The total synthesis of cannabisin G

Article abstract of DOI:10.2298/JSC091016128X

A convenient method for the synthesis of lignanamide cannabisin G, starting from vanillin, was developed. The convergent synthesis was based on the Stobbe reaction as C-C bond-forming steps to give the skeleton of lignan, which was condensed with a deriva

Full text of DOI:10.2298/JSC091016128X

J. Serb. Chem. Soc. 75 (12) 1617–1623 (2010)
UDC 633.888:542.913
JSCS–4081
Original scientific paper
The total synthesis of cannabisin G
*
YAMU XIA , YINGLAN GUO and YANLING WEN
College of Chemical Engineering, Qingdao University of Science
and Technology, Qingdao 266042, P. R. China
(Received 26 October 2009, revised 29 June 2010)
Abstract: A convenient method for the synthesis of lignanamide cannabisin G,
starting from vanillin, was developed. The convergent synthesis was based on
the Stobbe reaction as C–C bond-forming steps to give the skeleton of lignan,
which was condensed with a derivative of tyramine to obtain synthetic canna-
bisin G for the first time.
Keywords: synthesis; lignanamide; stobbe reaction; cannabisin G.
INTRODUCTION
Cannabisin G (1) was first isolated from the fruits of Cannabis sativa in
1
1995. C. sativa is an annual plant which belongs to the family Cannabaceae
2
from Central Asia. C. sativa has been utilized as an anti-asthma, anticonsti-
pation, anthelminthic drug in traditional Chinese medicine, and these uses are
3,4
still well-rooted in folk medicine today. Cannabinoids, flavonoids, stilbenoids,
terpenoids, alkaloids and lignanamides are some of the secondary metabolites
5
present in C. sativa. Cannabisin G belongs to the lignanamide group and is
classified as lignans of the arylnaphthalene derivative type. Natural products of
the lignanamide family displayed interesting and diverse biological activities,
6,7
including feeding deterrent activity and insecticidal effects. In 2002, it was
first reported that cannabisin G showed cytotoxic activity against human prostate
8
cancer LNCaP cells.
A synthetic approach to the lignanamide family has not hitherto been re-
ported. Herein, full details of the total synthesis of the lignanamide cannabisin G
(1) are provided.
In the retrosynthetic analysis (Scheme 1), cannabisin G must be developed
for the coupling of (E,E)-2 with tyramine. The key intermediate (E,E)-2 is ob-
tained by the condensation of vanillin with diethyl succinate.
*Corresponding author. E-mail: xiaym@qust.edu.cn
doi: 10.2298/JSC091016128X
1617
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XIA, GUO and WEN
Scheme 1. In the retrosynthetic analysis, cannabisin G must be developed by the coupling of
(E,E)-2 with tyramine. The key intermediate (E,E)-2 was obtained by the condensation of
vanillin and diethyl succinate, involving double Stobbe reactions.
As shown in Scheme 2, the synthesis involved the Stobbe reaction to cons-
truct the skeleton of lignan (C -C -C ), followed by condensation with tyramine
6
4
6
to obtain cannabisin G (1).
Scheme 2. Reaction scheme for the preparation of cannabisin G starting from vanillin.
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TOTAL SYNTHESIS OF CANNABISIN G
1619
EXPERIMENTAL
General
Melting points were taken on a Gallenkamp melting point apparatus and were uncor-
rected. The infrared spectra were recorded on a Nicolet Nexus 670 FTIR spectrometer. The
1H-NMR and 13C-NMR spectra were recorded on a Bruker AM−500 MHz spectrometer. The
mass spectra were recorded on a ZAB−HS spectrometer. HRMS were obtained on a Bruker
Daltonics APEXII47e spectrometer. Flash column chromatography was performed on silica
gel (200–300 mesh) and TLC inspections on silica gel GF254 plates.
4-Benzyloxy-3-methoxybenzaldehyde (3)
A mixture of vanillin (60.8 g, 400 mmol), benzyl bromide (68.4 g, 400 mmol) and an-
hydrous potassium carbonate (55.2 g, 400 mmol) in acetone (200 ml) was stirred overnight at
room temperature. The reaction mixture was filtered, and the solvent was removed in vacuo.
The residue was crystallized from EtOH to give the compound 3 as yellow crystals (92.0 g).
(E)-2-(4-benzyloxy-3-methoxybenzylidene)succinic acid (4)
Compound 3 (72.6 g, 300 mmol) and diethyl succinate (52.2 g, 300 mmol) were added to
a solution of NaOEt (40.8 g, 600 mmol) in EtOH (500 mL). The mixture was heated under N2
and was refluxed for 4 h, and then the ethanol was removed. The residue was cooled and aci-
dified with HCl (5 mol L-1, 60 ml). This was then extracted with EtOAc (3×70 mL). The
EtOAc layer was then re-extracted with saturated NaHCO3 solution (300 mL). Acidification
of the aq. NaHCO3 extract with HCl (5 mol L-1, 60 ml) provided an oily layer, which was again
extracted with EtOAc (3×70 mL). The combined organic layer was dried over MgSO4 and
concentrated in vacuo. This residue was added to a solution of 20 % aqueous NaOH (500 mL)
and refluxed for 3 h. After cooling to room temperature, the mixture was washed with EtOAc
(3×70 mL). After decolorizing with active carbon, the mixture was acidified with HCl (5 mol
L-1, 60 ml) whereby a white solid was obtained. The crude product was crystallized from
EtOH to give the diacid 4 as a yellow crystal (120.0 g).
(E)-Dimethyl 2-(4-benzyloxy-3-methoxybenzylidene)succinate (5)
The diacid 4 (68.4 g, 200 mmol) was added to an ice-cold solution containing an excess
of CH2N2 in Et2O. The mixture was stirred for 12 h, and concentrated in vacuo. Flash column
chromatography of the residue gave diester 5 as a yellow oil (71.8 g).
(E,E)-2,3-bis(4-benzyloxy-3-methoxybenzylidene)succinic acid (6)
Diester 5 (37.0 g, 100 mmol) on Stobbe condensation (following the above-mentioned
procedure) with compound 3 (24.2 g, 100 mmol) provided a light-yellow solid which was pu-
rified by recrystallization from MeOH to yield product 6 (42.5 g).
4-Benzyloxybenzaldehyde (7)
A mixture of 4-hydroxybenzaldehyde (24.4 g, 200 mmol), benzyl bromide (34.0 g, 200
mmol) and anhydrous potassium carbonate (27.6 g, 200 mmol) in acetone(100 ml) were stir-
red overnight at room temperature. The reaction mixture was filtered, and the solvent was
removed in vacuo. The residue was crystallized from EtOH to give the compound 7 as yellow
crystals (39.4 g).
1-Benzyloxy-4-(2-nitroethenyl)benzene (8)
To a mixture of nitromethane (9.2 g, 150 mmol) and compound 7 (31.8 g, 150 mmol) in
MeOH (200 mL) was added dropwise sodium hydroxide (8.0 g, 200 mmol) in water (200 mL)
under an ice bath. The reaction mixture was stirred for 5 h and then poured into 500 mL of
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XIA, GUO and WEN
HCl (2 M) in water. The mixture was filtered and the yellow crystalline mass was washed
with water and crystallized from EtOH to give product 8 as yellow crystals (32.1 g).
o-Benzyltyramine (9)
Compound 8 (12.8 g, 50 mmol) in dry Et2O was added to the solution of LiAlH4 (5.0 g,
132 mmol) in Et2O. The mixture was heated at reflux for 4 h under nitrogen. Then the reaction
was quenched with ice water and the resulting mixture filtered. The filtrate was dried over an-
hydrous MgSO4 and concentrated in vacuo. Flash column chromatography of the residue gave
product 9 (8.8 g).
Cannabisin G (1)
A solution of compound 6 (2.8 g, 5 mmol) in dry CH2Cl2 (20 mL) was added dropwise
to a solution of compound 9 (2.3 g, 10 mmol), N,N’-dicyclohexylcarbodiimideline, DCC (2.1
g, 10 mmol), and 4-dimethylaminopyridineline, DMAP (1.3 g, 10 mmol), in dry CH2Cl2 (100
mL) at 0 °C for 2 h under nitrogen. After stirring the mixture overnight at room temperature,
the reaction mixture was filtrated and the solvent was distilled off. Flash column
chromatography (petroleumether: ethyl acetate = 6:1) of the residue gave product 10 (4.2 g).
Product 10 (3.0 g, 3.0 mmol) was dissolved in 50 mL MeOH and stirred under a hyd-
rogen atmosphere (1 atm) for 7 h in the presence of 5 % Pd/C (1.5 g). The reaction mixture
was filtered through a pad of celite and then the solvent was removed in vacuo. Flash column
chromatography (petroleumether: ethyl acetate = 5:1) of the residue gave an amorphous powder
cannabisin G (1) (1.4 g).
RESULTS AND DISCUSSION
The analytic and spectroscopic data of cannabisin G and the intermediate
products are given below.
4-Benzyloxy-3-methoxybenzaldehyde (3). Yield: 95 %; m.p. 65−67 °C. IR
-1
(KBr, cm ): 3014, 2845, 1679, 1671, 1587, 1505, 1466, 1385, 1276, 1134, 1032.
1
H-NMR (500 MHz, DMSO−d , δ / ppm): 3.84 (3H, s, OCH ), 5.16 (2H, s,
6
3
ArCH O), 6.87−7.54 (8H, m, ArH), 9.85 (1H, s, ArCHO). EI−MS (m/z, (%)):
242 (M ) (12), 214 (7), 151 (2), 91 (100), 67 (13).
2
+
(E)-2-(4-Benzyloxy-3-methoxybenzylidene)succinic acid (4). Yield: 83 %;
–1
m.p. 131−133 °C. IR (KBr, cm ): 3250, 3060, 2912, 1709, 1615, 1497, 1484.
1
H-NMR (500 MHz, CDCl , δ / ppm): 3.57 (2H, s, CH ), 3.86 (3H, s, OCH ),
3
2
3
5.15 (2H, s, ArCH O), 6.68−7.43 (8H, m, ArH), 7.87 (1H, s, ArCH=C). EI−MS
2
+
(m/z, (%)): 342 (M ) (26), 324 (12), 297 (27), 175 (16), 91 (100).
(E)-Dimethyl 2-(4-benzyloxy-3-methoxybenzylidene)succinate (5). Yield: 97 %;
–1
IR (KBr, cm ): 3080, 2908, 1712 (CH COOCH ), 1641 (COOCH ), 1503,
2
3
3
1
1465. H-NMR (500 MHz, CDCl , δ / ppm): 3.69 (3H, s, COOCH ), 3.78 (3H, s,
3
3
COOCH ), 3.83 (3H, s, OCH ), 3.56 (2H, s, CH COOCH ), 5.15 (2H, s,
3
3
2
3
ArCH O), 6.68−7.45 (8H, m, ArH), 7.88 (1H, s, ArCH=C). EI−MS (m/z, (%)):
2
+
370 (M ) (36), 338 (18), 307 (14), 175 (23), 91 (100).
(E,E)-2,3-Bis(4-benzyloxy-3-methoxybenzylidene)succinic acid (6). Yield: 75 %;
–1
m.p. 151−153 °C. IR (KBr, cm ): 3350, 2900, 1740 (2×COOCH ), 1496, 1241,
3
1
1042. H-NMR (500 MHz, CDCl , δ / ppm): 3.78 (6H, s, 2×OCH ), 5.16 (4H, s,
3
3
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TOTAL SYNTHESIS OF CANNABISIN G
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2×ArCH O), 6.79 (2H, d, ArH, J = 8.5 Hz), 7.07 (2H, dd, ArH, J = 2.0 and 8.5
2
Hz), 7.19 (2H, d, ArH, J = 2.0 Hz), 7.28−7.40 (10H, m, ArH), 7.96 (2H, s,
13
2×ArCH=C). C-NMR (CDCl , 125 MHz, δ / ppm): 55.7 (2×OCH ), 70.7
3
3
(2×ArCH ), 112.7, 113.1, 123.3, 124.9, 127.2, 127.3, 128.0, 128.6 (2×ArCH=C),
2
136.4 (2×ArCH=C), 144.2, 149.2, 150.1, 172.7 (2×C=O). EI−MS (m/z, (%)): 566
+
(M ) (2.1), 549 (4.3), 325 (11), 175 (35), 151 (5.2), 91 (100). HRMS Calcd. for
+
C H O (M+H ): 567.2014, found: 567.2012.
34 31
8
–1
4-Benzyloxybenzaldehyde (7). Yield: 93 %; m.p. 72−74 °C. IR (KBr, cm ):
1
3034, 2840, 2739, 1690, 1601, 1570, 1510, 1453, 1321, 1262, 1166, 1021. H-
-NMR (500 MHz, CDCl , δ / ppm): 5.16 (2H, s, ArCH O), 7.05−7.84 (9H, m,
3
2
+
ArH), 9.88 (1H, s, ArCHO). EI−MS (m/z, (%)): 212 (M ) (17), 182 (0.8), 151
(1.8), 121 (1.5), 91 (100), 65 (12).
1-Benzyloxy-4-(2-nitroethenyl)benzene (8). Yield: 84 %; m.p. 113−115 °C. IR
-1
1
(KBr, cm ): 3110, 3042, 2960, 1635, 1607, 1550, 1510, 1346, 1265, 1164. H-
NMR (500 MHz, CDCl , δ / ppm): 5.15 (2H, s, ArCH O), 7.04 (2H, d, ArH, J =
3
2
8.5 Hz), 7.35−7.50 (7H, m, ArH), 7.52 (1H, d, ArCH=CH, J = 13.5 Hz), 7.98
+
(1H, d, ArCH=CH, J = 13.5 Hz). EI−MS (m/z, (%)): 255 (M ) 1.4), 238 (2.5),
226 (3.2), 151 (2.8), 121 (5.3), 91 (100), 65 (7.1).
o-Benzyltyramine (9). Yield: 78 %; m.p. 203−206 °C. IR (KBr, cm ): 3285,
3050, 3025, 2932, 2867, 2586, 1615, 1597, 1518, 1460, 1259, 1030. H-
–1
1
-NMR (500 MHz, CDCl , δ / ppm): 2.82−2.85 (2H, m, ArCH CH ), 2.94−2.98
3
2
2
(2H, m, ArCH CH ), 5.08 (2H, s, ArCH O), 6.95 (2H, d, ArH, J = 8.5 Hz), 7.18
2
2
2
13
(2H, d, ArH, J = 8.5 Hz), 7.31−7.45 (5H, m, ArH). C-NMR (125 MHz, CDCl ,
δ / ppm): 32.5 (ArCH CH ), 39.8 (ArCH CH ), 69.6 (ArCH O), 115.4, 128.1,
128.3, 128.9, 129.9, 130.2, 137.6, 157.6. EI−MS (m/z, (%)): 227 (M ) (8.7), 198
(1.2), 151 (4.9), 121 (23.6), 91 (100); HRMS Calcd. for C H NO (M+H ):
3
2
2
2
2
2
+
+
15 18
228.1383, found: 228.1389.
1
4,4’,4”,4”’-tetrabenzyloxy cannabisin G (10). Yield: 85 %. H-NMR (500
MHz, CDCl , δ / ppm): 2.48 (2H, dt, H-7”α, H-7”’α, J = 13.5, 7.0 Hz), 2.55 (2H,
3
dt, H-7”β, H-7”’β, J = 13.5 and 7.0 Hz), 3.28 (2H, dt, H-8”α, H-8”’α, J = 13.5,
7.0 Hz), 3.52 (2H, dt, H-8”β, H-8”’β, J = 13.5, 7.0 Hz), 3.78 (6H, s, 2×OCH ),
3
5.15 (4H, s, 2×ArCH ), 5.21 (4H, s, 2×ArCH ), 6.51−7.48 (34H, m, ArH), 7.96
2
2
+
(2H, s, 2×ArCH=C). HRMS Calcd. for C H N O (M+NH4 ): 1002.4688,
64 64
3
8
found: 1002.4683.
–1
Cannabisin G (1). Yield: 75 %. IR (KBr, cm ): 3356, 2910, 1659, 1615,
1
1517, 1194. H-NMR (500 MHz, CDCl , δ / ppm): 2.43 (2H, dt, H-7”α, H-7”’α,
3
J = 13.6, 6.5 Hz), 2.51 (2H, dt, H-7”β, H-7”’β, J = 13.6, 6.5 Hz), 3.25 (2H, dt, H-
-8”α, H-8’”α, J = 13.6, 6.5 Hz), 3.50 (2H, dt, H-8”β, H-8”’β, J = 13.6, 6.5 Hz),
13
3.75 (6H, s, 2×OCH ), 6.82−7.31 (14H, m, ArH), 7.89 (2H, s, 2×ArCH=C). C-
3
-NMR (125 MHz, CDCl , δ / ppm): 35.6 (C-7”, C-7”’), 42.7 (C-8”’, C-8”’), 56.8
3
(2×OCH ), 113.1, 116.2, 125.4, 127.6, 127.8 (C-8, C-8'), 130.2, 130.7, 140.8 (C-7,
3
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XIA, GUO and WEN
+
C-7'), 148.3, 149.2, 156.5, 166.8 (C-9, C-9'). EI−MS (m/z, (%)): 624 (M ) (0.2),
+
339 (18), 337 (9), 151 (23), 91 (100); HRMS Calcd. for C H N O (M+NH ):
642.2810, found: 642.2814. The data are consistent with the literature.
36 40
3
8
4
1
As is shown in Scheme 2, vanillin was used as the raw material and the
4-hydroxyl group of vanillin was protected with benzyl chloride to afford product
3. Compound 3 underwent Stobbe condensation with diethyl succinate in the
presence of sodium ethoxide in ethanol to produce compound 4. The (E)-confi-
guration of the olefinic double bond was evident from the appearance of the de-
1
9
shielded vinylic proton at δ 7.87 in its H-NMR spectrum. Compound 4 was
methylated with diazomethane in diethyl ether to yield the diester 5. The second
Stobbe condensation of 5 with 3 in methanol in the presence of sodium me-
thoxide yielded the key intermediate 6. The deshielded vinylic proton at δ 7.96 in
1
the H-NMR spectrum of 6 indicated the (E)-configuration for both olefinic
10,11
double bonds.
4-Hydroxybenzaldehyde was protected with benzyl chloride to give product
7. Condensation of 7 with nitromethane in the presence of sodium hydroxide
gave compound 8, which was followed by reduction with LiAlH to afford in-
4
termediate 9.
The intermediate 6 was condensed with compound 9 in CH Cl in the pre-
2
2
sence of DCC and DMAP, followed by hydrogenolysis with 5 % palladium on
charcoal catalyst at room temperature to remove the benzyl group and obtain the
target product cannabisin G (1). Although it is possible to affect cleavage of the
benzyl group in the presence of an olefin, in general, the degree of selectivity is
dependent upon the substitution pattern and the level of steric hindrance. Good
selectivity was achieved for hydrogenolysis of a benzyl group in the presence of
12
a trisubstituted conjugated olefin.
CONCLUSIONS
In summary, an efficient, high-yielding and convergent synthesis of a lignan-
amide cannabisin G with an overall yield of 22.3 % was developed. The syn-
thesis was based on the Stobbe reaction for the C–C bond-formation steps to give
the skeleton of lignan, which afforded the key intermediate diacid, which was
condensed with a derivative of tyramine to obtain the natural product cannabisin
G for the first time. The present method is a new avenue for the synthesis of a
variety of useful and biologically active lignanamides.
Acknowledgements. This work was supported by Shandong Provincial Natural Science
Foundation, China (No. ZR2010HM023) and Specialized Research Foundation for the
Doctoral Program of Higher Education, China (No. 20093719120004).
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TOTAL SYNTHESIS OF CANNABISIN G
1623
И З В О Д
ТОТАЛНА СИНТЕЗА КАНАБИСИНА G
YAMU XIA, YINGLAN GUO и YANLING WEN
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
Развијена је погодна синтеза лигнанамида канабисина G, полазећи од ванилина. Кон-
вергентна синтеза заснива се на Стобеовој реакцији, у којој се формира угљеник–угљеник
веза скелета лигнана, који је повезан са дериватом тирамина. Овим поступком први пут је
добијен синтетички канабисин G.
(Примљено 26. октобра 2009, ревидирано 29. јуна 2010)
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