Enantioselective syntheses of (S)- and (R)-8,9 dihydroxydihydromagnolol

Article abstract of DOI:10.1016/S0957-4166(98)00118-9

8,9-Dihydroxydihydromagnolol 5 was synthesized in four steps in which the synthesis of magnolol 4 was improved and the absolute configuration of 5 was confirmed as (R).

Full text of DOI:10.1016/S0957-4166(98)00118-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1377–1380
Enantioselective syntheses of (S)- and (R)-8,9-
dihydroxydihydromagnolol
Wenxin Gu,a Xuegong She,a Xinfu Pan a,∗ and Teng-Kuei Yang b
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
PR China
bDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 28 January 1998; accepted 18 March 1998
Abstract
8,9-Dihydroxydihydromagnolol 5 was synthesized in four steps in which the synthesis of magnolol 4 was
improved and the absolute configuration of 5 was confirmed as (R). © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
8,9-Dihydroxydihydromagnolol 5 was isolated from Magnoliae cortex which is a Chinese crude drug
used as a repressive drug for turgescence of the thorecoabdominal region, and a stomachic.1 Magnolol
4 was known to have varied bioactivity such as: antifungal, antibacterial, antimicrobial, antiulcer and
antisecretory activity.2,3
Here we report a convenient route in which 4 was synthesized in a higher yield than before,4 and by
selective Sharpless asymmetric dihydroxylation (AD) reactions of 4, (S)-5 and (R)-5 were synthesized
first and the absolute configuration of the natural product 5 was confirmed as (R).5
∗
Corresponding author. E-mail: panxf@lzu.edu.cn
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00118-9

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W. Gu et al. / Tetrahedron: Asymmetry 9 (1998) 1377–1380
2. Results
As shown in Scheme 1, 4-bromophenol 1 was protected with chloromethyl methyl ether at room
temperature to afford compound 2, which was converted to 3 by its Grignard reaction with allyl bromide,
followed by acidification. Oxidative coupling of 3 by DDQ and AlCl3 in MeNO2 at room temperature
gave magnolol 4,6 and selective AD of 4 by AD-mix-α and AD-mix-β in t-BuOH–H2O phase and
NaHCO3 at 0°C afforded (S)-5 and (R)-5, respectively.7,8
Scheme 1.
3. Experimental section
Melting points were measured on a Kofler apparatus and were uncorrected. AD-mix-α and AD-mix-
β were purchased from Aldrich. Enantiomeric excesses were determined by HPLC analysis, using a
Chiralcel OD column. The optical rotations were measured with a Jasco J-20C automatic recording
spectropolarimeter. Mass spectra were recorded on a ZAB-HS spectrometer. Elemental analyses were
performed on a Carlo Erba 1106 instrument. IR spectra were recorded on a Nicolet 170 SXFT-IR
1
spectrometer. H-NMR spectra were recorded on a Bruker AC-80 and AM-400 instruments. Chemical
shifts are referenced to TMS on the ‘δ’ scale. Standard flash chromatography was employed to purify the
crude reaction mixture using 200–300 mesh silica gel under a positive nitrogen pressure.
3.1. 4-Bromophenol methoxy methyl ether 2
To a stirred solution of 4-bromophenol 1 (2.00 g, 9.26 mmol) in 25 mL acetone was added K2CO3
(1.28 g). The mixture was stirred at room temperature for 15 mins and MOMCl (1.06 g, 1 mL) was
added dropwise over 5 mins. The mixture was stirred and refluxed for 2 h. The solvent was evaporated in
vacuo. Crude products were dissolved in water and then extracted with Et2O (3×50 mL). The combined
extracts were dried (Na2SO4), the Et2O was distilled off, the residue was flash chromatographed using
petroleum ether and ethyl acetate (16:1, v/v) as eluent. The colorless oil 2 (1.22 g) was obtained in 98%

W. Gu et al. / Tetrahedron: Asymmetry 9 (1998) 1377–1380
1379
yield. IR (cm−1): 2825, 1277, 1078, 922, 825, 590; EI-MS: m/z 216 (M+, 40), 186 (16), 155 (16), 76
1
(25), 45 (100); H-NMR (80 MHz, CDCl3): δ 3.47 (s, 3H, –OCH3), 5.15 (s, 2H, –OCH2), 6.93, 7.39
(dd, J=8.9, 8.7 Hz, 4H, Ar–H).
3.2. 4-Allylphenol 3
To a stirred Grignard reagent of 2, which was prepared with 2 (1 g, 4.6 mmol) and magnesium turnings
(0.12 g) in dry THF (20 mL), was added allyl bromide (0.6 g) at r.t. for 30 mins dropwise. The reaction
mixture was refluxed for 3 h, then cooled to r.t. 3 N HCl (30 mL) was added in portions, refluxed for 3
h, then cooled to r.t. The THF phase was separated and the water phase was extracted with Et2O (3×50
mL). The THF and the ether layers were combined, washed with brine and dried (Na2SO4). The residue
was flash chromatographed using petroleum ether and ethyl acetate (12:1, v/v) as eluent. The colorless oil
3 (0.53 g) was obtained in 86% yield. IR (cm−1): 3240, 1639, 1440, 1365, 1108, 1058, 999, 914, 823; EI-
MS: m/z 134 (M+, 100), 119 (36), 105 (20), 91 (44), 77 (37), 65 (8), 63 (10), 51 (17), 39 (16); 1H-NMR
(80 MHz, CDCl3): δ 3.38 (d, J=6.4 Hz, 2H, –CH2CH_CH2), 5.16 (d, J=13.8 Hz, 2H, –CH2CH_CH2),
5.93 (m, 1H, –CH2CH_CH2), 6.73–7.14 (dd, J=8.35, 8.36 Hz, 4H, Ar–H).
3.3. Magnolol 4
To a solution of 3 (0.3 g) in dry nitromethane (10 mL) was added AlCl3 (0.45 g) under nitrogen. After
stirring the mixture for 0.5 h, DDQ (0.38 g) in dry nitromethane (5 mL) was added dropwise and the
solution was stirred at r.t. for 1 h. A solution of 2 N HCl was added with stirring. The resulting mixture
was extracted with CH2Cl2 (3×25 mL). The combined extracts were dried (Na2SO4), the CH2Cl2 was
distilled off, and the residue was flash chromatographed using petroleum ether and ethyl acetate (6:1,
v/v) as eluent. A white powder 4 (0.23 g) was obtained in 77% yield; mp 101–103°C (lit:9 103°C). IR
(cm−1): 3167, 1639, 1610, 1498, 1411, 1373, 1230, 991, 908, 819; EI-MS: m/z 266 (M+, 100), 247 (18),
237 (23), 224 (10), 207 (15), 197 (26), 184 (22), 165 (12), 152 (11), 133 (9), 115 (15), 91 (8), 77 (12), 55
(5), 43 (8); 1H-NMR (400 MHz, CDCl3): δ 3.31 (br d, 4H, J=6.5 Hz, H-7, H-70), 4.98 (br d, 2H, J=10.1
Hz, H-9, H-90), 5.09 (br d, 2H, J=18.5 Hz, H-9, H-90), 5.92 (ddt, 2H, J=16.7, 10.8 Hz, H-8, H-80), 6.87
(d, 2H, J=8.1 Hz, Ar–H), 7.04 (dd, 2H, J=8.5 Hz, Ar–H), 7.11 (d, 2H, J=2.1 Hz, Ar–H). Found: C, 81.09;
H, 6.79. C18H18O2 requires C, 81.17; H, 6.81%. The above data were consistent with the literature.1,10
3.4. (S)-8,9-Dihydroxydihydromagnolol (S)-5
To a stirred solution of t-BuOH (2.5 mL) and H2O (2.5 mL) was added AD-mix-α (0.7 g) and NaHCO3
(0.13 g). The mixture was stirred at r.t. until both phases were clear, and then cooled to 0°C, 4 (0.13 g)
was added at once and the mixture was stirred vigorously at 0°C until TLC revealed the absence of 4.
The reaction was quenched at 0°C by addition of Na2SO3 (0.75 g), then warmed to r.t. and stirred for
0.5 h. The reaction mixture was extracted with CH2Cl2 (3×25 mL) and dried (Na2SO4), the CH2Cl2 was
distilled off. The residue was flash chromatographed using petroleum ether and ethyl acetate (4:1, v/v)
as eluent. A white powder (S)-5 (0.12 g, 90% ee) was obtained in 88% yield, and 59% overall yield from
1. (S)-5: mp 126–128°C. [α]D20 0.75 (c=1.50, CHCl3); IR (cm−1): 3346, 1638, 1605, 1415, 1222, 1076,
1
993, 911, 822; FAB: 301 (M+1), 239 (M+−C2H5O2); H-NMR (400 MHz, CDCl3): δ 2.58 (dd, 1H,
J=13.8 Hz, H-7), 2.78 (dd, 1H, J=14.0 Hz, H-7), 3.30 (br d, 2H, J=6.4 Hz, H-70), 3.42 (m, 2H, H-9), 3.90
(m, 1H, H-8), 4.99 (br d, 1H, J=9.8 Hz, H-90), 5.05 (br d, 1H, J=18.5 Hz, H-90), 5.96 (ddt, 1H, J=16.9,

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W. Gu et al. / Tetrahedron: Asymmetry 9 (1998) 1377–1380
10.8 Hz, H-80), 6.85–7.19 (m, 6H, Ar–H). Found: C, 71.79; H, 6.69. C18H20O4 requires C, 71.98; H,
6.71%.
3.5. (R)-8,9-Dihydroxydihydromagnolol (R)-5
By a procedure similar to the preparation of (S)-5, the reaction of 4 (0.13 g, 0.05 mmol), AD-mix-β
(0.7 g), t-BuOH (2.5 mL) and H2O (2.5 mL), gave (R)-5 as a white powder (0.13 g, 92% ee) in 89% yield,
20
and 60% overall yield: mp 143–145°C; [α]D −0.76 (c=1.50, CHCl3); IR (cm−1): 3346, 1638, 1605,
1415, 1222, 1076, 993, 911, 822; FAB: 301 (M+1), 239 (M+−C2H5O2); 1H-NMR (400 MHz, CDCl3): δ
2.58 (dd, 1H, J=13.8 Hz, H-7), 2.78 (dd, 1H, J=14.0 Hz, H-7), 3.30 (br d, 2H, J=6.4 Hz, H-70), 3.42 (m,
2H, H-9), 3.90 (m, 1H, H-8), 4.99 (br d, 1H, J=9.8 Hz, H-90), 5.05 (br d, 1H, J=18.5 Hz, H-90), 5.96 (ddt,
1H, J=16.9, 10.8 Hz, H-80), 6.85–7.19 (m, 6H, Ar–H). Found: C, 71.82; H, 6.72. C18H20O4 requires C,
71.98; H, 6.71%.
20
Lit:1 [α]D −0.8 (c=1.50, MeOH); EI-MS: m/z 300.134 (M+, C18H20O4, requires: 300.136), 282,
269, 239; 1H-NMR (acetone-d6): δ 2.64 (dd, 1H, J=14.7 Hz, H-7), 2.80 (dd, 1H, J=14.5 Hz, H-7), 3.35
(br d, 2H, J=7 Hz, H-70), 3.50 (m, 2H, H-9), 3.82 (m, 1H, H-8), 5.01 (br d, 1H, J=11 Hz, H-90), 5.06 (br
d, 1H, J=18 Hz, H-90), 6.00 (ddt, 1H, J=18, 11.7 Hz, H-80), 6.80–7.35 (m, 6H, Ar–H).
Acknowledgements
We are grateful to the National Natural Science Foundation of China for financial support.
References
1. Yahara, S.; Nishiyori, T.; Kohda, A.; Nohara, T.; Nishioka, I. Chem. Pharm. Bull., 1991, 39(8), 2024.
2. Clark, A. M.; El-Feraly, F. S.; Li, W. S. J. Pharm. Sci., 1981, 70, 951.
3. Erdtman, H.; Runeberg, J. Acta Chem. Scand., 1957, 11, 1060.
4. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc., 1994, 116, 1278.
5. Sartori, G.; Maggi, R.; Bigi, F.; Grand, M. J. Org. Chem., 1993, 58, 7271.
6. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; Daris, W. D.; Hartung, J.; Jeong, K. S.; Ogino, Y.; Shibata, T.;
Sharpless, K. B. J. Org. Chem., 1993, 58, 844.
7. Kolb, H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron: Asymmetry, 1993, 4, 133.
8. Arrington, M. P.; Bennani, Y. L.; Gobel, T.; Walsh, P. J.; Zhao, S. H.; Sharpless, K. B. Tetrahedron Lett., 1993, 34, 7375.
9. Sugi, Y. J. Pharm. Soc. Jpn, 1930, 50, 23.
10. El-Feraly, F. S.; Li, W. S. Lloydia, 1978, 41, 442.