Total synthesis of (±)-divanillyltetrahydrofuran ferulate

Article abstract of DOI:10.1007/s12039-010-0050-7

A convenient method for the synthesis of sesquilignan threo- and erythro-(±)-divanillyltetrahydrofuran ferulate is described. The synthesis was based on a unified synthetic strategy involving two Stobbe condensations to give the skeleton of lignan, and then reduction reaction to form meso- and threo-(±)-secoisolanciresinol. meso- and threo-(±)-secoisolanciresinol were separated by flash column chromatography, followed by intramolecular reaction with TsCl to afford the key intermediate meso- or threo-(±)-shonanin, then condensation with ferulaic acid to obtain sesquilignan threo- or its analogue erythro-(±)- divanillyltetrahydrofuran ferulate. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0050-7

J. Chem. Sci., Vol. 122, No. 3, May 2010, pp. 433–436. © Indian Academy of Sciences.
Total synthesis of ( )-divanillyltetrahydrofuran ferulate
YA-MU XIA1,*, JIA YOU and QI WANG
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
e-mail: xiaym@qust.edu.cn
MS received 19 August 2009; revised 22 January 2010; accepted 26 February 2010
Abstract. A convenient method for the synthesis of sesquilignan threo- and erythro-( )-divanillyl-
tetrahydrofuran ferulate is described. The synthesis was based on a unified synthetic strategy involving
two Stobbe condensations to give the skeleton of lignan, and then reduction reaction to form meso- and
threo-( )-secoisolanciresinol. meso- and threo-( )-secoisolanciresinol were separated by flash column
chromatography, followed by intramolecular reaction with TsCl to afford the key intermediate meso- or
threo-( )-shonanin, then condensation with ferulaic acid to obtain sesquilignan threo- or its analogue
erythro-( )-divanillyltetrahydrofuran ferulate.
Keywords. Synthesis; sesquilignan; stobbe reaction; divanillyltetrahydrofuran ferulate.
1. Introduction
modial activity of sesquilignans against a chloro-
quine-resistant and a chloroquine-sensitive strain of
plasmodium falciparum, the most dangerous human
malaria parasite.9 Two sesquilignans Chushizisins H
and I exhibited antioxidant activities against H2O2-
induced impairment in PC12 cell.10 Although many
sesquilignans have been found in plants and some
showed potent biological activities, only a few have
been synthesized. A paper has reported the synthesis
of Haedoxan A, raw material starting from other
known lignans of similar structure.11 In Ichihara’s
synthesis of dehydrolappaol a dimethyl ether, vari-
ous 2-alkyl-2-butenolactones were simply prepared
from cyclopentadiene-maleic anhydride adducts
through the retro-Diels-Alder reaction. The proce-
dure was applied for the synthesis of dehydrolappaol
A dimethyl ether.12
Here, we report the total syntheses of threo-( )-
divanillyltetrahydrofuran ferulate 1 and erythro-( )-
divanillyltetrahydrofuran ferulate 2. The syntheses
were based on a unified synthetic strategy involving
Stobbe reaction to construct the skeleton of lignan
(C6–C4–C6) and resolution of threo- and erythro-
isomers, followed by condensation with ferulaic acid
to furnish the target product 1 and 2.
Divanillyltetrahydrofuran ferulate was first isolated
from the Diospyros Kaki calyces in 1985, and the
natural plant was originally used both in Japanese
folk medicine and in traditional Chinese medicine
for the treatment of hiccough.1 Divanillyltetrahydro-
furan ferulate belong to the very interesting class of
sesquilignan of natural lignan on account of their
great number of structural possibilities. Sesquilignan
family are widely occurring, and are found in all
parts of producing plants, including the roots, stems,
leaves, fruit, and seeds.2 Recently, the identification
of some sesquilignans was reported in various kinds
of natural plants. Three sesquilignans threo-
fuaiacylglycerol-β-O-4-syringaresinol ether, threo-
fuaiacylglycerol-α-O-methyl-β-O-4-syringaresinol
ether and threo-syringylglycerol-α-O-methyl-β-O-4-
syringaresinol ether have been isolated for the first
time.3 Two new sesquilignans were identified from a
phytotoxic extract of Brassica fruticulosa L.4 Eight
new tetrahydrofuran-type sesquilignans, bonas-
pectins A–H, as well as two new 8-O-4′-type ses-
quineolignans, neobonaspectins A and B, were
isolated and characterized from the epigeal vegeta-
tive parts of Bonamia spectabilis (Choisy) HALL.
F.5 Sesquilignans exihibit a wide range of biological
activities, including antitumor, antioxidant and as
pesticides.6–8 A recent report described the antiplas-
As shown in scheme 1, cheaper Vanillin was used
as raw materials, and the 4-hydroxyl group of vanil-
lin was protected with benzyl chloride to afford the
product 3. Compound 3 underwent Stobbe conden-
sation with diethyl succinate in the presence of
sodium ethoxide in ethanol to produce compound 4.
*For correspondence
433

434
Ya-Mu Xia et al
Scheme 1.
Scheme 2.
Scheme 3.
The trans-(E)-configuration of the olefinic double duce a readily separable mixture (approximate 1 : 1)
bond was evident from the appearance of the de- of diols meso-9a and threo-( )-9b. Threo-( )-9b had
1
shielded vinylic proton at δ 7⋅87 in its H NMR consistently larger Rf values than those of the corre-
spectrum. Compound 4 was methylated with diazo- sponding meso-9a, and each pair was easily sepa-
methane in methanol to yield the diester 5. The sec- rated by flash column chromatography over silica gel.
ond Stobbe condensation of 5 with 3 in methanol in The configuration of threo-( )-9b was in agreement
the presence of sodium methoxide yielded com- with those reported in the literatures.16,17
pound 6. The deshielded vinylic proton at δ 7⋅96 in
The 4-hydroxyl group of meso-secoisolanciresinol
1
the H NMR spectrum of 6 indicated the trans-(E)- 9a or threo-( )-secoisolanciresinol 9b was protected
configuration for both the olefinic double bonds.13–15 with benzyl chloride to afford the compound meso-
Compound 6 was again methylated to produce a 10a or threo-( )-10b. Reaction of diol meso-10a
diester 7. Treatment of 7 with LiAlH4/AlCl3 afforded or threo-( )-10b with equimolar TsCl in pyridine
the unsaturated diol 8, followed by hydrogenation under dilution at room temperature gave the corre-
with a 10% palladium on charcoal catalyst to pro- sponding tetrahydrofuran meso-11a or threo-( )-

Total synthesis of ( )-divanillyltetrahydrofuran ferulate
435
3. Cutillo F, Dellagreca M, Gionti M, Previtera L and
Zarrelli A 2006 Phytochem. Anal 17 344
4. Cutillo F, Abrosca B D, Dellagreca M, Fiorentino A
and Zarrelli A 2003 J. Agric. Food Chem. 51 6165
5. Tofern B, Jenett-Siems K, Siems K, Jakupovic J and
Eich E 2000 Phytochemistry 53 119
6. Su B N, Takaishi Y and Kusumi T 1999 Tetrahedron
55 14571
7. Seo C S, Zheng M S, Woo M H, Lee C S, Lee S H,
Jeong B S, Chang H W, Jahng Y D, Lee E S and Son
J K 2008 J. Nat. Prod. 71 1771
8. Willfr S M, Ahotupa M O, Hemming J E, Reunanen
M H T, Eklund P C, Sjholm R E, Eckerman C S E,
Pohjamo S P and Holmbom B R 2003 J. Agric. Food
Chem. 51 7600
9. Kraft C, Jenett-siems K, Kohler I, Tofern-Reblina B,
Siemsb K, Bienzlec U and Eicha E 2002 Phyto-
chemistry 60 167
Scheme 4.
10. Mei R Q, Wang Y H, Du G H, Liu G M, Zhang L and
Cheng Y X 2009 J. Nat. Prod. 72 621
11. Ishibashi F and Taniguchi E 1998 Phytochemistry 49
613
12. Ichihara A, Nio N, Terayama Y, Kimura R and Sa-
kamura S 1979 Tetrahedron Lett. 3731
13. Datta P K, Yau C, Hooper T S, Yvon B L and Charl-
ton J L 2001 J. Org. Chem. 66 8606
14. Das B, Anjani G 1999 Phytochemistry 51 115
15. Liu J, Brooks N R 2002 Organic Lett. 4 3521
16. Karikome H, Mimaki Y and Sashida Y 1991 Phyto-
chemistry 30 315
11b, which were hydrogenated with 10% palladium
on charcoal catalyst to obtain the key intermediate
meso-shonanin 12a and threo-( )-shonanin 12b,
respectively (scheme 2).17–19
Ferulaic acid was esterified with MeOH, followed
by protection with MOMCl to produce the com-
pound 13. Hydrolysis of the ester 13 gave the inter-
mediate 14 (scheme 3).
As shown in scheme 4, the condensation of the
intermediate meso-12a with the acid 14 employing
DCC and DMAP, followed by deprotection of MOM
group using HCl at room temperatrue furnished the
target product erythro-( )-2. Following the proce-
dure described for the preparation of erythro-( )-2,
and starting with threo-( )-12b, compound threo-
( )-1 was obtained. The spectral data of threo-( )-1
were in agreement with those found in the litera-
ture.1,20
17. Wang Q, Yang Y, Li Y, Yu W and Hou Zi J 2006
Tetrahedron 62 6107
18. Fang J M, Hsu K C and Cheng Y S 1989 Phytochemi-
stry 28 3553
19. meso-Shonanin 12a: IR (KBr/cm–1): 3339, 2916,
1609, 1520, 1253, 1038, 928. 1H NMR (CDCl3,
500 MHz) δ: 2⋅44−2⋅50 (m, 4H, 2 × ArCH2CH),
2⋅78–2⋅85 (m, 2H, 2 × ArCH2CH), 3⋅61 (dd, 2H,
J = 8⋅0, 4⋅5 Hz, CH2O), 3⋅75 (dd, 2H, J = 8⋅0, 6⋅0 Hz,
CH2O), 3⋅82 (s, 6H, 2 × OCH3), 6⋅50–6⋅82 (m, 6H,
ArH). 13C NMR (CDCl3, 125 MHz) δ: 33⋅2 (C-7′, C-
7″), 43⋅8 (C-3, C-4), 55⋅9 (2 × OCH3), 72⋅3 (C-2, C-
5), 111⋅2 (C-2′, C-2″), 114⋅4 (C-5′, C-5″), 121⋅3 (C-
6′, C-6″), 132⋅5 (C-1′, C-1″), 143⋅9 (C-4′, C-4″),
146⋅5 (C-3′, C-3″). HRMS calcd for C20H28NO5
(M + NH+4): 362⋅1962; found: 362⋅1959. threo-( )-
Shonanin 12b: IR (KBr/cm–1): 3403, 2918, 1604,
Acknowledgements
This work was financially supported by Taishan
Scholar Project of Shandong Province (No.
2005011036), China and Specialized Research Fund
for the Doctoral Program of Higher Education of
China (No. 20093719120004) and Open Foundation
of Chemical Engineering Subject, Qingdao Univer-
sity of Science and Technology, China.
1
1515, 1261, 1042. H NMR (CDCl3, 500 MHz) δ:
2⋅11–2⋅18 (m, 2H, 2 × ArCH2CH), 2⋅51−2⋅61 (m, 4H,
2 × ArCH2CH), 3⋅53 (dd, 2H, J = 9⋅0, 5⋅5 Hz, CH2O),
3⋅82 (s, 6H, 2 × OCH3), 3⋅92 (dd, 2H, J = 9⋅0, 6⋅5 Hz,
CH2O), 6⋅51–6⋅90 (m, 6H, ArH). 13C NMR (CDCl3,
125 MHz) δ: 39⋅2 (C-7′, C-7″), 46⋅5 (C-3, C-4), 55⋅8
(2 × OCH3), 73⋅3 (C-2, C-5), 111⋅1 (C-2′, C-2″),
114⋅1 (C-5′, C-5″), 121⋅3 (C-6′, C-6″), 132⋅3 (C-1′,
C-1″), 143⋅9 (C-4′, C-4″), 146⋅4 (C-3′, C-3″). HRMS
calcd for C20H28NO5 (M + NH+4): 362⋅1962; found:
362⋅1964.
References
1. Matsuura S and Iinuma M 1985 Phytochemistry 24
626
2. Ward R S 1995 Nat. Prod. Rep. 12 183
20. erythro-( )-Divanillyltetrahydrofuran ferulate 2: IR
(KBr/cm–1): 3410, 2935, 1710, 1612, 1523, 1245,
1
1236, 928. H NMR (DMSO-d6, 500 MHz) δ: 2⋅45–

436
Ya-Mu Xia et al
1
2⋅55 (m, 4H, 2 × ArCH2CH), 2⋅73–2⋅82 (m, 2H,
2 × ArCH2CH), 3⋅78 (s, 3H, OCH3), 3⋅83 (s, 3H,
OCH3), 3⋅86 (s, 3H, OCH3 ), 3⋅98 (dd, 2H, J = 8⋅0,
6⋅0 Hz, CH2O), 4⋅16 (dd, 2H, J = 8⋅0, 5⋅5 Hz, CH2O),
6⋅55 (d, 1H, J = 16⋅0 Hz, CH=CHCO), 6⋅61–7⋅38 (m,
2935, 1700, 1620, 1520, 1240, 1216, 928. H NMR
(DMSO-d6, 500 MHz) δ: 2⋅12–2⋅16 (m, 2H, 2 ×
ArCH2CH), 2⋅73–2⋅76 (m, 4H, 2 × ArCH2CH), 3⋅72
(s, 3H, OCH3 ), 3⋅84 (s, 6H, 2 × OCH3), 3⋅94 (dd, 2H,
J = 9⋅0, 5⋅5 Hz, CH2O), 4⋅28 (dd, 2H, J = 9⋅0, 6⋅0 Hz,
CH2O), 6⋅53 (d, 1H, J = 16⋅0 Hz, CH=CHCO),
6⋅60−7⋅45 (m, 9H, ArH), 7⋅62 (d, 1H, J = 16⋅0 Hz,
CH=CHCO). 13C NMR (DMSO-d6, 125 MHz) δ: 33⋅6
(C-7′, C-7″), 39⋅0 (C-3), 39⋅5 (C-4), 55⋅3 (OCH3),
55⋅6 (OCH3), 56⋅0 (OCH3), 64⋅0 (C-2), 64⋅2 (C-5),
111⋅2, 111⋅8, 112⋅7, 114⋅8 (ArCH=CH), 115⋅0, 115⋅4,
121⋅2, 121⋅5, 122⋅0, 123⋅3, 125⋅7, 130⋅4, 130⋅7,
143⋅8, 144⋅1, 144⋅3, 145⋅0 (ArCH=CH), 147⋅2, 147⋅5,
149⋅1, 166⋅9 (C=O). HRMS calcd for C30H36NO8
(M + NH+4): 538⋅2436; found: 538⋅2440.
9H, ArH), 7⋅67 (d, 1H, J = 16⋅0 Hz, CH=CHCO). 13
C
NMR (DMSO-d6, 125 MHz) δ: 31⋅6 (C-7′, C-7″),
41⋅2 (C-4, C-3), 54⋅2 (OCH3), 55⋅7 (OCH3), 55⋅9
(OCH3), 62⋅5 (C-2), 62⋅7 (C-5), 111⋅0, 111⋅8, 112⋅1,
114⋅5 (ArCH=CH), 115⋅4, 115⋅5, 120⋅6, 121⋅1, 121⋅7,
123⋅0, 125⋅5, 130⋅2, 130⋅7, 144⋅6, 145⋅3 (ArCH=CH),
145⋅7, 147⋅3, 147⋅8, 149⋅3, 150⋅1, 165⋅5 (C=O).
HRMS calcd for C30H36NO8 (M + NH+4): 538⋅2436;
found: 538⋅2441. threo-( )-Divanillyltetrahydrofuran
ferulate 1: m.p. 174−176°C. IR (KBr/cm–1): 3390,