First asymmetric synthesis of chiral 1,4-benzodioxane lignans

Article abstract of DOI:10.1016/S0040-4039(00)00820-0

An asymmetric and regioselective total synthesis approach to 1,4-benzodioxane lignans was reported in which (2R,3R)- and (2S,3S)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodi oxan-6-carbaldehyde were synthesized firstly. A natural 1,4-benzodioxane neolignan was synthesized firstly by the synthesis approach. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00820-0

Tetrahedron Letters 41 (2000) 6079±6082
First asymmetric synthesis of chiral 1,4-benzodioxane
lignans
Wenxin Gu,a Xiaobi Jing,a Xinfu Pan,a,* Albert S. C. Chanb and Teng-Kuei Yangc
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, PR China
bDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
cDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 23 March 2000; revised 26 April 2000; accepted 19 May 2000
Abstract
An asymmetric and regioselective total synthesis approach to 1,4-benzodioxane lignans was reported in which
(2R,3R)- and (2S,3S)-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6-carbaldehyde were
synthesized ®rstly. A natural 1,4-benzodioxane neolignan was synthesized ®rstly by the synthesis approach.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; 1,4-benzodioxane; lignans; neolignan.
A framework of 1,4-benzodioxane has often been found in biologically active lignans. Silybin1
and americanin A2 are antihepatotoxic, and haedoxan A3 has insecticidal activity. These types of
natural products which show a variety of bioactivity have raised synthetic chemists' interests. In
recent years, several ecient syntheses of natural 1,4-benzodioxane lignans have been reported.4
Recently, we reported the total synthesis of (þ)-sinaiticin, a natural ¯avonolignan.5 An unsolved
problem in this area has been the asymmetric synthesis of chiral 1,4-benzodioxane lignans.6 We
now develop a ®rst asymmetric and regioselective synthetic approach to (2R,3R)- and (2S,3S)-3-
(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6-carbaldehyde, the important
key intermediates for syntheses of several important 1,4-benzodioxane lignans.7
* Corresponding author. E-mail: panxf@lzu.edu.cn
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00820-0

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As shown in Scheme 1, ferulic acid (1) was converted to a benzyl ether (2) in 94% yield by
esteri®cation with acidic methanol followed by treatment with benzyl chloride. Reduction of 2
gave the corresponding unsaturated alcohol (3) in 88% yield. Asymmetric dihydroxy reaction of 3 by
AD-mix-a a€ord (2S,3S)-4 in 92% e.e. and 94% yield.8 (2S,3S)-4 was treated with N-tosylimidazole9
in dry THF to give oxirane (2S,3S)-5 in 71% yield. A Mitsunobu reaction between (2S,3S)-5 and
4-benzyloxy-3-hydroxybenzaldhyde10 gave a characterized ether (2S,3R)-6 in 83% yield. In this
reaction the absolute con®guration of the C3-position was converted completely by an SN2-type
nucleophilic displacement of 4-benzyloxy-3-hydroxybenzaldehyde.11 Two benzyl groups of
(2S,3R)-6 were removed by hydrogenolysis under atmospheric pressure of hydrogen in the
presence of 5% palladized charcoal in ethyl acetate to a€ord (2S,3R)-712 in 90% yield as well as
the epoxide moiety keeping intact.13 (2S,3R)-7 underwent cyclization with potassium carbonate
to a€ord (2R,3R)-814 in 98% yield. In this reaction an intramolecular nucleophilic attack at C2-
position of oxirane by the phenol hydroxy in its potassium salt led to a complete conversion of
1
the absolute con®guration of C2-position and the formation of 1,4-benzodioxane.15 In the H
NMR spectrum of (2R,3R)-8 H-3 resonated a doublet signal at ꢀ 5.10 with a coupling constant
(J=8 Hz) indicating a typical trans-isomer and threo-con®guration. 13C NMR spectrum showed
ꢀ 61.5, 77.5, 79.5 indicating a six-membered 2-hydroxymethyl-3-aryl-1,4-benzodioxane skeleton.16
Similarly, asymmetric dihydroxy reaction of 3 by AD-mix-b a€orded (2R,3R)-9 in 91% e.e. and
90% yield.8 (2R,3R)-9 was treated in the same four steps to a€ord (2S,3S)-817 in good yield.
Scheme 1. Reactions and conditions: (i) MeOH, H2SO4, 90ꢀC, 16 h; (ii) BnCl, DMF, K2CO3, 160ꢀC, 3 h ((i) and (ii)
94%); (iii) LAH, THF, ^10ꢀC, 1 h (88%); (iv) AD-mix-a, t-BuOH, H2O, 0ꢀC, 20 h (94%); (v) N-tosylimidazole, NaH,
THF, rt, 2 h (71%); (vi) DEAD, Ph3P, 4-benzyloxy-3-hydroxybenzaldehyde, THF, rt, 24 h (83%); (vii) Pd/C (5%), H2,
EtOAc, rt, 6 h (90%); (viii) K2CO3, MeOH, rt, 1 h (98%); (ix) AD-mix-b, t-BuOH, H2O, 0ꢀC, 20 h (90%)
Advantages of the synthetic approach included: (i) 2-aryl- and 3-aryl-1,4-benzodioxane lignans
can be synthesized regioselectively when 3-benzyloxy-4-hydroxybenzaldehyde and 4-benzyloxy-3-
hydroxybenzaldehyde are used, respectively; (ii) SN2-type nucleophilic displaces on two chiral

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carbons leading to the complete conversion of the absolute con®guration of C2- and C3-positions,
so the absolute con®guration of 1,4-benzodioxane can be con®rmed and trans-isomer is a single
product.
The synthetic potential of the approach was explored in an attempt to ®rstly synthesize a natural
1,4-benzodioxane neolignan (2S,3S)-11 which was isolated from Juniperus chinensis18 (Scheme 2).
As shown in Scheme 2, the Wittig reaction of (2S,3S)-8 gave (2S,3S)-10 in 76% yield, which was
reduced by LAH in THF to a€ord (2S,3S)-1119 in 77% yield.
Scheme 2. Reactions and conditions: (i) MeO2CCHˆPPh3, THF, rt, 8 h, 76%; (ii) LAH, THF, 60ꢀC, 2 h, 77%
Acknowledgements
We are grateful to the National Science Foundation of China (No. 29972015) for ®nancial
support.
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12. Compound (2S,3R)-7: A white crystalline solid, mp 135±136ꢀC; [ꢁ]D +8.3 (c 1.0, CHCl3); H NMR (d6-acetone,
1
400 Hz): ꢀ 2.83 and 2.86 (2dd, 12.2 Hz, 2.5 Hz, 2H), 3.41 (m, 1H), 3.82 (s, 3H), 5.34 (d, 4 Hz, 1H), 6.80±7.43 (m,
6H), MS (m/z): 316 (M+, 5), 179 (28), 151 (14), 137 (100), 123 (26), 93 (19); anal. calcd for C17H16O6: C, 64.55; H,
5.10. Found: C, 64.27; H, 5.08; IR (KBr/cm^1): 3506, 3286, 3010, 2844, 1707, 1596, 1514, 1271, 1237.
13. Taniguchi, E.; Yamauchi, S.; Nagata, S.; Ohnishi, T. Biosci. Biotech. Biochem. 1992, 56, 630±635.
25
D
14. Compound (2R,3R)-8: A white solid, mp 112±113ꢀC; ‰ꢁŠ +13 (c 0.9, CHCl3); H NMR (d6-acetone, 400 Hz): ꢀ
1
3.51 and 3.78 (2dd, 12.5 Hz, 4.0 Hz, 2H), 3.76 (s, 3H), 4.15 (m, 1H), 5.10 (d, 8 Hz, 1H), 6.71±7.47 (m, 6H); 13C
NMR (d6-acetone, 100 Hz): 55.8, 61.5, 77.5, 79.5, 112.9±133.0, 191.2; FAB-MS: 317 (M+1); anal. calcd for
C17H16O6: C, 64.55; H, 5.10. Found: C, 64.48; H, 5.11; IR (KBr/cm^1): 3444, 3351, 2937, 2856, 1739, 1606, 1598,
1270, 1246.
15. Ganesh, T.; Krupadanam, G. L. D. Syn. Commun. 1998, 28, 3121±3131.

6082
16. Fukiyama, Y.; Hasegawa, T.; Toda, M.; Kodama, M. Chem. Pharm. Bull. 1992, 40, 252.
25
17. Compound (2S,3S)-8: A white solid, mp 137±139ꢀC; ‰ꢁŠ ^12 (c 1.0, CHCl3); H NMR (d6-acetone, 400 Hz): ꢀ
1
D
3.49 and 3.72 (2dd, 12.0 Hz, 4.0 Hz, 2H), 3.77 (s, 3H), 4.09 (m, 1H), 5.10 (d, 8 Hz, 1H), 6.67±7.50 (m, 6H); 13C
NMR (d6-acetone, 100 Hz): 55.9, 60.7, 76.6, 79.1, 110.6±140.7, 190.9; FAB-MS: 317 (M+1); anal. calcd for
C17H16O6: C, 64.55; H, 5.10. Found: C, 64.50; H, 5.09; IR (KBr/cm^1): 3437, 3360, 2942, 2842, 1717, 1620, 1587,
1266, 1250.
18. Fang, J. M.; Lee, C. K.; Cheng, Y. S. Phytochemistry 1992, 31, 3659±3661.
25
1
19. Compound (2S,3S)-11: A colorless oil, ‰ꢁŠ ^17 (c 0.8, MeOH); H NMR (d6-acetone, 400 Hz): ꢀ 1.77 (m, 2H),
D
2.64 (t, 2H, 7.7 Hz), 3.45 and 3.60 (2dd, 12.2, 4.0 Hz), 3.55 (t 2H, 6.5 Hz), 3.81 (s, 3H), 3.96 (m, 1H), 5.09 (d, 1H,
8.0 Hz), 6.74±7.24 (m, 6H); MS (m/z): 346 (M+, 70), 328 (55), 180 (63), 166 (81), 137 (100), 123 (42); anal. calcd for
C19H22O6: C, 65.88; H, 6.40. Found: C, 65.80; H, 6.38; IR (KBr/cm^1): 3410, 2929, 1602, 1521, 1278, 1136, 1024.