Synthetic access to optically active isoflavans by using allylic substitution

Article abstract of DOI:10.1016/j.tet.2009.10.116

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.

Full text of DOI:10.1016/j.tet.2009.10.116

Tetrahedron 66 (2010) 197–207
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic access to optically active isoflavans by using allylic substitution
*
Yuji Takashima, Yuki Kaneko, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was
demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key
step is the allylic substitution of (S)-6a (Ar1¼2,4-(MeO)2C6H3) and (R)-6b (Ar1¼2,4-(BnO)2C6H3) with
copper reagents derived from CuBr$Me2S and Ar2-MgBr (7a, Ar2¼4-MeOC6H4; 7b, 2,4-(MeO)2C6H3; 7c, 2-
MOMO-4-MeOC6H3), furnishing anti SN20 products (R)-8a and (S)-8b,c with 93–97% chirality transfer in
60–75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the
Ar1 moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent
cyclization with K2CO3 and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 September 2009
Received in revised form 30 October 2009
Accepted 31 October 2009
Available online 5 November 2009
Keywords:
Isoflavans
Equol
Sativan
Vestitol
Asymmetric synthesis
Allylic substitution
Picolinate
OR
OH
1. Introduction
O
S
The isoflavonoids are secondary metabolites of daidzein (1) and
formononetin (2) in the plants and act as phytoalexins in the de-
fense against pathogens of the plants.1 The isoflavans such as those
shown in Figure 1 are a subclass of the isoflavonoids and distinctive
by the chiral center at C3 of the pyran ring, which is created ster-
eoselectively by the specific enzyme involved in the plants, thereby
the (R)-isomers are produced in Leguminosae and Papilionoideae,
whereas the (S)-isomers are found in certain woods such as
Machaerium and Dalbergia species.1,2 On the other hand, daidzein
(1) ingested into our body by taking soy and foods thereof is
transformed to (S)-equol ((S)-3) and other metabolites by intestinal
bacteria such as gut microflora.3,4 Among these metabolites, (S)-3
stimulates an estrogenic response most effectively through binding
HO
HO
O
HO
HO
O
Daidzein, 1, R = H
Formononetin, 2, R = Me
(S)-Equol, (S)-3
MeO
HO
OMe
OMe
*
*
O
O
(R)-Sativan, (R)-4
(S)-Sativan, (S)-4
(R)-Vestitol, (R)-5
(S)-Vestitol, (S)-5
OH
MeO
HO
OMe
OH
OH
to the estrogen receptor
of (S)-3 to ER is 13 times more potent than the unnatural (R)-
isomer,6 whereas the (R)-isomer is ER
selective. On the basis of
b (ERb
).5 Interestingly, the binding affinity
R
R
b
OMe
a
MeO
O
HO
O
these biological properties (S)-3 is presently believed to be a dietary
phytoestrogen. However, there is a controversy report that equol
induces breast cancer cell proliferation at 100 nM levels.7 To bring
the discussion about propriety of (S)-3 as a health benefit to
a conclusion, further biological study using optically active equol,
other isoflavans, and their derivatives is an urgent demand.
Coluteol
Lespedezol G1
OR
MeO
OMe
OMe
S
other isoflavans (R = H, Me)
isolated from
Eysenhardtia polystacha (Ortega) Sarg.
HO
O
OMe
* Corresponding author. Tel./fax: þ81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
Figure 1. Daidzein, formononetin, and their isoflavan metabolites.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.116

198
Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
Ar2–MgBr (7)
So far, several racemic syntheses of the isoflavans have been
Ar1
Ar2
reported.8 In contrast, asymmetric synthesis has been studied9 only
for (S)-equol ((S)-3) by using the Evans asymmetric alkylation.10
However, the several steps involved in this method suffer from the
moderate yields, and application of the method for synthesis of
other isoflavans is not certain. Bacterial metabolism of daidzein11
and separation of the enantiomers using chiral HPLC6 have been
studied as well, though these methods are limited to a small scale.
Recently, we reported the allylic substitution of allylic picoli-
nates with copper reagents to furnish anti SN20 products.12 The
prime merit of the method is compatibility with a wide variety of
sp2-C copper reagents such as aryl and alkenyl reagents, which are
generally less reactive and less regioselective toward allylic esters
other than picolinates. An easy preparation of the copper reagents
from RMgBr and CuBr$Me2S and a wide range of the RMgBr/
CuBr$Me2S ratios (1–4:1) for the successful reaction are other ad-
vantages of this reaction. With this allylic substitution in mind, we
designed an approach to the isoflavans as outlined in Scheme 1,
which involves (1) substitution of (S)-6 with copper reagents de-
rived from Ar2-MgBr (7) and CuBr$Me2S to afford anti SN20 products
(R)-8, which possess the chiral center of (S)-isoflavans; (2) oxidative
conversion of (R)-8 to phenol derivatives (S)-9; (3) cyclization of
(S)-9 to construct the pyran ring. Likewise, (R)-6 would be trans-
formed to (R)-isoflavans. We selected (S)-equol ((S)-3), (R)-sativan
((R)-4), and (R)-vestitol ((R)-5) as targets. In addition, we expected
that the synthesis of the latter two would be a model study of more
complicated isoflavans possessing an ortho substituent on the ar-
omatic ring Ar2. In practice, synthesis of (S)-equol was accom-
plished successfully as communicated recently.13 Herein, we report
CuBr•Me2S
O
Ar1
N
O
via anti SN2'
(R)-8
(S)-6
oxidative
cleavage
Ar1 part
RO
Ar2
cyclization
(S)-isoflavans
X
OH
(S)-9
Similarly,
(R)-6
(R)-isoflavans
Scheme 1. Strategy to synthesize (S)- and (R)-isoflavans.
a full account of the study, in which the equal access to the both
enantiomers of the key substrates is secured.
2. Results and discussion
2.1. Synthesis of (S)-equol
We envisioned Wittig reaction between phosphonium salt 14
and (S)-17 (Scheme 2) for preparation of picolinate (S)-6a. To this
end, Wittig reaction of aldehyde 10 with Ph3P¼CH2 gave olefin 11,
[Ph3PCH3]+ Br–, BuLi
THF, 0 °C
1) 9-BBN
THF, 0 °C to rt
MeO
MeO
MeO
MeO
PPh3
+
PPh3 Br–
CHO
X
2) H2O2, 3 N NaOH
90%
then 10, 0 ºC to rt
EtOH, Δ
OMe
OMe
OMe
OMe
90%
91%
12, X = OH
13, X = Br
CBr4
PPh3
14
10
11
94%
MeO
1) 14, NaN(TMS)2
PyCO2H
DIBAL-H
THF, 0 ºC
TBDPSCl
CO2Et
OH
15
CO2Et
OTBDPS
16
CHO
OTBDPS
(S)-17
DCC, DMAP
94%
CH2Cl2, –78 °C
89%
2) –78 °C to rt
97%
imidazole
100%
OMe
OR
18, R = TBDPS
19, R = H
(S)-isomer
Bu4NF
95%
OMe
OH
OMe
4-MeOC6H4MgBr (7a)
MeO
(2 equiv)
OsO4 (cat.), NMO
acetone, H2O
CuBr•Me2S (1 equiv)
–70 to –50 °C, 1 h
HO
OMe
MeO
MeO
OMe
OMe
OCOPy
(S)-6a, 94% ee
97% chirality transfer
20
(R)-8a
75% (2 steps)
OH
OMe
OH
1) NaIO4
MeOH, H2O
K2CO3
BBr3
CH2Cl2
acetone
2) NaBH4
82%
HO
O
MeO
CBr4
X
HO
OH
Br
OMe
21, X = OH, 91% ee
22, X = Br
(S)-3
(S)-9a
PPh3
90%
74% (2 steps)
Scheme 2. Synthesis of (S)-equol ((S)-3).

Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
(3) Allylic substitution of trans picolinate 26
199
(1) Preparation of alcohol 12
1) [Ph3PCH2OMe]+ Br–
7a / CuBr•Me2S
(3 / 1.5 equiv)
NaN(TMS)2, 0 °C
26
then 10, 0 ºC to rt
Ar
R
–60 to –40 °C, 1 h
Ar-CHO
2) 1 N HCl, THF (1 : 1)
80 °C, 4 h
OMe
OMe
10
23, R = CHO
NaBH4
12, R = CH2OH
72%
+
95%
Ar
Ar
(2) Preparation of trans picolinate 26
27
rac-8a
1) BuLi
then MeCHO
55 : 45
1) CBr4, PPh3
23
Ar
2) BuLi
79%
2) LiAlH4
45%
24
OH
OCOPy
PyCO2H
Ar
Ar
DCC, DMAP
62%
25
26
Scheme 3. Related results to synthesis of (S)-equol. Ar¼2,4-(MeO)2C6H3–.
which upon hydroboration with 9-BBN produced alcohol 12 in 82%
overall yield. Alcohol 12 was converted to the salt 14 by bromina-
tion followed by reaction with PPh3 in EtOH.14 We also examined
another preparation of 12 consisting of Wittig reaction of 10 with
Ph3P¼CHOMe, hydrolysis of the resulting enol ether (E:Z¼6:4), and
subsequent reduction of aldehyde 23 with NaBH4 (Scheme 3).
However, the overall yield of 12 by this method was 10% lower than
that mentioned above (68% vs 82%). Wittig partner (S)-17 was
synthesized from ethyl (S)-lactate (15), the natural form, via alde-
hyde (S)-17 according to the literature procedure15 in good yield.
For the Wittig reaction, 14 was treated with NaN(TMS)2 at 0 ꢀC
and the corresponding ylide was subjected to reaction with (S)-17
initially at ꢁ78 ꢀC and then at temperatures gradually raised to
room temperature, producing cis olefin 18 (Jolefinic-H¼11 Hz) in 97%
yield. The TBDPS group of 18 was removed and the resulting alcohol
19 was esterified with PyCO2H, DCC, and DMAP to furnish picoli-
nate (S)-6a in 89% yield from 18. Enantiomeric excess (ee) of (S)-6a
was 94% by chiral HPLC and olefinic purity of (S)-6a over the trans
isomer 26a was 12–14:1 by 1H NMR spectroscopy. An authentic
sample of 26a was synthesized stereoselectively from aldehyde 23
according to a sequence of reactions delineated in Scheme 3.
According to the procedure reported,12 allylic substitution of (S)-
6a with the copper reagent (1 equiv) derived from 4-
MeOC6H4MgBr (7a) and CuBr$Me2S in a 2:1 ratio was carried out
between ꢁ70 and ꢁ50 ꢀC for 1 h (Scheme 2) to produce anti SN20
product (R)-8a regioselectively by 1H NMR spectroscopy. On the
other hand, substitution of trans picolinate 26 (in racemic form)
bromide 22 was successful to deliver bromophenol (S)-9a, which
upon reaction with K2CO3 in acetone furnished (S)-equol ((S)-2) in
74% yield from bromide 22. The ee was 91% by chiral HPLC, while
the 1H and 13C NMR spectra and mp were consistent with those
reported.9,11 The structure was also supported by APT experiment
(APT: Attached Proton Test).
2.2. Synthesis of (R)-sativan
To reproduce the phenol group at a later stage for construction
of the pyran ring of (R)-sativan and -vestitol, a benzyl protective
group was attached to 2,4-(HO)2C6H3CHO in 81% yield by benzy-
lation with BnCl and K2CO3 (Scheme 4). Subsequently, 28 was
transformed to a phosphonium salt 32 in 67% yield over four steps.
The key aldehyde (R)-17 for the (R)-isoflavans was synthesized
from methyl (R)-lactate 33 (unnatural form) in good yield. A
phosphorane generated from the salt 32 with NaN(TMS)2 at 0 ꢀC
was subjected to Wittig reaction with (R)-17 to produce cis olefin 34
in 90% yield. Deprotection of the TBDPS group was followed by
esterification with PyCO2H to furnish picolinate (R)-6b in good
yield. The enantiomeric purity of (R)-6b was 97% ee by 1H NMR
spectroscopy of the derived MTPA ester and a ratio of (R)-6b and
the trans isomer (synthesized by a similar method to that for 26)
was 12:1 by 1H NMR spectroscopy.
Arylation of (R)-6b with the copper reagent derived from 2,4-
(MeO)2C6H3MgBr (7b) (2 equiv) and CuBr$Me2S (1 equiv) at ꢁ60 ꢀC
to ꢁ50 ꢀC was not significantly interfered with by the ortho-MeO
group and completed within 1 h by TLC (Scheme 5). The 1H NMR
spectrum of crude (S)-8b disclosed no formation of the regioisomer.
Without purification, (S)-8b was transformed to the diol (structure
not shown), which upon oxidative cleavage followed by reduction
of the resulting aldehyde with NaBH4 produced alcohol 36 in 73%
yield from (R)-6b. Ee of 36 was 94% by chiral HPLC, indicating 97%
chirality transfer for the arylation. In contrast to the uneventful
conversion up to 36, bromination of alcohol 36 with CBr4 and PPh3
afforded a mixture of bromide 37 and unidentified byproducts.
Without separation, the mixture was subjected to debenzylation
using Pd/C under hydrogen followed by K2CO3-assisted cyclization
to afford a mixture of (R)-4 and furan 39 in a 1:1 ratio by 1H NMR
spectroscopy. The formation of the latter indicates that one of the
byproducts produced with bromide 37 was the isomer 38. The
migration of the 2,4-(MeO)2C6H3 group to the next carbon through
with the same copper reagent produced
a mixture of the
regioisomers rac-8a and 27 in a 55:45 ratio16 (Scheme 3). Since
complete separation of (R)-8a and the reagent-based byproducts by
chromatography was unsuccessful due to the close mobility on
silica gel, crude (S)-8a was subjected to OsO4-catalyzed dihydrox-
ylation and the resulting polar diol 20 (a diastereomeric mixture)
was separated from the byproducts in 75% yield from (S)-6a. The
diol moiety of 20 was cleaved with NaIO4 and subsequent in situ
reduction of the resulting aldehyde with NaBH4 afforded alcohol 21
in 82% yield. The enantiomeric excess of 21 determined by chiral
HPLC analysis was 91%, which indicates the allylic substitution of
(S)-6a proceeded with 97% or more chirality transfer.17
An attempted demethylation and simultaneous bromination of
21 with BBr318 was unsuccessful, giving unidentified products. After
several unsuccessful trials, we found that demethylation of

200
Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
[Ph3PCH3]+ Br–, BuLi
THF, 0 °C
1) 9-BBN
THF, 0 °C to rt
BnO
BnO
BnO
BnO
PPh3
+
X
PPh3 Br–
CHO
2) H2O2, 3 N NaOH
then 10, 0 ºC to rt
EtOH, Δ
OBn
OBn
OBn
OBn
32
100%
91%
85%
30, X = OH
CBr4
PPh3
28
29
31, X = Br
86%
BnO
1) TBDPSCl,
BnO
1) 32, NaN(TMS)2
THF, 0 ºC
imidazole, 95%
PyCO2H
CO2Me
OH
33
CHO
OTBDPS
(R)-17
2) DIBAL-H
–78 °C, 94%
DCC, DMAP
86%
2) –78 °C to rt
90%
OBn
OBn
OR
OCOPy
(R)-6b, 97% ee
34, R = TBDPS
35, R = H
(R)-isomer
Bu4NF
94%
Scheme 4. Synthesis of the key picolinate (R)-6b.
benzenium cation 40 as drawn in Eq. 1 is a likely process, and must
be driven by the two methoxy groups of the 2,4-(MeO)2C6H3 group
since such a migration was not observed with bromide 22, which
possesses the 4-MeOC6H4 group, instead.19 In an attempt to eluci-
date another alcohol derivative suited for the cyclization, conver-
sion of 36 to chloride, tosylate, and mesylate were examined, but
the products were unfortunately unstable.
We then examined the cyclization using the Mitsunobu reagent,
which has frequently been used for construction of the benzopyran
ring of the flavans, the isoflavans, and other classes of com-
pounds.8a,10,19b,20 The benzyl group in 36 was removed to produce
the phenol alcohol (R)-9b in 92% yield. Cyclization of (R)-9b with
PPh3 and DEAD proceeded cleanly to furnish a mixture of (R)-4 and
(NHCO2Et)2, which was hardly separated by chromatography. Fi-
nally, (NHCO2Et)2 in the mixture was removed by hydrolysis with
3 N LiOH in MeOH to allow easy chromatographic purification of
(R)-421 in 77% yield. The 1H NMR spectrum, [
a]D, and mp were
consistent with those reported.21a,b The structure was also sup-
ported by the APT spectrum.
OMe
MeO
OMe
(1)
38
+
OMe
Br–
Br
37
40
MeO
OMe
MeO
OBn
OMe
2,4-(MeO)2C6H3MgBr (7b)
1) OsO4 (cat.), NMO
acetone, H2O
CBr4, PPh3
72%
(2 equiv)
(R)-6b
CuBr•Me2S (1 equiv)
–60 to –50 °C, 1 h
2) NaIO4, MeOH, H2O
3) NaBH4
97% ee
BnO
BnO
OH
OBn
73% from (R)-6b
97% CT
(S)-8b
36, 94% ee
MeO
OMe
OMe
OMe
BnO
BnO
Br
Br
OBn
+
1) H2, 10% Pd/C
MeOH
37
(R)-4
+
O
HO
2) K2CO3
acetone
OMe
39
1 : 1
22%
OBn
OMe
38
MeO
O
OMe
MeO
OH
OMe
H2, 10% Pd/C
1) DEAD, PPh3, THF
36
MeOH
92%
2) 3 N LiOH, MeOH 80 ºC, 2 h
77%
HO
HO
OH
(R)-4
(R)-9b
Scheme 5. Synthesis of (R)-sativan ((R)-4) from (R)-6b.

Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
201
2.3. Synthesis of (R)-vestitol ((R)-5) from (R)-6b
prices. We believe that biological researches of the isoflavans would
be accelerated with the present method.
Due to difficulty in obtaining bromide 43 from a commercial
source, we synthesized it from 41. Bromination of 41 with Br2,
according to the literature procedure,22 took place regioselectively
with concomitant demethylation to produce bromophenol 42 in
56% yield (Scheme 6). Decarboxylation of 42 was completed in
quinoline under reflux and the OH group of the product was pro-
tected as the MOM ether to afford 43 in 73% yield, which was
converted to the Grignard reagent 7c as usual.
4. Experimental
4.1. General
Infrared (IR) spectra are reported in wave numbers (cmꢁ1). The
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured
in CDCl3 using SiMe4 (
¼77.1 ppm) as internal standards, respectively. Signal patterns are
indicated as br s, broad singlet; s, singlet; d, doublet; t, triplet; q,
d
¼0 ppm) and the center line of CDCl3 triplet
The copper reagent derived from 7c and CuBr$Me2S in a 2:1 ratio
underwent substitution with (R)-6b (97% ee) at ꢁ60 ꢀC to ꢁ50 ꢀC to
(d
CO2H
OMe
CO2H
OMe
Br2, CHCl3
1) quinoline, 150 °C, 1 h
Mg
MOMO
Br
OMe
MOMO
BrMg
OMe
MeO
HO
Br
rt, 2 days
56%
2) MOMCl, i-Pr2EtN
73%
42
43
7c
41
MOMO
OBn
OMe
MOMO
OBn
OMe
1) OsO4 (cat.), NMO
acetone, H2O
H2, 10% Pd/C
MeOH
7c (2 equiv)
(R)-6b
97% ee
CuBr•Me2S (1 equiv)
–60 to –50 °C, 1 h
2) NaIO4, MeOH, H2O
3) NaBH4
BnO
BnO
OH
60% from (R)-6b
>93% CT
44, 90% ee
(S)-8c
MOMO
OMe
MOMO
O
OMe
HO
OMe
3 N HCl, MeOH
1) DEAD, PPh3, THF
1 h, reflux
80%
2) 3 N LiOH, MeOH
80 ºC, 2 h
HO
OH
HO
HO
O
OH
(R)-5
46
45
87% from 44
Scheme 6. Synthesis of (R)-vestitol ((R)-5) from (R)-6b.
produce (S)-8c after 1 h. Absence of the regioisomer by 1H NMR
spectroscopy and the recorded reaction time for the completion
(1 h) indicate that the ortho-MOM-oxy group did not interfere with
the substitution as the MeO group did not. Without purification, (S)-
8c was converted to alcohol 44 by dihydroxylation followed by
oxidative cleavage of the resulting diol in 60% yield from (R)-6b.
Chiral HPLC analysis revealed 90% ee of 44 and thus 93% chirality
transfer for the substitution. Debenzylation of 44 gave phenol al-
cohol 45, which under the Mitsunobu conditions afforded a mixture
of benzophyran 46 and (NHCO2Et)2. The mixture was treated with
LiOH in aqueous MeOH to remove the latter, allowing easy purifi-
cation of 46 by chromatography in 87% yield from 44. Finally, the
MOM group was removed with 3 N HCl in MeOH to furnish (R)-5 in
80% yield with 90% ee by HPLC. The spectral data (1H and 13C NMR
quartet; m, multiplet. Coupling constants (J) are given in Hertz (Hz).
In some cases chemical shifts of carbons accompany plus (for C and
CH2) and minus (for CH and CH3) signs of APT (Attached Proton
Test) experiments. The following solvents were distilled before use:
THF (from Na/benzophenone), Et2O (from Na/benzophenone), and
CH2Cl2 (from CaH2).
4.2. Synthesis of (S)-equol
4.2.1. 2,4-Dimethoxy-1-vinylbenzene (11). To an ice-cold mixture of
[Ph3PCH3]þBrꢁ (216 mg, 0.605 mmol) in THF (1 mL) was added BuLi
(0.220 mL, 2.64 M in THF, 0.581 mmol). The mixture was stirred at
the same temperature for 1.5 h, and a solution of aldehyde 10
(53.3 mg, 0.321 mmol) in THF (1 mL) was added. The mixture was
stirred at room temperature for 1 h and diluted with saturated
NH4Cl. The resulting mixture was extracted with ether twice. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated to leave an oil, which was purified by chromatography
on silica gel with hexane/EtOAc (10:1) to afford olefin 11 (47.7 mg,
91%). The 1H NMR spectrum of 11 was identical with that reported.24
spectra) and [a]
D were consistent with those reported.23
3. Conclusion
We established a new access to optically active isoflavans, in
which allylic substitution is used to construct the requisite chiral
center with high chirality transfer. The copper reagents possessing
a substitution at the ortho position did not interfere with the sub-
stitution. This compatibility would allow synthesis of more com-
plicated isoflavans such as those listed in Figure 1. In addition, both
enantiomers of the starting lactate are available easily at reasonable
4.2.2. 2-(2,4-Dimethoxyphenyl)ethanol (12). To an ice-cold solution
of olefin 11 (2.09 g, 12.7 mmol) in THF (40 mL) was added 9-BBN
(50.8 mL, 0.5 M in THF, 25 mmol). The reaction was conducted at
ambient temperature for 18 h and quenched by addition of MeOH

202
Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
(40 mL). After 30 min of stirring, 3 N NaOH (40 mL, 120 mmol) and
35% H2O2 (6.6 mL, 75 mmol) were added slowly. The resulting mix-
ture was stirred at room temperature for 3 h and poured into H2O.
The product was extracted with ether twice. The combined organic
layers were washed with brine, dried over MgSO4, and concentrated
to afford a residual oil, which was purified by chromatography on
silica gel with hexane/EtOAc (from 5:1 to 1:2) to afford alcohol 12
(2.07 g, 90%) as colorless solids: IR (Nujol) 3331, 1212, 1126,
addition, the mixture was allowed to warm to ambient temperature,
stirred for 19 h, and poured into saturated NH4Cl. The product was
extracted with EtOAc twice. The combined extracts were washed
with brine, dried over MgSO4, and concentrated to afford a residual
oil, which was subjected to chromatography on silica gel with hex-
ane/EtOAc (20:1) to afford olefin 18 (2.99 g, 97%) as a yellow oil: IR
(neat) 1613, 1506, 1209, 1112, 822 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.05 (s, 9H), 1.17 (d, J¼6 Hz, 3H), 2.86 (dd, J¼16, 7 Hz, 1H), 2.98 (dd,
1042 cmꢁ1; 1H NMR (300 MHz, CDCl3)
J¼6 Hz, 2H), 3.74–3.85 (m, 8H), 6.42–6.48 (m, 2H), 7.07 (d, J¼8 Hz,
1H); 13C NMR (75 MHz, CDCl3)
d
1.63 (t, J¼6 Hz, 1H), 2.84 (t,
J¼16, 7 Hz, 1H), 3.68 (s, 3H), 3.76 (s, 3H), 4.68–4.82 (m, 1H), 5.35 (dt,
J¼11, 7 Hz,1H), 5.59 (dd, J¼11, 8 Hz,1H), 6.31 (dd, J¼8, 2 Hz,1H), 6.37
(d, J¼2 Hz,1H), 6.76 (d, J¼8 Hz,1H), 7.24–7.44 (m, 6H), 7.65–7.71 (m,
d
33.5 (þ), 55.4 (ꢁ), 55.5 (ꢁ), 63.1 (þ),
98.7 (ꢁ), 104.1 (ꢁ), 119.3 (þ), 131.2 (ꢁ), 158.6 (þ), 159.8 (þ); HRMS
4H); 13C NMR (75 MHz, CDCl3)
d
19.3 (þ), 24.7 (ꢁ), 27.0 (ꢁ), 27.3 (þ),
(FAB) calcd for C10H14O3Na [(MþNa)þ] 205.0841, found 205.0846.
55.2 (ꢁ), 55.4 (ꢁ), 66.1 (ꢁ), 98.4 (ꢁ), 103.9 (ꢁ), 121.4 (þ), 126.7 (ꢁ),
127.5 (ꢁ), 127.6 (ꢁ), 129.4 (ꢁ), 129.5 (ꢁ), 129.6 (ꢁ), 134.5 (þ), 134.8
(þ), 135.1 (ꢁ), 135.9 (ꢁ), 136.0 (ꢁ), 158.0 (þ), 159.2 (þ); HRMS (FAB)
calcd for C29H36O3SiNa [(MþNa)þ] 483.2331, found 483.2332.
4.2.3. 1-(2-Bromoethyl)-2,4-dimethoxybenzene (13). To an ice-cold
solution of alcohol 12 (202 mg, 1.11 mmol) and PPh3 (349 mg,
1.33 mmol) in CH2Cl2 (2 mL) was added CBr4 (406 mg, 1.22 mmol).
The mixture was stirred at room temperature for 2 h and concen-
trated to afford a residual oil, which was purified by chromatog-
raphy on silica gel with hexane/EtOAc (10:1) to afford bromide 13
(255 mg, 94%): IR (neat) 1613, 1507, 1209, 1143, 834 cmꢁ1; 1H NMR
4.2.7. (S,Z)-5-(2,4-Dimethoxyphenyl)pent-3-en-2-ol (19). To a solu-
tion of 18 (1.82 g, 3.79 mmol) in THF (20 mL) was added Bu4NF
(5.69 mL, 1.0 M in THF, 5.69 mmol). The solution was stirred at
room temperature for 23 h and poured into H2O. The product was
extracted with EtOAc twice. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated to afford
a residual oil, which was chromatographed on silica gel with hex-
ane/EtOAc (from 10:1 to 2:1) to afford alcohol 19 (0.799 g, 95%): IR
(neat) 3389, 1507, 1209, 1156, 834 cmꢁ1; 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d
3.10 (t, J¼8 Hz, 2H), 3.53 (t, J¼8 Hz, 2H), 3.798 (s,
3H), 3.803 (s, 3H), 6.40–6.47 (m, 2H), 7.05 (d, J¼8 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d
32.7 (þ), 34.1 (þ), 55.3 (ꢁ), 55.4 (ꢁ), 98.6 (ꢁ),
103.9 (ꢁ), 119.6 (þ), 131.0 (ꢁ), 158.5 (þ), 160.1 (þ).
4.2.4. (2-(2,4-Dimethoxyphenyl)ethyl)triphenylphosphonium
bro-
d
1.28 (d, J¼6 Hz, 3H), 3.25 (dd, J¼15, 6 Hz, 1H), 3.47 (dd, J¼15, 7 Hz,
mide (14). A solution of bromide 13 (97.8 mg, 0.399 mmol) and
PPh3 (171 mg, 0.652 mmol) in EtOH (1 mL) was refluxed for 40 h
and concentrated to afford a residual solid, which was recrystal-
lized from ether/CH2Cl2 to afford phosphonium salt 14 (181 mg,
0.357 mmol, 90%) as white solids: IR (Nujol) 1507, 1292, 1108, 1022,
1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.82 (dq, J¼7, 6 Hz, 1H), 5.45–5.58 (m,
2H), 6.43 (dd, J¼8.5, 2 Hz, 1H), 6.45 (br s, 1H), 7.03 (d, J¼8.5 Hz, 1H);
13C NMR (75 MHz, CDCl3)
d
23.2 (ꢁ), 28.0 (þ), 55.41 (ꢁ), 55.46 (ꢁ),
63.6 (ꢁ), 98.7 (ꢁ), 104.2 (ꢁ), 120.9 (þ), 129.9 (ꢁ), 134.0 (ꢁ), 158.0
(þ), 159.5 (þ); HRMS (FAB) calcd for C13H18O3Na [(MþNa)þ]
245.1154, found 245.1162.
745 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 2.90–3.03 (m, 2H), 3.68–
3.86 (m, 8H), 6.35 (d, J¼2 Hz, 1H), 6.41 (dd, J¼8, 2 Hz, 1H), 7.26 (d,
J¼8 Hz, 1H), 7.67–7.94 (m, 15H); 13C NMR (75 MHz, CDCl3)
d
23.2 (d,
4.2.8. (S,Z)-5-(2,4-Dimethoxyphenyl)pent-3-en-2-yl picolinate ((S)-
6a). To an ice-cold solution of picolinic acid (141 mg, 1.15 mmol)
and DMAP (111 mg, 0.909 mmol) in CH2Cl2 (4 mL) were added DCC
(252 mg, 1.22 mmol) and, after 30 min, a solution of alcohol 19
(208 mg, 0.936 mmol) in CH2Cl2 (3 mL). The mixture was stirred at
room temperature for 2.5 h, diluted with Et2O, and filtered through
a pad of Celite. The filtrate was concentrated, and the residual oil
was purified by chromatography on silica gel with hexane/EtOAc
(from 4:1 to 2:1) to afford the picolinate (S)-6a (286 mg, 94%): 94%
J¼14 Hz,) (þ), 23.5 (d, J¼29 Hz,) (þ), 55.4 (ꢁ), 55.5 (ꢁ), 98.6 (ꢁ),
104.6 (ꢁ), 118.2 (d, J¼14 Hz,) (þ), 118.6 (d, J¼85 Hz,) (þ), 130.5 (d,
J¼13 Hz,) (ꢁ), 131.2 (ꢁ), 133.7 (d, J¼10 Hz,) (ꢁ), 135.2 (d, J¼3 Hz,)
(ꢁ), 157.7 (þ), 160.4 (þ).
4.2.5. (S)-2-(tert-Butyldiphenylsilyloxy)propanal ((S)-17). A solu-
tion of ethyl lactate 15 (2.01 g, 17.0 mmol), TBDPSCl (6.51 mL,
25.4 mmol), and imidazole (2.32 g, 34.1 mmol) in CH2Cl2 (40 mL)
was stirred at room temperature for 4.5 h and poured into satu-
rated NH4Cl. The product was extracted with CH2Cl2 twice. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated to afford a residual oil, which was purified by chro-
matography on silica gel with hexane/EtOAc (from 1:0 to 100:1) to
afford silyl ether 16 (6.05 g, 100%), which showed an identical 1H
NMR spectrum to that reported.15
To a solution of the above silyl ether 16 (1.51 g, 4.24 mmol) in
CH2Cl2 (9 mL) was added DIBAL-H (4.63 mL, 1.0 M in THF,
4.63 mmol) at ꢁ78 ꢀC. After 1 h at ꢁ78 ꢀC, H2O (0.80 mL, 44 mmol)
and NaF (1.80 g, 42.9 mmol) were added carefully. The resulting
mixture was stirred at room temperature for 30 min and filtered
through a pad of Celite. The filtrate was concentrated, and the
residue was subjected to chromatography on silica gel with hexane/
EtOAc (from 1:0 to 10:1) to afford aldehyde (S)-17 (1.18 g, 89%),
which showed an identical 1H NMR spectrum to that reported.15
ee by HPLC analysis (Chiralcel AD-H, hexane/i-PrOH¼95/5, 1.0 mL/
27
min, tR/min¼24.6 (S), 34.4 (R)); [
a
]
þ88 (c 0.22, CHCl3); IR (neat)
1717, 1507, 1289, 1137, 1043 cmꢁ1; 1DH NMR (300 MHz, CDCl3)
d 1.51
(d, J¼6.5 Hz, 3H), 3.42 (dd, J¼15, 6 Hz, 1H), 3.54 (dd, J¼15, 6 Hz, 1H),
3.78 (s, 3H), 3.79 (s, 3H), 5.60–5.74 (m, 2H), 6.17 (dq, J¼8, 7 Hz, 1H),
6.40 (dd, J¼8, 3 Hz, 1H), 6.42 (d, J¼3 Hz, 1H), 7.07 (d, J¼8 Hz, 1H),
7.45 (ddd, J¼8, 5, 1.5 Hz, 1H), 7.82 (td, J¼8, 1.5 Hz, 1H), 8.12 (dt, J¼8,
1 Hz, 1H), 8.77–8.79 (m, 1H); 13C NMR (75 MHz, CDCl3)
d
21.0 (ꢁ),
28.0 (þ), 55.3 (ꢁ), 55.4 (ꢁ), 68.9 (ꢁ), 98.5 (ꢁ), 103.9 (ꢁ), 120.9 (þ),
125.2 (ꢁ), 126.7 (ꢁ), 129.0 (ꢁ), 129.9 (ꢁ), 131.9 (ꢁ), 136.9 (ꢁ), 148.7
(þ), 149.9 (ꢁ), 158.2 (þ), 159.4 (þ), 164.6 (þ); HRMS (FAB) calcd for
C19H21NO4Na [(MþNa)þ] 350.1368, found 350.1368.
4.2.9. (R,E)-2,4-Dimethoxy-1-(2-(4-methoxyphenyl)pent-3-enyl)-
benzene ((R)-8a). To an ice-cold suspension of CuBr$Me2S (68 mg,
0.331 mmol) in THF (5 mL) was added 4-MeOC6H4MgBr (0.64 mL,
0.95 M in THF, 0.608 mmol) dropwise. After 30 min of stirring, the
mixture was cooled to ꢁ70 ꢀC. A solution of picolinate (S)-6a
(100 mg, 0.305 mmol, 94% ee) in THF (3 mL) was added to the
mixture, which was stirred between ꢁ70 ꢀC and ꢁ50 ꢀC for 1 h.
Saturated NH4Cl and EtOAc were added to the mixture with vig-
orous stirring. The layers were separated and the aqueous layer was
extracted with EtOAc twice. The combined organic layers were
4.2.6. (S,Z)-1-(2,4-Dimethoxyphenyl)-4-(tert-butyldiphenyl-silyloxy)-
pent-2-ene (18). To an ice-cold solution of phosphonium salt 14
(4.88 g, 9.62 mmol) in THF (12 mL) was added NaN(TMS)2 (9.60 mL,
1.0 M in THF, 9.60 mmol). After 0.5 h at ice-bath temperature, the
mixture was cooled to ꢁ78 ꢀC and a solution of aldehyde (S)-17
(2.00 g, 6.40 mmol) in THF (20 mL) was added slowly. After the

Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
203
washed with brine, dried over MgSO4, and concentrated to afford
olefin (R)-8a, which was used for the next step without further
mixture was allowed to warm to ambient temperature, stirred for
19 h, and re-cooled to ꢁ50 ꢀC. The reaction was quenched by ad-
dition of H2O (1 mL) and most of the volatile materials were
evaporated. The resulting mixture was diluted with saturated
NH4Cl. The resulting mixture was extracted with EtOAc two times.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated to afford a residual solid mass, which was
chromatographed on silica gel with hexane/EtOAc (1:1) to afford
phenol (S)-9a, which was passed through a short column of silica
purification: 1H NMR (300 MHz, CDCl3)
d
1.61 (dq, J¼6, 1.5 Hz, 3H),
2.83 (dd, J¼13, 7.5 Hz,1H), 2.90 (dd, J¼13, 7.5 Hz,1H), 3.47 (dt, J¼7.5,
7 Hz, 1H), 3.75 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 5.29 (ddq, J¼15, 1,
6 Hz, 1H), 5.62 (ddq, J¼15, 7, 1.5 Hz, 1H), 6.31 (dd, J¼8.5, 2.5 Hz, 1H),
6.39 (d, J¼2.5 Hz, 1H), 6.74–6.84 (m, 3H), 7.01–7.11 (m, 2H).
4.2.10. (4S)-5-(2,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)-pen-
tane-2,3-diol (20). To an ice-cold solution of crude olefin (R)-8a and
NMO (53 mg, 0.45 mmol) in acetone and H2O (2:1, 3 mL) was added
OsO4 (0.77 mL, 0.02 M in t-BuOH, 0.015 mmol). The mixture was
stirred at room temperature for 5 h and poured into H2O. The
product was extracted with EtOAc twice. The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated to afford a residual oil, which was purified by chromatog-
raphy on silica gel with hexane/EtOAc (from 10:1 to 1:1) to afford
gel for the next step: 1H NMR (300 MHz, CDCl3)
d
2.82 (dd, J¼13.5,
7 Hz, 1H), 3.08 (dd, J¼13.5, 7 Hz, 1H), 3.16–3.28 (m, 1H), 3.54–3.66
(m, 2H), 4.79–5.00 (m, 3H), 6.25–6.30 (m, 2H), 6.72–6.83 (m, 3H),
7.00–7.05 (m, 1H).
4.2.14. (S)-Equol ((S)-3). A mixture of the above phenol (S)-9a and
K2CO3 (268 mg, 1.94 mmol) in acetone (6 mL) was stirred at 50 ꢀC
for 8 h, cooled to room temperature, and filtered through a pad of
Celite. The filtrate was concentrated and the residual solid mass
was purified by chromatography on silica gel with hexane/EtOAc
(from 1:3) to afford (S)-3 (110 mg, 74% from bromide 22) as white
solids: 91% ee by HPLC analysis (Chiralcel AD-H, hexane/i-
diol 20 (87 mg, 75% from (S)-6a): 1H NMR (300 MHz, CDCl3)
d 1.07
(d, J¼6 Hz, 1.5H), 1.16 (d, J¼6 Hz, 1.5H), 2.60–3.64 (m, 5H), 3.743 (s,
3H), 3.770 (s, 1.5H), 3.788 (s, 1.5H), 3.792 (s, 1.5H), 3.795 (s, 1.5H),
3.857 (s, 1.5H), 6.27 (dd, J¼8, 2 Hz, 0.5H), 6.38–6.49 (m, 1.5H), 6.66
(d, J¼8 Hz, 0.5H), 6.78 (d, J¼9 Hz, 1H), 6.84 (d, J¼9 Hz, 1H), 6.98 (d,
J¼8 Hz, 0.5H), 7.02 (d, J¼9 Hz, 1.5H), 7.26 (d, J¼9 Hz, 1.5H).
PrOH¼90/10, 1.0 mL/min, tR/min¼38.7 for (R)-isomer, 49.4 for (S)-
3); mp 190–191 ꢀC (lit.9 192–193 ꢀC; lit.11 190.8 ꢀC); [
a
]
ꢁ13 (c
25
D
0.21, EtOH);25 IR (Nujol) 3358, 1598, 1151, 1024, 829 cmꢁ1; 1H NMR
(300 MHz, (CD3)2SO) 2.70–2.90 (m, 2H), 2.95–3.07 (m,1H), 3.89 (t,
4.2.11. (S)-3-(2,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)propan-
1-ol (21). To an ice-cold solution of diol 20 (87 mg, 0.241 mmol) in
MeOH and H2O (2:3, 5 mL) was added NaIO4 (80 mg, 0.374 mmol).
After 0.5 h at 0 ꢀC, NaBH4 (55 mg, 1.47 mmol) was added. The
mixture was stirred at 0 ꢀC for 0.5 h and poured into saturated
NH4Cl. The product was extracted with EtOAc twice. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. Chromatography of the crude product on silica gel
with hexane/EtOAc (from 4:1 to 1:1) afforded alcohol 21 (59.7 mg,
d
J¼10.5 Hz, 1H), 4.10–4.18 (dm, J¼8 Hz, 1H), 6.19 (d, J¼2.5 Hz, 1H),
6.28 (dd, J¼8, 2.5 Hz, 1H), 6.72 (d, J¼8.5 Hz, 2H), 6.86 (d, J¼8 Hz,
1H), 7.10 (d, J¼8.5 Hz, 2H), 9.16 (s, 1H), 9.28 (s, 1H); 13C NMR
(75 MHz, (CD3)2SO)
d
31.3 (þ), 37.2 (ꢁ), 70.2 (þ), 102.5 (ꢁ), 108.0
(ꢁ), 112.6 (þ), 115.2 (ꢁ), 128.3 (ꢁ), 130.1 (ꢁ), 131.6 (þ), 154.5 (þ),
156.1 (þ), 156.5 (þ); HRMS (FAB) calcd for C15H14O3 [Mþ] 242.0943,
found 242.0943. The 1H and 13C NMR spectra of (S)-3 was identical
with that reported.9,11
82%) as solids: 91% ee by HPLC analysis (Chiralcel AD-H, hexane/i-
23
PrOH¼95/5, 1.0 mL/min, tR/min¼31.3 (R), 42.0 (S)); [
0.29, CHCl3); IR (Nujol) 3551, 1612, 1157, 1032, 839 cmꢁ1
(300 MHz, CDCl3)
a
]
þ61 (c
4.3. Synthesis of (R)-sativan
D
;
1H NMR
d
1.70 (t, J¼6 Hz, 1H), 2.77 (dd, J¼6, 3 Hz, 1H),
4.3.1. 2,4-Bis(benzyloxy)benzaldehyde (28). A mixture of 2,4-dihy-
2.91–3.09 (m, 2H), 3.70 (t, J¼6 Hz, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 3.80
(s, 3H), 6.35 (dd, J¼8.5, 2.5 Hz, 1H), 6.43 (d, J¼2.5 Hz, 1H), 6.82–6.89
(dm, J¼9 Hz, 3H), 7.12–7.17 (dm, J¼9 Hz, 2H); 13C NMR (75 MHz,
droxybenzaldehyde
(4.99 g,
36.1 mmol),
BnCl
(11.34 ml,
98.5 mmol), and K2CO3 (13.75 g, 99.5 mmol) in EtOH (50 mL) was
stirred at 80 ꢀC overnight, cooled to room temperature, and filtered
through a pad of Celite. The filtrate was concentrated to afford a re-
sidual oil, which was diluted with brine. The resulting mixture was
extracted with EtOAc twice. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo to
afford a residual solid, which was recrystallized from hexane/EtOAc
to afford ether 28 (1.86 g 81%) as white solids, which showed the
identical 1H NMR spectrum to that reported.26 Other data are: mp
85–86 ꢀC (hexane/EtOAc); IR (Nujol) 1608,1260,1015 cmꢁ1; 1H NMR
CDCl3)
d
32.4 (þ), 48.0 (ꢁ), 55.3 (ꢁ), 55.4 (ꢁ), 55.5 (ꢁ), 66.2 (þ), 98.5
(ꢁ), 104.1 (ꢁ), 113.9 (ꢁ), 120.6 (þ), 129.1 (ꢁ), 131.2 (ꢁ), 134.9 (þ),
158.31 (þ), 158.35 (þ), 159.4 (þ); HRMS (FAB) calcd for C18H22O4
[Mþ] 302.1518, found 302.1512.
4.2.12. (S)-1-(3-Bromo-2-(4-methoxyphenyl)propyl)-2,4-dimethoxy-
benzene (22). To an ice-cold solution of alcohol 21 (103 mg,
0.341 mmol) and PPh3 (135 mg, 0.515 mmol) in CH2Cl2 (1 mL) was
added CBr4 (123 mg, 0.371 mmol). The mixture was stirred at room
temperature for 3 h and concentrated to afford a residual oil, which
was purified by chromatography on silica gel with hexane/EtOAc
(300 MHz, CDCl3)
(dd, J¼8.5, 2 Hz,1H), 7.32–7.46 (m,10H), 7.84 (d, J¼8.5 Hz,1H),10.39
(s,1H); 13C NMR (75 MHz, CDCl3)
d
5.10 (s, 2H), 5.14 (s, 2H), 6.60 (d, J¼2 Hz,1H), 6.64
d
70.3 (þ), 70.4 (þ),100.0 (ꢁ),107.0
(from 1:0 to 10:1) to afford bromide 22 (113 mg, 90%) as white
(ꢁ), 119.4 (þ), 127.3 (ꢁ), 127.5 (ꢁ), 128.3 (ꢁ), 128.4 (ꢁ), 128.7 (ꢁ),
130.4 (ꢁ), 135.86 (þ), 135.90 (þ), 162.7 (þ), 165.1 (þ), 188.2 (ꢁ).
26
solids: [
a
]
þ31 (c 0.21, CHCl3); IR (Nujol) 1610, 1244, 1211, 1157,
1032 cmꢁ1D; 1H NMR (300 MHz, CDCl3)
d
2.86 (dd, J¼13.5, 7 Hz, 1H),
3.02 (dd, J¼13.5, 7.5 Hz, 1H), 3.20–3.31 (m, 1H), 3.54 (dd, J¼10,
7.5 Hz, 1H), 3.60 (dd, J¼10, 5.5 Hz, 1H), 3.76 (s, 3H), 3.77 (s, 3H), 3.79
(s, 3H), 6.34 (dd, J¼8, 2.5 Hz, 1H), 6.41 (d, J¼2.5 Hz, 1H), 6.80–6.90
(m, 3H), 7.08–7.12 (dm, J¼8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
4.3.2. 2,4-Bis(benzyloxy)-1-vinylbenzene (29). To an ice-cold mix-
ture of [Ph3PCH3]þBrꢁ (5.08 g, 14.2 mmol) in THF (40 mL) was
added BuLi (8.10 mL, 1.6 M in THF, 13.0 mmol). After 1 h at the ice-
bath temperature, a solution of aldehyde 28 (3.44 g, 10.8 mmol) in
THF (40 mL) was added. The reaction mixture was stirred at room
temperature overnight and diluted with saturated NH4Cl. The
resulting mixture was extracted with EtOAc and the product was
purified by chromatography to afford olefin 29 (2.90 g, 85%): IR
(neat) 1604, 1501, 1173, 1119, 1026 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
35.0 (þ), 39.0 (þ), 47.0 (ꢁ), 55.26 (ꢁ), 55.31 (ꢁ), 55.38 (ꢁ), 98.5
(ꢁ), 103.8 (ꢁ), 113.7 (ꢁ), 120.1 (þ), 128.7 (ꢁ), 131.1 (ꢁ), 134.7 (þ),
158.4 (þ), 158.5 (þ), 159.5 (þ); HRMS (FAB) calcd for C18H21BrO3
[Mþ] 364.0674, found 364.0678.
4.2.13. (S)-4-(3-Bromo-2-(4-hydroxyphenyl)propyl)benzene-1,3-diol
((S)-9a). To a solution of bromide 22 (201 mg, 0.550 mmol) in
CH2Cl2 (4 mL) was added BBr3 (0.175 mL, 1.82 mmol) at ꢁ78 ꢀC. The
d
5.03 (s, 2H), 5.04 (s, 2H), 5.14 (dd, J¼11.5, 1.5 Hz, 1H), 5.65 (dd,
J¼17.5, 1.5 Hz, 1H), 6.54–6.61 (m, 2H), 7.03 (dd, J¼17.5, 11.5 Hz, 1H),
7.28–7.49 (m, 11H); 13C NMR (75 MHz, CDCl3)
70.2 (þ), 70.3 (þ),
d

204
Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
23
100.7 (ꢁ), 106.3 (ꢁ), 112.4 (þ), 120.5 (þ), 127.3 (ꢁ), 127.4 (ꢁ), 127.6
(ꢁ), 128.0 (ꢁ), 128.1 (ꢁ), 128.6 (ꢁ), 128.7 (ꢁ), 131.2 (ꢁ), 136.9 (þ),
137.0 (þ), 157.0 (þ), 159.7 (þ); HRMS (FAB) calcd for C22H20O2 [Mþ]
316.1463, found 316.1459.
chromatography to afford olefin 34 (1.77 g, 90%): [
CHCl3); IR (neat) 1611, 1588, 1505, 1111, 701 cmꢁ1
(300 MHz, CDCl3)
a
]
ꢁ8.8 (c 0.92,
D
;
1H NMR
d
1.04 (s, 9H), 1.13 (d, J¼6.5 Hz, 3H), 2.89 (dd,
J¼16, 7 Hz, 1H), 3.10 (dd, J¼16, 8 Hz, 1H), 4.63–4.74 (m, 1H), 4.95 (s,
2H), 4.98 (s, 2H), 5.38 (dt, J¼11, 7 Hz, 1H), 5.59 (dd, J¼11, 8 Hz, 1H),
6.39 (dd, J¼8, 2.5 Hz,1H), 6.52 (d, J¼2.5 Hz,1H), 6.75 (d, J¼8 Hz,1H),
7.25–7.44 (m, 16H), 7.62–7.71 (m, 4H); 13C NMR (75 MHz, CDCl3)
4.3.3. 2-(2,4-Bis(benzyloxy)phenyl)ethanol (30). To an ice-cold so-
lution of olefin 29 (2.00 g, 6.32 mmol) in THF (20 mL) was added 9-
BBN (25.2 mL, 0.5 M in THF, 12.6 mmol). The solution was stirred at
ambient temperature for 14 h and diluted with MeOH (20 mL).
After 1 h of stirring, 3 N NaOH (21 mL, 63 mmol), and 35% H2O2
(3.3 mL, 38 mmol) were added slowly. The resulting mixture was
stirred at room temperature for 3 h, diluted with H2O, and extrac-
ted with EtOAc. The product was purified by chromatography to
afford alcohol 30 (1.91 g, 91%) as white solids: IR (Nujol) 3388, 1612,
d
19.2 (þ), 24.7 (ꢁ), 27.0 (ꢁ), 27.3 (þ), 66.0 (ꢁ), 69.9 (þ), 70.2 (þ),
100.5 (ꢁ), 105.3 (ꢁ), 122.0 (þ), 126.6 (ꢁ), 127.2 (ꢁ), 127.5 (ꢁ), 127.56
(ꢁ), 127.60 (ꢁ), 127.9 (ꢁ), 128.0 (ꢁ), 128.6 (ꢁ), 128.7 (ꢁ), 129.45 (ꢁ),
129.53 (ꢁ),129.6 (ꢁ),134.4 (þ),134.7 (þ),135.2 (ꢁ),135.9 (ꢁ),136.0
(ꢁ), 137.1 (þ), 157.0 (þ), 158.3 (þ); HRMS (FAB) calcd for
C41H44O3SiNa [(MþNa)þ] 635.2957, found 635.2953.
1505, 1168, 1027 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.61(br s, 1H)
4.3.8. (R,Z)-5-(2,4-Bis(benzyloxy)phenyl)-3-penten-2-ol (35). To
a solution of 34 (1.77 g, 2.89 mmol) in THF (15 mL) was added
Bu4NF (4.40 mL, 1.0 M in THF, 4.40 mmol). The solution was stirred
at room temperature for 25 h and diluted with H2O. The resulting
mixture was extracted with EtOAc and the product was purified by
2.88 (t, J¼6.5 Hz, 2H), 3.80 (t, J¼6.5 Hz, 2H), 5.02 (s, 2H), 5.03 (s, 2H),
6.53 (dd, J¼8, 2 Hz, 1H), 6.61 (d, J¼2 Hz, 1H), 7.08 (d, J¼8 Hz, 1H),
7.27–7.48 (m, 10H); 13C NMR (75 MHz, CDCl3)
d
33.6 (þ), 63.0 (þ),
70.1 (þ), 70.2 (þ), 100.8 (ꢁ), 105.6 (ꢁ), 119.9 (þ), 127.3 (ꢁ), 127.6 (ꢁ),
128.0 (ꢁ), 128.1 (ꢁ), 128.68 (ꢁ), 128.70 (ꢁ), 131.3 (ꢁ), 136.9 (þ),
137.0 (þ), 157.7 (þ), 158.9 (þ); HRMS (FAB) calcd for C22H22O3 [Mþ]
334.1569, found 334.1559.
chromatography to afford alcohol 35 (1.02 g, 94%) as white solids:
23
[a
]
þ21 (c 0.56, CHCl3); IR (Nujol) 3340, 1610, 1170 cmꢁ1; 1H NMR
D
(300 MHz, CDCl3)
d
1.19 (d, J¼6 Hz, 3H), 1.47 (br s, 1H), 3.38 (dd,
J¼15.5, 7 Hz, 1H), 3.46 (dd, J¼15.5, 7 Hz, 1H), 4.72 (dq, J¼6, 6 Hz,
1H), 5.00 (s, 2H), 5.02 (s, 2H), 5.42–5.61 (m, 2H), 6.52 (dd, J¼8.5,
2 Hz, 1H), 6.59 (d, J¼2 Hz, 1H), 7.04 (d, J¼8.5 Hz, 1H), 7.28–7.47 (m,
4.3.4. (1,3-Bis(benzyloxy)-4-(2-bromoethyl))benzene (31). A solu-
tion of alcohol 30 (3.90 g, 11.7 mmol), CBr4 (4.73 g, 14.3 mmol), and
PPh3 (4.07 g, 15.5 mmol) in CH2Cl2 (23 mL) was stirred at room
temperature for 2 h and the product was purified by chromatog-
raphy to afford bromide 31 (3.96 g, 86%): 1H NMR (300 MHz, CDCl3)
10H); 13C NMR (75 MHz, CDCl3)
d
23.4 (ꢁ), 28.0 (þ), 63.7 (ꢁ), 70.1
(þ), 70.2 (þ), 100.7 (ꢁ), 105.6 (ꢁ), 121.7 (þ), 127.4 (ꢁ), 127.6 (ꢁ),
128.0 (ꢁ), 128.1 (ꢁ), 128.6 (ꢁ), 129.4 (ꢁ), 129.8 (ꢁ), 134.2 (ꢁ), 136.9
(þ), 137.0 (þ), 157.2 (þ), 158.5 (þ); HRMS (FAB) calcd for C25H26O3
[Mþ] 374.1882, found 374.1887.
d
3.16 (t, J¼7.5 Hz, 2H), 3.57 (t, J¼7.5 Hz, 2H), 5.02 (s, 2H), 5.04 (s,
2H), 6.52 (dd, J¼8, 2 Hz, 1H), 6.59 (d, J¼2 Hz, 1H), 7.07 (d, J¼8 Hz,
1H), 7.28–7.45 (m, 10H).
4.3.9. ((R,Z)-4-(2,4-Bis(benzyloxy)phenyl)-1-methyl-2-butene)picoli-
nate ((R)-6b). To an ice-cold mixture of picolinic acid (392 mg,
3.18 mmol), DMAP (155 mg, 1.27 mmol), and DCC (704 mg,
3.41 mmol) in CH2Cl2 (7 mL) was added a solution of alcohol 35
(940 mg, 2.51 mmol) in CH2Cl2 (10 mL). The mixture was stirred at
room temperature overnight, diluted with Et2O, and filtered
through a pad of Celite. The product was purified by chromatog-
4.3.5. (2-(2,4-Bis(benzyloxy)phenyl)ethyl)triphenylphosphonium
bromide (32). A solution of bromide 31 (0.53 g, 1.33 mmol) and
PPh3 (0.54 g, 2.06 mmol) in EtOH (3.5 mL) was refluxed for 40 h and
concentrated. The residual solid was recrystallized from Et2O to
afford phosphonium salt 32 (0.89 g, 100%) as white solids: 1H NMR
(300 MHz, CDCl3)
4.94 (s, 2H), 5.02 (s, 2H), 6.52–6.57 (m, 2H), 7.30–7.45 (m, 13H),
7.52–7.61 (m, 5H), 7.64–7.79 (m, 8H).
d
2.96 (dt, J¼10, 6 Hz, 2H), 3.74ꢁ3.87 (m, 2H),
raphy to afford the picolinate (R)-6b (1.04 g, 86%): 97% ee by 1H
27
NMR spectroscopy of the derived MTPA ester; [
CHCl3); IR (Nujol) 1714, 1505, 1135, 744 cmꢁ1
CDCl3)
a
]
D
ꢁ61 (c 0.48,
;
1H NMR (500 MHz,
4.3.6. (R)-2-(tert-Butyldiphenylsilyloxy)propanal ((R)-17). A solu-
tion of methyl lactate 33 (1.99 g, 19.1 mmol), TBDPSCl (7.40 mL,
26.9 mmol), and imidazole (2.64 g, 38.8 mmol) in CH2Cl2 (50 mL)
was stirred at room temperature overnight and the crude product
was purified by chromatography to afford the silyl ether of 33
(6.25 g, 95%), which showed the identical 1H NMR spectrum to that
reported.15a,27
To a solution of the above silyl ether (6.25 g, 18.2 mmol) in
CH2Cl2 (35 mL) was added DIBAL-H (19.5 mL, 1.03 M in THF,
20.1 mmol) at ꢁ78 ꢀC. After 1 h at ꢁ78 ꢀC, H2O (3.30 mL, 183 mmol)
and NaF (7.60 g, 181 mmol) were added carefully. The resulting
mixture was stirred at room temperature for 30 min and filtered
through a pad of Celite. The product was purified by chromatog-
raphy to afford aldehyde (R)-17 (5.38 g, 94%), which showed the
identical 1H NMR spectrum to that reported.15a
d
1.42 (d, J¼6.5 Hz, 3H), 3.48 (dd, J¼15, 7.5 Hz, 1H), 3.62 (dd,
J¼15, 7.5 Hz, 1H), 5.00 (s, 2H), 5.04 (s, 2H), 5.64 (dd, J¼10.5, 8.5 Hz,
1H), 5.73 (dt, J¼10.5, 7.5 Hz, 1H), 6.11 (dq, J¼8.5, 6.5 Hz, 1H), 6.50
(dd, J¼8.5, 3 Hz, 1H), 6.58 (d, J¼3 Hz, 1H), 7.09 (d, J¼8.5 Hz, 1H),
7.27–7.43 (m, 10H), 7.45 (dd, J¼7.5, 4.5 Hz, 1H), 7.81 (dd, J¼7.5,
7.5 Hz, 1H), 8.11 (dm, J¼7.5 Hz, 1H), 8.77 (dm, J¼4.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3)
d
20.9 (ꢁ), 28.1 (þ), 68.9 (ꢁ), 70.0 (þ), 70.2
(þ), 100.6 (ꢁ), 105.5 (ꢁ), 121.5 (þ), 125.1 (ꢁ), 126.7 (ꢁ), 127.2 (ꢁ),
127.6 (ꢁ), 127.8 (ꢁ), 128.0 (ꢁ), 128.59 (ꢁ), 128.62 (ꢁ), 129.1 (ꢁ),
130.1 (ꢁ), 132.0 (ꢁ), 136.9 (ꢁ), 137.1 (þ), 148.6 (þ), 149.9 (ꢁ), 157.2
(þ),158.5 (þ),164.5 (þ); HRMS (FAB) calcd for C31H30NO4 [(MþH)þ]
480.2175, found 480.2188.
4.3.10. (S,E)-1,3-Bis(benzyloxy)-4-(2-(2,4-dimethoxyphenyl)pent-3-
enyl)benzene ((S)-8b). To an ice-cold suspension of CuBr$Me2S
(21.7 mg, 0.106 mmol) in THF (1.5 mL) was added 2,4-
(MeO)2C6H3MgBr (0.20 mL, 1.00 M in THF, 0.200 mmol) dropwise.
After 30 min of stirring, the resulting mixture was cooled to ꢁ60 ꢀC.
A solution of picolinate (R)-6b (49.9 mg, 0.104 mmol, 96.7% ee) in
THF (1 mL) was added dropwise to the reaction mixture. The re-
action mixture was allowed to warm to ꢁ50 ꢀC over 1 h and diluted
with saturated NH4Cl. The mixture was extracted with EtOAc and
4.3.7. (R,Z)-5-(2,4-Bis(benzyloxy)phenyl)-2-(tert-butyldiphenylsily-
loxy)-3-pentene (34). To an ice-cold solution of phosphonium salt
32 (3.22 g, 4.88 mmol) in THF (6 mL) was added NaN(TMS)2
(4.80 mL, 1.0 M in THF, 4.80 mmol). The mixture was stirred at 0 ꢀC
for 0.5 h and cooled to ꢁ78 ꢀC. A solution of aldehyde (R)-17 (1.00 g,
3.20 mmol) in THF (10 mL) was added to the mixture. The mixture
was allowed to warm to ambient temperature slowly, stirred
overnight, and diluted with saturated NH4Cl. The mixture
was extracted with EtOAc and the product was purified by
the product was passed through a short column of silica gel to af-
23
ford olefin (S)-8b, which was used for the next step: [
a
]
ꢁ4.2 (c
D
0.87, CHCl3); IR (neat) 1610, 1586, 1507, 1288, 1157 cmꢁ1
;
1H NMR

Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
205
(300 MHz, CDCl3)
d
1.58 (dm, J¼6.5 Hz, 3H), 2.87 (dd, J¼13.5, 7 Hz,
MeOH (0.7 mL) and 3 N LiOH (0.7 mL, 2.1 mmol). The mixture was
heated to 80 ꢀC for 2 h and diluted with H2O. The mixture was
extracted with EtOAc and the product was purified by chroma-
tography to afford sativan (R)-4 (15.0 mg, 77%) as yellow solids:
1H), 3.00 (dd, J¼13.5, 8 Hz, 1H), 3.59 (s, 3H), 3.77 (s, 3H), 3.92–4.05
(m, 1H), 4.98 (s, 2H), 5.02 (s, 2H), 5.29 (ddm, J¼15, 6.5 Hz, 1H), 5.68
(ddm, J¼15, 8 Hz,1H), 6.34–6.47 (m, 3H), 6.54 (d, J¼2.5 Hz,1H), 6.85
(d, J¼8.5 Hz, 1H), 7.06 (d, J¼8.5 Hz, 1H), 7.26–7.52 (m, 10H); 13C
93.8% ee by HPLC analysis (Chiralcel OD-H, hexane/i-PrOH¼94/6,
24
NMR (75 MHz, CDCl3)
d
18.1 (ꢁ), 35.7 (þ), 41.5 (ꢁ), 55.3 (ꢁ) 55.4 (ꢁ),
0.5 mL/min, 25 ꢀC; tR (min)¼41.4 (S), 55.3 (R)); [
a
]
D
ꢁ8 (c 0.28,
69.8 (þ), 70.1 (þ), 98.7 (ꢁ), 100.2 (ꢁ), 104.1 (ꢁ), 104.9 (ꢁ), 122.4 (þ),
124.4 (ꢁ), 126.1 (þ), 127.1 (ꢁ), 127.7 (ꢁ), 128.0 (ꢁ), 128.50 (ꢁ),
128.53 (ꢁ), 128.60 (ꢁ), 131.3 (ꢁ), 134.4 (þ), 137.2 (þ), 137.6 (þ) 157.6
(þ), 157.9 (þ), 158.0 (þ), 158.8 (þ); HRMS (FAB) calcd for
C33H34O4Na [(MþNa)þ] 517.2355, found 517.2363.
MeOH); mp 129–130 ꢀC (hexane/EtOAc); 1H NMR (300 MHz, CDCl3)
d
2.85 (dd, J¼15.5, 5.5 Hz, 1H), 2.96 (dd, J¼15.5, 10.5 Hz, 1H), 3.50–
3.62 (m, 1H), 3.80 (s, 6H), 3.99 (dd, J¼10, 10 Hz, 1H), 4.29 (dm,
J¼10 Hz, 1H), 5.16 (br s, 1H), 6.34–6.53 (m, 4H), 6.93 (d, J¼8 Hz, 1H),
7.01 (d, J¼8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
30.4 (þ), 31.6 (ꢁ),
55.39 (ꢁ), 55.44 (þ), 70.2 (ꢁ), 98.7 (ꢁ), 103.2 (ꢁ), 104.2 (ꢁ), 108.0
(ꢁ), 114.9 (þ), 121.9 (þ), 127.6 (ꢁ), 130.5 (ꢁ), 154.9 (þ), 155.1 (þ),
158.3 (þ), 159.7 (þ); HRMS (EI) calcd for C17H18O4 [Mþ] 286.1205,
4.3.11. (4R)-5-(2,4-Bis(benzyloxy)phenyl)-4-(2,4-dimethox-
yphenyl)pentane-2,3-diol. To an ice-cold solution of the above ole-
fin and NMO (17.8 mg, 0.152 mmol) in acetone and H2O (4:1, 1 mL)
was added OsO4 (0.50 mL, 0.02 M in t-BuOH, 0.010 mmol). The
mixture was stirred at room temperature overnight and diluted
with H2O. The resulting mixture was extracted with EtOAc and the
product was chromatographed to afford a diastereomeric mixture
of the corresponding diol (45.0 mg, 85% over two steps) as brown
amorphous solids.
found 286.1209. The 1H NMR spectrum, [
a]D, and mp were con-
24
sistent with those reported: 1H NMR spectrum (CDCl3),21a,b
[a]
D
ꢁ9.9 (c 0.33, MeOH);21b mp 128–129 ꢀC.21a
4.4. Synthesis of (R)-vestitol
4.4.1. 3-Bromo-2-hydroxy-6-methoxybenzoic acid (42)22. To an ice-
cold solution of acid 41 (10.0 g, 54.9 mmol) in CHCl3 (120 mL) was
added Br2 (2.8 mL, 54.6 mmol) in CHCl3 (100 mL). The mixture was
stirred at room temperature for two days and concentrated to af-
ford a residual solid, which was recrystallized from MeOH to afford
bromide 42 (7.61 g, 56%) as white solids: mp 144–145 ꢀC (MeOH);
4.3.12. (R)-3-(2,4-Bis(benzyloxy)phenyl)-2-(2,4-dimethoxyphenyl)-
propan-1-ol (36). To an ice-cold solution of the above diol (45.0 mg,
0.085 mmol) in MeOH and H2O (4:1, 1 mL) was added NaIO4
(31.0 mg, 0.142 mmol). After 2 h at room temperature, NaBH4
(22.7 mg, 0.600 mmol) was added to the mixture, which was stir-
red at room temperature for further 0.5 h. The mixture was diluted
with saturated NH4Cl and extracted with EtOAc twice. Chroma-
tography of the crude product afforded alcohol 36 (36.5 mg, 86%) as
brown amorphous solids: 94.0% ee by HPLC analysis (Chiralcel AD-
1H NMR (300 MHz, CDCl3)
J¼9 Hz, 1H), 11.36 (br s, 1H), 12.93 (s, 1H).
d
4.10 (s, 3H), 6.47 (d, J¼9 Hz,1H), 7.68 (d,
4.4.2. 2-Bromo-5-methoxyphenol. A solution of bromide 42 (1.97 g,
7.97 mmol) in quinoline (80 mL) was stirred at 150 ꢀC for 1 h and
diluted with EtOAc. The resulting mixture was extracted with 3 N
HCl three times. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to afford a re-
sidual oil, which was chromatographed on silica gel with hexane/
EtOAc (30:1) to afford bromide 2-bromo-5-methoxyphenol (1.24 g,
H, hexane/i-PrOH¼91/9, 0.5 mL/min, 25 ꢀC; tR (min)¼91.9 (S), 99.0
27
(R)); [
a
]
ꢁ12.9 (c 0.59, CHCl3); IR (neat) 3418, 1505, 696 cmꢁ1; 1H
D
NMR (300 MHz, CDCl3)
d
1.71 (br s, 1H), 2.85 (dd, J¼13.5, 6.5 Hz,
1H), 3.03 (dd, J¼13.5, 8.5 Hz, 1H), 3.45–3.56 (m, 1H), 3.66–3.84 (m,
2H), 3.68 (s, 3H), 3.78 (s, 3H), 5.00 (s, 2H), 5.03 (s, 2H), 6.39–6.46 (m,
2H), 6.47 (d, J¼2 Hz, 1H), 6.58 (d, J¼2 Hz, 1H), 6.93 (d, J¼9 Hz, 1H),
7.07 (d, J¼9 Hz, 1H), 7.28–7.50 (m, 10H); 13C NMR (75 MHz, CDCl3)
77%): 1H NMR (300 MHz, CDCl3)
d 3.77 (s, 3H), 5.51 (s, 1H), 6.41 (dd,
J¼9, 3 Hz, 1H), 6.60 (d, J¼3 Hz, 1H), 7.31 (d, J¼9 Hz, 1H); 13C NMR
d
31.0 (þ), 41.3 (ꢁ), 55.4 (ꢁ), 65.1 (þ), 70.2 (þ), 98.7 (ꢁ), 100.5 (ꢁ),
(75 MHz, CDCl3)
d
55.6 (ꢁ), 100.9 (þ), 101.7 (ꢁ), 108.4 (ꢁ), 132.0 (ꢁ),
104.1 (ꢁ), 105.5 (ꢁ), 121.9 (þ), 123.4 (þ), 127.4 (ꢁ), 127.6 (ꢁ), 127.97
(ꢁ), 128.03 (ꢁ), 128.6 (ꢁ), 128.8 (ꢁ), 131.3 (ꢁ), 137.0 (þ), 137.1 (þ),
157.5 (þ), 158.3 (þ), 158.4 (þ), 159.3 (þ); HRMS (FAB) calcd for
C31H32O5 [Mþ] 484.2250, found 484.2272.
153.0 (þ), 160.6 (þ). The 1H NMR spectrum of the product was
identical with that reported.28
4.4.3. 1-Bromo-4-methoxy-2-(methoxymethoxy)benzene (43). A sol-
ution of the above bromide (1.42 g, 6.99 mmol), MOMCl (1.58 mL,
21.0 mmol), and i-Pr2EtN (3.65 mL, 21.0 mmol) in CH2Cl2 (14 mL)
was stirred at room temperature overnight and diluted with H2O.
The resulting mixture was extracted with CH2Cl2 twice. The com-
bined organic layers were washed with 1 N HCl, saturated NaHCO3,
dried over MgSO4, and concentrated. The residual oil was purified
by chromatography on silica gel with hexane/EtOAc (from 20:1 to
10:1) to afford the MOM ether 43 (1.65 g, 95%): 1H NMR (300 MHz,
4.3.13. (R)-4-(2-(2,4-Dimethoxyphenyl)-3-hydroxypropyl)benzene-
1,3-diol ((R)-9b). A solution of alcohol 36 (35.6 mg, 0.073 mmol)
and 10% Pd/C (7.4 mg) in MeOH (1 mL) was stirred at room tem-
perature for 3 h under hydrogen, diluted with EtOAc, and filtered
through a pad of Celite. The product was purified by chromatog-
raphy on silica gel with hexane/EtOAc (2:1) to afford phenol (R)-9b
(20.6 mg, 92%) as white solids: mp 140–141 ꢀC (hexane/EtOAc);
27
[
a]
ꢁ43.9 (c 1.21, MeOH); 1H NMR (300 MHz, CD3OD)
d
2.66 (dd,
CDCl3)
d
3.52 (s, 3H), 3.78 (s, 3H), 5.23 (s, 2H), 6.47 (dd, J¼9, 3 Hz,
D
J¼14, 7 Hz, 1H), 2.93 (dd, J¼14, 7 Hz, 1H), 3.43 (tt, J¼7, 7 Hz, 1H),
3.60–3.75 (m, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 6.09 (dd, J¼8, 2 Hz, 1H),
6.23 (d, J¼2 Hz, 1H), 6.41 (dd, J¼8, 2 Hz, 1H), 6.45 (d, J¼2 Hz, 1H),
6.62 (dd, J¼8 Hz,1H), 7.04 (d, J¼8 Hz,1H); 13C NMR (75 MHz, CDCl3)
1H), 6.76 (d, J¼3 Hz, 1H), 7.41 (d, J¼9 Hz, 1H); 13C NMR (75 MHz,
CDCl3)
d
55.5 (ꢁ), 56.3 (ꢁ), 95.1 (þ), 103.2 (ꢁ), 103.4 (þ), 108.1 (ꢁ),
133.1 (ꢁ), 154.4 (þ), 160.0 (þ). The 1H NMR spectrum of the product
was identical with that reported.29
d
32.7 (þ), 43.2 (ꢁ), 56.5 (ꢁ), 56.7 (ꢁ), 66.5 (þ), 100.2 (ꢁ), 104.1 (ꢁ),
106.1 (ꢁ), 108.1 (ꢁ), 120.2 (þ), 125.5 (þ), 130.7 (ꢁ), 133.2 (ꢁ), 157.9
(þ), 158.1 (þ), 160.7 (þ), 161.4 (þ); HRMS (FAB) calcd for C17H20O5K
[(MþNa)þ] 343.0948, found 343.0948.
4.4.4. (S,E)-1,3-Bis(benzyloxy)-4-(2-(4-methoxy-2-methoxymethoxy-
phenyl)pent-3-enyl)benzene ((S)-8c). To an ice-cold suspension of
CuBr$Me2S (43.2 mg, 0.210 mmol) in THF (3 mL) was added 2-
MOMO-4-MeOC6H3MgBr (0.35 mL, 1.18 M in THF, 0.413 mmol)
dropwise. After 30 min of stirring, the resulting mixture was cooled
to ꢁ60 ꢀC. A solution of picolinate (R)-6b (101 mg, 0.210 mmol,
96.7% ee) in THF (2 mL) was added to the reaction mixture drop-
wise. The mixture was allowed to warm to ꢁ50 ꢀC over 1 h and
diluted with saturated NH4Cl with vigorous stirring. The mixture
4.3.14. (R)-Sativan ((R)-4). To an ice-cold solution of (R)-9b
(20.6 mg, 0.068 mmol) and PPh3 (183 mg, 0.698 mmol) in THF
(1.4 mL) was added DEAD (0.123 ml, 40% in toluene, 0.270 mmol).
After 2 h of stirring at room temperature, the resulting mixture was
concentrated to afford a residual solid, which was diluted with

206
Y. Takashima et al. / Tetrahedron 66 (2010) 197–207
was extracted with EtOAc and the product was purified by chro-
matography to afford olefin (S)-8c, which was passed through
a short column of silica gel for the next step: 1H NMR (300 MHz,
J¼8.5 Hz, 1H), 7.04 (d, J¼8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
30.6 (þ), 31.7 (ꢁ), 55.5 (ꢁ), 56.2 (ꢁ), 70.3 (þ), 94.5 (þ), 101.5 (ꢁ),
103.3 (ꢁ), 106.4 (ꢁ), 108.0 (ꢁ), 114.8 (þ), 122.3 (þ), 127.7 (ꢁ), 130.5
(ꢁ), 155.0 (þ), 155.2 (þ), 156.0 (þ), 159.6 (þ); HRMS (FAB) calcd for
C18H20O5 [Mþ] 316.1311, found 316.1308.
CDCl3) characteristic signals
d
1.59 (d, J¼6 Hz, 3H), 2.87 (dd, J¼14,
7.5 Hz, 1H), 3.04 (dd, J¼14, 7.5 Hz, 1H), 3.32 (s, 3H), 3.76 (s, 3H), 4.01
(dt, J¼7.5, 7.5 Hz, 1H), 5.31 (dq, J¼15, 6 Hz, 1H), 5.67 (dd, J¼15, 7.5,
2 Hz, 1H).
4.4.9. (R)-Vestitol ((R)-5). A solution of phenol 46 (14 mg,
0.044 mmol) and 3 N HCl (two drops) in MeOH (1 mL) was stirred
at 80 ꢀC for 1 h and diluted with H2O. The resulting mixture was
extracted with EtOAc twice. The combined organic layers were
washed with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to afford a residual oil, which was subjected
to chromatography on silica gel with hexane/EtOAc (10:1) to afford
(R)-5 (9.6 mg, 80%) as yellow solids: 89.9% ee by HPLC analysis
4.4.5. (4R)-5-(2,4-Bis(benzyloxy)phenyl)-4-(4-methoxy-2-(methoxy-
methoxy)phenyl)pentane-2,3-diol. To an ice-cold solution of the
above olefin (S)-8c and NMO (35.3 mg, 0.301 mmol) in acetone and
H2O (4:1, 2 mL) was added OsO4 (0.50 mL, 0.02 M in t-BuOH,
0.010 mmol). The mixture was stirred at room temperature over-
night and diluted with H2O. The resulting mixture was extracted
with EtOAc and the product was purified by chromatography to
afford the title diol (83.4 mg, 72% form (R)-6b) as brown amor-
phous solids.
(Chiralcel OD-H, hexane/i-PrOH¼92/8, 0.7 mL/min, 25 ꢀC; tR
23
(min)¼39.0 (S), 69.3 (R)); [
a
]
ꢁ16.5 (c 0.22, MeOH); 1H NMR
D
(300 MHz, CDCl3)
d
2.90 (dd, J¼15.5, 5 Hz, 1H), 2.99 (dd, J¼15.5,
10 Hz, 1H), 3.44–3.55 (m, 1H), 3.77 (s, 6H), 4.04 (dd, J¼10, 10 Hz,
1H), 4.33 (dm, J¼10 Hz,1H), 4.67 (br s,1H), 4.95 (br s,1H), 6.33–6.42
(m, 3H), 6.48 (dd, J¼8.5, 2.5 Hz, 1H), 6.94 (d, J¼8.5 Hz, 1H), 7.01 (d,
4.4.6. (R)-3-(2,4-Bis(benzyloxy)phenyl)-2-(4-methoxy-2-(methoxy-
methoxy)phenyl)propan-1-ol (44). To an ice-cold solution of the
above diol (83.4 mg, 0.149 mmol) in MeOH and H2O (4:1, 1.8 mL)
was added NaIO4 (58.9 mg, 0.269 mmol). After 3.5 h at room tem-
perature, NaBH4 (37 mg, 0.98 mmol) was added to the mixture,
which was stirred at room temperature further for 0.5 h. The
mixture was diluted with saturated NH4Cl and extracted with
EtOAc and the product was chromatographed to afford alcohol 44
(64.0 mg, 83%) as brown amorphous solids: 90.2% ee by HPLC
J¼8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 30.4, 31.8, 55.4, 70.0,
102.2, 103.3, 106.1, 108.0, 114.8, 119.9, 128.3, 130.5, 154.3, 154.9,
155.2, 159.4; HRMS (EI) calcd for C16H16O4 [Mþ] 272.1049, found
272.1046. The 1H and 13C NMR spectra and [
a] were consistent
D
with those reported: 1H and 13C NMR spectra (CDCl3),23c
[
a]
ꢁ18.9
22
D
(c 0.50, MeOH).23b
analysis (Chiralcel AD-H, hexane/i-PrOH¼90/10, 0.5 mL/min, 25 ꢀC;
23
Acknowledgements
tR (min)¼69.5 (S), 76.5 (R)); [
a
]
D
ꢁ26.6 (c 0.26, CHCl3); IR (neat)
3421, 1610, 1507, 1156 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.69 (br s,
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
1H), 2.84 (dd, J¼13.5, 6 Hz, 1H), 3.06 (dd, J¼13.5, 8 Hz, 1H), 3.36 (s,
3H), 3.49–3.58 (m, 1H), 3.68–3.76 (m, 1H), 3.77 (s, 3H), 4.98–5.07
(m, 6H), 6.45 (dd, J¼8.5, 3 Hz, 1H), 6.45 (dd, J¼8.5, 3 Hz, 1H), 6.50
(dd, J¼8.5, 3 Hz, 1H), 6.58 (d, J¼3 Hz, 1H), 6.66 (d, J¼3 Hz, 1H), 6.90
(d, J¼8.5 Hz, 1H), 7.09 (d, J¼8.5 Hz, 1H), 7.29–7.49 (m, 10H); 13C
References and notes
NMR (75 MHz, CDCl3)
d
31.2 (þ), 41.3 (ꢁ), 55.4 (ꢁ), 56.0 (ꢁ), 65.3
(þ), 70.2 (þ), 94.6 (þ), 100.5 (ꢁ), 101.5 (ꢁ), 105.5 (ꢁ), 106.3 (ꢁ),
121.7 (þ), 123.8 (þ), 127.4 (ꢁ), 127.6 (ꢁ), 128.1 (ꢁ), 128.67 (ꢁ),
128.69 (ꢁ), 128.8 (ꢁ), 131.3 (ꢁ), 137.0 (þ), 137.1 (þ), 156.1 (þ), 157.5
(þ), 158.4 (þ), 159.1 (þ); HRMS (FAB) calcd for C32H34O6 [Mþ]
514.2355, found 514.2369.
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23
phenol 46 (30.2 mg, 87% from 44) as yellow solids: [
a
]
ꢁ4.7 (c
D
0.29, CHCl3); 1H NMR (300 MHz, CDCl3)
d
2.86 (dd, J¼16, 5 Hz, 1H),
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25. However, the observed [
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D
was inconsistent with those reported: [
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]
D
ꢁ23.5
24
16. Chemical shifts of CH3 for the former and the latter are
respectively.
d
1.61 and 1.31 ppm,
(c not given, EtOH) for >99% ee;9
[
a
]
D
ꢁ23.0 (c not given, EtOH) for 100% ee11
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