Intramolecular biaryl coupling reaction of benzyl benzoate and phenyl benzoate derivatives, and its application to the formal synthesis of (-)-steganone

Article abstract of DOI:10.1016/j.tet.2006.10.059

Construction of the biaryl moiety of stegane and related compounds through an intramolecular biaryl coupling reaction is described. Undesired products were obtained by the intramolecular coupling reaction of benzyl benzoates (8, 13, and 14) because of the

Full text of DOI:10.1016/j.tet.2006.10.059

Tetrahedron 63 (2007) 396–408
Intramolecular biaryl coupling reaction of benzyl benzoate and
phenyl benzoate derivatives, and its application to the formal
synthesis of (L)-steganone
a
a, ,y
*
Shigemitsu Takeda,a Hitoshi Abe,a,b, Yasuo Takeuchi and Takashi Harayama
*
aFaculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
bAdvanced Science Research Center, Okayama University, Okayama 700-8530, Japan
Received 25 September 2006; revised 23 October 2006; accepted 23 October 2006
Available online 9 November 2006
Abstract—Construction of the biaryl moiety of stegane and related compounds through an intramolecular biaryl coupling reaction is de-
scribed. Undesired products were obtained by the intramolecular coupling reaction of benzyl benzoates (8, 13, and 14) because of their steric
and electrostatic properties, and only that of phenyl benzoates (26b and 26c) afforded the desired biaryl lactones in good yields. An asym-
metric formal synthesis of the title compound has been achieved using an enantioselective lactone-opening reaction followed by a four-step
conversion to the known compound.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
compounds, such as photocyclization,3 Suzuki–Miyaura
coupling,4 oxidative biaryl coupling,5 the SNAr reaction,6
Ullmann coupling,7 and the [2+2+2] three-component cycli-
zation reaction.8 In general, their axial chirality has been
formed in a diastereoselective manner, whereas the enantio-
selective formation of these targets has not been reported.
Stegane (1) and its related compounds (2, 3) are dibenzocy-
clooctadiene lignans isolated from Steganotaenia araliacea
in 1973 (Fig. 1).1 They have attracted considerable synthetic
interest because of their significant biological activities,
such as antileukemic property,2 and their structurally unique
features. One of the most outstanding features in their struc-
tures is an unsymmetrical biaryl moiety with an axial chiral-
ity. To date, various strategies have been attempted to form
a biaryl system in the synthesis of stegane and related
On the other hand, Bringmann has proposed a ‘lactone strat-
egy’ for the enantioselective preparation of axially chiral
biaryl compounds, which is quite an effective method to
synthesize the biaryl-type natural products involving axial
chirality in an optically active form.9
O
O
In this report, we investigated the intramolecular biaryl
coupling reaction of benzyl benzoate and phenyl benzoate
derivatives to provide the biaryl part of stegane and its
related compounds. Also we extended Bringmann’s ‘lactone
strategy’ to the first enantioselective formation of this axial
chirality.10
R2
R1
O
MeO
O
MeO
OMe
R1 = R2 = H : (-)-stegane (1)
2. Results and discussion
R1, R2 = O : (-)-steganone (2)
R1 = OAc, R2 = H : (-)-steganacin (3)
2.1. Coupling reaction of benzyl benzoate derivatives11
Figure 1.
Initially, we examined the Pd-mediated intramolecular cou-
pling reaction of benzyl benzoate (8). Benzoic acid (6) was
readily prepared from piperonyl alcohol by iodination12 of 4
followed by a two-step oxidization, and then esterification of
6 with 3,4,5-trimethoxybenzylalcohol (7) afforded the cou-
pling precursor (8) in good yield (Scheme 1). Although the
* Corresponding authors. Tel.: +81 862517965; fax: +81 862517926;
e-mail addresses: abe@pharm.okayama-u.ac.jp; harayama@kph.
bunri-u.ac.jp
Present address: Faculty of Pharmaceutical Sciences at Kagawa Campus,
Tokushima Bunri University, Sanuki-shi, Kagawa 769-2193, Japan.
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.059

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
397
O
I
O
O
CO2H
O
O
O
O
O
O
OH
OH
a
c
b
O
I
MeO
MeO
I
MeO
MeO
OH
4
5
6
OMe
7
OMe
8
Scheme 1. (a) I2, CF3CO2Ag, CHCl3, ꢀ5 ꢁC, 10 min, 83%; (b) (i) CrO3, c-H2SO4, H2O, acetone, 0–5 ꢁC, 5 min; (ii) H2O2, NaH2PO4, HClO2, MeCN, H2O, rt,
2 h, 73%; (c) 7, EDC, DMAP, CH2CI2, rt, 1 h, 66%.
coupling reaction of 8 under various reaction conditions was
investigated, the desired biaryl lactone (10) could not be ob-
tained; thus dehalogenation mainly occurred to give ester (9)
(Table 1). Especially, using a non-polar solvent and an
amine, such as toluene and iPr2NEt, afforded the dehalogen-
ated product in high yield (Table 1, run 1).
of a biaryl component; however, this process is generally in-
effective for unsymmetrical biaryl compounds because a
competitive homo-coupling cannot be avoided.13 Bisiodides
13 and 14 as coupling precursors were prepared via esterifi-
cation between the corresponding 2-iodo benzoic acids 6 and
12, and 2-iodo benzylalcohols 11 and 5, respectively
(Scheme 2). Alcohol (11) and benzoic acid (12) were synthe-
sized through a procedure similar to the synthesis of 5 and 6.
As shown in runs 1–3 of Table 2, the Ullmann coupling re-
action of 13 produced only the homo-coupling product
(15) and dehalogenated ester (16) without the desired
Because the Pd-mediated intramolecular coupling reaction
of monoiodide 8 was not successful, we attempted the
Ullmann coupling reaction of benzyl benzoate derivatives.
This method is a conventional technique for the formation
Table 1. Pd-catalyzed aryl–aryl coupling reaction of 8
O
O
O
O
O
O
O
O
O
O
Pd, Ligand
Base, Solvent
O
O
I
MeO
MeO
MeO
MeO
MeO
MeO
OMe
10
OMe
OMe
8
9
Run
Pd (mol %)
Ligand (mol %)
Base (mol %)
Solvent
Temp (ꢁC)
Time (h)
Yield (%)
9
10
1
2
3
4
Pd(OAc)2 (20)
Pd(acac)2 (100)
Pd(PPh3)2Cl2 (20)
Pd(PPh3)4 (20)
PPh3 (60)
POT (300)
—
iPr2NEt (200)
K2CO3 (200)
AcONa (200)
Ag2CO3 (200)
Toluene
DMF
DMA
Reflux
130
Reflux
Reflux
2.5
2.5
1.5
9
84
—
—
—
N.D.a
b
b
c
N.D.a
N.D.a
—
MeCN
a
N.D., not detected.
Compound 9 was the major product on TLC analysis.
Many spots were observed on TLC.
b
c
MeO
MeO
MeO
CO2H
I
OH
I
a
OH
b
MeO
MeO
MeO
OMe
OMe
OMe
7
11
12
O
O
O
O
O
c
c
O
O
I
I
I
I
6 + 11
5 + 12
MeO
MeO
MeO
O
MeO
OMe
13
OMe
14
Scheme 2. (a) I2, CF3CO2Ag, CHCl3, ꢀ5 ꢁC, 1 h, 79%; (b) (i) CrO3, c-H2SO4, H2O, acetone, 0–5 ꢁC, 5 min; (ii) H2O2, NaH2PO4, HClO2, MeCN, H2O, rt, 1 h,
92%; (c) EDC, DMAP, CH2Cl2, rt, 13: 1 h, 79%; 14: 2 h, 80%.

398
S. Takeda et al. / Tetrahedron 63 (2007) 396–408
Table 2. Ullmann-type coupling reaction of 13
O
O
O
O
O
O
O
O
O
O
O
Metal
I
O
O
O
I
X
+
O
O
I
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
OMe
10
OMe
13
OMe
X = I ; 16
X = H ; 9
OMe
2
15
Run
Conditions (mol %)
Yield (%)
15
16
9
10
1
2
3
4
5
8
6
7
Cu (800), DMF, reflux, 2 h
Cu (800), DMA, reflux, 2 h
Cu (800), DMSO, reflux, 2 h
52
25
—
—
—
—
—
—
16
49
—
—
—
—
a
i
Pd(OAc)2 (20), PPh3 (40), Pr2NEt (200), xylene, reflux, 2 h
Pd(acac)2 (20), DPPP (40), Pr2NEt (200), DMA, reflux, 1 h
18
15
—
75
33
41
—
—
—
i
Pd(PPh3)2Cl2 (20), (Bu3Sn)2 (100), Bu4NBr (150), Li2CO3 (200), toluene, reflux, 5 h
Ni(PPh3)Cl2 (20), PPh3 (200), Zn (100), KI (100), DMF, reflux 5 h
Zn (200), DMF, reflux, 4 h
a
28
72
—
a
Many spots were observed on TLC.
lactone (10) being isolated, when DMF or DMA was used
as a reaction medium (runs 1 and 2). DMSO gave only a
complex mixture (run 3). On the other hand, the Ullmann
coupling reaction of 14 in DMF produced a result nearly
similar to that above, namely, dimerization and dehalo-
genation of the starting material predominantly occurred
(Table 3, run 1). In this case, the desired lactone (20) was for-
tunately isolated although the yield was quite low. Here, we
carried out the degradation experiment of dimers 15 and 17
in order to confirm their structures (Scheme 3). Reduction of
15 and 17 with DIBAL produced the known bisbenzyl-
alcohols 2114 and 2215 as the main products. We also exam-
ined the coupling reaction of bisiodides 13 and 14 using
some other metal reagents (Table 2, runs 4–7, and Table 3,
runs 2 and 3);14,16 however, they produced only the dehalo-
genated products 9, 16, 18, and 19.
R2
R1
R3
a
15 or 17
HO
2
21 : R1, R2 = -OCH2O-; R3 = H
22 : R1 = R2 = R3 = -OMe
Scheme 3. (a) DIBAL, toluene, ꢀ78 ꢁC, 1 h, 21: 68%; 22: 74%.
factor interfered with these reactions. Thus, we intended to
investigate the next class of substrates, phenyl benzoate de-
rivatives.
2.2. Intramolecular biaryl coupling reaction of phenyl
benzoate derivatives
As mentioned above, the biaryl coupling reaction of benzyl
benzoate derivatives was not suitable for the preparation of
dibenzoxepinone skeleton. It was thought that the steric
Contrary to the benzyl benzoate derivatives, the Pd-medi-
ated intramolecular biaryl coupling reaction17 of phenyl
Table 3. Ullmann-type coupling reaction of 14
O
O
O
I
O
O
O
O
O
Metal
O
O
I
O
O
O
I
X
+
MeO
MeO
MeO
MeO
MeO
MeO
O
O
O
MeO
OMe
OMe
20
OMe
14
OMe
X = I ; 18
X = H ; 19
OMe
2
17
Run
Conditions (mol %)
Yield (%)
17
18
19
20
1
2
3
Cu (800), DMF, reflux, 2 h
Pd(OAc)2 (20), PPh3 (40), Pr2NEt (200), xylene, reflux, 0.5 h
Ni(PPh3)4 (100), DMF, reflux, 10 h
62
—
—
25
—
—
78
5
—
i
a
a
Many spots were observed on TLC.

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
399
benzoate derivatives has been studied well.18 This reaction is
a very effective method for the preparation of various diben-
zopyranones, so we planned to apply this method to phenyl
benzoate 26a at first. Ester 26a was prepared from the known
phenol 25a19 via a simple esterification with 6 (Scheme 4).
Although the coupling reaction of 26a was investigated in-
tensively, the desired lactone 27a could not be isolated,
and the dehalogenated product 28a and the hydrolyzed prod-
uct 25a were obtained instead (Table 4, runs 1 and 2). We as-
sumed that the methoxycarbonyl group on the aromatic ring
interfered with this reaction because of its electron-with-
drawing property. Accordingly, we selected phenyl benzo-
ates 26b and 26c, which possess a benzyl ether group
instead of a methoxycarbonyl group, as coupling precursors.
Both 26b and 26c were prepared as follows: 23a was re-
duced with DIBAL to benzylalcohol (24), which was subse-
quently protected with a MOM or TBS group. After that, the
resulting protected benzylalcohols 23b and 23c were
reduced to 25b and 25c, finally condensation with 6 was car-
ried out to afford the corresponding esters 26b and 26c, re-
spectively. The esters were intensively investigated for the
Pd-mediated biaryl coupling reaction under various condi-
tions. Runs 3–10 of Table 4 demonstrate that the reaction
of 26b and 26c proceeded to form the desired lactones 27b
and 27c in good yield. Moreover, we confirmed the ability
to apply this reaction to a gram-scale (w20 g) synthesis.
MeO2C
OBn
OMe
OBn
OMe
OBn
OMe
HO
R1O
a
b or c
OMe
23a
OMe
24
OMe
23b : R1 = MOM
23c : R1 = TBS
O
O
R2
R2
OBn
OMe
OH
O
d
e
I
R2
O
OMe
OMe
OMe
23a : R2 = -CO2Me
25a : R2 = -CO2Me
OMe
OMe
23b : R2 = -CH2OMOM
23c : R2 = -CH2OTBS
25b : R2 = -CH2OMOM
25c : R2 = -CH2OTBS
26a : R2 = -CO2Me
26b : R2 = -CH2OMOM
26c : R2 = -CH2OTBS
Scheme 4. (a) DIBAL, toluene, ꢀ78 ꢁC, 1 h, 96%; (b) MOMCl, iPr2NEt, DMF, 60 ꢁC, 1 h, 96% for 23b; (c) TBSCI, imidazole, CH2Cl2, rt, 5 min, quant. for 23c;
(d) H2, Pd–C, MeOH or AcOEt, rt, 83–100%; (e) 6, EDC, DMAP, CH2Cl2, rt, 84–100%.
Table 4. Pd-catalyzed aryl–aryl coupling reaction of 26
O
I
O
O
O
R
O
O
R
OH
R
Pd, Ligand
Base, Solvent
O
O
O
+
+
O
O
O
OMe
R
OMe
OMe
OMe
OMe
25a : R = -CO2Me
25b : R = -CH2OMOM
25c : R = -CH2OTBS
OMe
OMe
OMe
27a : R = -CO2Me
27b : R = -CH2OMOM
27c : R = -CH2OTBS
28a : R = -CO2Me
28b : R = -CH2OMOM
28c : R = -CH2OTBS
26a : R = -CO2Me
26b : R = -CH2OMOM
26c : R = -CH2OTBS
Substrate
Run
Pd (mol %)
Ligand (mol %)
Base (mol %)
Solvent
Temp (ꢁC)
Time (min)
Yield (%)
27
28
25
26a
26b
1
2
Pd(OAc)2 (200)
Pd(OAc)2 (100)
PPh3 (60)
K2CO3 (200)
iPr2NEt (200)
DMF
DMF
130
130
540
180
—
—
—
40
19
19
DPPP (100), nBu3P (100)
a
3
4
5
6
7
Pd(acac)2 (20)
Pd(OAc)2 (20)
Pd(PPh3)4 (20)
Pd(OAc)2 (10)
Pd(OAc)2 (30)
PPh3 (40)
PPh3 (40)
—
AcONa (200)
iPr2NEt (200)
Ag2CO3 (200)
K2CO3 (100)
K2CO3 (100)
Toluene
DMF
DMF
DMA
DMA
Reflux
Reflux
Reflux
Reflux
130
210
90
90
30
—
—
54
14
Trace
—
—
—
—
—
25
71
77
nBu3P (20)
—
30
26c
8
9
10
Pd(OAc)2 (30)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
—
K2CO3 (100)
K2CO3 (100)
K2CO3 (100)
DMA
DMA
DMA
130
130
Reflux
20
360
10
53
—
—
—
Trace
49b
Trace
nBu3P (20)
nBu3P (20)
31b
63
a
No reaction on TLC.
Determined by 1H NMR.
b

400
S. Takeda et al. / Tetrahedron 63 (2007) 396–408
Because, we could obtain the desired lactones in satisfactory
yield through the Pd-mediated intramolecular biaryl cou-
pling reaction of 26b and 26c, we next attempted the asym-
metric lactone-opening reaction of 27b and 27c.
In order to determine the absolute configuration of 30c, we
converted it into the known compound 33 (Scheme 5).4a
Methylation of the phenolic hydroxyl group followed by
oxidation with PDC afforded aldehyde 32 without racemiza-
tion. The treatment of 32 with methyl lithium at ꢀ78 ꢁC pro-
duced about a 5.5:1 diastereoisomeric mixture, which was
easily separated by column chromatography. O-Allylation
of the major diastereomer afforded 33, whereas the configu-
ration at the benzylic position was not determined. The ee of
the resulting 33 was 80% by HPLC analysis. All spectral
data for 33 including optical rotation were consistent with
those of the reported compound;4a therefore, the absolute
configuration of 30c was determined to be R.
2.3. Asymmetric lactone-opening reaction and determi-
nation of the absolute configuration
First, we investigated a dynamic kinetic resolution of 27b
and 27c through reduction with a chiral oxazaborolidine
(29)–borane complex.9,20 As shown in Table 5, asymmetric
reduction of 27b produced a lactone-opened product 30b in
good enantioselectivity (run 1) with moderate yield. When
this reaction was carried out at 0 ꢁC, the ee of 30b was
only 47% although the reaction rate was accelerated (run
2). Using a lower amount of the reducing agent (29–borane)
led to a moderate yield and ee (run 3). Generation of by-
product 31b was observed in each case. On the other hand,
asymmetric reduction of 27c afforded 30c in excellent yield
and good enantioselectivity (run 4). Under this reaction con-
dition, by-product 31c was not detected in contrast to the
case of 27b. However, undesired 31c was obtained in 51%
yield when the reaction was conducted at higher temperature
(run 5). We also examined another condition of dynamic
kinetic resolution, using BINAL9 or lithium menthoxide,9
which has been developed by Bringmann and co-workers.
However, in spite of our intensive efforts, we could not
obtain any fruitful results.
3. Conclusion
We investigated the intramolecular biaryl coupling reaction
of benzyl benzoate and phenyl benzoate derivatives and the
enantioselective lactone-opening reaction using chiral ox-
azaborolidine–borane complex in order to provide the biaryl
moiety of the stegane families. The coupling reaction of ben-
zyl benzoate derivatives was not suitable for this purpose,
whereas the Pd-mediated coupling reaction of phenyl benzo-
ate followed by asymmetric reduction successfully produced
a key intermediate of these targets. The synthesis of (ꢀ)-
steganone from 33 has already been reported.4a Thus, we
accomplished the formal total synthesis of (ꢀ)-steganone.
Table 5. Asymmetric lactone-opening reaction of 27 with a chiral oxazaborolidine–BH3 complex
Ph
H
Ph
O
O
O
O
O
O
O
N
B
Me
O
OH
OR
29
+
BH3
THF
O
O
HO
RO
RO
OMe
OMe
MeO
OMe
OMe
OMe
27b : R = MOM
27c : R = TBS
31b : R = MOM
31c : R = TBS
30b : R = MOM
30c : R = TBS
Substrate
Run
BH3 (mol %)
29 (mol %)
Temp (ꢁC)
Time (h)
Yield (%)
ee of 30a (%)
30
31
27b
1
2
3
400
400
200
300
300
50
ꢀ78 to rt
8
1.5
40
59
67
55
16
26
11
86
47
68
0
ꢀ40
27c
4
5
400
400
300
300
ꢀ78 to ꢀ40
17
17
97
49
—
51
83
78
ꢀ78 to 0
a
Determined by HPLC analysis using CHIRALCEL OD.
O
O
O
O
O
O
O
[α]2D0 = +1.8°
(CHCl3, c = 2.29)
lit.5b): [α]D25 = +2.3°
(CHCl3, c = 1.18)
OH
a, b
c, d
CHO
OTBS
HO
MeO
MeO
MeO
MeO
OTBS
OTBS
MeO
OMe
30c : 83%ee
OMe
32
OMe
33 : 80%ee
Scheme 5. (a) MeI, tBuOK, THF, rt, 48 h, 88%; (b) PDC, CH2CI2, rt, 12 h, 77%; (c) MeLi, THF, ꢀ78 ꢁC, 0.5 h, 55%; (d) allyl bromide, NaH, DMF, rt, 37 h, 66%.

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
401
4. Experimental
were added. The mixture was stirred for 1 h at rt, washed
with water and brine, and dried over anhydrous MgSO4. After
evaporation, the residue was recrystallized from CH2Cl2–
Et2O to afford 8 as colorless needles (754 mg, 66%), mp
119–121 ꢁC. IR (KBr) cmꢀ1: 1715, 1590, 1500, 1245,
4.1. General
Melting points were measured using a Yanagimoto micro
melting point hot-plate apparatus and are uncorrected. IR
spectra were recorded on a Jasco FTIR-350 spectrophoto-
meter. NMR spectra were taken with a Varian VXR-500
(500 MHz), MERCURY (300 MHz), VXR-200 (200 MHz),
or JNM-MY60FT (60 MHz) instrument. Chemical shifts
are given in d parts per million with TMS as an internal stan-
dard. FABMS was obtained with a VG-70SE instrument us-
ing m-nitrobenzyl alcohol as the matrix. Optical rotations
were determined on a JASCO Dip-4 digital polarimeter.
Elemental analysis was performed with a Yanaco MT-5
analyzer. Silica gel column chromatography was carried out
using Wakogel C-200 (Wako) or 9385 Kieselgel 60 (Merck).
TLC analysis was performed on Kieselgel 60 F254 (Merck)
plates.
1
1130, 1030. H NMR (200 MHz, CDCl3) d: 3.85 (3H, s,
Ar-4-OCH3), 3.88 (6H, s, Ar-3,5-OCH3), 5.26 (2H, s,
OCH2Ar), 6.04 (2H, s, OCH2O), 6.67 (2H, s, benzylalco-
hol-2,6-H), 7.37 (1H, s, 1,3-benzodioxole-7-H), 7.41 (1H, s,
1,3-benzodioxole-4-H). 13C NMR (125 MHz, CDCl3) d:
56.15, 60.80, 67.45, 84.95, 102.41, 105.70, 111.04, 120.89,
127.41, 131.11, 138.01, 148.09, 151.13, 153.29, 165.26.
Anal. Calcd for C18H17IO7: C, 45.78; H, 3.63. Found: C,
45.61; H, 3.75.
4.2. Typical procedure for the Pd-mediated coupling
reaction of benzyl benzoate 8 (Table 1, run 1)
To a solution of 8 (63.3 mg, 0.134 mmol) in toluene
(3 mL), PPh3 (21.1 mg, 0.0804 mmol), Pr2NEt (47.0 mL,
i
4.1.1. 5-Hydroxymethyl-6-iodo-1,3-benzodioxole (5).12 I2
(27.9 g, 0.110 mol) and CF3CO2Ag (24.1 g, 0.109 mol) were
added at ꢀ5 ꢁC to a solution of 4 (12.6 g, 82.8 mmol) in
CHCl3 (200 mL). After stirring at ꢀ5 ꢁC for 10 min, the
mixture was filtered with Celite, and the filtrate was washed
with saturated aqueous Na2S2O3 solution. The organic layer
was dried over anhydrous MgSO4, and the solvent was eva-
porated under reduced pressure. The residue was recrystal-
lized from CHCl3 to afford 5 as colorless needles (19.0 g,
83%), mp 107.5–109 ꢁC [lit.12 108–109 ꢁC (CHCl3)]. IR
(KBr) cmꢀ1: 3270, 1500, 1480, 1450, 1240, 1100, 1040,
0.270 mmol), and Pd(OAc)2 (6.0 mg, 0.027 mmol) were
successively added, and the mixture was refluxed for
2.5 h under argon atmosphere. After cooling, the mixture
was filtered, and the filtrate was diluted with ether, washed
with brine, and dried over anhydrous MgSO4. After eva-
poration, the resulting oil was subjected to silica gel column
chromatography with AcOEt–n-hexane (1:5) to produce 9
(38.9 mg, 84%).
4.2.1. 3,4,5-Trimethoxybenzyl 1,3-benzodioxole-5-car-
boxylate (9). Colorless needles, mp 118–119.5 ꢁC
(CH2Cl2–Et2O). IR (KBr) cmꢀ1: 1715, 1600, 1445, 1330,
1
925, 860. H NMR (60 MHz, DMSO-d6) d: 4.33 (2H, d,
J¼5.5 Hz, ArCH2OH), 5.34 (1H, t, J¼5.5 Hz, OH), 6.03
1
1280, 1125, 1030, 760. H NMR (200 MHz, CDCl3) d:
(2H, s, OCH2O), 7.04 (1H, s, Ar-4-H), 7.31 (1H, s, Ar-7-H).
3.85 (3H, s, Ar-4-OCH3), 3.88 (6H, s, Ar-3,5-OCH3), 5.25
(2H, s, OCH2Ar), 6.04 (2H, s, OCH2O), 6.66 (2H, s, benzyl-
alcohol-2,6-H), 6.84 (1H, d, J¼8.2 Hz, 1,3-benzodioxole-7-
H), 7.49 (1H, d, J¼1.6 Hz, 1,3-benzodioxole-4-H), 7.69
(1H, dd, J¼8.2, 1.6 Hz, 1,3-benzodioxole-6-H). 13C NMR
(50 MHz, CDCl3) d: 56.03, 60.71, 66.76, 101.73, 105.36,
107.87, 109.42, 123.92, 125.36, 131.58, 137.82, 147.63,
151.62, 153.21, 165.63. FABMS (positive ion mode) m/z:
346 [M]+, 347 [M+1]+. Anal. Calcd for C18H18O7: C,
62.42; H, 5.24. Found: C, 62.26; H, 4.98.
4.1.2. 6-Iodo-1,3-benzodioxole-5-carboxylic acid (6).21 To
a solution of 5 (1.00 g, 3.60 mmol) in acetone (5 mL), Jones
reagent (2.02 mL, 5.39 mmol for CrO3) was added dropwise
at 0–5 ꢁC. After stirring at 0 ꢁC for 5 min, the resulting mix-
ture was quenched with NaHSO3 solution, poured into water,
and extracted with AcOEt. The organic layer was succes-
sively washed with saturated aqueous NaHCO3 solution
and brine, and it was dried over anhydrous MgSO4. After
evaporation, the residue (1.03 g) was dissolved in MeCN–
H2O (20:1) (21 mL), and NaH2PO4$2H2O (116 mg,
0.744 mmol), 31% H2O2 (0.550 mL, 5.61 mmol), and 80%
NaClO2 (632 mg, 5.59 mmol) in H2O (1 mL) were added
at 0–5 ꢁC. After stirring at rt for 2 h, aqueous NaHSO3 solu-
tion was added to the reaction mixture and extracted with
AcOEt. The organic layer was collected, washed with brine,
and dried over anhydrous MgSO4. After evaporation, the res-
idue was recrystallized from AcOEt to afford 6 as colorless
prisms (767 mg, 73%), mp 216.5–219 ꢁC [lit.21 218.5–
221 ꢁC (MeOH)]. IR (KBr) cmꢀ1: 2700, 1710, 1620, 1500,
4.2.2. 2-Iodo-3,4,5-trimethoxybenzylalcohol (11).13 I2
(3.00 g, 11.8 mmol) and CF3CO2Ag (2.60 g, 11.8 mmol)
were added at ꢀ5 ꢁC to a solution of 7 (2.01 g,
10.1 mmol) in CHCl3 (100 mL). After stirring at ꢀ5 ꢁC
for 1 h, the mixture was filtered, and the filtrate was washed
with saturated aqueous Na2S2O3 solution. The organic layer
was dried over anhydrous MgSO4, and the solvent was eva-
porated off. The resulting residue was subjected to silica gel
column chromatography with AcOEt–n-hexane (1:3) to pro-
duce 11 (2.59 g, 79%). Colorless needles, mp 51–53 ꢁC
(Et2O–n-hexane) [lit.13 56.5–57.7 ꢁC (hexane)]. IR (KBr)
cmꢀ1: 3270, 1565, 1480, 1445, 1390, 1325, 1200, 1150,
1
1490, 1420, 1350, 1280, 1250, 1145, 1040, 920. H NMR
(60 MHz, CDCl3) d: 6.13 (2H, s, OCH2O), 7.32 (1H, s,
Ar-7-H), 7.49 (1H, s, Ar-4-H), 13.06 (1H, s, COOH).
FABMS (positive ion mode) m/z: 292 [M]+, 293 [M+1]+.
1
1100, 1020. H NMR (60 MHz, CDCl3) d: 3.87 (9H, s),
4.66 (2H, s), 6.94 (1H, s).
4.1.3. 3,4,5-Trimethoxybenzyl 6-iodo-1,3-benzodioxole-
5-carboxylate (8). To a solution of 6 (713 mg, 2.44 mmol)
and 7 (481 mg, 2.43 mmol) in CH2Cl2 (30 mL), EDC
(702 mg, 3.66 mmol) and DMAP (45.0 mg, 0.368 mmol)
4.2.3. 2-Iodo-3,4,5-trimethoxybenzoic acid (12).22 To a so-
lution of 11 (9.98 g, 30.8 mmol) in acetone (100 mL), Jones
reagent (10.0 mL, 26.7 mmol for CrO3) was added dropwise
at 0–5 ꢁC. After stirring at 0 ꢁC for 5 min, the reaction

402
S. Takeda et al. / Tetrahedron 63 (2007) 396–408
mixture was quenched with aqueous NaHSO3 solution,
poured into water, and extracted with ether. The organic
layer was successively washed with saturated aqueous
NaHCO3 solution and brine, and it was dried over anhydrous
MgSO4. After evaporation, the residue (10.8 g) was dis-
solved in MeCN–H2O (25:1) (104 mL). To the mixture,
NaH2PO4$2H2O (480 mg, 3.08 mmol), 31% H2O2 (3.00 mL,
30.8 mmol), and 80% NaClO2 (3.48 g, 30.8 mmol) in H2O
(4 mL) were added at 0–5 ꢁC. After stirring at rt for 1 h, to
the reaction mixture was added aqueous NaHSO3 solution
and extracted with ether. The organic layer was washed
with brine and dried over anhydrous MgSO4. After evapora-
tion, the residue was recrystallized from Et2O–n-hexane to
afford 12 as colorless needles (9.52 g, 91%), mp 147–
148 ꢁC [lit.22 135–142 ꢁC]. IR (KBr) cmꢀ1: 2960, 1700,
1580, 1480, 1410, 1380, 1335, 1235, 1110, 1000. 1H NMR
(60 MHz, CDCl3) d: 3.90–4.00 (9H, s, Ar-3,4,5-OCH3),
6.60 (1H, br, COOH), 7.45 (1H, s, Ar-6-H).
Calcd for C18H16I2O7: C, 36.14; H, 2.70. Found: C, 36.40;
H, 2.76.
4.3. Typical procedure for Ullmann coupling reaction
(Table 2, run 1)
Copper was purified by a published method.23 Under argon
atmosphere, a mixture of Cu (170 mg, 2.68 mmol) and DMF
(2 mL) was refluxed for 30 min, and a solution of 13
(200 mg, 0.334 mmol) in DMF (2 mL) was added via sy-
ringe; the mixture was then refluxed for a further 2 h. After
cooling, the mixture was filtered, and the filtrate was diluted
with ether. The solution was successively washed with 28%
aqueous ammonia solution, water, and brine and dried over
anhydrous MgSO4. After evaporation, the resulting oil was
subjected to silica gel column chromatography with ether–
chloroform (1:100) to produce 15 (81.6 mg, 52%) and 16
(24.4 mg, 16%).
4.2.4. 2-Iodo-3,4,5-trimethoxybenzyl 6-iodo-1,3-benzo-
dioxole-5-carboxylate (13). To a solution of 6 (2.80 g,
9.59 mmol) and 11 (1.82 g, 5.62 mmol) in CH2Cl2 (100 mL),
EDC (1.89 g, 9.86 mmol) and DMAP (145 mg, 1.19 mmol)
were successively added. The mixture was stirred for 3 h at
rt, washed with water and brine, and dried over anhydrous
MgSO4. After evaporation, the residue was recrystallized
from CH2Cl2–Et2O to afford 13 as colorless needles (2.67 g,
79%), mp 102–104 ꢁC. IR (KBr) cmꢀ1: 1730, 1480, 1380,
1240, 1135, 1030, 1000. 1H NMR (500 MHz, CDCl3)
d: 3.87 (3H, s, ArOCH3), 3.88 (3H, s, ArOCH3), 3.90 (3H,
s, ArOCH3), 5.35 (2H, s, OCH2Ar), 6.04 (2H, s, OCH2O),
6.92 (1H, s, benzylalcohol-6-H), 7.42 (1H, s, 1,3-benzodi-
oxole-7-H), 7.45 (1H, s, 1,3-benzodioxole-4-H). 13C NMR
(125 MHz, CDCl3) d: 56.25, 60.78, 60.93, 71.09, 85.16,
86.80, 102.40, 109.84, 111.23, 120.91, 127.00, 133.52,
142.09, 148.06, 151.19, 153.32, 153.68, 164.87. Anal.
Calcd for C18H15IO8: C, 36.14; H, 2.70. Found: C, 36.02;
H, 2.85.
4.3.1. 6,60-Bis(2-iodo-3,4,5-trimethoxybenzyl 1,3-benzo-
dioxole-5-carboxylate) (15). Colorless prisms, mp 150.5–
152.5 ꢁC (CH2Cl2–Et2O). IR (KBr) cmꢀ1: 2950, 1690,
1
1480, 1330, 1255, 1105, 1035, 1000. H NMR (200 MHz,
CDCl3) d: 3.85 (6H, s, ArOCH3), 3.89 (6H, s, ArOCH3),
3.91 (6H, s, ArOCH3), 4.99 (2H, d, J¼12.0 Hz, OCHHAr),
5.09 (2H, d, J¼12.0 Hz, OCHHAr), 5.98 (2H, d,
J¼1.4 Hz, OCHHO), 6.00 (2H, d, J¼1.4 Hz, OCHHO),
6.49 (2H, s, 1,3-benzodioxole-7 and 70-H), 6.64 (2H, s, ben-
zylalcohol-6 and 60-H), 7.30 (2H, s, 1,3-benzodioxole-4 and
40-H). 13C NMR (125 MHz, CDCl3) d: 30.88, 56.14, 60.70,
60.90, 70.70, 87.66, 101.99, 109.56, 110.01, 121.91, 133.46,
139.60, 141.98, 146.36, 150.13, 153.03, 153.39, 165.53.
Anal. Calcd for C36H32I2O14: C, 45.88; H, 3.42. Found: C,
46.05; H, 3.37.
4.3.2. 2-Iodo-3,4,5-trimethoxybenzyl 1,3-benzodioxole-5-
carboxylate (16). Colorless prisms, mp 120–122 ꢁC
(CH2Cl2–hexane). IR (KBr) cmꢀ1: 1705, 1500, 1330,
1
1280, 1260, 1105, 770. H NMR (200 MHz, CDCl3) d:
4.2.5. 6-Iodo-1,3-benzodioxole-5-ylmethyl 2-iodo-3,4,5-
trimethoxybenzoate (14). To a solution of 5 (2.50 g,
8.99 mmol) and 12 (3.95 g, 11.7 mmol) in CH2Cl2
(100 mL), EDC (2.76 g, 14.4 mmol) and DMAP (176 mg,
1.44 mmol) were successively added. After stirring for 2 h
at rt, 12 (608 mg, 1.80 mmol) and EDC (517 mg,
2.70 mmol) were added again to the mixture. The reaction
mixture was stirred for an additional 1 h at the same temper-
ature. The whole mixture was then washed with water and
brine, and dried over anhydrous MgSO4. After evaporation,
the resulting residue was subjected to silica gel column
chromatography with AcOEt–n-hexane (1:2) to produce
a colorless solid. Recrystallization from Et2O–n-hexane
afforded pure 14 as colorless needles (4.32 g, 80%) mp
125–126 ꢁC. IR (KBr) cmꢀ1: 2940, 1735, 1480, 1380,
3.85 (3H, s, ArOCH3), 3.87 (3H, s, ArOCH3), 3.89 (3H, s,
ArOCH3), 5.32 (2H, s, OCH2Ar), 6.03 (2H, s, OCH2O),
6.83 (1H, d, J¼8.2 Hz, 1,3-benzodioxole-7-H), 6.88 (1H, s,
benzylalcohol-6-H), 7.50 (1H, d, J¼1.7 Hz, 1,3-benzodiox-
ole-4-H), 7.70 (1H, dd, J¼8.2, 1.7 Hz, 1,3-benzodioxole-6-
H). 13C NMR (125 Hz, CDCl3) d: 56.14, 60.77, 60.91, 70.42,
86.68, 101.77, 107.97, 109.54, 109.58, 123.80, 125.53,
133.98, 141.99, 147.68, 151.71, 153.30, 153.63, 165.43.
FABMS (positive ion mode) m/z: 472 [M]+. Anal. Calcd
for C18H17IO7: C, 45.78; H, 3.63. Found: C, 45.50; H, 3.56.
4.3.3. 2,20-Bis(6-iodo-1,3-benzodioxole-5-ylmethyl 3,4,5-
trimethoxybenzoate) (17). Colorless prisms, mp 131–
133 ꢁC (CH2Cl2–Et2O–hexane). IR (CHCl3) cmꢀ1: 3020,
1710, 1480, 1325, 1220, 1205, 1100, 1040. 1H NMR
(200 MHz, CDCl3) d: 3.55 (6H, s, ArOCH3), 3.85 (6H, s,
ArOCH3), 3.92 (6H, s, ArOCH3), 4.99 (4H, d, J¼1.4 Hz,
OCH2Ar), 5.97 (4H, s, OCH2O), 6.57 (2H, s, 1,3-benzodiox-
ole-7 and 70-H), 7.18 (2H, s, 1,3-benzodioxole-4 and 40-H),
7.38 (2H, s, benzoic acid-6 and 60-H). 13C NMR (125 MHz,
CDCl3) d: 55.71, 60.49, 60.61, 70.55, 87.06, 101.72,
109.27, 110.01, 118.31, 124.51, 126.39, 131.37, 145.43,
148.16, 148.19, 150.88, 151.86, 166.19. Anal. Calcd for
C36H32I2O14: C, 45.88; H, 3.42. Found: C, 46.08; H, 3.62.
1
1330, 1240, 1215, 1100, 1040, 1010, 925, 865. H NMR
(500 MHz, CDCl3) d: 3.87 (3H, s, ArOCH3), 3.89 (3H, s,
ArOCH3), 3.91 (3H, s, ArOCH3), 5.30 (2H, s, OCH2Ar),
5.99 (2H, s, OCH2O), 7.05 (1H, s, 1,3-benzodioxole-7-H),
7.30 (2H, s, 1,3-benzodioxole-4-H and benzoic acid-6-H).
13C NMR (125 MHz, CDCl3) d: 56.28, 60.80, 61.01,
71.05, 84.13, 87.49, 101.86, 110.76, 110.89, 118.82,
130.36, 131.26, 145.00, 148.39, 148.60, 153.27, 153.84,
165.89. FABMS (positive ion mode) m/z: 598 [M]+. Anal.

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
403
4.3.4. 6-Iodo-1,3-benzodioxole-5-ylmethyl 3,4,5-trimeth-
oxybenzoate (18). Colorless needles, mp 152–153.5 ꢁC
(CH2Cl2–Et2O). IR (KBr) cmꢀ1: 2940, 1720, 1590, 1505,
4.4.1. 6,60-Bis(hydroxymethyl)-5,50-bi-1,3-benzodioxole
(21).14 Colorless needles, mp 182–182.5 ꢁC (CHCl3). IR
(KBr) cmꢀ1: 3300, 2900, 1500, 1480, 1245, 1065, 1040,
1
1
1480, 1460, 1420, 1340, 1230, 1135. H NMR (200 MHz,
930, 860. H NMR (200 MHZ, CDCl3–acetone) d: 4.22
CDCl3) d: 3.91 (6H, s, Ar-3,5-OCH3), 3.91 (3H, s, Ar-4-
OCH3), 5.29 (2H, s, OCH2Ar), 5.99 (2H, s, OCH2O), 6.98
(1H, s, 1,3-benzodioxole-7-H), 7.30 (1H, s, 1,3-benzodi-
oxole-4-H), 7.35 (2H, s, benzoic acid-2,6-H). 13C NMR
(50 MHz, CDCl3) d: 56.21, 60.85, 70.35, 87.14, 101.82,
106.95, 110.25, 118.85, 124.81, 131.74, 142.31, 148.37,
148.47, 152.88, 165.74. Anal. Calcd for C18H17IO7: C,
45.78; H, 3.63. Found: C, 45.93; H, 3.91.
(2H, br, OH, exchangeable with D2O), 4.22 (4H, s,
OCH2Ar), 6.01 (4H, s, OCH2O), 6.58 (2H, s, Ar-4, 40-H),
7.01 (2H, s, Ar-7, 70-H). Anal. Calcd for C16H14O6$0.5H2O:
C, 61.73; H, 4.86. Found: C, 61.75; H, 4.69.
4.4.2. 6,60-Hydroxymethyl-1,10,2,20,3,30-hexamethoxy-
1,10-biphenyl (22).15 Colorless prisms, mp 96.5–97.5 ꢁC
(Et2O–hexane) [lit.15 106–108 ꢁC (Et2O–hexane); optically
active form]. IR (KBr) cmꢀ1: 3400, 2950, 1600, 1490,
1
4.3.5. 1,2,3-Trimethoxy-9,10-methylenedioxy-7H-diben-
zo[c,e]oxepine-7-one (20). Colorless needles, mp 162–
166 ꢁC (CH2Cl2–Et2O). IR (KBr) cmꢀ1: 2950, 1710, 1600,
1460, 1400, 1325, 1195, 1130, 1105, 1010, 980. H NMR
(200 MHz, CDCl3) d: 3.67 (6H, s, ArOCH3), 3.89 (6H, s, Ar-
OCH3), 3.93 (6H, s, ArOCH3), 4.18 (4H, s, ArCH2OH), 6.89
(2H, s, Ar-H). FABMS (positive ion mode) m/z: 394 [M]+.
Anal. Calcd for C20H26O8: C, 60.90; H, 6.64. Found: C,
60.56; H, 6.86.
1
1510, 1490, 1410, 1330, 1250, 1110, 1040, 930, 890. H
NMR (200 MHz, CDCl3) d: 3.65 (3H, s, ArOCH3), 3.95
(3H, s, ArOCH3), 3.99 (3H, s, ArOCH3), 4.80 (1H, d,
J¼12.0 Hz, OCHHAr), 4.94 (1H, d, J¼12.0 Hz, OCHHAr),
6.02 (1H, d, J¼1.4 Hz, OCHHO), 6.07 (1H, d, J¼1.4 Hz,
OCHHO), 6.92 (1H, s, Ar-11-H), 7.62 (1H, s, Ar-4-H),
7.62 (1H, s, Ar-8-H). FABMS (positive ion mode) m/z:
344 [M]+. HRMS (FAB) Calcd for C18H16O7 [M]+:
344.0896. Found: 344.0858.
4.4.3. 3-Benzyloxy-4,5-dimethoxybenzylalcohol (24).24
To a solution of 23a (50.0 g, 0.165 mol) in toluene
(300 mL), DIBAL (1.0 M toluene solution, 500 mL,
0.500 mol) was added dropwise, and the mixture was then
stirred for 1 h at ꢀ78 ꢁC. A sodium hydroxide aqueous solu-
tion (1.0 M, 450 mL) was added, and the mixture was stirred
for 30 min at rt. After extraction with ether, the organic layer
was washed with brine, dried over anhydrous MgSO4, and
the solvent was evaporated to give 24 as a yellow oil
(43.5 g, 96%). IR (neat) cmꢀ1: 3440, 2950, 1735, 1590,
1505, 1480, 1430, 1380, 1330, 1240, 1120, 1010, 825,
740, 700. 1H NMR (200 MHz, CDCl3) d: 1.71 (1H, t,
J¼6.0 Hz, OH, exchangeable with D2O), 3.87 (3H, s,
ArOCH3), 3.87 (3H, s, ArOCH3), 4.59 (2H, d, J¼6.0 Hz,
ArCH2OH), 5.14 (2H, s, ArOCH2Ph), 6.62 (1H, s, Ar-2 or
6-H), 6.63 (1H, s, Ar-2 or 6-H), 7.30–7.47 (5H, m, C6H5).
FABMS (positive ion mode) m/z: 274 [M]+.
4.3.6. 1,3-Benzodioxole-5-ylmethyl 3,4,5-trimethoxyben-
zoate (19). PPh3 (35.1 mg, 0.134 mmol), Pr2NEt (116 mL,
i
0.666 mmol), and Pd(OAc)2 (15.0 mg, 0.0668 mmol) were
successively added to
a solution of 14 (200 mg,
0.334 mmol) in xylene (3 mL), and the mixture was refluxed
for 2.5 h under argon atmosphere. After cooling, the mixture
was filtered, and the filtrate was diluted with AcOEt, washed
with brine, and dried over anhydrous MgSO4. After evapora-
tion, the resulting oil was subjected to silica gel column chro-
matography with AcOEt–n-hexane (1:3.5) to produce 19
(89.9 mg, 78%). Colorless prisms, mp 141.5–143 ꢁC
(Et2O–n-hexane). IR (KBr) cmꢀ1: 2950, 1695, 1585, 1505,
1435, 1415, 1330, 1225, 1125, 1035, 1000, 965, 860, 760.
1H NMR (200 MHz, CDCl3) d: 3.90 (9H, s, Ar-3,4,5-
OCH3), 5.26 (2H, s, OCH2Ar), 5.98 (2H, s, OCH2O), 6.78–
6.95 (3H, m, 1,3-benzodioxole-4,6,7-H), 7.31 (2H, s, benzoic
acid-2,6-H). 13C NMR (125 Hz, CDCl3) d: 56.16, 60.82,
66.73, 101.10, 106.78, 108.16, 108.98, 122.23, 125.04,
129.72, 142.16, 147.57, 147.73, 152.82, 165.99. Anal.
Calcd for C18H18O7: C, 62.42; H, 5.24. Found: C, 62.20;
H, 5.07.
4.4.4. 1-Benzyloxy-2,3-dimethoxy-5-methoxymethoxy-
methylbenzene (23b). Pr2NEt (66.9 mL, 0.384 mol) and
i
MOMCl (29.2 mL, 0.384 mol) were successively added to
a solution of 24 (35.0 g, 0.128 mol) in DMF (250 mL) at
0 ꢁC. The mixture was stirred for 1 h at 60 ꢁC and poured
into water. After extraction with ether, the organic layer
was successively washed with 10% HCl solution, saturated
aqueous NaHCO3 solution, and brine. The solution was
dried over anhydrous MgSO4 and the solvent was evaporated
to give 23b as a pale yellow oil (39.2 g, 96%). IR (neat)
cmꢀ1: 2950, 1590, 1510, 1455, 1430, 1380, 1330, 1240,
4.4. Reduction of dimers 15 and 17
1
1120, 1055, 920, 825, 740. H NMR (200 MHz, CDCl3) d:
To a solution of 15 (100 mg, 0.106 mmol) in toluene (2 mL),
DIBAL (1.0 Mtoluene solution, 0.530 mL, 0.530 mmol)was
added dropwise at ꢀ78 ꢁC, and the mixture was then stirred
for 1 h at the same temperature. A sodium hydroxide aqueous
solution (1.0 M, 10 mL) was added, and the mixture was
stirred for 30 min at rt. After extraction with ether, the or-
ganic layer was washed with brine, dried over anhydrous
MgSO4, and the solvent was evaporated. The residue was
subjected to silica gel column chromatography with ether–
chloroform (1:20) to give 21 (21.9 mg, 68%) and alcohol
11 (46.0 mg, 67%). Reduction of 17 (200 mg, 0.212 mmol)
using the same procedure employed for 15 was carried out
to afford 22 (62.0 mg, 74%) and alcohol 5 (111 mg, 94%).
3.40 (3H, s, CH2OCH3), 3.87 (3H, s, ArOCH3), 3.87 (3H,
s, ArOCH3), 4.50 (2H, s, ArCH2O), 4.68 (2H, s, OCH2O),
5.14 (2H, s, ArOCH2Ph), 6.60 (1H, d, J¼1.6 Hz, Ar-2 or
6-H), 6.63 (1H, d, J¼1.6 Hz, Ar-2 or 6-H), 7.30–7.48 (5H,
m, C6H5). 13C NMR (50 MHz, CDCl3) d: 55.34, 56.03,
60.82, 69.16, 70.96, 95.51, 105.10, 106.96, 127.22,
127.78, 128.45, 133.29, 137.05, 138.10, 152.34, 153.38.
FABMS (positive ion mode) m/z: 318 [M]+. Anal. Calcd
for C18H22O5: C, 67.90; H, 6.97. Found: C, 67.99; H, 7.08.
4.4.5. 1-Benzyloxy-5-tert-butyldimethylsilyl-2,3-di-
methoxybenzene (23c). To a solution of TBSCl (2.16 g,
14.3 mmol) in CH2Cl2 (10 mL), a mixture of 24 (3.03 g,

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S. Takeda et al. / Tetrahedron 63 (2007) 396–408
11.0 mmol) and imidazole (1.12 g, 16.5 mmol) in CH2Cl2
(10 mL) was added. The reaction mixture was stirred for
5 min at rt, washed with water and brine, and dried over an-
hydrous MgSO4. After evaporation, the resulting oil was
subjected to silica gel column chromatography with
AcOEt–n-hexane (1:10) to produce 23c as a colorless oil
(4.29 g, quant). IR (neat) cmꢀ1: 2940, 1590, 1510, 1460,
101.68, 105.48, 134.20, 137.68, 149.06, 152.21. FABMS
(positive ion mode) m/z: 297 [Mꢀ1]+, 298 [M]+, 299
[M+1]+. HRMS (FAB) Calcd for C15H26O4Si [Mꢀ1]+:
297.1522. Found: 297.1522. [M+1]+: 299.1679. Found:
299.1651.
4.4.9. 2,3-Dimethoxy-5-methoxycarbonylphenyl 6-iodo-
1,3-benzodioxole-5-carboxylate (26a). To a solution of 6
(10.0 g, 34.2 mmol) and 25a (6.05 g, 28.5 mmol) in
CH2Cl2 (300 mL), EDC (9.84 g, 51.3 mmol) and DMAP
(3.48 g, 28.5 mmol) were successively added. The mixture
was stirred for 1 h at rt, washed with water and brine, and
dried over anhydrous MgSO4. After evaporation, the result-
ing residue was recrystallized from CH2Cl2–Et2O to afford
26a as colorless needles (12.7 g, 91%), mp 119–121 ꢁC. IR
(KBr) cmꢀ1: 1745, 1720, 1615, 1580, 1500, 1480, 1430,
1400, 1380, 1335, 1230, 1120, 1090, 1050, 1000, 940, 870,
760. 1H NMR (500 MHz, CDCl3) d: 3.91 (3H, s, ArOCH3),
3.93 (3H, s, ArOCH3), 3.95 (3H, s, COOCH3), 6.10 (2H, s,
OCH2O), 7.49 (1H, s, 1,3-benzodioxole-7-H), 7.52 (1H, d,
J¼1.5 Hz, phenol-4-H), 7.55 (1H, d, J¼1.5 Hz, phenol-6-
H), 7.65 (1H, s, 1,3-benzodioxol-4-H). 13C NMR
(125 MHz, CDCl3) d: 52.25, 56.22, 60.96, 86.21, 102.59,
111.41, 111.57, 117.09, 121.28, 125.06, 125.80, 143.41,
145.27, 148.20, 151.73, 153.20, 163.24, 165.97. Anal Calcd
for C18H15IO8: C, 44.46; H, 3.11. Found: C, 44.43; H, 3.36.
1
1430, 1370, 1330, 1255, 1235, 1120, 1010, 840, 780. H
NMR (200 MHz, CDCl3) d: 0.08 (6H, s, Si(CH3)2), 0.93
(9H, s, SiC(CH3)3), 3.86 (3H, s, ArOCH3), 3.87 (3H, s,
ArOCH3), 4.64 (2H, s, ArCH2OTBS), 5.14 (2H, s,
ArOCH2Ph), 6.58 (1H, s, Ar-2 or 6-H), 6.59 (1H, s, Ar-2
or 6-H), 7.30–7.48 (5H, m, C6H5). 13C NMR (50 MHz,
CDCl3) d: ꢀ5.32, 18.32, 25.88, 55.93, 60.83, 64.77, 70.86,
103.06, 104.88, 127.11, 127.71, 128.45, 136.98, 137.20,
137.33, 152.23, 153.23. Anal. Calcd for C22H32O4Si: C,
68.00; H, 8.30. Found: C, 68.02; H, 8.27.
4.4.6. Methyl 3-hydroxy-4,5-dimethoxybenzoate (25a).19
A mixture of 23a (10.2 g, 33.7 mmol) and 10% Pd–C
(108 mg) in MeOH (100 mL) was stirred under an H2 atmo-
sphere for 24 h at rt. Pd–C was filtered off and the filtrate was
evaporated. The resulting residue was recrystallized from
AcOEt to afford 25a as colorless prisms (6.00 g, 83%), mp
72–74 ꢁC [lit.19 72.5–73 ꢁC (AcOEt–hexane)]. IR (KBr)
cmꢀ1: 3405, 1710, 1600, 1505, 1435, 1360, 1275, 1200,
1165, 1115, 1010. 1H NMR (60 MHz, CDCl3) d: 3.89 (3H,
s, ArOCH3), 3.91 (3H, s, ArOCH3), 3.96 (3H, s, COOCH3),
5.89 (1H, s, OH), 7.20 (1H, d, J¼1.8 Hz, Ar-2-H), 7.32 (1H,
d, J¼1.8 Hz, Ar-6-H).
4.4.10. 2,3-Dimethoxy-5-methoxymethoxymethylphenyl
6-iodo-1,3-benzodioxole-5-carboxylate (26b). To a solu-
tion of 6 (8.67 g, 29.7 mmol) and 25b (4.52 g, 19.8 mmol)
in CH2Cl2 (200 mL), EDC (6.83 g, 35.6 mmol) and
DMAP (435 mg, 3.56 mmol) were successively added.
The mixture was stirred for 2 h at rt, washed with water
and brine, and dried over anhydrous MgSO4. After evapora-
tion, the resulting oil was subjected to silica gel column
chromatography with ether–chloroform (1:20) to give a yel-
low solid (9.75 g), and it was recrystallized from CH2Cl2–
Et2O–n-hexane to afford 26b as colorless prisms (8.33 g,
84%), mp 82–85 ꢁC. IR (KBr) cmꢀ1: 1740, 1500, 1480,
1380, 1350, 1325, 1240, 1220, 1130, 1090, 1045, 1005,
920. 1H NMR (200 MHz, CDCl3) d: 3.42 (3H, s,
OCH2OCH3), 3.85 (3H, s, ArOCH3), 3.91 (3H, s, ArOCH3),
4.56 (2H, s, OCH2Ar), 4.71 (2H, s, OCH2OCH3), 6.09 (2H,
s, ArOCH2OAr), 6.81 (1H, d, J¼2.0 Hz, phenol-4-H), 6.86
(1H, d, J¼2.0 Hz, phenol-6-H), 7.49 (1H, s, 1,3-benzodiox-
ole-7-H), 7.65 (1H, s, 1,3-benzodioxole-4-H). 13C NMR
(50 MHz, CDCl3) d: 55.36, 56.04, 60.83, 68.50, 85.98,
95.58, 102.52, 109.59, 111.51, 114.30, 121.15, 126.13,
133.51, 140.40, 143.77, 148.13, 151.55, 153.56, 163.39.
Anal. Calcd for C19H19IO8: C, 45.44; H, 3.81. Found: C,
45.13; H, 3.84.
4.4.7. 2,3-Dimethoxy-5-methoxymethoxymethylphenol
(25b). The mixture of 23b (35.1 g, 0.110 mol) and 5% Pd–
C (1.76 g) in MeOH (350 mL) was stirred under an H2 atmo-
sphere for 32 h at rt. Pd–C was filtered off and the filtrate was
evaporated to give 25b as a pale brown oil (26.8 g, quant). IR
(neat) cmꢀ1: 3260, 2940, 1600, 1510, 1460, 1430, 1380,
1350, 1235, 1200, 1145, 1100, 1045, 1000, 920, 825, 780,
700. 1H NMR (200 MHz, CDCl3) d: 3.42 (3H, s,
OCH2OCH3), 3.87 (3H, s, ArOCH3), 3.88 (3H, s, ArOCH3),
4.49 (2H, s, ArCH2O), 4.70 (2H, s, OCH2O), 5.79 (1H, s,
OH, exchangeable with D2O), 6.49 (1H, d, J¼1.8 Hz, Ar-4
or 6-H), 6.60 (1H, d, J¼1.8 Hz, Ar-4 or 6-H). 13C NMR
(50 MHz, CDCl3) d: 55.30, 55.75, 60.82, 69.00, 95.49,
103.55, 107.72, 133.90, 134.96, 149.22, 152.37. FABMS
(positive ion mode) m/z: 228 [M]+. HRMS (FAB) Calcd
for C11H16O5 [M]+: 228.0998. Found: 228.0969.
4.4.8. 5-tert-Butyldimethylsiloxymethyl-2,3-dimethoxy-
phenol (25c). The mixture of 23c (38.9 mg, 0.100 mmol)
and 5% Pd–C (1.3 mg) in AcOEt (1 mL) was stirred under
an H2 atmosphere for 10 h at rt. Pd–C was filtered off, and
the filtrate was evaporated. The resulting oil was subjected
to silica gel column chromatography with AcOEt–n-hexane
(1:3) to produce 25c (25.1 mg, 84%) as a pale yellow oil. IR
(neat) cmꢀ1: 3440, 2940, 1600, 1510, 1460, 1435, 1380,
4.4.11. 5-tert-Butyldimethylsiloxymethyl-2,3-dimethoxy-
phenyl 6-iodo-1,3-benzodioxole-5-carboxylate (26c). To
a solution of 6 (117 mg, 0.401 mmol) and 25c (101 mg,
0.338 mmol) in CH2Cl2 (3 mL), EDC (96.3 mg,
0.502 mmol) and DMAP (6.1 mg, 0.0499 mmol) were suc-
cessively added. The mixture was stirred for 2 h at rt, washed
with water and brine, and dried over anhydrous MgSO4. After
evaporation, the resulting residue was subjected to silica gel
column chromatography with ether–chloroform (1:100) to
produce 26c (194 mg, 100%). Colorless prisms, mp 70–
74 ꢁC (n-hexane). IR (KBr) cmꢀ1: 1730, 1600, 1470, 1360,
1
1350, 1260, 1200, 1140, 1100, 1000, 940, 840, 780. H
NMR (200 MHz, CDCl3) d: 0.10 (6H, s, Si(CH3)2), 0.95
(9H, s, SiC(CH3)3), 3.86 (3H, s, ArOCH3), 3.88 (3H, s, Ar-
OCH3), 4.64 (2H, s, ArCH2O), 5.76 (1H, s, OH, exchange-
able with D2O), 6.50 (1H, d, J¼1.6 Hz, Ar-4 or 6-H), 6.55
(1H, d, J¼1.8 Hz, Ar-4 or 6-H). 13C NMR (125 MHz,
CDCl3) d: ꢀ5.33, 18.34, 25.88, 55.66, 60.86, 64.68,

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
405
1
1320, 1250, 1140, 1035, 1005, 860, 840, 780. H NMR
(200 MHz, CDCl3) d: 0.11 (6H, s, Si(CH3)2), 0.95 (9H, s,
SiC(CH3)3), 3.84 (3H, s, ArOCH3), 3.89 (3H, s, ArOCH3),
4.70 (2H, s, ArCH2OTBS), 6.09 (2H, s, ArOCH2OAr), 6.73
(1H, d, J¼2.0 Hz, phenol-4-H), 6.87 (1H, d, J¼2.0 Hz, phe-
nol-6-H), 7.48 (1H, s, 1,3-benzodioxole-7-H), 7.64 (1H, s,
1,3-benzodioxole-4-H). 13C NMR (125 MHz, CDCl3) d:
ꢀ5.29, 18.35, 25.89, 55.96, 60.87, 64.29, 85.93, 102.51,
107.86, 111.55, 112.23, 121.15, 126.38, 137.20, 139.63,
143.73, 148.16, 151.52, 153.45, 163.58. Anal. Calcd for
C23H29IO7Si: C, 48.26; H, 5.11. Found: C, 47.98; H, 4.94.
s, ArOCH2OAr), 7.00 (1H, s, Ar-2-H), 7.81 (1H, s, Ar-11-
H), 7.89 (1H, s, Ar-7-H). 13C NMR (125 MHz, CDCl3) d:
56.04, 56.16, 61.36, 68.95, 95.66, 102.34, 105.44, 108.47,
112.53, 112.75, 115.56, 128.53, 132.09, 136.51, 145.82,
147.45, 152.03, 153.67, 160.10. Anal. Calcd for C19H18O8:
C, 60.96; H, 4.85. Found: C, 60.83; H, 4.84.
4.6.2. 2,3-Dimethoxy-5-methoxymethoxymethylphenyl
1,3-benzodioxole-5-carboxylate (28b). Colorless oil. 1H
NMR (200 MHz, CDCl3) d: 3.42 (3H, s, OCH2OCH3),
3.81 (3H, s, ArOCH3), 3.90 (3H, s, ArOCH3), 4.55 (2H, s,
ArCH2O), 4.71 (2H, s, OCH2OCH3), 6.08 (2H, s, ArO-
CH2OAr), 6.79 (1H, d, J¼1.8 Hz, phenol-4-H), 6.86 (1H,
d, J¼1.8 Hz, phenol-6-H), 6.91 (1H, d, J¼8.2 Hz, 1,3-ben-
zodioxole-7-H), 7.62 (1H, d, J¼1.8 Hz, 1,3-benzodioxole-
4-H), 7.83 (1H, dd, J¼8.2, 1.8 Hz, 1,3-benzodioxole-6-H).
4.5. Pd-catalyzed aryl–aryl coupling reaction of 26a
(Table 4, run 2)
The mixture of 26a (100 mg, 0.206 mmol), DPPP
(84.8 mg, 0.206 mmol), nBu3P (51.5 mL, 0.207 mmol),
iPr2NEt (71.8 mL, 0.412 mmol), and Pd(OAc)2 (46.3 mg,
0.206 mmol) in DMF (3 mL) was stirred for 3 h at
130 ꢁC under argon atmosphere. After cooling, the mixture
was diluted with ether and filtered. The filtrate was washed
with water and brine, dried over anhydrous MgSO4, and
the solvent was evaporated. The resulting residue was sub-
jected to silica gel column chromatography with AcOEt–n-
hexane (1:5) to give 28a (29.5 mg, 40%) and alcohol 25a
(8.4 mg, 19%).
4.7. Pd-catalyzed aryl–aryl coupling reaction of 26c
(Table 4, run 10)
n
The mixture of 26c (100 mg, 0.175 mmol), Bu3P (8.7 mL,
0.0349 mmol), K2CO3 (24.2 mg, 0.175 mmol), and
Pd(OAc)2 (3.9 mg, 0.0173 mmol) in DMA (3 mL) was re-
fluxed for 10 min under argon atmosphere. After cooling,
the mixture was diluted with ether and filtered. The filtrate
was washed with water and brine, dried over anhydrous
MgSO4, and the solvent was evaporated. The resulting resi-
due was subjected to silica gel column chromatography with
ether–chloroform (1:50) to give a pale yellow solid
(68.7 mg), and it was recrystallized from CHCl3–n-hexane
to afford 27c as colorless prisms (49.3 mg, 63%).
4.5.1. 2,3-Dimethoxy-5-methoxycarbonylphenyl 1,3-ben-
zodioxole-5-carboxylate (28a). Colorless prisms, mp 109–
111 ꢁC (CH2Cl2–Et2O). IR (KBr) cmꢀ1: 1720, 1605, 1505,
1450, 1340, 1260, 1230, 1155, 1120, 1090, 1040, 1000,
755. 1H NMR (500 MHz, CDCl3) d: 3.89 (3H, s, ArOCH3),
3.90 (3H, s, ArOCH3), 3.95 (3H, s, COOCH3), 6.09 (2H, s,
OCH2O), 6.91 (1H, d, J¼8.0 Hz, 1,3-benzodioxole-7-H),
7.51 (1H, d, J¼2.0 Hz, phenol-4-H), 7.54 (1H, d,
J¼2.0 Hz, phenol-6-H), 7.62 (1H, d, J¼2.0 Hz, 1,3-benzo-
dioxole-4-H), 7.83 (1H, dd, J¼8.0, 2.0 Hz, 1,3-benzodiox-
ole-6-H). 13C NMR (50 MHz, CDCl3) d: 52.19, 56.19,
60.84, 101.95, 108.13, 109.94, 111.15, 117.27, 122.74,
125.03, 126.34, 143.71, 145.37, 147.86, 152.27, 153.19,
163.98, 165.98. Anal. Calcd for C18H16O8: C, 60.00; H,
4.48. Found: C, 60.03; H, 4.58.
4.7.1. 1-tert-Butyldimethylsilyloxymethyl-3,4-dimeth-
oxy-8,9-methylenedioxybenzo[c]chromen-6-one (27c).
Colorless prisms, mp 142–143 ꢁC (CHCl3–n-hexane). IR
(KBr) cmꢀ1: 2960, 1740, 1500, 1480, 1380, 1240, 1220,
1
1120, 1090, 1060, 1040, 840. H NMR (200 MHz, CDCl3)
d: 0.18 (6H, s, Si(CH3)2), 0.96 (9H, s, SiC(CH3)3),
3.97 (3H, s, ArOCH3), 4.00 (3H, s, ArOCH3), 4.97 (2H, s,
ArCH2OTBS), 6.15 (2H, s, ArOCH2OAr), 7.03 (1H, s,
Ar-2-H), 7.81 (1H, s, Ar-11-H), 7.91 (1H, s, Ar-7-H). 13C
NMR (125 MHz, CDCl3) d: ꢀ5.06, 18.19, 25.76, 56.09,
61.40, 65.26, 102.31, 105.82, 108.52, 110.71, 112.25,
115.54, 132.30, 132.42, 136.09, 145.83, 147.38, 152.12,
153.75, 160.28. Anal. Calcd for C23H28O7Si: C, 62.14; H,
6.35. Found: C, 61.92; H, 6.19.
4.6. Pd-catalyzed aryl–aryl coupling reaction of 26b
(Table 4, run 7)
The mixture of 26b (181 mg, 0.360 mmol), K2CO3 (49.8 mg,
0.360 mmol), and Pd(OAc)2 (24.2 mg, 0.108 mmol) in DMA
(5 mL) was stirred for 30 min at 130 ꢁC under argon atmo-
sphere. After cooling, the mixture was diluted with AcOEt
and filtered. The filtrate was washed with water and brine,
dried over anhydrous MgSO4, and the solvent was evapo-
rated. The resulting residue was subjected to silica gel col-
umn chromatography with AcOEt–n-hexane (1:1) and then
ether–chloroform (1:10) to produce 27b (104 mg, 77%).
4.8. Asymmetric lactone-opening reaction of 27b (Table
5, run 1)
To the solution of (S)-5,5-diphenyl-2-methyl-3,4-propano-
1,3,2-oxazaborolidine (29, 111 mg, 0.400 mmol) in THF
(2 mL), 1.15 M BH3$THF solution (0.465 mL, 0.535 mmol)
was added dropwise at ꢀ78 ꢁC under an argon atmosphere.
After stirring for 5 min, the solution of 27b (50 mg,
0.134 mmol) in THF (1 mL) was added dropwise, and the
mixture was allowed to warm to 0 ꢁC. After stirring for 8 h,
the resulting mixture was quenched with water and extracted
with ether. The organic layer was washed with brine, dried
over anhydrous MgSO4, and the solvent was evaporated.
The resulting oil was subjected to silica gel column chroma-
tography with AcOEt–n-hexane (1:2) to give 30b as a color-
less solid (30.0 mg, 59%, 86% ee) and 31b (7.6 mg, 16%).
4.6.1. 3,4-Dimethoxy-1-methoxymethoxymethyl-8,9-
methylenedioxybenzo[c]chromen-6-one (27b). Colorlꢀes1s
prisms, mp 161–163 ꢁC (CH2Cl2–Et2O). IR (KBr) cm
:
2940, 1730, 1600, 1485, 1325, 1260, 1140, 1040, 1000,
930. 1H NMR (200 MHz, CDCl3) d: 3.52 (3H, s,
OCH2OCH3), 3.98 (3H, s, ArOCH3), 4.00 (3H, s, ArOCH3),
4.85 (2H, s, ArCH2O), 4.90 (2H, s, OCH2OCH3), 6.16 (2H,

406
S. Takeda et al. / Tetrahedron 63 (2007) 396–408
4.8.1. (L)-2-Hydroxy-20-hydroxymethyl-3,4-dimethoxy-
6-methoxymethoxymethyl-40,50-methylenedioxy-1,10-bi-
phenyl (30b). [a]2D4 ꢀ5.8 (c 0.432, CHCl3) [91.0% ee]. Mp
101–101.5 ꢁC (CHCl3–hexane). IR (KBr) cmꢀ1: 3490, 3150
(OH), 2900, 1610, 1485, 1460, 1230, 1140, 1110, 1050, 990,
925, 880. 1H NMR (200 MHZ, CDCl3) d: 2.78 (1H, br, OH,
exchangeable with D2O), 3.22 (3H, s, OCH2OCH3), 3.93
(3H, s, ArOCH3), 3.94 (3H, s, ArOCH3), 4.22 (1H, d,
J¼7.0 Hz, ArCHHOCH2), 4.23 (2H, s, ArCH2OH), 4.27
(1H, d, J¼7.0 Hz, ArCHHOCH2), 4.49 (1H, d, J¼6.8 Hz,
OCHHOCH3), 4.49 (1H, d, J¼6.8 Hz, OCHHOCH3), 5.84
(1H, s, OH, exchangeable with D2O), 5.99 (1H, d,
J¼1.4 Hz, ArOCHHOAr), 6.02 (1H, d, J¼1.4 Hz, ArOCH-
HOAr), 6.61 (1H, s, Ar-60-H), 6.65 (1H, s, Ar-5-H), 7.04
(1H, s, Ar-30-H). 13C NMR (50 MHz, CDCl3) d: 55.27,
55.78, 60.91, 63.12, 67.38, 95.78, 101.14, 105.05, 109.62,
110.26, 119.81, 127.36, 131.90, 134.18, 135.06, 146.76,
147.07, 147.48, 151.58. Anal. Calcd for C19H22O8: C,
60.31; H, 5.86. Found: C, 60.12; H, 5.83. HPLC condition:
column, CHIRALCEL OD; solvent, IPA/n-hexane¼1:9;
flow rate, 1.0 mL/min; wavelength, 254 nm; retention
time, 45.8 min [(+)-30b, 36.0 min].
(125 MHz, CDCl3) d: ꢀ5.46, ꢀ5.44, 18.30, 25.85, 55.68,
60.95, 62.96, 63.37, 101.14, 103.50, 109.63, 110.32,
118.02, 127.34, 133.91, 134.44, 135.27, 146.35, 147.19,
147.50, 151.58. Anal. Calcd for C23H32O7Si: C, 61.58; H,
7.19. Found: C, 61.50; H, 7.02. HPLC condition: column,
CHIRALCEL OD; solvent, IPA/n-hexane¼1:7; flow rate,
1.0 mL/min; wavelength, 254 nm; retention time, 15.8 min
[(S)-30c, 11.6 min].
4.9.2. 1-tert-Butyldimethylsilyloxymethyl-3,4-dimeth-
oxy-8,9-methylenedioxy-6H-benzo[c]chromen (31c). IR
(KBr) cmꢀ1: 2920, 1600, 1480, 1325, 1240, 1140, 1120,
1
1040, 990, 835, 780. H NMR (300 MHz, CDCl3) d: 0.17
(6H, s, Si(CH3)2), 0.98 (9H, s, SiC(CH3)3), 3.89 (3H, s,
ArOCH3), 3.92 (3H, s, ArOCH3), 4.83 (2H, s, ArCH2O),
4.87 (2H, s, ArCH2O), 6.00 (2H, s, OCH2O), 6.73 (1H, s,
Ar-H), 6.80 (1H, s, Ar-H), 7.38 (1H, s, Ar-H).
4.9.3. (R)-6-tert-Butyldimethylsiloxymethyl-20-hydroxy-
methyl-2,3,4-trimethoxy-40,50-methylenedioxy-1,10-bi-
phenyl. To a solution of 30c (200 mg, 0.446 mmol, 83% ee)
t
in THF (3 mL), BuOK (55.0 mg, 0.491 mmol) and MeI
(30.0 mL, 0.490 mmol) were successively added. The mix-
ture was stirred for 48 h at rt, poured into ice-water, and neu-
tralized with 10% HCl solution. After extraction with ether,
the organic layer was washed with brine, dried over anhy-
drous MgSO4, and the solvent was evaporated. The resulting
oil was subjected to silica gel column chromatography with
AcOEt–n-hexane (1:2) to give the title compound (181 mg,
88%, 83% ee), and the starting material 31c (23.2 mg, 12%,
86% ee) was recovered. [a]2D1 +19.4 (c 3.792, CHCl3) [83%
ee]. IR (KBr) cmꢀ1: 3520, 2960, 1480, 1400, 1320, 1230,
4.8.2. 3,4-Dimethoxy-1-methoxymethoxymethyl-8,9-
methylenedioxy-6H-benzo[c]chromen (31b). Colorless
prisms, mp 120–123 ꢁC (CH2Cl2). 1H NMR (300 MHz,
CDCl3) d: 3.51 (3H, s, OCH2OCH3), 3.88 (3H, s, ArOCH3),
3.92 (3H, s, ArOCH3), 4.72 (2H, s, ArCH2O), 4.84
(2H, s, ArCH2O), 4.87 (2H, s, OCH2OCH3), 5.99 (2H, s,
ArOCH2OAr), 6.73 (1H, s, Ar-H), 6.75 (1H, s, Ar-H), 7.40
(1H, s, Ar-H).
1
4.9. Asymmetric lactone-opening reaction of 27c (Table
5, run 4)
1140, 1105, 1040, 1005, 850. H NMR (200 MHz, CDCl3)
d: 0.00 (3H, s, SiCH3), 0.02 (3H, s, SiCH3), 0.89 (9H, s,
SiC(CH3)3), 2.92 (1H, br, OH, exchangeable with D2O),
3.60 (3H, s, Ar-2-OCH3), 3.90 (3H, s, ArOCH3), 3.93 (3H,
s, ArOCH3), 4.16 (2H, br s, ArCH2OH), 4.23 (1H, d,
J¼13.0 Hz, ArCHHOTBS), 4.38 (1H, d, J¼13.0 Hz, ArCH-
HOTBS), 6.02 (1H, d, J¼1.4 Hz, ArOCHHOAr), 6.04 (1H,
d, J¼1.4 Hz, ArOCHHOAr), 6.61 (1H, s, Ar-60-H), 6.95
(1H, s, Ar-5-H), 7.03 (1H, s, Ar-30-H). 13C NMR
(125 MHz, CDCl3) d: ꢀ5.48, ꢀ5.46, 18.26, 25.81, 55.80,
60.99, 61.17, 62.78, 63.54, 101.12, 106.99, 109.84,
109.99, 124.93, 127.95, 133.68, 135.06, 140.97, 146.89,
147.28, 150.55, 152.87. Anal. Calcd for C24H34O7Si: C,
62.31; H, 7.41. Found: C, 62.18; H, 7.07. HPLC condition:
column, CHIRALCEL OD; solvent, IPA/n-hexane¼1:15;
flow rate, 1.0 mL/min; wavelength, 254 nm; retention
time, 9.8 min [(S)-36, 7.4 min].
To a solution of (S)-5,5-diphenyl-2-methyl-3,4-propano-
1,3,2-oxazaborolidine (29, 402 mg, 1.45 mmol) in THF
(5 mL), 1.15 M BH3$THF solution (1.69 mL, 1.94 mmol)
was added dropwise at ꢀ78 ꢁC under an argon atmosphere.
After stirring for 5 min, the solution of 27c (215 mg,
0.484 mmol) in THF (2 mL) was added dropwise, and the
mixture was allowed to warm to ꢀ40 ꢁC. After stirring for
17 h, the resulting mixture was quenched with water and ex-
tracted with ether. The organic layer was washed with brine,
dried over anhydrous MgSO4, and the solvent was evapo-
rated. The resulting oil was subjected to silica gel column
chromatography with AcOEt–n-hexane (1:2) to give 30c
as a colorless solid (210 mg, 97%, 83% ee).
4.9.1. (R)-(L)-6-tert-Butyldimethylsiloxymethyl-2-hy-
droxy-20-hydroxymethyl-3,4-dimethoxy-40,50-methylene-
dioxy-1,10-biphenyl (30c). [a]D21 ꢀ10.5 (c 0.732, CHCl3)
[83% ee]. Mp 140–141 ꢁC (CHCl3–hexane). IR (KBr)
cmꢀ1: 3460, 3120, 2950, 1615, 1580, 1480, 1375, 1340,
4.9.4. (R)-6-tert-Butyldimethylsiloxymethyl-20-formyl-
2,3,4-trimethoxy-40,50-methylenedioxy-1,10-biphenyl
(32). The starting alcohol (181 mg, 0.391 mmol) in CH2Cl2
(1.5 mL) was added to a solution of PDC (294 mg,
0.781 mmol) in CH2Cl2 (1.5 mL) at 0 ꢁC, and the mixture
was stirred for 12 h at rt. The mixture was filtered with Cel-
ite, and the filtrate was washed with water and brine, dried
over anhydrous MgSO4, and the solvent was evaporated.
The resulting oil was subjected to silica gel column chroma-
tography with AcOEt–n-hexane (1:3) to give 32 (138 mg,
77%). [a]2D1 ꢀ1.2 (c 2.080, CHCl3). IR (KBr) cmꢀ1: 2920,
1680, 1610, 1480, 1400, 1325, 1270, 1240, 1140, 995,
1
1225, 1140, 1040, 990, 840. H NMR (200 MHZ, CDCl3)
d: 0.01 (6H, s, Si(CH3)2), 0.88 (9H, s, SiC(CH3)3), 2.52
(1H, br, OH, exchangeable with D2O), 3.92 (3H, s, Ar-
OCH3), 3.93 (3H, s, ArOCH3), 4.23 (2H, br s, ArCH2OH),
4.28 (1H, d, J¼13.0 Hz, ArCHHOTBS), 4.35 (1H, d,
J¼13.0 Hz, ArCHHOTBS), 5.83 (1H, s, OH, exchangeable
with D2O), 5.99 (1H, d, J¼1.4 Hz, ArOCHHOAr), 6.03
(1H, d, J¼1.4 Hz, ArOCHHOAr), 6.60 (1H, s, Ar-60-H),
6.73 (1H, s, Ar-5-H), 7.04 (1H, s, Ar-30-H). 13C NMR
1
850, 780. H NMR (500 MHz, CDCl3) d: ꢀ0.03 (3H, s,

S. Takeda et al. / Tetrahedron 63 (2007) 396–408
407
SiCH3), ꢀ0.02 (3H, s, SiCH3), 0.88 (9H, s, SiC(CH3)3), 3.62
(3H, s, Ar-2-OCH3), 3.88 (3H, s, ArOCH3), 3.92 (3H, s,
ArOCH3), 4.25 (1H, d, J¼13.0 Hz, ArCHHOTBS), 4.34
(1H, d, J¼13.0 Hz, ArCHHOTBS), 6.10 (1H, d, J¼1.5 Hz,
ArOCHHOAr), 6.12 (1H, d, J¼1.5 Hz, ArOCHHOAr),
6.68 (1H, s, Ar-60-H), 6.96 (1H, s, Ar-5-H), 7.46 (1H, s,
Ar-30-H), 9.50 (1H, s, CHO). 13C NMR (50 MHz, CDCl3)
d: ꢀ5.47, 18.23, 25.80, 55.86, 60.77, 60.88, 62.78, 102.03,
105.89, 106.23, 110.77, 121.59, 129.48, 135.37, 137.02,
140.73, 147.88, 151.18, 152.21, 153.56, 190.29. Anal. Calcd
for C24H32O7Si: C, 62.58; H, 7.00. Found: C, 62.60; H, 6.68.
[a]2D5 +2.3 (c 1.18, CHCl3)]. IR (KBr) cmꢀ1: 2930, 1600,
1480, 1400, 1235, 1140, 1040, 1000, 940, 840. H NMR
1
(300 MHz, CDCl3) d: 0.01 (3H, s, SiCH3), 0.04 (3H, s,
SiCH3), 0.92 (9H, s, SiC(CH3)3), 1.14 (3H, d, J¼6.3 Hz,
CH(OAllyl)CH3), 3.60 (3H, s, Ar-2-OCH3), 3.75–3.81
(1H, m, OCHHCH]CH2), 3.88 (3H, s, ArOCH3), 3.85–
3.93 (1H, m, OCHHCH]CH2), 3.92 (3H, s, ArOCH3),
4.14 (1H, d, J¼13.5 Hz, ArCHHOTBS), 4.15 (1H, q,
J¼6.3 Hz, CH(OAllyl)CH3), 4.37 (1H, d, J¼13.5 Hz,
ArCHHOTBS), 5.08 (1H, ddd, J¼8.7, 3.0, 2.5 Hz,
OCH2CH]CHH), 5.23 (1H, ddd, J¼15.6, 3.0, 2.5 Hz,
OCH2CH]CHH), 5.80–5.95 (1H, m), 6.01 (2H, s,
OCH2O), 6.52 (1H, s, Ar-H), 6.98 (1H, s, Ar-H), 7.10 (1H,
s, Ar-H). HPLC condition: column, CHIRALCEL AD; sol-
vent, IPA/n-hexane¼1:400; flow rate, 0.2 mL/min; wave-
length, 254 nm; retention time, 38.0 min [(ꢀ)-33, 32.3 min].
4.9.5. (D)-6-tert-Butyldimethylsiloxymethyl-20-(1-hy-
droxyethyl)-2,3,4-trimethoxy-40,50-methylenedioxy-1,10-
biphenyl. To a solution of 32 (135 mg, 0.293 mmol) in THF
(2 mL), 2.2 mol/L MeLi in Et2O solution (187 mL,
0.411 mmol) was added dropwise at ꢀ78 ꢁC under an argon
atmosphere. After stirring for 30 min, the resulting mixture
was quenched with saturated aqueous NH4Cl solution and
extracted with ether. The organic layer was washed with
brine, dried over anhydrous MgSO4, and the solvent was
evaporated. The resulting oil was subjected to silica gel col-
umn chromatography with Et2O–n-hexane (1:1) to give the
title compound (76.5 mg, 55%, 79% ee). [a]2D1 +33.9 (c
1.342, CHCl3) [79% ee]. IR (KBr) cmꢀ1: 3390, 2940,
1480, 1235, 1140, 1110, 1085, 1040, 840. 1H NMR
(300 MHz, CDCl3) d: 0.01 (3H, s, SiCH3), 0.03 (3H, s,
SiCH3), 0.92 (9H, s, SiC(CH3)3), 1.33 (3H, d, J¼6.3 Hz,
CH(OH)CH3), 3.56 (3H, s, Ar-2-OCH3), 3.90 (3H, s,
ArOCH3), 3.92 (3H, s, ArOCH3), 4.16 (1H, d, J¼13.5 Hz,
ArCHHOTBS), 4.43 (1H, q, J¼6.3 Hz, CH(OH)CH3),
4.45 (1H, d, J¼13.5 Hz, ArCHHOTBS), 6.01 (1H, d,
J¼2.0 Hz, OCHHO), 6.02 (1H, d, J¼2.0 Hz, OCHHO),
6.55 (1H, s, Ar-H), 7.02 (1H, s, Ar-H), 7.11 (1H, s, Ar-H).
13C NMR (75 MHz, CDCl3) d: ꢀ5.31, ꢀ5.27, 18.36,
21.97, 25.91, 55.81, 61.10, 61.24, 62.61, 66.29, 101.05,
105.77, 106.21, 109.64, 124.32, 126.73, 135.26, 137.65,
140.57, 146.40, 147.48, 150.13, 152.70. FABMS (positive
ion mode) m/z: 476 [M]+, 475 [Mꢀ1]+. Anal. Calcd for
C25H36O7Si: C, 63.00; H, 7.61. Found: C, 63.18; H, 7.54.
HPLC condition: column, CHIRALCEL OD; solvent, IPA/
n-hexane¼1:31; flow rate, 1.0 mL/min; wavelength,
254 nm; retention time, 16.5 min [(ꢀ)-form, 13.7 min].
Acknowledgements
A part of this work was supported by the Japan Society for
the Promotion of Science to H.A. (grant no. 18590005).
We also thank the SC-NMR Laboratory of Okayama Univer-
sity for the NMR experiments.
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