A facile enantioselective approach to neolignans

Article abstract of DOI:10.1016/S0957-4166(03)00085-5

An enantioselective and stereoselective synthesis of 8-O-4′ neolignans is reported in which a natural 8-O-4′ norneolignan is enantioselectively synthesized as a single erythro isomer. Furthermore the route has been adapted to allow the enantioselective sy

Full text of DOI:10.1016/S0957-4166(03)00085-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 701–704
A facile enantioselective approach to neolignans
Xiaochuan Chen,a Xinfeng Ren,a Kun Peng,a Xinfu Pan,a,* Albert S. C. Chanb and
Teng-Kuei Yangc
aCollege of Chemistry and Chemical Industry, State Key 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 22 November 2002; accepted 16 January 2003
Abstract—An enantioselective and stereoselective synthesis of 8-O-4% neolignans is reported in which a natural 8-O-4% norneolig-
nan is enantioselectively synthesized as a single erythro isomer. Furthermore the route has been adapted to allow the
enantioselective synthesis of 1,4-benzodioxane neolignans. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
approach a natural 8-O-4% neolignan 1,8 which was
isolated as a mixture of erythro and threo isomers from
Larix leptolepis, was synthesized enantioselectively. As
shown in Scheme 1, the synthesis of (7S,8S)-2 was
described in our previous paper.9 The benzylidene pro-
tection of (7S,8S)-2 was effected in CH2Cl2 with benz-
aldehyde dimethylacetal using a catalytic amount of
p-TSA to afford a mixture of the 1,3-benzylidene
(7S,8S)-3 and the 1,2-benzylidene (7S,8S)-4 in a 4:1
ratio, which could not be separated by silica gel column
chromatography. Fortunately we found (7S,8S)-4 in
the mixture was completely converted to the corre-
sponding ester (7S,8S)-5 using sterically hindered acid
chlorides such as p-TsCl or PhCOCl while (7S,8S)-3 in
the mixture remained unreacted. (7S,8S)-3 and (7S,8S)-
5 were readily separated by column chromatography
over silica gel, and pure (7S,8S)-3 was obtained in 67%
yield. Mitsunobu reaction10 between (7S,8S)-3 and
vanillin gave the characterized ether (7S,8R)-6 in 70%
yield. In this reaction the absolute configuration at C-8
in 3 was inverted completely by the SN2-type nucleo-
philic displacement with vanillin.
8-O-4% Neolignans have a wide range of biological
effects including anti-cercaria penetration, inhibition of
the growth of silkworm larvae, antileukemic and anti-
fungal activity, anti-leishmanial activity and so on.1,2
Moreover, this type of neolignan is structurally
analogous to the major interunit linkage of lignin, in
which about 40% of the arylpropane units are 8-O-4%
linked. Some 8-O-4% neolignans have often been used as
models for studying reactions of lignin.3 For these
reasons, this type of natural product is of great syn-
thetic and biological interest and several efficient
racemic syntheses of 8-O-4% neolignans have been
reported.4–6 However, most of the reported methods are
racemic syntheses and lead to mixtures of erythro and
threo isomers. An asymmetric synthesis of 8-O-4%
neolignans was reported in 1996, but equal amounts of
two diastereoisomers were obtained.7 Thus, stereoselec-
tivity and enantioselectivity remain unsolved problems
in the synthesis of 8-O-4% neolignans.
Cleavage of the benzylidene group from (7S,8R)-6 with
0.01N HCl in MeOH afforded the diol (7S,8R)-7. The
benzyl group of (7S,8R)-7 was removed by hydrogenol-
ysis under atmospheric pressure of hydrogen in the
presence of 5% Pd/C to afford (7S,8R)-1 in 89% yield.
We report herein
approach to erythro 8-O-4% neolignans. Using our
a novel asymmetric synthetic
1,4-Benzodioxane neolignans are another important
class of lignans which show cytotoxic and hepatopro-
tective activities.11,12 The structures of 1,4-benzodioxane
neolignans are analogous to those of 8-O-4% neolignans,
* Corresponding author. E-mail: panxf@lzu.edu.cn
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00085-5

702
X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 701–704
Scheme 1. Reagents and conditions: (i) PhCH(OMe)2, TsOH, CH2Cl2, rt, 2.5 h; (ii) TsCl, Et3N, CH2Cl2, rt, 8 h (v and vi 67%);
(iii) vanillin, Ph3P, DEAD, THF, ArOH, reflux, 24 h, 70%; (iv) HCl, MeOH, rt, 8 h, 93%; (v) 5% Pd/C, H2, MeOH, rt, 2 h, 89%.
we completed the following investigations (Scheme 2).
Mitsunobu reaction of the key intermediate (7S,8S)-3
with 4-benzyloxy-3-hydroxybenzaldehyde in place of
vanillin then provided the aryl alkyl ether (7S,8R)-8 in
41% yield. However, because the 4-Obn group in 4-ben-
zyloxy-3-hydroxybenzaldehyde is much bigger than the
3-OMe group in vanillin, the Mitsunobu reaction of
4-benzyloxy-3-hydroxybenzaldehyde with the rigid 1,3-
benzylidene (7S,8S)-3 was retarded by steric factors
and the yield of (7S,8R)-8 was drastically reduced in
comparison with that of (7S,8R)-6. Finally, deprotec-
tion and cyclization of (7S,8R)-8 upon heating in acetic
acid in the presence of 36% HCl, presumably via a
quinone methide intermediate,13 afforded the 1,4-ben-
zodioxane (2R,3R)-9 in 53% yield. In the 1H NMR
spectrum of (2R,3R)-9 H-2 resonated as a doublet
signal at l 5.12 with a coupling constant (J=8.1 Hz)
typical of the trans-configuration and threo-isomer.
Therefore in the cyclization to form (2R,3R)-7, the R
absolute configuration at C-2 must be induced by the
intact 3R-configuration. This is a new approach to the
asymmetric synthesis of 1,4-benzodioxane neolignans.
The 1,4-dioxane 9 has been used as the key intermedi-
ate in the synthesis of several important 1,4-benzodi-
oxan lignans such as isosilybin and hydnocarpin.14,15
In conclusion, we have demonstrated a highly enan-
tioselective synthesis of erythro-8-O-4% neolignans, and
Scheme 2. Reagents and conditions: (i) 4-benzyloxy-3-hydroxybenzaldhyde, Ph3P, DEAD, PhH, Ar, 70°C, 24 h, 41%; (ii)
AcOH:36% HCl (1:1), 65°C, 1 h, 53%.

X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 701–704
703
we have successfully adapted the route to allow the
asymmetric synthesis of 1,4-benzodioxane neolignans.
The route presented herein can thus be applied to the
asymmetric syntheses of both neolignans.
mmol) and diethylazodicarboxylate (0.24 mL, 1.5
mmol) was heated to reflux in anhydrous THF (12 mL)
for 24 h under argon. The mixture was concentrated
under reduced pressure, and the residue was chro-
matographed using petroleum ether:ethyl acetate (6:1)
gave (1S,2R)-6 (0.37 g, 70%) as a colorless gum, [h]D25
1
−51 (c 0.6, acetone); H NMR (CDCl3, 200 MHz): l
2. Experimental
3.83 (s, 3H, -OMe), 3.85 (s, 3H, -OMe), 4.28–4.68 (m,
3H, 8-H, 9-H), 4.91 (d, 1H, 9.0 Hz, 7-H), 5.11 (s, 2H,
PhCH2O-), 5.77 (s, 1H, PhCH-), 6.6–7.7 (m, 16H,
Ar-H), 9.79 (s, 1H, CHO); EI-MS: m/z 526[M]+ (0.8),
242 (10), 178 (10), 133 (8), 105 (12), 91 (100), 77 (9).
Anal. calcd for C32H30O7: C, 72.99; H, 5.74; found C,
73.04; H, 5.73%.
Melting point was measured on a Kofler apparatus and
was uncorrected. MS were performed on a HP 5988A
1
GC/MS instrument and a ZAB-HS instrument. H and
13C NMR spectra were recorded on a Bruker AM-80
FT NMR spectrometer, a Bruker AM-200 FT NMR
spectrometer and a Bruker AM-400 FT NMR spec-
trometer in CDCl3. Chemical shifts are referred to TMS
on the ‘l’ scale. Chiral analysis was performed on
Varian Dynamax SD-300 using Chiralcel column
CDMPC (150×4.6 mm D) with hexane/isopropyl alco-
hol as eluent. IR spectra were recorded on a Nicolet
FT-170 SX spectrometer. Microanalyses were per-
formed on a MOD-1106 elemental analyzer. Chro-
matography was employed to purify the crude reaction
mixture using 200–300 mesh silica gel.
2.3. (1S,2R)-1-(4-Benzyloxy-3-methoxyphenyl)-2-(4-for-
myl-2-methoxyphenoxy)propane-1,3-diol, 7
To a solution of HCl in MeOH (0.01N, 40 mL) was
added (1S,2R)-6 (0.2 g, 0.38 mmol), and the mixture
was stirred at rt for 8 h. The solution was neutralized
with sat. aq NaHCO3. Subsequently the solvent was
concentrated in vacuo and the residue was taken up in
AcOEt. The organic phase was separated, washed with
H2O, dried with Na2SO4 and concentrated. Column
chromatography using petroleum ether:ethyl acetate
(3:1, v/v) furnished (1S,2R)-7 (0.15 g, 93%) as a color-
2.1. (1S,2S)-1,3-O-Benzylidene-1-(4-benzyloxy-3-
methoxyphenyl)-1,2,3-propanetriol, 3
To a solution of (1S,2S)-2 (1.20 g, 3.9 mmol) in CH2Cl2
(100 mL) was added p-toluenesulfonic acid (20 mg) and
benzaldehyde dimethylacetal (0.62 mL, 4.1 mmol), the
mixture was stirred at rt for 2 h. The mixture was
neutralized with sat. aq NaHCO3 and the organic phase
was separated, washed with H2O, dried with Na2SO4
and concentrated. Column chromatography using
petroleum ether:ethyl acetate (6:1, v/v) furnished a mix-
ture of (1S,2S)-3 and (1S,2S)-4 (1.30 g, 4:1).
1
less gum, [h]2D5 −36 (c 0.4, acetone); H NMR (CDCl3,
200 MHz): l 3.75–4.10 (m, 2H, 9-H), 3.88, 3.91 (2×s,
6H, OMe), 4.42 (m, 1H, 8-H), 5.00 (d, 1H, 5.2 Hz,
7-H), 5.14 (s, 2H, PhCH2O-), 6.8–7.6 (m, 11H, Ar-H),
9.85 (split s, 1H, -CHO). EI-MS: m/z 438 [M]+ (0.9),
243 (17), 242 (26), 178 (6), 151 (6), 91 (100), 65 (9).
Anal. calcd for C25H26O7: C, 68.48; H, 5.98; found C,
68.47; H, 5.99%.
To the solution of (1S,2S)-3 and (1S,2S)-4 (1.30 g, 3.3
mmol) in CH2Cl2 (50 mL) containing Et3N (1 mL) was
added p-toluenesulfonyl chloride (0.63 g, 3.3 mmol)
and the mixture was stirred for 8 h at rt. The excess
p-toluenesulfonyl chloride was destroyed by the addi-
tion of MeOH (1 mL) and the solvent was concentrated
under reduced pressure. The residue was taken up in
ethyl acetate and washed with NaHCO3. The organic
phase was dried (Na2SO4) and concentrated; chro-
matography over silica gel eluted with petroleum
ether:ethyl acetate (6:1, v/v) gave pure (1S,2S)-3 (1.03
2.4. (1S,2R)-1-(4-Hydroxy-3-methoxyphenyl)-2-(4-for-
myl-2-methoxyphenoxy)propane-1,3-diol, 1
To a stirred solution of (1S,2R)-7 (50 mg, 0.11 mmol)
in methanol (7 mL) was added 10% palladized charcoal
(5 mg). After stirring for 2 h at room temperature
under atmospheric pressure of hydrogen, the solvent
was concentrated under reduced pressure. The residue
was purified by chromatography on silica gel eluted
with petroleum ether:ethyl acetate (2:1, v/v) to afford
(1S,2R)-1 (35 mg, 89%). Colorless gum, [h]2D5 −12 (c 0.4,
1
g, 67%). Colorless gum, [h]2D5 +55 (c 0.7, acetone); H
NMR (CDCl3, 200 MHz): l 3.79 (br.s, 1H, 8-H), 3.90
(s, 3H, -OMe), 4.23 (d, 11.9 Hz, 1H, 9-H), 4.36 (dd,
11.9, 1.8 Hz, 1H, 9-H), 5.02 (s, 1H, 7-H), 5.16 (s, 2H,
PhCH2O-), 5.77 (s, 1H, PhCH-), 6.8–7.7 (m, 13H,
Ar-H); EI-MS: m/z 392[M]+(0.7), 243 (9), 107 (15), 91
(100), 77 (10), 65 (10), 57 (11), 43 (18). Anal. calcd for
C24H24O5: C, 73.45; H, 6.16; found C, 73.47; H, 6.11%.
1
acetone); H NMR (CDCl3, 200 MHz): l 3.75–4.10 (m,
2H, 9-H), 3.86, 3.90 (2×s, 6H, OMe), 4.40 (m, 1H,
8-H), 4.98 (d, 1H, 5.2 Hz, 7-H), 6.8–7.1 and 7.3–7.5 (m,
6H, Ar-H), 9.83 (split s, 1H, -CHO). 13C NMR (CDCl3,
100 MHz): l 55.9, 56.0, 61.3 (9-C), 73.4 (7-C), 85.6
(8-C), 108.9, 110.2, 114.3, 117.6, 119.3, 126.6, 131.8,
145.4, 146.7, 151.4, 152.8, 190.8. EI-MS: m/z 348 [M]+
(0.4), 195 (1), 178 (100), 153 (68), 152 (61), 151 (40), 137
(21), 93 (38). IR (film): 3450, 1678, 1590, 1510, 1462,
1427, 1271, 1237, 1157, 1133, 1029, 912, 864, 815, 782,
732 cm−1. Anal. calcd for C18H20O7: C, 62.06; H, 5.79;
found C, 62.10; H, 5.78%.
2.2. (1S,2R)-1,3-O-Benzylidene-1-(4-benzyloxy-3-
methoxyphenyl)-2-(4-formyl-2-methoxyphenoxy)propane-
1,3-diol, 6
A mixture of (1S,2S)-3 (0.40 g, 1.0 mmol), vanillin
(0.23 g, 1.5 mmol), triphenylphosphine (0.40 g, 1.5

704
X. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 701–704
Acknowledgements
2.5. (1S,2R)-1,3-O-Benzylidene-2-(2-benzyloxy-5-
formylphenoxy)-1-(4-benzyloxy-3-methoxyphenyl)-pro-
pane-1,3-diol, 8
We are grateful to the National Science Foundation of
China (No. 29972015) for financial support.
A mixture of (1S,2S)-3 (0.10 g, 0.26 mmol), 4-benzyl-
oxy-3-hydroxybenzaldhyde (87 mg, 0.38 mmol),
triphenylphosphine (0.10 g, 0.38 mmol) and diethyl-
azodicarboxylate (0.06 mL, 0.38 mmol) was heated at
70°C in anhydrous PhH (8 mL) for 24 h under argon.
The mixture was concentrated under reduced pressure
and the residue was chromatographed using petroleum
ether:ethyl acetate (6:1) gave (1S,2R)-8 (63 mg, 41%) as
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a colorless gum, [h]D25 −22 (c 0.5, acetone); H NMR
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