untitled European Journal of Chemistry 6 (4) (2015) 367‐373 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.4.367‐373.1298 European Journal of Chemistry Journal webpage: www.eurjchem.com New route for synthesis of 3‐ and 5‐caffeoylquinic acids via protected quinic acids La Ode Kadidae, Akira Usami, Tomoya Koyama, Mitsunori Honda * and Ko‐Ki Kunimoto Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma‐Machi, Kanazawa, 920‐1192, Japan * Corresponding author at: Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma‐Machi, Kanazawa, 920‐1192, Japan. Tel.: +81.76.234.4789. Fax: +81.76.234.4800. E‐mail address: honda@se.kanazawa‐u.ac.jp (M. Honda). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.4.367‐373.1298 Received: 10 July 2015 Received in revised form: 04 August 2015 Accepted: 08 August 2015 Published online: 31 December 2015 Printed: 31 December 2015 Caffeoylquinic acids (CQAs) are a group of the phenylpropanoids produced by certain plant species, which have various biological activities including antioxidant, antibacterial, anticancer, and others. Several synthetic routes have been developed using quinic acids (QAs) and caffeic acid derivatives as starting materials. In this study, alternative pathways of 3‐ and 5‐CQAs preparation using protected quinic acids are described. Both CQAs were achieved by removal of the protecting groups of compound 9 and 18 with acid hydrolysis using dilute HCl solution. These compounds (9 and 18) are novel, resulted from esterification reaction of diacetyl caffeoyl chloride and protected quinic acids. The hydroxyl groups of quinic acid in this case were protected with 2,2‐dimethoxy propane or tert‐butyldimethylsilyl (TBS) chloride. KEYWORDS Hydrolysis Esterification Chemical synthesis Caffeoylquinic acids Protected quinic acids Dimethoxy caffeoyl chloride Cite this: Eur. J. Chem. 2015, 6(4), 367‐373 1. Introduction Caffeoylquinic acids (CQAs) and its derivatives are secondary metabolites that are found in a wide variety of natural sources. Coffee products and apple are among those sources constituting high percentage of CQAs [1‐3]. Some vegetables, for example, sweet potato and leeks also constitute these compounds [4,5]. Owing to their antioxidant and other biological effects [6‐8], convenient methods of CQAs have been sought for practical synthesis. As a result, numerous scientific papers have been published on the chemical and enzymatic synthetic methods, such as by Hemmerle et al. [9] and Lorentz et al. [10] Among these methods, Sefkow and co‐workers’ [11,12] have reported for the first time a complete package of CQAs syntheses. They synthesized 1‐, 3‐, 4‐, and 5‐CQA with performing esterification of suitable protected quinic acids with acid chloride of caffeic acid. However, the preparation of protected quinic acids (QAs) of Sefkow’s method is really hard to trace. Meanwhile, Dokli et al. [13] reported the syntheses of 3‐, 4‐ and 5‐feruloylquinic acids utilizing but with little modifi‐ cations of the Sefkow’s protocol, especially on protected quinic acids. Inspired by the aforementioned reports, the present article is reporting the synthesis of 3‐ and 5‐CQAs utilizing methyl 3,4‐o‐isopropylidene‐1,5‐quinate and an overlooked protected quinic acid, (1R, 3R, 4S, 5R)‐4‐tert‐butyldimethylsiloxy‐1, 3‐di hydroxycyclohexane‐1,5‐carbolactone as the starting mate‐ rials. These quinic acid derivatives were then esterified with caffeoyl chloride to obtain the correspondent esters of protected CQAs. Removal of all protected groups was carried out in dilute concentrations of HCl to attain the relevant CQAs. To complement the description of the synthesis of 3‐ and 5‐ CQAs, 1‐ and 4‐CQAs were also synthesized and described in this article. 2. Experimental 2.1. General procedures All reactions were conducted in dried glassware under argon atmosphere. Reagents used were commercially available with high grade of purity and solvents were purified using known methods. Thin layer chromatographic (TLC) analyses were performed on Kieselgel 60 F254 plates from Merck. Detection was carried out under UV light or spraying with 20% ethanolic sulfuric acid. Flash chromatography for substance purifications was performed on Silica Gel 60N, 40‐ 50 μm. 368 Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 Scheme 1 Solvents evaporation was performed using Iwaki Rotary Evaporator REN‐1000 with reduced pressure. JEOL NMR of JNM‐LA400 and 500 were utilized in analyses of 1H and 13C NMR spectra. JEOL JMS‐700 was used to record High Resolution Mass Spectrophotometer (HRMS) spectra. HORIBA FT‐720 FT‐IR Spectrometer was used to record infrared spectra. Compound 5 and 12 were prepared according to references [14,15], respectively. 2.2. Preparation of protected 1‐CQA (7) To a solution of acetone quinide (5) (400 mg, 1.87 mmol) in dichloromethane (10 mL), pyridine (8 mL), DMAP (11.4 mg, 0.09 mmol) and diacetyl caffeoyl chloride (3) (Scheme 1) (580 mg, 2.06 mmol) were added, respectively. The mixture was stirred for 15 h at room temperature. The resultant reaction mixture was diluted with dichloromethane (80 mL), washed with 2 M HCl and brine (2 × 10 mL) each. The organic phase was dried over MgSO4 and the solvents were evaporated under reduced pressure to give crude product. This product was purified over column chromatography on silica gel (n‐ hexane:EtOAc, 2:1, v:v) to give the desired compound 7 (Scheme 2), as powder. Color: White. Yield: 75%. 1H NMR (400 MHz, CDCl3, δ, ppm): 1.35 (s, 3H, CH3‐CO2CH3), 1.54 (s, 3H, CH3CO2CH3), 2.30 (s, 3H, CH3CO‐O), 2.31 (s, 3H, CH3CO‐O), 2.42 (dd, 1H, J = 14.5, 3.0 Hz, Cyclohexyl‐H), 2.53 (ddd, 1H, J = 14.4, 7.7, 2.3 Hz, Cyclohexyl‐H), 2.64 (d, 1H, J = 11.5 Hz, Cyclohexyl‐ H), 3.11 (dd, 1H, J = 11.6, 6.2 Hz, Cyclohexyl‐H), 4.35 (d, 1H, J = 5.4 Hz, CH‐O‐CO), 4.57 (dd, 1H, J = 7.1, 3.0 Hz, CH‐O‐CO), 4.82 (dd, 1H, J = 6.3, 2.4 Hz, CH‐O‐CH2), 6.39 (d, 1H, J = 15.9 Hz, CO‐ CH‐CH‐Ph), 7.24 (d, 1H, J = 8.3 Hz, Ar‐H), 7.36 (d, 1H, J = 2.0 Hz, Ar‐H), 7.41 (dd, 1H, J = 8.4, 2.1 Hz, Ar‐H), 7.66 (d, 1H, J = 15.9 Hz, Ph‐CH‐CH‐CO). NMR data were in good agreement with literature data [11]. 2.3. Preparation of 1‐CQA (8) As much as 184 mg (0.40 mmol) of protected 1‐CQA (7) was suspended in a mixture of THF (4 mL) and 2 M HCl (16 mL). The mixture was stirred at room temperature and TLC (MeOH:EtOAc, 1:1, v:v) was used to monitor the progress of reaction. After the complete disappearance of the protected 1‐ CQA spot (7 days), the reaction is stopped and added with dichloromethane (5 mL) forming two layers. The aqueous phase was separated, saturated with solid NaCl, and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give desired 1‐CQA, compound 8 (Scheme 2) as powder. Color: Pale yellow. Yield: 89%. 1H NMR (400 MHz, CD3OD, δ, ppm): 1.89 (dd, 1H, J = 13.8, 9.9 Hz, Cyclohexyl‐H), 2.19 (dd, 1H, J = 14.8, 3.3 Hz, Cyclohexyl‐H), 2.42 (d, 1H, J = 12.4 Hz, Cyclohexyl‐H), 2.56 (d, 1H, J = 12.9 Hz, Cyclohexyl‐H), 3.46 (dd, 1H, J = 8.4, 3.5 Hz, CH‐OHCH2), 4.07 (ddd, 1H, J = 15.5, 6.0, 3.0 Hz, CH‐OHCH2), 4.14 (dd, 1H, J = 8.2, 3.8 Hz, CH‐OHCOH), 6.27 (d, 1H, J =15.9 Hz, CO‐CH‐CH‐Ph), 6.77 (d, 1H, J = 8.1 Hz, Ar‐H), 6.94 (dd, 1H, J = 8.2, 1.8 Hz, Ar‐H), 7.04 (d, 1H, J = 2.0 Hz, Ar‐H), 7.54 (d, 1H, J = 15.9 Hz, Ph‐CH‐CH‐CO). NMR data were in good agreement with literature data [11]. 2.4. Preparation of methyl 3,4‐O‐isopropylidene‐1,5‐quinate (6) To a solution of acetone quinide (5) (750 mg, 3.51 mmol) in methanol (30 mL), sodium methoxide (302.8 mg, 4.21 mmol) was added and the mixture was stirred at room temperature for 5 h. Acetic acid (150 μL) was added to the mixture after which was cooled to 0 C, then let it to warm back to room temperature. Solvent was evaporated under reduced pressure to get crude product that was purified over column chromatography on silica gel (n‐hexane:EtOAc, 1:1, v:v) to give the desired product, compound 6 (Scheme 2). Color: Colorless liquid. Yield: 78%. Rf = 0.17. 1H NMR (400 MHz, CDCl3, δ, ppm): 1.38 (s, 3H, CH3CO2CH3), 1.55 (s, 3H CH3CO2CH3), 1.88 (dd, 1H, J = 13.5, 10.9 Hz, Cyclohexyl‐H), 2.08 (dd, 1H, J = 13.7, 4.1 Hz, Cyclohexyl‐H), 2.26 (d, 2H, J = 3.9 Hz, Cyclohexyl‐H), 2.63 (s, broad, 1H, OH), 3.41 (s, broad, 1H, OH), 3.82 (s, 3H, CO‐O‐CH3), 3.99 (t, 1H, J = 6.3 Hz, CH‐O), 4.11‐4.17 (m, 1H, CH‐O), 4.46‐4.49 (m, 1H, CH‐OH). NMR data were in good agreement with literature data [16]. 2.5. Synthesis of protected 5‐CQA (9) and 1,5‐diCQA (10) To a stirred solution of methyl quinate (6) (400 mg, 1.62 mmol) in dichloromethane (15 mL), pyridine (6 mL), DMAP (11.4 mg, 0.09 mmol) and diacetyl caffeoyl chloride (3) (690 mg, 2.44 mmol) were respectively added. The mixture was continued to stir up to 15 h at room temperature. The resultant reaction mixture was diluted with dichloromethane (80 mL), washed with 2 M HCl, NaHCO3 and brine (2 × 20 mL) each. The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford crude ester. This was purified over column chromatography on silica gel (dichloromethane:diethyl ether, 1:1, v:v) to give methyl 3,4‐O‐ isopropylidene‐5‐diacetylcaffeoyl quinate (9) and methyl 3,4‐ O‐isopropylidene‐1,5‐diacetylcaffeoyl quinate (10), Scheme 2, as waxy solid. Methyl 3,4‐o‐isopropylidene‐5‐diacetylcaffeoyl quinate (9): Color: Off white. Yield: 58%. FT‐IR (KBr, , cm‐1): 3482 (OH), 3072 (C‐H, aromatic) 2987 (C‐H, alkyl), 1774 (C=O, ester), 1716 (C=O, ester), 1638 (C=C, alkenyl), 1506 (C=C, aromatic), 1207 (C‐O‐C, ester), 1179 (C‐O‐C, ester). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.38 (s, 3H, CH3CO2CH3), 1.60 (s, 3H CH3CO2CH3), 1.93 (dd, 1H, J = 13.2, 11.0 Hz, Cyclohexyl‐H), 2.22‐2.27 (1H, Cyclohexyl‐H), 2.31 (s, 3H, CH3CO‐O), 2.32 (s, 3H, CH3CO‐O), 2.33 (d, 2H, J = 3.4 Hz, Cyclohexyl‐H), 3.45 (s, broad, 1H, OH), 3.79 (s, 3H, CO‐O‐CH3), 4.21 (dd, 1H, J = 7.2, 5.7 Hz, CH‐O‐lactone), 4.55 (dd, 1H, J = 8.8, 3.7 Hz, CH‐O‐lactone) 5.42‐5.48 (m, 1H, CH‐O‐Caff), 6.38 (d, 1H, J = 15.9 Hz, CO‐CH‐ Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 369 O O HO O O HO HO OH OH COOH 2,2-Dimethoxy- propane p-TsOH EtOAc reflux, 3 h 88% 4 5 AcO OAc O O O O O O HO OH O O COOH HO HO OH 3 CH2Cl2 r.t.. 18 h 75% H2O, THF r.t., 7 days 89% 1 3 4 5 1M HCl O O HO O O HO O O OH COOMe 1. NaOMe/MeOH 2. AcOH 0 oC - r.t., 5 h 78% 6 3 5 AcO OAc O HO O O O COOMe AcO OAc O O O O COOMe AcO AcO O O + H2O, THF r.t., 4 days 88% 1M HCl OH OHO HO HO OH O COOH 7 1-CQA (8) 10 5-CQA (11) a. b. DMAP Pyridine DMAP Pyridine CH2Cl2 r.t.. 18 h 58% 3% 9 Scheme 2 CH‐Ph), 7.22 (d, 1H, J = 8.3 Hz, Ar‐H), 7.35 (d, 1H, J = 1.7 Hz, Ar‐ H), 7.40 (dd, 1H, J = 8.3, 1.7 Hz, Ar‐H), 7.63 (d, 1H, J = 15.9 Hz, Ph‐CH‐CH‐CO). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.68 (1C, COOCH3), 168.07 (1C, COOPh), 168.00 (1C, COOPh), 165.58 (1C, COCH‐Olefinic), 143.47 (1C, Olefinic‐C), 143.24 (1C, Ar‐C), 142.36 (1C, Ar‐C), 133.17 (1C, Ar‐C), 126.37 (1C, Ar‐C), 123.92 (1C, Ar‐C), 122.74 (1C, Ar‐C), 119.04 (1C, C‐(CH3)2), 109.61 (1C, Olefinic‐C), 77.20 (1C, Cyclohexyl‐C), 73.79 (1C, Cyclo hexyl‐C), 73.57 (1C, Cyclohexyl‐C), 70.90 (1C, Cyclohexyl‐C), 53.10 (1C, CH3‐O), 36.84 (1C, Cyclohexyl‐C), 34.28 (1C, Cyclo hexyl‐C), 27.967 (1C, CH3‐C), 25.78 (1C, CH3‐C), 20.66 (1C, CH3‐ COOPh), 20.62 (1C, CH3‐COOPh). HRMS FAB+: m/z: calculated for C24H29O11 [M+H+] = 493.1710, found 493.1716. Methyl 3,4‐O‐isopropylidene‐1,5‐diacetylcaffeoyl quinate (10): Color: White. Yield: 3%. FT‐IR (KBr, , cm‐1): 3068 (C‐H, aromatic) 2926 (C‐H, alkyl), 1775 (C=O, ester), 1716 (C=O, ester), 1638 (C=C, alkenyl), 1505 (C=C, aromatic), 1205 (C‐O‐C, ester), 1179 (C‐O‐C, ester). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.33 (s, 3H, CH3CO2CH3), 1.50 (s, 3H, CH3CO2CH3), 1.92 (t, 1H, J = 12.3 Hz, Cyclohexyl‐H), 2.28 (s, 3H, CH3CO‐O), 2.29 (s, 3H, CH3CO‐O), 2.30 (s, 3H, CH3CO‐O), 2.31 (s, 3H, CH3CO‐O), 2.48 (dd, 1H, J = 16.0, 4.6 Hz, Cyclohexyl‐H), 2.54 (d, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.89 (d, 1H, J = 16.6 Hz, Cyclohexyl‐H), 3.73 (s, 3H, CO‐O‐CH3), 4.18 (t, 1H, J = 6.6 Hz, CH‐O‐lactone), 4.51 (dd, 1H, J = 7.4, 5.2 Hz, CH‐O‐lactone), 5.45‐5.50 (m, 1H, CH‐O‐caff), 6.38 (d, 1H, J = 16.0 Hz, CO‐CH‐CH‐Ph), 6.41 (d, 1H, J = 17.2 Hz, CO‐CH‐CH‐Ph), 7.21 (d, 1H, J = 5.2 Hz, Ar‐H), 7.23 (d, 1H, J = 5.2 Hz, Ar‐H), 7.35 (d, 2H, J = 10.3 Hz, Ar‐H), 7.40 (t, 2H, J = 9.5 Hz, Ar‐H), 7.64 (d, 1H, J = 15.5 Hz, Ph‐CH‐CH‐CO), 7.68 (d, 1H, J = 6.0 Hz, Ph‐CH‐CH‐CO). HRMS FAB+: m/z: calculated for C37H39O16 [M+H+] = 739.2238, found 739.2229. 2.6. Synthesis of 5‐CQA (11) As much as 172 mg (0.35 mmol) of protected 5‐CQA (9) was suspended in a mixture of THF (3 mL) and 1 M HCl (15 mL). The mixture was stirred at room temperature and TLC (MeOH:EtOAc, 1:1, v:v) was used to monitor the progress of reaction. After the complete disappearance of the protected 5‐ CQA spot (4 days), the reaction is stopped and added with dichloromethane (5 mL) forming two layers. The aqueous phase was separated, saturated with solid NaCl, and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated with evaporator under reduced pressure to give the desired product, compound 11 (Scheme 2) as powder. Color: Pale Yellow. Yield: 88%. 1H NMR (400 MHz, CD3OD, δ, ppm): 2.04‐2.08 (m, 2H, CH2, Cyclohexyl‐ H), 2.19 ‐2.23 (m, 2H, CH2, Cyclohexyl‐H), 3.73 (dd, 1H, J = 8.6, 2.9 Hz, CH‐OH), 4.16‐4.18 (m, 1H, CH‐OH), 5.33 (td, 1H, J = 8.9, 4.4 Hz, CH‐O‐Caff), 6.26 (d, 1H, J = 16.0 Hz, CO‐CH‐CH‐Ph), 6.78 (d, 1H, J = 8.0 Hz, Ar‐H), 6.96 (dd, 1H, J = 8.3, 2.0 Hz, Ar‐H), 7.05 (d, 1H, J =1.7 Hz, Ar‐H), 7.56 (d, 1H, J = 16.0 Hz, Ph‐CH‐CH‐CO). NMR data were in good agreement with literature data [11]. 370 Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 2.7. Preparation of (1R,3R,4S,5R)‐3‐tert‐butyldimethyl siloxy‐1,4‐dihydroxycyclohexane ‐1,5‐carbolactone (13) To a solution of lactone (12) (400 mg, 2.28 mmol) in DMF (4 mL) at 0 °C, imidazole (204 mg, 3.01 mmol), DMAP (65 mg, 0.48 mmol), and TBSCl (448 mg, 3.00 mmol) were respectively added. The mixture was stirred for 2 h at 0 C and extended 3 more hours at room temperature. The resultant reaction mixture was added with EtOAc (20 mL) forming some white precipitant. The mixture was filtered through celite and solvents were evaporated under reduced pressure to afford crude material. Purification was done by column chroma‐ tography on silica gel (n‐hexane:diethyl ether, 1:1, v:v) to give the desired product, compound 13 (Scheme 3), as waxy solid. Color: White. Yield: 62%. Rf = 0.12. 1H NMR (400 MHz, CDCl3, δ, ppm): 0.09 (s, 6H, Si(CH3)2, 0.90 (s, 9H, C(CH3)3, 1.98‐2.03 (m, 2H, Cyclohexyl‐H), 2.30 (dq, 1H, J = 11.7, 2.9 Hz, Cyclohexyl‐H), 2.60 (s, broad, 1H, OH), 2.64 (d, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.96 (s, broad, 1H, OH), 3.91 (d, 1H, 10.3 Hz, CH‐OTBS), 3.98 (t, 1H, J = 4.6 Hz, CH‐OH), 4.88 (t, 1H, J = 5.4 Hz, CH‐O‐CO). NMR data were in good agreement with literature data [15]. 2.8. Synthesis of protected 4‐CQA (15) and 1,4‐CQA (16) To a solution of monosilyl protected compound 13 (465 mg, 1.62 mmol), DMAP (30 mg, 0.24 mmol), and caffeoyl chloride (3) (846 mg, 2.92 mmol) were added. The mixture was stirred for 24 h at room temperature. Upon the completion of reaction, the mixture was dissolved with dichloromethane (30 mL), poured into crushed ice before titrating it with 1 M HCl to pH  2. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic phase was dried over MgSO4, filtered and solvent was evaporated under reduced pressure to give 1.1 g crude. Purification was done by column chromatography on silica gel (n‐ hexane:diethyl ether:dichloromethane, 1:1:1, v:v:v) to give compound 15 and 16, Scheme 3, as waxy solid. 4‐((E)‐3‐(((1R,3R,4S,5R)‐3‐((tert‐butyldimethylsilyl)oxy)‐1‐ hydroxy‐7‐oxo‐6‐oxabicyclo[3.2.1]octan‐4‐yl)oxy)‐3‐oxoprop‐1‐ en‐1‐yl)‐1,2‐phenylene diacetate (15): Color: Off white. Yield: 52%. 1H NMR (400 MHz, CDCl3, δ, ppm): 0.02 (s, 3H, Si‐CH3), 0.05 (s, 3H, Si‐CH3), 0.80 (s, 9H, C(CH3)3, 2.05 ‐2.09 (m, 2H, Cyclohexyl‐H), 2.30 (s, 3H, CH3CO‐O), 2.31 (s, 3H, CH3CO‐O), 2.42 (dd, 1H, J = 12.2, 5.9 Hz, Cyclohexyl‐H), 2.54 (d, 1H, J = 12.0 Hz, Cyclohexyl‐H), 3.20 (s, broad, 1H, OH), 4.04 (td, 1H, J = 8.8, 4.7 Hz, CH‐OTBS), 4.85 (t, 1H, J = 5.4 Hz, CH‐O‐Caff), 5.44 (t, 1H, J = 4.9 Hz, CH‐O‐CO), 6.44 (d, 1H, J = 16.1Hz, CO‐CH‐CH‐ Ph), 7.25 (d, 1H, J = 8.3 Hz, Ar‐H), 7.40 (d, 1H, J = 2.2 Hz, Ar‐H), 7.43 (dd, 1H, J = 8.4, 2.1 Hz, Ar‐H), 7.66 (d, 1H, J =15.9 Hz, Ph‐ CH‐CH‐CO). NMR data were in good agreement with literature data [11]. (1R, 3R, 4S, 5R)‐3‐tert‐butyldimethylsiloxy‐1,4‐diacetyl caffeoylcyclohexane‐1,5‐carbolactone (16): Color: Off white. Yield: 15%. FT‐IR (KBr, , cm‐1): 3077 (C‐H, aromatic) 2933 (C‐ H, alkyl), 2857 (C‐H, alkyl), 1775 (C=O, ester), 1724 (C=O, ester), 1637 (C=C, alkenyl), 1506 (C=C, aromatic), 1255 (SiCH3), 1205 (C‐O‐C, ester), 1179 (C‐O‐C, ester), 1060 (Si‐O). 1H NMR (500 MHz, CDCl3, δ, ppm): 0.05 (s, 3H, Si‐CH3), 0.08 (s, 3H Si‐CH3), 0.82 (s, 9H, C(CH3)3), 2.27 (d, 1H, J = 12.4 Hz, Cyclohexyl‐H), 2.31 (s, 3H, CH3CO‐O), 2.31 (s, 3H, CH3CO‐O), 2.32 (s, 3H, CH3CO‐O), 2.32 (s, 3H, CH3CO‐O), 2.36 (d, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.64 (d, 1H, Cyclohexyl‐H), 3.17 (dq, 1H, J = 11.0, 3.0 Hz, Cyclohexyl‐H), 4.12 – 4.16 (m, 1H, CH‐ OTBS), 4.93 (t, 1H, J = 5.4 Hz, CH‐O‐Caff), 5.48 (t, 1H, J = 4.6 Hz, CH‐O‐CO), 6.42 (d, 1H, J = 16.0 Hz, CO‐CH‐CH‐Ph), 6.46 (d, 1H, J = 15.5 Hz, CO‐CH‐CH‐Ph), 7.24 (d, 1H, J = 1.7 Hz, Ar‐H), 7.26 (d, 1H, J = 1.7 Hz, Ar‐H), 7.39 (d, 2H, J = 13.2, 1.7 Hz, Ar‐H), 7.43 (td, 2H, J = 7.7, 1.7 Hz, Ar‐H), 7.66 (d, 1H, J = 5.7 Hz, Ph‐CH‐CH‐ CO), 7.70 (d, 1H, J = 5.7 Hz, Ph‐CH‐CH‐CO). 13C NMR (125 MHz, CDCl3, δ, ppm): 171.99 (1C, COO‐lactone), 168.07 (1C, 1C, COOCH3), 168.00 (1C, 1C, COOCH3), 167.97 (1C, 1C, COOCH3), 167.92 (1C, 1C, COOCH3), 165.08 (1C, COOCH‐Olefinic), 164.52 (1C, COOH‐Olefinic), 144.75 (2C, Olefinic‐C), 144.15 (1C, Olefinic‐C), 143.83 (1C, Ar‐C), 143.72 (1C, Ar‐C), 142.44 (1C, Ar‐C), 132.92 (1C, Ar‐C), 132.74 (1C, Ar‐C), 126.58 1C, Ar‐C), 126.54 (1C, Ar‐C), 124.02 (1C, Ar‐C), 124.00 (1C, Ar‐C), 122.97 (1C, Ar‐C), 122.84 (1C, Ar‐C), 118.23 (1C, Ar‐C), 117.89 (1C, Olefinic‐C), 76.51 (1C, Cyclohexyl‐C), 74.22 (1C, Cyclohexyl‐C), 66.89 (1C, Cyclohexyl‐C), 65.69 (1C, Cyclohexyl‐C), 37.61 (1C, Cyclohexyl‐C), 34.23 (1C, Cyclohexyl‐C), 25.53 (1C, C(CH3)3), 20.64 (3C, CH3‐C), 20.60 (2C, CH3COOPh), 17.87 (2C, CH3COOPh), ‐5.14 (2C, CH3‐Si). HRMS FAB+: m/z: calculated for C39H45O15Si [M+H+] = 781.2528, found 781.2531. 2.9. Synthesis of 4‐CQA (17) As much as 213 mg (0.40 mmol) of protected 4‐CQA (15) was suspended in a mixture of THF (3 mL) and 1 M HCl (15 mL). The mixture was stirred at room temperature and TLC (MeOH:EtOAc, 1:1, v:v) was used to monitor the progress of reaction. After the complete disappearance of the protected 4‐ CQA spot (8 days), the reaction is stopped and added with dichloromethane (5 mL) forming two layers. The aqueous phase was separated, saturated with solid NaCl, and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated with evaporator under reduced pressure to give 4‐CQA, compound 17 (Scheme 3), as powder. Color: Yellow. Yield: 40%. 1H NMR (400 MHz, CD3OD, δ, ppm): 1.99‐2.22 (m, 4H, Cyclohexyl‐H), 4.26‐4.30 (m, 2H, 2CH‐OH), 4.80 (dd, 1H, J = 9.2, 2.9 Hz, CH‐O‐CO), 6.37 (d, 1H, J = 16.0 Hz, CO‐CH‐CH‐Ph), 6.78 (d, 1H, J = 8.0 Hz, Ar‐H), 6.94‐ 7.07 (m, 2H, Ar‐H), 7.65 (d, 1H, J = 15.5 Hz, Ph‐CH‐CH‐CO). NMR data were in good agreement with literature data [11]. 2.10. Preparation of (1R,3R,4S,5R)‐4‐tert‐butyldimethyl siloxy‐1,3‐dihydroxy cyclohexane‐1,5‐carbolactone (14) To a solution of quinic acid lactone (12) (510 mg, 2.93 mmol) in DMF (4.8 mL) at 0 °C, dry triethylamine (0.5 mL), DMAP (50 mg, 0.41 mmol), tetrabutyl ammonium iodide (54 mg, 0.145 mmol) and TBSCl (505 mg, 3.37 mmol) were respectively added. The mixture was stirred for 24 h at 90 °C. After cooling to room temperature, the resultant reaction mixture was added with EtOAc (50 mL) forming some white precipitant which was filtered through celite and solvents were evaporated under reduced pressure to afford crude material. Purification was done by column chromatography on silica gel (n‐hexane:diethyl ether, 1:1, v:v) to give the desired product, compound 14 (Scheme 3), as solid. Color: White. Yield: 32%. Rf = 0.09. 1H NMR (500 MHz, CDCl3, δ, ppm): 0.14 (s, 3H, Si‐CH3), 0.17 (s, 3H, Si‐CH3), 0.94 (s, 9H, C(CH3)3), 1.85 (t, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.07 (s, broad 1H, OH), 2.18 (dq, 1H, J = 12.0, 3.2 Hz, Cyclohexyl‐H), 2.30 (dq, 1H, J = 11.5, 3.1 Hz, Cyclohexyl‐H), 2.53 (d, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.73 (s, broad, 1H, OH), 3.79 – 3.84 (m, 1H, CH‐OTBS), 4.10 (t, 1H, J = 4.6 Hz, CHOH), 4.68 (t, 1H, J = 5.4 Hz, CH‐O‐CO). NMR data were in good agreement with literature data [15]. 2.11. Synthesis of protected 3‐CQA (18) To a solution of monosilyl protected compound (14) (335 mg, 1.46 mmol) and DMAP (22 mg, 0.17 mmol), caffeoyl chloride (3) (583 mg, 2.63 mmol) were added. The mixture was stirred for 24 h at room temperature. Upon the completion of reaction, the resultant reaction mixture was dissolved with 22 ml dichloromethane then poured into crushed ice before titrating it with 1 M HCl to pH  2. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic phase was dried over MgSO4, filtered and solvent was evaporated under reduced pressure to give 824 mg crude. Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 371 Scheme 3 372 Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 Purification by column chromatography on silica gel (n‐ hexane:EtOAc, 1:1, v:v), gave the desired product of (1R, 3R, 4S, 5R)‐4‐tert‐butyldimethylsiloxy‐1‐hydroxy,3‐diacetyl caffeoyl cyclohexane‐1,5‐carbolactone (18), Scheme 3, as solid. Color: White. Yield: 53%. FT‐IR (KBr, , cm‐1): 3448 (OH), 3059 (C‐H, aromatic) 2954 (C‐H, alkyl), 2931 (C‐H, alkyl), 1780 (C=O, ester), 1716 (C=O, ester), 1638 (C=C, alkenyl), 1506 (C=C, aromatic), 1255 (Si‐CH3), 1206 (C‐O‐C, ester), 1178 (C‐O‐C, ester), 1094 (Si‐O). 1H NMR (400 MHz, CDCl3, δ, ppm): 0.03 (s, 3H, Si‐CH3), 0.05 (s, 3H, Si‐CH3), 0.91 (s, 9H, C(CH3)3), 2.15‐ 2.21 (m, 2H, Cyclohexyl‐H), 2.31 (s, 3H, CH3CO‐O), 2.32 (s, 3H, CH3CO‐O), 2.33‐2.38 (m, 1H, Cyclohexyl‐H), 2.64 (d, 1H, J = 11.5 Hz, Cyclohexyl‐H), 2.97 (s, broad, 1H, OH), 4.37 (t, 1H, J = 4.6 Hz, CH‐OTBS), 4.60 (t, 1H, J = 5.1 Hz, CH‐O‐Caff), 4.99 – 5.04 (m, 1H, CH‐O‐CO), 6.33 (d, 1H, J = 15.9 Hz, CO‐CH‐CH‐Ph), 7.20 (d, 1H, J = 8.3 Hz, Ar‐H), 7.37 (d, 1H, J = 2.0 Hz, Ar‐H), 7.37 (1H, dd, J = 8.5, 2.0 Hz, Ar‐H), 7.62 (d, 1H, J =16.1 Hz Ph‐CH‐CH‐CO). 13C NMR (100 MHz, CDCl3, δ, ppm): 177.47 (1C, COO‐lactone), 168.09 (1C, COOCH3), 168.03 (1C, COOCH3), 165.25 (1C, COOCH‐Olefinic), 143.73 (1C, Olefinic‐C), 143.52 (1C, Ar‐C), 142.27 (1C, Ar‐C), 132.79 (1C, Ar‐C), 126.35 (1C, Ar‐C), 123.88 (1C, Ar‐C), 122,65 (1C, Ar‐C), 118.28 (1C, Olefinic‐C), 77.21 (1C, Cyclohexyl‐C), 72.07 (1C, Cyclohexyl‐C), 68.74 (1C, Cyclo hexyl‐C), 64.36 (1C, Cyclohexyl‐C), 36.32 (1C, Cyclohexyl‐C), 35.71 (1C, Cyclohexyl‐C), 25.51 (1C, C(CH3)3), 25.49 (1C, CH3‐ C), 25.45 (1C, CH3‐C), 20.50 (1C, CH3‐C), 20.45 (1C, CH3 COOPh), 17.77 (1C, CH3COOPh), ‐4.93 (1C, CH3Si), ‐5.03 (1C, CH3‐Si). HRMS FAB+: m/z: calculated for C26H35O10Si [M+H+] = 535.1999, found 535.2005. 2.12. Synthesis of 3‐CQA (19) As much as 213 mg (0.4 mmol) of protected 3‐CQA (18) was suspended in a mixture of THF (4 mL) and 2 M HCl (16 mL). The mixture was stirred at room temperature and TLC (MeOH:EtOAc, 1:1, v:v) was used to monitor the progress of reaction. After the complete disappearance of the protected 3‐ CQA spot (7 days), the reaction is stopped and added with dichloromethane (5 mL) forming two layers. The aqueous phase was separated, saturated with solid NaCl, and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated with evaporator under reduced pressure to the desired product, 3‐CQA, compound 19 (Scheme 3) as powder. Color: Yellow. Yield: 41%. 1H NMR (400 MHz, CD3OD, δ, ppm): 1.96‐3.3 (m, 4H, Cyclohexyl‐H), 3.64 (dd, 1H, J = 8.4, 3.3 Hz, CH‐OH‐COH), 4.15 (td, 1H, J = 9.1, 3.9 Hz, CH‐OH‐OCaff), 5.36 (m, 1H, CH‐O‐Caff), 6.31 (d, 1H, J = 15.9 Hz, CO‐CH‐CH‐Ph), 6.77 (d, 1H, J = 8.1 Hz, Ar‐H), 6.94 (dd, 1H, J = 8.1, 20 Hz, Ar‐H), 7.05 (d, 1H, J = 2.0 Hz, Ar‐H), 7.59 (d, 1H, J = 15.9 Hz, Ph‐CH‐CH‐CO). NMR data were in good agreement with literature data [11]. 3. Results and discussion Although the main objective of this article is reporting our findings in the preparations of the 3‐ and 5‐CQAs using precursors as mentioned in the introduction section, the optimized synthetic results of the 1‐ and 4‐CQAs are also inclusive. This is necessary since the methods employed and the routes of syntheses are in correlation to one and another. 3.1. Preparation of diacetyl caffeic acid chloride Acid chloride 3 used in this work was prepared as depicted in Scheme 1, according to a known procedure [12], from caffeic acid (1) in two steps with the overall yield of 97%. 3.2. Synthesis of 1‐ and 5‐CQA Syntheses of 1‐ and 5‐CQA were depicted in Scheme 2. Treatment of (‐)‐quinic acid (4) with 2,2‐dimethoxypropane in a refluxing EtOAc and in the presence of acid catalyst, p‐TsOH, was a simple way to prepare lactone (5), according to Dokli’s method [13]. This lactone, in fact, possess only one hydroxyl group located at the required site to undergo an esterification reaction with acid chloride (3) to produce protected 1‐CQA (7). Synthesis of compound 7 was carried out at ambient temperature in dichloromethane in the presence of basic catalyst, DMAP, attaining 75% yield from compound 5. 1‐CQA (8) was obtained from cleaving all the protecting groups using 2 M HClaq:THF (4:1, v:v) at room temperature for 7 days, with 89% yield from compound 7. The lower side of the Scheme 2 is the stages for synthesizing 5‐CQA. Lactone 5 underwent methanolysis with NaOMe:MeOH at room temperature, to give crude product. After purification with column chromatography over silica gel, the desired compound 6 was obtained with 78% yield from compound 5. Protected 5‐CQA was synthe‐ sized from esterification of compound 3 with compound 6, employing exactly the same condition as synthesizing compound 7, to give 58% of the protected CQA (9) and minute amounts of compound 10. The 5‐CQA (11) was achieved at 88% yield after treating compound 9 with 1 M HCl for 4 days at room temperature. 3.3. Synthesis of 3‐ and 4‐CQAs 3‐ and 4‐CQAs were synthesized according to Scheme 3. Lactone 12 was afforded with high yield by refluxing quinic acid 4 in the mixture of toluene and DMF and in the presence of p‐TsOH. Selective hydroxyl group protection with TBSCl is governed by altering the temperature condition applied in the reaction. At lower temperature, compound 13 was more favorable while at higher temperature the isomer 14 was dominant. TBS lactone 13 was prepared by stirring compound 12 with TBSCl in DMF and in the presence of basic catalyst DMAP and imidazole, and adjusting the temperature from 0 °C to room temperature. After purification with column chromatography, the desired product was obtained, with 62% yield from compound 12. This substance was used to synthesize protected 4‐CQA by reacting it with compound 3 to give 60% yield of compound 15 and 15% of compound 16. 4‐ CQA was attained (40% yield) after stirring compound 15 with 1 M HCl for 8 days. Employing the same procedure as synthesizing compound 13, except at higher temperature, compound 14 was unsuccessful to afford. Products were traces of the two isomers. To overcome this drawback, tetra‐ butylammonium iodide and triethylamine (TEA) were used instead of imidazole. With this procedure, 32% of the desired compound 14 was afforded and used to synthesize the protected 3‐CQA (18) with 53% yield. This ester was hydrolyzed with 1 M HCl for 7 days attaining the unprotected ester of compound 19, 41% yield. 4. Conclusion We have developed a convenient method for the synthesis of 3‐ and 5‐CQAs utilizing the methyl 3,4‐o‐isopropylidene‐1,5‐ quinate and (1R,3R,4S,5R)‐4‐tert‐butyldimethylsiloxy‐1,3‐ dihydroxycyclohexane‐1,5‐carbolactone as their starting materials. These starting materials underwent esterification with diacetylcaffeoyl chloride to give protected 3‐ and 5‐CQAs. The 3‐CQA and 5‐CQA were achieved by hydrolysis of the protected esters with dilute concentration of HCl. Acknowledgements This work has been done as a part of doctoral research work at Kanazawa University, and was supported by Kanazawa University SAKIGAKE Project and Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 15K05585, and was promoted by Center of Innovation (COI) program “Construction of next‐generation infrastructure using Kadidae et al. / European Journal of Chemistry 6 (4) (2015) 367‐373 373 innovative materials: Realization of a safe and secure society that can coexist with the Earth for centuries” supported by Ministry of Education, Culture, Sports, Science and Technology (MEXT) and The Japan Science and Technology Agency (JST). I would also like to thank the Department of Research and Higher Education of the Republic of Indonesia for the scholarship. References [1]. Clifford, M. N. J. Sci. Food Agr. 1999, 79, 362‐372. [2]. Jaiswal, R.; Matei, M. F.; Golon, A.; Wittb, M.; Kuhnert, N. Food Funct. 2012, 3, 976‐984. [3]. Upadhyay, R.; Rao, L. J. M. Crit. 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