesis, photophysical properties and theoretical studies of new bis-quinolin curcuminoid BF2-complexes and their decomplexed derivatives. Spectrochim. Acta—Part A Mol. Biomol. Spectrosc. 2020, 230, 118065. [Google Scholar] [CrossRef]
  79. Laali, K.K.; Zwarycz, A.T.; Bunge, S.D.; Borosky, G.L.; Nukaya, M.; Kennedy, G.D. Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer. ChemMedChem 2019, 14, 1173–1184. [Google Scholar] [CrossRef] [Green Version]
  80. Xu, Y.; Jiang, J.Q. Technologies for boron removal. Ind. Eng. Chem. Res. 2008, 47, 16–24. [Google Scholar] [CrossRef]
  81. Goldberg, S.; Glaubig, R.A. Boron Adsorption on Aluminum and Iron Oxide Minerals. Soil Sci. Soc. Am. J. 1985, 49, 1374–1379. [Google Scholar] [CrossRef]
  82. Tabelin, C.B.; Hashimoto, A.; Igarashi, T.; Yoneda, T. Leaching of boron, arsenic and selenium from sedimentary rocks: II. pH dependence, speciation and mechanisms of release. Sci. Total Environ. 2014, 473–474, 244–253. [Google Scholar] [CrossRef] [PubMed]
  83. McPhail, M.; Page, L.A.; Bingham, F.T. Adsorption Interactions of Monosilicic and Boric Acid on Hydrous Oxides of Iron and Aluminum. Soil Sci. Soc. Am. J. 1972, 36, 510–514. [Google Scholar] [CrossRef]
  84. Toner, C.V.; Sparks, D.L. Chemical Relaxation and Double Layer Model Analysis of Boron Adsorption on Alumina. Soil Sci. Soc. Am. J. 1995, 59, 395–404. [Google Scholar] [CrossRef]
  85. Ranjbar, F.; Jalali, M. Surface complexation model of boron adsorption by calcareous soils. Int. J. Environ. Sci. Technol. 2014, 11, 1317–1326. [Google Scholar] [CrossRef] [Green Version]
  86. Sims, J.R.; Bingham, F.T. Retention of Boron by Layer Silicates, Sesquioxides, and Soil Materials: III. Iron- and Aluminum-Coated Layer Silicates and Soil Materials. Soil Sci. Soc. Am. J. 1968, 32, 369–373. [Google Scholar] [CrossRef]
  87. Martichonok, V.V.; Chiang, P.K.; Dornbush, P.J.; Land, K.M. On regioselectivity of aldol condensation of aromatic aldehydes with borate complex of acetylacetone. Synth. Commun. 2014, 44, 1245–1250. [Google Scholar] [CrossRef]
  88. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem.—Int. Ed. 2001, 40, 2004–2021. [Google Scholar] [CrossRef]
  89. Armarego, W.L.F.; Perrin, D.D. Purification of Laboratory Chemicals, 4th ed.; Butterworth Heinemann: Oxford, UK, 1997. [Google Scholar]
  90. MNova Software. Available online: https://mestrelab.com/download/mnova/ (accessed on 1 December 2022).
  91. Jayaprakasha, G.K.; Jagan Mohan Rao, L.; Sakariah, K.K. Improved HPLC method for the determination of curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin. J. Agric. Food Chem. 2002, 50, 3668–3672. [Google Scholar] [CrossRef]
Molecules 28 00289 sch001 550
Scheme 1. Synthesis of synthon I.
Scheme 1. Synthesis of synthon I.
Molecules 28 00289 sch001
Molecules 28 00289 sch002 550
Scheme 2. Synthesis of curcuminoid-BF2 complexes.
Scheme 2. Synthesis of curcuminoid-BF2 complexes.
Molecules 28 00289 sch002
Molecules 28 00289 g001 550
Figure 1. Crude 1H-NMR spectrum of Curcumin-BF2, DMSO-d6, 400 MHz, in the region 0.5–3.0 ppm. Note the presence of butylamine and tributyl borate residues.
Figure 1. Crude 1H-NMR spectrum of Curcumin-BF2, DMSO-d6, 400 MHz, in the region 0.5–3.0 ppm. Note the presence of butylamine and tributyl borate residues.
Molecules 28 00289 g001
Molecules 28 00289 g002 550
Figure 2. Spectrum 1H-NMR of Curcumin-BF2 (after washing with water/acetone 90::10, DMSO-d6, 400 MHz).
Figure 2. Spectrum 1H-NMR of Curcumin-BF2 (after washing with water/acetone 90::10, DMSO-d6, 400 MHz).
Molecules 28 00289 g002
Molecules 28 00289 sch003 550
Scheme 3. “Unclick” reaction of BF2 group.
Scheme 3. “Unclick” reaction of BF2 group.
Molecules 28 00289 sch003
Molecules 28 00289 sch004 550
Scheme 4. Remotion of the BF2 group mediated by alumina.
Scheme 4. Remotion of the BF2 group mediated by alumina.
Molecules 28 00289 sch004
Molecules 28 00289 g003 550
Figure 3. 1H-NMR spectrum of curcumin obtained from synthesis DMSO-d6, 400MHz.
Figure 3. 1H-NMR spectrum of curcumin obtained from synthesis DMSO-d6, 400MHz.
Molecules 28 00289 g003
Table
Table 1. Synthesis curcuminoid-BF2 complexes.
Table 1. Synthesis curcuminoid-BF2 complexes.
AldehydeCurcuminoid-BF2Yield A
Vanillin190%
4-hidroxybenzaldehyde285%
Furfural380%
2-Thiophene carboxaldehyde495%
A = represents the average from 3 lots after washing with water/acetone (90:10) and drying at vacuum. All reactions were carried out during 12 h.
Table
Table 2. “Unclick” reaction conditions for the BF2 group.
Table 2. “Unclick” reaction conditions for the BF2 group.
Curcuminoid-BF2SolventMetal OxideTime in Reflux (h)CurcuminoidYield A
1EtOHBSilica725 (Curcumin)52%
1EtOHCMolecular sieves 4Å24574%
1EtOHDAlumina24560%
1MeOHSilica24570%
1MeOHMolecular sieves 4Å245<80%
1MeOHAlumina24585%
2MeOHSilica246(bis-demethoxycurcumin)<50%
2MeOHMolecular sieves 4Å24665%
2MeOHAlumina24678%
3MeOHSilica727<30%
3MeOHMolecular sieves 4Å24788%
3MeOHAlumina24781%
4MeOHSilica72860%
4MeOHMolecular sieves 4Å24886%
4MeOHAlumina24892%
A = represents the average of 3 batches from crude; B = SiO2 high-purity grade, average pore size 60 Å (52–73 Å), 70–230 mesh, 63–200 μm, for column chromatography, C = Na12[(AlO2)12(SiO2)12] xH2O, D = Al2O3 grade III.
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Obregón-Mendoza, M.A.; Meza-Morales, W.; Alvarez-Ricardo, Y.; Estévez-Carmona, M.M.; Enríquez, R.G. High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach. Molecules 2023, 28, 289. https://doi.org/10.3390/molecules28010289

AMA Style

Obregón-Mendoza MA, Meza-Morales W, Alvarez-Ricardo Y, Estévez-Carmona MM, Enríquez RG. High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach. Molecules. 2023; 28(1):289. https://doi.org/10.3390/molecules28010289

Chicago/Turabian Style

Obregón-Mendoza, Marco A., William Meza-Morales, Yair Alvarez-Ricardo, M. Mirian Estévez-Carmona, and Raúl G. Enríquez. 2023. "High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach" Molecules 28, no. 1: 289. https://doi.org/10.3390/molecules28010289

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