Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the enantioselective syntheses of furofuran lignans

Article abstract of DOI:10.1016/j.tet.2016.10.058

A new electrochemical method for the asymmetric oxidative dimerization of cinnamic acid derivatives has been developed. This method enabled the enantioselective syntheses of furofuran lignans, yangambin, sesamin and eudesmin.

Full text of DOI:10.1016/j.tet.2016.10.058

Tetrahedron xxx (2016) 1e7
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electochemical asymmetric dimerization of cinnamic acid derivatives
and application to the enantioselective syntheses of furofuran lignans
Naoki Mori, Akiko Furuta, Hidenori Watanabe*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-
8657, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new electrochemical method for the asymmetric oxidative dimerization of cinnamic acid derivatives
has been developed. This method enabled the enantioselective syntheses of furofuran lignans, yan-
gambin, sesamin and eudesmin.
Received 26 September 2016
Received in revised form
20 October 2016
Accepted 23 October 2016
Available online xxx
© 2016 Elsevier Ltd. All rights reserved.
Keywords:
Furofuran lignan
Electrochemical oxidation
Yangambin
Sesamin
Eudesmin
1. Introduction
shows selective inhibition against platelet activating factor,14 T-cell
proliferation,15 antioxidant16 and neuritogenic17 activities. Concise
There are a number of lignans1 in plants and furofuran lignans,
one of the largest subclass of them, have various biological activ-
ities such as antitumor, antimitotic, antiviral and antimicrobial
activities. The diversity of their bioactivities has attracted the
attention of chemists, and the stereocontrolled synthesis of the
substituted 3,7-dioxabicyclo[3,3,0]octane skeleton has also been a
challenging target to synthetic chemists.2 Furofuran lignans in our
research interests are shown in Fig. 1. Yangambin was first obtained
as a dimethylated derivative of lirioresinol-B3 isolated from tulip
tree, Liriodendron tulipifera L., and then isolated from Chinese me-
dicinal plant, Magnolia fargesii.4 Yangambin displays selective in-
hibition against platelet activating factor,5 protective effects against
cardiovascular collapse and anaphylactic shock, anti-allergic
properties, analgesic activity, depressant effect in the central ner-
vous system6 and apoptosis induction.7 Sesamin,8 which is a major
constituent of sesame seed, is very famous of its antihypertensive,9
anticancer10 and antioxidant9d properties. Eudesmine has been
isolated from Araucaria angustifolia,11 Humbertia madagascar-
iensis12 and the bark of Mangnolia kubus13 up to the present. It
enantioselective syntheses of yangambin, sesamin and eudesmin
have been reported by several research groups.18
We have previously developed an asymmetric oxidative
dimerization of 3,4,5-trimethoxycinnamic acid derivative 1a by
using Yuzikhin's condition19 (PbO2, TFA, CH2Cl2) (Scheme 1) and
applied it to the efficient syntheses of furofuran lignans, yangambin
(5 steps, 30% yield, 100% e.e.) and caruilignan A (6 steps, 30% yield,
100% e.e.).20 Although other substrates (1b ~ d) with less oxygen
atom on the benzene ring were subjected to the same condition, it
was found that a trace amount of the desired bislactones (2b ~ d)
was obtained along with an innegligible amount of aldehyde 3,
which was produced by oxidative cleavage of the double bond.
Therefore, we proposed electrochemical oxidation21 as an alter-
native method to suppress the generation of 3 by setting factors
such as solvent, supporting electrolyte, volumes of electric current
and voltage suitable for each substrate. Herein, we report a new
electrochemical method for the asymmetric oxidative dimerization
of cinnamic acid derivatives and the enantioselective syntheses of
furofuran lignans, yangambin, sesamin and eudesmin.
2. Results and discussion
* Corresponding author.
E-mail address: ashuten@mail.ecc.u-tokyo.ac.jp (H. Watanabe).
Four substrates (1a ~ d) for electrochemical oxidation were
http://dx.doi.org/10.1016/j.tet.2016.10.058
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Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

2
N. Mori et al. / Tetrahedron xxx (2016) 1e7
Fig. 1. Structures of furofuran lignans.
Scheme 1. Synthetic strategies for furofuran lignans.
prepared by the same method reported previously20 (Scheme 2).
Cinnamic acid derivatives (4a ~ d) were condensed with -proline t-
butyl ester followed by treatment with TFA to give desired car-
boxylic acids (1a ~ d).
decreased compared to those of 3,4,5-trimethoxycinnamic acid
derivative 1a, but was better (24%) than that of Yuzikhin's racemic
synthesis19 (15%). On the other hand, bislactones 2c and 2d were
obtained in low chemical yield (8e10%), while enantiomeric excess
of 3,4-dimethoxycinnamic acid derivative 2c was tolerable
(85e87% e.e.). The low chemical yields of 2c and 2d were due to
decompositions of the starting materials 1c and 1d during the re-
actions. Interestingly, in our experiments, chemical yields were
better in the case of the substrates with more oxygenated benzene
ring, which was opposite to the results of Yuzikhin's racemic
synthesis.19
Next, we searched for more effective supporting electrolytes and
protonic acids in the reaction of 3,4-dimethoxycinnamic acid de-
rivative 1c. Seven supporting electrolytes were tested and the re-
sults were summarized in Table 2. Although the desired bislactone
2c was obtained with the use of Et4NClO4, Et4NOTFA, n-Bu4NPF6 or
n-Bu4NHSO4, chemical yield could not be improved dramatically
(entry 1e4). Tetraalkylammonium salts with halide ion were not
effective to this reaction (entry 5e7). Furthermore, other protonic
acids (TfOH, HSO3F, MsOH, HClO4, HBF4$Et2O) were also tested, but
a trace amount of desired bislactone 2c was obtained only when
TfOH was used.
L
After screening suitable reaction conditions, oxidative dimer-
ization of each substrate was found to proceed under Ronlan's
electrochemical conditions22 (Pt anode, n-Bu4NBF4, CH2Cl2/TFA)
without the formation of aldehyde 3. So we examined chemical
yield and enantiomeric excess of bislactones (2a ~ d), which could
be obtained under Ronlan's conditions (Table 1). Since chemical
yield of 2a was almost the same between CH2Cl2/TFA ¼ 5:1 and
2:1 at 0 ꢀC, solvent ratio was set to CH2Cl2/TFA ¼ 5:1 to avoid
crystallization of TFA at lower temperature, and same volumes
(1.8 mA/cm3) of electric current flowed. Enantiomeric excess was
determined by chiral HPLC analysis of 7a ~ d (7a: yangambin, 7b:
sesamin, 7c: eudesmin), which were obtained from 2a ~ d by
reduction with Ca(BH4)2 and subsequent ether formation. At first,
the reaction of 3,4,5-trimethoxycinnamic acid derivative 1a was
performed at various temperatures (r.t., 0 ꢀC, ꢁ20 ꢀC, ꢁ40 ꢀC), and it
became clear that chemical yield as well as enantiomeric excess
were higher at lower temperature. Since electric current was
sometimes hard to be kept the same flow at ꢁ40 ꢀC in spite of
getting the best result (52% yield, 91% e.e.), reactions of other
In summary, we have developed a new electrochemical method
for the asymmetric oxidative dimerization of cinnamic acid de-
rivatives. Three natural furofuran lignans, yangambin, sesamin and
eudesmin could be synthesized with high enantiomeric excess by
this electrochemical method.
substrates were carried out at
methylenedioxycinnamic acid derivative 1b, chemical yield
0
ꢀC or ꢁ20 ꢀC. On 3,4-
3. Experimental
3.1. General
Optical rotations were recorded with a JASCO DIP-1000 polar-
Scheme 2. Preparation of the substrates.
imeter. IR spectra were measured with a JASCO FT/IR-230
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

N. Mori et al. / Tetrahedron xxx (2016) 1e7
3
Table 1
Electochemical asymmetric dimerization of 1a ~ d and synthesis of furofuran lignans 7a ~ d.
Substrate
Temp. (ꢀC)
F/mol
Yield of 2 (%)
e.e. of 7 (%)
Yield of ( )-2 (%)d
r.t.
0
1.4
1.4
1.6
1.4
38
42
47
52
70
73
82
91
14
ꢁ20
ꢁ40c
0
ꢁ20
0.7b
1.3
16 (26)a
24 (32)a
72
83
15
28
53
0
ꢁ20
0.7b
1.3
10 (22)a
8 (9)a
85
87
0
ꢁ20
0.7b
1.3
8 (9)a
8 (9)a
40
39
a
(): based on recovery.
Decomposition of the product was observed when more than 0.7 F/mol passed.
6 equiv. of n-Bu4NBF4 were added.
b
c
d
Yuzikhin's racemic synthesis:
spectrophotometer. 1H NMR (300 MHz) and 13C NMR (125 MHz)
data were recorded by JEOL JNM AL300 or JEOL JNM LA 500.
Chemical shifts (d) were referenced to the residual solvent peak
as the internal standard (CDCl3: dH ¼ 7.26, dC ¼ 77.0; CD3OD:
dH ¼ 3.30, dC ¼ 49.0). Mass spectra were recorded on JEOL JMS
T100LC. HPLC was performed using a HITACHI UV Detector L-2400
and HITACHI Pump L-2130. Electrochemical oxidation reaction was
performed on POTENTIOSTAT/GALVANOSTAT HA-151A. Melting
points were measured with a Yanaco micro meltingpoint apparatus
and are uncorrected. Column chromatography was performed on
Kanto silica gel 60N (0.060e0.200 mm) and TLC was carried out on
Merck glass plates precoated with silica gel 60 F254 (0.25 mm).
Table 2
Screening of supporting electrolytes.
Entry
Electrolyte
Yield (%)
1
2
3
4
5
6
7
Et4NClO4
Et4NOTFA
n-Bu4NPF6
n-Bu4NHSO4
n-Bu4NCl
n-Bu4Nl
12 (21)a
12 (24)a
11 (21)a
6 (14)a
3
0
0
Et4NBr
a
(): based on recovery.
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

4
N. Mori et al. / Tetrahedron xxx (2016) 1e7
3.2. tert-Butyl (S)-1-[(E)-3-(3,4,5-trimethoxyphenyl)propenoyl]
3.5. (1S,2R,3R,4S)-2,3-Bis(hydroxymethyl)-1,4-bis(3,4,5-
pyrrolidine-2-carboxylate (5a)
trimethoxyphenyl)butane-1,4-diol (6a)
To a solution of HOBt (2.56 g, 19.0 mmol),
L
-proline tert-
CaCl2 (119 mg,1.07 mmol) and NaBH4 (81.3 mg, 2.15 mmol) were
added to EtOH (1.9 mL). After stirring at room temperature for
15 min, 2a (72.8 mg, 0.153 mmol) in EtOH (0.5 mL) and THF (1.5 mL)
was added to the mixture. After stirring at room temperature
overnight, the reaction mixture was poured into diluted HCl and
extracted with CHCl3. The organic layer was washed with sat.
(NH4)2SO4 solution, dried with anhyd MgSO4 and concentrated in
vacuo. The residue was chromatographed over silica gel. Elution
butyl ester (2.50 g, 14.6 mmol), 3,4,5-trimethoxycinnamic acid
(3.48 g, 14.6 mmol) in THF (50 mL) was added DCC
(3.92 g, 19.0 mmol) at 0 ꢀC. After stirring at room temperature
for 3 h, the reaction mixture was filtered through Celite®. The
filtrate was poured into sat. NaHCO3 solution and extracted with
EtOAc. The organic layer was washed with sat. NH4Cl solution
and brine, dried with anhyd MgSO4 and concentrated in vacuo.
The residue was chromatographed over silica gel. Elution with
with tolueneeacetone (1:1e0:1) gave 6a (33.3 mg, 45%) as colorless
21
hexaneeEtOAc (3:1e1:1) gave 5a (4.56 g, 80%) as colorless
crystals; mp 202e204 ꢀC; [
a
]
D
e29 (c ¼ 0.51, MeOH). IR (KBr):
17
crystals; mp 44e46 ꢀC; [
a
]
e61 (c ¼ 0.90, CHCl3). IR (KBr):
3306, 2940, 1594, 1508, 1458, 1418, 1332, 1235, 1127, 922 cmꢁ1. 1H
D
2975, 1736, 1652, 1582, 1506, 1413, 1331, 1153, 1126, 1005 cmꢁ1. 1H
NMR (300 MHz, CDCl3, several peaks appeared separately as
NMR (300 MHz, CD3OD):
d
¼ 2.19e2.25 (2H, m), 3.72 (18H, s),
3.75e3.88 (4H, m), 4.81 (2H, d, J ¼ 4.0 Hz), 6.37 (4H, s). 13C NMR
amide rotamers):
d
¼ 1.44 (3H, s), 1.48 (6H, s), 1.86e2.20 (4H, m),
(125 MHz, CD3OD):
d
¼ 46.1, 56.2, 61.0, 61.8, 74.2, 103.9, 137.2, 141.3,
3.72 (1H, m), 3.86 (1H, m), 3.87 (3H, s), 3.89 (2H, s), 3.90 (4H, s),
4.48 (1H, m), 6.47 (1/3H, d, J ¼ 15.3 Hz), 6.63 (2/3H, d,
J ¼ 15.3 Hz), 6.71 (2/3H, s), 6.71 (4/3H, s), 7.61 (1/3H, d,
J ¼ 15.3 Hz), 7.63 (2/3H, d, J ¼ 15.3 Hz). 13C NMR (125 MHz,
153.9. Anal. Calcd for C24H34O10: C, 59.74; H, 7.10. Found: C, 59.28;
H, 7.20.
3.6. (1S,3aR,4S,6aR)-1,3a,4,6a-Tetrahydro-1,4-bis(3,4,5-
trimethoxyphenyl)-3H,6H-furo[3,4-c]furan (7a, yangambin)
CDCl3):
d
¼ 22.7, 24.6, 27.6, 27.8, 29.1, 31.4, 46.8, 47.0, 55.8, 55.9,
56.2, 56.3, 59.7, 59.8, 81.2, 82.1, 104.8, 104.9, 117.4, 117.5, 130.6,
130.8, 139.4, 142.3, 142.6, 153.3, 164.6, 165.1, 171.4, 171.7. Anal.
Calcd for C21H29NO6: C, 64.43; H, 7.47; N, 3.58. Found: C, 64.16; H,
7.46; N, 3.48.
To a solution of 6a (32.3 mg, 66.9
were added DMAP (2.5 mg, 20.5
m
mol) in pyridine (0.6 mL)
m
mol) and MsCl (16.0 mL,
207 mmol) at 0 ꢀC. After stirring at 0 ꢀC for 6 h, the mixture was
warmed to room temperature and stirring was continued for 62 h.
The reaction mixture was poured into H2O and extracted with
EtOAc. The organic layer was dried with anhyd MgSO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel. Elution with hexaneeEtOAc (1:1) gave 7a (19.5 mg, 69%,
91% e.e.). Recrystallization from EtOAc gave colorless crystals
3.3. (S)-1-[(E)-3-(3,4,5-Trimethoxyphenyl)propenoyl]pyrrolidine-
2-carboxylic acid (1a)
A solution of 5a (769 mg, 1.97 mmol) in TFA (8 mL) was stirred at
0
ꢀC for 4 h. The reaction mixture was concentrated in vacuo and
(9.1 mg, 47%, 98% e.e.); mp 125e126 ꢀC; [
a
]
19 þ43 (c ¼ 0.38, CHCl3)
D
the residue was chromatographed over silica gel. Elution with
29
{Lit.23
[
a
]
þ46 (c ¼ 0.4, CHCl3)}. Enantiomeric excess was deter-
D
EtOAc gave 1a (543 mg, 82%) as colorless crystals; mp 100e102 ꢀC;
mined by HPLC with a CHIRALCEL® OD column (EtOH), 1.0 mL/min;
major enantiomer tr ¼ 5.63 min, minor enantiomer tr ¼ 8.62 min.
IR (KBr): 2952, 2825, 1589, 1509, 1463, 1421, 1329, 1237, 1129,
[
a
]
17 e216 (c ¼ 1.0, CHCl3). IR (KBr): 2941, 1735, 1646, 1583, 1505,
D
1455, 1333, 1243, 1125, 1002 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼ 1.97 (1H, m), 2.07e2.13 (2H, m), 2.64 (1H, br d, J ¼ 12.3 Hz), 3.70
998 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼ 3.09e3.12 (2H, m), 3.84
(1H, m), 3.80 (1H, m), 3.89 (3H, s), 3.90 (6 H, s), 4.76 (1H, d,
(6H, s), 3.88 (12H, s), 3.94 (2H, dd, J ¼ 9.2, 3.7 Hz), 4.31 (2H, dd,
J ¼ 8.1 Hz), 6.58 (1H, d, J ¼ 15.3 Hz), 6.77 (2H, s), 7.76 (1H, d,
J ¼ 9.2, 7.0 Hz), 4.75 (2H, d, J ¼ 3.7 Hz), 6.57 (4H, s). 13C NMR
J ¼ 15.3 Hz). 13C NMR (125 MHz, CDCl3):
d
¼ 24.7, 27.4, 47.8, 55.9,
(125 MHz, CDCl3):
153.4. Anal. Calcd for C24H30O8: C, 64.56; H, 6.77. Found: C, 64.56; H,
6.81.
d
¼ 54.3, 56.1, 60.8, 71.9, 85.9, 102.7, 136.7, 137.4,
56.4, 60.6, 105.4, 115.5, 129.9, 140.1, 145.1, 153.4, 167.6, 172.4. Anal.
Calcd for C17H21NO6: C, 60.89; H, 6.31; N, 4.18. Found: C, 60.42; H,
6.58; N, 4.24.
3.7. tert-Butyl (S)-1-[(E)-3-(3,4-methylenedioxyphenyl)propenoyl]
3.4. (1S,4S,5S,8S)-4,8-Bis(3,4,5-trimethoxyphenyl)-3,7-
pyrrolidine-2-carboxylate (5b)
dioxabicyclo[3.3.0]octane-2,6-dione (2a)
To a solution of HOBt (3.08 g, 22.8 mmol), L-proline tert-butyl
To a 100 mL vial container were added 1a (101 mg, 0.301 mmol),
CH2Cl2 (5 mL), n-Bu4NBF4 (596 mg, 1.81 mmol) and TFA (1 mL). The
reaction vial container was then fitted with a Pt anode (ca. 1.7 cm2)
and a Pt cathode (ca. 1.7 cm2). A constant current of 3 mA was
applied to the solution at ꢁ40 ꢀC for 226 min until a total of 1.4 F/
mol of charge had been passed. The reaction mixture was
concentrated in vacuo. The residue was poured into water and
extracted with EtOAc. The organic layer was washed with brine,
dried with anhyd MgSO4 and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with hexaneeEtOAc
(1:1) gave 2a (36.8 mg, 52%) as colorless crystals; mp 179e181 ꢀC;
ester (2.99 g, 17.7 mmol), 3,4-methylenedioxycinnamic acid (3.37 g,
17.5 mmol) in THF (60 mL) was added DCC (4.71 g, 22.8 mmol) at
0
ꢀC. After stirring at room temperature for 3 h, the reaction
mixture was filtered through Celite®. The filtrate was poured into
sat. NaHCO3 solution and extracted with EtOAc. The organic layer
was washed with sat. NH4Cl solution and brine, dried with anhyd
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed over silica gel. Elution with hexaneeEtOAc (2:1e1:2) gave
5b (4.88 g, 81%) as pale yellow crystals; mp 106e107 ꢀC; [
(c ¼ 1.0, CHCl3). IR (KBr): 3009, 2975, 2929, 2877, 1736, 1650, 1599,
1501, 1490, 1446, 1421, 1351, 1256, 1166, 1039, 924, 810 cmꢁ1 1H
NMR (300 MHz, CDCl3, several peaks appeared separately as amide
rotamers):
a]
21 e66
D
.
[
a]
18 þ31 (c ¼ 0.70, CHCl3). IR (KBr): 2946, 2831, 1768, 1595, 1509,
D
1456, 1418, 1360, 1327, 1236, 1124, 1009 cmꢁ1. 1H NMR (300 MHz,
d
¼ 1.44 (3H, s), 1.48 (6H, s), 1.94e2.23 (4H, m),
CDCl3):
d
¼ 3.54 (2H, s), 3.82 (6H, s), 3.87 (12H, s), 5.88 (2H, s), 6.49
3.66e3.82 (2H, m), 4.48 (1H, m), 6.00 (2H, s), 6.41 (1/3H, d,
J ¼ 15.3 Hz), 6.57 (2/3H, d, J ¼ 15.3 Hz), 6.80 (1H, d, J ¼ 7.8 Hz),
6.98e7.04 (2H, m), 7.61 (1/3H, d, J ¼ 15.3 Hz), 7.62 (2/3H, d,
(4H, s). 13C NMR (125 MHz, CDCl3):
d
¼ 48.4, 56.3, 60.8, 81.5, 101.3,
133.6, 138.3, 153.9, 174.9. Anal. Calcd for C24H26O10: C, 60.76; H,
5.52. Found: C, 60.46; H, 5.64.
J ¼ 15.3 Hz). 13C NMR (125 MHz, CDCl3):
d
¼ 22.7, 24.7, 27.9, 28.0,
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

N. Mori et al. / Tetrahedron xxx (2016) 1e7
5
29.2, 31.4, 46.7, 46.9, 59.7, 60.3, 81.1, 82.1, 101.4, 106.4, 108.5, 116.2,
3.11. (1S,3aR,4S,6aR)-1,3a,4,6a-Tetrahydro-1,4-bis(3,4-
123.9, 129.6, 142.0, 142.2, 148.1, 149.0, 164.8, 165.3, 171.5, 171.7. Anal.
Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C, 66.06; H,
6.76; N, 4.17.
methylenedioxyphenyl)-3H,6H-furo[3,4-c]furan (7b, sesamin)
To a solution of 6b (27.3 mg, 69.9
m
mol) in pyridine (0.6 mL)
L, 220 mol)
were added DMAP (2.6 mg, 21.3 mol) and MsCl (17.0
m
m
m
at 0 ꢀC. After stirring at 0 ꢀC for 6 h, the mixture was warmed to
room temperature and stirring was continued for 33 h. The reaction
mixture was poured into H2O and extracted with EtOAc. The
organic layer was dried with anhyd MgSO4 and concentrated in
vacuo. The residue was chromatographed over silica gel. Elution
3.8. (S)-1-[(E)-3-(3,4-methylenedioxyphenyl)propenoyl]
pyrrolidine-2-carboxylic acid (1b)
A solution of 5b (4.67 g, 13.5 mmol) in TFA (45 mL) was stirred at
0
ꢀC for 5 h. The reaction mixture was concentrated in vacuo and
with hexaneeEtOAc (2:1) gave 7b (17.3 mg, 70%, 83% e.e.) as
the residue was chromatographed over silica gel. Elution with
18
colorless crystals; mp 121e122 ꢀC; [
a
]
]
þ49 (c ¼ 0.26, CHCl3)
D
hexane-EtOAc (2:3e0:1) gave 1b (3.52 g, 90%) as colorless crystals;
{Lit.2e (1R,3aS,4R,6aS)-7b (98% e.e.): [
a
26 e66.8 (c ¼ 0.30, CHCl3)}.
mp 175e177 ꢀC; [
a
]
D
22 e275 (c ¼ 1.0, CHCl3). IR (KBr): 2966, 2891,
D
Enantiomeric excess was determined by HPLC with a CHIRALCEL®
OD column (EtOH), 1.0 mL/min; major enantiomer tr ¼ 6.66 min,
minor enantiomer tr ¼ 14.2 min. IR (KBr): 2968, 2902, 2850, 2782,
1500, 1442, 1365, 1250, 1194, 1095, 1058, 1036, 969, 927, 857, 803,
2584, 1941, 1714, 1643, 1604, 1556, 1501, 1446, 1362, 1327, 1256,
1104, 1033, 976, 925, 810, 755, 614 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼ 1.95 (1H, m), 2.03e2.18 (2H, m), 2.64 (1H, br d, J ¼ 11.0 Hz),
3.53e3.83 (2H, m), 4.75 (1H, dd, J ¼ 8.1, 1.5 Hz), 6.03 (2H, s), 6.53
782 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼ 3.04e3.06 (2H, m), 3.87
(1H, d, J ¼ 15.4 Hz), 6.83 (1H, d, J ¼ 8.4 Hz), 7.02e7.12 (2H, m), 7.75
(1H, d, J ¼ 15.4 Hz). 13C NMR (125 MHz, CDCl3):
d
¼ 25.0, 27.2, 48.1,
(2H, dd, J ¼ 9.2, 3.7 Hz), 4.23 (2H, dd, J ¼ 9.2, 6.6 Hz), 4.71 (2H, d,
J ¼ 4.4 Hz), 5.95 (4H, s), 6.86e6.75 (6H, m). 13C NMR (125 MHz,
60.9, 101.9, 106.7, 108.9, 114.2, 125.2, 129.0, 145.3, 148.6, 150.1, 168.5,
171.9. Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C,
62.22; H, 5.27; N, 4.85.
CDCl3):
d
¼ 54.3, 85.8, 101.1, 106.5, 108.2, 119.4, 135.0, 147.1, 147.9.
Anal. Calcd for C20H18O6: C, 67.79; H, 5.12. Found: C, 67.67; H, 5.23.
3.12. tert-Butyl (S)-1-[(E)-3-(3,4-dimethoxyphenyl)propenoyl]
pyrrolidine-2-carboxylate (5c)
3.9. (1S,4S,5S,8S)-4,8-Bis(3,4-methylenedioxyphenyl)-3,7-
dioxabicyclo[3.3.0]octane-2,6-dione (2b)
To a solution of HOBt (5.47 g, 40.5 mmol), L-proline tert-butyl
To a 100 mL vial container were added 1b (300 mg, 1.04 mmol),
CH2Cl2 (15 mL), n-Bu4NBF4 (346 mg, 1.05 mmol) and TFA (3 mL).
The reaction vial container was then fitted with a Pt anode (ca.
5 cm2) and a Pt cathode (ca. 5 cm2). A constant current of 9 mA was
applied to the solution at ꢁ20 ꢀC for 241 min until a total of 1.3 F/
mol of charge had been passed. The reaction mixture was
concentrated in vacuo. The residue was poured into water and
extracted with EtOAc. The organic layer was washed with brine,
dried with anhyd MgSO4 and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with hexaneeEtOAc
(1:1e0:1) gave 2b (48.2 mg, 24%) as colorless crystals, together
with the recovered starting material (72.0 mg, 24%); mp
ester (5.32 g, 31.1 mmol), 3,4-dimethoxycinnamic acid (6.48 g,
31.1 mmol) in THF (100 mL) was added DCC (8.34 g, 40.4 mmol) at
0
ꢀC. After stirring at room temperature for 5 h, the reaction
mixture was filtered through Celite®. The filtrate was poured into
sat. NaHCO3 solution and extracted with EtOAc. The organic layer
was washed with sat. NH4Cl solution and brine, dried with anhyd
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed over silica gel. Elution with hexaneeEtOAc (1:1e1:6) gave
22
5c (8.56 g, 76%) as a colorless oil; [
a
]
D
e61 (c ¼ 0.73, CHCl3). IR
(neat): 2969, 1737, 1650, 1597, 1514, 1422, 1265, 1154, 1024 cmꢁ1. 1H
NMR (300 MHz, CDCl3, several peaks appeared separately as amide
192e194 ꢀC, [
a]
23 þ44 (c ¼ 0.52, CHCl3). IR (KBr): 2990, 2908, 1767,
rotamers):
d
¼ 1.43 (3H, s), 1.47 (6H, s), 1.89e2.36 (4H, m),
D
1503,1448,1351,1319,1258,1171,1034,1014, 923, 809, 795 cmꢁ1. 1H
3.62e3.88 (2H, m), 3.90 (4H, s), 3.91 (2H, s), 4.50 (1H, m), 6.44 (1/
3H, d, J ¼ 15.4 Hz), 6.60 (2/3H, d, J ¼ 15.4 Hz), 6.85 (1H, d, J ¼ 8.1 Hz),
6.98e7.14 (2H, m), 7.63 (1/3H, d, J ¼ 15.4 Hz), 7.65 (2/3H, d,
NMR (300 MHz, CDCl3):
6.84e6.73 (6H, m). 13C NMR (125 MHz, CDCl3):
105.2, 108.7, 118.5, 131.7, 148.3, 148.5, 174.6. Anal. Calcd for
20H14O8: C, 62.83; H, 3.69. Found: C, 62.66; H, 3.53.
d
¼ 3.53 (2H, s), 5.82 (2H, s), 5.99 (4H, s),
d
¼ 48.2, 81.8, 101.6,
J ¼ 15.4 Hz). 13C NMR (125 MHz, CDCl3):
d
¼ 22.8, 24.7, 27.9, 28.0,
29.2, 31.4, 46.7, 47.0, 55.9, 59.8, 60.3, 81.1, 82.0, 109.8, 110.0, 111.0,
116.0, 121.9, 128.2, 142.2, 142.5, 149.0, 150.5, 164.9, 165.4, 171.5,
171.8 cmꢁ1. HRMS (EI) [MþNa]þ calcd for C20H27NNaO5: 384.1787;
found: 384.1739.
C
3.10. (1S,2R,3R,4S)-2,3-Bis(hydroxymethyl)-1,4-bis(3,4-
methylenedioxyphenyl)butane-1,4-diol (6b)
CaCl2 (156 mg, 1.41 mmol) and NaBH4 (114 mg, 1.91 mmol) were
added to EtOH (2.5 mL). After stirring at room temperature for
15 min, 2b (76.9 mg, 0.201 mmol) in EtOH (1 mL) and THF (1 mL)
was added to the mixture. After stirring at room temperature for
23 h, the reaction mixture was poured into diluted HCl and
extracted with CHCl3. The organic layer was washed with sat.
(NH4)2SO4 solution, dried with anhyd Na2SO4 and concentrated in
vacuo. The residue was chromatographed over silica gel. Elution
with benzeneeacetone (1:1e0:1) gave 6b (48.1 mg, 61%) as color-
3.13. (S)-1-[(E)-3-(3,4-Dimethoxyphenyl)propenoyl]pyrrolidine-2-
carboxylic acid (1c)
A solution of 5c (8.56 g, 23.7 mmol) in TFA (96 mL) was stirred at
0
ꢀC for 5 h. The reaction mixture was concentrated in vacuo.
Recrystallization from CH2Cl2 2g2ave 1c (4.81 g, 67%) as colorless
crystals; mp 190e191 ꢀC; [
e309 (c ¼ 0.50, CHCl3). IR (KBr):
2964, 1723, 1644, 1569, 1516, 1442, 1264, 1139, 1020, 764 cmꢁ1. 1H
NMR (300 MHz, CDCl3):
a]
D
d
¼ 1.94 (1H, m), 2.06e2.17 (2H, m), 2.66
less crystals; mp 202e204 ꢀC, [
a
]
26 e21 (c ¼ 0.11, MeOH). IR (KBr):
(1H, br d, J ¼ 12.0 Hz), 3.63e3.81 (2H, m), 3.93 (6H, s), 4.76 (1H, dd,
J ¼ 8.1, 1.8 Hz), 6.55 (1H, d, J ¼ 15.4 Hz), 6.89 (1H, d, J ¼ 8.4 Hz), 7.04
(1H, d, J ¼ 1.8 Hz), 7.17 (1H, dd, J ¼ 8.4, 1.8 Hz), 7.80 (1H, d,
D
3217, 2878, 1504, 1442, 1329, 1248, 1116, 1029, 929, 898, 827, 813,
790, 723, 679, 639 cmꢁ1. 1H NMR (300 MHz, CD3OD):
(2H, m), 3.67e3.83 (4H, m), 4.75 (2H, d, J ¼ 3.7 Hz), 5.88 (1H, s), 5.92
(1H, s), 6.40e6.62 (6H, m). 13C NMR (125 MHz, CD3OD):
d
¼ 2.12e2.21
J ¼ 15.4 Hz). 13C NMR (125 MHz, CDCl3):
d
¼ 24.8, 26.9, 47.9, 56.0,
d
¼ 45.9,
60.7, 110.2, 111.1, 113.8, 122.7, 127.3, 145.4, 149.2, 151.4, 168.4, 171.7.
Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
63.02; H, 6.27; N, 4.61.
61.9, 73.9, 102.1, 107.3, 108.3, 120.0, 139.0, 147.6, 148.7. Anal. Calcd
for C20H22O8: C, 61.53; H, 5.68. Found: C, 61.22; H, 5.72.
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

6
N. Mori et al. / Tetrahedron xxx (2016) 1e7
3.14. (1S,4S,5S,8S)-4,8-Bis(3,4-dimethoxyphenyl)-3,7-dioxabicyclo
3.17. tert-Butyl (S)-1-[(E)-3-(4-methoxyphenyl)propenoyl]
[3.3.0]octane-2,6-dione (2c)
pyrrolidine-2-carboxylate (5d)
To a 100 mL vial container were added 1c (300 mg, 0.985 mmol),
CH2Cl2 (15 mL), n-Bu4NBF4 (340 mg, 1.03 mmol) and TFA (3 mL).
The reaction vial container was then fitted with a Pt anode (ca.
5 cm2) and a Pt cathode (ca. 5 cm2). A constant current of 9 mA was
applied to the solution at ꢁ20 ꢀC for 229 min until a total of 1.3 F/
mol of charge had been passed. The reaction mixture was
concentrated in vacuo. The residue was poured into water and
extracted with EtOAc. The organic layer was washed with brine,
dried with anhyd MgSO4 and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with hexaneeEtOAc
(1:1e0:1) gave 2c (16.1 mg, 8%) as colorless crystals, together with
the recovered starting material (45.7 mg, 15%); mp 209e210 ꢀC;
To a solution of HOBt (3.10 g, 22.9 mmol), L-proline tert-butyl
ester (3.00 g, 17.5 mmol), 4-methoxycinnamic acid (3.13 g,
17.6 mmol) in THF (60 mL) was added DCC (4.71 g, 22.8 mmol) at
0
ꢀC. After stirring at room temperature for 6 h, the reaction
mixture was filtered through Celite®. The filtrate was poured into
sat. NaHCO3 solution and extracted with EtOAc. The organic layer
was washed with sat. NH4Cl solution and brine, dried with anhyd
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed over silica gel. Elution with hexaneeEtOAc (2:1e1:1) gave
23
5d (5.10 g, 88%) as a pale yellow solid; mp 83e85 ꢀC; [
a
]
e75
D
(c ¼ 1.0, CHCl3). IR (KBr): 3008, 2964, 2931, 2881, 2834, 1734, 1651,
1603, 1513, 1429, 1249, 1166, 1033, 981, 827 cmꢁ1 1H NMR
(300 MHz, CDCl3, several peaks appeared separately as amide
rotamers):
.
[
a
]
þ45 (c ¼ 1.0, CHCl3). IR (KBr): 3014, 2967, 2843, 1784, 1593,
D
1522, 1459, 1428, 1384, 1341, 1321, 1265, 1231, 1201, 1167, 1146, 1035,
1020, 997, 960, 868, 823, 806, 763, 717, 616 cmꢁ1 1H NMR
(300 MHz, CDCl3):
¼ 3.57 (2H, s), 3.88 (6H, s), 3.89 (6H, s), 5.89
(2H, s), 6.77e6.88 (6H, m). 13C NMR (125 MHz, CDCl3):
¼ 48.4,
56.1, 81.8, 107.9, 111.4, 116.7, 130.4, 149.6, 174.9. Anal. Calcd for
22H22O8: C, 63.76; H, 5.35. Found: C, 63.51; H, 5.34.
d
¼ 1.43 (3H, s), 1.48 (6H, s), 1.89e2.23 (4H, m),
.
3.62e3.91 (2H, m), 3.83 (3H, s), 4.48 (1H, m), 6.46 (1/3H, d,
J ¼ 15.4 Hz), 6.62 (2/3H, d, J ¼ 15.4 Hz), 6.89 (2H, d, J ¼ 8.8 Hz), 7.44
(2/3H, d, J ¼ 8.8 Hz), 7.47 (4/3H, d, J ¼ 8.8 Hz), 7.66 (1/3H, d,
J ¼ 15.4 Hz), 7.67 (2/3H, d, J ¼ 15.4 Hz). 13C NMR (125 MHz, CDCl3):
d
d
C
d
¼ 22.5, 24.4, 27.6, 27.7, 28.9, 31.1, 46.5, 46.7, 55.0, 59.5, 60.0, 80.8,
81.8, 113.9, 115.6, 127.6, 129.1, 129.2, 141.6, 141.8, 160.6, 164.7, 165.2,
171.3, 171.5. Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23.
Found: C, 68.94; H, 7.61; N, 4.26.
3.15. (1S,2R,3R,4S)-2,3-Bis(hydroxymethyl)-1,4-bis(3,4-
dimethoxyphenyl)butane-1,4-diol (6c)
CaCl2 (178 mg,1.60 mmol) and NaBH4 (124 mg, 3.28 mmol) were
added to EtOH (2.8 mL). After stirring at r.t. for 25 min, 2c (94.3 mg,
0.228 mmol) was added to the mixture in one portion. After stirring
at room temperature for 17 h, the reaction mixture was poured into
diluted HCl and extracted with CHCl3. The organic layer was
washed with sat. (NH4)2SO4 solution, dried with anhyd MgSO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel. Elution with tolueneeacetone (1:1e0:1) gave 6c (73.6 mg,
3.18. (S)-1-[(E)-3-(4-Methoxyphenyl)propenoyl]pyrrolidine-2-
carboxylic acid (1d)
A solution of 5d (3.54 g, 10.7 mmol) in TFA (36 mL) was stirred at
0
ꢀC for 5 h. The reaction mixture was concentrated in vacuo.
Recrystallization from CH2Cl2 gave 1d (1.85 g, 63%) as colorless
crystals; mp 195e197 ꢀC; [
e301 (c ¼ 0.30, CHCl3). IR (KBr):
2973, 1717, 1639, 1603, 1512, 1446, 1259, 1175, 1021, 1004, 828 cmꢁ1
1H NMR (300 MHz, CDCl3):
a
]
D
.
76%) as colorless crystals; mp 139e141 ꢀC; [
MeOH). IR (KBr): 3469, 3339, 2907, 2870, 1598, 1518, 1466, 1256,
1136, 1025, 896, 843, 802, 765, 664 cmꢁ1 1H NMR (300 MHz,
CD3OD):
¼ 2.14e2.24 (2H, m), 3.67 (6H, s), 3.69e3.86 (4H, m),
a
]
D
e33 (c ¼ 0.38,
d
¼ 1.93 (1H, m), 2.04e2.14 (2H, m), 2.66
(1H, br d, J ¼ 12.0 Hz), 3.60e3.80 (2H, m), 3.85 (3H, s), 4.76 (1H, dd,
J ¼ 8.1, 1.5 Hz), 6.57 (1H, d, J ¼ 15.4 Hz), 6.92 (2H, d, J ¼ 8.8 Hz), 7.52
(2H, d, J ¼ 8.8 Hz), 7.81 (1H, d, J ¼ 15.4 Hz). 13C NMR (125 MHz,
.
d
3.81 (6H, s), 4.77 (2H, d, J ¼ 3.3 Hz), 6.49e6.59 (4H, m), 6.69 (2H, d,
CDCl3):
d
¼ 24.9, 26.6, 48.0, 55.4, 60.8, 113.3, 114.4, 127.0, 130.1,
J ¼ 8.1 Hz). 13C NMR (125 MHz, CD3OD):
d
¼ 45.9, 55.9, 56.2, 62.0,
145.3, 161.7, 168.9, 171.2. Anal. Calcd for C15H17NO4: C, 65.44; H,
6.22; N, 5.09. Found: C, 65.45; H, 6.32; N, 5.08.
74.0, 110.3, 111.9, 119.1, 137.7, 148.8, 149.8. Anal. Calcd for C22H30O8:
C, 62.55; H, 7.16. Found: C, 62.22; H, 7.10.
3.16. (1S,3aR,4S,6aR)-1,3a,4,6a-Tetrahydro-1,4-bis(3,4-
3.19. (1S,4S,5S,8S)-4,8-Bis(4-methoxyphenyl)-3,7-dioxabicyclo
dimethoxyphenyl)-3H,6H-furo[3,4-c]furan (7c, eudesmin)
[3.3.0]octane-2,6-dione (2d)
To a solution of 6c (46.2 mg, 109
mmol) in pyridine (0.9 mL) were
To a 100 mL vial container were added 1d (500 mg,
added DMAP (4.4 mg, 36.0 mol) and MsCl (25.0
m
m
L, 328 mol) at
m
1.82 mmol), CH2Cl2 (25 mL), n-Bu4NBF4 (597 mg, 1.81 mmol) and
TFA (5 mL). The reaction vial container was then fitted with a Pt
anode (ca. 8 cm2) and a Pt cathode (ca. 8 cm2). A constant current
of 15 mA was applied to the solution at ꢁ20 ꢀC for 255 min until
a total of 1.3 F/mol of charge had been passed. The reaction
mixture was concentrated in vacuo. The residue was poured into
water and extracted with EtOAc. The organic layer was washed
with brine, dried with anhyd MgSO4 and concentrated in vacuo.
The residue was chromatographed over silica gel. Elution with
hexaneeEtOAc (1:1e0:1) gave 2d (25.8 mg, 8%) as colorless
0 ꢀC. After stirring at 0 ꢀC for 6 h, the mixture was warmed to room
temperature and stirring was continued for 34 h. The reaction
mixture was poured into H2O and extracted with EtOAc. The
organic layer was dried with anhyd MgSO4 and concentrated in
vacuo. The residue was chromatographed over silica gel. Elution
with hexaneeEtOAc (1:1) gave 7c (24.2 mg, 57%, 87% e.e.) as
27
colorless crystals; mp 96e97 ꢀC; [
a]
þ62 (c ¼ 0.67, CHCl3) {Lit.2a
D
23
(1R,3aS,4R,6aS)-7c (99% e.e.): [a]
e64 (c ¼ 1.1, CHCl3)}. Enan-
D
tiomeric excess was determined by HPLC with a CHIRALCEL® OD
column (EtOH), 1.0 mL/min; major enantiomer tr ¼ 7.38 min, minor
enantiomer tr ¼ 8.75 min. IR (KBr): 2963, 2937, 2839, 1590, 1519,
crystals, together with the recovered starting material (76.0 mg,
21
15%); mp 155e156 ꢀC; [
a
]
þ28 (c ¼ 0.43, CHCl3). IR (KBr):
D
1467, 1448, 1264, 1142, 1025, 815, 744 cmꢁ1
.
1H NMR (300 MHz,
3057, 2967, 2842, 1784, 1615, 1518, 1361, 1254, 1173, 1044, 1017,
CDCl3):
(6H, s), 4.26 (2H, dd, J ¼ 9.2, 7.0 Hz), 4.76 (2H, d, J ¼ 4.4 Hz),
6.81e6.94 (6H, m). 13C NMR (125 MHz, CDCl3):
d
¼ 3.10e3.14 (2H, m), 3.85e3.95 (2H, m), 3.88 (6H, s), 3.90
817 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
¼ 3.56 (2H, s), 3.81 (6H,
s), 5.89 (2H, s), 6.92 (4H, d, J ¼ 7.0 Hz), 7.23 (4H, d, J ¼ 7.0 Hz). 13
C
d
¼ 54.1, 55.9, 71.7,
NMR (125 MHz, CDCl3):
d
¼ 48.2, 55.4, 81.8, 114.5, 126.2, 129.9,
85.8, 109.1, 111.0, 118.2, 133.5, 148.6, 149.2. Anal. Calcd for C22H22O8:
C, 68.38; H, 6.78. Found: C, 68.16; H, 6.82.
160.1, 174.9. Anal. Calcd for C20H18O6: C, 67.79; H, 5.12. Found: C,
67.77; H, 5.20.
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058

N. Mori et al. / Tetrahedron xxx (2016) 1e7
(b) Ward RS. Nat Prod Rep. 1995;12:183;
7
3.20. (1S,2R,3R,4S)-2,3-Bis(hydroxymethyl)-1,4-bis(4-
methoxyphenyl)-butane-1,4-diol (6d)
(c) Ward RS. Nat Prod Rep. 1997;14:143;
(d) Ward RS. Nat Prod Rep. 1999;16:75.
2. For selected examples, see: (a) Oeveren AV, Jansen JFGA, Feringa BL. J Org Chem.
1994;59:5999;
(b) Roy SC, Rana KK, Guin C. J Org Chem. 2002;67:3242;
(c) Kise N, Fujimoto A, Moriyama N, Ueda N. Tetrahedron Asymmetry. 2003;14:
2495;
(d) Swain NA, Brown RCD, Bruton G. J Org Chem. 2004;69:122;
(e) Banerjee B, Roy SC. Synthesis. 2005:2913;
CaCl2 (80.7 mg, 0.727 mmol) and NaBH4 (55.0 mg, 1.45 mmol)
were added to EtOH (2 mL). After stirring at r.t. for 15 min, 2d
(36.8 mg, 0.104 mmol) in THF (1.5 mL) was added to the mixture.
After stirring at room temperature for 27 h, the reaction mixture
was poured into diluted HCl and extracted with CHCl3. The organic
layer was washed with sat. (NH4)2SO4 solution, dried with anhyd
MgSO4 and concentrated in vacuo. The residue was chromato-
(f) Kim J-C, Kim K-H, Jung J-C, Park O-S. Tetrahedron Asymmetry. 2006;17:3;
(g) Jung J-C, Kim J-C, Moon H-I, Park O-S. Tetrahedron Lett. 2006;47:6433;
(h) Syed MK, Murray C, Casey M. Eur J Org Chem. 2014:5549;
(i) Kawabe Y, Ishikawa R, Akao Y, et al. Org Lett. 2014;16:1976;
(j) Inai M, Ishikawa R, Yoshida N, et al. Synthesis. 2015;47:3513;
(k) Albertson AKF, Lumb J-P. Angew Chem Int Ed. 2015;54:2204.
3. Dickey EE. J Org Chem. 1958;23:179.
4. (a) Hirose M, Satoh Y, Hagitani A. Nippon Kagaku Zasshi. 1968;89:887;
(b) Kakisawa H, Chen YP, Hsu HY. Phytochemistry. 1972;11:2289.
5. (a) Castro-Faria-Neto HC, Bozza PT, Cruz HN, et al. Planta Med. 1995;61:101;
(b) Castro-Faria-Neto HC, Bozza PT, Cruz HN, et al. Planta Med. 1995;61:106.
6. Marques RCP, de Medeiros SRB, Dias CS, Barbosa-Filho JM, Agenz-Lima LF.
Mutat Res. 2003;536:117. and references cited therein.
7. Hausott B, Greger H, Marian B. J Cancer Res Clin Oncol. 2003;129:569.
8. For isolations, see: (a) Peinemann K. Arch Pharm. 1896;234:238;
(b) Bertram SH, Van der Steur JPK, Waterman HI. Biochem Z. 1928;197:1.
9. (a) Matsumura Y, Kita S, Morimoto S, et al. Biol Pharm Bull. 1995;18:1016;
(b) Kita S, Matsumura Y, Morimoto S, et al. Biol Pharm Bull. 1995;18:1283;
(c) Matsumura Y, Kita S, Tanida Y, et al. Biol Pharm Bull. 1998;21:469;
(d) Nakano D, Itoh C, Takaoka M, Kiso Y, Tanaka T, Matsumura Y. Biol Pharm
Bull. 2002;25:1247.
10. (a) Hirose N, Doi F, Ueki T, et al. Anticancer Res. 1992;12:1259;
(b) Hibasami H, Fujikawa T, Takeda H, et al. Oncol Rep. 2000;7:1213;
(c) Miyahara Y, Komiya T, Katsuzaki H, et al. Int J Mol Med. 2000;6:43.
11. Dryselius E, Lindberg B. Acta Chem Scand. 1956;10:445.
12. Combes G, Billet D, Mentzer C. Bull Soc Chim Fr. 1959:2014.
13. Iida T, Nakano M, Ito K. Phytochemistry. 1982;21:673.
graphed over silica gel. Elution with tolueneeacetone (1:1e0:1)
27
gave 6d (16.6 mg, 44%) as colorless crystals; mp 188e190 ꢀC; [
a]
D
e7.4 (c ¼ 0.14, MeOH). IR (KBr): 3227, 2906, 1613, 1517, 1255, 1178,
1024, 999, 835, 737, 692 cmꢁ1 1H NMR (300 MHz, CD3OD):
.
d
¼ 2.18e2.29 (2H, m), 3.62e3.70 (4H, m), 3.78 (6H, s), 4.78 (2H, d,
J ¼ 4.8 Hz), 6.71 (4H, d, J ¼ 8.8 Hz), 6.97 (4H, d, J ¼ 8.8 Hz). 13C NMR
(125 MHz, CD3OD):
159.9. Anal. Calcd for C20H26O6: C, 66.28; H, 7.23. Found: C, 66.14; H,
7.20.
d
¼ 46.3, 55.6, 61.5, 73.8, 114.4, 128.1, 137.0,
3.21. (1S,3aR,4S,6aR)-1,3a,4,6a-Tetrahydro-1,4-bis(4-
methoxyphenyl)-3H,6H-furo[3,4-c]furan (7d)
To a solution of 6d (17.0 mg, 46.0
mmol) in pyridine (0.4 mL)
were added DMAP (1.7 mg, 13.9 mol) and MsCl (11.0
m
m
L, 140 mol)
m
at 0 ꢀC. After stirring at 0 ꢀC for 6 h, the mixture was warmed to
room temperature and stirring was continued for 22 h. The reaction
mixture was poured into H2O and extracted with EtOAc. The
organic layer was dried with anhyd MgSO4 and concentrated in
vacuo. The residue was chromatographed over silica gel. Elution
14. Pan JX, Hensens OD, Zink DH, Chang MN, Hwang SB. Phytochemistry. 1987;26:
1377.
15. Cho JY, Yoo ES, Baik KU, Park MH. Arch Pharm Res. 1999;22:348.
16. (a) Lee J, Lee D, Jang DS, et al. Chem Pharm Bull. 2007;55:137;
(b) Mbaze LM, Lado JA, Wansi JD, et al. Phytochemistry. 2009;70:1442.
17. Yang YJ, Park JI, Lee H, et al. Arch Pharm Res. 2006;29:1114.
18. For the synthesis of yangambin, see: Ref. 2g (5 steps, 16% yield, e.e. not re-
ported); Ref. 2h (7 steps, 15% yield, 83% e.e.). For the synthesis of sesamin, see:
Ref. 2c (8 steps, 10% yield, >99% e.e.); Ref. 2e (3 steps, 32% yield, 98% e.e.);
Ref. 2f (5 steps, 20% yield, >99% e.e.); Ref. 2j (8 steps, 15% yield, 97% e.e.). For
the synthesis of eudesmin, see: Ref. 2a (5 steps, 16% yield, 99% e.e.); Ref. 2c (8
steps, 9% yield, >99% e.e.); Ref. 2g (5 steps, 15% yield, e.e. not reported).
19. Yuzikhin OS, Vasil’ev AV, Rudenko AP. Russ J Org Chem. 2000;36:1743.
20. Mori N, Watanabe H, Kitahara T. Synthesis. 2006:400.
with hexaneeEtOAc (2:1) gave 7d (9.8 mg, 55%) as colorless crys-
27
tals; mp 98e100 ꢀC; 39% e.e., [
a
]
þ18 (c ¼ 0.25, CHCl3). Enan-
D
tiomeric excess was determined by HPLC with a CHIRALCEL® OD
column (EtOH), 1.0 mL/min; major enantiomer tr ¼ 6.74 min, minor
enantiomer tr ¼ 10.2 min. IR (KBr): 2963, 2851, 1612, 1517, 1459,
1307, 1247, 1174, 1043, 1027, 957, 817 cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d
¼ 3.04e3.16 (2H, m), 3.81 (6H, s), 3.87 (2H, dd, J ¼ 9.2,
3.7 Hz), 4.24 (2H, dd, J ¼ 9.2, 7.0 Hz), 4.76 (2H, d, J ¼ 4.4 Hz), 6.89
(4H, d, J ¼ 8.8 Hz), 7.28 (4H, d, J ¼ 8.8 Hz). 13C NMR (125 MHz,
21. For reviews, see: (a) Weinberg NL, Weinberg HR. Chem Rev. 1968;68:449;
(b) Moeller KD. Tetrahedron. 2000;56:9527.
22. Ronlan A, Bechgaard K, Parker VD. Acta Chem Scand. 1973;27:2375.
23. Lee CK, Chang MH. J Chin Chem Soc (Taipei). 2000;47:555.
CDCl3):
d
¼ 54.1, 55.2, 71.6, 85.6,113.9,127.3,133.0,159.1. Anal. Calcd
for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.51; H, 6.82.
References
1. For reviews, see: (a) Ward RS. Nat Prod Rep. 1993;10:1;
Please cite this article in press as: Mori N, et al., Electochemical asymmetric dimerization of cinnamic acid derivatives and application to the
enantioselective syntheses of furofuran lignans, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.058