Synthesis of highly oxygenated biphenyl derivative in an optically active form through palladium-mediated intramolecular biaryl coupling reaction

Article abstract of DOI:10.3987/COM-08-S(N)8

Optically active 6,6'-dihydroxymethyl-2,2'-3,3'-4,4'-hexamethoxybiphenyl (1) was prepared via the Pd-mediated biaryl coupling reaction of a phenyl benzoate derivative and the following enantioselective lactone opening reaction. The Japan Institute of Hete

Full text of DOI:10.3987/COM-08-S(N)8

HETEROCYCLES, Vol. 76, No. 1, 2008
291
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 291 - 303. © The Japan Institute of Heterocyclic Chemistry
Received, 4th January, 2008, Accepted, 28th February, 2008, Published online, 29th February, 2008. COM-08-S(N)8
SYNTHESIS OF HIGHLY OXYGENATED BIPHENYL DERIVATIVE IN
AN OPTICALLY ACTIVE FORM THROUGH PALLADIUM-MEDIATED
INTRAMOLECULAR BIARYL COUPLING REACTION
Hitoshi Abe,a,* Masatsugu Arai,b Keisuke Nishioka,b Tatsuya Kida,b
Kazuma Shioe,b Yasuo Takeuchi,b and Takashi Harayamac,*
a) Advanced Science Research Center, Okayama University, Okayama
700-8530, Japan, b) Graduate School of Medicine, Dentistry, and
Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan, c)
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri
University, Sanuki-shi, Kagawa 769-2193, Japan
abe@pharm.okayama-u.ac.jp; harayama@kph.bunri-u.ac.jp
Abstract – Optically active 6,6’-dihydroxymethyl-2,2’-3,3’-4,4’-hexamethoxy-
biphenyl (1) was prepared via the Pd-mediated biaryl coupling reaction of a
phenyl benzoate derivative and the following enantioselective lactone opening
reaction.
INTRODUCTION
Biaryl compounds with an axial chirality exhibit interesting and important properties in various fields of
chemistry.1 Many kinds of optically active biaryl compounds have been developed as chiral ligands2 or
Brφnsted acid,3 and have demonstrated that they are practically efficient for a variety of catalytic
asymmetric reactions.4
The chiral biaryl structure is also found in several classes of natural products such as lignans, alkaloids,
etc.5 Some of them exhibit unique biological activities, therefore, the synthetic investigations have been
considered as important studies.
In this report, we focused on the asymmetric synthesis of 6,6’-dihydroxymethyl-2,2’-3,3’-4,4’-
hexamethoxybiphenyl (1), which is significantly related to the ellagitannin chemistry.6 To our
knowledge, this molecule in a non-racemic form has been prepared only in a diastereoselective manner or
by an optical resolution,7 while no enantioselective preparation of this compound has been reported.
Thus we envisioned that the Bringmann’s “lactone concept” would be effective for the preparation of 1 in

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an optically active form.8,9
The alternative preparation of 1 is also described, which involves an optical resolution using a chiral
alkoxide derived from glucose.
RESULTS AND DISCUSSION
Synthetic Outline
Our synthetic plan for 1 is depicted in Scheme 1. The palladium-mediated biaryl coupling reaction of
phenyl benzoates has been known as a good method for the preparation of dibenzopyranones.10 The
enantioselective reduction of the lactone ring would be expected to generate the biphenyl compound in a
non-racemic form, which can then be transformed into 1.
OMe
OMe
OMe
OMe
OMe
OMe
OMe
MeO
OH
OH
PGO
MeO
MeO
PGO
MeO
PGO
MeO
MeO
MeO
O
O
OH
OH
I
O
O
MeO
MeO
MeO
OMe
OMe
OMe
OMe
1 (optically active)
PG = protecting group
Scheme 1 Synthetic outline for optically active 1
Biaryl coupling reaction of phenyl benzoate
We initially prepared the phenyl benzoate derivatives (2a-2c) as the precursors of the
6H-dibenzo[b,d]pyran-6-ones. A simple condensation reaction using EDC successfully produced the
corresponding esters (2a-2c) from the phenols (3a-3c)11 and benzoic acid (4)7b (Scheme 2).
OMe
OMe
EDC
DMAP
I
RO
OMe
OMe
O
MeO
MeO
CO2H
I
+
MeO
MeO
CH2Cl2
RO
O
OH
OMe
OMe
3a : R = Ac
3b : R = MOM
3c : R = TBS
4
2a : R = Ac (87%)
2b : R = MOM (83%)
2c : R = TBS (82%)
Scheme 2 Preparation of esters 2a-2c
The palladium-mediated coupling reaction of the prepared esters (2a-2c) was examined under various
conditions (Table 1). We first tried 10 mol% Pd(OAc)2 with nBu3P or Ph3P as a ligand at high
temperature (runs 1-3). In these cases, the desired lactone (5a) was obtained in low yields, and an

HETEROCYCLES, Vol. 76, No. 1, 2008
293
unexpected tetracyclic compound 6 was isolated as a by-product. When 25 mol% of the Pd catalysts
were employed at a lower temperature, better results were observed without the generation of 6 (runs 4
and 5). Both changing the base from NaOAc to K2CO3 and changing the ligand from Ph3P to nBu3P
were not effective (runs 6 and 8). When using 10 mol% of Pd(OAc)2, the reactivity was dramatically
reduced (run 7).
Table 1 Pd-mediated biaryl coupling reaction of 2a-2c
MeO
MeO
OMe
OMe
OMe
OMe
Pd, ligand
base
RO
OHC
MeO
O
O
O
O
O
2a-2c
MeO
O
O
DMA
MeO
MeO
MeO
OMe
5a : R = Ac
OMe
OMe
6
7
5b : R = MOM
5c : R = TBS
Pd
[mol%]
ligand
bath temp.
base
product (Yield, %)
run ester
time
[mol%]
(℃)
[mol%]
200
180
170
120
120
120
120
120
120
120
120
120
5a (19)
5a (34)
5a (26)
5a (88)
5a (82)
5a (37)
5a (45)
5a (35)
5b (80)
5b (76)
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
NaOAc [200]
NaOAc [200]
K2CO3 [100]
NaOAc [200]
NaOAc [200]
K2CO3 [100]
NaOAc [200]
NaOAc [200]
NaOAc [200]
NaOAc [200]
NaOAc [200]
NaOAc [200]
15 min
30min
30 min
3 h
6 (6)
nBu3P[20]
Ph3P [20]
Ph3P [20]
---
Pd(OAc)2 [10]
Pd(OAc)2 [10]
Pd(OAc)2 [10]
PdCl2(Ph3P)2 [25]
Pd(OAc)2 [25]
Pd(OAc)2 [25]
Pd(OAc)2 [10]
Pd(OAc)2 [25]
PdCl2(Ph3P)2 [25]
Pd(OAc)2 [25]
PdCl2(Ph3P)2 [25]
Pd(OAc)2 [25]
6 (15)
6 (19)
3
4
3 h
5
Ph3P [50]
Ph3P [50]
Ph3P [20]
nBu3P[50]
---
6
2 h
24 h
8 h
6 (8)
7
8
9
5 h
4 h
10
11
12
Ph3P [50]
---
3 h
7 (25)
7 (18)
5c (62)
3 h
Ph3P [50]
The MOM-protected substrate 2b was also transformed into 5b in good yields using 25 mol% Pd(OAc)2
o
or PdCl2(Ph3P)2 at 120 C. On the other hand, the reaction of the siloxy compound 2c did not give a
satisfactory result; an aldehyde 7 was unexpectedly generated (runs 11-12).
Enantioselective synthesis of optically active 1
Since the key intermediate lactone was successfully obtained, we next examined the further
transformation of the optically active biaryl compound using 5a (Scheme 3). The enantioselective
reduction of 5a was performed with the combination of the chiral oxazaborolidine (S)-8 and borane.12
This reductive lactone-ring opening produced the biphenyl 9 in a high enantioselectivity. The reduction
of the acetoxy group in 9 and the successive methylation of the phenolic hydroxy group in 10 gave (S)-1
with a slight loss of enantiomeric purity.

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HETEROCYCLES, Vol. 76, No. 1, 2008
The absolute configuration of the product was determined by comparison of the sign of the optical
rotation with the reported data.7i, 7h
OMe
OMe
OMe
OMe
OMe
Ph
Ph
O
B
Me
H
N
MeO
MeO
MeO
OH
OH
AcO
MeO
OAc
OH
OH
OH
MeO
MeO
O
HO
MeO
HO
MeO
LiAlH4
THF
MeI, tBuOK
THF
O
(S)-8 (300 mol%)
MeO
MeO
MeO
MeO
BH3 (400 mol%)
THF, -40oC
OMe
OMe
5a
OMe
OMe
(S)-1 (86%, 93% ee)
(96%, 97%ee)
9
10 (98%)
Scheme 3 Transformation of 5a into (S)-1
Lactone ring opening with sugar alkoxide
As an alternative method for the preparation of the optically active 1, we attempted a diastereoselective
manner using a glucose derivative as the chiral auxiliary. The sugar alkoxide, which was easily derived
from glucose, was employed as a nucleophile. Table 1 summarizes the results of the reaction between
5b and the sugar alkoxide which was prepared from 1113 and base. Although several conditions were
investigated, no diastereoselectivity was observed except for the case when using DMF as the solvent
(run 3) in which a slight selectivity was recognized.
Table 2 Lactone ring opening of 5b with sugar alkoxide
MeO
HO
HO
BnO
MeO
O
OMe
OBn
OMOM
O
HO
MeO
11
O
5b
MeO
O
OMe
base, solvent
HO
OMe
BnO
OBn
12
base (eq.)
NaH (1.0)
temp. (℃)
yield (%)
run
1
solvent
THF
d.r. a)
0
-80
0
88
89
94
89
1.0 : 1.0
1.0 : 1.0
1.4 : 1.0
1.0 : 1.0
NaH (1.0)
NaH (1.0)
nBuLi (1.0)
2
THF
3
DMF
0
4
toluene
a) Determined by 1H-NMR: see the experimental section.
The inseparable 1:1 mixture of 12 was methylated to produce the hexamethoxy compounds 13 and 14 by
treatment with dimethyl sulfate (Scheme 4). Fortunately, 13 and 14 could be separated from each other

HETEROCYCLES, Vol. 76, No. 1, 2008
295
by silica gel column chromatography. One diastereomer 13 was transformed into (S)-1 by the reduction
with LiAlH4 and successive hydrolysis. The other isomer 14 was also subjected to the same process and
(R)-1 was produced.
OMe
OMe
MeO
MeO
i) LiAlH, THF
ii) HCl
OH
OH
OMOM
COOR
MeO
MeO
MeO
MeO
1) (MeO)2SO2
K2CO3
MeO
MeO
OMe
OMe
acetone
12
13 (33%)
(S)-1 (88%, 91% ee)
2) separation
OMe
MeO
OMe
i) LiAlH, THF
ii) HCl
MeO
OH
OMOM
COOR
MeO
MeO
MeO
MeO
O
OMe
OBn
OH
R =
MeO
OMe
MeO
HO
OMe
14 (35%)
OBn
(R)-1 (86%, >99% ee)
Scheme 4 Transformation of 12 into (S)- and (R)-1
CONCLUSION
The asymmetric synthesis of 6,6’-dihydroxymethyl-2,2’-3,3’-4,4’-hexamethoxybiphenyl (1) was
demonstrated using the Pd-mediated biaryl coupling reaction of phenyl benzoate followed by the
enantioselective reduction of the lactone ring. Also, (S)- and (R)-1 were separately prepared through the
nucleophilic lactone ring opening reaction using a sugar alkoxide.
EXPERIMENTAL
The melting points were measured using a Yanagimoto micro melting point hot-plate apparatus and are
uncorrected. The IR spectra were recorded using a JASCO FTIR-350 spectrophotometer. The NMR
spectra were taken by a Varian VXR-500 (500 MHz) or MERCURY (300 MHz) instrument. The
chemical shifts are given in δ ppm with TMS as the internal standard. The MS was obtained using a
VG-Autospec instrument. The optical rotations were determined by a Shimadzu SPD-6A polarimeter.
The elemental analysis was performed by a Yanaco MT-5 instrument. The silica gel column
chromatography was carried out using 9385 Kieselgel 60 (Merck). The TLC analysis was performed on
Kieselgel 60 F254 (Merck) plates.
5-Acetoxymethyl-2,3-dimethoxyphenyl 2-iodo-3,4,5-trimethoxybenzoate (2a)
Under an argon atmosphere, a solution of 3a (3.50 g, 15.5 mmol),11a 4 (5.78 g, 17.1 mmol),7b,14 EDC

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(4.92 g, 26.7 mmol), and DMAP (418 mg, 3.42 mmol) in CH2Cl2 (MeOH-free, 100 mL) was stirred for 6
h at rt. The reaction mixture was poured into water and then extracted with CH2Cl2. The organic layer
was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica
gel column chromatography with Et2O-hexane (2:1).
Colorless needles, mp 89-91 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 2.12 (3H, s, OCOCH3), 3.88 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.92 (3H,
s, OCH3), 3.93 (3H, s, OCH3), 3.96 (3H, s, OCH3), 5.06 (2H, s, OCH2Ar), 6.86 (1H, d, J=2.0 Hz), 6.87
(1H, d, J=2.0 Hz), 7.49 (1H, s).
13C-NMR (75 MHz, CDCl3) δ: 21.1, 56.2, 56.4, 60.90, 60.95, 61.1, 65.8, 85.1, 110.5, 111.3, 115.1, 129.2,
131.4, 140.9, 143.7, 145.5, 153.2, 153.5, 154.0, 164.1, 170.6.
IR (KBr) cm-1 : 2940, 1745 (C=O), 1510, 1480, 1430, 1380, 1330, 1230, 1165, 1140, 1100, 1000.
Anal. Calcd for C21H23IO9 : C, 46.17 ; H, 4.24. Found : C, 46.17 ; H, 4.22.
2,3-Dimethoxy-5-methoxymethoxymethylphenyl 2-iodo-3,4,5-trimethoxybenzoate (2b)
Under an argon atmosphere, a solution of 3b (3.80 g, 16.6 mmol),11b 4 (6.19 g, 18.3 mmol),7b,14 EDC
(5.26 g, 27.5 mmol), and DMAP (450 mg, 3.66 mmol) in CH2Cl2 (MeOH-free, 100 mL) was stirred for 6
h at rt. The reaction mixture was poured into water and then extracted with CH2Cl2. The organic layer
was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica
gel column chromatography with Et2O-CHCl3 (1:20).
Pale yellow oil.
1H-NMR (500 MHz, CDCl3) δ: 3.42 (3H, s, CH2OCH3), 3.87 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.91
(3H, s, OCH3), 3.93 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.57 (2H, s, ArCH2O), 4.72 (2H, s, OCH2O),
6.85 (1H, d, J=2.0 Hz, phenol-4 or 6-H), 6.87 (1H, d, J=2.0 Hz, phenoxy-4 or 6-H), 7.49 (1H, s,
benzoyl-6-H).
IR (neat) cm -1 : 1750 (C=O), 1500, 1480, 1460, 1430, 1380, 1340, 1200, 1170, 1140, 1100, 1050, 1000.
FAB-Mass (positive ion mode) m/z : 548 [M]+.
5-tert-Butyldimethylsilyloxymethyl-2,3-dimethoxyphenyl 2-iodo-3,4,5-trimethoxybenzoate (2c)
Under an argon atmosphere, a solution of 3c (550 mg, 1.84 mmol),11b 4 (653 mg, 1.93 mmol),7b,14 EDC
(555 mg, 2.90 mmol), and DMAP (47.2 mg, 0.386 mmol) in CH2Cl2 (MeOH-free, 20 mL) was stirred for
1 h at rt. The reaction mixture was poured into water and then extracted with CH2Cl2. The organic
layer was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to
silica gel column chromatography with AcOEt-CHCl3 (1:4).
Colorless oil.

HETEROCYCLES, Vol. 76, No. 1, 2008
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1H-NMR (300 MHz, CDCl3) δ: 0.12 (6H, s, Si(CH3)2), 0.96 (9H, s, SiC(CH3)3), 3.87 (3H, s, OCH3), 3.90
(3H, s, OCH3), 3.91 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.71 (2H, s, ArCH2O), 6.79
(1H, d, J=1.95 Hz, phenoxy-4 or 6-H), 6.88 (1H, d, J=1.95 Hz, phenoxy-4 or 6-H), 7.48 (1H, s,
benzoyl-6-H).
13C-NMR (75 MHz, CDCl3) δ: -5.14, 18.4, 26.0, 56.0, 56.3, 60.9, 61.1, 64.3, 84.8, 107.8, 111.1, 112.1,
129.6, 137.2, 139.4, 143.6, 145.3, 153.2, 153.3, 153.9, 164.3.
IR (neat) cm -1 : 1750 (C=O), 1500, 1480, 1460, 1430, 1390, 1340, 1200, 1170, 1140, 1100, 1080, 1000.
FAB-Mass (positive ion mode) m/z : 618 [M]+.
HRMS (FAB) calcd for C25H35IO8Si [M]+ : 618.1145. Found : 618.1097.
General procedure for the coupling reaction (Table 1)
A mixture of 2 (0.183 mmol), palladium reagent, ligand, base, and DMA (2 mL) was heated in an oil bath.
After cooling, the solid material was removed by filtration. The filtrate was poured into water and then
extracted with CH2Cl2. The organic layer was washed with brine, dried with MgSO4, and evaporated to
give a residue which was subjected to silica gel column chromatography with AcOEt-hexane.
1-Acetoxymethyl-3,4,8,9,10-pentamethoxy-6H-dibenzo[b,d]pyran-6-one (5a)
Colorless prisms, mp 168-169 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 2.03 (3H, s, OCOCH3), 3.56 (3H, s, OCH3), 3.97 (3H, s, OCH3), 3.99 (3H,
s, OCH3), 4.01 (3H, s, OCH3), 4.08 (3H, s, OCH3), 5.23 (2H, s, ArCH2O), 6.96 (1H, s, 2-H), 7.66 (1H, s,
7-H).
13C-NMR (75 MHz, CDCl3) δ: 21.1, 56.3, 56.4, 61.4, 61.5, 61.6, 65.9, 107.9, 108.9, 109.8, 117.9, 122.8,
129.5, 135.5, 144.2, 148.2, 149.1, 152.7, 153.2, 160.4, 170.5.
IR (KBr) cm-1 : 1740 (C=O), 1730 (C=O), 1600, 1480, 1380, 1350, 1330, 1230, 1100.
FAB-Mass (positive ion mode) m/z : 418 [M]+, 419 [M+1]+.
HRMS (FAB) calcd for C21H22O9 [M]+ : 418.1264. Found: 418.1254.
Anal. Calcd for C21H22O9 : C, 60.28 ; H, 5.30. Found : C, 60.20 ; H, 5.30.
3,4,8,9,10-Pentamethoxy-1-methoxymethoxymethyl-6H-dibenzo[b,d]pyran-6-one (5b)
Colorless prisms, mp 145-147 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 3.33 (3H, s, OCH2OCH3), 3.53 (3H, s, 10-OCH3), 3.99 (3H, s, OCH3),
4.00 (3H, s, OCH3), 4.01 (3H, s, OCH3), 4.86 (3H, s, OCH3), 4.59 (2H, s, CH2O), 4.70 (2H, s,
OCH2OCH3), 7.17 (1H, s, 2-H), 7.67 (1H, s, 7-H).
13C-NMR (75 MHz, CDCl3) δ: 55.5, 56.1, 56.3, 61.3, 61.4, 61.5, 68.9, 96.1, 108.0, 108.7, 109.5, 117.9,

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123.1, 131.9, 135.1, 144.1, 148.2, 149.3, 152.8, 153.1, 160.7.
IR (KBr) cm-1 : 1730 (C=O), 1480, 1350, 1330, 1150, 1120, 1005, 1050, 1000.
Anal. Calcd for C21H24O9 : C, 59.99 ; H, 5.75. Found : C, 59.78 ; H, 5.68
1-tert-Butyldimethylsilyloxymethyl-3,4,8,9,10-pentamethoxy-6H-dibenzo[b,d]pyran-6-one (5c)
Colorless needles, mp 165-167 oC (Et2O).
1H-NMR (300 MHz, CDCl3) δ: -0.04 (6H, s, Si(CH3)2), 0.87 (9H, s, SiC(CH3)3), 3.50 (3H, s, 10-OCH3),
3.97 (3H, s, OCH3), 3.999 (3H, s, OCH3), 4.003 (3H, s, OCH3), 4.08 (3H, s, OCH3), 4.75 (2H, s,
ArCH2O), 7.27 (1H, s, 2-H), 7.68 (1H, s, 7-H).
13C-NMR (75 MHz, CDCl3) δ: -5.4, 18.3, 25.8, 55.9, 56.4, 61.2, 61.4, 61.6, 64.2, 107.95, 108.04, 108.6,
117.9, 123.1, 134.7, 135.2, 143.9, 148.3, 149.3, 152.8, 153.0, 160.8.
IR (KBr) cm-1 : 1735 (C=O), 1480, 1340, 1120, 1080.
Anal. Calcd for C25H34O8Si : C, 61.20 ; H, 6.99. Found : C, 61.35 ; H, 6.86.
2,3,7,8-Tetramethoxy-5H,10H-chromeno[6,5,4,3-c,d,e]chromen-5-one (6)
Colorless needles, mp 244-246 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 3.93 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.02 (3H, s, OCH3), 4.04 (3H, s,
OCH3), 5.44 (2H, s, ArCH2O), 6.60 (1H, s, 1-H), 7.34 (1H, s, 6-H).
13C-NMR (75 MHz, CDCl3) δ: 56.4, 56.6, 61.3, 61.6, 67.7, 77.2, 103.8, 104.1, 105.9, 112.5, 116.7, 121.8,
142.2, 142.3, 142.5, 153.8, 153.9, 160.1.
IR (KBr) cm-1 : 1730 (C=O), 1610, 1490, 1400, 1380, 1330, 1240, 1110, 1000.
FAB-Mass (positive ion mode) m/z : 345 [M+1]+.
HRMS (FAB) calcd for C18H16O7 [M]+ : 344.0896. Found : 344.0864.
Anal. Calcd for C18H16O7 : C, 62.79 ; H, 4.68. Found : C, 62.70 ; H, 4.68.
1-Formyl-3,4,8,9,10-pentamethoxy-6H-dibenzo[b,d]pyran-6-one (7)
Colorless needles, mp 218-224 oC (CH2Cl2-Et2O).
1H-NMR (300 MHz, CDCl3) δ: 3.54 (3H, s, 10-OCH3), 4.01 (3H, s, OCH3), 4.02 (3H, s, OCH3), 4.08 (3H,
s, OCH3), 4.09 (3H, s, OCH3), 7.41 (1H, s, 2 or 7-H), 7.73 (1H, s, 2 or 7-H), 9.86 (1H, s, CHO).
13C-NMR (75 MHz, CDCl3) δ: 56.3, 56.5, 60.2, 61.5, 61.7, 108.1, 108.5, 111.0, 117.5, 121.2, 128.3,
139.5, 144.6, 148.6, 148.8, 152.9, 154.1, 160.0, 187.3.
IR (KBr) cm-1 : 1730 (C=O), 1690 (C=O), 1600, 1480, 1350, 1330, 1100.
(S)-6-Acetoxymethyl-2-hydroxy-6’-hydroxymethyl-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (9)

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To a solution of (S)-8 (596 mg, 2.15 mmol) in THF (20 mL), a BH3-THF solution (2.87 mmol) was added
at 0 oC under an argon atmosphere. The mixture was warmed to rt, stirred for 30 min, and then cooled to
o
-40 C. A solution of 5a (300 mg, 0.717 mmol) in THF (40 mL) was dropwise added to the mixture.
After 12 h, the entire mixture whole was poured into water and extracted with Et2O. The organic layer
was washed with brine, dried over MgSO4, and the solvent evaporated. The resulting residue was
purified by silica gel column chromatography using AcOEt.
Colorless needles, mp 129-130 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 1.87 (1H, bs, CH2OH), 1.98 (3H, s, OCOCH3), 3.58 (3H, s, 2’-OCH3),
3.90 (3H, s, OCH3), 3.93 (6H, s, 2 × OCH3), 3.95 (3H, s, OCH3), 4.28 (2H, s, ArCH2OH), 4.71 (1H, d, A
of AB, J=12.5 Hz, ArCHAHBOAc), 4.79 (1H, d, B of AB, J= 12.5 Hz, ArCHAHBOAc), 5.88 (1H, br, OH),
6.63 (1H, s, 5 or 5’-H), 6.94 (1H, s, 5 or 5’-H).
13C-NMR (75 MHz, CDCl3) δ: 21.0, 55.8, 55.9, 60.8, 61.0, 61.1, 63.5, 64.5, 94.8, 104.5, 108.0, 115.27,
119.9, 131.2, 135.0, 135.8, 141.6, 146.7, 151.5, 153.4, 170.4.
IR (KBr) cm-1: 3460 (OH), 3140 (OH), 1735 (C=O), 1240, 1110.
Anal. Calcd for C21H26O9 : C, 59.71 ; H, 6.20. Found : C, 59.88 ; H, 6.35.
[α]D22 = -7.0°(CHCl3, c 0.490) [97% ee]. The ee was determined by HPLC analysis.
HPLC conditions : column, CHIRALPACK AD; eluent, IPA:hexane = 1:4; flow rate,
1.0 mL/min; wavelength, 254 nm; retention time, 20.2 min.[(R)-form: 14.6 min.]
(S)-2-Hydroxy-6,6’-dihydroxymethyl-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (10)
To a suspension of LiAlH4 (17.0 mg, 0.473 mmol) and THF (5 mL), a solution of 9 (100 mg, 0.237 mmol,
o
97%ee) in THF (5 mL) was dropwise added at 0 C, and then the mixture was stirred for 12 h at -10 oC.
The reaction was quenched with a 10% NaOH aqueous solution. After extraction with ether, the organic
layer was dried over MgSO4 and the solvent was evaporated to give a residue which was subjected to
silica gel column chromatography using AcOEt-hexane (5:1).
Colorless needles, mp 154-155 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 3.20 (2H, br, CH2OH exchange with D2O), 3.57 (3H, s, 2’-OCH3), 3.91
(3H, s, OCH3), 3.93 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.17 (2H, s, 6-CH2OH), 4.24
(1H, d, A of AB, J=11.7 Hz, 6’-CHAHBOH), 4.24 (1H, d, A of AB, J=11.7 Hz, 6’-CHAHBOH), 6.70 (1H,
s, 5 or 5’-H), 6.92 (1H, s, 5 or 5’-H).
13C-NMR (75 MHz, CDCl3) δ: 55.7, 55.9, 61.4, 63.4, 63.7, 105.4, 108.7, 114.7, 121.1, 134.9, 135.7,
135.9, 141.9, 146.7, 151.2, 151.8, 153.3.
IR (KBr) cm-1: 3480 (OH), 3320 (OH), 3160 (OH), 1600, 1460, 1400, 1320, 1100, 1000.
Anal. Calcd for C19H24O8 : C, 59.99; H, 6.36. Found:C, 59.92; H, 6.40.

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[α]D24 +19.8 °(CHCl3, c 0.540) [96% ee]. The ee was determined by HPLC analysis.
HPLC conditions : column, CHIRALPACK AD; eluent, IPA:hexane = 1:4; flow rate, 1.0 mL/min;
wavelength, 254 nm; retention time, 16.6 min.[(R)-form: 13.8 min.]
(S)- 6,6’-Dihydroxymethyl-2,2’,3,3’,4,4’-hexamethoxy-1,1’-biphenyl ((S)-1)7
To a stirring solution of 10 (55 mg, 0.145 mmol) in THF (10 mL), MeI (9.28 µL, 0.149 mmol) and
tBuOK (16.8 mg, 0.149 mmol) were successively added at 0 oC. The mixture was allowed to warm to rt.
After 72 h, the mixture was poured into water and extracted with Et2O. The organic layer was washed
with brine, dried over MgSO4, and the solvent evaporated to give a residue which was subjected to silica
gel column chromatography using AcOEt-CHCl3 (1:1).
Colorless needles, mp 127-128 oC (CH2Cl2-hexane).
1H-NMR (300 MHz, CDCl3) δ: 2.25 (2H, br, CH2OH), 3.67 (6H, s, 2,2’-OCH3), 3.89 (6H, s, OCH3), 3.94
(6H, s, OCH3), 4.19 (4H, s, 6,6’-CH2OH), 6.89 (2H, s, 5,5’-H).
13C-NMR (75 MHz, CDCl3) δ: 56.0, 60.92, 60.93, 63.7, 108.7, 121.5, 135.5, 141.5, 150.8, 153.1.
IR ( KBr ) cm-1: 3500 (OH), 3400 (OH), 1600, 1460, 1400, 1120, 1100.
Anal. Calcd for C20H26O8 : C, 60.90 ; H, 6.64. Found : C, 60.98 ; H, 6.49.
[α]D26 = +43.1°(CHCl3, c 0.490) [93% ee]. The ee was determined by HPLC analysis.
HPLC conditions : column, CHIRALCELL OD; eluent, IPA:hexane = 1:4; flow rate, 1.0 mL/min;
wavelength, 254 nm; retention time, 8.1 min. [(R)-1, 5.9 min.]
General procedure for Table 2
To a mixture of 11 (116 mg, 0.309 mmol), NaH (60% in mineral oil) (12.4 mg, 0.309 mmol), and THF
o
(10 mL), a solution of 5b (130 mg, 0.309 mmol) in THF (5 mL) was dropwise added at 0 C. After
check of TLC, the mixture was poured into water and extracted with AcOEt. The organic layer was
washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica gel
column chromatography using AcOEt-hexane (1:1). An inseparable diastereomeric mixture of 12 (216
1
mg) was obtained. The ratio of diastereomers was determined by H-NMR analysis after the next
transformation.
Methyl 2,3-di-O-benzyl-6-O-[(S)-3,4,5-trimethoxy-2-(2,3,4-trimethoxy-6-methoxymethoxymethyl-
phenyl)-benzoyl]-α-D-glucopyranoside (13) and Methyl 2,3-di-O-benzyl-6-O-[(R)-3,4,5-trimethoxy-
2-(2,3,4-trimethoxy-6-methoxymethoxymethylphenyl)-benzoyl]-α-D-glucopyranoside (14)
A mixture of 12 (1:1 mixture of diastereomers, 216 mg, 0.271 mmol), (MeO)2SO2 (28 µL, 0.298 mmol),
K2CO3 (37 mg, 0.271 mmol), and acetone (10 mL) was heated under reflux for 5 h, and then poured into

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water. After extraction with ether, the organic layer was washed with brine, dried over MgSO4, and the
solvent evaporated. Purification with silica gel column chromatography using AcOEt-hexane (1:1) gave
14 (76.7 mg, 35%) and 13 (72.3 mg, 33%).
13: Colorless oil.
1H-NMR (500 MHz, CDCl3) δ: 2.75 (1H, dd, J=9.5, 9.5 Hz), 3.25 (3H, s, OCH3), 3.30 (3H, s, OCH3),
3.31 (1H, dd, J=3.8, 9.8 Hz), 3.56 (3H, s, OCH3), 3.59 - 3.90 (3H, m), 3.65 (3H, s, OCH3), 3.71 (3H, s,
OCH3), 3.85 (3H, s, OCH3), 3.93 (6H, s, 2 × OCH3), 4.06 (1H, d, A of AB, J=11.3 Hz), 4.11 (1H, dd,
J=1.8, 12.3Hz), 4.24 (1H, d, B of AB, J=11.3 Hz), 4.43 (1H, d, J=3.5 Hz), 4.44 (1H, d, A of AB, J=6.3
Hz), 4.52 (1H, d, B of AB, J=6.3 Hz), 4.51 (1H, dd, J=3.5, 9.0 Hz) 4.66 (1H, d, A of AB, J=12.0 Hz),
4.83 (1H, d, B of AB, J=12.0 Hz), 4.78 (1H, d, A of AB, J=11.3 Hz), 4.89 (1H, d, B of AB, J=11.3 Hz),
6.75 (1H, s), 7.28 - 7.45 (11H, m).
13C-NMR (75 MHz, CDCl3) δ: 55.1, 55.3, 56.0, 60.50, 60.53, 60.6, 60.8, 63.9, 68.2, 69.0, 73.5, 75.7, 80.0,
81.4, 96.2, 98.3, 107.9, 109.8, 123.4, 124.7, 125.6, 127.5, 127.7, 127.96, 127.99, 128.1, 128.2, 130.5,
138.4, 139.0, 141.3, 145.6, 151.0, 151.4, 152.1, 152.4, 167.1.
IR (CHCl3) cm-1 : 3500 (OH), 1720 (C=O), 1590, 1485, 1460, 1390, 1330, 1100.
FAB-Mass (positive ion mode) m/z : 809 [M+1]+.
14: Colorless oil.
1H-NMR (500 MHz, CDCl3) δ: 3.17 (1H, dd, J=9.3, 9.3 Hz), 3.20 (3H, s, OCH3), 3.35 (3H, s, OCH3),
3.42 (1H, dd, J=3.5, 9.5 Hz), 3.56 - 3.65 (2H, m), 3.59 (3H, s, OCH3), 3.63 (3H, s, OCH3), 3.71 (1H, dd,
J=9.3, 9.3 Hz), 3.82 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.93 (3H, s, OCH3), 4.12
(1H, d, A of AB, J=12.5 Hz), 4.21 (1H, d, B of AB, J=12.5 Hz), 4.24 (1H, s), 4.25 (1H, d, J=1.5 Hz),
4.46 (2H, s), 4.56 (1H, d, J=3.5 Hz), 4.66 (1H, d, A of AB, J=12.3 Hz), 4.73 (1H, d, A of AB, J=11.5 Hz),
4.75 (1H, d, B of AB, J=12.3 Hz), 4.96 (1H, d, B of AB, J=11.5 Hz), 6.82 (1H, s), 7.29 - 7.38 (11H, m).
13C-NMR (75 MHz, CDCl3) δ: 55.1, 55.2, 55.7, 56.0, 60.5, 60.6, 60.7, 60.8, 63.4, 67.2, 69.2, 69.7, 73.1,
75.5, 79.5, 81.2, 95.7, 98.0, 106.4, 109.3, 122.4, 124.8, 125.8, 127.6, 127.8, 127.9, 127.9, 128.2, 128.3,
131.4, 137.9, 138.7, 140.9, 145.5, 150.8, 151.6, 152.1, 152.5, 166.6.
IR (CHCl3) cm-1 : 3480 (OH), 1700 (C=O), 1590, 1490, 1480, 1395, 1330, 1230, 1155, 1100.
FAB-Mass (positive ion mode) m/z : 831 [M+Na]+.
Transformation of 13 into (S)-1
To a suspension of LiAlH4 (6.0 mg, 0.161 mmol) and THF (1 mL), a solution of 13 (65.2 mg, 0.081
o
mmol) in THF (2 mL) was dropwise added at 0 C, and then the mixture was stirred for 1 h at the same
temperature. The reaction was quenched with a 5N HCl aqueous solution, and then the mixture was
o
stirred for 4 h at 50 C. After extraction with Et2O, the organic layer was dried over MgSO4 and the

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solvent was evaporated to give a residue which was subjected to silica gel column chromatography using
AcOEt-hexane (2:1). Thus (S)-1 (55.9 mg, 88%, 91%ee) was obtained.
Transformation of 14 into (R)-1
Using a method similar to the one just described, (R)-1 was obtained from 14.
ACKNOWLEDGEMENT
A part of this work was financially supported by the Japan Society for Promotion of Science for H. A.
(Grant No. 18590005). We also thank the SC-NMR Laboratory of Okayama University for use of their
facilities.
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