Total synthesis of Cannabisin B

Article abstract of DOI:10.3184/174751915X14425727961796

Cannabisin B, a naturally occurring lignanamide, has been synthesised for the first time in 15% overall yield. The convergent synthesis is based on the Stobbe reaction and Friedel-Crafts alkylation reaction as the C-C bond-forming steps to afford the skel

Full text of DOI:10.3184/174751915X14425727961796

6
06 RESEARCH PAPER
VOL. 39 OCTOBER, 606–608
JOURNAL OF CHEMICAL RESEARCH 2015
Total synthesis of Cannabisin B
Yamu Xia*, Huaizheng Zhang, Chenchen Li, Gaochao Dong and Zhen Liu
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
Cannabisin B, a naturally occurring lignanamide, has been synthesised for the first time in 15% overall yield. The convergent synthesis
is based on the Stobbe reaction and Friedel–Crafts alkylation reaction as the C–C bond-forming steps to afford the skeleton of the
lignanamide which was then condensed with 4-methoxyphenethylamine to obtain Cannabisin B.
Keywords: Cannabisin B, lignanamide, phenyldihydronaphthalene, 4-methoxyphenethylamine
Cannabisin B (1) was first isolated from Cannabis sativa in
the regulation of the AKT/mTOR pathway and S phase cell
cycle arrest in human hepatocarcinoma HepG2 cells. Thus,
it may be regarded as a promising drug for the treatment of
1
1992 and belongs to the group of the lignanamides which are a
class of naturally occurring products that arise biosynthetically
from phenylpropanoids and tyramine. This type of compound is
widely distributed in plants, and they have been isolated from
19
hepatoblastoma disease in the future. We now report full
details of the synthesis of the lignanamide Cannabisin B (1). As
shown in Scheme 1, the key intermediate dihydronaphthalene
diacid 6 was obtained through four steps from veratraldehyde
(2) and the synthesis involves the use of the Stobbe and
Aldol reactions. Thus, we obtained the desired lignanamide
Cannabisin B (1) efficiently, after a condensation reaction with
4-methoxyphenethylamine (Scheme 2).
2
3
4
Aptenia cordifolia, Mitrephora thorelii, Lycium chinense,
5
6
Solanum melongena L, Peperomia tetraphylla, Porcelia
macrocarpa and exhibit a wide range of biological activities,
such as anti-inflammatory, antiproliferative and insecticidal
properties . Because of the potential medicinal properties, as
7
8–13
5
8
5
well as the novel architectures, the total synthesis of several
members of the lignanamide family has received considerable
14
Results and discussion
interest. Li et al. reported the synthesis of Cannabisin G with
15
oxidative coupling as the key reaction. Uwe et al. developed
As shown in Scheme 1, the required diester 3 could be easily
formed from veratraldehyde (2) and diethyl succinate applying
the Stobbe reaction, followed by an esterification with SOCl2
a new method to construct the lignanamide skeletons using the
laccase/O catalyst system. Later, a regioselective biomimetic
2
8
oxidative cyclisation strategy was used in the construction
of the synthetic intermediates and then Cannabisin D was
and EtOH according to the construction method of Fabrice.
Compound 3 reacted with veratraldehyde (2) under basic
conditionstogenerateintermediate4creatingthefive-membered
lactone ring. Compound 4 is a new type of diarylbutyrolactone
lignan containing an unsaturated bond and has a γ-substituted-
α-alkylidene-γ-butyrolactone sub-structure which has analogies
with diacylglycerol (DAG) lactones and protein kinase C
16
obtained. Recently, our group also carried out some work
directed towards the lignanamides and reported the synthesis of
17,18
Cannabisin G and F.
As a phenyldihydronaphthalene lignanamide derivative,
Cannabisin B (1) could induce autophagic cell death through
(
1) Diethyl succinate
MeO
MeO
CHO
MeO
MeO
COOEt
COOEt
(
1) LDA, THF
EtONa, Reflux
(
2
2) SOCl , EtOH
(2) 2, AcOH, rt
3
2
COOEt
O
MeO
MeO
COOH
MeO
MeO
TFA, rt
OMe
OMe
COOEt
OMe
O
5
4
MeO
MeO
COOH
OMe
NaOH, EtOH
COOH
OMe
OMe
6
Scheme 1 Synthesis of dihydronaphthalene diacid 6.
*
Correspondent. E-mail: xiaym@qust.edu.cn; qdzyxww@163.com

JOURNAL OF CHEMICAL RESEARCH 2015 607
OMe
O
H
N
MeO
MeO
MeO
MeO
COOH
COOH
(
1) SOCl
2
, rt
N
H
(
2) DCM, Et N,
3
4
-Methoxyphenethylamine
O
OMe
OMe
OMe
OMe
OMe
6
7
OH
O
O
HO
HO
H
N
BBr , DCM
3
N
H
OH
OH
OH
1
Scheme 2 Synthesis of Cannabisin B (1).
(
PK-C) displays an enhanced affinity due to the α-alkylidine
performed on silica gel (200–300 mesh) and GF254 plates respectively
(Qingdao Haiyang Chemical Co. Ltd, China). Veratraldehyde, lithium
2
0,21
group.
The creation of 4 is also applicable to the synthesis of
γ-butyrolactones compounds. Under acid-catalysed conditions,
compound 4 is involved in an intramolecular rearrangement
with the opening of the lactone ring and then intermediate 5 was
obtained. Compound 5 is a novel phenyldihydronaphthalene
lignin and, interestingly, a new route is created for the selective
synthesis of the phenyldihydronaphthalene compounds as
monoesters. Subsequently, hydrolysis of the ester group
afforded the key intermediate diacid 6 having the skeleton of
phenyldihydronaphthalene lignanamides. Compounds 4, 5 and
diisopropylamide (LDA), triethylamine (Et
3
N), trifluoroacetic acid
(
TFA), 4-methoxyphenethylamine and the solvents were commercially
available products (Sinopharm Chemical Reagent Co. Ltd, Tianjin,
China; Alfa Aesar, USA).
8
(
E)-Diethyl 2-(3,4-dimethoxybenzylidene)succinate (3): Yellow oil;
1
yield 3.02 g (92%). H NMR (500 MHz, CDCl ) δ 7.78 (s, 1H, ArCH),
3
7
.01–6.72 (m, 3H, ArH), 4.22 (q, 2H, J = 7.1 Hz, CHCCO CH ), 4.14
2 2
(
q, 2H, J = 7.2 Hz, CO CH ), 3.85 (s, 3H, OCH ), 3.83 (s, 3H, OCH ),
2
2
3
3
3
.53 (s, 2H, CH ), 1.29 (t, 3H, J = 7.1 Hz, CHCO CH CH ), 1.22 (t, 3H,
2
2
2
3
13
J = 7.2 Hz, CO CH CH ); C NMR (125 MHz, CDCl ) δ 171.1 (C=O),
6
are racemates and were compared with spectral data from
2
2
3
3
1,20,22-24
167.3 (C=O), 149.5, 148.6, 141.4, 127.5, 124.2, 122.4, 112.0, 110.9, 60.8,
the literature,
where they are determined to have threo
6
0.7, 55.7, 55.6, 33.7, 14.1, 14.0. HRMS calcd for C H O : 322.1416;
17
22
6
configurations. In this short synthetic route, we took advantage
of the formation of phenyldihydronaphthalene ring to get the
lignanamide skeleton efficiently and simply.
found: 322.1436. Physical and spectral data are in accordance with
8
, 25
those previously reported.
Threo-(±)-(E)-ethyl 4-(3,4-dimethoxybenzylidene)-2-(3,4-dimethoxy-
phenyl)-5-oxotetrahydrofuran-3-carboxylate (4): The diester 3 (2.5 g,
As shown in Scheme 2, by reaction with SOCl , intermediate
2
6
4
was converted to an acylchloride, which was condensed with
7
.7 mmol) in THF (25 mL) was added to a solution of LDA (4.3 mL,
3.5 g, 32.6 mmol) in THF (25 mL) under a nitrogen atmosphere at
78 °C and the mixture was stirred for 10 min. Subsequently, the
-methoxyphenethylamine in the presence of Et N at ambient
3
temperature to give intermediate 7. Finally, removal of the
protecting group using BBr in DCM afforded Cannabisin B
–
3
solution of compound 2 (3.0 g, 18.1 mmol) in THF (20 mL) was added
and stirred for 1 h. The reaction was quenched with glacial acetic acid
(1). This strategy is novel and concise.
(
1.85 mL, 1.9 g, 32.3 mmol). Then, the mixture was warmed to room
temperature and extracted with EtOAc (3 × 20 mL) and washed with
0% HCl (2 × 20 mL) and 30% NaHCO aq (2 × 20 mL) followed by
Conclusions
In summary, an efficient and facile method for the synthesis
of Cannabisin B (1) has been developed for the first time. The
synthetic strategy used convergent methods and the formation
of the key intermediate phenyldihydronaphthalene diacid
starting from veratraldehyde (2). Finally, Cannabisin B (1) was
obtained in an overall yield of 15%. The synthesis and bio-
activity of Cannabisin B (1) derivatives are being studied in our
laboratory.
2
3
drying over anhydrous MgSO . The filtrate was concentrated and
purified by column chromatography to give compound 4 as a yellow
amorphous powder; yield 3.02 g (88%). H NMR (500 MHz, CDCl )
δ 7.71 (d, 1H, J = 2.0 Hz, ArCHC), 7.14–7.12 (m, 1H, ArH), 7.08–7.04
(m, 1H, ArH), 6.94-6.81 (m, 4H, ArH), 5.65 (d, 1H, J = 3.0 Hz,
CHOCO), 4.23–4.17 (m, 2H, COOCH ), 3.95 (s, 1H, CHCOO), 3.90
(s, 3H, OCH ), 3.89 (s, 3H, OCH ), 3.87 (s, 3H, OCH ), 3.86 (s, 3H,
OCH ), 1.18 (t, 3H, J = 7.0 Hz, CH CH ); C NMR (125 MHz, CDCl3)
4
1
3
2
3
3
3
1
3
3
2
3
Experimental
All chemicals in this study were used without further purification
unless specified. Melting points were taken on a Gallenkamp melting
δ 171.2 (CO), 170.2 (CO), 151.3, 149.4, 149.3, 149.1, 140.8, 131.8,
126.2, 125.1, 119.0, 117.6, 112.3, 111.3, 111.1, 108.1, 80.2, 62.2, 56.0,
53.7, 14.0. HRMS calcd for C H O : 442.1628; found: 442.1632.
Threo-(±)-4-(3,4-dimethoxyphenyl)-3-(ethoxycarbonyl)-6,7-
dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (5): The
solution of compound 4 (2.5 g, 5.7 mmol) in TFA (5 mL) was kept
2
4
26
8
1
point apparatus which were uncorrected. The H NMR (500 MHz) and
13
C NMR (125 MHz) spectra were recorded on a Bruker AM-500 MHz
spectrometer. HRMS spectra were obtained on a Bruker Daltonics
APEXII47e spectrometer. Flash column chromatography and TLC was
stirring for 4 h, and the reaction was quenched with H O (30 mL). The
2

6
08 JOURNAL OF CHEMICAL RESEARCH 2015
resulting mixture was extracted with EtOAc (3 × 30 mL), and then the
EtOAc (3 × 10 mL). The organic layer was washed with saturated
EtOAc layer was re-extracted with saturated NaHCO aq (3 × 30 mL).
NaCl aq (10 mL), dried over anhydrous MgSO and flash column
3
4
-1
The NaHCO aq extract was acidified with HCl (5 mol L , 3 × 20 mL)
chromatography of the residue gave compound 1: anamorphous
3
1
and extracted with EtOAc (3 × 30 mL). The combined organic layer
powder; yield 0.12 g (65%). H NMR (500 MHz, DMSO-d ) δ 7.32 (s,
6
was dried over anhydrous MgSO and concentrated under reduced
1H, ArCHC), 6.97 (d, 2H, J = 8.2 Hz, ArH), 6.81 (d, 2H, J = 8.2 Hz,
ArH), 6.77 (s, 1H, ArH), 6.69 (d, 2H, J = 8.2 Hz, ArH), 6.66 (d, 2H,
J = 8.2 Hz, ArH), 6.64 (d, 1H, J = 8.0 Hz, ArH), 6.51 (s, 1H, ArH),
6.48 (d, 1H, J = 2.0 Hz, ArH), 6.42 (dd, 1H, J = 8.0, 2.0 Hz, ArH),
4.29 (d, 1H, J = 4.0 Hz, ArCHAr), 3.66 (d, 1H, J = 4.0 Hz, CHCO),
4
pressure to give the compound 5: a yellow amorphous powder; yield
1
1
.51 g (60%). H NMR (500 MHz, CDCl ) δ 7.76 (s, 1H, ArCHC),
3
6
1
2
.89–6.63 (m, 4H, ArH), 6.43 (dd, 1H, J = 8.5, 2.0 Hz, ArH), 4.66 (d,
H, J = 2.5 Hz, ArCH), 4.10–4.08 (m, 2H, COOCH ), 3.95 (d, 1H, J =
.5 Hz, CHCOO), 3.92 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.82 (s, 3H,
OCH ), 3.80 (s, 3H, OCH ), 1.16 (t, 3H, J = 7.0 Hz, CH CH ); C NMR
2
3
3
3.36 (ddt, 2H, J = 14.0, 7.0, 6.0 Hz, CHCCONCH ), 3.22 (ddt, 2H, J =
2
13
3
3
2
3
14.0, 7.0, 6.0 Hz, NCH ), 2.68 (t, 2H, J =7.0 Hz, ArCH ), 2.46 (t, 2H,
2
2
(
1
125 MHz, CDCl ) δ 175.4 (CO), 173.3 (CO), 149.8, 148.7, 147.8, 147.6,
13
3
J =7.0 Hz, ArCH ); C NMR (125 MHz, CDCl ) δ 174.7 (CO), 170.5
2
3
35.2, 134.5, 130.9, 130.5, 125.2, 121.0, 111.6, 111.4, 111.3, 111.0, 61.1,
(
CO), 156.7, 156.6, 148.4, 146.0, 145.4, 144.9, 136.3, 134.8, 131.4,
131.3, 131.2, 130.8, 130.8, 130.7, 130.7, 127.3, 125.0, 120.3, 117.2, 116.8,
16.2, 116.2, 116.2, 116.2, 116.2, 116.2, 51.2, 47.3, 42.7, 42.5, 35.6, 35.5.
HRMS calcd for C H N O : 596.2159; found: 596.2162. Physical and
5
4
5.8, 49.0, 46.7, 14.0. HRMS calcd for C H O : 442.1628; found:
2
4
26
8
42.1631.
Threo- (± ) -1- (3,4-dimethoxyphenyl) - 6,7-dimethoxy-1,2-
1
3
4
32
2
8
2
3,26
dihydronaphthalene-2,3-dicarboxylic acid (6):
Yellow amorphous
1
spectral data are in accordance with those previously reported.
1
powder; yield 1.32 g (94%). H NMR (500 MHz, CDCl ) δ 7.80 (s,
3
1H, ArCHC), 7.23 (s, 1H, ArH), 6.89 (s, 1H, ArH), 6.67 (d, 1H, J = 2.0
This work was supported by National Natural Science
Foundation of China (grant no. 21472105).
Hz, ArH), 6.65 (d, 1H, J = 8.5 Hz, ArH), 6.48 (dd, 1H, J = 8.5, 2.0 Hz,
ArH), 4.67 (broad s, 1H, ArCHAr), 3.98 (d, 1H, J = 4.0 Hz, CHCO),
3
.91 (s, 3H, OCH ), 3.85 (s, 3H, OCH ), 3.82 (s, 3H, OCH ), 3.79 (s, 3H,
3
3
3
Received 13 July 2015; accepted 16 September 2015
Paper 1503488 doi: 10.3184/174751915X14425727961796
Published online: 2 October 2015
13
OCH ); C NMR (125 MHz, CDCl ) δ 178.3 (CO), 172.3 (CO), 148.8,
3
3
148.3, 147.9, 140.1, 134.7, 130.3, 120.9, 119.4, 112.0, 111.9, 111.5, 110.0,
56.0, 55.8, 46.8, 45.2, 20.8. HRMS calcd for C H O : 414.1315; found:
2
2
22
8
3
2
414.1319. The data are consistent with the literature.
Reference
Threo-(±)-1-(3,4-dimethoxyphenyl)-6,7-dimethoxy-N2,N3-bis(4-
1
I. Sakakibara, Y. Ikeya, K. Hayashi and H. Mitsuhashi, Phytochemistry,
992, 31, 3219.
M. DellaGreca, L. Previtera, R. Purcaro and A. Zarrelli, Tetrahedron,
006, 62, 2877.
methoxyphenethyl)-1,2-dihydronaphthalene-2,3-dicarboxamide (7):
The mixture of compound 6 (1.0 g, 2.4 mmol) and SOCl (2 mL) was
stirred for 1.5 h at –10 °C. The solvent was evaporated under reduced
pressure and the intermediate was obtained as a yellow oil. The
solution of the intermediate in DCM (10 mL) was added dropwise to a
1
2
2
2
3
4
F. Ge, C.P. Tang and Y. Ye, Helv. Chim. Acta, 2008, 91, 1023.
J.X. Zhang, S.H. Guan, R.H. Feng, Y. Wang and Z.Y. Wu, J. Nat. Prod.,
2013, 76, 51.
mixture of 4-methoxyphenethylamine (1.1 g, 7.2 mmol), Et N (1.7 mL,
3
5
J. Sun, Y.F. Gu, X.Q. Su, Y.F. Zhao, J. Li and P.F. Tu, Fitoterapia, 2014,
1.2 mmol) and DCM (5 mL) under a nitrogen atmosphere. After 3 h
9
8, 110.
of stirring, evaporation under reduced pressure removed DCM and
EtOAc (15 mL) was added, the organic layers were washed with 10%
HCl (30 mL) and H O (30 mL) followed by drying over anhydrous
MgSO . The filtrate was concentrated and purified by column
chromatography to afford compound 7: a white solid; m.p. 196 °C (lit.
6
7
8
Y.Z. Li, A.P. Tong and J. Huang, Chem. Biodivers., 2012, 9, 769.
M.H. Chaves and N.F. Roque, Phytochemistry, 1997, 46, 879.
F. Bailly, R.A. Toillon, O. Tomavo and N. Jouy, Bioorg. Med. Chem. Lett.,
2013, 23, 574.
2
4
1
9
P.P. Wang, G.W. Zhao, W. Xia, E.J. Han and L. Xiang, Chin. J. Nat. Med.,
2014, 12, 377.
1
1
96–197 °C); yield 0.86 g (52%). H NMR (500 MHz, CDCl ) δ 7.22
3
10
C.Y. Ma, W.K. Liu and C.T. Che, J. Nat. Prod., 2002, 65, 206.
(s, 1H, ArCHC), 6.99 (d, 2H, J = 8.7 Hz, ArH), 6.93 (d, 2H, J = 8.7
11 K.H. Kim, E. Moon, S.Y. Kim and K.R. Lee, J. Agric. Food. Chem., 2010,
Hz, ArH), 6.78 (d, 2H, J = 8.7 Hz, ArH), 6.74 (d, 2H, J = 8.7 Hz, ArH),
5
8, 4779.
6
6
4
.70 (s, 1H, ArH), 6.65 (s, 1H, ArH), 6.63 (d, 1H, J = 8.3 Hz, ArH),
.57 (d, 1H, J = 2.1 Hz, ArH), 6.34 (dd, 1H, J = 8.3, 2.1 Hz, ArH),
1
2
L. Lajide, P. Escoubas and J. Mizutani, Phytochemistry, 1995, 40, 1105.
E.S. Garcia and P. Azambuja, Toxicon, 2004, 44, 431.
13
.66 (d, 1H, J = 2.0 Hz, ArCHAr), 3.87 (s, 3H, OCH ), 3.80 (s, 3H,
3
14 D.W. Li, W.L. Li, Q. Wang, Z.Q. Yang and Z.J. Hou, Bioorg. Med. Chem.
Lett., 2010, 20, 5095.
OCH ), 3.78 (s, 3H, OCH ), 3.76 (s, 3H, OCH ), 3.74 (s, 6H, OCH × 2),
3
3
3
3
3
.57 (d, 1H, J = 2.0 Hz, CHCO), 3.45 (ddd, 2H, J = 14.0, 7.0, 6.0 Hz,
15 M.A. Constantin, J. Conrad and U. Beifuss, Green. Chem., 2012, 14, 2375.
1
6
W.L. Li, H. Liu, J.Y. Xu, P. Zang, and W.B. Li, Eur. J. Org. Chem., 2014,
014, 3475.
Y.M. Xia, Y.L. Guo and Y.L. Wen, J. Serb. Chem. Soc., 2010, 75, 1617.
18 Y.M. Xia, J. Xia and C. Chai, Chem. Pap., 2014, 68, 384.
CHCCONCH ), 3.34 (ddt, 2H, J = 14.0, 7.0, 6.0 Hz, NCH ), 2.71 (t,
2
ArCH ); C NMR (125 MHz, CDCl ) δ 171.4 (CO), 168.5 (CO), 158.3,
2
2
2
H, J = 7.0 Hz, ArCH ), 2.65–2.62 (m, 1H, ArCH ), 2.58–2.55 (m, 1H,
2 2
17
13
2
3
1
1
58.0, 150.8, 148.6, 148.0, 147.7, 135.4, 131.9, 130.9, 130.7, 130.6, 129.6,
29.6, 129.5, 129.5, 126.6, 123.6, 119.6, 114.0, 113.8, 112.1, 111.3, 111.1,
19
T.P. Chen, J.X. Hao, J.F. He and J.C. Zhang, Food. Chem., 2013, 138, 1034.
2
0 P.V. Ramachandran, G. Garner and D. Pratihar, Org. Lett., 2007, 9, 4753.
1
11.0, 56.0, 55.6, 55.6, 55.6, 55.2, 55.1, 49.6, 44.6, 41.3, 41.3, 34.6, 34.6.
21 T.G. Elford, A. Ulaczyk-Lesanko, P.G. De and G.D. Wright, J. Comb.
Chem., 2009, 11, 155.
22 S. Lee, S.U. Kim and E. Kim, Bull. Kor. Chem. Soc., 2007, 28, 1824.
23 I. Agata, T. Hatano, S. Nishibe and T. Okuda, Phytochemistry, 1989, 28,
HRMS calcd for C H N O : 680.3098; found: 680.3101. Physical and
spectral data are in accordance with those previously reported.
4
0
44
2
8
1
-1
Cannabisin B (1): The solution of BBr3 in DCM (1.0 mol L ,
.0 mL, 6.0 mmol, 8.7 equiv.) was added to a solution of compound
(0.21 g, 0.3 mmol, 1.0 equiv.) in DCM (15 mL), the mixture was
2
447.
Y. Kashiwada, M. Nishizawa, T. Yamagishi and T. Tanaka, J. Nat. Prod.,
995, 58, 392.
6
7
2
4
1
stirred for 2 h at –10 °C and warmed slowly to room temperature. The
25 C. Cow, C. Leung and J. Charlton, Can. J. Chem., 2000, 78, 553.
reaction was quenched with H O and the mixture was extracted with
26 M. Nishizawa, M. Tsuda and K. Hayashi, Phytochemistry, 1990, 29, 2645.
2