Regioselective Oxidation Approaches to Concise Synthesis of (±)-Canabisin D

Article abstract of DOI:10.1002/cjoc.201500054

The regioselective effects of tert-butyl or bromine as the position-protecting group of feruloytyamide on the oxidative coupling reactions for the synthesis of natural (±)-canabisin D were investigated in detail. The coupling yield of 8-8-coupled aryldihydronaphthalene product of 5-Br-feruloytyamide was higher than that of tert-butyl substituted precursor under FeCl₃·6H₂O-acetone-water oxidative condition. FeCl₃·6H₂O-catalyzed oxidative coupling reactions of feruloytyamide protected by tert-butyl or bromine group produced the desired 8-8-coupled aryldihydronaphthalene products, which underwent the debutylation or debromination to concisely synthesize (±)-canabisin D.

Full text of DOI:10.1002/cjoc.201500054

FULL PAPER
DOI: 10.1002/cjoc.201500054
Regioselective Oxidation Approaches to Concise Synthesis of
(±)-Canabisin D
Wenling Li,* Qian Liu, Hao Liu, Peilan Chen, Xi Yang, and Yingying Liu
School of Chemical and Biological Engineering, Lanzhou Jiaotong University,
Lanzhou, Gansu 730070, China
The regioselective effects of tert-butyl or bromine as the position-protecting group of feruloytyamide on the
oxidative coupling reactions for the synthesis of natural (±)-canabisin D were investigated in detail. The coupling
yield of 8-8-coupled aryldihydronaphthalene product of 5-Br-feruloytyamide was higher than that of tert-butyl sub-
stituted precursor under FeCl3•6H2O-acetone-water oxidative condition.
Keywords oxidative coupling, biomimetic synthesis, regioselectivity, liganamides, canabisin D
Introduction
difficulties.[3] Biomimetic oxidative coupling reaction
was the most concise approach to the diverse structures
of liganamides. However, random coupling modes be-
tween various radical mesomers such as M8, M5 and
MO-4 in the oxidative reactions of precursor invariably
lead to a variety of coupling products due to the lack of
regioselective control. As reported in literature, the di-
rect oxidative dimerization of 1 catalyzed by different
oxidants (FeCl3•6H2O, HPR-H2O2 or Cu (NO3)2•3H2O)
afforded 8-8-coupled product 2 and 8-5-coupled product
3 in low yields (7%－20%),[2] which largely restricted
the application of this biomimetic strategy in the syn-
thesis of natural liganamides including 2－5.
Canabisin D (2) and its analogues 3－5, a small
family of naturally occurring liganamides, were formed
via a single-electron oxidative dimerization of N-trans-
feruloyltyramine (1) in vivo (Figure 1). They were
found in the fruits or seeds of several plants and exhib-
ited obvious termite antifeedant activity and other po-
tential insects or pathogens deterrent roles.[1,2] Never-
theless, little attention was typically focused on the
study of the structure-activity relationship of these liga-
namides over the past two decades, which probably re-
sulted from their scare natural sources or the synthetic
OH
OH
OH
O
OH
2'
O
MeO
HO
N
H
α
2
7
MeO
HO
N
H
6'
β
H
8
N
6
O
HN
N-trans-feruloyltyramine (1)
OH
HN
O
O
OMe
O
OMe
OH
OH
canabisin D (2)
OH
O
OH
MeO
HO
OH
O
OMe
grossamide (3)
N
H
H
N
MeO
HO
N
H
O
O
H
N
OH
MeO
OMe
OH
O
OH
canabisin E (5)
canabisin G (4)
Figure 1 Several representive natural liganamides.
*
E-mail: liwl@mail.lzjtu.cn; Fax: 0086-0931-4938755
Received January 15, 2015; accepted March 3, 2015; published online March 30, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500054 or from the author.
Chin. J. Chem. 2015, 33, 717—722 © 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
717

Li et al.
FULL PAPER
In 2006, Hou group efficiently synthesized several
natural lignans and a liganamide—canabisin G (4) by
introducing tert-butyl protecting groups into ferulic acid
or its esters for hindering 8-5 coupling mode predomi-
nated in the traditional biomimetic synthesis and in-
creasing the yields of 8-8-coupling products.[4] Recently,
our group followed their regioselective biomimetic
strategy to indirectly prepare some aryldihydronaphtha-
lene ligans, and canabisin D (2) with the condensation
of 8-8-cyclic-diferulic acids with tyramine hydrochlo-
ride (7) as the last step.[5] In this paper, we hope to ex-
plore a concise synthetic approach to (±)-2 by using the
direct oxidative dimerization of feruloyltyramine de-
rivatives protected by positioning groups as the key re-
actions.
[V(CH2Cl2)∶V(MeOH)＝30∶1] to give dimer 10 (0.16
g, 42%) and 11 (0.05 g, 14%) as well as unreacted 8
(0.14 g). 10: an amorphous powder; Rf ＝ 0.24
1
[V(CH2Cl2)∶V(MeOH)＝20∶1]; H NMR (400 MHz,
d-acetone) δ: 1.24 (s, 9H, C(CH3)3), 1.49 (s, 9H,
C(CH3)3), 2.51 (t, J＝7.2 Hz, 2H, ArCH2), 2.66 (t, J＝
7.2 Hz, 2H, ArCH2), 3.14－3.20 (m, 2H, NHCH2),
3.29－3.33 (m, 2H, NHCH2), 3.71 (s, 3H, OCH3), 3.80
(s, 1H, 8'-H), 3.92 (s, 3H, OCH3), 5.81 (s, 1H, 7'-H),
6.30 (s, 1H, 2'-H), 6.50 (s, 1H, 6'-H), 6.69 (d, J＝7.8 Hz,
2H, Ar-H), 6.71 (d, J＝10 Hz, 2H, Ar-H), 6.87 (d, J＝
10 Hz, 2H, Ar-H), 6.96 (d, J＝7.8 Hz, 2H, Ar-H), 7.11
(s, 1H, OH), 7.18 (s, 1H, 2-H), 7.35－7.38 (m, 2H, NH),
7.76 (s, 1H, 7-H), 8.12 (br s, 1H, OH); 13C NMR (100
MHz, d-acetone) δ: 32.3 (6C), 35.3, 35.6, 35.7, 39.1,
42.1, 42.3, 42.6, 50.4, 56.5, 56.6, 109.8, 111.0, 116.0
(2C), 116.1 (2C), 119.4, 125.9, 130.5 (6C), 131.2 (2C),
134.7, 134.9, 135.1, 135.3, 143.5, 146.9, 148.0, 148.4,
156.6, 156.7, 168.7, 171.8; IR (neat) ν: 3375 (OH), 1656
(C ＝ O), 1610, 1518 cm － 1. ESI-HRMS calcd for
C44H52N2O8 ＋ H 737.3796, found 737.3806. 11: an
amorphous powder; Rf＝0.25 [V(CH2Cl2)∶V(MeOH)＝
Experimental
Structural determinations of the isolated compounds
1
1
were based on H, 13C NMR, NOESY, H-1H COSY,
HMBC spectra, and HRMS analysis. All NMR spectra
were recorded on a Varian Mercury 400 MHz instru-
ment in a solvent as indicated. HRMS spectra were
measured on an Autostec-3090 mass spectrometer. All
solvents were freshly purified and dried by standard
techniques prior to use. Purification of products was
performed by column chromatography (CC) on silica
gel (200－300 mush), purchased from QingDao Marine
Chemical Co. (QingDao, China).
1
20∶1]; H NMR (400 MHz, d-acetone) δ: 1.27 (s, 9H,
C(CH3)3), 1.39 (s, 9H, C(CH3)3), 2.57 (t, J＝7.2 Hz, 2H,
ArCH2), 2.73 (t, J＝7.2 Hz, 2H, ArCH2), 3.22－3.33 (m,
2H, NHCH2), 3.43－3.46 (m, 2H, NHCH2), 3.69 (s, 3H,
OCH3), 3.78 (s, 4H, 8'-H, OCH3), 5.03 (s, 1H, 7'-H),
6.62 (s, 1H, 2'-H), 6.69 (s, 1H, 6'-H), 6.72 (d, J＝7.6 Hz,
2H, Ar-H), 6.74 (d, J＝6.4 Hz, 2H, Ar-H), 6.95 (s, 1H,
6-H), 6.96 (d, J＝6.4 Hz, 2H, Ar-H), 7.01 (d, J＝7.6 Hz,
2H, Ar-H), 7.28 (s, 1H, 7-H), 7.65－7.67 (m, 1H, NH),
7.85－7.87 (m, 1H, NH); 13C NMR (100 MHz, CD3Cl)
δ: 29.5 (6C), 34.7 (2C), 38.8 (2C), 39.7, 41.3, 41.6, 49.0,
56.2, 61.7, 107.9, 115.6 (2C), 115.8 (2C), 118.2, 123.1,
123.8, 125.3, 128.4, 129.8 (4C), 130.2, 130.4, 132.4,
133.8, 135.2, 135.7, 143.1, 145.3, 146.7, 150.5, 154.7,
154.9, 169.0, 172.1; IR (neat) ν: 3345 (OH), 1668 (C＝
O), 1611, 1528 cm−1. ESI-HRMS calcd for C44H52N2O8
＋H 737.3796, found 737.3804.
E-3-(3-tert-Butyl-4-hydroxy-5-methoxyphenyl)-N-
2-[4-hydroxylphenylethyl]-2-propenamide (8) To a
solution of acid 6 (0.71 g, 3.2 mmol) in dry acetonitrile
(50 mL) was added N-hydroxysuccinimide (NHS) (0.46
g, 4 mmol). After stirred for 5 min, the mixture was
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (0.75 g, 4 mmol) under ice bath
and continued to stir for 24 h. Tyramine hydrochloride
(7) (0.69 g, 4 mmol) and triethylamine (3.5 mL) were
then added to the reaction system and stirred at room
temperature for 7 h. The reaction mixture was diluted
with EtOAc (60 mL) and washed with 5% citric acid,
saturated aqueous NaHCO3 and brine, and dried over
MgSO4. The solvent was evaporated in vacuo and the
residue was purified by column chromatography
[V(petroleum ether)∶V(EtOAc)＝1∶1] to afford 8
(0.99 g, 85%) as an amorphous powder. All the spec-
trum data were consistent with the literature values.[4c]
FeCl3•6H2O-catalyzed oxidative coupling of 8
FeCl3•6H2O (3.14 g, 11.6 mmol) was dissolved in water
(13 mL) and slowly added to the solution of amide 8
(0.53 g, 1.43 mmol) in acetone (26 mL). The reaction
mixture was stirred at room temperature under argon
atmosphere for 41 h. After the removal of the acetone
under reduced pressure, the resulting residue was ex-
tracted with EtOAc three times (40 mL). The combined
organic layer was washed with brine, dried over anhy-
drous MgSO4 and evaporated in vacuo. The crude prod-
ucts were subjected to silica gel column chromatography
Debutylation reaction of 10 To a solution of
compound 10 (58.0 mg, 0.079 mmol) in benzene (8 mL)
and CH3NO2 (1.5 mL) was added AlCl3 (0.72 g, 5.4
mmol) at 50 ℃. The mixture was stirred at the same
temperature for 7 h, and then the reaction was quenched
with ice, extracted with EtOAc (15 mL). The combined
organic layers were washed with brine, dried over
MgSO4 and evaporated in vacuo. The residue was puri-
fied by column chromatography [V(CH2Cl2)∶V(MeOH)
＝25∶1] to afford compound 12 (45 mg, 85%) as an
amorphous powder. Rf＝0.42 [V(CH2Cl2)∶V(MeOH)＝
1
15∶1]; H NMR (400 MHz, d-acetone) δ: 1.49 (s, 9H,
C(CH3)3), 2.52 (t, J＝7.2 Hz, 2H, ArCH2), 2.66 (t, J＝
7.2 Hz, 2H, ArCH2), 3.14－3.19 (m, 1H, NHCH2),
3.30－3.33 (m, 1H, NHCH2), 3.33－3.37 (m, 2H,
NHCH2), 3.71 (s, 3H, OCH3), 3.74 (s, 1H, 8'-H), 3.91 (s,
3H, OCH3), 5.82 (s, 1H, 7'-H), 6.17 (d, J＝7.8 Hz, 1H,
6'-H), 6.60 (d, J＝7.8 Hz, 1H, 5'-H), 6.66 (d, J＝7.8 Hz,
2H, Ar-H), 6.71 (d, J＝8.0 Hz, 2H, Ar-H), 6.70 (s, 1H,
718
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Chin. J. Chem. 2015, 33, 717—722

Regioselective Oxidation Approaches to Concise Synthesis of (±)-Canabisin D
2'-H), 6.85 (s, 1H, 2-H), 6.87 (d, J＝8.0 Hz, 2H, Ar-H),
6.94 (d, J＝7.8 Hz, 2H, Ar-H), 7.16 (s, 1H, 7-H), 7.36－
7.44 (m, 4H, NH); 13C NMR (100 MHz, d-acetone) δ:
32.4 (3C), 35.5, 35.7, 39.0, 42.0, 42.2, 42.4, 50.7, 56.3,
56.5, 110.9, 112.6, 115.2, 116.0 (4C), 121.5, 125.9,
126.7, 130.3, 130.5 (6C), 131.2, 134.7, 136.8, 145.6,
146.9, 148.1, 148.3, 156.5, 156.6, 168.9, 171.6; IR (neat)
ν: 3410 (OH), 1670 (C ＝ O), 1604, 1514 cm−1.
ESI-HRMS calcd for C40H44N2O8＋H: 681.3170, found
681.3172.
(m, 1H, NH); 13C NMR (100 MHz, d-acetone) δ: 29.5
(3C), 35.2, 35.6, 35.7, 39.6, 42.0, 42.4, 48.9, 56.3, 61.4,
112.5, 115.4, 116.0 (4C), 120.9, 123.6, 124.3, 127.3,
130.6 (6C), 131.1, 131.2, 133.0, 135.6, 145.9, 146.5,
148.0, 151.3, 156.6, 156.7, 169.9, 171.6; IR (neat) ν:
3379 (OH), 1653 (C＝O), 1609, 1512 cm−1. ESI-HRMS
calcd for C40H44N2O8＋H: 681.3170, found 681.3175.
Debutylation reaction of 13 Dimer 13 (21 mg,
0.031 mmol) was dissolved in 0.5 mL of CF3SO3H at
room temperature under argon. The reaction mixture
was stirred for 15 min and poured into 3 mL of water.
The resulting mixture was extracted with EtOAc three
times (10 mL). The combined organic layer was washed
with brine, dried over anhydrous MgSO4 and evaporated
in vacuo. The crude products were subjected to prepara-
tive TLC [V(CH2Cl2)∶V(MeOH)＝20∶1] to give
liganamide 14 (15.6 mg, 82%) as an amorphous powder.
Synthesis of (±)-canabisin D (2) Dimer 12 (25
mg, 0.034 mmol) was dissolved in 0.5 mL of CF3SO3H
at room temperature under argon. The reaction mixture
was stirred for 15 min and poured into 3 mL of water.
The resulting mixture was extracted with EtOAc three
times (10 mL). The combined organic layer was washed
with brine, dried over anhydrous MgSO4 and evaporated
in vacuo. The crude products were subjected to prepara-
tive TLC [V(CH2Cl2)∶V(MeOH)＝20∶1] to give
(±)-2 (18.4 mg, 87%) as an amorphous powder. Rf＝
1
Rf＝0.27 [V(CH2Cl2)∶V(MeOH)＝15∶1]; H NMR
(400 MHz, d-acetone) δ: 2.56 (t, J＝7.2 Hz, 2H, ArCH2),
2.70 (t, J＝7.2 Hz, 2H, ArCH2), 3.18－3.23 (m, 1H,
NHCH2), 3.29－3.32 (m, 1H, NHCH2), 3.38－3.42 (m,
2H, NHCH2), 3.69 (s, 4H, 8'-H, OCH3), 3.74 (s, 3H,
OCH3), 5.10 (s, 1H, 7'-H), 6.40 (d, J＝8.0 Hz, 1H, 6'-H),
6.60 (d, J＝8.0 Hz, 1H, 5'-H), 6.73 (d, J＝7.6 Hz, 4H,
Ar-H), 6.80 (d, J＝7.6 Hz, 1H, 5-H), 6.82 (s, 1H, 2'-H),
6.93 (d, J＝7.6 Hz, 3H, 6-H, Ar-H), 6.98 (d, J＝7.6 Hz,
2H, Ar-H), 7.23 (s, 1H, 7-H), 7.61－7.63 (m, 1H, NH),
7.79 － 7.82 (m, 1H, NH); 13C NMR (100 MHz,
d-acetone) δ: 35.5, 35.7, 39.8, 42.1, 42.4, 49.1, 56.3,
60.6, 112.4, 115.4, 115.6, 116.0 (2C), 116.1 (2C), 120.9,
125.5, 125.8, 127.6, 130.5 (2C), 130.6 (3C), 131.1,
132.5, 133.9, 135.6, 145.9, 146.4, 148.1, 153.1, 156.6,
156.7, 169.8, 171.6; IR (neat) ν: 3364 (OH), 1660 (C＝
O), 1612, 1515 cm−1. ESI-HRMS calcd for C36H36-
N2O8−H 623.2388, found 623.2392.
HRP-H2O2-catalyzed oxidative coupling of 8
HRP (20 mg, RZ＞3, activity≥300 u/mg) was dis-
solved in buffer solution (pH＝6) (10 mL), to which a
solution of compound 6 (0.36 g, 0.97 mmol) in acetone
(40 mL) was added at room temperature under argon
atmosphere. After stirring for 10 min, the mixture was
treated with hydrogen peroxide (3%, 10 mL) and con-
tinued to stir for 6 h. The reaction mixture was
quenched with water and extracted with EtOAc (50 mL).
The organic layer was washed with saturated brine and
then dried over MgSO4. The solvent was removed under
reduced pressure and the residue was purified on a silica
gel [V(CH2Cl2)∶V(MeOH)＝30∶1] to give pure 10
(16 mg, 10%) and unreacted starting material 8 (0.20 g).
Cu (NO3)2•3H2O-catalyzed oxidative coupling of 8
Cu (NO3)2•3H2O (0.28 g, 0.16 mmol) was slowly added
to the solution of amide 8 (50 mg, 0.14 mmol) in etha-
nol (8 mL). The reaction mixture was stirred at room
temperature under argon atmosphere for 24 h. After the
removal of the ethanol under reduced pressure, the re-
sulting residue was extracted with EtOAc three times.
The combined organic layer was washed with brine,
dried over anhydrous MgSO4 and evaporated in vacuo.
1
0.28 [V(CH2Cl2)∶V(MeOH)＝15∶1]; H NMR (400
MHz, d-acetone) δ: 2.55 (t, J＝7.2 Hz, 2H, ArCH2),
2.71 (t, J＝7.2 Hz, 2H, ArCH2), 3.19－3.30 (m, 2H,
NHCH2), 3.40－3.43 (m, 2H, NHCH2), 3.67 (s, 1H,
8'-H), 3.74 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.59 (s,
1H, 7'-H), 6.39 (d, J＝8.0 Hz, 1H, 6'-H), 6.62 (d, J＝8.0
Hz, 1H, 5'-H), 6.67 (s, 1H, 5-H), 6.72 (d, J＝8.0 Hz, 2H,
Ar-H), 6.74 (d, J＝8.0 Hz, 2H, Ar-H), 6.79 (s, 1H, 2'-H),
6.86 (s, 1H, 2-H), 6.93 (d, J＝8.0 Hz, 2H, Ar-H), 7.00
(d, J＝8.0 Hz, 2H, Ar-H), 7.24 (s, 1H, 7-H), 7.57－7.62
(m, 2H, NH); 13C NMR (100 MHz, d-acetone) δ: 35.5,
35.6, 42.1, 42.4, 45.5, 49.6, 56.3, 56.4, 112.2, 112.6,
115.5, 116.0 (2C), 116.1 (2C), 117.1, 120.9, 124.4,
127.9, 130.5 (2C), 130.6 (3C), 131.1, 132.6, 133.2,
136.5, 146.0, 147.3, 148.1, 149.0, 156.6, 156.7, 169.5,
171.8; IR (neat) ν: 3402 (OH), 1644 (C＝O), 1608,
1522 cm−1. ESI-HRMS calcd for C36H36N2O8−H
623.2388, found 623.2394.
Debutylation reaction of 11 To a solution of
compound 11 (43.0 mg, 0.06 mmol) in benzene (5 mL)
and CH3NO2 (1 mL) was added AlCl3 (0.73 g, 5.4 mmol)
at 50 ℃. The mixture was stirred at the same tempera-
ture for 20 h, and then the reaction was quenched with
ice, extracted with EtOAc (15 mL). The combined or-
ganic layers were washed with brine, dried over MgSO4
and evaporated in vacuo. The residue was purified by
column chromatography [V(CH2Cl2)∶V(MeOH)＝20∶
1] to afford unreacted 10 (12.5 mg) and compound 13
(23.4 mg, 83%) as an amorphous powder. Rf＝0.41
1
[V(CH2Cl2)∶V(MeOH)＝15∶1]; H NMR (400 MHz,
d-acetone) δ: 1.39 (s, 9H, C(CH3)3), 2.56 (t, J＝7.2 Hz,
2H, ArCH2), 2.71 (t, J＝7.2 Hz, 2H, ArCH2), 3.19－
3.27 (m, 2H, NHCH2), 3.39－3.43 (m, 2H, NHCH2),
3.69 (s, 1H, 8'-H), 3.74 (s, 6H, OCH3), 5.04 (s, 1H,
7'-H), 6.38 (d, J＝8.0 Hz, 1H, 6'-H), 6.60 (d, J＝8.0 Hz,
1H, 5'-H), 6.73 (d, J＝8.4 Hz, 4H, Ar-H), 6.84 (s, 1H,
2'-H), 6.95 (s, 1H, 6-H), 6.96 (d, J＝8.4 Hz, 4H, Ar-H),
7.24 (s, 1H, 7-H), 7.60－7.62 (m, 1H, NH), 7.92－7.94
Chin. J. Chem. 2015, 33, 717—722
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
FULL PAPER
The crude products were subjected to silica gel column
chromatography [V(CH2Cl2)∶V(MeOH)＝30∶1] to
give unreacted 8 (15 mg) and dimer 10 (4 mg, 12%).
E-3-(3-Br-4-hydroxy-5-methoxyphenyl)-N-2-[4-
hydroxylphenylethyl]-2-propenamide (16) To a so-
lution of acid 15 (0.5 g, 1.84 mmol) in dry acetonitrile
(50 mL) was added NHS (0.26 g, 2.3 mmol). After
stirred for 5 min, the mixture was added EDC (0.44 g,
2.3 mmol) under ice bath and continued to stir for 20 h.
Tyramine hydrochloride (7) (0.4 g, 2.3 mmol) and
triethylamine (2.5 mL) were then added to the reaction
system and stirred at room temperature for 8 h. The re-
action mixture was diluted with EtOAc (50 mL) and
washed with 5% citric acid, saturated aqueous NaHCO3
and brine, and dried over MgSO4. The solvent was
evaporated in vacuo and the residue was purified by
column chromatography [V(CH2Cl2)∶V(MeOH)＝25∶
1] to afford 16 (0.57 g, 80%) as an amorphous powder.
805.0554, found 805.0556.
Debromination of 17 Excess LiAlH4 (0.11 g, 2.88
mmol) was added to a solution of 17 (45 mg, 0.058
mmol) in dry THF (10 mL) at room temperature and the
mixture continued to stir at 50 ℃ for 20 h. The ice wa-
ter (1 mL) was slowly added to quench the reaction and
the resulting mixture was extracted with EtOAc three
times (15 mL). The combined organic layer was washed
with brine, dried over anhydrous MgSO4 and evaporated
in vacuo. The crude products were subjected to silica gel
column chromatography [V(CH2Cl2)∶V(MeOH)＝15∶
1] to give (±)-2 (30 mg, 82%) as an amorphous pow-
der.
Results and Discussion
The total synthesis of canabisin D (2) commenced
with the preparation of the coupling precursors. First,
we selected 5-tert-butyl feruloyltyramine (8) on the ba-
sis of the previous regioselective strategy, which was
produced by the reaction of 5-tert-butyl ferulic acid (6)
with 7 in 85% yield (Scheme 1).[4c] The oxidative cou-
pling reaction of 8 catalyzed by FeCl3•6H2O was con-
ducted in the acetone-water system at room temperature.
As we expected, 8-8-coupled products were predomi-
nately formed, which included the target 10 and unde-
sired 11, as well as trace amount of 9. This reaction
mechanism can be best explained by the presence of
unstable intermediate 9, which was easily generated at
the start and underwent further 6π electrocyclization to
form dihydronaphthalene structures under the acidic
oxidative condition.[6] The ring closure at the para posi-
tion of the OMe group (C-6) provided the desired 10 in
42% yield, while a small quantity of isomer 11 was si-
multaneously formed when the cyclization occurred at
the less steric position ortho to the OMe group (C-2).
The isomeric aryldihydronaphthalene structures 10 and
11 were elucidated by the key NOE correlation between
7'-H and tert-butyl group at C-5 or between 7-H and
OMe group at C-2, respectively. The steric effect of
bulky tert-butyl group at C-5 in 10 resulted in a lower
shift of the butyl group at δ 1.49 as well as 7'-H at 5.81
compared to those in 11 (at δ 1.39 and 5.03 respectively),
which further validated their structural correctness.
Their trans configurations were both deduced from the
small coupling constants between 7'-H and 8'-H (J＜1.0
Hz).
1
Rf＝0.35 [V(CH2Cl2)∶V(MeOH)＝20∶1]; H NMR
(400 MHz, d-acetone) δ: 2.74－2.77 (m, 2H, ArCH2),
3.49－3.54 (m, 2H, NHCH2), 3.87 (s, 3H, OCH3), 6.60
(d, J＝15.6 Hz, 1H, 8-H), 6.77 (d, J＝8.0 Hz, 2H, Ar-H),
7.05 (d, J＝8.0 Hz, 2H, Ar-H), 7.14 (s, 1H, 2-H), 7.31 (s,
1H, 6-H), 7.44 (d, J＝15.6 Hz, 1H, 7-H), 7.44－7.48 (m,
1H, NH); 13C NMR (100 MHz, d-acetone) δ: 35.6, 42.0,
56.7, 109.7, 110.4, 116.1 (2C), 121.3, 125.3, 128.7,
130.5 (2C), 130.9, 139.2, 146.5, 149.2, 156.7, 166.4; IR
(neat) ν: 3356 (OH), 1652 (C＝O), 1614, 1520 cm−1.
ESI-HRMS calcd for C18H18BrO4＋H 392.0492, found
392.0486.
FeCl3•6H2O-catalyzed oxidative coupling of 16
FeCl3•6H2O (1.2 g, 4.4 mmol) was dissolved in water (4
mL) and slowly added to the solution of amide 16 (0.14
g, 0.36 mmol) in acetone (8 mL). The reaction mixture
was stirred at room temperature under argon atmosphere
for 40 h. After the removal of the acetone under reduced
pressure, the resulting residue was extracted with EtOAc
three times (25 mL). The combined organic layer was
washed with brine, dried over anhydrous MgSO4 and
evaporated in vacuo. The crude products were subjected
to silica gel column chromatography [V(CH2Cl2) ∶
V(MeOH)＝20∶1] to give unreacted 16 (30 mg) and
dimer 17 (86 mg, 78%) as an amorphous powder. Rf＝
1
0.12 [V(CH2Cl2)∶V(MeOH)＝20∶1]; H NMR (400
MHz, d-acetone) δ: 2.45 (t, J＝7.2 Hz, 2H, ArCH2),
2.57 (t, J＝7.2 Hz, 2H, ArCH2), 3.03－3.27 (m, 4H,
NHCH2), 3.59 (s, 1H, 8'-H), 3.68 (s, 3H, OCH3), 3.78 (s,
3H, OCH3), 4.98 (s, 1H, 7'-H), 6.35 (s, 1H, 2-H), 6.58－
6.63 (m, 4H, Ar-H), 6.78 (s, 1H, 2'-H), 6.82－6.87 (m,
4H, Ar-H), 7.14 (s, 1H, 6'-H), 7.59－7.62 (m, 1H, NH),
7.68－7.72 (m, 1H, NH), 7.96 (s, 1H, OH), 8.03 (s, 1H,
7-H), 8.45 (s, 1H, OH); 13C NMR (100 MHz, d-acetone)
δ: 35.5, 35.6, 42.1, 42.5, 44.9, 49.9, 56.8 (2C), 108.9,
115.6, 111.7, 113.6, 116.0 (2C), 116.1 (2C), 124.2,
125.7, 129.2, 130.6, 131.1 (2C), 131.7 (4C), 132.2,
135.1, 145.4, 147.2, 148.3, 149.0, 156.6, 156.7, 170.0,
170.9; IR (neat) ν: 3365 (OH), 1666 (C＝O), 1617,
1528 cm−1. ESI-HRMS calcd for C36H34Br2N2O8＋Na
The removal of tert-butyl protecting groups from the
two coupling intermediates 10 or 11 was preliminarily
performed in the presence of AlCl3 and benzene at 50
℃ (Scheme 2). However, only one butyl group was
cleaved to produce 12 or 13 even if AlCl3 amount was
increased or the reaction time was prolonged. Then, the
strong acid CF3SO3H was attempted to remove the rest
of the protecting group,[7] which smoothly resulted in
our target product 2 or an unnatural lignanamide 14 in
good yield.
720
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 717—722

Regioselective Oxidation Approaches to Concise Synthesis of (±)-Canabisin D
Scheme 1 Regioselective oxidative coupling products of 8
MeO
HO
CONHR
MeO
HO
CO2H
.
FeCl3 6H2O
EDC, NHS, TEA
acetonitrile
85%
HO
+
+
-
NH3Cl
acetone-H2O
Bu-t
Bu-t
OH
tyramine hydrochloride (7)
8
6
R =
7
2
7
6
MeO
HO
CONHR
t-Bu
CONHR
CONHR
2
MeO
HO
CONHR
CONHR
CONHR
HO
7'
7'
6
Bu-t
+
OMe
electrocyclization
Bu-t
t-Bu
OMe
t-Bu
OMe
t-Bu
OMe
OH
10 (42%)
OH
OH
9
11 (14%)
Scheme 2 Debutylation of coupling products 10 and 11
MeO
HO
CONHR
CONHR
MeO
AlCl3
CONHR
CONHR
HO
MeNO2
CF3SO3H
Bu-t
10
benzene
50 oC
85%
r.t.
87%
OMe
OMe
OH
OH
(±)-2
12
t-Bu
CONHR
CONHR
CONHR
CONHR
AlCl3
MeNO2
HO
HO
CF3SO3H
OMe
11
OMe
benzene
50 oC
r.t.
82%
OMe
OMe
83%
OH
OH
14
13
Next, the catalytic oxidation of precursor 8 under
HRP-H2O2 at pH＝6 condition or in Cu (NO3)2•3H2O
system was carried out to improve the coupling yield of
10. Disappointingly, the desired 10 was obtained as a
single 8-8-coupled product in poor yield (＜15%) and
most of 8 remained unreacted under the two oxidation
conditions.
At this point, although the regioselective oxidative
strategy initially designed for the synthesis of natural
lignanamide 2 proved practicable, the low coupling
yields of 10 in three different catalytic systems were not
satisfactory. Thus, we considered a revised method by
using Br as the position-protecting group to replace the
tert-butyl group of precursor 8,[8] which may not only
play the same role as butyl group to hinder the 8-5 cou-
pling mode, but also reduce the steric effects of the pro-
tecting group on the further intramolecular cyclization
of 8-8-coupled intermediate.
Subsequently, the key coupling precursor 5-Br-
feruloyltramine (16) was synthesized by the condensa-
tion of 5-Br-ferulic acid (15) with 7 in 80% yield
(Scheme 3). Acid 15 was easily prepared according to
the literature procedure.[9] FeCl3•6H2O was still selected
to catalyze the oxidative dimerization of 16 in view of
Scheme 3 Oxidative coupling reaction of 16 towards the synthesis of (±)-2
MeO
HO
CONHR
CONHR
MeO
HO
CO2H
.
FeCl3 6H2O
LiAlH4 /THF
MeO
HO
CONHR
OH
tyramine hydrochloride (7)
(±)-2
Br
Br
50 oC
82%
acetone-H2O
78%
EDC, NHS, TEA
acetonitrile
80%
Br
Br
OMe
16
15
OH
R =
17
Chin. J. Chem. 2015, 33, 717—722
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
721

Li et al.
FULL PAPER
National Natural Science Foundation of China (No.
21462024) and the Scientific Research Foundation for
the Returned Overseas Chinese Scholars of State Educa-
tion Ministry (2013).
its relatively higher selectivity compared to HRP-H2O2
or Cu (NO3)2•3H2O catalyst. To our delight, 8-8-cou-
pled aryldihydronaphthalene product 17 was predomi-
nantly generated in 78% yield, which was further treated
with excess LiAlH4 in THF to carry out the global de-
bromination and finally accomplished the concise syn-
thesis of racemic 2.
References
[1] (a) Yoshihara, T.; Yamaguchi, K.; Takamatsu, S.; Sakamura, S. Ag-
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Phytochemistry 1995, 40, 1105.
Conclusions
In summary, a regioselectively controlled strategy
for the synthesis of natural liganamide 2 has been de-
veloped by introducing tert-butyl group or Br atom into
the C-5 of N-trans-feruloyltramine precursor to hamper
the 8-5 coupling product. The direct oxidative coupling
reactions of modified precursor 8 or 16 catalyzed by
FeCl3•6H2O in acetone-H2O system afforded the ex-
pected 8-8-coupled product 10 or 17, which underwent
the final debutylation or debromination to achieve the
synthesis of (±)-canabisin D (2). In contrast, Br atom
as the position-protecting group of feruloyltramine pre-
cursor had obvious advantages over the bulky tert-butyl
group in the regioselective coupling reaction. This
biomimetic synthetic strategy can be extensively inves-
tigated in the synthesis of a variety of naturally occur-
ring liganamides for the further study of their struc-
ture-activity relationship and the corresponding research
is currently in progress in our laboratory.
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Acknowledgement
[9] Whaley, W. M.; Meadow, M.; Dean, W. L. J. Org. Chem. 1954, 19,
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This research work was financially supported by the
(Cheng, F.)
722
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 717—722