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Total Synthesis of

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Total Synthesis of

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    Total Synthesis of

    threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxy

    propane-1,2-diol

    5 XIA Yamu, LIU Haixin, DAI Xiaoli

    (College of Chemical Engineering, Qingdao University of Science and Technology,

    ShanDong QingDao 266042)

    Abstract: Ficus beecheyana's rhizomes have long been used as a folk medicine to treat rheumatism and diabetes. threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol was isolated

    10 from the roots of this plant. In the paper, the asymmetric synthesis of threo-(2S,3R)-3-(4-Hydroxy-3,5- dimethoxyphenyl)-3-ethoxypropane-1,2-diol was reported for the first time, and based on the asymmetric dihydroxylation as a key reaction. The target compound was obtained through six steps. Keywords: Asymmetric synthesis; Sharpless dihydroxylation reaction; Grignard reaction

    15 0 Introduction

    threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol (1) was

    [1] isolated from the roots of Ficus beecheyanain 2002. Ficus beecheyana Hook. & Arn.

    (Moraceae) is a semideciduous tree with brown, tomentose branches and is widely distributed in

    [2]east Asia, especially in mainland China, Hong Kong, Vietnam, and Taiwan. Its rhizomes have

    [3-4] 20 long been used as a folk medicine to treat rheumatism and diabetes, and as a carminative.

    This report provide the total synthesis of threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-

    3-ethoxypropane-1,2-diol(1). The synthesis involved a Grignard reaction to construct the skeleton of natural product, followed by asymmetric dihydroxylation reaction to give the

    [5] threo-(2S,3R)-diol(Scheme 1). The target compound(1) was obtained through six steps.

     OHMgCl CHO CO H 3HCOCHOHCOCHOHCO333 BnBr OPiperidine, H 2 THF,;0? Acetone, rt BnO HCO HOBnO feflux 3 OCH OCHOCH 3OCH 333 2 3 4 5

     O O O HCO 3COHHCO33H, Pd/C 2OH AD-;mi;x-;β;; H EtI, Na OH OH OH 0? HOTHF, rt BnOBnO OCH 3OCHOCH 33 6 7 1 25Scheme1. Synthesis route of the target product

    1 Experimental

    Melting points were taken on Kofler melting point apparatus and are uncorrected. Optical

    30 rotations were determined on a Perkin-Elmer 341 polarimeter. Infrared spectra were recorded on a

    113Nicolet NEXUS 670 and Nicolet AVATAR 360 FT?IR. The H NMR and C NMR spectra were

    recorded on a Mercury Plus-300 MHz spectrometer. Mass spectra were recorded on a ZAB?HS

     spectrometer. Flash column chromatography was performed on silica gel (200300mesh) and TLC

    Foundations: Specialized Research Fund for the Doctoral Program of High Education of China (No. 20093719120004); National Natural Science Foundation of Shandong (No. ZR2010HM023)

    Brief author introduction:Xia Yamu, (1974-), male, Ph. D, Associate Prefessor, Medicinal Chemistry. E-mail: xiaym@qust.edu.cn

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    inspections on silica gel GFplates. 254

    35 4-hydroxy-3,5-dimethoxybenzaldehyde(3): A solution of 3,4,5-trimethoxybenzaldehyde

    (15.6g, 80mmol) in piperidine/HO (1:1, 100mL) was heated under reflux for 48 h and the cooled 2

    mixture was poured into 3 N HCl. The mixture was extracted with AcOEt. The organic layer was

    dried over magnesium sulfate, filtered, then concentrated in vacuo. Flash column chromatography

    1 of residue gave compound 3 as a white crystal (10.5g, 72%). M.p. 111?112?. HNMR (300MHz,

    40 CDCl), δ: 3.97(s, 6H), 7.16(s, 2H), 9.82(s, 1H). 3

    4-benzyloxy-3,5-dimethoxybenzaldehyde(4): To a well-stirred solution of KCO(3.5g, 23

    25mmol) and compound 3 (9.0g, 50mmol) in ethanol was added dropwise benzyl bromide (8.5g,

    50mmol). The mixture was stirred for 6 h, then concentrated in vacuo. The residue was dissolved

    in AcOEt (100mL), filtered, and washed with 10% aqueous NaOH and NaCl saturated solution for 45 3 times respectively. The extract was dried over magnesium sulfate, filtered, then concentrated in

    vacuo to remove AcOEt. The solids were recrystallised in CHOH to yield the compound 4 as a 251colourless crystal (12.9 g, 95%). H NMR (60 MHz, CDCl), δ: 3.9 (s, 6H), 5.2 (s, 2H), 7.2 (s, 2H), 3

    7.3 ~ 7.6 (m, 5H), 9.8 (s, 1H).

    1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-en-1-ol(5): The compound 4 (10.9g, 40mmol) and

    50 vinylmagnesium chloride (3.5g, 40mmol) in dry THF was stirred for 8h, and then quenched with

    saturated ammonium chloride solution (100mL). The mixture extracted with CHCl. The 22

    combined organic extracts were dried with magnesium sulfate, and concentrated in vacuo. Flash

    column chromatography of the residue gave compound 5 as a white crystal (10.8g, 90%). IR

    -11~ (KBr), /cm: 3451, 2938, 1591, 1501, 1458, 1417, 1328, 1230, 1126, 987, 922, 836. H NMR v

    55 (300 MHz, CDCl), δ: 3.81 (s, 6H, 2 × OCH), 4.98 (s, 2H, ArCH), 5.09 (d, 1H, J = 5.7 Hz, 332

    CHOH), 5.34 (d, 1H, J = 10.5 Hz, CH=CH), 5.19 (d, 1H, J = 16.5 Hz, CH=CH), 6.04 (m, 1H, 2213CH=CH), 6.57 (s, 2H, ArH), 7.25 ~ 7.50 (m, 5H, ArH). C NMR (75 MHz, CDCl), δ: 55.9 (2 × 23

    OCH), 74.9 (ArCHO), 75.3 (ArCHOH), 103.2, 103.2, 115.1(CH=CH), 127.7, 128.0, 128.0, 322+128.4, 128.4, 136.2, 137.8, 138.4 (CH=CH), 139.9, 153.5, 153.5. EI-MS, m/z: 300 (M, 19), 249 2

    60 (2), 223(3), 209 (5), 91 (100).

    1-ethoxyallyl-1-(4-benzyloxy-3,5-dimethoxybenzene)-2-propylene(6): Compound 5 (6.0g,

    20mmol) and NaH (0.5g 20mmol) were added at room temperature to dry THF. The mixture was

    stirred for 30 minute, then added iodoethane (3.2g, 20mmol), stirred for 12 h, and then quenched

    with saturated ammonium chloride solution. The combined organic extracts were washed with 65 brine, dried with magnesium sulfate, and concentrated in vacuo. Flash chromatography of the

    -1~ residue over silica gel gave compound 6 (5.4 g, 82%) as a pale yellow oil. IR (KBr), v/cm:

    12972, 1591, 1501, 1458, 1418, 1331, 1230, 1126, 991, 923, 833. H NMR (300 MHz, CDCl), δ: 3

    1.25 (t, 3H, J = 7.2 Hz, CHCH), 3.47 (q, 2H, J = 7.2 Hz, CHCH), 3.82 (s, 6H, 2 × OCH), 4.66 23233

    (d, 1H, J = 6.3 Hz, ArCHOCH), 4.99 (s, 2H, ArCHOAr), 5.19 (d, 1H, J = 10.5 Hz, CH=CH), 222

    70 5.26 (d, 1H, J = 17.5 Hz, CH=CH), 5.94 (m, 1H, CH=CH), 6.56 (s, 2H, ArH), 7.24 ~ 7.51 (m, 22135H, ArH). C NMR (75 MHz, CDCl), δ: 15.2 (OCHCH), 55.9 (2 × OCH), 63.9 (OCHCH), 323323

    74.9 (ArCHOH), 82.9 (ArCHOCH), 103.5, 103.5, 116.1 (CH=CH), 127.7, 128.0, 128.0, 128.4, 22+128.4, 136.1, 137.0, 137.8 (CH=CH), 138.9, 153.4, 153.4. EI-MS, m/z: 328 (M, 14), 237 (40), 2

    209 (4), 193 (33), 91 (100).

    75 threo-(2S,3R)-3-(4-benzyloxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol(7): AD-mix-

    β (14g) was added to piperidine/HO(1:1), The mixture was stirred at room temperature until 2

    clarify, added methanesulfonamide (0.95g). The solution was allowed to cool to 0?, added 6

    (3.3g, 10mmol), and stirred at 0? for 30 h, and then quenched with sodium sulfite, and stirred for 豆丁网地址,/msn369

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     40 minute. The solution was extracted with AcOEt (3 × 25mL). The combined organic extracts

    were dried with magnesium sulfate, and concentrated in vacuo. Flash chromatography of the 80 20= +32.0 (c 0.8, CHCl). residue over silica gel gave compound 7 (1.7g, 47%) as a white solid. [α] D3 -1~ IR (KBr), v/cm: 3411, 2936, 1590, 1500, m1458, 1418, 1325, 1233, 1124, 1031, 980, 914, 837. 1 H NMR (300 MHz, CDCl), δ: 1.25 (t, 3H, J = 7.0 Hz, CHCH), 3.51 (m, 2H, OCHCH), 3.47 32323 1H, J = 9.2 Hz, J = 3.0 Hz, CHOH), 3.52 (dd, 1H, J = 9.2 Hz, J = 3.0 Hz, CHOH), 3.82 (s, (dd,22

    7H, 2 × OCH, CHOHCHOH), 4.27 (d, 1H, J = 7.8 Hz, ArCHOCH), 5.00 (s, 2H, ArCHOAr), 85 3222 136.54 (s, 2H, ArH), 7.24 ~ 7.49 (m, 5H, ArH). C NMR (75 MHz, CDCl), δ: 15.2 (OCHCH), 323 56.1 (2 × OCH), 62.4 (CHOH), 64.4 (CHOHCHOH), 65.0 (OCHCH), 74.9 (ArCHOH), 82.6 32223

     (ArCHOCH), 103.7, 104.0, 127.8, 128.1, 128.1, 128.4, 128.4, 134.1, 136.6, 137.7, 153.4, 153.4. 2 +EI-MS, m/z: 362 (M, 2), 301 (21), 211 (15), 123 (8), 91 (100).

    ): 10% threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol(190

     palladised charcoal (0.1g) was added to a stirred solution of compound 7 (1.1g, 3mmol) in methanol (50mL). After stirring for 12 h at room temperature under atmospheric pressure of

     hydrogen, the solvent was filtered and concentrated under reduced pressure. Flash chromatography of the residue over silica gel gave compound 1 (0.74 g, 90%) as a white solid. -120~ [α]= +27.6 (c 0.4, CHCl). IR (KBr), v/cm: 3417, 2937, 1707, 1612, 1516, 1461, 1428, 1327, 95 D31 1216, 1114, 1031, 911, 837. H NMR (300 MHz, CDCl), δ: 1.25 (t, 3H, J = 7.0 Hz, CHCH), 323 3.40 (m, 2H, OCHCH), 3.52 (dd, 1H, J = 11.2 Hz, J = 4.0 Hz, CHOH), 3.76 (dd, 1H, J = 11.2 232 Hz, J = 3.0 Hz, CHOH), 3.82 (m, 7H, 2 × OCH, CHOHCHOH), 4.25 (d, 1H, J = 7.8 Hz, 232 13ArCHOCH), 6.54 (s, 2H, ArH). C NMR (75 MHz, CDCl), δ: 15.3 (OCHCH), 56.3 (2 × 2323

    OCH), 62.3 (CHOH), 64.3 (CHCHO), 75.4 (CHOHCHOH), 82.6 (ArCHOCH), 103.9, 103.9, 100 323222 + 129.4, 134.5, 147.1, 147.1. EI-MS, m/z: 272 (M, 4), 237 (2), 211 (100). 2 Results and discussion The synthesis route of threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane- 1,2-diol(1) is outlined in Scheme 1. Synthesis of the first part began from 3,4,5-trimethoxybenzaldehyde(2). Demethylation of compound 2 by treatment with piperidine and 105 [6] HO yielded compound 3. This method was effective to cleave the 4-O-methyl group of 2 [7]3,4,5-trimethoxybenzaldehyde(2). Protection of 3 with benzyl bromide afforded compound 4. It

     was anticipated that condensation of 4 with vinylmagnesium chloride would furnish allyl alcohol [8][9-10] 5, followed by alkylation reaction with iodoethane to give ether 6. Compound 6 was treated

    with AD-mix-β to provide the key intermediate threo-(2S,3R)-diol(7). Compound 7 was reduced 110 by Hwith Pd/C to give the target product threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3- 2 [11] ethoxypropane-1,2-diol(7). The spectroscopic data of compound(1) was in agreement with the [1,4]literature. 3 Conclusion we have developed an efficient and practical synthesis of natural product(1). The synthesis 115

     was based on Grignard reaction to construct the skeleton of the target compound, and Sharpless dihydroxylation reaction with AD-mix-β to give the dihydroxy compound(7). Finally,

     threo-(2S,3R)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol(1) was obtained with the about 21% total yields. Acknowledgements 120

    This work was financially supported by the Specialized Research Fund for the Doctoral

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    Program of High Education of China (No. 20093719120004) and National Natural Science

     Foundation of Shandong (No. ZR2010HM023).

     125References [1] Lee T. H., Kuo Y. C., Wang G. J.. et al., J. Nat. Prod., 2002, 65: 1497-1500. [2] Huang T. C.. National Science Council of the Republic of China, 1996, Vol. 2: 154. [3] Chiu N. Y., Chang K. H.. The Illustrated Medicinal Plants of Taiwan, 1992, Vol. 3: 40. [4] Kikuzaki H., Hara S., Kawai Y., Nakatani N.. Phytochemistry, 1999, 52: 1307-1312. 130 [5] K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, D. Q. Xu and X. L. Zhang. J. Org. Chem., 1992, 57: 2768. [6] Junwei Ding, Rongwei Qi, Haitang Zhou, Bin Jiao and Yamu Xia. Journal of Chemical Research, 2011, September: 519-521. [7] A. J. Quillinan and F. Scheinamann. J. Chem. Soc., 1973, 1329.

    135 [8] A. E. Jensen, W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P. Knochel. Synthesis, 2002, 565.

     [9] Maximilian A. Silvestri, Deborah Miles, Arlene P. Rothwell, Karl V. Wood and Mark Cushman. Rapid

     Commun. Mass Spectrom, 2003, 17: 1703-1708. [10] Tariq Javed and Ghassan F. Shattat. J. Heterocyclic Chem., 2005, 42: 217-220. [11] Bruns R., Kopf J., Köll P.. Chem. Eur. J., 2000, 6: 1337?1345.

    140 (1R,2S)-1-乙氧基-1-(4'-羟基-3',5'-二甲氧基苯基)-2,3-

     丙二醇的全合成 夏亚穆!刘海新!戴晓丽 ?青岛科技大学化工学院!山东 青岛 266042 摘要,天仙果的根茎在中医中常用于治疗 风湿病、糖尿病!(1R,2S)-1-乙氧基-1-(4'-羟基-3',5'- 二甲氧基苯基)-2,3-丙二醇是从其中分离145 出的天然产物。本文首次报道了(1R,2S)-1-乙氧基 -1-(4'-羟基-3',5'-二甲氧基苯基)-2,3-丙二醇的合成!首先利用格氏反应构建化合物骨架结构!

     AD-mix-β 试剂氧化获得手性双羟化产物!最终经六步反应得到目标化合物。 关键词,手 性合成(Sharpless 双羟化(格氏反应

     中图分类号,O621.3

    150

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