The first synthesis of uralenol, 5′-prenylated quercetin, via palladium-catalyzed O-dimethylallylation reaction with concurrent acetyl migration

Article abstract of DOI:10.1055/s-0033-1338559

The first synthesis of uralenol, 5′-prenylated quercetin, is described. The key step is a palladium-catalyzed O-1,1-dimethylallylation reaction, with concurrent acetyl migration to afford the desired intermediate as a major isomer, which was purified by r

Full text of DOI:10.1055/s-0033-1338559

170▌
PAPER
paper
The First Synthesis of Uralenol, 5′-Prenylated Quercetin, via Palladium-
Catalyzed O-Dimethylallylation Reaction with Concurrent Acetyl Migration
Synthesis of Uralenol
Tomoyuki Kawamura,a Moemi Hayashi,a Rie Mukai,b Junji Terao,b Hisao Nemoto*a
a
Department of Pharmaceutical Chemistry, Division of Heath Biosciences, Graduate School of the University of Tokushima, 1-78-1,
Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337284; E-mail: nem@ph.tokushima-u.ac.jp
b
Department of Food Science, Institute of Health Biosciences, Graduate School of the University of Tokushima, 3-18-15, Kuramoto-cho,
Tokushima 770-8503, Japan
Received: 18.09.2013; Accepted after revision: 25.10.2013
droxyl group is reprotected with an orthogonal protecting
Abstract: The first synthesis of uralenol, 5′-prenylated quercetin, is
group to afford the compound such as 7 (Scheme 2). Be-
described. The key step is a palladium-catalyzed O-1,1-dimethylal-
cause of a dipole moment interaction with the neighboring
carbonyl group, deprotection of the acetyl groups at C-3
lylation reaction, with concurrent acetyl migration to afford the de-
sired intermediate as a major isomer, which was purified by
recrystallization. Finally, Claisen rearrangement, followed by de- and C-5 proceeds more slowly than at the other acetyl
protection of all phenolic protecting groups, afforded uralenol in ex-
cellent yield.
groups. Accordingly, the key step is the discrimination of
deprotection between the 4′- and 3′-acetyl group. Unfortu-
Key words: palladium, prenylation, quercetin, flavonoids, rear-
rangement
nately, no appropriate method of discrimination was
available6 at the beginning of this synthetic study. Howev-
er, we were ultimately successful in this regard by virtue
of careful observation.
The bioactivity of prenylated flavonoids is more attractive
than that of unmodified flavonoids, since the changed
conformation resulting from prenylation can have effects
such as slowing down metabolism.1 One such prenylated
flavonoids, uralenol (1), which was first isolated from the
leaves of Glycyrrhiza uralensis Fisch by Wang et al.,1h
displays many types of biological activity2 (Scheme 1).
Synthesis was carried out as illustrated in Scheme 2. First,
commercially available quercetin was acetylated to afford
the peracetylated derivative 5, which was transformed to
mono-deacetylated compound 6 in 84% yield via a known
procedure.7 Treatment of 6 with chloromethyl methyl
ether afforded 7 in 95% yield.
Next, the conversion of 7 into 8a was examined using
thiophenol with imidazole in N-methylpyrrolidone
(NMP) by reference to a previous paper8 to afford a mix-
ture of 8a and 8b (ca. 76:24) in 92% combined yield with-
out deacetylation at either the 3- or 5-position. The
mixture of 8a and 8b9 was treated with the carbonate 9 in
the presence of a catalytic amount of tetrakis(triphe-
nylphosphine)palladium to afford a mixture of 10a and
10b in reproducibly 92% yield. However, the molar ratio
of 10a and 10b was irreproducible (approximately 70–
80:30–20). It was concluded that the reason for this irre-
producibility was the low-energy-gap equilibrium be-
tween 8a and 8b via 1,2-acetyl migration, although it is
In this paper, we report the first synthesis of uralenol. The
key step was based on our recently reported procedure,3
palladium-catalyzed 1,1-dimethylallylation (Kaiho’s
method,4 step A) at O-4′ on the B ring, followed by pre-
nylation at C-5′ via Claisen rearrangement in acetic
anhydride5 (step B). Although it was difficult to prepare
an appropriate synthetic intermediate for uralenol as a sin-
gle isomer due to the low energy gap for acetyl migration
between the 3′- and 4′-positions, a combination of palladi-
um-catalyzed O-dimethylallylation and acetyl migration
predominantly afforded the desired synthetic intermediate
for uralenol.
The synthetic strategy was as follows. Compound 4, well known that the palladium-catalyzed reactions with
whose hydroxyl groups were protected except the one at carbonates, similar to that in step A, proceed under essen-
4′-position, is an important precursor. Once 4 can be pre- tially neutral conditions.
pared, our procedure for obtaining 2 from 4 via 3 is easily
applicable to the introduction of a prenyl group at C-5′.
Therefore, the most reactive acetyl group at C-7, the para-
position of carbonyl functionality of the peracetylquerce-
We eventually noticed that the irreproducibility was due
to the presence of trace amounts of residual imidazole,
which had been used in the previous step. Therefore, we
examined the reaction in the presence of 0.01 equivalent
tin (5) can be deprotected, after which the resulting hy-
of various additives (Table 1).
As shown in entry 1, 10a and 10b were reproducibly ob-
tained with a molar ratio of 71:29 when the imidazole was
SYNTHESIS 2014, 46, 0170–0174
Advanced online publication: 22.11.2013
exhaustively removed.10 When either 2,6-lutidine or 4-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338559; Art ID: SS-2013-F0630-OP
© Georg Thieme Verlag Stuttgart · New York
(dimethylamino)pyridine (DMAP) was used, the palladi-

PAPER
Synthesis of Uralenol
171
OH
3'
OAc
OH
2'
3
OAc
1
8
4'
B
2
HO
O
RO
O
O
1'
5'
7
A
4
6
OH
OAc
5
2
OH
O
OAc
uralenol (1)
step B
OAc
OAc
OH
O
step A
RO
O
RO
O
O
OAc
OAc
OAc
O
3
4
OAc
difficult to
discriminate
OAc
OAc
AcO
O
O
OAc
peracetyl quercetin (5)
AcO
least deprotectable due to dipole moment interaction with
carbonyl group
most deprotectable due to electronic influence of carbonyl group at
para-position
Scheme 1
um-catalyzed reaction was disrupted (Table 1, entries 2 Claisen rearrangement of purified 10a smoothly proceed-
and 3). In the presence of 4-toluenesulfonic acid monohy- ed in acetic anhydride3 to afford the desired 5′-prenylated
drate (p-TsOH·H2O), the resulting molar ratio of 10a and product 11 in 95% isolated yield. Finally, the methoxy-
10b was 79:21 (entry 4). The most suitable ratio for the methyl group was deprotected using carbon tetrabromide
synthesis of uralenol was achieved using pyridine (entry in isopropyl alcohol,11 followed by deprotection of the
5) and diisopropylethylamine (i-Pr2NEt) (entry 6). Be- other four acetyl groups by ammonium acetate to give
cause of the chemical yield, we chose pyridine as the most uralenol (1) in 96% overall yield from 11.
appropriate base, obtaining a mixture of 10a and 10b with
In conclusion, the first synthesis of uralenol (1) was ac-
a molar ratio of 87:13 in 92% yield. After a single recrys-
complished in 8 steps and in 53% overall yield from quer-
tallization, pure 10a was isolated in 79% overall yield
cetin. It is noted that even the mild palladium-catalyzed
reaction with carbonates under essentially neutral condi-
from a mixture of 8a and 8b.
tions could not prevent the 1,2-acetyl migration between
the ortho-phenolic groups. However, this disadvantage
was finally utilized to increase the selectivity and overall
chemical yield of the reaction via the newly examined
concerted acetyl migration and palladium-catalyzed O-
Table 1 Molar Ratio of 10a and 10b after Pd-Catalyzed O-Dimeth-
ylallylation from a Mixture of 8a and 8b (76:24) with Additives (0.01
equiv)
1,1-dimethylallylation using an amine purposely added as
a base.
Entry
Additive
Molar ratio of 10a and 10b
1
2
3
4
5
6
–
71:29
–
Melting points were obtained on a Yanagimoto-model 20 melting
point apparatus and were uncorrected. IR spectra were recorded on
DMAP
1
2,6-lutidine
p-TsOH·H2O
pyridine
i-Pr2NEt
–
a Jasco FT-IR 6200 spectrophotometer. H NMR spectra were re-
corded in CDCl3 or CD3OD and referenced to TMS using Jeol
JNM-AL 300 (300 MHz), Jeol JNM-AL 400 (400 MHz), or Bruker
AV400N (400 MHz) spectrometers. 13C NMR were recorded in
CDCl3 or acetone-d6 and referenced to CDCl3 (δ = 77.0) or CD3OD
(δ = 49.9) using a Jeol JNM-AL 300 (75 MHz) spectrometer. Col-
umn chromatography was performed on silica gel (Kanto Kagaku
79:21
87:13
84:17
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 170–174

172
T. Kawamura et al.
PAPER
OAc
OAc
Ac2O (excess)
PhSH (1.2 equiv)
pyridine (3.0 equiv)
imidazole (0.35 equiv)
HO
O
O
5
quercetin
neat, 130–140 °C
100%
NMP, 0 °C
84%
OAc
6
AcO
OAc
OAc
MOMCl (1.2 equiv)
DIPEA (2.0 equiv)
PhSH (1.4 equiv)
imidazole (0.40 equiv)
MOMO
O
O
acetone, r.t., 2 h
95%
NMP, –20 °C, 20 h
92%
OAc
7
AcO
OH
OAc
O
O
OAc
OH
O
9 (3.0 equiv)
MOMO
O
O
MOMO
O
O
+
Pd(PPh3)4 (0.050 equiv)
pyridine (0.010 equiv)
THF, 0–5 °C, 20 h
92%
OAc
OAc
AcO
AcO
76 : 24
8a
8b
OAc
O
O
OAc
recrystallization
MOMO
O
O
+
10a
MOMO
O
EtOAc–hexane (1:1)
79% from
a mixture of 8a and 8b
OAc
10a
OAc
AcO
AcO
O
10b
87 : 13
OAc
OAc
1) CBr4 (0.050 equiv)
iPrOH, reflux, 5 h
pyridine (3.0 equiv)
MOMO
O
O
uralenol (1)
Ac2O, 120–130 °C, 5 h
95%
2) NH4OAc (10 equiv)
iPrOH, 60–65 °C, 5 h
96% (2 steps)
OAc
11
AcO
Scheme 2
N-60). TLC was performed on precoated plates (0.25 mm, silica gel
Merck Kieselgel 60F254). All reactions were performed in oven-
dried glassware under positive pressure of argon, unless otherwise
noted. Reaction mixtures were stirred magnetically. MeOH was dis-
tilled over Mg. NMP was distilled over CaH2. Anhydrous THF and
Ac2O were purchased from Wako Chemicals Co. Inc.
FT-IR (KBr): 3503, 2943, 1773, 1636, 1506, 1442, 1372, 1264,
1201, 1083, 1023, 936, 871, 847, 814, 793, 676, 601, 552, 498, 468
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 8.4, 2.0 Hz, 1 H),
7.69 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 2.4
Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 5.26 (s, 2 H), 3.50 (s, 3 H), 2.43
(s, 3 H), 2.34 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 170.1 (C), 169.5 (C), 168.0 (C),
167.8 (C), 167.7 (C), 161.4 (C), 157.8 (C), 153.2 (C), 150.6 (C),
144.2 (C), 142.1 (C), 133.8 (C), 128.0 (C), 126.4 (CH), 123.8 (CH),
123.7 (CH), 111.7 (C), 109.9 (CH), 101.5 (CH), 94.5 (CH2), 56.5
(CH3), 21.1 (CH3), 20.7 (2 × CH3), 20.5 (CH3).
4-[3,5-Diacetoxy-7-(methoxymethoxy)-4-oxo-4H-chromen-2-
yl]-1,2-phenylene Diacetate (7)
To a solution of tetraacetylated quercetin 66 (10.0 g, 21.3 mmol,
1.00 equiv) and i-Pr2NEt (5.6 mL, 31.9 mmol, 1.50 equiv) in ace-
tone (85 mL, 0.25 M) was added chloromethyl methyl ether (1.9
mL, 25.5 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred for
2 h at r.t. The resulting mixture was diluted with EtOAc (1.0 L), and
the EtOAc layer was washed with aq 1 M HCl (300 mL) and brine
(300 mL). The organic phase was dried (Na2SO4) and concentrated
in vacuo. The residue was recrystallized from EtOAc–hexane (2:1)
to give 7 as a white powder; yield: 10.4 g (20.2 mmol, 95%); mp
173–174 °C.
2-(3-Acetoxy-4-hydroxyphenyl)-7-(methoxymethoxy)-4-oxo-
4H-chromene-3,5-diyl Diacetate (8a)/2-(4-Acetoxy-3-hydroxy-
phenyl)-7-(methoxymethoxy)-4-oxo-4H-chromene-3,5-diyl Di-
acetate (8b)
To a suspension of 7 (10.0 g, 19.4 mmol, 1.00 equiv) in NMP (40
mL, 0.50 M) were added imidazole (0.528 g, 7.76 mmol, 0.400
equiv) and thiophenol (2.8 mL, 27.2 mmol, 1.40 equiv) at –20 °C,
Synthesis 2014, 46, 170–174
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Uralenol
173
and the mixture was stirred for 20 h at the same temperature. The
resulting mixture was diluted with EtOAc (1.0 L) and washed with
aq 1 M HCl (0.50 L), H2O (0.50 L), and brine (0.50 L). The organic
phase was dried (Na2SO4) and concentrated in vacuo. The residue
was purified by column chlomatography (silica gel, hexane–EtOAc,
2:3) to give a mixture of 8a and 8b (8.43 g, 17.8 mmol, 92%, 76:24)
as a pale yellow amorphous powder. Although pure 8a was obtained
by recrystallization of the mixture of 8a and 8b, it was difficult to
record the spectral data of 8a because 8a was converted into a mix-
ture of 8a and 8b within a short time. Only 1H NMR was available.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.55 (m, 2 H), 7.00 (d,
J = 3.2 Hz, 1 H), 6.97 (d, J = 11.2 Hz, 1 H), 6.72 (d, J = 3.2 Hz, 1
H), 6.50 (s, phenolic OH, 1 H), 5.27 (s, 2 H), 3.51 (s, 3 H), 2.44 (s,
3 H), 2.35 (s, 3 H), 2.33 (s, 3 H).
Urarenol (1)
To a suspension of 11 (7.00 g, 12.0 mmol, 1.00 equiv) in i-PrOH
(120 mL, 0.10 M) was added CBr4 (0.199 g, 0.60 mmol, 0.05 equiv)
at r.t. and the mixture was stirred for 5 h at reflux. After cooling to
r.t., NH4OAc (9.25 g, 120 mmol, 10.0 equiv) was added to the re-
sulting solution and the mixture was stirred for 5 h at 60 °C. After
cooling to r.t., the mixture was concentrated in vacuo, and the resi-
due was recrystallized from MeOH–H2O (85:15) to give 1 as pale
yellow needles; yield: 4.27 g (11.5 mmol, 96%); mp 176–178 °C.
FT-IR (KBr): 3462, 1734, 1653, 1559, 1522, 1457, 1339, 1161
cm–1.
1H NMR (400 MHz, CD3OD): δ = 7.61 (d, J = 2.0 Hz, 1 H), 7.55 (d,
J = 2.0 Hz, 1 H), 6.36 (d, J = 2.0 Hz, 1 H), 6.18 (d, J = 2.0 Hz, 1 H),
5.34–5.39 (m, 1 H), 3.37 (d, J = 7.6 Hz, 2 H), 1.76 (s, 6 H).
13C NMR (75 MHz, CD3OD): δ = 177.5 (C), 165.7 (C), 162.7 (C),
158.4 (C), 148.5 (C), 146.9 (C), 145.9 (C), 137.3 (C), 133.4 (C),
129.6 (CH), 123.9 (C), 123.3 (C), 122.1 (CH), 113.5 (CH), 104.6
(CH), 99.3 (CH), 94.4 (CH), 29.3 (CH2), 25.9 (CH3), 17.9 (CH3).
2-{3-Acetoxy-4-[(2-methylbut-3-en-2-yl)oxy]phenyl}-7-(meth-
oxymethoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (10a)
To a solution of 8a/8b (8.00 g, 16.9 mmol, 1.00 equiv) in THF (170
mL, 0.10 M) were added pyridine (14 mL, 0.169 mmol, 0.01 equiv),
the mixed carbonate 9 (90 wt%, 10.5 g, 50.7 mmol, 3.00 equiv), and
Pd(PPh3)4 (0.976 g, 0.845 mmol, 0.05 equiv) at 0–5 °C, and the mix-
ture was stirred for 20 h at the same temperature. The resulting mix-
ture was filtered through a Celite pad, and the residue was then
washed with EtOAc (3 × 100 mL). The combined eluents were con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (silica gel, hexane–EtOAc, 1:1) to give a mixture of 10a and
10b (8.40 g, 15.5 mmol, 92%, 10a/10b = 87:13) as a pale yellow
amorphous powder. The mixture was recrystallized from EtOAc–
hexane (1:1) to give the single isomer 10a as a white powder; yield:
7.22 g (13.4 mmol, 79% from 8a/8b); mp 124–125 °C.
Acknowledgment
This work was supported by the Program for Promotion of Basic
and Applied Researches for Innovations in Bio-oriented Industry
(Japan).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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tgioSrantnugIifoop
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FT-IR (KBr): 3446, 2987, 1773, 1633, 1506, 1434, 1365, 1286,
1203, 1076, 1021, 948, 858, 793, 697, 600 cm–1.
References
1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 8.8, 2.0 Hz, 1 H),
7.54 (d, J = 2.0 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.05 (d, J = 2.4
Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.13 (dd, J = 17.6, 10.8 Hz, 1
H), 5.27 (d, J = 17.6 Hz, 1 H), 5.26 (s, 2 H), 5.22 (d, J = 10.8 Hz, 1
H), 3.50 (s, 3 H), 2.43 (s, 3 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 1.52 (s,
6 H).
13C NMR (75 MHz, CDCl3): δ = 170.3 (C), 169.7 (C), 168.7 (C),
168.1 (C), 161.3 (C), 157.9 (C), 154.0 (C), 150.8 (C), 150.7 (C),
143.4 (CH), 142.4 (C), 133.3 (C), 126.3 (CH), 122.8 (CH), 122.6
(C), 119.5 (CH), 114.4 (CH2), 111.7 (C), 109.7 (CH), 101.5 (CH),
94.5 (CH2), 81.6 (C), 56.4 (CH3), 26.9 (2 × CH3), 21.0 (CH3), 20.5
(2 × CH3).
(1) (a) Yazaki, K.; Sasaki, K.; Tsurumaru, Y. Phytochemistry
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2008, 71, 2068. (f) Meragelman, K. M.; MaKee, T. C.;
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Goffeau, A.; Pietro, A. D. Biochemistry 2000, 39, 6910.
(h) Jia, S. S.; Ma, C. M.; Wang, J. M. Acta. Pharm. Sin.
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(2) (a) Zheng, Z.-P.; Cheng, K.-W.; Chao, J.; Wu, J.; Wang, M.
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T. Y.; Li, J.; Shen, Q. Bioorg. Med. Chem. 2002, 12, 3387.
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H. Synthesis 2012, 44, 1308.
(4) (a) Kaiho, T.; Miyamoto, M.; Nobori, T.; Katakami, T. Yuki
Gosei Kagaku Kyokaishi 2004, 62, 27. (b) Kaiho, T.;
Yokoyama, T.; Mori, H.; Fujiwara, J.; Nobori, T.; Odaka,
H.; Kamiya, J.; Maruyama, M.; Sugawara, T. Japanese
Patent JP 06-128238, 1994; Chem. Abstr. 1995, 123, 55900.
(5) When acetic anhydride was used as the solvent, the chemical
yield and chemoselectivity of Claisen rearrangement were
dramatically improved; see ref. 3.
2-[3,4-Diacetoxy-5-(3-methylbut-2-enyl)phenyl]-7-(methoxy-
methoxy)-4-oxo-4H-chromene-3,5-diyl Diacetate (11)
A solution of 10a (7.00 g, 13.0 mmol, 1.00 equiv) in Ac2O (130 mL,
0.10 M) and pyridine (3.2 mL, 39.0 mmol, 3.00 equiv) was heated
to 120–130 °C and stirred for 5 h at the same temperature. After
cooling to r.t., the resulting mixture was concentrated in vacuo. The
residue was recrystallized from EtOAc and hexane (2:1) to give 11
as a white powder; yield: 7.19 g (12.4 mmol, 95%); mp 152–154
°C).
FT-IR (KBr): 3503, 2913, 1771, 1621, 1488, 1443, 1372, 1290,
1178, 1079, 1012, 950, 842, 788, 680, 604, 521, 472 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 2.0 Hz, 1 H), 7.53 (d,
J = 2.0 Hz, 1 H), 7.05 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H),
5.27 (s, 1 H), 5.20–5.25 (m, 1 H), 3.51 (s, 1 H), 3.31 (d, J = 6.8 Hz,
2 H), 2.43 (s, 3 H), 2.34 (s, 3 H), 2.31 (s, 6 H), 1.77 (s, 3 H), 1.71 (s,
3 H).
13C NMR (75 MHz, CDCl3): δ = 170.4 (C), 169.8 (C), 168.3 (2 ×
C), 168.0 (C), 161.6 (C), 158.1 (C), 153.9 (C), 150.9 (C), 143.0 (C),
142.8 (C), 136.6 (C), 134.9 (C), 134.0 (CH), 127.9 (C), 127.2 (CH),
121.5 (CH), 120.5 (CH), 112.0 (C), 110.0 (CH), 101.8 (CH), 94.7
(CH2), 56.6 (CH3), 28.8 (CH2), 25.8 (CH3), 21.2 (CH3), 20.8 (CH3),
20.5 (CH3), 20.4 (CH3), 17.9 (CH3).
(6) Differentiation of C-4′ from C-3′ with migratory group such
as acetyl group has not been reported prior to our result
reported herein. In contrast, selective O-methylation of C-4′
of quercetin via six steps was reported: Li, N.-G.; Shi, Z.-H.;
© Georg Thieme Verlag Stuttgart · New York
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174
T. Kawamura et al.
PAPER
Tang, Y.-P.; Yang, J.-P.; Duan, J.-A. Beilstein J. Org. Chem.
2009, 5, No. 60.
(7) (a) Picq, M.; Prigent, A. F.; Nemoz, G.; Andre, A. C.;
Pacheco, H. J. Med. Chem. 1982, 25, 1192. (b) Li, M.; Han,
X.; Yu, B. J. Org. Chem. 2003, 68, 6842.
recrystallization, because recrystallization of a mixture of 8a
and 8b (76:24) afforded pure 8a in 84% (which is greater
than 76%) yield. Accordingly, the best purification point in
the synthesis of uralenol was after obtaining a mixture of 10a
and 10b because 10 has no phenolic proton.
(8) Peng, W.; Li, Y.; Zhu, C.; Han, X.; Yu, B. Carbohydr. Res.
2005, 340, 1682.
(10) Pd-catalyzed O-dimethylallylation at the 7-position of
tetraacetylated quercetin was reported in our recent paper
(see, ref. 3). During the reaction, no acetyl migration was
detected probably because the phenolic hydroxide was not
located at the ortho-position of any of the acetoxy groups in
the starting materials.
(9) In fact, pure 8a was isolated from a mixture of 8a and 8b by
recrystallization. Unfortunately, however, the purified 8a
reverted to a mixture of 8a and 8b after a short time.
Furthermore, even when Pd-catalyzed O-dimethylallylation
was carried out immediately after isolation of pure 8a, a
mixture of 10a and 10b was obtained. Incidentally,
isomerization from 8b to 8a was also observed during
(11) Shinozuka, T.; Yamamoto, Y.; Hasegawa, T.; Saito, K.;
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Synthesis 2014, 46, 170–174
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