Unified total synthesis of amorfrutins A and C via the Claisen rearrangement

Article abstract of DOI:10.1080/09168451.2019.1618699

A concise, unified total synthesis of the two prenylated aromatic polyketides amorfrutins A and C, which exhibit various medicinally important biological profiles such as antimicrobial, PPAR? modulating and quorum sensing inhibitory activities, has been a

Full text of DOI:10.1080/09168451.2019.1618699

Bioscience, Biotechnology, and Biochemistry
ISSN: 0916-8451 (Print) 1347-6947 (Online) Journal homepage: https://www.tandfonline.com/loi/tbbb20
Unified total synthesis of amorfrutins A and C via
the Claisen rearrangement
Tadafumi Fujita, Shigefumi Kuwahara & Yusuke Ogura
To cite this article: Tadafumi Fujita, Shigefumi Kuwahara & Yusuke Ogura (2019): Unified total
synthesis of amorfrutins A and C via the Claisen rearrangement, Bioscience, Biotechnology, and
Biochemistry, DOI: 10.1080/09168451.2019.1618699
To link to this article: https://doi.org/10.1080/09168451.2019.1618699
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BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY
https://doi.org/10.1080/09168451.2019.1618699
Unified total synthesis of amorfrutins A and C via the Claisen rearrangement
Tadafumi Fujita, Shigefumi Kuwahara and Yusuke Ogura
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
ABSTRACT
ARTICLE HISTORY
Received 27 March 2019
Accepted 27 April 2019
A concise, unified total synthesis of the two prenylated aromatic polyketides amorfrutins
A and C, which exhibit various medicinally important biological profiles such as antimicrobial,
PPARγ modulating and quorum sensing inhibitory activities, has been achieved from com-
mercially available 3,5-dimethoxybenzaldehyde in 38% and 10% overall yields through nine
and ten steps, respectively. The key transformation for the synthesis of amorfrutin A was the
Claisen rearrangement of a mono-O-(1,1-dimethylallyl)resorcinol derivative to install the C3-
prenyl substituent, while that for the synthesis of amorfrutin C was the double Claisen
rearrangement of a di-O-(1,1-dimethylallyl)resorcinol derivative to introduce the two prenyl
groups at the C3 and C5 positions all at once.
KEYWORDS
Amorfrutin; total synthesis;
Claisen rearrangement;
Amorpha fruticosa;
Glycyrrhiza acanthocarpa
Amorfturin A (1) (Figure 1) is a polyketide–terpe-
noid hybrid meroterpene isolated first from the bas-
tard indigobush Amorpha fruitcosa [1] and later from
the two perennial herbs Glycyrrhiza acanthocarpa [2]
and G. foetida [3]. It belongs to the amorfrutin family
of natural products [4] and structurally features
a salicylic acid nucleus substituted at the C3, C4,
and C6 positions with a prenyl, a methoxy, and
a 2-phenylethyl group, respectively. The fully substi-
yields of 38–58% together with substantial amounts of
O-prenylated byproduct C [8,11,12,14]. The indirect
conversion of A (R = CO2Me) into B via montmor-
illonite K10-catalyzed rearrangement of C, which
could be prepared O-selectively from A in 92% yield,
also resulted in a modest yield of 38% over two steps
[16]. The unique and efficient decarboxylative prenyl
migration–aromatization approach (method 2) suc-
cessfully converted D into desired product E in 62%
isolated yield [13]. As for amorfrutin C (2), the Sauer
group employed base-induced condensation between
F and G to obtain 56% yield of H with two prenyl
groups properly and efficiently installed (Scheme 1(b))
[17]. In Xie’s synthesis of 2, the two prenyl groups
were introduced into m-dibromobenzene derivative
I in a stepwise manner, but the yield of the two-step
sequence leading to K via J was 36%, leaving room for
improvement [18].
tuted aromatic compound amorfrutin
C
(2),
a congener of amorfrutin A (1) with an additional
prenyl substituent at the C5 position, is also
a member of this family recently discovered from
G. foetida [5]. Until now, a variety of biological activ-
ities have been reported for 1, 2, and other members
of this family, including antimicrobial [1,6], NF-κB
(nuclear transcription factor-κB) inhibitory [7],
PPARγ (peroxisome proliferator-activated receptor
gamma) modulating [3,8–10], anti-HCV (hepatitis
C virus) [11], and quorum sensing inhibitory proper-
ties [12]. These medicinally important biological
activities of amorfrutins coupled with their unique
The preceding studies were, as described above,
directed toward the synthesis of each of amorfrutins
A and C, and no strategy enabling the synthesis of the
two natural products in a unified manner has been
reported so far. In this article, we describe a unified
total synthesis of the two amorfrutins using the
Claisen rearrangement as the key reaction.
poly-substituted
aromatic
architectures
have
prompted considerable synthetic efforts toward 1
and 2, which culminated in six total syntheses of
amorfrutin A (1) [8,11–16] as well as two total synth-
eses of amorfrutin C (2) [17,18].
The previously reported total syntheses of 1 can be
categorized into 2 types according to the method to
install the C3-prenyl substituent (Scheme 1(a)):
C-prenylation of resorcinol derivative A (R1 = CO2Me,
CO2Et, or CHO) (method 1) and Pd(0)-catalyzed
migratory prenylation–aromatization of substituted
dioxinone D (method 2). The C-prenylation of
A gave desired C-prenylation product B in moderate
Results and discussion
Our retrosynthetic analysis of amorfrutins A (1) and
C (2) is outlined in Scheme 2. The target molecule 1
would be obtainable via the Claisen rearrangement of
aryl ether 3a bearing a 1,1-dimethylallyl (reverse-
prenyl) group [19] on the oxygen atom at the C2
position, while the 3,5-diprenylated congener 2
would be derived through the double Claisen
CONTACT Yusuke Ogura
aysk.ogura@mail.ecc.u-tokyo.ac.jp
© 2019 Japan Society for Bioscience, Biotechnology, and Agrochemistry

2
T. FUJITA ET AL.
hydrogenation to install the 2-phenylethyl side chain
and the Vilsmeier-Haack reaction to introduce a car-
bonyl functionality at the C1 position.
We first undertook the synthesis of amorfrutin
A (1) (Scheme 3). Known bibenzyl compound 7,
obtained by the Horner–Wadsworth–Emmons olefi-
nation of 5 with 6 and subsequent catalytic hydro-
genation of the resulting stilbene intermediate
according to the literature [20,21], was subjected to
the Vilsmeier–Haack reaction to give 8 as a single
formylation product in 81% yield [22]. The Pinnick
oxidation of the aromatic aldehyde 8 followed by
esterification of the carboxylic acid thus produced
afforded 4 in an excellent yield of 93% for the 2
steps. Selective mono-demethylation of the methyl
ether moiety at the C2 position of 4 with BBr3 (1.1
equiv) provided phenol 9 in 77% yield [23].
Treatment of 9 with carbonate 10 in the presence of
a catalytic amount of Pd(PPh3)4 and 4Å molecular
sieves in THF effected a Tsuji–Trost-type etherifica-
tion [24], furnishing the aryl reverse-prenyl ether 3a
almost quantitatively. It is worth mentioning that the
addition of pulverized activated 4Å molecular sieves
was necessary to obtain reproducibly high yields of
3a. The Claisen rearrangement of 3a to 11 was per-
formed in 77% yield by heating a solution of 3a in
xylene under microwave irradiation conditions.
Finally, saponification of the ester 11 furnished amor-
frutin A (1) in 94% yield. It should be noted that we
first attempted the oxidation of o-hydroxy aldehyde
12 prepared from 8 in 3 steps, but all attempted
conditions including the Jones and the Pinnick oxi-
dation conditions, 1-Me-AZADO/PhI(OAc)2, and
AgNO3/KOH resulted in low yields of up to 32%.
Figure 1. Structures of amorfrutins A (1) and C (2).
Scheme 1. Previous methods to install the C3-prenyl substi-
tuent of 1 (a) and C3- and C5-prenyl groups of 2 (b).
Scheme 2. Retrosynthetic analysis of amorfrutins A (1) and C (2).
rearrangement of 2,4-di-O-(reverse-prenyl) ether 3b.
The aryl ethers, 3a and 3b, would be prepared
from m-dimethoxybenzene derivative
4
as
a common precursor by selective demethylation of
the methyl ether moiety ortho to the ester group
followed by reverse-prenylation and demethylation
of the two methyl ether moieties at the C2 and C4
positions followed by double reverse-prenylation,
respectively. The dimethoxy benzoate 4 should be
prepared from known aromatic aldehyde 5 via its
Scheme 3. Synthesis of amorfrutin A (1).
Reagents and conditions: (a) POCl3, DMF, –4ºC to rt, 21 h, 81%; (b)
NaClO2, NaH2PO4, 2-methyl-2-butene, THF/H2O (6:1), rt, 12 h; (c) K2CO3,
EtI, MeCN, 46ºC, 40 min, 93% from 8; (d) BBr3, CH2Cl2, –78ºC, 4 h, 77%;
(e) Pd(PPh3)4, 4Å MS, THF, –20ºC, 19.5 h, 98%; (f) microwave irradiation,
o-xylene, reflux, 70 min, 77%; (g) KOH, EtOH/H2O (1:1), 80ºC, 6 h, 94%; (h)
BBr3, CH2Cl2, –78ºC to rt, 2.5 h, 90%; (i) 10, Pd(PPh3)4, 4Å MS, THF, 0°C,
16.5 h, quant; (j) o-xylene, reflux, 2 h, 77%; (k) NaClO2, NaH2PO4,
2-methyl-2-butene, THF/H2O (12:1), rt, 6 h, 32%.
olefination with phosphonate
6
followed by

SYNTHESIS OF AMORFRUTINS A AND C
3
Experimental
General procedure
IR spectra were recorded by a Jasco FT/IR-4100 spec-
trometer using an ATR (ZnSe) attachment. NMR
spectra were recorded with TMS as an internal stan-
dard in CDCl3 by a Varian 400-MRTT spectrometer
1
(400 MHz for H and 100 MHz for 13C) or a Varian
1
600TT spectrometer (600 MHz for H and 150 MHz
Scheme 4. Synthesis of amorfrutin C (2).
for 13C) unless otherwise stated. Optical rotation
values were measured with a Jasco P-2200 polari-
meter. Mass spectra were obtained with Jeol JMS-
700 spectrometer operated in the FAB mode. Merck
silica gel 60 (63–200 μm) was used for column chro-
matography unless otherwise stated. Analytical thin-
layer chromatography was performed using Merck
silica gel 60 F254 plates (0.25 mm thick). Solvents
for reactions were distilled prior to use: THF from
Na and benzophenone; CH2Cl2 and DMF from
CaH2. All air- or moisture-sensitive reactions were
conducted under a nitrogen atmosphere unless other-
wise stated.
Reagents and conditions: (a) BBr3, CH2Cl2, 0ºC, 36 h, 75%; (b) Pd(PPh3)4, 10,
4Å MS, THF, –20ºC, 18 h, quant; (c) microwave irradiation, o-xylene, reflux, 3
h, 52%; (d) MeI, K2CO3, acetone, rt, 19 h, 50%; (e) KOH, EtOH/H2O (5:1), 70ºC,
70 h, 75%.
The synthesis of amorfrutin C (2) was implemen-
ted by a five-step sequence from the common inter-
mediate 4 as shown in Scheme 4. Demethylation of
both the C2 and C4 methoxy groups of 4 by treat-
ment with an excess amount of BBr3 afforded
a resorcinol intermediate in 75% yield, although it
required a higher temperature (0°C) and a longer
reaction time (36 h) as compared to those employed
for mono-demethylation of 4 to afford 9 (–78°C, 4 h;
see Scheme 3). Reverse-prenylation of the two phe-
nolic hydroxyls of the intermediate proceeded
uneventfully to furnish a quantitative yield of 3b,
which was then heated under microwave irradiation
conditions to perform its double Claisen rearrange-
ment to 13. This reaction gave a mixture of several
products after complete consumption of the starting
material 3b, from which the desired product 13 was
successfully isolated in a moderate yield of 52%.
Finally, selective O-methylation of the C4-OH group
of 13 with MeI and K2CO3 in acetone [17] followed
by saponification of the resulting ester 14 completed
the total synthesis of amorfrutin C (2). The spectro-
scopic data of the synthetic amorfrutin C (2) were in
good agreement with those of natural product [5,18].
2,4-dimethoxy-6-(2-phenylethyl)benzaldehyde (8)
A stock solution of the Vilsmeier reagent (ca. 2.0 M in
DMF) was prepared in advance from DMF (31.5 mL)
and POCl3 (7.20 mL, 77.3 mmol). The solution
(18 mL, 36 mmol) was added dropwise to a stirred
solution of 1,3-dimethoxy-5-(2-phenylethyl) benzene
(3.53 g, 14.6 mmol) in DMF (24.0 mL) at – 4°C. The
reaction mixture was warmed to room temperature
and stirred for 21 h. The reaction mixture was
quenched with satd aq NH4Cl while cooling with an
ice bath and extracted three times with EtOAc. The
extract was successively washed with 5% aq LiCl and
brine, dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by SiO2 column
chromatography (hexane/EtOAc = 9:1) to give alde-
hyde 8 (3.17 g, 81%) as a white solid, whose spectral
data were identical to those reported in the litera-
ture [22].
Conclusion
The concise total synthesis of amorfrutin A (1) has been
accomplished from commercially available 3,5-
dimethoxybenzaldehyde 5 in 38% overall yield by a
nine-step sequence (or from the known compound 7 in
48% overall yield through 7 steps) that involves the
Claisen rearrangement of the mono-reverse-prenylated
intermediate 3a as the key step. Amorfrutin C (2), 5-pre-
nylated congener of 1, has also been synthesized in ten
steps from 5 in 10% overall yield by exploiting the double
Claisen rearrangement of 2,4-di-O-reverse-prenylated
intermediate 3b, which was derived from them-di-
methoxybenzene derivertive 4, a common synthetic pre-
cursor of the two amorfrutins. Synthetic efforts toward
other members of this class of natural products are now
in progress and will be reported in due course.
Ethyl 2,4-dimethoxy-6-(2-phenylethyl)benzoate (4)
To a stirred solution of 8 (202 mg, 0.747 mmol) in
THF/H2O (6:1, 7 mL) was successively added NaH2PO4
(258 mg, 2.15 mmol), 2-methyl-2-butene (800 μL, 7.55
mmol) and NaClO2 (75% dispersion in H2O, 270 mg,
2.24 mmol) at room temperature. After stirring for 12 h,
the reaction mixture was diluted with brine and extracted
three times with CH2Cl2. The extract was dried (Na2SO4),
filtered and concentrated in vacuo and the residue was
taken up in MeCN (2.20 mL). To the solution was suc-
cessively added K2CO3 (310 mg, 2.24 mmol) and EtI (300
µL, 3.75 mmol) at room temperature. The mixture was

4
T. FUJITA ET AL.
warmed to 46ºC and stirred for 40 min. The mixture was
diluted with brine at room temperature and extracted
three times with EtOAc. The extract was dried (Na2
SO4), filtered and concentrated in vacuo. The residue
was purified by SiO2 column chromatography (hexane/
EtOAc = 4:1) to give 4 (219 mg, 93% from 8) as a colorless
oil. IR: υmax 1723 (s), 1602 (s), 1587 (m), 1496 (m);
1H NMR (400 MHz, CDCl3): δ 1.37 (3H, t, J = 7.1 Hz),
2.83–2.93 (4H, m), 3.75 (3H, s), 3.81 (3H, s), 4.38 (2H, q,
J = 7.2 Hz), 6.24 (1H, d, J = 2.2 Hz), 6.33 (1H, d, J = 2.2
Hz), 7.16–7.22 (3H, m), 7.26–7.31 (2H, m); 13C NMR
(100 MHz, CDCl3): δ14.3, 36.1, 37.6, 55.3, 55.9, 61.1, 96.6,
105.9, 116.6, 126.0, 128.36 (2C), 128.42 (2C), 141.5, 141.7,
158.0, 161.2, 168.3; HRMS (FAB): m/z calcd for C19H23
O4, 315.1591; found, 315.1599 ([M + H]+).
Hz), 1.46 (6H, s), 2.80–2.91 (4H, m), 3.68 (3H, s),
4.35 (2H, q, J = 7.2 Hz), 5.16 (1H, dd, J = 0.9, 10.9
Hz), 5.23 (1H, dd, J = 0.9, 17.6 Hz), 6.19 (1H, dd, J =
10.9, 17.7 Hz), 6.29 (1H, d, J = 2.3 Hz), 6.58 (1H, d,
J = 2.3 Hz), 7.15–7.21 (3H, m), 7.24–7.30 (2H, m);
13C NMR (100 MHz, CDCl3): δ 14.4, 26.9 (2C), 36.1,
37.6, 55.2, 60.9, 80.6, 103.7, 107.6, 113.4, 120.6, 125.9,
128.3 (2C), 128.4 (2C), 140.9, 141.6, 144.8, 154.9,
160.1, 168.7; HRMS (FAB): m/z calcd for C23H29O4,
369.2060; found, 369.2067 ([M + H]+).
Ethyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-en-
1-yl)-6-(2-phenylethyl)benzoate (11)
A solution of 3a (99.0 mg, 0.269 mmol) in o-xylene
(2.00 mL) in a microwave reaction vessel was heated
to reflux under irradiation of microwave (300 W,
CEM Discover Microwave System) for 70 min. The
reaction mixture was concentrated in vacuo and the
residue was purified by SiO2 column chromatography
(hexane/EtOAc = 20:1) to give 11 (76 mg, 77%) as
a white solid. Mp 64ºC; IR: υmax 3027 (m), 1727 (s),
Ethyl 2-hydroxy-4-methoxy-6-(2-phenylethyl)-
benzoate (9)
To a stirred solution of 4 (128 mg, 0.407 mmol) in
CH2Cl2 (4.10 mL) was added dropwise a solution of
BBr3 (1.0 M in CH Cl2, 440 µL, 0.44 mmol) at – 78ºC.
2
1
After stirring for 4 h at the same temperature, the
reaction mixture was quenched with satd aq NaHCO3
and extracted three times with CH2Cl2. The extract
was washed with brine, dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by
SiO2 column chromatography (hexane/EtOAc = 10:1)
to give 9 (94.0 mg, 77%) as a white solid. Mp 51–52
ºC; IR: υmax 1651 (vs), 1616 (s), 1322 (m), 1257 (s);
1H NMR (400 MHz, CDCl3): δ 1.39 (3H, t, J = 7.1
Hz), 2.84–2.90 (2H, m), 3.18–3.24 (2H, m), 3.77 (3H,
s), 4.44 (2H, q, J = 7.2 Hz), 6.25 (1H, d, J = 2.7 Hz),
6.36 (1H, d, J = 2.7 Hz), 7.15–7.23 (3H, m), 7.27–7.32
(2H, m), 11.9 (1H, s, OH); 13C NMR (100 MHz,
CDCl3): δ 14.3, 38.0, 38.4, 55.3, 61.4, 99.2, 104.8,
110.9, 126.0, 128.2 (2C), 128.3 (2C), 141.8, 146.7,
163.9, 165.6, 171.4; HRMS (FAB): m/z calcd for C18
H21O4, 301.1434; found, 301.1438 ([M + H]+).
1650 (w), 1602 (s), 1459 (m), 1158 (s); H NMR (400
MHz, CDCl3): δ 1.39 (3H, t, J = 7.2 Hz), 1.66–1.69
(3H, m), 1.78 (3H, br s), 2.85–2.91 (2H, m), 3.19–3.25
(2H, m), 3.33 (2H, d, J = 7.0 Hz), 3.77 (3H, s), 4.44
(2H, q, J = 7.1 Hz), 5.17–5.23 (1H, m), 6.16 (1H, s),
7.15–7.23 (3H, m), 7.24–7.32 (2H, m), 11.8 (1H, s,
OH); 13C NMR (100 MHz, CDCl3): δ 14.3, 17.8, 22.0,
25.8, 38.2, 38.8, 55.4, 61.3, 105.3, 106.0, 115.2, 122.4,
125.9, 128.31 (2C), 128.34 (2C), 131.6, 141.9, 143.9,
161.0, 161.9, 171.7; HRMS (FAB): m/z calcd for C23
H28O4Na, 391.1880; found, 391.1882 ([M+ Na]+).
2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-
6-(2-phenylethyl)benzoic acid: amorfrutin a (1)
To a stirred solution of 11 (53.0 mg, 0.144 mmol) in
a mixed solvent of EtOH and H2O (1:1, 1.40 mL) was
added KOH (343 mg, 6.11 mmol) at room tempera-
ture. The reaction mixture was warmed to 80ºC,
stirred for 5 h, and then concentrated in vacuo. The
residue was acidified with 2 M HCl (pH 3) and
extracted five times with CHCl3. The extract was
washed with brine, dried (Na2SO4), filtered and con-
centrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/EtOAc = 10:1) to
give 1 (46 mg, 94%) as a white solid. An analytical
sample was recrystallized from hexane/EtOAc to give
NMR spectroscopically pure 1 as colorless prisms.
Mp 151–152ºC; IR: υmax 3025 (m), 2926 (br), 1627
(s), 1610 (s), 1455 (m), 1267 (s); 1H NMR (400 MHz,
CDCl3): δ 1.68 (3H, d, J = 0.9 Hz), 1.79 (3H, br s),
2.88–2.97 (2H, m), 3.22–3.31 (2H, m), 3.35 (2H, d, J =
7.0 Hz), 3.79 (3H, s), 5.17–5.24 (1H, m), 6.22 (1H, s),
7.17–7.23 (3H, m), 7.27–7.33 (2H, m), 11.6 (1H, br s,
OH);13C NMR (100 MHz, CDCl3): δ 17.8, 22.0, 25.8,
Ethyl 4-methoxy-2-[(2-methylbut-3-en-2-yl)oxy]-
6-(2-phenylethyl)benzoate (3a)
To a stirred solution of 9 (83.0 mg, 0.276 mmol) and
tert-butyl (2-methylbut-3-en-2-yl) carbonate (10)
(180 mg, 0.966 mmol) in degassed THF (550 µL)
was added pulverized 4Å molecular sieves (276 mg)
at room temperature. After cooling to – 20ºC,
Pd(PPh3)4 (16.0 mg, 0.0138 mmol) was added por-
tionwise and the resulting suspension was stirred for
19.5 h. The reaction mixture was filtered through
a pad of Celite and the filtrate was concentrated in
vacuo. The residue was purified by SiO2 column
chromatography (pentane/Et2O = 8:1) to give 3a
(100 mg, 98%) as a colorless oil. IR: υmax 3025 (m),
1725 (s), 1602 (s), 1579 (m), 1199 (m), 1158 (s);
1H NMR (400 MHz, CDCl3): δ 1.37 (3H, t, J = 7.1

SYNTHESIS OF AMORFRUTINS A AND C
5
38.1, 39.2, 55.5, 103.6, 106.5, 115.3, 122.1, 125.9, 128.4
(2C), 128.5 (2C), 131.8, 141.9, 145.8, 162.1, 162.9,
176.0; HRMS (FAB): m/z calcd for C21H24O4Na,
363.1567; found, 363.1570 ([M+ Na]+).
for C27H35O4, 423.2530; found, 423.2539 ([M
+ H]+).
Ethyl 2,4-dihydroxy-3,5-bis(3-methylbut-2-en-
1-yl)-6-(2-phenylethyl)benzoate (13)
Ethyl 2,4-bis[(2-methylbut-3-en-2-yl)oxy]-
6-(2-phenylethyl)benzoate (3b)
A stirred solution of 3b (808 mg, 1.91 mmol) in
o-xylene (2.0 mL) in a microwave reaction vessel
was heated to reflux under irradiation of microwave
(300 W, CEM Discover Microwave System) for 3
h. The reaction mixture was concentrated in vacuo
and the residue was purified two times by SiO2 col-
umn chromatography (hexane/EtOAc = 9:1 and then
CH2Cl2/benzene = 1:1) to give 13 (420 mg, 52%) as
a pale yellow oil. IR: υmax 3403 (br), 3020 (w), 1647
(s), 1605 (m), 1311(s), 1267(s), 1199(s); 1H NMR (400
MHz, CDCl3): δ 1.36 (3H, t, J = 7.1 Hz), 1.71 (3H, d,
J = 1.2 Hz), 1.75 (6H, s), 1.83 (3H, br s), 2.81–2.88
(2H, m), 3.19–3.26 (2H, m), 3.36 (2H, br d, J = 6.4
Hz), 3.45 (2H, br d, J = 7.0 Hz), 4.44 (2H, q, J = 7.2
Hz), 5.03–5.09 (1H, m), 5.22–5.29 (1H, m), 6.02 (1H,
s), 7.18–7.25 (3H, m), 7.28–7.34 (2H, m), 11.7 (1H, s,
OH);13C NMR (100 MHz, CDCl3): δ 14.4, 17.9, 18.0,
22.4, 25.1, 25.7, 25.8, 32.6, 37.1, 61.5, 105.8, 112.3,
119.3, 121.7, 122.9, 125.9, 128.0 (2C), 128.4 (2C),
133.3, 134.9, 141.1, 142.1, 158.3, 160.0, 172.0; HRMS
(FAB): m/z calcd for C27H34O4Na, 445.2349; found,
445.2355 ([M+ Na]+).
To a stirred solution of 4 (3.05 g, 9.70 mmol) in
CH2Cl2 (60.0 mL) was added dropwise a solution of
BBr3 (1.0 M in CH Cl2, 50.0 mL, 48.5 mmol) at 0 ºC.
2
After stirring for 36 h, the reaction mixture was
quenched with satd aq NaHCO3 and extracted four
times with CHCl3. The extract was successively
washed with water and brine, dried (Na2SO4), fil-
tered and concentrated in vacuo. The residue was
purified by SiO2 column chromatography (hexane/
EtOAc = 8:1) to give ethyl 2,4-dihydroxy-6-(2-phe-
nylethyl)benzoate (2.08 g, 75%) as a pale yellow
solid. Mp 89–90ºC; IR: υmax 3381 (br), 1652 (s),
1
1618 (s), 1495 (m), 1314 (s), 1262 (s); H NMR
(400 MHz, CDCl3): δ 1.39 (3H, t, J = 7.2 Hz),
2.84–2.90 (2H, m), 3.17–3.23 (2H, m), 4.44 (2H,
q, J = 7.2 Hz), 5.10–5.13 (1H, m), 6.18 (1H, d, J =
2.6 Hz), 6.30 (1H, d, J = 2.6 Hz), 7.15–7.23 (3H, m),
7.25–7.33 (2H, m) 11.8 (1H, s, OH);13C NMR (100
MHz, CDCl3): δ 14.1, 37.8, 38.1, 61.6, 101.6, 104.9,
111.3, 125.9, 128.1 (2C), 128.3 (2C), 141.6, 147.6,
160.6, 164.9, 171.5; HRMS (FAB): m/z calcd for C17
H19O4, 287.1278; found, 287.1288 ([M + H]+). To
a stirred solution of the dihydroxy benzoate
obtained above (517 mg, 1.81 mmol) and tert-
butyl (2-methylbut-3-en-2-yl) carbonate (2.06 g,
11.1 mmol) in THF (3.60 mL) was added pulver-
ized 4Å molecular sieves (1.38 g) at room tempera-
ture. After cooling to – 20ºC, Pd(PPh3)4 (209 mg,
0.181 mmol) was added portionwise and the result-
ing suspension was stirred for 18 h. The reaction
mixture was filtered through a pad of Celite and the
filtrate was concentrated in vacuo. The residue was
purified by SiO2 column chromatography
(pentane/Et2O = 9:1, containing 1% Et3N) to give
3b (770 mg, quant) as a pale yellow oil. IR: υmax
Ethyl 2-hydroxy-4-methoxy-3,5-bis(3-methylbut-
2-en-1-yl)-6-(2-phenylethyl)benzoate (14)
To a stirred solution of 13 (82.0 mg, 0.194 mmol) in
acetone (1.90 mL) was added portionwise K2CO3
(26.0 mg, 0.188 mmol) at room temperature. After
stirring for 5 min, the reaction mixture was cooled
to – 1ºC. To the mixture was added MeI (12.0 μL,
0.193 mmol) and the mixture was warmed to room
temperature and stirred for 19 h. The reaction mixture
was concentrated in vacuo and the residue was diluted
with a mixed solvent of H2O, hexane and Et2O (1:1:1).
The mixture was neutralized with 1 M HCl and
extracted three times with Et2O. The extract was dried
(Na2SO4), filtered and concentrated in vacuo. The resi-
due was purified by SiO2 column chromatography
(hexane/EtOAc = 24:1) to give 14 (42 mg, 50%) as
a colorless oil. IR: υmax 3382 (br), 1651 (s), 1317 (s),
1264 (s), 1198 (s); 1H NMR (400 MHz, CDCl3): δ 1.36
(3H, t, J = 7.1 Hz), 1.66 (3H, d, J = 1.3 Hz), 1.70 (3H, d,
J = 1.2 Hz), 1.71 (3H, d, J = 0.9 Hz), 1.79 (3H, d, J = 0.8
Hz), 2.78–2.85 (2H, m), 3.19–3.26 (2H, m), 3.34 (2H, d,
J = 6.1 Hz), 3.39 (2H, d, J = 6.6 Hz), 3.71 (3H, s), 4.45
(2H, q, J = 7.2 Hz), 4.99–5.06 (1H, m), 5.22–5.28
(1H, m), 7.17–7.24 (3H, m), 7.27–7.33 (2H, m), 11.2
(1H, s, OH);13C NMR (100 MHz, CDCl3): δ 14.3, 17.9,
1
3025 (w), 1730 (s), 1602 (s), 1264 (m); H NMR
(400 MHz, CDCl3): δ 1.34–1.39 (9H, m), 1.43 (6H,
s), 2.76–2.89 (4H, m), 4.35 (2H, q, J = 7.2 Hz),
5.06–5.21 (4H, m), 6.03 (1H, dd, J = 10.7, 17.8
Hz), 6.13 (1H, dd, J = 10.9, 17.6 Hz), 6.41 (1H, d,
J = 2.1 Hz), 6.65 (1H, d, J = 2.1 Hz), 7.13–7.19
(3H, m), 7.23–7.29 (2H, m);13C NMR (100 MHz,
CDCl3): δ 14.3, 26.86 (2C), 26.90 (2C), 35.7, 37.4,
60.8, 79.6, 80.4, 109.5, 113.1, 113.2, 115.4, 121.4,
125.8, 128.27 (2C), 128.34 (2C), 139.9, 141.6, 144.0,
144.5, 154.0, 156.7, 168.8; HRMS (FAB): m/z calcd

6
T. FUJITA ET AL.
18.0, 23.5, 25.3, 25.6, 25.7, 32.4, 37.3, 61.5, 61.7, 109.7,
121.2, 122.8, 124.2, 125.9, 126.1, 128.0 (2C), 128.3 (2C),
131.5, 131.7, 141.4, 142.1, 160.1, 161.4, 171.6; HRMS
(FAB): m/z calcd for C28H36O4Na, 459.2506; found,
459.2510 ([M+ Na]+).
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C (2)
To a stirred solution of 14 (51.0 mg, 0.117 mmol) in
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ified by SiO2 column chromatography (hexane/EtOAc =
3:1) to give 2 (36 mg, 75%) as a white solid. An analytical
sample was recrystallized from hexane/EtOAc to give
NMR spectroscopically pure 2 as colorless needles. Mp
112–113ºC; IR: υmax 3025 (m), 2970 (br), 1634 (s), 1590
(m), 1452 (m), 1259 (s); 1H NMR (600 MHz, CD3OD): δ
1.67 (6H, br s), 1.72 (3H, s), 1.78 (3H, s), 2.75–2.81
(2H, m), 3.16–3.21 (2H, m), 3.33–3.36 (4H, m), 3.67
(3H, s), 4.99–5.04 (1H, m), 5.20–5.25 (1H, m),
7.13–7.21 (3H, m), 7.25 (2H, t, J = 7.4 Hz);13C NMR
(150 MHz, CD3OD): δ 18.0, 18.2, 24.3, 25.8, 25.9, 26.2,
34.4, 38.7, 61.9, 110.8, 122.0, 124.3, 125.7, 126.87, 126.93,
129.27, 129.32, 131.9 (2C), 132.1 (2C), 143.5, 143.8, 161.9,
162.5, 175.0; HRMS (FAB): m/z calcd for C26H32O4Na,
431.2193; found, 431.2198 ([M+ Na]+).
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Author contribution
Y.O. and S.K. designed the synthetic route. Y.O. and S.
K. wrote the manuscript. T.F. conducted the synthetic
experiments with the aid of Y.O.
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Disclosure statement
No potential conflict of interest was reported by the
authors.
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ORCID
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amorfrutin C and pseudo-amorfrutin A. Eur J Org
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Shigefumi Kuwahara
6875
http://orcid.org/0000-0002-5839-
Yusuke Ogura
http://orcid.org/0000-0002-8646-9322

SYNTHESIS OF AMORFRUTINS A AND C
7
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