Chemical synthesis of funicone analogs

Article abstract of DOI:10.1016/j.tet.2012.04.010

Deoxyfunicone, rapicone and their 5,6-epoxy-derivatives are γ-pyrone compounds with cytostatic and antiproliferative properties. Here we describe a synthesis of these compounds by carbonylative Stille coupling between kojic acid derivatives and functional

Full text of DOI:10.1016/j.tet.2012.04.010

Tetrahedron 68 (2012) 4107e4111
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Chemical synthesis of funicone analogsq
*
Emiliano Manzo , Maria Letizia Ciavatta
Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare, Via Campi Flegrei 34, 80078-I Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Deoxyfunicone, rapicone and their 5,6-epoxy-derivatives are g-pyrone compounds with cytostatic and
Received 30 January 2012
Received in revised form 15 March 2012
Accepted 2 April 2012
antiproliferative properties. Here we describe a synthesis of these compounds by carbonylative Stille
coupling between kojic acid derivatives and functionalized iodo aryl compounds. The main advantages of
this patent pending synthetic strategy lie in the simplicity and clean conversion of products, and in the
possibility to obtain a high number of analogs by minor changes of the synthetic synthons.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 9 April 2012
Keywords:
Rapicone
Deoxyfunicone
Funicone analogs
Chemical synthesis
O
O
O
CO2Me
O
O
O
CO2Me
1. Introduction
R
As part of our continuing research of bioactive secondary me-
tabolites from natural sources, fungal compounds have attracted
our attention for their interesting biological activities.1
MeO
OMe
MeO
OMe
1. R = OH
2. R = H
In this regard the g-pyrone motif is present in a large number of
3
bioactive natural products of polyketide origin.2 Funicone (1)3 and
structurally-related compounds form a characteristic subclass that
Fig. 1. Funicone (1) and structurally-related deoxyfunicone (2) and rapicone (3).
is characterized by a keto bridge between a substituted
g-pyrone
ring and -resorcyclic acid (Fig.1). The family embraces a number of
a
2. Results and discussion
derivatives showing promising biomedical potential as fungicides,
antiviral and antitumor candidates.2e-4 Funicone (1) was first iso-
lated from Penicillium funiculosum3 but structural analogs have
been reported from many other terrestrial fungi.
Chemical preparations of g-pyrone compounds have been pre-
viously reported, and traditionally rely on a biomimetic approach
based on cyclization of triketide precursor (Fig. 2).9
In view of the pharmaceutical development of this family of
polyketides, we have elaborated a short and versatile synthesis of
funicone analogs from commercially available compounds (patent
pending). To illustrate the potential of the synthetic strategy, here
we report preparation of deoxyfunicone2a,5 (2), a HIV-1-integrase
inhibitor,5,6 and rapicone7 (3), a phytopatogenic fungi antagonist,
which differ only for the alkyl substituents at C-2 of the pyrone ring,
as well as the synthesis of fungal 5,6-epoxy-derivatives.8
To the best of our knowledge, this is the first report on synthesis
of members of the funicone family.
Recently, Kamino and co-workers10 introduced
a
general
method to prepare 5-substituted
g-pyrone compounds from 5-
stannane derivatives of the commercially available kojic acid by
Stille carbonylative coupling with iodo benzene.11 The methodol-
ogy is highly versatile and replacement of the last reagent with
functionalized iodo aryl derivatives gives theoretically access to the
funicone skeleton of 2 and 3 in one step (Fig. 3).
O
O
O
H+
R
R1
R
R1
q
Patent pending; application no. PCT/IB2011/054262.
OH
OH
* Corresponding author. Tel.: þ39 081 8675310; fax: þ39 081 8041770; e-mail
addresses: emanzo@icb.cnr.it, emanzo@icmib.na.cnr.it (E. Manzo).
Fig. 2. General synthetic procedures for g-pyrones preparation.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.010

4108
E. Manzo, M.L. Ciavatta / Tetrahedron 68 (2012) 4107e4111
O
O
CO2Me
CO
CO2Me
O
O
[Pd(allyl)Cl]2
SnMe3
I
DMF
5
1'
+
4'
5'
2
R
MeO
OMe
MeO
OMe
R
O
2. R = 1-propenyl
3. R = Me
R = 1-propenyl
R = Me
Fig. 3. Synthesis of deoxyfunicone (2) and rapicone (3) by Kamino’s procedure.
For the preparation of the stannane precursors (Scheme 1), kojic
acid was chlorinated by thionyl chloride in dichloromethane to give
4. Triphenylphosphorylation of this product followed by Wittig
reaction with acetaldehyde led to trans 1-propenyl derivative 5
from which the stannane precursor 7 was obtained by a simple
sequence of transformations including activation of enolic function
with triflic anhydride and substitution with hexamethylditin in
presence of palladium(II) acetate, triphenylphosphine and lithium
chloride.11,12 The stannane 10 was obtained in the same way after
preparation of the methyl derivative 8 by zinc reduction13 of the
chloro intermediate 4.
Furthermore, in agreement with the literature,15e17 the partial
deactivation of the aromatic reagent also favored the competitive
reaction of homocoupling of the stannane intermediates (Fig. 6).
Finally, oxidation of deoxyfunicone (2) and rapicone (3) with
hydrogen peroxide in presence of lithium diisopropylamide and
trimethylborate (Scheme 2),18 gave 5,6-epoxy-deoxyfunicone (12)8
and 5,6-epoxy-rapicone (13), respectively.
In this manner, all a series of funicone-related compounds,
starting from the precursor 14, various types of aldehydes and
differently functionalized iodo aryl derivatives, could be prepared
(Fig. 7).
1) THF
Triphenylphosphine
O
O
2) CH3CN / K2CO3
18-crown-6-etere
Acetaldehyde
OH
R
triflic anhydride
O
O
O
O
Me3SnSnMe3
Pd(OAc)2
PPh3
OH CH2Cl2
OH
5 66%
6. R = OTf, 70%
SOCl2
7. R = SnMe3, 81%
HO
Cl
LiCl
O
O
Zn/HCl
H2O
70°C
O
O
kojic acid
triflic anhydride
4 88%
OH
R
O
Me3SnSnMe3
Pd(OAc)2
PPh3
O
8 70%
9. R = OTf, 73%
10. R = SnMe3, 78%
LiCl
Scheme 1. Preparation of stannane precursors for the synthesis of deoxyfunicone (2) and rapicone (3).
More simply, the iodo benzo-intermediate 11 was prepared by
iodination of the commercially available methyl-3,5-
3. Conclusion
dimethoxybenzoate with silver trifluoroacetate and iodine
(Fig. 4).14 As expected, coupling of 11 with the stannanes 7 and 10
under Kamino’s conditions gave deoxyfunicone (2) and rapicone (3)
with 33% and 35% yields, respectively.
In summary, access to natural and unusual compounds of the
funicone family was achieved by a versatile and simple chemical
procedure involving Stille carbonylative coupling11 between kojic
acid derivatives stannane- and iodo-precursors in carbon monox-
ide atmosphere with allylpalladium(II) chloride dimer as catalyst.10
The synthetic procedure is of general application and gives access
to a large variety of funicone-related compounds of biomedical
interest simply starting from modified precursors. With this aim
carbon-3 oxidation of deoxyfunicone (2) and rapicone (3) is in
progress opening the way to the preparation of all another series of
funicone analogs.
CO2Me
CHCl3
CO2Me
Silver trifluoroacetate (1eq)
I2 (1eq)
I
MeO
OMe
MeO
OMe
7%
Methyl -3,5 dimethoxybenzoate
Fig. 4. Preparation of iodo benzo-precursor.
4. Experimental section
The coupling was less efficient than we could expect on the basis
of Kamino’s report,10 which is likely due to the two electron-
donating methoxy groups on the aromatic ring that counteract
the electron-withdrawing effect of the ester moiety.15 In confir-
mation of this, the coupling yield increased to 73% with unfunc-
tionalized aryl iodide (Fig. 5).
4.1. General experimental procedures
1D and 2D NMR spectra were recorded on a Bruker Avance-400
and on a Bruker DRX-600 equipped with TXI CryoProbeÔ in CDCl3,
CD2Cl2 and DMSO-d6 (
d values are reported referred to CHCl3, CH2Cl2
and DMSO protons at 7.25, 5.32, and 2.49 ppm, respectively) and 13
C

E. Manzo, M.L. Ciavatta / Tetrahedron 68 (2012) 4107e4111
4109
O
CO
O
O
O
[Pd(allyl)Cl]2
SnMe3
I
DMF
5
1'
+
4'
2
5'
O
2a, 73%
7
Fig. 5. Coupling reaction between the stannane intermediate 7 and unfunctionalized aryl iodide.
4.33 (2H, s, H2-7); 13C NMR (100 MHz, CDCl3):
d
¼174.3 (C, C4), 162.9
(C, C2), 146.2 (C, C5), 138.1 (CH, C6), 112.3 (CH, C3), 41.1 (CH2, C7);
O
O
O
HRESIMS: m/z calcd for C6H535ClNaO3: 182.9825; found: 182.9833.
4.2.2. Compound 5. Compound 4 (0.450 g, 0.003 mol) was dissolved
in 7 mL of anhydrous THF and triphenylphosphine (1.570 g,
0.006 mol) was added; after stirring for four days at 67 ꢀC, the pre-
cipitate was filtered obtaining triphenylphosphonium chloride,
dissolved in 12 mL of acetonitrile and potassium carbonate (0.410 g,
R
O
R
Fig. 6.
g-pyrone dimers producted by homocoupling of the stannane intermediates.
O
O
CO2Me
O
O
CO2Me
LDA
B(OMe)3
AcOH/H2O2
O
R
O
MeO
OMe
R
O
MeO
OMe
12. R = 1-propenyl, 66%
13. R = Me, 65%
2. R = 1-propenyl
3. R = Me
Scheme 2. Preparation of 5,6-epoxy-deoxyfunicone (12) and 5,6-epoxy-rapicone (13).
O
OH
Ph3+P
Cl-
R1
R1
O
O
O
I
14
R3
R2
R3
R2
R4
O
O
R4
H
Fig. 7. General synthetic scheme for funicone-related derivatives.
NMR were recorded on a Bruker DPX-300 (75.0 MHz) and Bruker
DRX-600 (150 MHz) (dC values are reported to CHCl3, CH2Cl2 and
DMSO carbon at 77.0, 53.8 and 39.5 ppm, respectively); IR spectra
were recorded on Biorad FTS 155 spectrometer; HRESIMS were car-
0.003 mol); dicyclohexyl-18-crown-6 (10 mg, 0.027 mmol) and ac-
etaldehyde (0.400 g, 0.009 mol) were added; after stirring overnight
at room temperature, the reaction mixture was purified by silica gel
chromatography using a gradient of CHCl3/CH3OH to give 5 (0.282 g,
66%) as a white solid; Rf (CHCl3/CH3OH, 9:1)¼0.67; 1H NMR
ried out on a Micromass Q-TOF micro; TLC plates (KieselGel 60 F254
)
were from Merck (Darmstadt, Germany), silica gel powder (Kieselgel
60 0.063e0.200 mm) was from Merck (Darmstadt, Germany).
Kojic acid, methyl-3,5-dimethoxybenzoate, all the solvents and
reagents were purchased by SigmaeAldrich.
(400 MHz, CDCl3):
d
¼8.00 (1H, s, H-6), 6.68 (1H, dq, J¼15.2, 6.9 Hz, H-
8), 6.27 (1H, s, H-3), 6.08 (1H, br d, J¼15.2 Hz, H-7), 1.92 (3H, d,
J¼6.9 Hz, H3-9); 13C NMR (100 MHz, CDCl3):
¼171.2 (C, C4),163.0 (C,
d
C2), 148.7 (CH), 138.1 (CH), 122.1 (CH), 113.5 (CH), 19.1 (CH3, C9);
HRESIMS: m/z calcd for C8H8NaO3: 175.0371; found: 175.0362.
4.2. Synthetic procedures
4.2.3. Compound 6. Compound 5 (0.282 g, 0.0019 mol) was dis-
solved in 4 mL of pyridine and triflic anhydride (1.128 g, 0.0040 mol)
was added slowly under argon atmosphere; after stirring overnight
at room temperature, the mixture was evaporated and purified by
silica gel chromatography using a gradient of CHCl3/CH3OH to give 6
(0.378 g, 70%) as a pale yellow oil; Rf (Light petroleum ether/ethyl-
4.2.1. Compound 4. Kojic acid (1.000 g, 0.007 mol) was dissolved in
10 mL of anhydrous dichloromethane and thionyl chloride (1.070 g,
1.3 equiv) was added; after stirring overnight at room temperature,
the reaction mixture was evaporated and purified by silica gel
chromatography using a gradient of CHCl3/CH3OH to give 4
(0.986 g, 88%) as a pale yellow oil; Rf (CHCl3/CH3OH 9:1)¼0.51; 1H
acetate 3:7)¼0.83; 1H NMR (400 MHz, CDCl3):
¼8.01 (1H, s, H-6),
d
6.70 (1H, dq, J¼15.2, 6.9 Hz, H-8), 6.30 (1H, s, H-3), 6.10 (1H, br d,
NMR (400 MHz, CDCl3):
d
¼7.89 (1H, s, H-6), 6.57 (1H, br s, H-3),

4110
E. Manzo, M.L. Ciavatta / Tetrahedron 68 (2012) 4107e4111
J¼15.2 Hz, H-7), 1.97 (3H, d, J¼6.9 Hz, H3-9); 13C NMR (100 MHz,
(400 MHz, CDCl3):
d
¼6.74 (1H, d, J¼2.3 Hz, H-30), 6.45(1H, d, J¼2.3 Hz,
CDCl3):
d
¼171.1 (C, C4), 162.7 (C, C2), 148.5 (CH), 138.0 (CH), 120.7
H-50), 3.88 (3H, s, OMe), 3.80 (3H, s, OMe), 3.76 (3H, s, OMe); 13C NMR
(CH), 113.1(CH), 18.5 (CH3, C9); HRESIMS: m/z calcd for
C9H7F3NaO5S: 306.9864; found: 306.9855.
(100 MHz, CDCl3):
(CH),101.7 (CH), 57.0 (OCH3), 56.7 (OCH3), 52.8 (OCH3); HRESIMS: m/z
d¼168.2 (C), 161.9 (C), 159.9 (C), 139.2 (C), 107.8
calcd for C10H11NaIO4: 344.9600; found: 344.9607.
4.2.4. Compound 7. Compound 6 (0.045 g, 0.158 mmol) was dis-
solved in 2 mL of anhydrous DMF and palladium(II) acetate (0.2 mg,
3% mol), hexamethylditin (0.049 g, 0.152 mmol), triphenylphosphine
(0.2 mg, 3% mol) and lithium chloride (0.033 g, 0.79 mmol) were
added; after stirring for 21 h at room temperature, the mixture was
portioned between aqueous buffer (pH¼7) and diethyl ether; the
organic phase was purified by silica gel chromatography using a gra-
dient of light petroleum ether and ethyl acetate obtaining 7 (0.038 g,
81%) as a white solid; Rf (Light petroleum ether/ethylacetate 3:7)¼
4.2.9. Compound 2. Compound 7 (0.030 g, 0.1 mmol) was dissolved
in 2 mL of anhydrous DMF in monoxide carbon atmosphere;
compound 11 (0.161 g, 0.5 mmol), allylpalladium(II) chloride dimer
(2.7 mg, 0.015 mmol) were added; after stirring one day at room
temperature, the mixture was portioned between water and ethyl
acetate and the organic phase was purified by silica gel chroma-
tography using a gradient of n-hexane and ethyl acetate obtaining 2
(0.012 g, 33%) as a pale yellow oil; Rf (Light petroleum ether/eth-
ylacetate 3:7)¼0.12; IR (liquid film) vmax 2934, 2849, 1714, 1683,
0.90; 1H NMR (400 MHz, CDCl3):
d¼7.41 (1H, s, H-6), 6.59 (1H, dq,
J¼15.2, 6.9 Hz, H-8), 6.02 (1H, s, H-3), 6.02 (1H, d, J¼15.2 Hz, H-7),1.92
1637,1606,1444 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d¼8.52 (1H, s, H-
(3H, d, J¼6.9 Hz, H3-9), 0.30 (9H, s, MeSn); 13C NMR (100 MHz, CDCl3):
6), 7.08 (1H, d, J¼1.9 Hz, H-30), 6.68 (1H, dq, J¼15.2, 6.9 Hz, H-8),
6.64 (1H, d, J¼1.9 Hz, H-50), 6.09 (1H, s, H-3), 6.07 (1H, d, J¼15.2 Hz,
H-7), 3.86 (3H, s, OMe), 3.78 (3H, s, OMe), 3.73 (3H, s, OMe), 1.94
d
¼182.7 (C, C4), 165.9 (C, C2), 157.1 (CH, C6), 145.6 (C, C5), 134.9 (CH,
C8), 125.1 (CH, C7), 112.6 (C, C3), 19.6 (CH3, C9), -9.6 (SnCH3); HRE-
SIMS: m/z calcd for C11H16NaO2Sn: 323.0070; found: 323.0082.
(3H, d, J¼6.9 Hz, H3-9). 13C NMR (100 MHz, CDCl3):
¼191.5 (C, C10),
d
175.7 (C, C4), 166.1 (C, C70), 161.1 (C, C2), 160.4 (C, C40), 160.4 (CH,
C6), 157.3 (C, C60), 136.2 (CH, C8), 129.9 (C, C20), 126.4 (C, C10), 126.0
(C, C5), 122.8 (CH, C7), 115.1 (CH, C3), 105.1 (CH, C30), 103.0 (CH, C50),
56.0 (CH3, C90), 55.5 (CH3, C100), 52.2 (CH3, C80), 18.6 (CH3, C9);
HRESIMS: m/z calcd for C19H18NaO7: 381.0950; found: 381.00943.
4.2.5. Compound 8. Compound 4 (0.450 g, 0.003 mol) was added to
6 mL of distilled water and heated to 50 ꢀC with stirring; zinc dust
(0.384 g, 0.006 mol) was added followed by the dropwise addition of
concentrated hydrochloric acid (3.7 mL) over 1 h with vigorous
stirring maintaining the temperature at 75 ꢀC; the reaction mixture
wasstirredforother 3 hat 70ꢀC. Theexcess ofzinc waseliminated by
hot filtration and the filtrate was extracted with CH2Cl2 obtaining
obtaining 8 (0.264 g, 70%) as a white solid; Rf (CHCl3/CH3OH, 9:1)¼
4.2.10. Compound 3. Compound 10 (0.030 g, 0.1 mmol) was dis-
solved in 2 mL of anhydrous DMF in monoxide carbon atmosphere;
compound 11 (0.161 g, 0.5 mmol), allylpalladium(II) chloride dimer
(2.7 mg, 0.015 mmol) were added; after stirring one day at room
temperature, the mixture was portioned between water and ethyl
acetate and the organic phase was purified by silica gel chromatog-
raphy using a gradient of n-hexane and ethyl acetate obtaining 3
(0.013 g, 35%) as a pale yellow oil; Rf (Light petroleum ether/ethyl-
acetate 3:7)¼0.12; IR (liquid film) vmax 2931, 2839, 1718, 1679, 1653,
0.52; 1H NMR (400 MHz, CDCl3):
d
¼7.68 (1H, s, H-6), 6.19 (1H, s, H-3),
2.21 (3H, s, H3-7); 13C NMR (100 MHz, CDCl3):
d
¼174.3 (C, C4), 166.4
(C, C2), 145.3 (C, C5), 137.9 (CH, C3), 111.3 (CH, C6), 20.0 (CH3, C7);
HRESIMS: m/z calcd for C6H6NaO3: 149.0215; found: 149.0220.
4.2.6. Compound 9. Compound 8 (0.264 g, 0.0021 mol) was dis-
solved in
4
mL of pyridine and triflic anhydride (2.900 g,
1602,1556 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
¼8.50 (1H, s, H-6), 7.07
0.0084 mol) was added slowly under argon atmosphere; after
stirring overnight at room temperature, the mixture was evapo-
rated and purified by silica gel chromatography using a gradient of
CHCl3/CH3OH to give 9 (0.393 g, 73%) as a pale yellow oil; Rf (Light
petroleum ether/ethylacetate 3:7)¼0.70; 1H NMR (400 MHz,
(1H, d, J¼2.0 Hz, H-30), 6.63 (1H, d, J¼2.0 Hz, H-50), 6.12 (1H, s, H-3),
3.86 (3H, s, OMe), 3.78 (3H, s, OMe), 3.72 (3H, s, OMe), 2.27 (3H, s, H3-
7). 13C NMR (100 MHz, CDCl3):
d
¼191.6 (C,C8), 175.4 (C, C4), 166.6 (C,
C70),165.0 (C, C2),160.8 (C, C40),160.8 (CH, C6),157.1 (C, C60),129.9 (C,
C20), 126.2 (C, C10), 126.1 (C, C5), 117.2 (CH, C3), 105.1 (CH, C30), 103.0
(CH, C50), 55.9 (CH3, C90), 55.5 (CH3, C100), 52.3 (CH3, C80), 19.2 (CH3,
C7); HRESIMS: m/z calcd for C17H16NaO7: 355.0794; found: 355.0802.
CDCl3):
d
¼8.01 (1H, s, H-6), 6.34 (1H, s, H-3), 2.34 (3H, s, H3-7);
HRESIMS: m/z calcd for C7H5F3NaO5S: 280.9707; found: 280.9713.
4.2.7. Compound 10. Compound 9 (0.393 g, 1.5 mmol) was dis-
solved in 2 mL of anhydrous DMF and palladium(II) acetate (1.9 mg,
3% mol), hexamethylditin (0.466 g, 1.44 mmol), triphenylphosphine
(1.9 mg, 3% mol) and lithium chloride (0.314 g, 7.5 mmol) were
added; after stirring for 21 h at room temperature, the mixture was
portioned between aqueous buffer (pH¼7) and diethyl ether; the
organic phase was purified by silica gel chromatography using
a gradient of light petroleum ether and ethyl acetate obtaining 10
(0.309 g, 78%) as a pale yellow oil; Rf (Light petroleum ether/eth-
4.2.11. Compound 2a. Compound 7 (0.010 g, 0.03 mmol) was dis-
solved in 1 mL of anhydrous DMF in monoxide carbon atmosphere;
aryl iodide (0.031 g, 0.15 mmol), allylpalladium(II) chloride dimer
(1 mg, 0.005 mmol) were added; after stirring one day at room
temperature, the mixture was portioned between water and ethyl
acetate and the organic phase was purified by silica gel chroma-
tography using a gradient of n-hexane and ethyl acetate obtaining 2a
(0.005 g, 73%) as a pale yellow oil; Rf (Light petroleum ether/ethyl-
acetate 3:7)¼0.12; IR (liquid film) vmax 2923, 2841, 1663, 1617, 1610,
ylacetate 3:7)¼0.71; 1H NMR (400 MHz, CDCl3):
d
¼7.37 (1H, s, H-6),
1414 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d¼8.05 (1H, s, H-6), 7.86 (2H,
6.00 (1H, s, H-3), 2.17 (3H, s, H3-7), 0.24 (9H, s, MeSn); 13C NMR
d, J¼7.5 Hz, H-20, H-60), 7.58 (1H, t, J¼7.5 Hz, H-40), 7.46 (1H, dd, J¼7.5,
7.5 Hz, H-30, H-50), 6.67 (1H, dq, J¼15.2, 6.9 Hz, H-8), 6.09 (1H, s, H-3),
6.07 (1H, d, J¼15.2 Hz, H-7), 1.95 (3H, d, J¼6.9 Hz, H3-9); HRESIMS:
m/z calcd for C15H12NaO3: 263.0684; found: 263.0690.
(100 MHz, CDCl3):
126.6 (C, C5), 113.7 (CH, C3), 20.6 (CH3, C7), -9.5 (SnCH3); HRESIMS:
d
¼182.7 (C, C4), 165.9 (C, C2), 157.1 (CH, C6),
m/z calcd for C9H14NaO2Sn: 296.9913; found: 296.9907.
4.2.8. Compound 11. Methyl-3,5-dimethoxybenzoate (2.000 g,
0.0103 mol) was dissolved in 50 mL of chloroform; iodine (1.330 g,
0.0103 mol) and silver trifluoroacetate (1.71 g, 0.0103 mol) were
added; after stirring for 5 h at room temperature, the mixture was
purified by silica gel chromatography using a gradient of light pe-
troleum ether and diethyl ether getting 11 (2.500 g, 77%) as a pale
yellowoil;Rf (Light petroleumether/diethyl ether 1:1)¼0.60; 1H NMR
4.2.12. Compound 12. Three different solutions were prepared:
Solution S1: Lithium diisopropylamide (5 mg) dissolved in
1.5 mL of anhydrous THF at ꢁ78 ꢀC.
Solution S2: Compound 2 (15 mg (0.042 mmol)) dissolved in
1 mL of anhydrous THF.
Solution S3: Trimethylborate (5
hydrous THF.
mL) dissolved in 0.5 mL of an-

E. Manzo, M.L. Ciavatta / Tetrahedron 68 (2012) 4107e4111
4111
S2 was added to S1 at ꢁ78 ꢀC; after stirring for 30 min, S3 was
Supplementary data
added slowly; the temperature was increased to room temperature
and 4
m
L of acetic acid and 5
m
L of hydrogen peroxide (30%) were
Full experimental procedures and spectral data of all syn-
thetic compounds. Supplementary data associated with this ar-
ticle can be found, in the online version, at doi:10.1016/
j.tet.2012.04.010.
added; after portioning between water and ethyl acetate, the organic
phase was purified by silica gel chromatography using a gradientof n-
hexane and ethyl acetate obtaining 12 (10 mg, 66%) as a pale yellow
oil; Rf (Light petroleum ether/ethylacetate 3:7)¼0.50; IR (liquid
film) vmax 2922, 2829, 1718, 1682, 1630, 1602, 1555 cmꢁ1 1H NMR
;
¼6.87 (1H, d, J¼2.0 Hz, H-30), 6.68 (1H, dq, J¼15.2,
References and notes
(400 MHz, CDCl3):
d
6.1Hz, H-8), 6.54(1H,d, J¼2.0Hz,H-50), 5.94(1H,brd,J¼15.2Hz,H-7),
1. (a) Nicoletti, R.; Manzo, E.; Ciavatta, M. L. Int. J. Mol. Sci. 2009, 10, 1430e1444;
(b) Nicoletti, R.; Ciavatta, M. L.; Buommino, E.; Tufano, M. A. Int. J. Biomed.
Pharm. Sci. 2008, 1e23; (c) Ciavatta, M. L.; Lopez-Gresa, M. P.; Gavagnin, M.;
Nicoletti, R.; Manzo, E.; Mollo, E.; Guo, Y.-W.; Cimino, G. Tetrahedron 2008, 64,
5365e5369; (d) Nicoletti, R.; Lopez-Gresa, M. P.; Manzo, E.; Carella, A.; Ciavatta,
M. L. Mycopathologia 2007, 163, 295e301.
2. (a) Sassa, T.; Nukina, M.; Suzuki, Y. Agric. Biol. Chem. 1991, 55, 2415e2416; (b)
Wang, C.-Y.; Wang, B.-G.; Brauers, G.; Guan, H.-S.; Proksch, P.; Ebel, R. J. Nat.
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Org. Chem. 1989, 54, 5371e5374; (d) Proksa, B. Chem. Pap. 2010, 64, 696e714;
(e) Mizushina, Y.; Motoshima, H.; Yamaguchi, Y.; Takeuchi, T.; Hirano, K.;
Sugawara, F.; Yoshida, H. Mar. Drugs 2009, 7, 624e639; (f) Boukouvalas, J.;
Wang, J. X. Org. Lett. 2008, 10, 3397e3399.
3. Merlini, L.; Nasini, G.; Selva, A. Tetrahedron 1970, 26, 2739e2749.
4. (a) Stammati, A.; Nicoletti, R.; De Stefano, S.; Zampaglioni, F.; Zucco, F. Altern.
Lab. Anim. 2002, 30, 69e75; (b) Nicoletti, R.; Buommino, E.; De Filippis, A.;
Lopez-Greza, M. P.; Manzo, E.; Carella, A.; Petrazzuolo, M.; Tufano, M. A. World J.
Microbiol. Biotechnol. 2008, 24, 189e195.
5. Singh, S. B.; Jayasuriya, H.; Dewey, R.; Polishook, J. D.; Dombrowski, A. W.; Zink,
D. L.; Guan, Z.; Collado, J.; Platas, G.; Pelaez, F.; Felock, P. J.; Hazuda, D. J. J. Ind.
Microbiol. Biotechnol. 2003, 30, 721e731.
6. Singh, S. B.; Pelaez, F.; Hazuda, D. J.; Lingham, R. B. Drugs Future 2005, 30,
277e299.
7. Nozawa, K.; Nakajima, S.; Kawai, K. I.; Udagawa, S. I. Phytochemistry 1992, 31,
4177e4179.
8. Komai, S.; Hosoe, T.; Itabashi, T.; Nozawa, K.; Okada, K.; de Campos Takaki, G. M.;
Chikamori, M.; Yaguchi, T.;Fukushima, K.; Miyaji, M.;Kawai, K. Mycotoxins 2001, 54,
15e19.
9. (a) Li, C.-S.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565e3568; (b) Tyvorskii, V.
I.; Bobrov, D. N.; Kulinkovich, O. G.; Kimpe, N. D.; Tehrani, K. A. Tetrahedron
1998, 54, 2819e2826; (c) Zawacki, F. J.; Crimmins, M. T. Tetrahedron Lett. 1996,
37, 6499e6502; (d) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1990, 31, 5619e5620; (e) Koreeda, M.; Akagi, H. Tetrahedron Lett. 1980, 21,
1197e1200; (f) Miller, A. K.; Trauner, D. Synlett 2006, 2295e2316.
10. Kamino, T.; Kuramochi, K.; Kobayashi, S. Tetrahedron Lett. 2003, 44, 7349e7351.
11. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508e524.
12. Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K. S.; Faron, K. L.; Gilbertson, S.
R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277e279.
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5.61 (1H, s, H-6), 5.48 (1H, s, H-3), 3.86 (6H, s, OMe), 3.76 (3H, s, OMe),
1.91 (3H, d, J¼6.1 Hz, H3-9). 13C NMR (100 MHz, CDCl3):
¼190.3 (C,
d
C10), 185.4 (C, C4), 167.5 (C, C70), 163.0 (C, C40), 161.2 (C, C2), 158.8 (C,
C60), 137.8 (CH, C8), 134.3 (C, C20), 124.1 (CH, C7), 119.7 (C, C10), 106.1
(CH, C30),104.3 (CH, C3),101.4(CH, C50), 81.6(CH, C6), 62.6(C, C5), 56.0
(CH3, C90), 55.8 (CH3, C100), 52.9 (CH3, C80), 18.4 (CH3, C9); HRESIMS:
m/z calcd for C19H18O8Na: 397.0899; found: 397.0907.
4.2.13. Compound 13. Three different solutions were prepared:
Solution S1: Lithium diisopropylamide (5 mg) dissolved in
1.5 mL of anhydrous THF at ꢁ78 ꢀC.
Solution S2: Compound 3 (15 mg (0.042 mmol)) dissolved in
1 mL of anhydrous THF.
Solution S3: Trimethylborate (5
hydrous THF.
mL) dissolved in 0.5 mL of an-
S2 was added to S1 at ꢁ78 ꢀC; after stirring for 30 min, S3 was
added slowly; the temperature was increased to room tempera-
ture and 4 mL of acetic acid and 5 mL of hydrogen peroxide (30%)
were added; after portioning between water and ethyl acetate, the
organic phase was purified by silica gel chromatography using
a gradient of n-hexane and ethyl acetate obtaining 13 (10 mg, 65%)
as a pale yellow oil; Rf (Light petroleum ether/ethylacetate 3:7)¼
0.47; IR (liquid film) vmax 2918, 2840, 1716, 1685, 1628, 1604,
1555 cmꢁ1
;
1H NMR (400 MHz, CD2Cl2):
d
¼6.84 (1H, d, J¼2.0 Hz,
H-30), 6.58 (1H, d, J¼2.0 Hz, H-50), 5.53 (1H, s, H-6), 5.48 (1H, s, H-
3), 3.88 (3H, s, OMe), 3.84 (3H, s, OMe), 3.78 (3H, s, OMe), 2.08
(3H, s, H3-7). 13C NMR (100 MHz, CD2Cl2):
d¼190.5 (C, C8), 185.2
(C, C4), 168.2 (C, C7’), 167.4 (C, C2), 163.9 (C, C40), 159.8 (C, C60),
135.2 (CH, C20), 119.3 (C, C10), 106.8 (CH, C30), 105.1 (CH, C3), 101.3
(CH, C50), 81.9 (CH, C6), 62.9 (C, C5), 56.5 (CH3, C90), 56.3 (CH3,
C100), 53.4 (CH3, C80), 20.6 (CH3, C7); HRESIMS: m/z calcd for
C17H16O8Na: 371.0743; found: 371.0752.
14. Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 2553e2563.
15. (a) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 2572e2574; (b) Milstein,
D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992e4998.
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1191e1192; (b) See, E. G.; Dubois, E.; Beau, J. M. Tetrahedron Lett. 1990, 31,
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Unstersteller, E. Angew. Chem., Int. Ed. 1996, 35, 889e891.
Acknowledgements
Authors thank Mr. A. Esposito for NMR spectra, Mr. C. Iodice for
spectrophotometric measurements and Mr. M. Zampa for mass
spectra analysis.
18. Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Varma, R. S. J. Chem. Soc.,
Perkin Trans. 1 1985, 799e808.