A concise total synthesis of biologically active frutinones via tributylphosphine-catalyzed tandem acyl transfer-cyclization

Article abstract of DOI:10.1016/j.tet.2014.03.073

A concise and step-economical total synthesis of biologically active frutinones has been achieved. Tributylphosphine (PBu₃) efficiently induced the tandem acyl transfer-cyclization of carbonates 5 to afford 3-methoxycarbonylflavone derivatives 4 in excellent yields. Finally, concomitant deprotection and lactonization under acidic conditions furnished the desired frutinones A (1a), B (1b), and the proposed structure of frutinone C (1c).

Full text of DOI:10.1016/j.tet.2014.03.073

Tetrahedron 70 (2014) 3452e3458
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A concise total synthesis of biologically active frutinones via
tributylphosphine-catalyzed tandem acyl transfer-cyclization
*
Masahito Yoshida, Koya Saito, Yuta Fujino, Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and step-economical total synthesis of biologically active frutinones has been achieved.
Tributylphosphine (PBu3) efficiently induced the tandem acyl transfer-cyclization of carbonates 5 to
afford 3-methoxycarbonylflavone derivatives 4 in excellent yields. Finally, concomitant deprotection and
lactonization under acidic conditions furnished the desired frutinones A (1a), B (1b), and the proposed
structure of frutinone C (1c).
Received 17 December 2013
Received in revised form 20 March 2014
Accepted 23 March 2014
Available online 1 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Flavone
Regioselective
Tandem reaction
Organocatalyst
1. Introduction
reported methods have low tolerance for functionality, and provide
limited access to chromonocoumarin derivatives. Therefore, we
Naturally occurring biologically active molecules are remarkable
source of lead compounds in drug disocovery.1 Flavonoids, gener-
ally obtained from the natural plants, are examples of natural
products that are promising drug candidates because of their an-
tioxidant, anti-inflammatory and other biological activites.2 In
considered that the development of a diversity-oriented strategy
for the synthesis of the chromonocoumarin structure would be
useful in the elucidation of structure-activity relationships of fru-
tinones and the other 3-acylflavones. We report herein a concise
and diversity-oriented total synthesis of biologically active flavo-
noid frutinones via tributylphosphine-catalyzed tandem acyl
transfer-cyclization. Because the 3-acylflavone scaffold is a key
component of the frutinone structure, the introduction of a car-
boxylic acid or ester moiety at the C-3 position in the flavone
skeleton is important for achieving the total synthesis of 1. To date,
several synthetic methods for the introduction of the ester moiety
have been reported such as classical intramolecular FriedeleCrafts
particular, flavones consisting of a g-benzopyranone structure with
aromatic substituents at the C-2 position, such as quercetin,3
nobiletin,4 and baicalin,5 exhibit interesting biological properties.
In fact, the g-benzopyranone skeleton can also be found in other
biologically active natural products such as pluramycins, and thus
the development of a methodology for the selective synthesis of the
g-benzopyranone structure would be conducible to further drug
discovery.6 Frutinones (1), isolated from the leaves and root bark of
Polygala fruticosa, consist of a unique chromonocoumarin struc-
ture.7 Among the frutinone derivatives, frutinone A (1a) exhibits
strong fungicidal activity against Cladosporium cucumerinum,7 and
it has been recently reported to strongly inhibit cytochrome P450
1A2 (CYP1A2).8 Thus, the chromonocoumarin structure may also be
an intriguing scaffold for drug discovery and development. To date,
chromonocoumarin framework has been synthesized via coupling
of the cis-disalicylide with malonate derivative9a or condensation
of 3-alkoxycarbonylcoumarin with resorcinol.9b However, the
acylation of b
-phenoxymalonate,10 anionic direct acylation of the
flavone skeleton,11 base-promoted intramolecular O-arylation of
enol derivatives12 and so on13 (Fig. 1).
The above reported methods efficiently introduce an acyl group
at the C-3 position in flavone skeleton, however, the harsh condi-
tions that are required may limit the tolerance for a wide array of
functionalities and thus prevent the development of a diversity-
oriented synthesis of the 3-acylflavones. Recently, we have re-
ported that a catalytic amount of the Lewis base 9-azajulolidine (9-
AJ)14 effectively induces the rearrangement of the aroyl group in 2
and regioselective cyclization of the resulting phenoxide under
ambient conditions to afford 3-aroylflavones 3 in excellent yields
(Fig. 2).15 We envisaged that Lewis base-catalyzed tandem acyl
transfer-cyclization we developed would be applied to a concise
* Corresponding author. Tel.: þ81 22 795 6865; fax: þ81 22 795 6864; e-mail
address: doi_taka@mail.pharm.tohoku.ac.jp (T. Doi).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.073

M. Yoshida et al. / Tetrahedron 70 (2014) 3452e3458
3453
Scheme 1. Retrosynthesis of frutinones (1).
Table 1
Fig. 1. Synthesis of 3-alkoxycarbonylflavone derivatives.
Investigation of tandem acyl transfer-cyclization
Entry Reagent
(mol %)
Solvent
Temp (ꢀC) Time
Ratio
Yield
of 9a:10aa of 9a (%)b
1
2
3
4
9-AJ (30)
9-AJ (30)
9-AJ (30)
9-AJ (30)
PBu3 (30) Toluene
PCy3 (30) Toluene
PPh3 (30) Toluene
DMF
Toluene
Toluene
30
30
100
4 h
25 h
3 h
3 h
5 min
62:38
93:7
>95:5
>95:5
>95:5
52
90
97
84
99
97
55
(CH2Cl)2 reflux
5
30
30
30
6
15 min >95:5
50 h 59:41
7c,d
a
The ratio of 9a and 10a was determined by crude 1H NMR.
Isolated yield.
Reaction was not complete.
b
c
d
5-exo-Cyclized aurone was also observed.
Fig. 2. 9-Azajulolidine-catalyzed tandem acyl transfer-cyclization.
and toluene at the high temperature selectively provided 9a in
good yield, indicating that the reaction conditions, particularly the
solvents and temperature, significantly influence the yield and se-
lectivity for 9a (entries 3 and 4). After extensive studies utilizing the
other Lewis bases, such as trialkyl- and triaryl-phosphines, it was
found that 30 mol % of PBu3 efficiently catalyzed the tandem acyl
transfer-cyclization of 8a to afford 9a in 99% yield (entry 5). It
should be noted that the reaction was easily triggered by the ad-
dition of PBu3 due to its high nucleophilicity18 and proceeded
smoothly to afford the desired product 9a. On the other hand, when
PCy3 was used as the catalyst, formation of 9a was sluggish because
1,4-addition of PCy3 to the ynone was slower due to the steric
hindrance of PCy3 (entry 6). In addition, the reaction in the pres-
ence of PPh3 was not complete, and a mixture of 9a and 10a was
obtained (entry 7). The addition of PPh3 to 8 is expected to be
slower than that of PBu3 because of the lower nucleophilicity
compared with that of the trialkylphosphines, such as PBu3 and
PCy3.18 Furthermore, a 5-exo cyclized aurone was also formed in the
reaction with PPh3.19 It is conceivable that deacylation partially
occurred under the reaction conditions to generate a phenol de-
rivative after 1,4-addition of PPh3 to 8a, and the subsequent non-
regioselective cyclization of the resulting o-alkynoylphenol pro-
ceeded to the afford flavone and aurone (entry 7).
introduction of other acyl groups such as carboxylic acids or esters
at the C-3 position in the flavone skeleton leading to frutinones.
Our retrosynthetic strategy for 1 is illustrated in Scheme 1. The
desired frutinones (1) can be obtained by lactonization of 3-
methoxycarbonylflavone 4 via removal of the MOM group. The
desired 4 would be prepared by Lewis base-catalyzed tandem acyl
transfer-cyclization of carbonates 5, which can be synthesized via
the Pd(0)-catalyzed carbonylative Sonogashira coupling reaction of
iodobenzene 6 and phenylacetylene 7. A variety of biologically ac-
tive frutinone derivatives could thus be synthesized via integrated
multi-component synthetic approaches,16 and the tandem reaction
sequence would be an efficient and step-economical approach17 for
the synthesis of naturally occurring flavonoid derivatives.
2. Results and discussion
To construct the chromonocoumarin structure via the above-
mentioned tandem reaction we developed,15 rearrangement of an
alkoxycarbonyl group at the C-3 position in the flavone skeleton is
required. Thus, the tandem acyl transfer-cyclization of methyl car-
bonate 8a was investigated and the results are depicted in Table 1.
The reaction was initially attempted in the presence of 30 mol % 9-
AJ in DMF according to the conditions used for Lewis base-catalyzed
3-acylflavone synthesis; however, a mixture of the desired 3-
methoxycarbonylflavone 9a and the unexpected flavone 10a was
obtained in a ratio of 62:38 (entry 1). The reaction conditions were
further optimized in order to improve the yield of 9a. It was found
that the reactions in non-polar solvents, such as 1,2-dichloroethane
With the optimized conditions for the tandem acyl transfer-
cyclization in hand, the scope of the PBu3-catalyzed tandem re-
action of various carbonates 8 was investigated, and the results are
depicted in Table 2. Reactions of ethyl carbonate 8b and isopropyl
carbonate 8c were smoothly complete within 15 min to provide the
corresponding 3-acyl derivatives 9b and 9c in excellent yields

3454
M. Yoshida et al. / Tetrahedron 70 (2014) 3452e3458
Table 2
Since a variety of the alkyl carbonates 8aei are tolerated in the
PBu3-catalyzed tandem acyl transfer-cyclization, the total synthesis
of frutinones (1) via time-integrated synthetic approaches16 uti-
lizing the developed tandem reaction was then attempted. Pd(0)-
catalyzed carbonylative Sonogashira coupling of iodobenzenes 621
and alkynes 722 was performed at 80 ꢀC in the presence of CuI
under 50 atm of carbon monoxide to provide the desired 5aec in
moderate yields with no double carbonylative product observed
under high-pressure conditions.23 On the other hand, the carbon-
ylation of 6 did not efficiently proceed under 30 atm or less of
carbon monoxide, and the Sonogashira coupling predominated.
Importantly, the PBu3-catalyzed tandem acyl transfer-cyclization of
5aec smoothly proceeded at 30 ꢀC in toluene, providing the cor-
responding desired products 4aec in 92e98 % yields. Finally, re-
moval of the protecting groups followed by lactone formation
under acidic conditions furnished the desired frutinones (1aec) in
good yields (Scheme 3).
Substrate scope for PBu3-catalyzed tandem acyl transfer-cyclization
Entry Substrate R1
R2
Time
Product Yield (%)a
1
2
3
4
5
6
7
8
9
10
8b
8c
8d
8e
8f
8g
8h
8i
Et
i-Pr
t-Bu
Allyl
H
H
H
H
H
H
15 min 9b
15 min 9c
30 min 9d
5 min
5 min
5 min
96
93
99
99
97
99
83
97
6
9e
9f
9g
Bn
2,2,2-Trichloroethyl
Me
Me
Ph
OMe 15 min 9h
F
H
H
5 min
12 h
22 h
9i
9j
8j
8k
p-MeOC6H4
9k
27
a
Isolated yield.
O
OMe
O
OMe
R
R
a)
O
I
O
O
(entries 1 and 2). In addition, the sterically hindered tert-butox-
ycarbonyl group of 8d was also tolerated in the PBu3-catalyzed
tandem reaction, and the desired 9d was obtained in 99% yield
(entry 3). Furthermore, the substrates 8e and 8f possessing allyloxy
and benzyloxy carbonyl moieties at the R1 position were quanti-
tatively converted to 9e and 9f, respectively (entries 4 and 5). No-
tably, the electron-withdrawing 2,2,2-trichloroethoxy carbonyl
group in 8g was also smoothly transferred under the reaction
conditions, and the desired 3-acylflavone 9g was obtained in 99%
yield (entry 6). However, the presence of a substituent R2 at the
para-position of the benzene ring affected the electrophilicity of the
ynone system; e.g., the reaction of 8h with an electron-donating
methoxy group as substituent R2 proceeded slowly to give 9h in
83% yield because of the decrease of electrophilicity of the ynone,
while 8i possessing an electron-withdrawing fluoride atom as the
R2 substituent was consumed within 5 min to afford the desired 9i
in 97% yield (entries 7 and 8). According to the above observations,
it was noteworthy that PBu3 effectively induces the tandem acyl
transfer-cyclization of the alkyl carbonates 8aei to afford 9aei in
good to excellent yields, and the reaction conditions are robust
with respect to the substituent effect, such as a steric hindrance. On
the other hands, reaction of the substrate 8j involving a phenyl
carbonate was problematic to obtain the corresponding 3-
acylflavone 9j (6%) and inseparable byproducts. 5-Exo cyclized
aurone was also observed in the resulting byproducts, thereby an o-
alkynoylphenoxide ion would be formed by cleavage of the
diphenoxycarbonate moiety.20 Interestingly, p-methoxyphenyl
group in 8k would slightly suppress the side reaction because of its
electron-donation, and the desired 9k was afforded in 27% yield.
We also investigated the reaction of the carbamate derivatives
8l and 8m, however the desired reaction did not proceed and the
substrate 8l was partially recovered (Scheme 2). Electrophilicity of
the carbamate moiety is lower than that of the carbonate group
because of electron-donation from the nitrogen atom, thereby the
acyl transfer would not occur under the reaction conditions.
R
R
OMOM
OMOM
6a: R = H
7a: R = H
5a: 77%
5b: 46%
5c: 73%
6b: R = OTHP 7b: R = OMe
R
R
O
O
O
b)
c)
R
R
O
OMOM
OMe
O
O
O
4a (R = R = H): 92%
Frutinone A (1a) (R = R = H): 75%
4b (R = H, R = OMe): 98%
4c (R = OTHP, R = H): 94%
Frutinone B (1b) (R = H, R = OMe): 74%
Frutinone C (1c) (R = OH, R = H): 75%
Scheme 3. Total synthesis of frutinones (1). Regents and conditions: a) Pd(PPh3)4
(1 mol%), CuI (2 mol%), NEt3 (3 equiv), CO (50 atm), DMF, 80 ꢀC, 12 h, b) PBu3 (30 mol%),
toluene, rt, 0.5e2.5 h, c) 4 M HCledioxane, rt, 1.5 h.
Spectral data for synthetic frutinones A (1a) and B (1b) were in
good agreement with those of the natural products,7 while the
spectra of the synthetic frutinone C (1c) was not identical to that
reported for the natural compound 1c. The chemical shifts in the 1H
and 13C NMR of the natural and synthetic 1c are depicted in Table 3.
It can be seen that the chemical shifts for H-5 and H-7 in the syn-
thetic 1c were substantially different from the reported data. It
should also be noted that the proton of the phenol in synthetic 1c
was detectable in the 1H NMR, while this peak was not observed for
natural 1c.
In order to confirm the structure of 1c, we next investigated the
methylation of the synthetic 1c leading to the reported methyl
ether 11 (Scheme 4). Methylation of the phenol in 1c with iodo-
methane afforded 11, and the spectral data for synthetic 11 were in
good agreement with that reported for the ether derivatized from
the natural frutinone C. Furthermore, the structure of 11 was un-
ambiguously confirmed by single crystal X-ray crystallographic
analysis.24 Based on the above observations, it should be noted that
the chromonocoumarin structure was correctly formed and the
position of the free phenolic hydroxyl group in 1c was established
to be C-8 on the chromonocoumarin skeleton. These results suggest
that the proposed structure of frutinone C (1c) was obtained as well
as the other frutinones, and that the natural frutinone C may have
been isolated as a phenolic salt during isolation from the plants.
O
NR
PBu (30 mol%)
O
O
O
O
NR
toluene
30 °C, 24 h
O
3. Conclusion
8l: R=Et
9l: 0% (50%)
9m: 0%
8m: R=Ph
Yield of the recovered substrate
In conclusion, we have demonstrated a Lewis base-catalyzed
tandem acyl transfer-cyclization of carbonate derivatives and ap-
plied this reaction to the total synthesis of frutinones. Several Lewis
Scheme 2. Investigation of tandem acyl transfer-cyclization of the carbamate de-
rivatives 8l and 8m.

M. Yoshida et al. / Tetrahedron 70 (2014) 3452e3458
3455
Table 3
purchased from Wako (for peptide synthesis, grade: 99.5%). All
reactions in solution-phase were monitored by thin-layer chro-
matography carried out on 0.2 mm E. Merck silica gel plates (60F-
254) with UV light, and visualized with anisaldehyde, 10% ethanolic
phosphomolybdic acid. Silica gel 60N (Kanto Chemical Co.
100e210 mm) was used for column chromatography. 1H NMR
spectra (400 MHz) and 13C NMR spectra (100 MHz) were recorded
on JEOL JNM-Al400 spectrometers in the indicated solvent.
Chemical shifts of natural and synthetic frutinone C (1c)
1H NMR (DMSO-d6)
13C NMR (DMSO-d6)
Lit.
Obs.
Lit.
Obs.
Chemical shifts (d) are reported in units parts per million (ppm)
1
2
3
4
5
6
7
8
relative to the signal for internal tetramethylsilane (0 ppm for 1H)
for solutions in CDCl3. NMR spectral data are reported as follows:
chloroform (7.26 ppm for 1H) or chloroform-d (77.0 ppm for 13C),
dimethyl sulfoxide-d6 (2.49 ppm for 1H) or dimethyl sulfoxide-d6
(39.5 ppm for 13C) when internal standard is not indicated. Multi-
plicities are reported by the following abbreviations: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), dd (double dou-
blet), dt (double triplet), ddd (double double doublet), ddt (double
double triplet), dddd (double double double doublet), br s (broad
singlet), br d (broad doublet), J (coupling constants in Hertz). Mass
spectra and high-resolution mass spectra were measured on JEOL
JMS-DX303 and MS-AX500 instruments. IR spectra were recorded
on a Shimadzu FTIR-8400. Only the strongest and/or structurally
164.3
104.6
172.6
119.6
126.1
127.1
146.5
164.3
104.5
172.6
114.9
126.4
120.7
146.6
7.87
7.50
7.83
7.54
7.37
7.37
8-OH
4a
8a
10
20
30
40
50
60
100
N.D.
10.7
125.1
142.6
113.5
124.4
125.0
135.8
116.9
153.8
155.8
125.3
143.5
113.5
124.6
124.7
135.5
116.7
153.6
155.6
8.29
7.59
7.89
7.52
8.40
7.54
7.86
7.50
important absorption are reported as the IR data afforded in cmꢁ1
.
Melting points were measured on Round Science Inc. RFS-10 and
are not corrected.
4.2. General procedure for the synthesis of 3-acylflavone de-
rivatives 9 via PBu3-catalyzed tandem acyl transfer-cyclization
To a solution of alkynone 8ae8i in dry toluene (20 mL/mmol)
was added PBu3 (0.300 equiv) at room temperature under argon.
After being stirred at 30 ꢀC, the reaction mixture was concentrated
in vacuo and then the resulting residue was purified by column
chromatography on silica gel (eluted with hexane/ethyl acetate¼7/
1 to 3/1) to afford 3-acylflavone derivatives 9ae9i.
ORTEP structure of 11
Scheme 4. Synthesis of frutinone C methyl ether (11).
4.2.1. Methyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
bases were investigated in the tandem acyl transfer-cyclization,
and a catalytic amount of PBu3 was observed to effectively pro-
moted the reaction of 8, and the desired 3-acylflavones 9 were
selectively produced in excellent yields. The developed tandem
reaction was then applied to the concise synthesis of biologically
active flavonoid frutinones (1). The Pd(0)-catalyzed carbonylative
Sonogashira coupling of iodobenzenes 6 and phenylacetylenes 7
afforded the precursors 5. Subsequently, PBu3-catalyzed tandem
(9a). Yield: 97%, Reaction time:
5
d
min, white solid, mp
8.26 (dd, 1H, J¼7.8, 1.4 Hz),
98e100 ꢀC. 1H NMR (400 MHz, CDCl3)
7.75e7.70 (m, 3H), 7.58e7.43 (m, 5H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 175.0, 165.6, 163.1, 155.8, 134.3, 131.9, 131.6,
128.8, 128.0, 126.1, 125.7, 123.1, 118.1, 118.0, 52.7; FTIR (neat) 1736,
1645, 1465, 1383, 1092, 760 cmꢁ1; HRMS[EI] calcd for C17H12O4
[M]þ 280.0736, found 280.0746.
acyl transfer-cyclization of
5 successfully provided the 3-
4.2.2. Ethyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
acylflavones 4 in excellent yields. Finally, formation of the chro-
monocoumarin structure under acidic conditions furnished the
desired frutinones A (1a), B (1b) and C (1c), although the spectral
data for 1c were not identical to those for the compound previously
reported as frutinone C. However, the spectral data for the methyl
ether 11 were in good agreement with those previously reported
for the ether derivatized from natural frutinone C. A variety of the
substrates are tolerated under the reaction conditions, and thus the
developed method should be useful for the synthesis of 3-
alkoxycarbonyl- or 3-carboxylflavones including biologically ac-
tive natural products.
(9b). Yield: 96%, Reaction time: 15 min, white solid, mp
91e93 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.27 (dd, 1H, J¼8.0, 1.6 Hz),
7.77e7.70 (m, 3H), 7.60e7.43 (m, 5H), 4.28 (q, 2H, J¼7.2 Hz), 1.17 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 174.8, 164.9, 162.9, 155.7,
134.2, 131.8, 131.5, 128.6, 127.9, 125.9, 125.5, 123.0, 118.2, 117.9, 61.7,
13.7; FTIR (neat) 1733, 1645, 1620, 1465, 1393, 1381, 1091, 759 cmꢁ1
HRMS[EI] calcd for C18H14O4 [M]þ 294.0892, found 294.0876.
;
4.2.3. 2-Methylpropyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
(9c). Yield: 93%, reaction time: 15 min, pale yellow oil. 1H NMR
(400 MHz, CDCl3)
d
8.27 (dd, 1H, J¼8.0, 1.6 Hz), 7.77 (m, 2H), 7.72
(ddd, 1H, J¼8.0, 8.0, 1.6 Hz), 7.58e7.43 (m, 5H), 5.18 (sep, 1H,
4. Experimental section
4.1. General
J¼6.4 Hz), 1.17 (d, 6H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d 174.9,
164.4, 162.7,155.7, 134.2,131.9, 131.4, 128.6,128.1,126.0,125.5,123.1,
118.6, 118.0, 69.5, 21.4; FTIR (neat) 1730, 1646, 1622, 1569, 1465,
1385, 1089, 759 cmꢁ1; HRMS[EI] calcd for C19H16O4 [M]þ 308.1049,
found 308.1050.
All commercially available reagents were used as received. Dry
THF and CH2Cl2 (Kanto Chemical Co.) were obtained by passing
commercially available pre-dried, oxygen-free formulations. MeOH
was distilled from iodide and magnesium turnings. DMF was
4.2.4. tert-Butyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
(9d). Yield: 99%, reaction time: 30 min, pale yellow oil. 1H NMR

3456
M. Yoshida et al. / Tetrahedron 70 (2014) 3452e3458
(400 MHz, CDCl3)
d
8.25 (dd, 1H, J¼8.0, 1.6 Hz), 7.81 (d, 2H,
d
174.8, 163.6, 163.5, 155.9, 150.5, 134.4, 131.92, 131.87, 129.4, 129.0,
J¼8.0 Hz), 7.70 (ddd, 1H, J¼8.0, 8.0, 1.6 Hz), 7.58e7.48 (m, 4H), 7.43
128.3, 126.1, 125.9, 123.2, 121.4, 118.1; FTIR (neat) 1753, 1646, 1622,
1465, 1384, 1186, 1075, 759 cmꢁ1; HRMS[FAB] calcd for C22H15O4
[MþH]þ 343.0970, found 343.0977.
(ddd, 1H, J¼8.0, 8.0, 0.8 Hz), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
175.2, 164.0, 162.2, 155.9, 134.1, 132.1, 131.4, 128.6, 128.2, 126.0,
125.4, 123.3, 120.0, 118.0, 82.9, 27.8; FTIR (neat) 1729, 1646, 1623,
1465, 1383, 1092, 761 cmꢁ1; HRMS[FAB] calcd for C20H19O4 [MþH]þ
323.1283, found 323.1270.
4.2.11. p-Methoxyphenyl 4-oxo-2-phenyl-4H-chromene-3-
carboxylate (9k). Yield: 27%, Reaction time: 22 h, light yellow oil.
1H NMR (400 MHz, CDCl3)
d
8.31 (dd, 1H, J¼8.0, 1.6 Hz), 7.86 (m,
4.2.5. Prop-2-en-1-yl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
2H), 7.75 (ddd, 1H, J¼8.0, 7.8, 1.6 Hz), 7.64e7.55 (m, 4H), 7.49 (ddd,
1H, J¼8.0, 8.0, 1.2 Hz), 6.92 (d, 2H, J¼9.2 Hz), 6.86 (d, 2H, J¼9.2 Hz),
(9e). Yield: 99%, reaction time:
5
min, white solid, mp
103e105 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.19 (dd, 1H, J¼8.0, 1.6 Hz),
3.79 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.8, 163.9, 163.5, 157.5,
7.68e7.62 (m, 3H), 7.51e7.35 (m, 5H), 5.72 (ddt, 1H, J¼17.6, 10.8,
6.0 Hz), 5.17 (dd, 1H, J¼17.6, 1.6 Hz), 5.10 (dd, 1H, J¼10.8, 1.6 Hz),
155.9, 143.9, 134.4, 132.0, 131.8, 128.9, 128.3, 126.1, 125.9, 123.2,
122.1, 118.1, 117.8, 114.4, 55.6; FTIR (neat) 1752, 1644, 1505, 1465,
1384, 1188, 1074 cmꢁ1; HRMS[ESI] calcd for C23H16O5Na [MþNa]þ
395.0895, found 395.0877.
4.63 (d, 2H, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
d 174.9, 164.7,
163.2, 155.8, 134.3, 131.8, 131.6, 131.1, 128.7, 128.1, 126.0, 125.6, 123.1,
119.0, 118.04, 118.00, 66.3; FTIR (neat) 1735, 1645, 1465, 1387, 1091,
760 cmꢁ1; HRMS[EI] calcd for C19H14O4 [M]þ 306.0892, found
306.0902.
4.3. General procedure for synthesis of alkynone derivatives 5
via Pd-catalyzed carbonylative Sonogashira coupling
4.2.6. Benzyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
In a 50 mL of autoclave containing a glass tube was placed
iodophenyl carbonate 6ae6b (1.00 equiv), ethynyl benzene 7ae7b
(1.20 equiv), triethylamine (3.00 equiv), DMF (6.00 mL/mmol),
Pd(PPh3)4 (0.0100 equiv) and CuI (0.0200 equiv). The autoclave was
filled with carbon monoxide (50 atm) after purged with carbon
monoxide three times. The reaction was carried out under an ap-
propriate carbon monoxide pressure at 80 ꢀC for 12 h. The reaction
mixture was diluted with water. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were washed with saturated aqueous NH4Cl,
brine, dried over MgSO4, and filtered. The filtrate was concentrated
in vacuo and then the resulting residue was purified by column
chromatography on silica gel (eluted with hexane/ethyl
acetate¼15/1 to 7/1) to afford alkynone 5ae5c.
(9f). Yield: 97%, reaction time:
5
d
min, white solid, mp
8.26 (dd, 1H, J¼7.8, 1.6 Hz),
152e154 ꢀC. 1H NMR (400 MHz, CDCl3)
7.70 (ddd, 1H, J¼7.6, 6.0, 1.6 Hz), 7.64 (d, 2H, J¼7.6 Hz), 7.50 (m, 2H),
7.43 (dd, 1H, J¼7.8, 7.6 Hz), 7.36 (dd, 1H, J¼8.0, 7.6 Hz), 7.28 (m, 3H),
7.17 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 174.8, 164.8, 163.3, 155.7,
134.8, 134.3, 131.7, 131.5, 128.7, 128.6, 128.4, 128.2, 128.0, 126.0,
125.7, 123.1, 118.00, 117.96, 67.6; FTIR (neat) 1734, 1645, 1465, 1388,
1091, 759 cmꢁ1; HRMS[EI] calcd for C23H16O4 [M]þ 356.1049, found
356.1021.
4.2.7. 2,2,2-Trichloroethyl 4-oxo-2-phenyl-4H-chromene-3-
carboxylate (9g). Yield: 99%, reaction time: 5 min, colorless crys-
tal, mp 154e156 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.28 (dd, 1H, J¼8.4,
1.2 Hz), 7.75 (m, 3H), 7.52 (m, 5H), 4.79 (s, 2H); 13C NMR (100 MHz,
CDCl3) 174.4, 164.3, 163.5, 155.7, 134.5, 131.8, 131.7, 128.9, 128.2,
d
4.3.1. 2-{3-[2-(Methoxymethoxy)phenyl]prop-2-ynoyl}phenyl
126.1, 125.9, 122.9, 118.1, 116.9, 93.9, 75.2; FTIR (neat) 1752, 1647,
1465, 1388, 1102, 780, 761 cmꢁ1; HRMS[EI] calcd for C18H11Cl3O4
[M]þ 395.9723, found 395.9716.
methyl carbonate (5a). Yield: 77%, pale yellow oil. 1H NMR
(400 MHz, CDCl3)
d
8.50 (dd, 1H, J¼7.6, 1.6 Hz), 7.65e7.59 (m, 2H),
7.45e7.40 (m, 2H), 7.23 (dd, 1H, J¼8.2, 1.0 Hz), 7.17 (dd, 1H, J¼8.4,
1.2 Hz), 7.03 (ddd, 1H, J¼7.6, 7.6, 1.2 Hz), 5.31 (s, 2H), 3.92 (s, 3H),
4.2.8. Methyl 4-oxo-2-(4-methoxyphenyl)-4H-chromene-3-
3.54 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 175.7, 159.5, 153.6, 150.3,
carboxylate (9h). Yield: 83%, Reaction time: 15 min, light yellow
134.69, 134.68, 133.8, 132.5, 129.3, 126.3, 123.4, 121.7, 114.5, 110.2,
94.7, 91.4, 90.0, 56.4, 55.5; FTIR (neat) 2197, 1767, 1641, 1263, 1216,
1009 cmꢁ1; HRMS[EI] calcd for C19H16O6 [M]þ 340.0947, found
340.0945.
oil. 1H NMR (400 MHz, CDCl3)
d
8.26 (dd, 1H, J¼8.0, 1.6 Hz), 7.71 (m,
3H), 7.52 (d, 1H, J¼8.4 Hz), 7.44 (ddd, 1H, J¼8.0, 8.0, 1.6 Hz), 7.01 (d,
2H, J¼8.8 Hz), 3.89 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
175.0, 166.0, 162.8, 162.3, 155.7, 134.1, 129.7, 126.0, 125.5, 124.0,
123.0, 117.9, 117.0, 114.3, 55.4, 52.7; FTIR (neat) 1734, 1642, 1618,
1606, 1383, 1091 cmꢁ1; HRMS[EI] calcd for C18H14O5 [M]þ 310.0841,
found 310.0831.
4.3.2. 2-{3-[3-Methoxy-2-(methoxymethoxy)phenyl]prop-2-ynoyl}
phenyl methyl carbonate (5b). Yield: 46%, pale yellow oil. 1H NMR
(400 MHz, CDCl3)
d
8.42 (dd, 1H, J¼7.8, 1.4 Hz), 7.63 (ddd, 1H,
J¼7.6, 7.6, 1.4 Hz), 7.44 (ddd, 1H, J¼7.8, 7.6, 1.6 Hz), 7.21 (m, 2H),
4.2.9. Methyl 4-oxo-2-(4-fluorophenyl)-4H-chromene-3-carboxylate
(9i). Yield: 97%, Reaction time: 5 min, light yellow oil. 1H NMR
7.11e7.03 (m, 2H), 5.28 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.60 (s,
3H); 13C NMR (100 MHz, CDCl3)
d 175.7, 153.7, 152.5, 150.3, 148.6,
(400 MHz, CDCl3)
d
8.27 (dd, 1H, J¼8.0, 1.6 Hz), 7.79e7.71 (m, 3H, c
134.8, 133.7, 129.3, 126.5, 126.1, 124.4, 123.5, 115.4, 115.4, 98.8,
90.9, 89.9, 57.8, 56.0, 55.6; FTIR (neat) 2197, 1767, 1641, 1263,
1218 cmꢁ1; HRMS[EI] calcd for C20H18O7 [M]þ 370.1053, found
370.1062.
and e), 7.52 (d, 1H, J¼8.4 Hz), 7.46 (dd, 1H, J¼8.0, 8.0 Hz), 7.21 (dd,
2H, J¼8.6, 8.6 Hz), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.9,
165.9, 165.5, 163.3 (d, 1JCeF¼252 Hz), 162.0, 155.7, 134.4, 130.4, 130.3
3
4
(d, JCeF¼9.10 Hz), 128.08, 128.05 (d, JCeF¼3.30 Hz), 126.1, 125.8,
2
123.0, 118.04, 117.99, 116.3, 116.0 (d, JCeF¼22.3 Hz), 52.8; FTIR
4.3.3. 2-{3-[2-(Methoxymethoxy)phenyl]prop-2-ynoyl}-6-(oxan-2-
yloxy)phenyl methyl carbonate (5c). Yield: 73%, colorless crystal, mp
(neat) 1735, 1645, 1466, 1383, 1092 cmꢁ1; HRMS[EI] calcd for
C
17H11FO4 [M]þ 298.0641, found 298.0646.
104e106 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.98 (dd, 1H, J¼8.0, 1.6 Hz),
7.59 (dd, 1H, J¼8.0, 1.6 Hz), 7.48 (dd, 1H, J¼8.0, 1.6 Hz), 7.41 (ddd, 1H,
J¼8.0, 8.0, 1.6 Hz), 7.31 (dd, 1H, J¼8.0, 8.0 Hz), 7.17 (d, 1H, J¼8.0 Hz,
k), 7.02 (dd,1H, J¼8.0, 8.0 Hz), 5.50 (m, 1H), 5.30 (s, 2H), 3.89 (s, 3H),
3.89 (m, 1H), 3.61 (m, 1H), 3.53 (s, 3H), 2.01e1.82 (m, 3H), 1.76e1.59
4.2.10. Phenyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate
(9j). Yield: 6%, Reaction time: 12 h, colorless crystal, mp
135e137 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.32 (dd, 1H, J¼7.8, 1.6 Hz),
7.87 (m, 2H), 7.76 (ddd, 1H, J¼8.8, 7.8, 1.6 Hz), 7.64e7.55 (m, 4H),
7.49 (ddd, 1H, J¼7.8, 7.8, 0.8 Hz), 7.36 (dd, 2H, J¼8.0, 8.0 Hz), 7.22 (t,
1H, J¼8.0 Hz), 7.01 (d, 2H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 175.6, 159.5, 153.2, 149.5,
140.3, 134.7, 132.4, 130.7, 126.3, 125.1, 121.79, 121.76, 114.8, 110.6,
96.9, 94.8, 91.9, 89.7, 61.6, 56.5, 55.6, 30.1, 25.1, 18.0; FTIR (neat)

M. Yoshida et al. / Tetrahedron 70 (2014) 3452e3458
3457
2954, 2196, 1769, 1643, 1273, 1202, 966 cmꢁ1; HRMS[ESI] calcd for
C
117.4, 113.2, 105.1; FTIR (neat) 1758, 1657, 1619, 1552, 1465, 1422,
761 cmꢁ1; HRMS[EI] calcd for C16H8O4 [M]þ 264.0423, found
264.0431.
24H24O8Na [MþNa]þ 463.1369, found 463.1363.
4.4. General procedure for the synthesis of 3-acylflavone de-
rivatives 4 via PBu3-Catalyzed tandem acyl transfer-
cyclization
4.5.2. Frutinone
B
(1b). Purification: Recrystalization from
dichloromethane, yield: 74%, reaction time: 15 min, colorless
crystal, mp 279e281 ꢀC (lit. 279e280 ꢀC),7 1H NMR (400 MHz,
To a solution of carbonates 5ae5c (1.00 equiv) in dry toluene
(20.0 mL/mmol) was added PBu3 (0.300 equiv) at room tempera-
ture under argon. After being stirred at 30 ꢀC, the reaction mixture
was concentrated in vacuo and then the resulting residue was
purified by column chromatography (eluted with hexane/ethyl
acetate¼10/1 to 5/1) on silica gel to afford 3-acylflavones 4ae4c.
CDCl3/CD3OD 10:1)
d
8.36 (dd, 1H, J¼7.8, 1.4 Hz), 8.22 (dd, 1H, J¼8.0,
1.4 Hz), 7.82e7.74 (m, 2H), 7.64 (d, 1H, J¼8.4 Hz), 7.52 (dd, 1H, J¼7.8,
7.8 Hz), 7.48e7.41 (m, 2H); 13C NMR (100 MHz, CDCl3/CD3OD 10:1)
d
173.0, 165.0, 156.3, 154.4, 154.3, 135.6, 134.8, 127.0, 126.6, 124.8,
124.5, 124.2, 117.8, 117.4, 113.2, 105.1; FTIR (neat) 1748, 1738, 1618,
1558, 1488, 1473, 1459, 1406, 1272, 770 cmꢁ1; HRMS[EI] calcd for
C
16H8O4 [M]þ 264.0423, found 264.0431.
4.4.1. Methyl 2-[2-(methoxymethoxy)phenyl]-4-oxo-4H-chromene-
3-carboxylate (4a). Yield: 92%, Reaction time: 30 min, colorless
4.5.3. Frutinone C (1c). Purification: Wash with MeOH, yield: 75%,
reaction time: 1.5 h, white solid, mp>300 ꢀC (decomposition), 1H
crystal, mp 102e104 ꢀC, 1H NMR (400 MHz, CDCl3)
d 8.29 (dd, 1H,
J¼7.6, 1.6 Hz), 7.70 (ddd, 1H, J¼8.6, 7.0, 1.6 Hz), 7.51e7.42 (m, 4H),
NMR (400 MHz, DMSO-d6)
d
8.34 (dd, 1H, J¼8.0, 1.6 Hz), 7.78 (ddd,
7.25 (d,1H, J¼8.4 Hz), 7.12 (dd,1H, J¼7.2, 7.2 Hz), 5.18 (s, 2H), 3.67 (s,
1H, J¼8.6, 7.4, 1.6 Hz), 7.48e7.41 (m, 3H), 7.28 (m, 2H); 13C NMR
3H), 3.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
174.6, 164.7, 163.4,
(100 MHz, DMSO-d6) d 172.7, 164.4, 155.7, 153.6, 146.8, 143.5, 135.5,
155.9, 154.7, 134.1, 132.5, 129.8, 126.1, 125.5, 123.4, 122.4, 121.6,
119.3, 118.0, 114.8, 94.6, 56.2, 52.1; FTIR (neat) 1739, 1647, 1465,
1383, 1089, 759 cmꢁ1; HRMS[EI] calcd for [M]þ C19H16O6 340.0947,
found 340.0953.
126.4, 125.3, 124.8, 124.6, 120.8, 116.7114.8, 113.5, 104.5; FTIR (neat)
1728, 1714, 1588, 1550, 1492, 1418, 767 cmꢁ1; HRMS[FAB] calcd for
C
16H9O5 [MþH]þ 281.0450, found 281.0468.
4.6. Frutinone C methyl ether (11)
4.4.2. Methyl 2-[3-methoxy-2-(methoxymethoxy)phenyl]-4-oxo-4H-
chromene-3-carboxylate (4b). Yield: 98%, Reaction time: 1 h, white
To a solution of frutinone C (1c) (2.00 mg, 7.14 mmol) in dry
solid, mp 127e129 ꢀC, 1H NMR (400 MHz, CDCl3)
d 8.29 (dd, 1H,
acetone (2.00 mL) was added potassium carbonate (148 mg,
ꢀ
J¼8.0, 1.8 Hz), 7.72 (ddd, 1H, J¼8.4, 7.2, 1.8 Hz), 7.51 (dd, 1H, J¼8.4,
1.07 mmol, 150 equiv), MS 4 A (100 mg), and iodomethane (152 ml,
1.07 mmol,150 equiv) at 0 ꢀC. After the reaction mixture was stirred
under room temperature for 6.5 h, the reaction mixture was filtered
through a pad of CeliteÒ and washed with ethyl acetate. The filtrate
was washed with 1 M HCl, saturated aqueous NaHCO3, brine, dried
over MgSO4, and filtered. The filtrate was concentrated in vacuo and
then the resulting residue was purified by column chromatography
on silica gel (eluted with hexane/ethyl acetate¼1/1) to afford
0.8 Hz), 7.46 (ddd, 1H, J¼8.0, 7.2, 0.8 Hz), 7.20 (dd, 1H, J¼8.0, 8.0 Hz),
7.11 (m, 2H), 5.09 (s, 2H), 3.90 (s, 3H), 3.74 (s, 3H), 3.25 (s, 3H); 13
C
NMR (100 MHz, CDCl3)
d 174.6, 164.7, 163.5, 155.9, 152.5, 144.0,
134.2, 127.7, 126.2, 125.7, 124.5, 123.4, 121.3, 119.5, 118.1, 115.2, 98.9,
57.3, 56.0, 52.4; FTIR (neat) 2921, 1737, 1649, 1465, 1382, 1265,
1071 cmꢁ1; HRMS[EI] calcd for [M]þ C20H18O7 370.1053, found
370.1052.
methyl ester 11 (2.1 mg, 7.14
m
mol, 99%) as a colorless needle. Mp
302e304 ꢀC (lit. 259e260 ꢀC).7 1H NMR (400 MHz, CDCl3)
d
8.29
4.4.3. Methyl 2-[2-(methoxymethoxy)phenyl]-8-(oxan-2-yloxy)-4-
oxo-4H-chromene-3-carboxylate (4c). Yield: 94%, reaction time:
(dd, 1H, J¼8.0, 1.6 Hz), 7.90 (dd, 1H, J¼8.0, 1.6 Hz), 7.75 (ddd, 1H,
2.5 h, white solid, mp 137e139 ꢀC, 1H NMR (400 MHz, CDCl3)
d 7.89
J¼8.6, 7.4,1.6 Hz), 7.48e7.40 (m, 3H), 7.28 (m,1H, c), 4.08 (s, 3H); 13
C
(dd, 1H, J¼8.0, 1.6 Hz), 7.55e7.45 (m, 3H), 7.33 (dd, 1H, J¼8.0,
8.0 Hz), 7.26 (d,1H, J¼8.0 Hz), 7.13 (dd,1H, J¼8.0, 8.0 Hz), 5.53 (t,1H,
J¼2.8 Hz), 5.17 (s, 2H), 3.91 (m, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.45
(s, 3H), 2.01e1.83 (m, 3H), 1.75e1.57 (m, 3H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3)
d 173.0, 164.6, 156.4, 154.2, 148.8, 144.6,
135.5, 126.3, 125.5, 124.8, 124.5, 117.4, 117.2, 115.7, 113.4, 104.9, 56.5;
FTIR (neat) 1752, 1610, 1553, 1492, 1421, 764 cmꢁ1; HRMS[EI] calcd
for C17H10O5 [M]þ 294.0528, found 294.0531.
CDCl3)
d 174.6, 164.8, 163.1, 155.1, 147.2, 146.0, 132.5, 130.0, 125.2,
124.7, 122.8, 121.8, 120.5, 119.1, 118.3, 115.3, 97.7, 95.0, 62.1, 56.3,
52.1, 30.1, 25.0, 18.4; FTIR (neat) 2950, 1739, 1647, 1583, 1576, 1489,
1386, 1100, 757 cmꢁ1; HRMS[ESI] calcd for C24H24O8Na [MþNa]þ
463.1369, found 463.1363.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas (No. 2105), and partially supported by
Platform for Drug Discovery, Informatics, and Structural Life Sci-
ence from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We also thank Profs. Kurt Hostettmann, Mat-
thias Hamburger (Univ. Basel), and Jean-Luc Wolfender (Univ. Ge-
neva) for their great efforts to search for the original sample of
frutinone C though it has not been found.
4.5. General procedure for the synthesis of frutinones (1)
from 3-acylflavone 4
To a 3-acylflavones 4ae4c (1.00 equiv) was added a solution of
4 M HCl/dioxane (20 mL/mmol) at 0 ꢀC under argon. After being
stirred at room temperature, the reaction mixture was concen-
trated in vacuo and then the resulting residue was purified by the
following method to afford frutinones (1ae1c).
Supplementary data
Experimental procedure and characterization data for 6, 7, and
8. Copies of 1H and 13C NMR spectra for all synthetic compounds.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.073.
4.5.1. Frutinone
A
(1a). Purification: Recrystalization from
dichloromethane, yield: 75%, reaction time: 15 min, colorless
crystal, mp 234e235 ꢀC (lit. 235e236 ꢀC),7 1H NMR (400 MHz,
CDCl3)
7.82e7.74 (m, 2H), 7.64 (d, 1H, J¼8.4 Hz), 7.52 (dd, 1H, J¼7.8, 7.8 Hz),
7.48e7.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
173.0, 165.0, 156.3,
154.4, 154.3, 135.6, 134.8, 127.0, 126.6, 124.8, 124.5, 124.2, 117.8,
d
8.36 (dd, 1H, J¼7.8, 1.4 Hz), 8.22 (dd, 1H, J¼8.0, 1.4 Hz),
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2007e2010; (b) EI-Deen, I. M.; Ibraham, H. K. Egypt. J. Chem. 2007, 50, 403e423.
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21. The synthesis of 6 is described in Supplementary data.
12. (a) Coppola, G. M.; Dodsworth, R. W. Synthesis 1981, 523e524; (b) Lin, J.-P.;
22. (a) Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 23, 4425e4427; (b)
€
Long, Y.-Q. Chem. Commun. 2013, 5313e5315.
Kiehne, U.; Lutzen, A. Eur. J. Org. Chem. 2007, 5703e5711.
13. (a) Babin, P.; Dunoques, J.; Pftrald, M. Tetrahedron 1981, 37, 1131e1139; (b)
Cushman, M.; Nagarathnam, D.; Burg, D. L.; Geahlen, R. L. J. Med. Chem. 1991, 34,
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23. Yamamoto, A. Bull. Chem. Soc. Jpn. 1995, 68, 433e446.
24. The structure of 11 was confirmed by X-ray crystallographic analysis. CCDC
972537 (11) contains the supplementary crystallographic data for this paper.