untitled European Journal of Chemistry 4 (3) (2013) 191‐194 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.3.191‐194.768 European Journal of Chemistry Journal homepage: www.eurjchem.com A simple stereoselective synthesis of (+)‐[6]‐gingerdiol Rathod Aravind Kumar, Jajula Kashanna, Paramesh Jangili, and Biswanath Das * Organic Chemistry Division‐I, CSIR‐Indian Institute of Chemical Technology, Hyderabad‐500007, India *Corresponding author at: Organic Chemistry Division‐I, CSIR‐Indian Institute of Chemical Technology, Hyderabad‐500007, India. Tel.: +91.40.27160512; fax: +91.40.27193241. E‐mail address: biswanathdas@yahoo.com (B. Das). ARTICLE INFORMATION ABSTRACT Received: 11 March 2013 Received in revised form: 03 April 2013 Accepted: 12 April 2013 Online: 30 September 2013 KEYWORDS A simple stereoselective synthesis of (+)‐[6]‐gingerdiol has been accomplished starting from vanillin. The synthetic sequence involves Mouroka allylation, diasterioselective iodine induced electrophilic cyclization and ring‐opening of an epoxide as the key steps. Vanilline Gingerdiol Syn‐epoxy alcohol Maruoka allylation Electrophilic cyclization Stereoselective synthesis 1. Introduction (+)‐[6]‐Gingerdiol (1) is an important constituent of the rhizomes of ginger (Zingiber officinale) [1,2]. The compound possesses a trisubstituted aromatic ring bearing an aliphatic chain. The side chain contains two hydroxyl groups with β‐ configuration. The compound exhibits various important medicinal properties including anti‐oxidant, anti‐inflammatory and anti‐fungal activities [3‐5]. The synthesis of the compound was achieved earlier by a French group applying the demetallation of tricarboxyliron diene complexes [6]. In continuation of our work on the stereoselective construction of bioactive natural products here we report a simple synthesis of (+)‐[6]‐gingerdiol (1) [7‐12] via alternative route. 2. Experimental All the chemicals were purchased from Sigma Aldrich with purity not less than 99.9%. All reactions were carried out under an inert atmosphere of N2. Analytical Thin Layer Chromato‐ graphy (TLC) was carried out by using silica gel 60 F254 pre‐ coated plates. Visualization was accomplished with UV lamp and I2 stain. All products were characterized by their NMR and Mass spectra. 2.1. Instrumentation 1H NMR and 13C NMR were recorded on Varian Gemini 200 MHz (1H) and 50 MHz (13C) spectrometers in CDCl3 using TMS as the internal standard and chemical shifts were reported in parts per million (ppm, ) downfield from the tetramethyl silane. FT‐IR spectra were recorded with Perkin Elmer RX1 FT‐ IR spectrophotometer and Mass spectra were recorded with VG Autospec instrument in m/z ratio. Optical rotations were determined with Jasco Dip 360 digital polarimeter at 25 °C. Column chromatography was carried out with silica gel (BDH 100‐200 Mesh) and TLC with silica gel 60 F254 precoated plates. 2.2. Synthesis 2.2.1. 4‐(tert‐Butyl dimethyl silyloxy)‐3‐methoxy benzaldehyde (5) To a stirred solution of compound 4 (1.0 g, 6.57 mmol) and imidazole (1.78 g, 26.28 mmol) in dry DCM (15 mL) was added tert‐butyl chloro (dimethyl) silane (TBS‐Cl) (1.98 g, 13.15 mmol) slowly at 0 °C. The mixture was then kept at room temperature for 5 h, and then quenched with H2O. The dichloro methane (DCM) layer was separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with H2O, brine, and dried (anhydrous Na2SO4). The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (2% EtOAc/hexane) to form 5 as a colorless oil (Scheme 1). Yield: 88%, 1.54 g. IR (KBr, ν, cm‐1): 1728, 1636, 1512, 1462, 1282. 1H NMR (200 MHz, CDCl3, δ, ppm): 9.80 (s, 1H, Ar‐CHO), 7.38 (d, 1H, J = 2.0 Hz, o‐Ar‐H ), 7.30 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 6.91 (d, 1H, J = 8.0 Hz, m‐Ar‐H), 3.85 (s, 3H, Ar‐O‐CH3), 1.00 (s, 9H, Si‐C(CH3)3), 0.20 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 189.8, 151.4, 150.8, 130.4, 125.8, 120.6, 110.0, 55.2, 25.3, 18.1. ESI‐MS (m/z): 289 [M+Na]+. [α]D25 = +5.65 (c 1.75, CHCl3). Anal. calcd. for C14H22O3Si: C, 63.15; H, 8.27. Found: C, 63.05; H, 8.28%. 2.2.2. (E)‐Ethyl 3‐(4‐(tert‐butyldimethylsilyloxy)‐3‐methoxy‐ phenyl) acrylate (6) To a solution of aldehyde, 5, (1.54 g, 5.78 mmol) in dry DCM (10 mL) ethyl (triphenyl phosphornylidene) acetate (3.017 g, 8.67 mmol) was added and the mixture was stirred at ambient temperature for 8 h. It was concentrated in vacuum, and the residue was purified by column chromatography (20% EtOAc/hexane) to afford compound 6 (Scheme 1). Yield: 81%, 1.57 g. IR (KBr, ν, cm‐1): 1720, 1612, 1513, 1443, 1247. 192 Kumar et al. / European Journal of Chemistry 4 (3) (2013) 191‐194 Reagents and conditions: a) TBSCl, imidazole, CH2Cl2. 5 h, 88%: b) PPh3CHCOOEt, CH2Cl2, rt, 6 h, 81%; c) NiCl2, NaBH4, MeOH, 0 °C, 15 min then 1 h rt, N2 condition, 91%; d) DIBAL‐H, CH2Cl2, MeOH, ‐78 °C to ‐10 °C, 0.5 h, 77%; e) (COCl)2, DMSO, Et3N, CH2Cl2, ‐78 °C , 0.5 h, 81%; f) (S,S)‐I, Bu3SnCH2CH=CH2, CH2Cl2, ‐15 °C to ‐0 °C, 20 h, 79%; g) BOC2O, DMAP, MeCN, 5 h, 77%; h) I2, MeCN, ‐20 °C, 6 h, 67%; i) TBAF, THF, 5 h, 78%; j) K2CO3, MeOH, 20 °C, 30 min, 84%; k) n‐C4H9MgBr, CuI, ‐30 °C, 2 h, 71%. Scheme 1 1H NMR (200 MHz, CDCl3, δ, ppm): 7.81 (d, 1H, J = 16.0 Hz, Ar‐ CH=CH), 7.25‐7.17 (m, 2H, o‐Ar‐H), 7.02 (d, 1H, J = 8.0 Hz, m‐Ar‐ H), 6.49 (d, 1H, J = 16.0 Hz, Ar‐CH=CH), 4.43 (q, 2H, J = 7.0 Hz, O‐CH2‐CH3), 4.02 (s, 3H, Ar‐O‐CH3), 1.53 (t, 3H, J = 7.0 Hz, O‐ CH2‐CH3), 1.18 (s, 9H, Si‐C(CH3)3), 0.19 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 172.2, 150.8, 143.8, 134.0, 120.8, 120.0, 112.1, 60.0, 55.3, 25.8, 18.2, ‐4.9. ESI‐MS (m/z): 337 [M+H]+. [α]D25 = +22.65 (c 0.17, CHCl3). Anal. calcd. for C18H28O4Si: C, 64.28; H, 8.39. Found: C, 64.19; H, 8.34%. 2.2.3. Ethyl 3‐(4‐(tert‐butyl dimethyl silyloxy)‐3‐methoxy‐ phenyl) propanoate (7) To a solution of the compound 6 (1.57 g, 4.68 mmol) in dry MeOH (15 mL) at 0 °C was added NiCl2 (0.22 g, 0.936 mmol), after stirring 15 min at 0 °C then added NaBH4 (0.35 g, 9.36 mmol) portion wise under N2 condition. Then allow the residue to room temperature and stirr for 1 h, and the residue was quenched with NH4Cl. The MeOH layer was separated and the aqueous layer was washed with DCM (2 x 10 mL) and combined organic layer washed with H2O, brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuum, and the residue was purified by column chromatography on silica gel (2% EtOAc/hexane), to afford the pure compound 7 (Scheme 1). Yield: 91%, 1.43 g. IR (KBr, ν, cm‐1): 1735, 1603, 1513, 1465, 1259. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.79 (d, 1H, J = 8.0 Hz, m‐Ar‐H), 6.72 (d, 1H, J = 2.0 Hz, o‐Ar‐H), 6.66 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 4.18 (q, 2H, J = 7.0 Hz, O‐CH2‐CH3), 3.85 (s, 3H, Ar‐O‐CH3), 2.92 (t, 2H, J = 7.0 Hz, Ar‐CH2‐CH2), 2.69‐ 2.60 (m, 2H, Ar‐CH2=CH2), 1.30 (t, 3H, J = 7.0 Hz, O‐CH2‐CH3), 1.08 (s, 9H, Si‐C(CH3)3), 0.20 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 173.3, 151.2, 143.8, 121.0, 120.2, 112.5, 60.1, 55.2, 35.6, 35.4, 25.4, 19.1, 14.8, ‐4.9. ESI‐MS (m/z): 339 [M+H]+. [α]D25 = +4.99 (c 0.75, CHCl3). Anal. calcd. for C18H30O4Si: C, 63.90; H, 8.93. Found: C, 63.81; H, 8.89%. 2.2.4. 3‐(4‐(tert‐Butyl dimethyl silyloxy)‐3‐methoxy phenyl)‐ propan‐1‐ol (8) To a solution of compound 7 (1.43 g, 4.23 mmol) in dry DCM (10 mL) cooled to ‐78 oC DIBAL‐H (7.58 mL, 10.62 mmol) was added drop wise and the mixture was then stirred at the same temperature for 1 h. The reaction mixture was quenched by slowly addition of dry MeOH (10 mL) and was brought to room temperature. Saturated aqueous sodium potassium tarterate solution (10 mL) was added to the reaction mixture and stirred until two layers separated (2 h). Dichloro methane was evaporated and the residue was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum, purification of the residue by column chromatography (30% EtOAc/hexane) afforded pure compound 8 (Scheme 1). Yield: 77%, 0.964 g. IR (KBr, ν, cm‐1): 3363, 1512, 1466, 1285. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.72 (d, 1H, J = 8.0 Hz, m‐Ar‐ H), 6.66 (d, 1H, J = 2.0 Hz, o‐Ar‐H), 6.60 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 3.79, (s, 3H, Ar‐O‐CH3), 3.69 (brs, 1H, 3'‐CH2‐OH), 3.62 Kumar et al. / European Journal of Chemistry 4 (3) (2013) 191‐194 193 (t, 2H, J = 7.0 Hz, 3'‐CH2‐OH), 2.61 (t, 2H, J = 7.0 Hz, Ar‐CH2), 1.91‐1.79 (m, 2H, Ar‐CH2‐CH2), 1.00 (s, 9H, Si‐C(CH3)3), 0.14 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 150.8, 143.1, 135.2, 120.5, 120.2, 112.7, 62.1, 55.3, 34.3, 32.0, 26.1, 18.4, ‐4.9. ESI‐MS (m/z): 297 [M+H]+. [α]D25 = +4.32 (c 1.50, CHCl3). Anal. calcd. for C16H28O3Si: C, 64.86; H, 9.45. Found: C, 64.78; H, 9.49%. 2.2.5. 3‐(4‐(tert‐butyldimethyl silyloxy)‐3‐methoxy phenyl)‐ propanal (3) To a solution of oxalyl chloride (0.42 mL, 4.875 mmol) in dry DCM (5 mL) at ‐78 °C, DMSO (0.73 mL, 10.4 mmol) was added drop wise with stirring under N2 condition, after 15 min compound 8 (0.964 g, 3.25 mmol) was added to the reaction mixture. After stirring for 0.5 h at ‐78 °C, Et3N (2.2 mL, 16.25 mmol) was added and the mixture was stirred for another 0.5 h at ‐78 oC and then for 0.5 h at 0 oC. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) at 0 oC and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The aldehyde, 3, thus obtained (0.775 g, 2.63 mmol) was directly used after flash column chromatography for the next reaction (Scheme 1). 2.2.6. (R)‐1‐(4‐(tert‐butyl dimethyl silyloxy)‐3‐methoxy phenyl) hex‐5‐en‐3‐ol (2) To a solution of TiCl4 (0.28 mL, 2.63 mmol) in dry DCM (10 mL) was added dried Ti(OiPr)4 (2.48 mL, 7.89 mmol) at 0 oC under nitrogen atmosphere and was allowed to warm to r.t., after 1 h silver(I)oxide (0.060 g, 0.263 mmol) was added at room temperature and the mixture was stirred for 5 h under exclusion of direct light. The mixture was diluted with DCM (30 mL), and treated with (S)‐BINOL (0.150 g, 0.526 mmol) at r.t, for 2 h to furnish the chiral bis‐Ti(IV)oxide (S,S)‐I. The in situ generated (S,S)‐I was cooled to ‐15 oC and treated sequentially with aldehyde 3 (0.775 g, 2.63 mmol) and allyltributyltin (tributyl (prop‐2‐en‐1‐yl) stannane (1.22 mL, 3.419 mmol) at the same temperature. The mixture was allowed to warm to 0 °C and stirred for 20 h, then the mixture was quenched with saturated aqueous NaHCO3 (50 mL), and extracted with Et2O (3 x 30 mL). The organic extracts were dried over anhydrous Na2SO4. Evaporation of the solvents and purification of the residue by column chromatography on silica gel (2% EtOAc/hexane) gave compound 2 (Scheme 1). Yield: 79%, 0.699 g. IR (KBr, ν, cm‐1): 3445, 2929, 1648, 1513, 1463, 1283. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.70 (d, 1H, J = 8.0 Hz, m‐Ar‐ H), 6.62 (d, 1H, J = 2.0 Hz, o‐Ar‐H), 6.59 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 5.72 (m, 1H, CH2‐CH=CH2), 5.12‐5.01 (m, 2H, CH2‐ CH=CH2), 3.79, (s, 3H, Ar‐O‐CH3), 3.67 (brs, 1H, 3'‐CH(OH)), 3.62 (m, 1H, 3'‐CH(OH)), 2.70‐2.51 (m, 2H, Ar‐CH2‐CH2), 2.46‐ 2.31 (m, 2H, 4'‐CH2), 1.30‐1.22 (m, 2H, Ar‐CH2‐CH2), 1.00 (s, 9H, Si‐C(CH3)3), 0.12 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 150.5, 143.2, 135.2, 120.6, 120.5, 116.8, 113.0, 71.0, 55.3, 34.2, 32.0, 25.9, 18.2, ‐4.8. ESI‐MS (m/z): 337 [M+H]+. [α]D25 = +50.65 (c 2.55, CHCl3). Anal. calcd. for C19H32O3Si: C, 67.85; H, 9.52. Found: C, 67.78; H, 9.52%. 2.2.7. (R)‐tert‐butyl 1‐(4‐(tert‐butyl dimethyl silyloxy)‐3‐ methoxy phenyl) hex‐5‐en‐3‐yl carbonate (9) To a stirred solution of compound 2 (0.200 g, 0.595 mmol) in dry MeCN (10 mL) were added (BOc)2O (0.75 mL, 3.12 mmol) and DMAP (0.101 g, 0.832 mmol) at 0 oC. After 5 h of stirring the solvent was evaporated under reduced pressure. The residue was taken up in EtOH (15 mL), and imidazole was added in catalytic amount. The resulting mixture was washed with 5% HCl solution, dried (anhydrous Na2SO4), filtered, and concentrated in vacuo, purification of the residue by column chromatography on SiO2 (1% EtOAc/hexane) gave compound 9 (Scheme 1). Yield: 78%, 0.199 g. IR (KBr, ν, cm‐1): 1710, 1631, 1520, 1486, 1263. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.69 (d, 1H, J = 8.0, m‐Ar‐H), 6.61 (d, 1H, J = 2.0 Hz, o‐Ar‐H), 6.55 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 5.73 (m, 1H, 5'‐CH), 5.11‐5.02 (m, 2H, 6'‐CH2), 4.68 (m, 1H, 3'‐CH(OH)), 3.78 (s, 3H, Ar‐O‐CH3), 2.69‐2.52 (m, 2H, Ar‐CH2‐CH2), 2.41‐2.32 (m, 2H, 4'‐CH2), 1.90 (s, 9H, CO‐O‐C(CH3)3), 1.38‐1.21 (m, 2H, Ar‐CH2‐CH2), 1.00 (s, 9H, Si‐C(CH3)3), 0.11 (s, 6H, Si‐(CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 157.2, 151.3, 143.8, 134.6, 120.8, 120.6, 112.5, 85.3, 80.2, 55.1, 35.3, 35.2, 30.8, 25.4, 18.0, ‐4.9. ESI‐MS (m/z): 459 [M+Na]+. Anal. calcd. for C24H40O5Si: C, 66.05; H, 9.17. Found: C, 66.09; H, 9.18%. 2.2.8. (4R,6R)‐4‐(4‐(tert‐butyl dimethyl silyloxy)‐3‐methoxy phenethyl)‐6‐(iodomethyl)‐1,3‐dioxan‐2‐one (10) A mixture of compound 9 (0.060 g, 0.137 mmol) and I2 (0.034 g, 1.374 mmol) in 10 mL of dry MeCN was stirred mechanically under N2 atmosphere at ‐20 oC for 6 h. The mixture was partitioned between 300 mL of 20% aqueous Na2S2O3/5% aqueous NaHCO3 and 100 mL of Et2O. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (10% EtOAc/hexane) to give pure compound 10 (Scheme 1). Yield: 84%, 0.046 g. IR (KBr, ν, cm‐1): 1697, 1454, 1372, 1156. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.83 (d, 1H, J = 8.0 Hz, m‐Ar‐H), 6.69‐ 6.61 (m, 2H, o‐Ar‐H), 4.21 (m, 1H, 5'‐CH), 4.10 (m, 1H, 3'‐CH), 3.88 (s, 3H, Ar‐O‐CH3), 3.21‐3.10 (m, 2H, 6'‐CH2‐I), 2.71‐2.53 (m, 2H, Ar‐CH2), 2.29 (m, 1H, 4'‐CHa), 2.03 (m, 1H, 4'‐CHb), 1.82‐ 1.64 (m, 2H, Ar‐CH2‐CH2) 1.21 (s, 9H, Si‐C(CH3)3), 0.01 (s, 6H, Si‐ (CH3)2). 13C NMR (50 MHz, CDCl3, δ, ppm): 150.1, 148.2, 142.7, 134.3, 120.0, 119.9, 111.8, 77.4, 75.5, 55.4, 33.8, 31.0, 25.1, 17.9, 5.2, ‐5.1. ESI‐MS (m/z): 507 [M+H]+. [α]D25 = ‐7.27 (c 1.15, CHCl3). Anal. calcd. for C20H31IO5Si: C, 47.43; H, 6.12. Found: C, 47.50; H, 6.11%. 2.2.9. (4R,6R)–4‐(4‐hydroxy‐3‐methoxyphenethyl)‐6‐(iodo‐ methyl)‐1,3‐dioxan‐2‐one (11) To a ice cooled solution of compound 10 (0.046 g, 0.092 mmol), in THF (10 mL) was added TBAF (1M THF 0.70 mL, 0.70 mmol). After 15 min of stirring the mixture was brought to room temperature and stirred for another 5 h. After completion of the reaction the mixture was concentrated and purified by column chromatography and the compound 11 was directly utilized immediately to next reaction. 2.2.10. 4‐((R)‐3‐hydroxy‐4‐((R)‐oxiran‐2‐yl)butyl)‐2‐ methoxy‐phenol (12) Compound 11 (0.028 g, 0.072 mmol) and K2CO3 (0.031 g, 0.228 mmol) in 10 mL of dry MeOH was stirred at 20 oC for 30 min. Et2O was added and the mixture was washed with 20% aqueous Na2S2O3/5% aqueous NaHCO3. The organic portion was separated, dried over anhydrous, and evaporated. The crude product was purified by column chromatography on silica gel (30% EtOAc/hexane) to give compound 12 (Scheme 1). Yield: 84%, 0.014 g. IR (KBr, ν, cm‐1): 3311, 1416, 1369, 1254. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.82 (d, 1H, J = 8.0 Hz, m‐Ar‐H), 6.68‐6.60 (m, 2H, o‐Ar‐H), 5.53 (brs, 1H, p‐Ar‐OH), 3.83 (s, 3H, Ar‐O‐CH3), 3.70 (m, 1H, 3'‐CH), 3.56 (brs, 1H, 3'‐CH‐ OH), 3.14 (m, 1H, 6'‐CHa), 3.08 (m, 1H, 5'‐CH), 2.65, (m, 1H, 6'‐ CHb), 2.61,‐2.52 (m, 2H, Ar‐CH2), 1.83‐1.61 (m, 4H, 2'‐CH2 & 4'‐ CH2). 13C NMR (50 MHz, CDCl3, δ, ppm): 150.3, 143.4, 134.6, 120.2, 120.0, 112.1, 67.8, 56.0, 51.0, 46.3, 38.2, 37.0, 32.1. ESI‐ MS (m/z): 238 [M]+. [α]D25 = +19.37 (c 0.20, CHCl3). Anal. calcd. for C13H18O4: C, 65.54; H, 7.56. Found: C, 65.49; H, 7.51%. 194 Kumar et al. / European Journal of Chemistry 4 (3) (2013) 191‐194 2.2.11. (3R, 5S)‐1‐(4‐hydroxy‐3‐Methoxyphenyl) decane‐3,5‐ diol (1) To copper iodide (0.002 g, 0.0116 mmol) in anhydrous THF (5 mL) (0.08 mL, 0.087 mmol), n‐butyl magnesium chloride was added drop wise at ‐30 °C and after 5 min compound 12 (0.014g, 0.058 mmol) was added. The mixture was allowed to warm at 0 °C and maintained at this temperature for 2 h, and the mixture was extracted with DCM (2 x 10 mL) and the extract was dried over anhyd. Na2SO4. The crude product was subjected to purification by column chromatography on silica gel (20% EtOAc/hexane) to give pure compound 1 (Scheme 1). Yield: 71%, 0.012 g. IR (KBr, ν, cm‐1): 3414, 1564, 1442, 1250. 1H NMR (200 MHz, CDCl3, δ, ppm): 6.83 (d, 1H, J = 8.0 Hz, m‐Ar‐ H), 6.70 (d, 1H, J = 2.0 Hz, o‐Ar‐H), 6.64 (dd, 1H, J = 8.0, 2.0 Hz, o‐Ar‐H), 5.53 (brs, 1H, p‐Ar‐OH), 4.02 (m, 1H, 3'‐CH(OH)), 3.88 (s, 3H, Ar‐O‐CH3), 3.86 (m, 1H, 5'‐CH(OH)), 3.58 (brs, 2H, 3'‐CH‐ OH & 5'‐CH‐OH), 2.72‐2.64 (m, 2H, Ar‐CH2), 1.78‐1.62 (m, 2H, Ar‐CH2‐CH2), 1.47‐1.22 (m, 10H, 4',6',7' & 8'‐CH2), 0.89 (t, 3H, J = 7.0 Hz, 10'‐CH3). 13C NMR (50 MHz, CDCl3, δ, ppm): 151.3, 142.5, 134.2, 120.2, 120.0, 112.1, 67.8, 56.0, 51.0, 46.3, 38.2, 37.0, 32.1, 20.4, 18.3, 14.2. ESI‐MS (m/z): 296 [M]+. [α]D25 = +7.32 (c 1.52, CHCl3). Anal. calcd. for C17H28O4: C, 68.92; H, 9.46. Found: C, 68.81; H, 9.52%. 3. Results and discussion The present synthesis of (+)‐[6]‐gingerdiol (1) was initiated by protecting the hydroxyl group of vanillin (4) by treatment with TBSCl and imidazole to form the TBS‐ether (5) (Scheme 1). The compound 5 underwent Wittig olifination with PPh2CHCOOEt to produce the unsaturated ester 6 which was reduced with NaBH4/NiCl2 to form the saturated ester, 7. The reduction of this ester 7 with DIBAL‐H to the corresponding alcohol, 8, followed by Swern oxidation yielded the desired aldehyde 3. This aldehyde (3) was subjected to Maruoka asymmetric allylation [13] using the titanium complex (S, S)‐I (Figure 1) and allyl (tributyl) tin to produce the homoallylic alcohol, 2 (ee 97%). The later was treated with di (tert‐ butyl) carbonate in the presence of DMAP to form the homoallylic tert‐ butyl carbonate, 9. The treatment of compound 9 with I2 in MeCN at ‐20 OC furnished the iodocarbonate 10 which was subsequently treated with K2CO3 in MeOH to afford the syn‐ epoxy alcohol 11 The cleavage of the TBS ether group also took place simultaneously [14,15]. Finally, the reaction of compound 11 with Grignard reagent, n‐C4H9MgBr using CuI produced the target molecule, (+)‐[6]‐gingerdiol (1) [16]. The optical and spectral properties of the compound were found to be identical to those reported for the natural product [1,2]. Ti O O OiPr O Ti OiPrO O Figure 1. Structure of complex catalyst (S, S)‐I. 4. Conclusion In conclusion, we have developed an efficient stereoselective synthesis of (+)‐[6]‐gingerdiol involving some simple steps and easily available reagents. To our knowledge, this is the second report of the synthesis of this medicinally important compound. The method may be utilized for the preparation of various analogues of this compound. 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