A new approach for synthesis of erythro 8-0-4′ neolignans

Article abstract of DOI:10.1081/SCC-120002402

Erythro- 1-(4-hydroxy-3-methoxyphenyl)-2- (4-formyl-2-methoxy-phenoxy)-propane-1,3-diol, a 8-0-4′ norneolignan, has been stereoselectively synthesized in eight steps from ferulic acid. In this new route to prepare erythro 8-0-4′ neolignans the cis addition of mCPBA to a double bond with high regioselectivity was a key step, and its mechanism is discussed.

Full text of DOI:10.1081/SCC-120002402

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A NEW APPROACH FOR SYNTHESIS OF ERYTHRO 8-
O-4′ NEOLIGNANS
XiaoChuan Chen a , WenXin Gu a , XiaoBi Jing a & XinFu Pan b
a Department of Chemistry , National Laboratory of Applied Organic Chemistry , Lanzhou
University , Lanzhou, 730000, P. R. China
b Department of Chemistry , National Laboratory of Applied Organic Chemistry , Lanzhou
University , Lanzhou, 730000, P. R. China
Published online: 16 Aug 2006.
To cite this article: XiaoChuan Chen , WenXin Gu , XiaoBi Jing & XinFu Pan (2002) A NEW APPROACH FOR SYNTHESIS OF
ERYTHRO 8-O-4′ NEOLIGNANS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:4, 557-564, DOI: 10.1081/SCC-120002402
To link to this article: http://dx.doi.org/10.1081/SCC-120002402
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SYNTHETIC COMMUNICATIONS, 32(4), 557–564 (2002)
A NEW APPROACH FOR SYNTHESIS
OF ERYTHRO 8-O-40 NEOLIGNANS
XiaoChuan Chen, WenXin Gu,
XiaoBi Jing, andXinFu Pan *
Department of Chemistry, National Laboratory of
Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
ABSTRACT
Erythro-1-(4-hydroxy-3-methoxyphenyl)-2-(4-formyl-2-meth-
oxy-phenoxy)-propane-1,3-diol, a 8-O-40 norneolignan, has
been stereoselectively synthesized in eight steps from ferulic
acid. In this new route to prepare erythro 8-O-40 neolignans
the cis addition of mCPBA to a double bond with high regio-
selectivity was a key step, and its mechanism is discussed.
1-(4-hydroxy-3-methoxyphenyl)-2-(4-formyl-2-methoxyphenoxy)-
propane-1,3-diol 9, a natural 8-O-40 norneolignan, was isolated as a mixture
of erythro and threo isomers from wood of Larix leptolesis.1 This kind of
neolignan have shown various biological activities.2–4
As reported previously, the synthesis of 8-O-40 neolignans was mainly
achieved using oxidative coupling of monolignols4,5 and reduction of
ketones which were prepared from bromoketones and phenols in basic
conditions,6 but these methods led to the mixture of erythro and threo
*Corresponding author.
557
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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CHEN ET AL.
isomers in all the cases tested. A stereoselective synthetic route to directly
obtain a single diastereoisomer has not been reported. Herein, we developed
a stereoselective synthetic approach to the erythro isomer of 8-O-40 neo-
lignans, by which a 8-O-40 norneolignan 9 was synthesized from ferulic acid.
As shown in Scheme 1, ferulic acid 1 was converted into compound
4 through esterification, etherification and reduction in good yields.
Reagents and conditions: i. MeOH, H2SO4, 85ꢀC, 36 h, 95%; ii. BnBr, K2CO3,
DMF, 60ꢀC, 2 h, 98%; iii. LAH, THF, À15ꢀC, 1 h, 86%; iv. m-CPBA, CH2Cl2,
0ꢀC, 12 h, 74%; v. PhCOCl, Et3N, CH2Cl2, À10ꢀC, 6 h, 83%; vi. vanillin, Ph3P,
DEAD, THF, Ar, r.t., 16 h, 75%; vii. K2CO3, MeOH : H2O (9 : 1), r.t., 2 h, 98%;
viii. 5% Pd/C, H2, MeOH, r.t., 6 h, 77%.
Scheme 1.
Compound 4 was treated with mCPBA to directly afford compound 5
with threo configuration, which was confirmed by the H-9 signal in its
1H-NMR spectrum,7 but not the corresponding epoxide. Selective protec-
tion of primary hydroxy group of 5 using benzoyl chloride and triethylamine
afforded compound 6. Mitsunobu reaction between 6 and vanillin gave
aryl alkyl ether 7. In this reaction the configuration of the C-8 position in
6 was converted completely by a SN2 nucleophilic displacement by vanillin.8
Removal of the m-chlorobenzoyl and benzoyl groups with K2CO3 in
aqueous methanol furnished compound 8. After hydrogenolysis of 8
under atmospheric pressure of hydrogen in the presence of 5% Pd/C,
compound 9 was obtained as single erythro isomer.

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ERYTHRO 8-O-40 NEOLIGNANS SYNTHESIS
559
In our route the mCPBA step is interesting and novel. In fact, the
reaction was a cis addition of mCPBA to double bond of 4 with high
regioselectivity, not epoxidation of 4. This result was mainly due to the
presence of the 4-OBn group on the aryl ring in 4. When compound 10,
E-cinnamyl alcohol, was treated with mCPBA under the same conditions as
4, it give the epoxide 11 in high yield (Scheme 2). Highly stereoselective
and regioselective cleavage of epoxide ring of 11 with benzoic acid in the
Reaction and conditions: i. m-CPBA, CH2Cl2, 0ꢀC, 14 h, 88%; ii. PhCOOH, Ti(O-i-
Pr)4, CH2Cl2, Ar, r.t., 3h, 86%.
Scheme 2.
presence of titanium isopropoxide successfully afforded the erythro diol 12.9
The signals due to H-9 of 12 (erythro) were clearly shifted further downfield
than those of 5 (threo) in the 1H-NMR spectrum, which confirmed the threo
configuration of 5. Therefore, we suspect the reaction of 4 with mCPBA
proceeds in the following way (Scheme 3).
Scheme 3.

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CHEN ET AL.
As the phenyl group with 4-OBn and 3-OMe substituents is a powerful
electron-release group, it increases the electron density and nucleophilic
property of the double bond in 4. The electrophilic peroxide oxygen in
mCPBA attacks the double bond of 4,10 and forms a three-member cyclic
transition state. As the 4-OBn on the phenyl group can stabilize the electron
deficient C-7, the bond between C-7 and the peroxide oxygen is polarized
further. The increasing polarization leads to the electron rich carboxyl
group of mCPBA attacking C-7 on the same face as epoxidation, and the
bond between C-7 and the peroxide oxygen is cleaved simultaneously to
form compound 5. Therefore, because of the presence of 4-OH or 4-OMe
groups on the aryl rings in all natural 8-O-40 neolignans, our route can be
used as an effective approach to synthesize erythro 8-O-40 neolignans.
EXPERIMENTAL
Melting points were measured on a Kofler apparatus and were uncor-
rected. MS were performed on a HP 5988A GC/MS instrument and a
ZAB-HS instrument. IR spectra were recorded on a Nicolet FT-170 SX
1
spectrometer. H-NMR 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 spectrometer in CDCl3. Chemical shifts are
referred to TMS on the ‘‘d’’ scale. Microanalyses were performed on a
MOD-1106 elemental analyzer. Chromatography was employed to purify
the crude reaction mixture using 200–300 mesh silica gel.
Compound 2 and 3 were synthesized by the reported procedure.11,12
(2E )-3-(4-Benzyloxy-3-methoxyphenyl)-2-propene-1-ol(4).LAH(1.24 g,
32.7 mmol) was added to anhydrous THF (70 mL). After stirring for 20 min,
the suspension was cooled to À15ꢀC. 3 (6.50 g, 21.8 mmol) was added to the
stirred suspension in portions maintained under À10ꢀC. After 1 h, the reac-
tion was worked up with water (2.5 mL). The mixture was filtered, and the
filter cake was washed thoroughly with ethyl acetate. The combined filtrate
and washings were concentrated under reduced pressure. The residue was
chromatographed on silica gel eluted with petroleum ether : acetone (10 : 1)
to give pure 4 (5.06 g, 86%). White needle crystal, mp: 79–80ꢀC. H-NMR
1
(200 MHz): d 3.87 (s, 3H, OMe), 4.25 (dd, 2H, 5.8 Hz, 1.2 Hz, 9-H), 5.12
(s, 2H, PhCH2O-), 6.20 (dt, 1H, 15.8 Hz, 5.8 Hz, 8-H), 6.50 (d, 1H, 15.8 Hz,
7-H), 6.8–7.5 (m, 8H, Ar-H). EI-MS: m/z 270 [M]þ (25), 179 (12), 151 (8),
119 (18), 91 (100), 84 (18). Anal. calcd for C17H18O3: C, 75.53; H, 6.71%;
found C, 75.55; H, 6.70%.
Threo-1-O-m-chlorobenzoyl-1-(4-benzyloxy-3-methoxyphenyl)-1,2,3-
propanetriol (5). To a solution of 4 (3.00 g, 11.1 mmol) in CH2Cl2 at 0ꢀC was

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ERYTHRO 8-O-40 NEOLIGNANS SYNTHESIS
561
added mCPBA (4.11 g, 16.7 mmol) in portions. After being stirred for 4 h at
0ꢀC, the mixture was kept in the refrigerator overnight. The filtered solution
was washed successively with Na2SO3, NaHCO3, water and brine. The
combined aqueous phase were extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and concentrated. Purification of
crude product by chromatography on silica gel (petroleum ether : acetone,
3: 1) gave 5 (3.64 g, 74%). Pale yellow solid, mp: 61–63ꢀC. 1H-NMR
(400 MHz): d 3.47 (dd, 1H, 11.5 Hz, 5.7 Hz, 9-H), 3.59 (dd, 2H, 11.5 Hz,
3.5 Hz, 9-H), 3.90 (s, 3H, OMe), 4.09 (m, 1H, 8-H), 5.14 (s, 2H, PhCH2O-),
6.01 (d, 1H, 7.4 Hz, 7-H), 6.85–7.05, 7.20–7.60 and 7.90–8.05 (m, 12H, Ar-
H). EI-MS: m/z 442 [M]þ (0.47), 442 [M þ 2]þ (0.17), 286 (4), 243(12), 156
(15), 139 (31), 91 (100). Anal. calcd for C24H23O6Cl: C, 65.09; H, 5.23; Cl,
8.00%; found C, 65.08; H, 5.24; Cl, 8.00%.
Threo-1-O-m-chlorobenzoyl-3-O-benzoyl-1-(4-benzyloxy-3-methoxy-
phenyl)-1,2,3-propanetriol (6). To a solution of 5 (2.00 g, 4.5 mmol) in anhy-
drous THF (70 mL) containing Et3N (2 mL), maintained at À10ꢀC, was
added dropwise a solution of benzoyl chloride (0.56 mL, 4.7 mmol) in anhy-
drous THF (5 mL) and the mixture was stirred for 6 h at À10ꢀC. The excess
of benzoyl chloride was destroyed by adding MeOH (2 mL), the solvent was
concentrated under reduced pressure. The residue was taken up in ethyl
acetate and washed with NaHCO3. The organic phase was dried (MgSO4)
and concentrated; Chromatography over silica gel eluted with petroleum
ether : acetone (9 : 1) gave pure 6 (2.05 g, 83%) as a colorless gum.
1H-NMR (80 MHz): d 3.87 (s, 3H, OMe), 4.2–4.7 (m, 3H, 8-H, 9-H), 5.14
(s, 2H, PhCH2O-), 6.10 (d, 1H, 5.6 Hz, 7-H), 6.8–8.1 (m, 17H, Ar-H).
EI-MS: m/z 546 [M]þ (0.81), 548 [M þ 2]þ (0.29), 390 (4), 243 (7), 139
(46), 105 (59), 91 (100). Anal. calcd for C31H27O7Cl: C, 68.07; H, 4.97;
Cl, 6.48%; found C, 68.09; H, 4.96; Cl, 6.46%.
Erythro-1-O-m-chlorobenzoyl-3-O-benzoyl-1-(4-benzyloxy-3-methoxy-
phenyl)-2-(4-formyl-2-methoxy-phenoxy)-propane-1,3-diol (7). A mixture of 6
(1.16 g, 2.1 mmol), vanillin (0.48 g, 3.2 mmol), triphenylphosphine (0.83 g,
3.2 mmol) and diethylazodicarboxylate (0.5 mL, 3.2 mmol) in anhydrous
THF (40 mL) was stirred for 16 h at room temperature under argon. The
mixture was concentrated under reduced pressure, and the residue was
chromatographed on silica gel eluted with petroleum ether : acetone (9 : 1)
1
gave pure 7 (1.08 g, 75 %) as a colorless gum. H-NMR (200 MHz): d 3.83,
3.90 (2 ꢁ s, 6H, OMe), 4.80 (m, 2H, 9-H), 5.09 (s, 2H, PhCH2O-), 5.18
(m, 1H, 8-H), 5.92 (d, 1H, 5.6 Hz, 7-H), 6.8–8.1 (m, 20H, Ar-H), 9.80
(split s, 1H, -CHO). EI-MS: m/z 680 [M]þ (3.7), 682 [M þ 2]þ (1.4),
529 (23), 407 (29), 299 (5), 161 (20), 139 (100), 105 (44), 91 (54). Anal.
calcd for C39H33O9Cl: C, 68.77; H, 4.88; Cl, 5.20%; found C, 68.80; H,
4.86; Cl, 5.18%.

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CHEN ET AL.
Erythro-1-(4-benzyloxy-3-methoxyphenyl)-2-(4-formyl-2-methoxy-phe-
noxy)-propane-1,3-diol (8). To a stirred solution of 7 (0.67 g, 0.98 mmol) in
methanol and water (9 : 1, 20 mL) was added potassium carbonate (0.82 g,
5.9 mmol). After being stirred for 2 h at room temperature, the solvent was
evaporated under reduced pressure, and water was added to the residue. The
mixture was extracted with ethyl acetate thoroughly. The combined organic
layers were washed with brine, dried with MgSO4 and concentrated. The
residue was purified by chromatography on silica gel eluted with petroleum
1
ether : acetone (4 : 1) to afford 8 (0.42 g, 98%) as a colorless gum. H-NMR
(200 MHz): d 3.75–4.10 (m, 2H, 9-H), 3.83, 3.87 (2 ꢁ s, 6H, OMe), 4.40 (m,
1H, 8-H), 4.98 (d, 1H, 5.2 Hz, 7-H), 5.13(s, 2H, PhCH 2O-), 6.8–7.7 (m, 11H,
Ar-H), 9.85 (split s, 1H, -CHO). EI-MS: m/z 438 [M]þ (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%.
Erythro-1-(4-hydroxy-3-methoxyphenyl)-2-(4-formyl-2-methoxy-phe-
noxy)-propane-1,3-diol (9). To a stirred solution of 8 (110 mg, 0.25 mmol)
in methanol (10 mL) was added 5% palladized charcoal (4 mg). After
being stirred for 6 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
1
ether : acetone (5 : 2) to afford 9 (67 mg, 77%) as a colorless gum. H-NMR
(200 MHz): d 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 (100 MHz): d 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]þ (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 cmÀ1. Anal. calcd for C18H20O7: C, 62.06; H, 5.79%; found C,
62.10; H, 5.78%.
(E )-3-Phenyl-2,3-epoxypropan-1-ol (11). To a solution of 10 (1.80 g,
13.4 mmol) in CH2Cl2 at 0ꢀC was added mCPBA (5.00 g, 20.1 mmol) in
portions. After being stirred for 5 h at 0ꢀC, the mixture was kept in the
refrigerator overnight. The filtered solution was washed successively with
Na2SO3, NaHCO3, water and brine. The combined aqueous phase were
extracted with CH2Cl2. The combined organic layers were dried (MgSO4)
and concentrated. Purification of crude product by chromatography on
silica gel (petroleum ether : acetone, 10 : 1) gave pure 11 (1.78 g, 88%) as a
colorless oil. 1H-NMR (200 MHz): d 3.21 (m, 1H, 8-H), 3.74 (dd, 1H,
12.8 Hz, 4.2 Hz, 9-H), 3.89 (d, 1H, 2.0 Hz, 7-H), 4.00 (dd, 1H, 12.8 Hz,
2.4 Hz, 9-H), 7.22–7.33 (m, 5H, Ar-H). EI-MS: m/z 150 [M]þ (8), 132
(20), 119 (23), 107 (100), 105 (41), 104 (40), 91 (85), 90 (88), 89 (87), 79 (78),

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563
77 (61), 51 (47). Anal. calcd for C9H10O2: C, 71.98; H, 6.71%; found C,
71.97; H, 6.73%.
Erythro-1-O-benzoyl-1-phenyl-1,2,3-propanetriol (12). Titanium iso-
propoxide was added to a solution of 11 (45 mg, 0.30 mmol) in anhydrous
CH2Cl2 (2 ml) containing the benzoic acid (40 mg, 0.33 mmol) at room
temperature under Ar. After being stirred for 3h, the work-up was
done by adding 15% tartaric acid aqueous solution, stirring until
clear phases were reached followed by extraction with ethyl acetate
thoroughly. The combined organic layers were concentrated, and the
residue was purified by chromatography on silica gel eluted with petroleum
ether : acetone (3: 1) to afford 12 (70 mg, 86%) as a colorless gum.
1H-NMR (200 MHz): d 3.71 (dd, 1H, 11.8 Hz, 5.8 Hz, 9-H), 3.80 (dd, 1H,
11.8 Hz, 3.4 Hz, 9-H), 4.09 (m, 1H, 8-H), 5.97 (d, 1H, 7.2 Hz, 7-H),
7.25–7.62 (m, 8H, Ar-H), 8.04–8.08 (m, 2H, Ar-H). EI-MS: m/z 272
[M]þ (0.1), 212 (26), 194 (3), 165 (2), 123 (4), 107 (12), 105 (100), 91 (9),
77 (22). Anal. calcd for C16H16O4: C, 70.58; H, 5.92%; found C, 70.60;
H, 5.92%.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science
Foundation of China (No. 29972015).
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Received in the UK January 2, 2001

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