Efficient synthesis of frutinone A and its derivatives through palladium-catalyzed C-H activation/carbonylation

Article abstract of DOI:10.1002/asia.201402876

Frutinone A, a biologically active ingredient of an antimicrobial herbal extract, demonstrates potent inhibitory activity towards the CYP1A2 enzyme. A three-step total synthesis of frutinone A with an overall yield of 44 is presented. The construction of

Full text of DOI:10.1002/asia.201402876

COMMUNICATION
DOI: 10.1002/asia.201402876
Efficient Synthesis of Frutinone A and Its Derivatives through Palladium-
À
Catalyzed C H Activation/Carbonylation
[
a, b]
[a, b]
[a, b]
[a, b]
Yongje Shin,
Changho Yoo,
Youngtaek Moon,
Yunho Lee,*
and
[
a, b]
Sungwoo Hong*
Abstract: Frutinone A, a biologically active ingredient of an
antimicrobial herbal extract, demonstrates potent inhibitory
activity towards the CYP1A2 enzyme. A three-step total
synthesis of frutinone A with an overall yield of 44% is pre-
sented. The construction of the chromone-annelated cou-
marin core was achieved through palladium-catalyzed CÀH
carbonylation of 2-phenolchromones. The straightforward
synthetic route allowed facile substitutions around the fruti-
none A core and thus rapid exploration of the structure–ac-
tivity relationship (SAR) profile of the derivatives. The in-
hibitory activity of the synthesized frutinone A derivatives
were determined for CYP1A2, and ten compounds exhibit-
ed one-to-two digit nanomolar inhibitory activity towards
the CYP1A2 enzyme.
Scheme 1. Synthetic approach to frutinone A.
of frutinone A and its derivatives by exploring CÀH bond
functionalization, which involves the use of the innate nucle-
ophilic characteristics of chromones for the efficient synthe-
Frutinone A (1a), isolated from the leaves and root bark
of Polygala fruticosa, possesses a chromonocoumarin struc-
tural scaffold. Frutinone A shows various biological activi-
ties, including antibacterial, antioxidant, and potent cyto-
[4]
sis of frutinone A derivatives. Our retrosynthetic strategy
for frutinone A is illustrated in Scheme 1. In view of recent
[5]
advances in CÀH bond carbonylation, we envisaged that
[1]
chrome P450 1A2 (CYP1A2) inhibition. This intriguing
molecule continues to attract considerable attention from
research groups, and several synthetic approaches to obtain
the chromone-annelated coumarin architecture might be
constructed from 2-phenylflavone through a palladium-cata-
lyzed CÀH activation/carbonylation process. Through these
[2]
the frutinone scaffold have been developed. However, pre-
viously developed synthetic routes to frutinone A suffer
from the drawbacks of having multiple steps and low-to-
moderate yields. A potential alternative synthetic route to
efforts, we established an efficient palladium catalytic proto-
col for the facile construction of a chromone-annelated cou-
marin motif. Herein, we report a straightforward synthetic
approach that is broadly applicable to readily accessible
chromone systems for the synthesis frutinone A derivatives,
and evaluate the biological characteristics of the derivatives
obtained.
[3]
frutinone A would be to use CÀH functionalization, which
enables the construction of complicated target molecules in
fewer reaction steps without pre-functionalization of the
starting materials. To identify more potent CYP1A2 inhibi-
tors, we were particularly interested in an efficient synthesis
To construct the chromonocoumarin framework, we ini-
tially focused on the direct CÀH bond functionalization/car-
bonylation reaction. The feasibility of this process was
tested by using the reaction of 2-phenolchromone 1a as
II
a model substrate in the presence of the Pd catalyst under
[
a] Y. Shin, C. Yoo, Y. Moon, Prof. Y. Lee, Prof. S. Hong
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Korea)
1
atm CO; representative screening data are listed in
Table 1. We found that the reactions that used Cu(OAc) as
an oxidant and Na CO as a base at 1108C provided a notice-
AHCTUNGTRENNUNG
2
2
3
E-mail: hongorg@kaist.ac.kr
able product, albeit only in 6% yield (Table 1, entry 1). Of
the palladium sources tested, Pd(OAc) displayed the best
yunholee@kaist.ac.kr
AHCTUNGTRENNUNG
2
[
b] Y. Shin, C. Yoo, Y. Moon, Prof. Y. Lee, Prof. S. Hong
Center for Catalytic Hydrocarbon Functionalization
Institute for Basic Science (IBS)
catalytic reactivity. Further investigations of the reaction
conditions revealed that the choice of solvent was critical
for the efficiency of the reaction, with no detectable desired
product being obtained in polar solvents, such as 1,4-diox-
ane. However, the product yield dramatically increased to
Daejeon, 305-701 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402876.
Chem. Asian J. 2014, 00, 0 – 0
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

www.chemasianj.org
Sungwoo Hong, Yunho Lee et al.
[
a]
Table 1. Optimization of the reaction conditions.
Entry
Catalyst
(10 mol%)
Oxidant
ACHTUNGTRENNUNG( 2 equiv)
Solvent
toluene
1,4-dioxane
xylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
T [8C]
Yield [%]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
1
2
3
4
5
6
7
8
9
Pd
Pd(OAc)
Pd(OAc)
Pd(OAc)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc)
2
2
2
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
A
H
U
G
R
N
U
G
2
2
2
2
2
110
110
110
110
110
110
110
125
125
125
6
–
44
61
–
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
T
N
T
E
N
N
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
E
N
N
–
ACHTUNGTRENNUNG
Pd
Pd(OAc)
Pd(OAc)
Pd(OPiv)
Pd(OAc)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc)
2
–
7
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
AgOAc
17
86
83
42
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
Cu
Cu
Cu(OAc)
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
A
H
U
G
R
N
U
G
2
2
[
b]
1
0
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
ACHTUNGTRENNUNG
[
(
3
a] Reactions were conducted with 1a, PdL
2 equiv), Na CO (2 equiv), and PivOH (4 equiv) in solvent at 1258C for
h under CO (1 atm). [b] Conditions: Pd(OAc) (2.5 mol%) under oth-
erwise identical conditions. Piv=pivaloyl.
2
(10 mol%), and oxidant
2
3
A
H
U
T
E
N
N
2
Scheme 2. Proposed mechanism for the present reaction.
44% in xylene (Table 1, entry 3) and 61% in mesitylene
mones in the presence of a catalytic amount of Fe
ACHTUNGTRENNUNG( OTf) ,
2
(
Table 1, entry 4). In the absence of Pd(OAc) , the intramo-
ACHTUNGTRENNUNG
which thereby gave a variety of flavone analogues as major
2
[7]
lecular CÀO coupling reaction preferentially proceeded to
products under mild conditions. This protocol was subject-
ed to a straightforward synthetic route to frutinone A and
its derivatives, as outlined in Scheme 2. Thus, required 2-
phenol chromone 1a was conveniently prepared by palladi-
um-catalyzed 1,4-addition of methoxyphenylboronic acid 4
to chromone 3, followed by the demethylation of 5 with
[6]
provide flavone-fused benzofuran in 42% yield and no de-
sired product was obtained. The oxidizing agent was also
critical to the efficiency of the transformation, with the de-
sired product (2a) being obtained in only 7% yield in the
absence of Cu
ACHTUNGTRENNUNG( OAc) (Table 1, entry 6). A variety of oxidiz-
2
II
ing agents, including Cu , benzoquinone (BQ), K S O ,
(
MnO were evaluated, and Cu(OAc) was found to be the
most effective and economical oxidant. Under the optimized
BBr . Next, a palladium-catalyzed CÀH activation/carbony-
2
2
8
3
2,2,6,6-tetramethyl-piperidin-1-yl)oxy
(TEMPO),
and
lation reaction was applied and frutinone A was obtained by
starting from commercially available chromone 3 in a total
yield of 44% over three steps (see Scheme 3).
AHCTUNGTRENNUNG
2
2
reaction conditions, the CÀH activation/carbonylation of 1a
(
1 equiv) in the presence of Pd ACHUTNGERTNNUNG( OAc) (10 mol%), Cu-
2
ACHTUNGTRENNUNG( OAc) (2 equiv), Na CO (2 equiv), and PivOH (4 equiv) in
2 2 3
mesitylene at 1258C under 1 atm CO afforded product 2a in
the highest yield (86%). Under these reaction conditions,
no benzofuran side product from an intramolecular CÀO
coupling reaction was observed.
A plausible mechanism for the CÀH activation/carbonyla-
tion process is outlined in Scheme 2. Initially, six-membered
palladacycle I is formed by the chelation of the hydroxyl
II
group of 1a with the CO-ligated Pd complex, followed by
CÀH activation through electrophilic cyclopalladation at the
C3 position of the flavone derivative. Then, the migratory
insertion of coordinated CO into the arylÀPd bond forms
Scheme 3. Total synthesis of frutinone A; DDQ=2,3-Dichloro-5,6-dicya-
no-1,4-benzoquinone.
seven-membered palladacycle II. Next, palladacycle II trans-
0
forms desired product 2a and Pd species through reductive
0
II
elimination. Finally, Pd is oxidized in the presence of Cu
CYP1A2 has been shown to be involved in the activation
of carcinogens and mutagens by controlling drug metabo-
lism, which indicates that CYP1A2 inhibition could poten-
tially be exploited clinically in areas such as cancer preven-
II
to regenerate Pd and complete the catalytic cycle.
Having determined the optimized CÀH activation/carbon-
ylation conditions, we next turned our attention to the effi-
cient and step-economical synthetic route to frutinone A.
Recently, our group reported a practical method for the pal-
ladium-catalyzed 1,4-addition of arylboronic acids to chro-
[8]
tion. With the goal of identifying more potent CYP1A2 in-
hibitors, we investigated the binding modes of frutinone A
in the active site of CYP1A2 in a comparative fashion.
&
&
Chem. Asian J. 2014, 00, 0 – 0
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Sungwoo Hong, Yunho Lee et al.
[
a]
Table 2. Substrate scope.
Compound Yield
%]
[
b]
[b]
Compound
Yield
[%]
[
8
8
7
5
6
9
4
2
75
68
63
76
Figure 1. Calculated binding mode of frutinone A (blue) and compound
j (green) in the active site of CYP1A2. Heme is shown as dark grey
sticks in the top-left corner. Each dotted line indicates a hydrogen bond.
2
Figure 1 shows the lowest-energy conformation of frutino-
ne A in the active site of CYP1A2, as calculated by using
63
56
62
[9]
the modified AutoDock program. From the overall struc-
tural features derived from the docking simulations, the car-
bonyl oxygen of the lactone ring appeared to form a hydro-
gen bond with the side-chain hydroxyl group of Thr124. Fru-
tinone A could be further stabilized in the active site of
CYP1A2 through a p-stacking interaction with the Phe226
residue, and hydrophobic interactions with the side chains
of Ala317, Gly316, Asp320, Leu497, Phe125, Leu382, and
Hem900. The docking studies indicated that the presence of
an additional small substituent on the frutinone A core
would be tolerated in its function on CYP1A2 without caus-
ing an unfavorable steric clash. For example, frutinone A
derivative 2j exhibited similar configurations and compara-
ble interactions with the amino acid residues in the active
site (Figure 1). Moreover, 2j appears to be more deeply lo-
cated in the hydrophobic pocket, which allows a stronger in-
teraction with the side chain of Phe226 through p–p stack-
ing. The structural analysis suggested the need to widen the
exploration of analogues that incorporate small groups
around the frutinone A scaffold.
7
4
7
3
65
48
60
5
6
6
8
Based on our structural analysis, we planned to install
a variety of small-sized substituents around the frutinone A
core with a view to expanding the SAR profile in the hope
of identifying derivatives with enhanced potency. The fruti-
none A scaffold could be easily equipped with an additional
substituent by using the newly developed synthetic ap-
proach. Substituted 2-phenol chromones were efficiently
prepared in a two-step sequence, as shown in Scheme 2.
Subsequently, the palladium-catalyzed CÀH activation/car-
[
(
a] Conditions: Flavone (1 equiv), Pd
A
H
U
G
R
N
U
G
2
(10 mol%), Cu ACHTUNGTRENNUNG( OAc)
2
2 equiv), Na CO (2 equiv), and PivOH (4 equiv) in mesitylene under
2
3
CO (1 atm) at 120–1308C for 3–21 h. [b] Yield of the isolated product.
The IC50 values of the synthesized derivatives were deter-
[10]
mined for CYP1A2. Of the derivatives tested, ten com-
pounds were found to have one-to-two digit nanomolar in-
hibitory activities towards CYP1A2, as summarized in
Table 3. Notably, compound 2j, which contains a fluoro
group at the 3’ position, showed potent inhibitory activity
towards CYP1A2 (IC =2.65 nm), whereas substitution with
bonylation reaction of a range of 2-phenol chromones suc-
cessfully provided the desired frutinone A derivatives in
moderate-to-good yields, as illustrated in Table 2.
5
0
Chem. Asian J. 2014, 00, 0 – 0
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

www.chemasianj.org
Sungwoo Hong, Yunho Lee et al.
Table 3. Inhibitory activities potency profiles over CYP1A2.
Monod, E. Frenk, K. Hostettmann, Planta Med. 1994, 60, 41; d) M.
Born, P. A. Carrupt, R. Zini, F. Bree, J. P. Tillement, K. Hostett-
mann, B. Testa, Helvetica Chimica Acta 1996, 79, 1147.
Compound
CYP1A2
IC50 [nM]
Compound
CYP1A2
IC50 [nM]
[
2] a) F. M. Dean, K. B. Hindley, S. J. Small, J. Chem. Soc. Perkin Trans.
2
2
2
2
2
a
b
c
d
e
5.33
51.2
14.6
52.0
45.3
2j
2.65
44.6
12.9
11.0
12.6
1
2
2
1972, 2007; b) I. M. El-Deen, H. K. Ibraham, Egypt. J. Chem.
007, 50, 403; c) M. Yoshida, K. Saito, Y. Fujino, T. Doi, Tetrahedron
014, 70, 3452.
2k
2n
2o
2r
[
3] For selected recent reviews on CÀH activation, see: a) J. Wencel-
Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740;
b) W. Shi, C. Liu, A. Lei, Chem. Soc. Rev. 2011, 40, 2761; c) C. Liu,
H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780; d) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; e) D. A. Colby,
R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624; f) L.-M.
Xu, B.-J. Li, Z. Yang, Z.-J. Shi, Chem. Soc. Rev. 2010, 39, 712; g) R.
Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
the bulkier chloro group at this position led to reduced ac-
tivity (2k: IC =44.6 nm). Note that compound 2o, with
50
a chloro group at the 4’ position, exerted potent effects on
CYP1A2 (IC =11.0 nm).
2
009, 38, 3242; h) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215; i) S.-H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev.
011, 40, 5068; j) J. A. Ashenhurst, Chem. Soc. Rev. 2010, 39, 540;
k) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112,
879; l) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651;
50
2
In summary, we have developed an efficient method for
synthesizing the chromone-annelated coumarin motif
through palladium-catalyzed CÀH activation/carbonylation
5
m) L. Ackermann, Chem. Rev. 2011, 111, 1315; n) L. Ackermann,
Acc. Chem. Res. 2014, 47, 281.
of 2-phenolchromone derivatives in the presence of CO. The
developed reaction was subjected to the concise synthesis of
a variety of frutinone A derivatives. Several compounds in-
hibited the activity of the CYP1A2 enzyme in the nanomo-
lar range. Further studies aimed at broadening the synthetic
application toward other heterocycles are in progress.
[4] For selected reports, see: a) H. Geo, M. J. Niphakis, G. I. Georg, J.
Am. Chem. Soc. 2008, 130, 3708; b) D. Kim, S. Hong, Org. Lett.
2
011, 13, 4466; c) L. Klier, T. Bresser, T. A. Nigst, K. Karaghioso, P.
Knochel, J. Am. Chem. Soc. 2012, 134, 13584; d) Y. Moon, D. Kwon,
S. Hong, Angew. Chem. Int. Ed. 2012, 51, 11333; Angew. Chem.
2012, 124, 11495; e) F. Chen, Z. Feng, C.-Y. He, H.-Y. Wang, Y.-L.
Guo, X. Zhang, Org. Lett. 2012, 14, 1176; f) Y. Moon, S. Hong,
Chem. Commun. 2012, 48, 7191; g) M. Min, H. Choe, S. Hong,
Asian J. Org. Chem. 2012, 1, 47.
Experimental Section
[
5] For selected reports, see: a) K. Orito, A. Horibata, T. Nakamura, H.
Ushito, H. Nagasaki, M. Yuguchi, S. Yamashita, M. Tokuda, J. Am.
Chem. Soc. 2004, 126, 14342; b) R. Giri, J.-Q. Yu, J. Am. Chem. Soc.
2008, 130, 14082; c) Z.-H. Guan, Z.-H. Ren, S. M. Spinella, S. Yu,
Y.-M. Liang, X. Zhang, J. Am. Chem. Soc. 2009, 131, 729; d) N. Ha-
segawa, V. Charra, S. Inoue, Y. Fukumoto, N. Chatani, J. Am. Chem.
Soc. 2011, 133, 8070; e) B. Ma, Y. Wang, J. Peng, Q. Zhu, J. Org.
Chem. 2011, 76, 6362; f) B. Haffemayer, M. Gulias, M. J. Guant,
Chem. Sci. 2011, 2, 312; g) Y. Lu, D. Leow, X, Wang, K. E. Eagle,
J.-Q. Yu, Chem. Sci. 2011, 2, 967; h) D. Liang, Z. Hu, J. Peng, J.
Huang, Q. Zhu, Chem. Commun. 2013, 49, 173; i) S. Luo, F.-X. Luo,
X.-S. Zhang, Z.-J. Shi, Angew. Chem. Int. Ed. 2013, 52, 10598;
Angew. Chem. 2013, 125, 10792; j) W. Li, C. Liu, H. Zhang, K. Ye,
G. Zhang, W. Zhang, Z. Duan, S. You, A. Lei, Angew. Chem. Int.
Ed. 2014, 53, 2443; Angew. Chem. 2014, 126, 2475; k) L. Wang, Y.
Wang, C. Liu, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 5657; Angew.
Chem. 2014, 126, 5763; l) R. Shi, L. Lu, H. Zhang, B. Chen, Y. Sha,
C. Liu, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 10582; Angew.
Chem. 2013, 125, 10776; m) H. Zhang, R. Shi, P. Gan, C. Liu, A.
Ding, Q. Wang, A. Lei, Angew. Chem. Int. Ed. 2012, 51, 5204;
Angew. Chem. 2012, 124, 5294; n) H. Zhang, D. Liu, C. Chen, C.
Liu, A. Lei, Chem. Eur. J. 2011, 17, 9581; o) J. Ferguson, F. Zeng, H.
Alper, Org. Lett. 2012, 14, 5602; p) A. Seoane, N. Casanova, N. Qui-
Çones, J. L. MascareÇas, M. Gulꢂas, J. Am. Chem. Soc. 2014, 136,
834; q) K. Inamoto, J. Kadokawa, Y. Kondo, Org. Lett. 2013, 15,
Representative Experimental Procedure (2a)
2
-Phenol chromone 1a (0.1 mmol), Pd
2 2
ACHTUNGTRENNUNG( OAc) (10 mol%), Cu ACHTUNRGTENNUGN( OAc)
(
2 equiv), Na CO (2 equiv), and PivOH (4 equiv) were combined in me-
2
3
sitylene (0.1m) in a 20 mL Schlenk tube. Then, a balloon charged with
CO gas was connected to the Schlenk tube. The reaction mixture was
heated at 1258C for 3 h, and monitored by TLC with ethylacetate/n-
hexane (1:1) as the mobile phase. After cooling to RT, the mixture was
quenched with water (10 mL) and the aqueous phase was extracted with
CH
anhydrous MgSO
by flash chromatography (ethylacetate/n-hexane 1:1) on silica gel to give
2
Cl
2
(3ꢁ20 mL). The organic phases were combined and dried over
4
. After removal of the solvent, the residue was purified
1
the desired product (22.7 mg, 86%). H NMR (400 MHz, CDCl
3
): d=
8
2
7
.34 (dd, J=8.0, 1.7 Hz, 1H), 8.21 (dd, J=8.0, 1.6 Hz, 1H), 7.83–7.70 (m,
H), 7.62 (dd, J=8.4, 1.0 Hz, 1H), 7.50 (ddd, J=8.1, 7.2, 1.1 Hz, 1H),
.45 (ddd, J=8.1, 7.3, 1.1 Hz, 1H), 7.39 ppm (dd, J=8.4, 1.0 Hz, 1H);
1
3
C NMR (100 MHz, CDCl
3
): d=173.1, 165.1, 156.4, 154.5, 154.4, 135.7,
1
34.9, 127.0, 126.7, 125.0, 124.6, 124.3, 118.0, 117.5, 113.4, 105.2 ppm;
+
HRMS ESI: m/z calculated for C16
8 4
H NaO : 287.0320, found: 287.0289
+
[
M+Na] .
Acknowledgements
3
962.
This research was supported by IBS-R010-G1.
[6] a) Y. Moon, Y. Kim, H. Hong, S. Hong, Chem. Commun. 2013, 49,
8
323; b) Y. Kim, Y. Moon, D. Kang, S. Hong, Org. Biomol. Chem.
014, 12, 3413.
2
Keywords: carbonylation
frutinone A · palladium · structure–activity relationships
·
CÀH functionalization
·
[
[
7] D. Kim, K. Ham, S. Hong, Org. Biomol. Chem. 2012, 10, 7305.
8] U. Fuhr, K. Klittich, A. H. Staib, Br. J. Clin. Pharmacol. 1993, 35,
4
31.
[
9] H. Park, O. Chi, J. Kim, S. Hong, J. Chem. Inf. Mod. 2011, 51, 2986.
[
10] The IC50 determinations were performed at the Reaction Biology
Corp. (Malvern, PA, USA).
[
1] a) R. S. Thelingwani, K. Dhansay, P. Smith, K. Chibale, C. M. Masi-
mirembwa, Xenobiotica 2012, 42, 989; b) E. R. Di Paolo, M. O.
Hamburger, H. Stoeckli-Evans, C. Rogers, K. Hostettmann, Helveti-
ca Chimica Acta 1989, 72, 1455; c) L. Rahalison, M. Hamburger, M.
Received: July 24, 2014
Published online: && &&, 0000
&
&
Chem. Asian J. 2014, 00, 0 – 0
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

COMMUNICATION
Bearing frutinone: A three-step total
synthesis of frutinone A (see scheme)
with an overall yield of 44% is pre-
sented. The construction of the chro-
mone-annelated coumarin core was
achieved through palladium-catalyzed
CÀH carbonylation of 2-phenolchro-
CÀH Activation
Yongje Shin, Changho Yoo,
Youngtaek Moon, Yunho Lee,*
Sungwoo Hong*
&&&& — &&&&
Efficient Synthesis of Frutinone A and
Its Derivatives through Palladium-
Catalyzed CÀH Activation/Carbonyla-
mones. The straightforward synthetic
route allowed facile substitutions
around the frutinone A core and thus
rapid exploration of the structure–
activity relationship profile of the
derivatives.
tion
Chem. Asian J. 2014, 00, 0 – 0
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ