A New Protocol for Total Synthesis of Natural Product Frutinone A and Its Derivatives

Article abstract of DOI:10.1071/CH15267

A new protocol for total synthesis of natural product frutinone A was accomplished in three steps by using inexpensive 2′-hydroxyacetophenone as starting material. The key intermediate 3-(2-chlorobenzoyl)-4-hydroxycoumarin was synthesized in one pot through Baker-Venkataraman rearrangement of 2-acetylphenyl 2-chlorobenzoate followed by introduction of methyl chloroformate under basic conditions. Then, base-promoted intramolecular nucleophilic substitution reaction of 3-(2-chlorobenzoyl)-4-hydroxycoumarin provided frutinone A in excellent yield. The synthetic route features good yield, transition metal-free and mild reaction conditions, and high tolerance for functionality, thereby allowing easy substitutions around the frutinone A core.

Full text of DOI:10.1071/CH15267

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15267
A New Protocol for Total Synthesis of Natural Product
Frutinone A and Its Derivatives
A B
,
A B
,
A B
,
Kang Lei,
Dong-Wei Sun,
Yuan-Yuan Tao,
A B C
, ,
and Xiao-Hua Xu
A
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Number 94,
Weijin Road, Nankai District, Tianjin 300071, China.
B
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, China.
C
Corresponding author. Email: xiaohuaxu@nankai.edu.cn
A new protocol for total synthesis of natural product frutinone A was accomplished in three steps by using inexpensive
20-hydroxyacetophenone as starting material. The key intermediate 3-(2-chlorobenzoyl)-4-hydroxycoumarin was synthe-
sized in one pot through Baker–Venkataraman rearrangement of 2-acetylphenyl 2-chlorobenzoate followed by introduc-
tion of methyl chloroformate under basic conditions. Then, base-promoted intramolecular nucleophilic substitution
reaction of 3-(2-chlorobenzoyl)-4-hydroxycoumarin provided frutinone A in excellent yield. The synthetic route features
good yield, transition metal-free and mild reaction conditions, and high tolerance for functionality, thereby allowing easy
substitutions around the frutinone A core.
Manuscript received: 12 May 2015.
Manuscript accepted: 16 June 2015.
Published online: 17 July 2015.
Introduction
For example, the starting material used in their strategy is
commercial unavailable, the synthesis route uses an expensive
transition metal catalyst, and uses highly toxic carbon monoxide
as reactant. Thus, we considered that an alternate strategy, which
would provide easy access to frutinone A derivatives and avoid
the use of expensive transition metals and toxic reagents, would
be necessary.
Because the 4-hydroxycoumarin scaffold is a key component
of the frutinones, the introduction of a 2-halogenated benzoyl at
the C-3 position in the 4-hydroxycoumarin skeleton is important
for achieving the total synthesis of frutinone A (Fig. 1). Several
methods for the synthesis of 3-benzyol-4-hydroxycoumarin
were reported during the last several decades.[10–13] Tradition-
ally, the method used for the introduction of the benzoyl at the
C-3 position in the 4-hydroxycoumarin skeleton is as fol-
lows.[10–12] In the first step, 4-hydroxycoumarin is initially
O-acylated with acyl chloride or carboxylic acid and in the
second step, O–C isomerization catalyzed by potassium cyanide
(KCN) leads to the synthesis of 3-benzyol-4-hydroxycoumarin.
However, the method has limited application because it requires
prolonged reaction times and KCN is a highly toxic reagent.
Thus, an alternate method for the preparation of 3-benzoyl-4-
hydroxycoumarin is justified.
Frutinones are natural-occurring chromonocoumarins, existing
in Polygala plants such as P. dalmaisiana, P. gazensis, and
P. fruticosa.[1–3] To date, frutinone A, frutinone B, and frutinone C
(Fig. 1) have already been isolated. Among these three, fruti-
none A exhibits strong fungicidal activity against Cladosporium
cucumerinum[1] and has been reported to strongly inhibit cyto-
chrome P450 1A2 (CYP1A2).[4] Although frutinone A has
been synthesized by several methods over the last several
decades,[5–7] the reported methods have limited applications
because of poor starting material availability and low yields,
thereby resulting in limited access to its derivatives. Recently,
Doi and coworkers have developed a strategy for the synthesis of
frutinone A.[8] More recently, the synthesis of frutinone A and
its derivatives using C–H functionalization was also reported by
Hong et al.[9] However, their strategy has some disadvantages.
O
O
O
R1
O
O
R1
O
X
O
R2
HO
Baker–Venkataraman rearrangement is base-catalyzed
acyl transfer reaction that converts a-acyloxyketones to
b-diketones.[14] In a typical reaction (Fig. 2, Path a), base
abstraction of one of the a-hydrogens of the aromatic ketone 1
occurs, which results in the formation of enolate 2. Intramo-
lecular attack of the enolate occurs onto the ester carbonyl to
form the cyclic-charged hemiacetal 3, the tetrahedral
R2
Frutinone A R1 ꢀ R2 ꢀ H
Frutinone B R1 ꢀ OCH3, R2 ꢀ H
Frutinone C R1 ꢀ H, R2 ꢀ OH
3-Benzoyl-4-hydroxycoumarin
X ꢀ Halogen
Fig. 1. Design for the synthesis of frutinone A from 4-hydroxylcoumarin
scaffold.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
K. Lei et al.
O
O
ꢁ
O
O
Ar
O
O
Ar
O
Base
Ar
H
ꢁ
O
O
1
2
3
ꢁ
O
OH
O
ꢂ
O
H
Ar
Ar
O
Path a
O
4
5
Path b
ꢁ
O
H
O
O
O
Ar
O
O
Base
Ar
O
O
O
O
O
O
O
Ar
O
O
ꢁ
6
7
8
OH
O
O
O
Ar
Ar
O
O
O
O
9
Fig. 2. Proposed mechanism for synthesis of 3-benzoyl-4-hydroxylcoumarin scaffold.
Cl
O
Cl
O
O
O
O
Baker–
Venkataraman
rearrangement
Intramolecular
nucleophilic
substitution
OH
O
O
O
Cl
R1
OH
O
Cl
O
R2
R2
R2
O
O
Condensation
reaction
R1
R1
R1
R2
10
11
12
13
Scheme 1. Synthetic route of frutinone A and its derivatives.
intermediate of which subsequently collapses to form the more
stable phenolate 4, which is protonated during acid workup to
give the 1,3-diketone 5. The modular nature of this mechanism
stimulated us to search an alternate route for rapid synthesis of 3-
benzoyl-4-hydroxycoumarin (Fig. 2, Path b). We envisaged that
the diketone 6 would be formed when methyl chloroformate was
added to phenolate 4 before acid workup. Subsequently, intra-
molecular attack of the enolate 7 occurs onto the ester carbonyl
to form the cyclic-charged hemiacetal 8 under basic conditions,
which would collapse to give the triketone 9.
Based on the above consideration, we herein report a new
protocol for total synthesis of frutinone A and its derivatives
from commercially available 20-hydroxyacetophenone deriva-
tives as starting materials. Our synthetic strategy for frutinone
A and its derivatives is illustrated in Scheme 1. Aromatic ketone
11 could be synthesized via the condensation reaction of
20-hydroxyacetophenone derivatives 10 with a series of
2-chlorobenzoyl chloride. The desired frutinone derivatives 13
would be obtained by intramolecular nucleophilic substitu-
tion reaction of triketones 12, which would be prepared via
Baker–Venkataraman rearrangement of aromatic ketones 11
followed by introduction of methyl chloroformate under basic
conditions.
Results and Discussion
The total synthesis of frutinone A and its derivatives was
started from commercial available 20-hydroxyacetophenone
derivatives 10. According to the references,[15–17] the reaction
of 20-hydroxyacetophenone derivatives with a series of
2-chlorobenzoyl chloride in pyridine provided 2-acetylphenyl
2-chlorobenzoate derivatives 11 in good-to-excellent yields.
Subsequently, constructing the skeleton of triketones 12 via
the above-mentioned method was investigated and the synthesis
of 12-1 was selected as a model to optimize the reaction
conditions. The reaction of 2-acetylphenyl 2-chlorobenzoate
11-1 with several cheap and commercially available bases
(2.2 equiv.) in tetrahydrofuran (THF) followed by introduction
of methyl chloroformate (1.1 equiv.), initially attempted at room
temperature (entries 1–4, Table 1). Fortunately, the desired
product 12-1 was isolated in a moderate yield with sodium
hydride (NaH) or potassium tert-butoxide (t-KOBu) as base, and

Synthesis of Frutinone A and Its Derivatives
C
Table 1. Optimization of the reaction for 3-(2-chlorobenzoyl)-4-hydroxycoumarinA
O
O
Cl
O
O
O
1. Base
O
2. Methyl chloroformate
Cl
OH
11-1
12-1
Entry
Solvent
Base
Amount [equiv.]
Temperature [8C]
Time [h]
Yield [%]B
1
THF
K2CO3
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
3.0
4.0
25
25
25
25
25
25
25
0
6
6
0
0
2
THF
Cs2CO3
t-KOBu
NaH
3
THF
6
37
39
36
28
47
38
61
22
0
4
THF
6
5
Dioxane
Toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NaH
6
6
NaH
6
7
NaH
6
8
NaH
6
9
NaH
50
75
100
50
50
50
50
6
10
11
12
13
14
15
NaH
6
NaH
6
NaH
9
63
61
60
61
NaH
12
6
NaH
NaH
6
AReaction conditions: compound 11-1 (5 mmol) and solvent (10 mL); BIsolated yield.
NaH was found to be the best base. The reaction conditions were
Table 2. Scope of Baker–Venkataraman rearrangement of the
aromatic ketone 12A
further optimized in order to improve the yield of triketone 12-1.
It was found that reaction in N,N-dimethylformamide (DMF)
provided triketone 12-1 in 47 % yield, which is higher than that
obtained in THF, 1,4-dioxane, or toluene (entries 4–6, Table 1).
The yield increased consistently with increasing temperatures
from 08C to 508C, and this yield increase was maintained at 508C
(entries 7–9, Table 1). Further increases in the temperature lead
to a yield decrease. Moreover, the desired product was not
obtained, and 4-hydroxycoumarin was isolated in 59 % yield as
the main product at 1008C (entries 10 and 11, Table 1). In
addition, the yield increased with time from 61 % (6 h) to a
maximum level of 63 % (9 h) (entries 9, 12, 13, Table 1). Thus,
extending the reaction time beyond 6 h did not change the yield
significantly. Furthermore, increasing the amount of sodium
hydride did not result in any changes in the yield (entries 14 and
15, Table 1). The results indicated that the reaction conditions,
particularly the solvent and temperature, significantly influence
the yield of 3-(2-chlorobenzoyl)-4-hydroxycoumarin.
Under the optimal established conditions, the scope and
generality of the reaction was examined subsequently. The
results are depicted in Table 2. Twenty 3-(2-chlorobenzoyl)-4-
hydroxycoumarin derivatives were obtained under the optimal
conditions with yields ranging from 38 % to 72 %. Notably, the
electronic properties of substituents on the aromatic rings of
20-hydroxyacetophenone and 2-chlorobenzoyl acid affected the
yield. When the aromatic ring of 2-chlorobenzoyl acid had an
electron-donating group, yields were relatively low (such as
compounds 12-10 and 12-11; Table 2). The yields were lower
when the aromatic ring of 20-hydroxyacetophenone bore an
electron-donating group when compared with that obtained
when the aromatic ring bore an electron-withdrawing group
(such as compounds 12-17 to 12-20; Table 2). Furthermore, the
position of substituent on the aromatic rings of 2-chlorobenzoyl
Cl
O
O
O
O
OH
Cl
5
5ꢄ
8ꢄ
3
6ꢄ
7ꢄ
1. NaH
R2
R2
O
2. Methylchloroformate
6
4
O
R1
DMF, 50ꢃC, 6 h
R1
12
11
Compound
R1
R2
Yield [%]B
12-1
H
H
61
68
70
64
38
71
69
66
72
47
56
62
66
70
68
64
59
50
55
52
12-2
H
3-Cl
4-Cl
5-Cl
6-F
4-F
5-F
12-3
H
12-4
H
12-5
H
12-6
H
12-7
H
12-8
H
4-Br
12-9
H
4-SO2Me
3-OMe
4-OMe
H
12-10
12-11
12-12
12-13
12-14
12-15
12-16
12-17
12-18
12-19
12-20
H
H
70-F
60-F
60-F
60-Br
60-Br
50-OMe
50-OMe
60-Me
70-OMe
4-Cl
H
4-Cl
H
4-Cl
H
H
H
AReaction conditions: compound 11 (5 mmol), NaH (2.2 equiv.), DMF
(10 mL), 508C, 2 h, and methyl chloroformate (1.1 equiv.), 508C, 4 h;
BIsolated yield.

D
K. Lei et al.
Table 3. Optimization of the reaction for frutinone AA
Table 4. Scope of intramolecular nucleophilic substitution reaction of
the triketone 12A
O
O
O
O
8
ꢄ
Base
O
O
OH
O
X
7
ꢄ
O
O
R1
O
K3PO4
O
OH
Cl
6ꢄ
R2
5
ꢄ
DMF, 150ꢃC
O
6
O
O
R1
5
R2
3
12-1
Frutinone A
Temperature [8C] Time [h] Yield [%]B
4
12
13
Entry Solvent
Base
Compound
X
R1
R2
Yield [%]B
1
DMF
DMF
DMF
DMF
K2CO3
KOH
100
100
100
100
100
70
2
2
2
2
2
2
2
2
2
2
2
1
3
4
2
2
0
0
2
13-1
Cl
Cl
Cl
Cl
F
H
H
94
90
96
91
97
94
91
94
92
80
81
90
95
90
93
91
89
90
85
89
3
NaH
34
48
0
13-2
H
3-Cl
4-Cl
5-Cl
6-Cl
4-F
4
K3PO4
13-3
H
5
Toluene K3PO4
THF K3PO4
Dioxane K3PO4
13-4
H
6
0
13-5
H
7
100
120
130
140
150
150
150
150
150
150
0
13-6
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
59
63
79
94
72
94
93
93
92
13-7
H
5-F
9
13-8
H
4-Br
10
11
12
13
14
15c
16d
13-9
H
4-SO2Me
3-OMe
4-OMe
H
13-10
13-11
13-12
13-13
13-14
13-15
13-16
13-17
13-18
13-19
13-20
H
H
70-F
60-F
60-F
60-Br
60-Br
50-OMe
50-OMe
60-Me
4-Cl
H
4-Cl
H
AReaction conditions: compound 12-1 (1 mmol), solvent (10 mL), base
(1.0 equiv.); BIsolated yield; CBase (2.0 equiv.); DBase (3.0 equiv.).
4-Cl
H
H
70- OMe
H
acid affected the yield. Especially, the yield considerably
decreased when the aromatic ring of 2-chlorobenzoyl acid bore
one substituent at 6-position (such as compound 12-5; Table 2).
Because we have acquired a new protocol to the triketones
12, our attention turned to constructing the frutinone A frame-
work. The reaction of 12-1 with a base was performed in DMF to
obtain frutinone A, and this reaction was selected as a model to
optimize the reaction conditions. The results are summarized in
Table 3. A moderate yield of frutinone A could be obtained in
the presence of potassium phosphate (K3PO4) (entry 4, Table 3),
and DMF was found to be the best reaction medium (entry 4,
Table 3). Under the conditions of K3PO4 and DMF, yields
increased consistently with increasing temperatures from
1008C to 1508C, and this yield increase was maintained up to
1508C (entries 4, 8–11, Table 3). In addition, yields increased
with time from 72 % (1 h) to a maximum level of 94 % (2 h)
(entries 11 and 12, Table 3). Extending the reaction time beyond
2 h did not change the yield significantly. In addition, increasing
the amount of K3PO4 did not result in a yield change (entries 13
and 14, Table 3). Thus, we conclude that the optimal conditions
were as follows: 1508C, 2 h, and K3PO4 (1.0 equiv.) in DMF.
Subsequently, a series of frutinone A derivatives were synthe-
sized with excellent yields ranging from 80 % to 97 % under the
optimal condition. (Table 4)
AReaction conditions: compound 12 (2 mmol), K3PO4 (1.0 equiv.), DMF
(10 mL), 1508C, 2 h; BIsolated yield.
derivatives were obtained with yields ranging from 31 % to 62 %
using the protocol.
Experimental
General
Unless otherwise stated, all reactions were carried out under an
argon atmosphere, and all commercially available reagents were
used without further purification. 1H NMR and 13C NMR were
obtained at 400 MHz using Bruker AV400 spectrometer in
CDCl3 or d6-DMSO solution with TMS as the internal standard.
Chemical shift values (d) are given in ppm. Multiplicity was
indicated as follows: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiple), dd (doublet of doublet). Coupling
constants were reported in Hertz (Hz). High-resolution mass
spectroscopy HRMS) was conducted on an Ionspec 7.0T spec-
trometer by electrospray ionization Fourier transform ion
cyclotron resonance (ESI-FTICR) technique. The melting
points were determined on an X-4 binocular microscope melting
point apparatus (Beijing Tech. Instruments Co., Beijing, China)
and were uncorrected.
Conclusions
General Synthetic Procedure for Compound 11
In conclusion, we have demonstrated a new and concise protocol
for the total synthesis of frutinone A. The key intermediate
compound 3-benzoyl-4-hydroxycoumarin was synthesized based
on Baker–Venkataraman rearrangement of 2-acetylphenyl ben-
zoate. Then, base-promoted intramolecular nucleophilic sub-
stitution reaction of 3-(2-chlorobenzoyl)-4-hydroxycoumarin
provided frutinone A in excellent yield. Twenty frutinone A
A mixture of 20-hydroxyacetophenone (10.0 mmol) and 2-
chlorobenzoyl chloride (15.0 mmol) were stirred in dry pyridine
(10 mL) at room temperature for 2 h. The reaction mixture was
then poured into a mixture of crushed ice (15 mL) and concen-
trated HCl (5 mL), extracted twice with dichloromethane,
washed thrice with aqueous K2CO3, and then washed thrice with

Synthesis of Frutinone A and Its Derivatives
E
water. The solvent was removed under reduced pressure. The
residue was recrystallized from ethanol to give 2-acetylphenyl
2-chlorobenzoate (11-1). The remaining compounds were pre-
pared using a similar procedure to that used for preparing 11-1.
8.8, 4.8), 7.43 (1H, t, J 7.6), 7.26 (2H, m), 2.60 (3H, s). dC
(CDCl3, 100 MHz) 196.36, 161.72, 160.96, 158.49, 147.67,
132.71, 131.61 (d), 131.61 (d), 129.56, 128.49 (d), 125.53,
122.91, 119.49 (d), 118.14 (d), 28.09. HRMS m/z 293.0380;
calcd for C15H10ClFO3 293.0303.
2-Acetylphenyl 2-Chlorobenzoate (11-1)
2-Acetylphenyl 4-Bromo-2-chlorobenzoate (11-8)
White solid, 92 % yield, mp 53–558C. dH (CDCl3, 400 MHz)
8.20 (1H, d, J 7.6), 7.89 (1H, d, J 7.7), 7.62 (1H, t, J 7.7), 7.59–
7.49 (2H, m), 7.47–7.37 (2H, m), 7.30 (1H, d, J 8.2,), 2.59
(3H, s). dC (CDCl3, 100 MHz) 197.57, 163.81, 148.93, 134.45,
133.56, 133.27, 132.18, 131.12, 130.98, 130.37, 129.05, 126.87,
126.36, 123.95, 29.39. HRMS m/z 275.0467; calcd for
C15H11ClO3 275.0397.
White solid, 88 % yield, mp 75–768C. dH (CDCl3, 400 MHz)
8.09 (1H, d, J 8.4), 7.90 (1H, d, J 7.8), 7.73 (1H, s), 7.67–7.56
(2H, m), 7.42 (1H, t, J 7.6), 7.28 (1H, d, J 7.7), 2.58 (3H, s). dC
(CDCl3, 100 MHz) 197.43, 163.13, 148.76, 135.61, 133.98,
133.68, 133.36, 130.60, 130.52, 130.27, 127.86, 127.33,
126.49, 123.96, 29.19. HRMS m/z 352.9580; calcd for
C15H10BrClO3 352.9502.
2-Acetylphenyl 2,3-Dichlorobenzoate (11-2)
2-Acetylphenyl 2-Chloro-4-(methylsulfonyl)benzoate
(11-9)
White solid, 83 % yield, mp 95–968C. dH (CDCl3, 400 MHz)
8.08 (1H, d, J 7.6), 7.90 (1H, d, J 7.7), 7.69 (1H, d, J 8.0), 7.63
(1H, t, J 7.7), 7.46–7.35 (2H, m), 7.30 (1H, d, J 8.4), 2.60 (3H, s).
dC (CDCl3, 100 MHz) 196.44, 162.46, 147.70, 133.67, 132.68,
132.67, 131.13, 130.81, 129.57, 129.48, 128.86, 126.37, 125.51,
122.87, 28.13. HRMS m/z 309.0084; calcd for C15H10Cl2O3
309.0007.
Light yellow solid, 91 % yield, mp 103–1058C. dH (CDCl3,
400 MHz) 8.40 (1H, d, J 8.1), 8.12 (1H, d, J 1.3), 8.00 (1H, dd,
J 8.1, 1.5), 7.94 (1H, dd, J 7.7, 1.1), 7.70–7.62 (1H, m), 7.45 (1H,
t, J 7.4), 7.30 (1H, d, J 8.3), 3.13 (3H, s), 2.61 (3H, s). dC (CDCl3,
100 MHz) 197.47, 162.74, 148.52, 144.37, 135.35, 134.43,
134.02, 133.04, 130.86, 129.94, 129.88, 126.83, 125.65,
123.97, 44.39, 28.95. HRMS m/z 353.0249; calcd for
C16H13ClO5S 353.0172.
2-Acetylphenyl 2,4-Dichlorobenzoate (11-3)
White solid, 93 % yield, mp 63–658C. dH (CDCl3, 400 MHz)
8.15 (1H, d, J 8.4), 7.87 (1H, d, J 7.7), 7.58 (1H, t, J 9.2), 7.54
(1H, s), 7.39 (2H, m), 7.25 (1H, d, J 7.8), 2.56 (3H, s). dC
(CDCl3, 100 MHz) 197.48, 163.00, 148.77, 139.12, 135.64,
133.68, 133.32, 131.17, 130.61, 130.53, 127.38, 127.31,
126.48, 123.97, 29.19. HRMS m/z 309.0083; calcd for
C15H10Cl2O3 309.0007.
2-Acetylphenyl 2-Chloro-3-methoxybenzoate (11-10)
White solid, 83 % yield, mp 106–1088C. dH (CDCl3,
400 MHz) 7.89 (1H, d, J 7.7), 7.73 (1H, d, J 7.7), 7.62 (1H, t,
J 7.7), 7.40 (2H, t, J 8.0), 7.32 (1H, d, J 8.1), 7.17 (1H, d, J 8.2),
3.98 (3H, s), 2.59 (3H, s). dC (CDCl3, 100 MHz) 196.57, 163.06,
154.81, 147.90, 132.51, 129.98, 129.29, 126.39, 125.33, 122.88,
122.08, 114.29, 55.58, 28.44. HRMS m/z 305.0579; calcd for
C16H13ClO4 305.0502.
2-Acetylphenyl 2,5-Dichlorobenzoate (11-4)
White solid, 88 % yield, mp 104–1068C. dH (CDCl3,
400 MHz) 8.19 (1H, s), 7.91 (1H, d, J 7.8), 7.63 (1H, t, J 7.8),
7.53–7.45 (2H, m), 7.42 (1H, t, J 7.6), 7.28 (1H, d, J 7.8), 2.60
(3H, s), dC (CDCl3, 100 MHz) 197.37, 162.69, 148.70, 133.74,
133.19, 132.92, 132.78, 132.36, 132.02, 130.58, 130.50, 130.31,
126.58, 123.91, 29.11. HRMS m/z 309.0084; calcd for
C15H10Cl2O3 309.0007.
2-Acetylphenyl 2-Chloro-4-methoxybenzoate (11-11)
White solid, 86 % yield, mp 110–1118C. dH (CDCl3,
400 MHz) 8.22 (1H, d, J 8.8), 7.88 (1H, dd, J 7.8, 1.5), 7.60
(1H, td, J 8.0, 1.6), 7.38 (1H, td, J 7.7, 0.9), 7.28 (1H, d, J 2.7),
7.06 (1H, d, J 2.5), 6.94 (1H, dd, J 8.8, 2.5), 3.90 (1H, s), 2.57
(1H, s). dC (CDCl3, 100 MHz) 197.68, 163.25, 163.21, 149.13,
136.94, 134.81, 134.29, 133.45, 131.19, 130.27, 126.16, 124.04,
120.32, 116.79, 112.85, 55.84, 29.57. HRMS m/z 305.0579;
calcd for C16H13ClO4 305.0502.
2-Acetylphenyl 2-Chloro-6-fluorobenzoate (11-5)
White solid, 85 % yield, mp 70–718C. dH (CDCl3, 400 MHz)
7.84 (1H, dd, J 7.8, 1.6), 7.60 (1H, td, J 8.0, 1.6), 7.50–7.29 (4H,
m), 7.15 (1H, t, J 8.7), 2.60 (3H, s). dC (CDCl3, 100 MHz)
197.56, 161.54, 159.01, 148.54, 133.34, 133.14 (d), 132.57 (d),
131.74, 130.12, 126.72, 126.00 (d), 123.45, 121.11 (d), 114.87
(d), 30.01. HRMS m/z 293.0380; calcd for C15H10ClFO3
293.0303.
2-Acetyl-5-Fluorophenyl 2-Chlorobenzoate (11-12)
White solid, 91 % yield, mp 71–728C. dH (CDCl3, 400 MHz)
8.19 (1H, d, J 7.6), 7.99–7.90 (1H, m), 7.56 (2H, s), 7.45 (1H, t,
J 5.6), 7.12 (1H, t, J 7.2), 7.05 (1H, d, J 8.6), 2.57 (3H, s). dC
(CDCl3, 100 MHz) 195.96, 166.32, 163.55 (d), 150.76 (d),
134.65, 133.55, 132.43 (d), 132.29, 131.39, 128.51, 127.31,
126.93, 113.56 (d), 111.99 (d), 29.37. HRMS m/z 293.0381;
calcd for C15H10ClFO3 293.0303.
2-Acetylphenyl 2-Chloro-4-fluorobenzoate (11-6)
White solid, 89 % yield, mp 78–798C. dH (CDCl3, 400 MHz)
8.27 (1H, dd, J 8.8, 6.2), 7.90 (1H, d, J 7.8), 7.63 (1H, t, J 7.7),
7.41 (1H, t, J 7.6), 7.32–7.24 (2H, m), 7.15 (1H, td, J 8.8, 2.4),
2.59 (3H, s). dC (CDCl3, 100 MHz) 197.50, 165.86, 163.09 (d),
148.83, 136.62 (d), 134.47 (d), 133.65, 130.70, 130.48, 126.43,
125.14, 123.99, 118.84 (d), 114.39 (d), 29.21. HRMS m/z
293.0380; calcd for C15H10ClFO3 293.0303.
2-Acetyl-4-fluorophenyl 2,4-Dichlorobenzoate (11-13)
White solid, 89 % yield, mp 114–1158C. dH (CDCl3,
400 MHz) 8.14 (1H, d, J 8.5), 7.60–7.55 (2H, m), 7.43 (1H,
dd, J 8.5, 2.0), 7.33 (1H, m), 7.26 (1H, dd, J 8.9, 4.7), 2.57 (3H,
s). dC (CDCl3, 100 MHz) 196.13, 163.00, 161.28, 158.82,
144.61, 139.39, 135.74, 133.28, 131.89, 131.29, 127.37,
126.99, 125.59 (d), 120.37 (d), 117.02 (d), 29.18. HRMS m/z
326.9991; calcd for C15H9Cl2FO3 326.9913.
2-Acetylphenyl 2-Chloro-5-fluorobenzoate (11-7)
Light yellow solid, 84 % yield, mp 103–1058C. dH (CDCl3,
400 MHz) 7.96–7.89 (2H, m), 7.63 (1H, t, J 7.7), 7.51 (2H, dd, J

F
K. Lei et al.
2-Acetyl-4-fluorophenyl 2-Chlorobenzoate (11-14)
General Synthetic Procedure for Compound 12
White solid, 86 % yield, mp 68–708C. dH (CDCl3, 400 MHz)
To a solution of 2-acetylphenyl 2-chlorobenzoate (11-1)
(5.0 mmol) in DMF (10 mL), NaH (12.5 mmol) was added and
stirred for 2 h at 508C. Then, methyl chloroformate (5.5 mmol)
was added to the above solution, and the mixture was stirred for
4 h at 508C. After the reaction was complete (monitored by
thin layer chromatography (TLC)), the above mixture was
poured into a mixture of crushed ice (15 mL) and concentrated
HCl (5 mL). A white solid was precipitated. The formed pre-
cipitate was filtered, washed with cold ethanol (3 ꢀ 10 mL),
and then dried under vacuum to provide 3-(2-chlorobenzoyl)-
4-hydroxycoumarin (12-1). The remaining compounds
were prepared using a similar procedure to that employed to
prepare 12-1.
8.17 (1H, d, J 8.1), 7.59–7.48 (3H, m), 7.47–7.39 (1H, m),
7.35–7.19 (2H, m), 2.57 (3H, s). dC (CDCl3, 100 MHz)
195.16, 162.75, 160.19, 157.73, 143.71, 133.48, 132.45,
131.12, 130.32, 127.60, 125.88, 124.53 (d), 119.23 (d), 115.78
(d), 28.32. HRMS m/z 293.0381; calcd for C15H10ClFO3
293.0303.
2-Acetyl-4-bromophenyl 2,4-Dichlorobenzoate (11-15)
White solid, 90 % yield, mp 99–1018C. dH (CDCl3,
400 MHz) 8.14 (1H, d, J 8.5), 7.99 (1H, d, J 2.4), 7.72 (1H,
dd, J 8.6, 2.4), 7.57 (1H, d, J 2.0), 7.43 (1H, dd, J 8.5, 2.0), 7.17
(1H, d, J 8.6), 2.57 (1H, s). dC (CDCl3, 100 MHz) 196.09,
162.66, 147.72, 139.46, 136.39, 135.78, 133.32, 133.24, 132.22,
131.31, 127.38, 126.86, 125.73, 119.59, 119.59, 29.22. HRMS
m/z 386.9189; calcd for C15H9BrCl2O3 386.9112.
3-(2-Chlorobenzoyl)-4-hydroxycoumarin (12-1)
White solid, yield 61 %, mp 126–1278C. dH (CDCl3,
400 MHz) 8.13 (1H, dd, J 8.0, 1.4), 7.72 (1H, m), 7.45–7.41
(2H, m), 7.40–7.36 (2H, m), 7.33–7.30 (2H, m). dC (CDCl3,
100 MHz) 200.02, 177.97, 155.36, 138.70, 136.55, 131.19,
130.14, 129.50, 127.20, 126.89, 125.72, 124.58, 117.30,
114.94, 102.19. HRMS m/z 301.0261; calcd for C16H9ClO4
301.0189.
2-Acetyl-4-bromophenyl 2-Chlorobenzoate (11-16)
Light yellow solid, 87 % yield, mp 79–808C. dH (CDCl3,
400 MHz) 8.18–8.13 (1H, m), 7.98 (1H, d, J 2.4), 7.72 (1H, dd,
J 8.6, 2.4), 7.56–7.53 (2H, m), 7.44 (1H, m), 7.19 (1H, d, J 8.6),
2.57 (3H, s). dC (CDCl3, 100 MHz) 196.19, 163.46, 147.89,
136.28, 134.60, 133.56, 133.09, 132.56, 132.21, 131.39, 128.53,
126.93, 125.72, 119.49, 29.41. HRMS m/z 352.9580; calcd for
C15H10BrClO3 352.9502.
3-(2, 3-Dichlorobenzoyl)-4-hydroxycoumarin (12-2)
Light yellow solid, 68.0 % yield, mp 154–1568C. dH (CDCl3,
400 MHz) 8.16 (1H, d, J 7.8), 7.77 (1H, t, J 7.7), 7.59 (1H, d,
J 8.0), 7.42 (1H, t, J 7.5), 7.36 (2H, t, J 7.8), 7.23 (1H, d, J 7.4).
dC (CDCl3, 100 MHz) 199.02, 178.12, 158.57, 155.42, 140.72,
136.80, 133.33, 131.62, 128.43, 127.81, 125.75, 124.97, 124.69,
117.35, 114.77, 101.88. HRMS m/z 334.9872; calcd for
C16H8Cl2O4 334.9800.
2-Acetyl-3-methoxyphenyl 2,4-Dichlorobenzoate
(11-17)
White solid, 83 % yield, mp 84–858C. dH (CDCl3, 400 MHz)
7.98 (1H, d, J 8.4), 7.52 (1H, d, J 2.0), 7.45–7.31 (1H, m), 6.94–
6.79 (2H, m), 3.90 (3H, s), 2.53 (3H, s). dC (CDCl3, 100 MHz)
199.47, 161.80, 156.70, 146.47, 138.09, 134.51, 132.07, 130.30,
130.10, 126.20 (d), 123.10, 114.15, 108.12, 55.03, 30.76. HRMS
m/z 339.0113; calcd for C16H12Cl2O4 339.0113.
3-(2, 4-Dichlorobenzoyl)-4-hydroxycoumarin (12-3)
Pale yellow solid, 70 % yield, mp 186–1878C. dH (CDCl3,
400 MHz) 8.12 (1H, dd, J 8.0, 1.5), 7.77–7.69 (1H, m), 7.44 (1H, d,
J 1.9), 7.41–7.29 (3H, m), 7.28–7.23 (1H, m). dC (CDCl3,
100 MHz) 198.99, 177.97, 158.69, 155.37, 137.20, 136.75,
136.62, 131.21, 129.52, 128.25, 127.34, 125.74, 124.68,
117.32, 114.78, 102.12. HRMS m/z 334.9878; calcd for
C16H8Cl2O4 334.9800.
2-Acetyl-3-methoxyphenyl 2-Chlorobenzoate (11-18)
White solid, 91 % yield, mp 64–658C. dH (CDCl3, 400 MHz)
8.28–7.82 (1H, m), 7.53–7.47 (2H, m), 7.46–7.37 (2H, m), 6.90
(2H, d, J 8.3), 3.91 (3H, s), 2.56 (3H, s). dC (CDCl3, 100 MHz)
200.60, 163.66, 157.61, 147.57, 134.30, 133.25, 132.00, 131.22,
131.18, 128.90, 126.85, 124.35, 115.23, 109.04, 56.06, 31.80.
HRMS m/z 305.0579; calcd for C16H13ClO4 305.0502.
3-(2, 5-Dichlorobenzoyl)-4-hydroxycoumarin (12-4)
Pale yellow solid, 64 % yield, mp 246–2498C. dH (CDCl3,
400 MHz) 8.15 (1H, dd, J 8.0, 1.5), 7.80–7.73 (1H, m), 7.45–
7.37 (3H, m), 7.37–7.30 (2H, m). dC (CDCl3, 100 MHz) 198.40,
177.98, 158.58, 155.41, 139.95, 136.83, 132.95, 131.02, 130.66,
128.46, 127.14, 125.76, 124.70, 117.34, 114.71, 102.00. HRMS
m/z 334.9873; calcd for C16H8Cl2O4 334.9800.
2-Acetyl-4-methylphenyl 2-Chlorobenzoate (11-19)
Light yellow solid, 93 % yield, mp 80–818C. dH (CDCl3,
400 MHz) 8.23–8.11 (1H, m), 7.68 (1H, d, J 1.5), 7.52 (2H, m),
7.42 (2H, m), 7.17 (1H, d, J 8.2), 2.57 (3H, s), 2.45 (3H, s). dC
(CDCl3, 100 MHz) 197.74, 164.03, 146.75, 136.20, 134.37,
134.14, 133.22, 132.13, 131.24, 130.77, 130.57, 129.16,
126.86, 123.63, 29.44, 20.91. HRMS m/z 305.0502; calcd for
C16H13ClO3 289.0553.
3-(2-Chloro-6-fluorobenzoyl)-4-hydroxycoumarin (12-5)
Pale yellow solid, 38 % yield, mp 143–1448C. dH (CDCl3,
400 MHz) 8.16 (1H, d, J 7.9), 7.76 (1H, t, J 7.8), 7.40 (2H, dd,
J 14.4, 7.9), 7.33 (1H, d, J 8.4), 7.28 (1H, d, J 7.9), 7.11 (1H, t,
J 8.6). dC (CDCl3, 100 MHz) 194.63, 177.06, 158.89, 157.41,
156.40, 154.39, 135.78, 130.24 (d), 129.83 (d), 124.74, 124.30
(d), 123.63, 116.29, 113.72, 113.20 (d), 101.50. HRMS m/z
319.0165; calcd for C16H8ClFO4 319.0095.
2-Acetyl-5-methoxyphenyl 2-Chlorobenzoate (11-20)
White solid, 88 %, mp 74–768C. dH (CDCl3, 400 MHz) 8.21
(1H, dd, J 7.8, 1.0, 1H), 7.88 (1H, d, J 8.8), 7.49 (1H, m), 7.43–
7.35 (2H, m), 6.87 (1H, dd, J 8.8, 2.5), 6.75 (1H, d, J 2.5), 3.87
(3H, s), 2.52 (3H, s). dC (CDCl3, 100 MHz) 195.73, 163.85,
163.68, 151.22, 134.44, 133.24, 132.62, 132.34, 131.23, 129.06,
126.87, 123.12, 111.98, 109.43, 55.81, 29.03. HRMS m/z
305.0581; calcd for C16H13ClO4 305.0502.
3-(2-Chloro-4-fluorobenzoyl)-4-hydroxycoumarin (12-6)
Pale yellow solid, 71 % yield, mp 174–1768C. dH (CDCl3,
400 MHz) 8.15 (1H, d, J8.0), 7.75 (1H, t, J7.8), 7.42–7.33 (3H, m),

Synthesis of Frutinone A and Its Derivatives
G
7.21 (1H, dd, J 8.5, 2.0), 7.14–7.09 (1H, td, J 8.3, 2.1). dC
(CDCl3, 100 MHz) 199.04, 177.95, 164.53, 162.01, 158.73,
155.35, 136.68, 135.03 (d), 131.79 (d), 129.00 (d), 125.73,
124.64, 117.26 (d), 114.83, 114.37 (d), 102.19. HRMS m/z
319.0165; calcd for C16H8ClFO4 319.0095.
166.32, 158.25, 157.00 (d), 138.44, 131.25, 130.18, 129.51,
128.18 (d), 127.04 (d), 113.20 (d), 111.67, 104.72 (d), 101.43.
HRMS m/z 319.0166; calcd for C16H8ClFO4 319.0095.
3-(2,4-Dichlorobenzoyl)-6-fluoro-4-hydroxycoumarin
(12-13)
3-(2-Chloro-5-fluorobenzoyl)-4-hydroxycoumarin (12-7)
Light yellow solid, 66 % yield, mp 137–1398C. dH (CDCl3,
400 MHz) 8.17 (1H, dd, J 8.9, 6.0), 7.47 (1H, d, J 1.8), 7.38 (1H,
dd, J 8.2, 1.9), 7.28 (1H, s), 7.14 (1H, td, J 8.5, 2.3), 7.05 (1H, dd,
J 8.9, 2.3). dC (CDCl3, 100 MHz) 199.04, 177.09, 160.03,
158.42, 157.58, 151.53, 136.87, 131.26, 129.56, 128.31,
127.40, 124.52 (d), 119.22 (d), 115.69 (d), 110.98 (d), 102.31.
HRMS m/z 352.9786; calcd for C16H7Cl2FO4 352.9705.
Pale yellow solid, 69 % yield, mp 176–1788C. dH (CDCl3,
400 MHz) 8.15 (1H, d, J 8.0), 7.76 (1H, t, J 7.8), 7.41 (2H, m),
7.34 (1H, d, J 8.4), 7.14 (1H, td, J 8.4, 2.7), 7.06 (1H, dd, J 7.9,
2.7). dC (CDCl3, 100 MHz) 198.45, 178.00, 162.36, 159.89,
158.56, 155.42, 140.02 (d), 136.79, 131.01 (d), 125.74, 125.11
(d), 124.68, 118.08 (d), 117.34, 114.52 (d), 101.97. HRMS m/z
319.0165; calcd for C16H8ClFO4 319.0095.
3-(2-Chlorobenzoyl)-6-fluoro-4-hydroxycoumarin
(12-14)
3-(4-Bromo-2-chlorobenzoyl)-4-hydroxycoumarin
(12-8)
Pale yellow solid, 70 % yield, mp 140–1428C. dH (CDCl3,
400 MHz) 7.80 (1H, dd, J 7.8, 3.0), 7.49–7.43 (3H, m), 7.42–
7.38 (1H, m), 7.36–7.31 (2H, m). dC (CDCl3, 100 MHz) 200.08,
177.09, 159.98, 158.34, 157.53, 151.55, 138.41, 131.37, 130.19,
129.52, 127.09 (d), 124.28 (d), 119.16 (d), 115.86, 111.06,
110.81, 102.37, 77.36, 77.05, 76.73. HRMS m/z 319.0167; calcd
for C16H7ClFO4 319.0095.
Pale yellow solid, 66 % yield, mp 183–1858C. dH (CDCl3,
400 MHz) 8.12 (1H, dd, J 8.0, 1.4), 7.77–7.69 (1H, m), 7.60 (1H,
d, J 1.7), 7.51 (1H, dd, J 8.2, 1.7), 7.38 (1H, dd, J 11.3, 4.0), 7.32
(1H, d, J 8.4), 7.19 (1H, d, J 8.2). dC (CDCl3, 100 MHz) 199.03,
177.98, 158.70, 155.36, 137.65, 136.78, 132.26, 131.23, 130.23,
128.38, 125.75, 124.70, 124.52, 117.33, 114.77, 102.09. HRMS
m/z 378.9361; calcd for C16H8BrClO4 378.9294.
6-Bromo-3-(2,4-dichlorobenzoyl)-4-hydroxycoumarin
(12-15)
3-(2-Chloro-4-(methylsulfonyl)benzoyl)-4-
hydroxycoumarin (12-9)
Pale yellow solid, 68 % yield, mp 221–2238C. dH (CDCl3,
400 MHz) 8.23 (1H, d, J 2.4), 7.80 (1H, dd, J 8.8, 2.4), 7.45 (1H,
d, J 1.8), 7.37 (1H, dd, J 8.2, 1.8), 7.24 (2H, dd, m). dC (CDCl3,
100 MHz) 199.00, 176.73, 158.07, 154.14, 139.42, 136.91,
136.82, 131.26, 129.57, 128.32, 128.07, 127.40, 119.11,
117.51, 116.31, 102.34. HRMS m/z 412.8976; calcd for
C16H7BrCl2O4 411.8905.
Pale yellow solid, 72 % yield, mp 223–2258C. dH (CDCl3,
400 MHz) 16.25 (1H, s), 8.17 (1H, d, J 7.4), 8.04 (1H, s), 7.96
(1H, d, J 7.2), 7.79 (1H, t, J 7.3), 7.51 (1H, d, J 7.7), 7.43 (1H, t, J
7.5), 7.35 (1H, d, J 8.2), 3.15 (3H, s). dC (CDCl3, 100 MHz)
198.28, 178.17, 158.75, 155.45, 143.77, 142.60, 137.16, 131.39,
128.53, 127.92, 126.03, 125.85, 124.92, 117.42, 114.58, 101.84,
44.54. HRMS m/z 379.0041; calcd for C17H11ClO6S 378.9965.
6-Bromo-3-(2-chlorobenzoyl)-4-hydroxycoumarin
(12-16)
3-(2-Chloro-3-methoxybenzoyl)-4-hydroxycoumarin
(12-10)
Pale yellow solid, 64 % yield, mp 159–1608C. dH (CDCl3,
400 MHz) 8.26 (1H, d, J 1.9), 7.82 (1H, dd, J 8.8, 2.0), 7.46 (2H,
d, J 3.7), 7.44–7.37 (1H, m), 7.34 (1H, d, J 7.4), 7.23 (1H, d, J
8.8). dC (CDCl3, 100 MHz) 200.01, 176.74, 158.05, 154.16,
139.21, 138.33, 131.39, 130.21, 129.52, 128.06, 127.28, 126.91,
119.08, 117.38, 116.49, 102.41. HRMS m/z 378.9358; calcd for
C16H8BrClO4 378.9294.
Pale yellow solid, 47 % yield, mp 152–1558C. dH (CDCl3,
400 MHz) 8.05 (1H, d, J 7.8), 7.64 (1H, t, J 7.8), 7.34–7.17 (3H,
m), 6.96 (1H, d, J 8.2), 6.83 (1H, d, J 7.6), 3.86 (3H, s). dC
(CDCl3, 100 MHz) 199.89, 177.98, 158.48, 155.40, 154.95,
140.14, 136.52, 127.91, 125.70, 124.53, 118.52, 118.46,
117.28, 114.94, 113.24, 102.16, 77.38, 77.07, 76.75, 56.35.
HRMS m/z 331.0370; calcd for C17H11ClO5 331.0295.
3-(2,4-Dichlorobenzoyl)-5-methoxy-4-
hydroxycoumarin (12-17)
3-(2-Chloro-4-Methoxybenzoyl)-4-hydroxycoumarin
(12-11)
Pale yellow solid, 59 % yield, mp 176–1798C. dH (CDCl3,
400 MHz) 7.65 (1H, t, J 8.4), 7.46 (1H, d, J 1.6), 7.37 (1H, dd, J
8.2, 1.6), 7.28 (1H, s), 6.92 (1H, d, J 8.3), 6.83 (1H, d, J 8.5), 4.05
(3H, s). dC (CDCl3, 100 MHz) 197.27, 179.43, 159.63, 157.52,
155.93, 136.34, 136.17, 135.32, 130.14, 128.45, 127.19, 126.25,
108.71, 105.66, 104.20, 100.27, 55.64. HRMS m/z 364.9980;
calcd for C17H10Cl2O5 364.9905.
Light yellow solid, 56 % yield, mp 195–1978C. dH (CDCl3,
400 MHz) 8.04 (1H, d, J 7.4), 7.64 (1H, t, J 7.3), 7.35–7.22 (3H,
m), 6.89 (1H, d, J 2.1), 6.82 (1H, dd, J 8.5, 2.1), 3.78 (3H, s). dC
(CDCl3, 100 MHz) 199.30, 177.70, 161.73, 158.89, 155.27,
136.29, 132.14, 130.92, 129.39, 125.65, 124.46, 117.22,
115.12, 112.79, 102.43, 55.66. HRMS m/z 331.0372; calcd for
C17H11ClO5 331.0295.
3-(2-Chlorobenzoyl)-5-methoxy-4-hydroxycoumarin
3-(2-Chlorobenzoyl)-7-fluoro-4-hydroxycoumarin
(12-18)
(12-12)
Pale yellow solid, 50 % yield, mp 208–2118C. dH (CDCl3,
400 MHz) 7.62 (1H, t, J 8.4), 7.45–7.34 (3H, m), 7.31 (1H, dd,
J 6.8, 1.8), 6.90 (1H, dd, J 8.4, 0.7), 6.81(1H, d, J 8.4), 4.04 (3H, s).
dC (CDCl3, 100 MHz) 199.38, 180.51, 160.59, 158.55, 156.97,
138.79, 137.04, 130.97, 130.09, 129.45, 127.19, 126.85, 109.74,
Light yellow solid, 62 % yield, mp 148–1508C. dH (CDCl3,
400 MHz) 8.17 (1H, dd, J 8.7, 6.1), 7.46 (2H, d, J 3.2), 7.44–7.37
(1H, m), 7.34 (1H, d, J 7.1), 7.13 (1H, td, J 8.6, 2.1), 7.04 (1H,
dd, J 8.9, 2.0). dC (CDCl3, 100 MHz) 199.91, 177.48, 168.90,

H
K. Lei et al.
106.59, 105.32, 101.35, 56.67. HRMS m/z 331.0368; calcd for
C17H10ClO5 331.0295.
7.57 (2H, m). HRMS m/z 320.9928; calcd for C16H7ClO4
321.0033.
3-(2-Chlorobenzoyl)-6-methyl-4-hydroxycoumarin
(12-19)
Compound 13-5
White solid, 97 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.32 (1H, d, J 7.7), 8.01–7.77 (3H, m), 7.61 (1H, d, J 7.3), 7.55
(2H, dd, J 16.4, 8.2). dC (DMSO, 100 MHz) 171.73, 164.25,
156.26, 155.87, 154.22, 136.28, 135.09, 132.53, 129.75, 125.39,
124.92, 121.35, 118.58, 117.32, 113.39, 105.92. HRMS m/z
299.0110; calcd for C16H7ClO4 299.0033.
Light yellow solid, 55 % yield, mp 177–1798C. dH (CDCl3,
400 MHz) 7.92 (1H, d, J 1.1), 7.54 (1H, dd, J 8.5, 2.1), 7.47–7.43
(2H, m), 7.42–7.37 (1H, m), 7.36 ꢁ7.32 (1H, m), 7.22 (1H, d, J
8.5), 2.48 (3H, s). dC (CDCl3, 100 MHz) 200.01, 178.01, 158.86,
153.62, 138.81, 137.75, 134.47, 131.08, 130.14, 129.47, 127.19,
126.84,S 125.08, 117.06, 114.57, 102.16, 20.83. HRMS m/z
315.0421; calcd for C17H11ClO4 315.0346.
Compound 13-6
White solid, 94 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.29 (1H, d, J 7.6), 8.20 (1H, t, J 7.2), 7.90 (2H, d, J 7.7), 7.62–
7.40 (3H, m). dC (DMSO, 100 MHz) 171.74, 166.57, 165.15,
164.05, 155.45, 155.19 (d), 153.72, 135.89, 128.52 (d), 124.64
(d), 121.24, 116.91, 114.93 (d), 113.13, 105.63 (d). HRMS m/z
283.0407; calcd for C16H7FO4 283.0328.
3-(2-Chlorobenzoyl)-7-methoxy-4-hydroxycoumarin
(12-20)
White solid, 52 % yield, mp 204–2068C. dH (CDCl3,
400 MHz) 8.04 (1H, d, J 8.9), 7.48–7.36 (3H, m), 7.35–7.31
(1H, m), 6.94 (1H, dd, J 8.9, 2.4), 6.77 (1H, d, J 2.3), 3.94 (3H, s).
dC (CDCl3, 100 MHz) 199.50, 177.92, 166.80, 159.03, 157.84,
138.92, 130.91, 130.10, 129.45, 127.15, 127.12, 126.82, 113.63,
107.95, 100.50, 100.44, 56.11. HRMS m/z 329.0218; calcd for
C17H11ClO5 329.0295.
Compound 13-7
White solid, 91 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.34 (1H, d, J 7.8), 8.03 (1H, d, J 6.3), 7.94–7.78 (3H, m), 7.55
(2H, m). HRMS m/z 283.0403; calcd for C16H7FO4 283.0328.
General Synthetic Procedure for Compound 13
To a solution of compound 12-1 (1.0 mmol) in DMF (10 mL),
potassium phosphate (1.0 mmol) was added, and the mixture
was heated to 1508C for 2 h. After the reaction was complete and
cooled down, the mixture was poured into ice water (30 mL),
and a yellow solid was precipitated. The formed precipitate was
filtered, washed with cold water (3 ꢀ 10 mL), and then dried
under vacuum to give the natural product frutinone A 13-1. The
remaining target compounds were prepared using a similar
procedure to that used to prepare 13-1.
Compound 13-8
White solid, 94 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.33 (1H, d, J 8.5), 8.30 (1H, s), 8.05 (1H, d, J 8.1), 7.90 (1H, t,
J 7.4), 7.79 (1H, d, J 8.6), 7.56 (2H, m). dC (DMSO, 100 MHz)
172.06, 164.97, 155.43, 154.30, 153.78, 135.95, 129.77, 127.96,
127.43, 124.93, 124.49, 123.26, 121.48, 116.90, 113.15, 105.01.
HRMS m/z 342.9602; calcd for C16H7BrO4 342.9528.
Compound 13-9
Compound 13-1
White solid, 92 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.55 (1H, s), 8.39 (2H, dd, J 27.0, 7.7), 8.09 (1H, d, J 7.3), 7.90
(1H, t, J 7.1), 7.56 (2H, m), 3.42 (3H, s). dC (DMSO, 100 MHz)
172.39, 165.95, 155.86, 154.33, 154.21, 146.48, 136.67, 127.89,
127.64, 125.52, 125.25, 124.52, 118.65, 117.41, 113.55, 105.80,
43.55. HRMS m/z 343.0276; calcd for C17H10O6S 343.0198.
White solid 94 % yield, mp 240–2428C. dH (CDCl3,
400 MHz) 8.37 (1H, dd, J 7.9, 1.6), 8.23 (1H, dd, J 8.0, 1.5),
7.83–7.71 (2H, m), 7.64 (1H, d, J 8.3), 7.56–7.50 (1H, m), 7.49–
7.40 (2H, m). dC (CDCl3, 100 MHz) 173.00, 164.97, 156.29,
154.40, 154.30, 135.57, 134.79, 126.96, 126.62, 124.79, 124.52,
124.19, 117.79, 117.44, 113.25, 105.11. HRMS m/z 265.0498;
calcd for C16H8O4 265.0423.
Compound 13-10
White solid, 80.0 % yield, mp 289–2918C. dH (DMSO,
400 MHz) 8.14 (1H, d, J 7.4), 7.88 (1H, t, J 7.3), 7.66 (1H, d,
J 7.5), 7.61–7.39 (4H, m), 4.06 (3H, s). dC (DMSO, 100 MHz)
172.93, 164.80, 156.04, 154.12, 148.99, 144.50, 136.14, 126.92,
125.49, 124.46, 117.40, 117.11, 116.50, 113.90, 105.21, 57.21.
HRMS m/z 295.0606; calcd for C17H10O5 295.0528.
Compound 13-2
White solid, 90 % yield, mp 294–2968C. dH (DMSO,
400 MHz) 8.18 (1H, d, J 7.7), 8.07 (2H, d, J 7.9), 7.90 (1H, t,
J 7.6), 7.58 (2H, t, J 7.9), 7.53 (1H, d, J 8.4). dC (DMSO,
100 MHz) 171.78, 164.44, 155.20, 153.71, 149.49, 136.04,
134.97, 126.92, 125.46, 125.17, 124.58, 123.98, 122.03,
116.97, 112.98, 104.76. HRMS m/z 299.0110; calcd for
C16H7ClO4 299.0033.
Compound 13-11
White solid, 81 % yield, mp 231–2328C. dH (DMSO,
400 MHz) 8.30 (1H, d, J 7.7), 8.03 (1H, d, J 8.8), 7.86 (1H, t,
J 7.6), 7.53 (2H, m), 7.45 (1H, s), 7.15 (1H, d, J 8.5), 3.96 (3H, s).
dC (DMSO, 100 MHz) 171.78, 164.73, 164.44, 155.88, 155.63,
153.63, 135.54, 127.10, 124.78, 124.30, 117.68, 116.84, 115.25,
113.36, 104.67, 101.36, 56.32. HRMS m/z 295.0607; calcd for
C17H10O5 295.0528.
Compound 13-3
White solid, 96 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.30 (1H, d, J 7.8), 8.18–8.07 (2H, m), 7.89 (1H, t, J 7.7), 7.65
(1H, d, J 8.5), 7.55 (2H, dd, J 19.2, 8.0). dC (DMSO, 100 MHz)
172.40, 165.52, 155.91, 154.88, 154.26, 139.70, 136.44, 127.94,
127.46, 125.42, 124.95, 123.48, 119.06, 117.40, 113.63, 105.50.
HRMS m/z 320.9928; calcd for C16H7ClO4 321.0033.
Compound 13-12
Compound 13-4
White solid, 90 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.42 (1H, m, J 7.6), 8.15 (1H, d, J 7.5), 7.93 (2H, q, J 8.3), 7.59
(2H, dd, J 19.6, 8.6), 7.48 (1H, t, J 8.2). dC (DMSO, 100 MHz)
White solid, 91 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.36 (1H, d, J 7.6), 8.09 (1H, s), 8.01 (2H, s), 7.91 (1H, t, J 7.8),

Synthesis of Frutinone A and Its Derivatives
I
172.43, 167.40, 164.86, 164.50, 155.44, 155.22 (d), 154.08,
135.19, 127.18 (d), 126.63, 125.58, 123.95, 118.48, 113.16 (d),
110.41, 104.47 (d). HRMS m/z 283.0404; calcd for C16H7FO4
283.0328.
7.69 (1H, d, J 8.6), 7.60 (1H, t, J 6.9), 7.41 (1H, d, J 8.5), 2.48
(3H, s). dC (DMSO, 100 MHz) 173.09, 165.37, 156.22, 154.62,
152.43, 137.17, 135.61, 134.88, 127.03, 126.08, 124.54, 124.28,
118.93, 117.16, 113.45, 105.22, 20.83. HRMS m/z 279.0654;
calcd for C17H10O4 279.0579.
Compound 13-13
White solid, 95 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.20–8.10 (3H, m), 7.79 (1H, td, J 8.7, 3.0), 7.63 (2H, m). dC
(DMSO, 100 MHz) 171.83, 164.34, 159.49, 157.08, 155.26,
154.34, 150.23, 139.27, 127.27 (d), 124.19–121.88 (t),
119.25 (d), 118.63, 114.23 (d), 110.04 (d), 105.32. HRMS
m/z 317.0015; calcd for C16H6ClFO4 316.9939.
Compound 13-20
White solid, 89 % yield, mp 290–2938C. dH (DMSO,
400 MHz) 8.22 (1H, d, J 8.8), 8.13 (1H, d, J 7.7), 7.87 (2H,
m), 7.57 (1H, t, J 7.3), 7.13 (1H, d, J 9.1), 7.11 (1H, s), 3.94 (3H,
s). dC (DMSO, 100 MHz) 172.91, 166.03, 165.59, 156.51,
156.39, 154.58, 135.40, 126.86, 126.38, 126.04, 124.42,
118.80, 114.01, 106.54, 103.13, 101.21, 56.89. HRMS m/z
295.0607; calcd for C17H10O5 295.0528.
Compound 13-14
White solid, 90 % yield, mp 296–2988C. dH (DMSO,
400 MHz) 8.19 (1H, dd, J 8.1, 2.2), 8.14 (1H, d, J 7.8), 7.94
(2H, bs), 7.77 (1H, td, J 8.8, 2.6), 7.60 (2H, dd, J 8.8, 4.2). dC
(DMSO, 100 MHz) 172.96, 164.66, 159.97, 157.56, 155.91,
154.58, 150.66, 135.73, 127.17, 126.07, 124.54, 123.65 (d),
119.65 (d), 119.07, 114.87, 110.57 (d), 105.61. HRMS m/z
283.0404; calcd for C16H7FO4 283.0328.
Supplementary Material
Copies of 1H and 13C NMR spectra are available on the Journal’s
website.
Acknowledgements
This study was undertaken with the financial support of the Special Fund for
Agro-scientific Research in the Public Interest (Grant No. 201403030).
Compound 13-15
White solid, 93 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.54 (1H, d, J 2.1), 8.25 (1H, s), 8.13 (1H, d, J 8.5), 8.05 (1H, dd,
J 8.9, 2.2), 7.66 (1H, dd, J 8.5, 1.7), 7.52 (1H, d, J 8.8). HRMS
m/z 376.9211; calcd for C16H6BrClO4 376.9138.
References
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K. Hosterttmann, Phytochem. Anal. 1997, 8, 32. doi:10.1002/(SICI)
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Compound 13-16
White solid, 91 % yield, mp .3008C. dH (DMSO, 400 MHz)
8.54 (1H, s), 8.15 (1H, d, J 7.5), 8.06–7.87 (3H, m), 7.61 (1H, t, J
7.1), 7.52 (1H, d, J 8.6). dC (DMSO, 100 MHz) 172.91, 164.31,
155.66, 154.63, 153.27, 138.50, 135.74, 127.20, 127.07, 126.03,
124.52, 119.70, 119.19, 117.11, 115.82, 105.69. HRMS m/z
342.9598; calcd for C16H7BrO4 342.9528.
[5] M. D. Dean, K. B. Hindley, S. Small, J. Chem. Soc., Perkin Trans. 1
1972, 16, 2007. doi:10.1039/P19720002007
Compound 13-17
[6] F. Eiden, H. D. Schweiger, Synthesis 1974, 1974, 511. doi:10.1055/
S-1974-23363
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White solid, 89 % yield, mp 282–2848C. dH (DMSO,
400 MHz) 8.10 (1H, d, J 8.5), 7.99 (1H, d, J 1.8), 7.78 (1H, t,
J 8.4), 7.62 (1H, dd, J 8.5, 1.9), 7.09 (1H, d, J 8.4), 7.03 (1H, d, J
8.2), 4.09 (3H, s). dC (DMSO, 100 MHz) 171.72, 166.64,
158.67, 155.23, 155.08, 154.21, 139.17, 136.41, 127.14,
126.95, 122.78, 118.54, 108.78, 107.67, 104.12, 102.98,
56.79. HRMS m/z 329.0216; calcd for C17H9ClO5 329.0139.
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878. doi:10.1002/ASIA.201402876
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583. doi:10.1021/JO990735Q
Compound 13-18
White solid, 90.0 % yield, mp 291–2938C. dH (DMSO,
400 MHz) 8.12 (1H, d, J 7.7), 7.90 (1H, t, J 7.4), 7.77 (2H, t, J
7.0), 7.58 (1H, t, J 7.3), 7.10 (1H, d, J 8.4), 7.03 (1H, d, J 8.3),
4.08 (3H, s). dC (DMSO, 100 MHz) 172.92, 169.44, 167.00,
159.11, 155.92, 155.58, 154.49, 136.67, 135.41, 127.00, 125.80,
124.38, 119.12, 109.35, 108.19, 103.72, 57.36. HRMS m/z
295.0606; calcd for C17H10O5 295.0528.
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Compound 13-19
White solid, 95 % yield, mp 296–2988C. dH (DMSO,
400 MHz) 8.14 (1H, d, J 9.5), 8.12 (1H, s), 7.92 (2H, q, J 8.3),
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