Ultrasound-assisted reaction of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide with potassium salt of curcumin under PTC conditions

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<ul><li><p>isyrd</p><p>P</p><p>Ce</p><p>m 25 N</p><p>are several advantages of the phase transfer catalysis sys- in two-phase system under PTC conditions being slowwould require acceleration and such reactions are usuallycarried out at higher temperatures. In case of heat-labilesubstrates this impediment could be overcome by use ofultrasound. Ultrasound accelerated chemical reactions, infact, are well known and documented in literature [1]. It</p><p>* Corresponding author. Tel.: +91 821 2512352; fax: +91 821 2517233.E-mail addresses: psrinivas@cftri.res.in, pullabhatla_s@yahoo.co.uk</p><p>(P. Srinivas).</p><p>Available online at www.sciencedirect.com</p><p>Ultrasonics Sonochemistry 151. Introduction</p><p>Phase transfer catalysis (PTC) technique is extremelyuseful for carrying out reactions between substances ofpreferential solubility in dierent solvent phases. For exam-ple, one of the reactants can be an organic compound dis-solved in an organic medium and the other one a salt of analcohol or phenol soluble in the aqueous phase. The cata-lyst does play a very critical role in these biphasic reactions.Its choice and the careful monitoring of the reaction condi-tions are essential features that govern the course of thereaction and determine the yields of the products. There</p><p>tems over single-phase systems, such as an increased reac-tion rate, lower reaction temperature, avoiding the needfor expensive anhydrous or aprotic solvents and the useof water along with an organic solvent as the reaction med-ium. Catalysts extensively employed in PTC reactionsinclude quaternary ammonium or phosphate salts or crownethers/cryptates. Quaternary ammonium salts with theirinherent capability to dissolve in both aqueous and organicliquids are the catalysts of choice for most phase transferapplications. The eciency of phase transfer catalysis isinuenced by the bulkiness of the groups attached to thephase transfer catalyst. However, certain reactions studiedAbstract</p><p>Reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with potassium salt of curcumin [bis-1,7-(3 0-methoxy-4 0-hydroxy)phe-nyl-5-hydroxy-1,4,6-heptatrien-3-one] under either thermal or high pressure conditions aect the labile substrate, curcumin, thus result-ing in drastic reduction in the yields of the glucosides. This drawback could be eectively overcome by carrying out the biphasic reactionin the presence of a phase transfer catalyst under the eect of ultrasound. The reaction under the sonochemical conditions was faster andresulted in the increased yield of the glucoside products. The reaction was investigated in detail with a view to optimizing the yield of theglucosides. The detailed study clearly indicated the important role of the nature and quantity of the phase transfer catalyst employed inthe reaction. Also, the selectivity with respect to the formation of mono- or di-b-glucosides under both mono- and biphasic reaction con-ditions was clearly discernable. The study establishes a simple synthetic protocol for the glucoside derivatives of curcumin in high yieldsand selectivity using ultrasonic waves. 2007 Elsevier B.V. All rights reserved.</p><p>Keywords: Ultrasound; Phase transfer catalyst; Curcumin; Mono- and di-b-glucosides; SelectivityUltrasound-ass2,3,4,6-tetra-O-acetyl-a-D-glucop</p><p>salt of curcumin un</p><p>Kattera S. Parvathy,</p><p>Department of Plantation Products, Spices and Flavour Technology,</p><p>Received 28 July 2007; received in revised forAvailable online1350-4177/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.ultsonch.2007.09.007ted reaction ofanosyl bromide with potassiumer PTC conditions</p><p>ullabhatla Srinivas *</p><p>ntral Food Technological Research Institute, Mysore 570 020, India</p><p>5 August 2007; accepted 18 September 2007ovember 2007</p><p>www.elsevier.com/locate/ultsonch</p><p>(2008) 571577</p></li><li><p>nicsis demonstrated as an alternative energy source for organicreactions normally accomplished by employing higher tem-peratures. Improved yields and increased selectivity arereported when ultrasound is employed in homogeneousas well as heterogeneous reactions [2]. Eect of ultrasoundon PTC reactions has been reported [36]. Ultrasound as atechnique of synthesis is extensively used in synthesis oforganometallics, in enzyme catalyzed reactions and manyother synthetic reactions involving reaction mixtures hav-ing more heterogeneity in their solubility.</p><p>In our studies on curcumin a natural yellow colorantof turmeric, which is a spice used primarily as a food col-orant and also to avor several foods study of the synthe-sis of its glucoside derivative was investigated. Curcumin, isa nutraceutical compound used worldwide for medicinal aswell as food purposes [7,8]. It has attracted special atten-tion due to its potent pharmacological activities such asto protect cells from b-amyloid insult in Alzheimers dis-ease [9] and cancer preventive properties [10]. Biologicalactivities of curcumin chelated to metal ions as well as anti-oxidant eects of curcumin are also documented in litera-ture [11,12]. However, curcumin is insoluble in water atacidic and neutral pH. Though it is soluble under alkalineconditions, the color of the chromophore changes to deepred and it also undergoes degradation. Its low solubilityin aqueous systems is a disadvantage as it renders its usein water based food products dicult. The alkyl and arylportion of the molecule makes it lipophilic and hence, sol-uble only in fats and organic media. In order to make itwater soluble, it is envisaged that attachment of a polargroup or molecule would enhance the hydrophilicity ofthe molecule. This can be achieved, for example, by makingsuitable sugar derivatives. Basically, the reaction of Koe-nigsKnorr synthesis of glycosides tried under classicalcondition involves formation of glycosyl halides followedby the glycosyl transfer in the presence of heavy metal salts[13] to get the glycoside. Known methods of preparation ofcurcumin sugar derivatives employ the reaction of a-D-tet-raacetohaloglucose with curcumin under biphasic condi-tions in the presence of a phase transfer catalyst at highertemperatures but give very low yields [14,15]. Condensa-tion reaction of arylaldehyde with acetyl acetoneB2O3complex also gives curcumin glycoside boron complex[16]. Attempts are also made to synthesize curcumin gluco-side by enzymatic means using amyloglucosidase [17] andCatharanthus roseus cell cultures by supplying curcuminexogenously [18]. Lower yields, higher temperatures andlonger reaction times are the drawbacks of chemical andenzymatic synthetic methods reported.</p><p>In the present work, reaction of 2,3,4,6-tetraO-acetyl-a-D-glucopyranosyl bromide with potassium salt of curcu-min under biphasic conditions using phase transfer cata-lysts was studied under the inuence of ultrasound forthe synthesis of curcumin glucoside, as a new approachto KoenigsKnorr reaction. The results of synthesis of cur-</p><p>572 K.S. Parvathy, P. Srinivas / Ultrasocumin glucoside under both mono- and biphasic conditionswill be discussed.2. Method</p><p>2.1. Apparatus and materials</p><p>All the solvents and reagents employed in the synthesiswere of analytical reagent grade. Column chromatographyof the compounds was carried out using silica gel (100200mesh size). 1H NMR spectra for the compounds wererecorded on a Bruker Avance 500 MHz spectrometer usingdeuterated solvents, CDCl3 and DMSO-d6. Coupling con-stants (J values) are given in Hz. Mass spectral analyses ofthe synthetic compounds were carried out using MS(Waters Q-Tof Ultima) in the ES positive mode. Ultra-sound device used for the reaction was Vibracell with ahigh intensity tapered probe of tip diameter 6.5 mm fromSonics and Materials Inc., Newtown, USA. For the reac-tions, the ultrasound reactor was set at 25% amplitudeand pulse cycle of 25 s (on) and 5 s (o) with frequencyof 40 KHz and an output power of 750 W. Thin-layerchromatographic (TLC) analysis was performed on silcagel 60 F254 (Merck KgaA, 64271 Darmstadt, Germany)coated on alumina sheet and 3% methanol in chloroformwas used as the developing solvent. Isolation of the prod-ucts was by column chromatography on silica gel (100200mesh) with chloroform as the eluent. High performanceliquid chromatography of these samples was carried outon reverse phase C-18 column with methanol: water(70:30) containing triuroacetic acid (0.1%) as the mobilephase at ow rate of 1 ml/ min and monochromatic detec-tion at 423 nm.</p><p>2.2. Preparation of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide [19]</p><p>To acetic anhydride (145 g, 1.42 mol) cooled to 4 C,perchloric acid (1 ml) was added drop-wise maintainingthe temperature below 4 C. Glucose (35 g, 0.194 mol)was then added slowly maintaining the temperaturebetween 30 and 40 C. After cooling the reaction mixtureto 20 C, red phosphorus (10.25 g) was added followedby drop-wise addition of bromine (20 ml) maintaining thetemperature below 20 C. Water (12 ml) was then addedover a period of 1 h maintaining temperature below20 C. The reaction mixture was stirred for 2 h, and thendiluting with dichloromethane (100 ml), ltered throughglass wool. The organic layer was washed with cold satu-rated solution of sodium bicarbonate followed by chilledwater. The organic phase was ltered through activated sil-ica gel and the solvent distilled under reduced pressure. Theproduct was crystallized from diethyl etherhexane (1:2)mixture and stored in an airtight amber colored glass bottleat 4 C in a refrigerator. [65 g, 81%, m.p. 87 C, NMR(CDCl3): 2.04 (s, 3H); 2.06 (s, 3H); 2.10 (s, 3H); 2.11 (s,3H); 4.13(dd, 1H, J = 1.5 Hz and J = 12.5 Hz); 4.294.35(m, 2H); 4.85(1H, dd, J = 4 Hz and J = 10 Hz); 5.17 (t,</p><p>Sonochemistry 15 (2008) 5715771H, J = 9.5 Hz); 5.56 (t, 1H, J = 9.5 Hz); 6.62 (d, 1H,J = 4 Hz).</p></li><li><p>2.3. General procedure for the preparation of curcumin</p><p>glucoside tetraacetate (CGTA)</p><p>2.3.1. Biphasic reaction conditions</p><p>To a solution of curcumin (1, Scheme 1, 1 g, 2.7 mmol)in chloroform (40 ml), aqueous KOH (0.6 g, 10.8 mmol in20 ml water) was added followed by the addition of a solu-tion of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide(2.2 g, 5.35 mmol) in chloroform (40 ml). To the reactionmixture an aqueous solution of benzyltributylammoniumchloride (0.5 g, 1.6 mmol in 20 ml water) was added. Themixture was sonicated until the completion of the reaction(4 h), which was indicated, by phase separation and analy-sis by TLC. The organic layer was washed with water,dried over anhydrous sodium sulfate and distilled underreduced pressure. The crude sample was loaded onto silicagel (100200 mesh) column and eluted out with CHCl3.Pure fractions were pooled and evaporated to aord curcu-min mono and di-b-glucoside tetraacetates in 78% yield (2and 3).</p><p>2.3.2. Monophasic reaction conditions</p><p>Potassium salt of curcumin (1.1 g, 2.7 mmol) was takenalong with benzyl tributylammonium chloride (0.5 g,1.6 mmol) and 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosylbromide (2.2 g, 5.35 mmol) in DMSO (30 ml) and was son-icated until the completion of the reaction (20 h). Then, sol-vent in the reaction mixture was evaporated under reducedpressure. The residue was dissolved in chloroform and theorganic layer washed with water, dried over anhydroussodium sulfate and distilled under vacuum. The crude sam-ple loaded onto silica gel (100200 mesh) column andeluted out with distilled CHCl3. Pure fractions were pooledand evaporated to aord curcumin mono-b-glucoside tet-raacetate in 50% yield (2).</p><p>2.4. General procedure for the preparation of curcumin</p><p>glucoside (CG)</p><p>To a solution of curcumin di-b-glucoside tetraacetate (3,1 g) in dry methanol (10 ml), sodium methoxide, prepared</p><p>Compound Structure number</p><p>R R' </p><p>Curcumin 1 OH OH </p><p>Curcumin mono- -glucoside</p><p>tetraacetate 2</p><p>OH</p><p>H</p><p>R'R</p><p>OMeO OH</p><p>MeO</p><p>H</p><p>OHO</p><p>AccO</p><p>O</p><p>OAc</p><p>HH</p><p>H</p><p>HAcOAcO</p><p>O</p><p>K.S. Parvathy, P. Srinivas / Ultrasonics Sonochemistry 15 (2008) 571577 573Curcumin di- -glucoside tetra- </p><p>acetate</p><p>3</p><p>Curcumin mono- -glucoside 4 O</p><p>Curcumin di- -glucoside 5</p><p>H</p><p>A</p><p>Scheme 1. Curcumin and itO</p><p>OAc</p><p>HH</p><p>H</p><p>H</p><p>HAcOAcO</p><p>OAc</p><p>O</p><p>O</p><p>OH</p><p>HH</p><p>H</p><p>H</p><p>OH</p><p>O</p><p>O</p><p>OH</p><p>HH</p><p>H</p><p>H</p><p>HOHOH</p><p>OH</p><p>O</p><p>O</p><p>OAc</p><p>HH</p><p>H</p><p>H</p><p>HO</p><p>OAc</p><p>O</p><p>H OAc</p><p>O</p><p>OH</p><p>HH</p><p>H</p><p>H</p><p>HOHOH</p><p>OH</p><p>Os glucoside derivatives.</p></li><li><p>Table 1The eect of phase transfer catalyst on the yields of products ofultrasound-assisted reaction of potassium salt curcumin with a-2,3,4,6-tetra-O-acetyl-1-bromoglucose</p><p>Entry Catalysta Time (h) Yield (%) X:Yb</p><p>1 Benzyltributylammonium chloride 4 78 0.4:12 Cetyltributylammonium bromide 4 50 1:03 Tetrabutylammonium bromide No reaction</p><p>a Potassium salt of curcumin to catalyst ratio: 1:0.59.b X and Y-compounds 2 and 3 (Scheme 1).</p><p>Q+PhO-+ KX)))))</p><p>AQUEOUS PHASE </p><p>ORGANIC PHASE </p><p>Q+X- + PhO- K+</p><p>Q+X- + PhOR Q+PhO- + RX</p><p>Q - Quaternary ammonium salt (Phase transfer catalyst) PhOH - Curcumin RX - 2, 3, 4, 6-TetraO-acetyl-D-glucopyranosyl bromide </p><p>Scheme 2. Mechanism of the reaction of potassium salt of curcumin with</p><p>nics Sonochemistry 15 (2008) 571577by dissolving sodium (60 mg) in dry methanol (8 ml), wasadded and the mixture was stirred. The deacetylation reac-tion was monitored on TLC. At the end of the reaction(0.5 h), the solution was neutralized by the addition offreshly regenerated Dowex (IR-120) H+ resin. The resinwas ltered and the solvent distilled under reduced pressureto aord pure curcumin di-b-glucoside in 95% yield (5).</p><p>3. Results and discussion</p><p>Reaction of a solution of curcumin in chloroform withaqueous KOH led to facile formation of potassium saltof curcumin indicated by the decolorization of the organiclayer with concomitant transfer of the pigment to the aque-ous phase. A solution of 2,3,4,6-tetra-O-acetyl-a-D-gluco-pyranosyl bromide in chloroform was added, whichconstituted a biphasic system with the glycosyl halide inthe organic phase and the potassium salt of the phenolicsubstrate, curcumin, in the aqueous phase. Aqueous solu-tion of benzyltributylammonium chloride was then addedand the contents were stirred which resulted in the forma-tion of a homogeneous mixture. The reaction mixture wasreuxed for 12 h under stirring until the aqueous andorganic phases got separated and the aqueous layer becamecolorless. The organic layer after work up and chromato-graphic separation aorded mixture of mono- and digluco-side tetracetates of curcumin in an isolated yield of 15%.The reaction was also carried out under pressure of10 bar and with stirring in a pressure vessel for 4 h andthe reaction product puried by chromatography to aordcurcumin glucoside tetracetates in 10% yield. The resultsindicated that the reactions employing higher temperaturesand pressures led to formation of intractable products,apparently due to the labile nature of curcumin, which isprone to degradation under high pH and temperatures.This aected the overall yield of the targeted glucosides.The use of ultrasound as an alternative source for provid-ing the activation energy for this reaction was thus envis-aged. Also, in our earlier work on reaction of SN1-activehalides with zinc thiocyanate [2], we showed that ultra-sound accelerated the nucleophilic substitution reactionand aorded superior selectivity with respect to prepon...</p></li></ul>