Total syntheses and biological evaluation of 3-O-methylfunicone and its derivatives prepared by TMPZnCl·LiCl-mediated halogenation and carbonylative stille cross-coupling

Article abstract of DOI:10.1002/ejoc.201201256

The total syntheses of the natural product 3-O-methylfunicone (1), a member of the funicone class of compounds, and its derivatives is reported. The key reactions in the construction of the biaryl ketone core are a regioselective TMPZnCl·LiCl halogenation and a carbonylative Stille cross-coupling reaction. In addition, the inhibitory activities of the funicones against Y-family DNA polymerase κ (pol κ) and polymerase η (pol η) were determined. We found that 1 and 12 exhibit inhibitory activity against pol η and 1 also against pol κ. The total syntheses of the natural product 3-O-methylfunicone and its derivatives has been accomplished. The key reactions are TMPZnCl·LiCl-mediated iodination and a carbonylative Stille cross-coupling reaction. In addition, the inhibitory effect of the synthesized compounds have been evaluated against Y-family DNA polymerases κ and η by primer extension experiments. Copyright

Full text of DOI:10.1002/ejoc.201201256

FULL PAPER
DOI: 10.1002/ejoc.201201256
Total Syntheses and Biological Evaluation of 3-O-Methylfunicone and Its
Derivatives Prepared by TMPZnCl·LiCl-Mediated Halogenation and
Carbonylative Stille Cross-Coupling
Michael Ehrlich[a] and Thomas Carell*[a]
Keywords: Medicinal chemistry / Total synthesis / Natural products / Enzymes / Inhibitors / Carbonylation / Cross-coupling
The total syntheses of the natural product 3-O-methylfun-
coupling reaction. In addition, the inhibitory activities of the
icone (1), a member of the funicone class of compounds, and funicones against Y-family DNA polymerase κ (pol κ) and
its derivatives is reported. The key reactions in the construc-
tion of the biaryl ketone core are regioselective
TMPZnCl·LiCl halogenation and a carbonylative Stille cross-
polymerase η (pol η) were determined. We found that 1 and
12 exhibit inhibitory activity against pol η and 1 also against
pol κ.
a
Introduction
The aim of chemotherapeutic agents such as cisplatin is
the induction of apoptosis in tumor cells by impairment of
DNA replication.[1] The compounds typically cause DNA
lesions, which block not only replication but also transcrip-
tion processes. DNA lesion repair mechanisms are able to
remove these lesions. In particular, translesion DNA syn-
thesis (TLS), which establishes a lesion tolerance mecha-
nism, is a process that promotes the development of chem-
oresistance.[2] Application of chemotherapeutic agents in
combination with specific TLS polymerase inhibitors is
consequently a strategy that would reduce the risk of de-
veloping resistance and thereby improve the therapeutic
efficiency. Thus, selective inhibition of TLS DNA polymer-
ases is a topic of great interest.[3] Specific inhibitory activity
against Y-family polymerases, especially against polymer-
ase κ (pol κ), has been reported for the natural product 3-
O-methylfunicone (1, 3-OMF).[4] This metabolite of Peni-
cillium pinophilum also shows general fungitoxic activity[5]
Figure 1. Structures of members of the funicone class of com-
pounds.
and exhibits antiproliferative effects.[6] Compound 1 is a Results and Discussion
natural product and a member of the funicone class of com-
In a retrosynthetic analysis of the funicone class of com-
pounds (Figure 1), which includes several biologically active
natural products like funicone (2), which also exhibits fun-
gitoxicity.[7] Other members of the funicone class include
rapicone (3)[8] and deoxyfunicone.[9] The latter is an inhibi-
tor of the HIV integrase,[10] reduces plant growth,[11] and
shows antifungal activities.[12]
pounds, the core skeleton was reduced to an α-resorcylic
acid derivative connected to a γ-pyranone ring through a
ketone bridge. Such structures are efficiently assembled by
carbonylative Stille cross-coupling reactions, as described
recently in a publication that appeared in the course of this
work.[13] In addition, we envisioned a regioselective func-
tionalization of maltol derivatives to obtain the cross-cou-
pling nucleophile (Scheme 1).
We selected the pyranone ring structure of maltol deriva-
tives as convenient commercially available synthons. Start-
ing from ethylmaltol, the free hydroxy group was readily
methylated to introduce the methoxy group at the 3Ј-posi-
tion of the pyranone core, affording methylated ethylmaltol
[a] Center for Integrated Protein Science, Department of
Chemistry, Ludwig-Maximilians University Munich,
Butenandtstr. 5–13, 81377 Munich, Germany
Fax: +49-89-2180-77756
E-mail: Thomas.Carell@cup.uni-muenchen.de
Homepage: www.carellgroup.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201256.
Eur. J. Org. Chem. 2013, 77–83
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M. Ehrlich, T. Carell
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Scheme 1. Retrosynthetic analysis of 3-O-methylfunicone and its derivatives.
in an excellent yield of 97% (see Scheme 4). The challenging carbonyl group followed by subsequent deprotonation of
task in this route was the subsequent regioselective halo- the α position and zincation. Iodination of the regioselec-
genation at the position α to the carbonyl group (Table 1). tively formed zinc species afforded the regioselective func-
Various established iodination methods using, for example, tionalized compound in 54% yield (Table 1, entry 5,
NIS, I2/mCPBA, I2/CAN, or ICl only gave products mono- Scheme 4). In addition, in the synthesis of 3-OMF by using
and diiodinated at the secondary position of the ethyl tail this new iodination method, we achieved an excellent yield
(Table 1, entries 1–4). We therefore switched to a new halo- of 99% yield (Table 1, entry 6, Scheme 5).
genation method involving the use of TMPZnCl·LiCl re-
To evaluate the optimal reaction conditions for the carb-
cently reported by Knochel and co-workers.[14] Indeed, by onylative Stille cross-coupling reaction, first an appropriate
using this method we accomplished the desired regioselec- test system was established. Due to the high structural anal-
tive mono-iodination at the position α to the carbonyl ogy of the coupling product 4 to the final targets of the
group. The high regioselectivity can be attributed to the co- synthesis, iodide 5 as electrophile and stannane 6 as nucleo-
ordination of the hindered zinc amide to the oxygen of the phile were chosen. Iodide 5 was accessed by a regioselective
monoiodination of methyl 3,5-dimethoxybenzoate. The sec-
ond coupling partner stannane 6 was synthesized starting
from kojic acid according to a modified protocol of
Kamino and Kobayashi (Scheme 2).[15]
Table 1. Regioselective iodination at the position α to the carbonyl
group of maltol derivatives.
With both coupling partners in hand, several carb-
onylative cross-coupling conditions were screened to ident-
ify suitable reaction conditions to couple the sterically hin-
dered aryl halide 5 as electrophile with an electron-deficient
heterocycle 6 as nucleophile (Scheme 2).[16] We found the
best results involved the use of the Pd(OAc)2/X-Phos cata-
lyst system[17] with CsF as additive in dioxane. The CsF is
believed to facilitate the Stille cross-coupling reaction based
on the high fluorophilicity of tin.[18] By applying an internal
CO pressure of 5 bar at 95 °C, the yield increased to 46%
(53% based on recovered starting material) in this test sys-
Entry
R
Reagents
Solvent Yield [%]
1
2
3
4
5
6
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
NIS
MeCN
DMF
0
0
I2/mCPBA
I2/CAN
ICl
MeCN
DCM
0
0
TMPZnCl·LiCl/I2 THF
54
99
CHOTBSCH2CH3 TMPZnCl·LiCl/I2 THF
Scheme 2. Synthesis of the cross-coupling partners 5 and 6 and optimization of the carbonylative Stille cross-coupling conditions.
78 Eur. J. Org. Chem. 2013, 77–83
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Total Synthesis and Biological Evaluation of 3-O-Methylfunicones
Scheme 3. Total synthesis of rapicone (3).
tem and to 67% in the synthesis of 3-OMF (1; see tion of the pyranone core. To this end, ethylmaltol was cho-
Scheme 5). Our conditions have to be compared with those sen as a convenient synthon. The methylated ethylmaltol 9
reported during the preparation of this manuscript by was regioselectively iodinated as described above to provide
Manzo and Ciavatta.[13] In contrast to the 35% yield re- iodide 10 (Scheme 4), which was stannylated with hexa-
ported by using the known catalyst [Pd(allyl)Cl]2,[15] our methylditin and the Pd(OAc)2/X-Phos catalyst system in
catalyst system together with CsF afforded significantly combination with LiCl as additive to afford stannane 11 in
higher yields.
In summary, the TMPZnCl·LiCL-mediated regioselec- synthetic funicone derivative 12 in 64% yield (Scheme 4).
tive functionalization of maltol derivatives in combination We finally applied both developed methods to the syn-
good yield. Finally, the coupling of 11 with 5 provided the
with the carbonylative Stille cross-coupling reaction has led thesis of 3-OMF (1) (Scheme 5). Starting from maltol, the
to a new and concise synthetic route towards funicone de- methoxy group was introduced by methylation with iodo-
rivatives bearing a methoxy group at the 3Ј-position of the methane to afford 13 in 95% yield. Regioselective mono-
pyranone ring.
bromination at the allylic position was achieved by using
Next, we used the developed conditions for the synthesis NBS and AIBN to provide bromide 14. In the next step,
of rapicone (3) (Scheme 3). Starting from kojic acid, de- bromide 14 was substituted in aqueous dioxane to afford
functionalization according to the protocol of Ozturk et alcohol 15, which was subsequently oxidized with Dess–
al.[19] gave rise to allo maltol. To convert this synthon into Martin periodinane to yield aldehyde 16 in 98% yield. Un-
a tin–organyl, the hydroxy group was triflated to provide 7. fortunately, the intended olefination to introduce the (E)-
Subsequent direct stannylation with hexamethylditin af- propenyl tail to the pyranone core was not possible using
forded the cross-coupling partner 8. The carbonylative Stille standard olefination methods. We therefore established the
cross-coupling reaction with 5 using the Pd(OAc)2/X-Phos E double bond by addition of diethylzinc to introduce a
system yielded the final product rapicone (3) as expected hydroxy group followed by elimination. Diethylzinc was
based on the results of the model reaction in 50% yield.
added to 16 by using (2S)-3-exo-morpholinoisoborneol
To obtain further members of the funicone class for fu- [(–)-MIB] as additive.[20] The secondary alcohol 17 was TBS-
ture structure–activity relationship studies, we next synthe- protected to give 18. At this point, the protected pyranone
sized a derivative bearing a methoxy moiety at the 3Ј-posi- 18 was regioselectively iodinated at the α position with
Scheme 4. Total synthesis of 12.
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M. Ehrlich, T. Carell
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Scheme 5. Total synthesis of 3-O-methylfunicone (1).
TMPZn·LiCl in 99% yield. Subsequent direct stannylation compounds were determined by subsequent analysis of the
of iodide 19 with Sn2Me6, [Pd(PPh3)4], and LiCl as additive degree of primer elongation by denaturing polyacrylamide
provided stannane 20. Carbonylative Stille cross-coupling gel electrophoresis (PAGE). The data are shown in Fig-
yielded the precursor 21 of 3-OMF in 67% yield. Finally, ure 3.
deprotection and dehydration was accomplished in a one-
Determination of the inhibitory effect of 1 confirmed
pot reaction with pTSA to yield exclusively the E isomer of that the compound indeed inhibits both pol κ and pol η. To
the final target 3-OMF (1). The analytical data are consis- achieve full inhibition of the polymerase, a concentration of
tent with those previously reported for the isolated natural 5 mm of 1 was necessary. No inhibition of either polymerase
product.[4,21]
was detected at a concentration of 500 μm (Figure 3), which
To determine the inhibitory activity of the synthesized shows that the inhibitor possesses IC50 values in the mm
compounds 1, 3, and 12, primer extension assays with the range. This result is in sharp contrast to previously reported
purified TLS polymerases pol η and pol κ were per- IC50 values of 12.5 and 50.1 μm against pol κ and pol η,
formed.[22] The inhibitor assay is depicted in Figure 2 and respectively.[4] The discrepancy may result from the higher
is based on an in vitro primer extension reaction performed polymerase concentrations used in our primer extension as-
with one of the two TLS polymerases and a fluorescein- say. Rapicone (3) showed no inhibition of pol η and only
labeled primer (13mer). The primer was hybridized to a weak inhibition of pol κ at a concentration of 5 mm. An
template strand (30mer). The primer extension reaction was inhibitory effect of 12 was determined at a concentration
performed in the presence of different inhibitors at increas- of 1 mm against pol η, but no inhibition against pol κ was
ing concentrations. The inhibitory activities of the tested observed (see Figure S4 in Supporting Information).
80
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Total Synthesis and Biological Evaluation of 3-O-Methylfunicones
compounds 1 and 12 show inhibitory activity against pol η
and that 1 is also able to inhibit pol κ, although high con-
centrations were required. Thus, compounds 1 and 12 are
consequently good starting points for further structural op-
timization with the goal of inhibiting low fidelity polymer-
ases with high efficiency.
Experimental Section
General Methods: All nonaqueous reactions were performed under
dry nitrogen or argon in flame- or oven-dried glassware. Commer-
cial reagents from Sigma–Aldrich, ABCR, or Acros were used as
received unless otherwise indicated. Nonaqueous reagents were
transferred under nitrogen through a syringe or cannula. Solutions
were concentrated in vacuo on a Heidolph rotary evaporator. Chro-
matographic purification of products was performed by using flash
column chromatography on Merck Geduran Si 60 (40–63 μm) silica
gel (normal phase). TLC was performed on Merck 60 (silica gel
F254) plates. The developed chromatogram was visualized by fluo-
rescence quenching. 1H, 13C, 19F, and 119Sn NMR spectra were
recorded in deuteriated solvents with Bruker ARX 300, Varian
VXR400S, Varian Inova 400, Bruker AMX 600, and JEOL Eclipse
270 spectrometers and calibrated to the residual solvent peak. Mul-
tiplicities are abbreviated as follows: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. ESI and high-resolution ESI
mass spectra were obtained with a Thermo Finnigan LTQ FT-ICR
mass spectrometer. Acetonitrile for HPLC-ESI-MS analysis was
purchased from VWR, HPLC gradient grade. IR measurements
were performed with a Perkin–Elmer Spectrum BX FT-IR spec-
trometer with a diamond-ATR (Attenuated Total Reflection) setup.
Melting points were determined with a Büchi melting point B540
instrument.
Figure 2. Schematic depiction of the primer extension assay.
a) Primer extension reaction of a fluorescein-labeled 13mer primer
hybridized to a 30mer template strand by a TLS polymerase.
b) Primer extension reaction inhibited by addition of a TLS poly-
merase inhibitor. The degree of elongation of the fluorescein-lab-
eled primer (13nt) was analyzed by using denaturing PAGE. It
shows a new band for the fully elongated primer in lane a and the
non-elongated primer in lane b. The lane denoted neg is a negative
control without polymerase and lane Mk is a fragment length
marker.
General Procedure 1 (GP1). Carbonylative Stille Cross-Coupling Re-
action: A dry argon-flushed pressure reactor system (miniclave
steel, Büchi) was charged with catalyst, stannane, iodide, and, when
indicated, additives. This mixture was dissolved in degassed solvent
(5–10 mL). Subsequently the reactor was sealed and flushed twice
with CO. The reactor was then heated to the indicated reaction
temperature and stirred at an internally defined CO pressure. After
the indicated reaction time, the resulting reaction mixture was con-
centrated and purified by column chromatography on silica gel to
afford the cross-coupling product.
Figure 3. Primer extension assay of inhibitor 3-OMF (1) denatur-
ing PAGE-urea gel is shown. The 5Ј-fluorescein-labeled DNA
primer was visualized by the gel-imaging system. Extension by
pol η (1 μm, lanes 1–3) and pol κ (0.5 μm; lanes 6–9). Concentra-
tions of 3-OMF: 0 (positive control, lanes 1 and 6), 0.05 (lane 7),
0.5 (lanes 2 and 8), and 5 mm (lanes 3 and 9). The lanes denoted
neg. (lanes 4 and 10) are negative controls without polymerase.
Fragment length marker 13–30nt (Mk, lane 5).
Rapicone (3): The carbonylative Stille cross-coupling reaction was
carried out according to GP1. Two ground palladium(II) acetate/
X-Phos ChemDose® tablets (2 μmol loading per tablet, Pd/P = 1:2),
2-methyl-5-(trimethylstannyl)-4H-pyran-4-one
(8;
49 mg,
0.18 mmol, 1.0 equiv.), methyl 2-iodo-3,5-dimethoxybenzoate (5;
103 mg, 0.32 mmol, 1.8 equiv.), and dry caesium fluoride (60 mg,
0.37 mmol, 2.2 equiv.) were dissolved in degassed dioxane (5 mL).
The reactor was heated to 95 °C for 72 h with an internal carbon
monoxide pressure of 5 bar. The resulting reaction mixture was
concentrated and purified by column chromatography on silica gel
(iHex/EtOAc = 1:1) to afford rapicone (3; 30 mg, 50%) as a color-
less solid, m.p. 162–163 °C. Rf (iHex/EtOAc = 1:4) = 0.36. 1H
NMR (600 MHz, CDCl3): δ = 8.50 (s, 1 H), 7.08 (d, J = 2.2 Hz, 1
H), 6.63 (d, J = 2.2 Hz, 1 H), 6.12–6.11 (m, 1 H), 3.86 (s, 3 H),
3.78 (s, 3 H), 3.72 (s, 3 H), 2.27 (d, J = 0.7 Hz, 3 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 192.0, 175.7, 166.6, 165.2, 161.1,
161.0, 157.5, 130.0, 126.2, 126.1, 117.5, 105.4, 103.2, 56.2, 55.8,
Conclusions
A TMPZnCl·LiCl-mediated regioselective iodination of
maltol derivatives has been reported. Furthermore, a new
catalyst system for carbonylative Stille cross-coupling reac-
tions was identified that has enabled a more efficient syn-
thesis of funicone-related natural products. The protocol al-
lowed the preparation of 3-OMF (1) and its derivatives 3
and 12. In addition, the inhibitory activities of 1, 3, and 12
52.5, 19.5 ppm. IR: ν = 2956 (w), 1713 (m), 1678 (s), 1652 (s), 1602
˜
against pol κ and pol η were investigated; it was found that (s), 1436 (m), 1398 (m), 1320 (s), 1250 (s), 1217 (s), 1140 (s), 1060
Eur. J. Org. Chem. 2013, 77–83
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M. Ehrlich, T. Carell
FULL PAPER
(s), 894 (s), 791 (s), 657 (m) cm–1. HRMS (ESI+): calcd. for
(w), 2929 (w), 2856 (w), 2349 (w), 1828 (w), 1637 (s), 1562 (w),
1463 (w), 1444 (w), 1390 (w), 1344 (w), 1294 (w), 1239 (s), 1201
(w), 1101 (s), 1060 (m), 1004 (w), 970 (w), 939 (w), 898 (m), 849 (w),
835 (s), 800 (w), 776 (s), 722 (w), 673 (w) cm–1. HRMS (ESI+):
calcd. for [C15H26IO4Si]+ 425.0640; found 425.0644 [M + H]+.
[C17H17O7]+ 333.0969; found 333.0969 [M + H]+.
2-Ethyl-5-iodo-3-methoxy-4H-pyran-4-one (10): In a dry, argon-
flushed Schlenk flask equipped with a magnetic stirring bar and a
septum, 2-ethyl-3-methoxy-4H-pyran-4-one (9; 400 mg, 2.59 mmol,
1.0 equiv.) was dissolved in THF (6 mL) and TMPZnCl·LiCl
(2.6 mL, 2.85 mmol, 1.1 equiv.) was added dropwise at room tem-
perature and stirred for 30 min. Iodine (790 mg, 3.11 mmol,
1.2 equiv.) was added to this violet solution and the dark-brown
reaction mixture was stirred for 90 min and then concentrated. The
resulting residue was purified by column chromatography on silica
gel (iHex/EtOAc = 9:1) to afford 2-ethyl-5-iodo-3-methoxy-4H-
Methyl 2-(6-{1-[(tert-Butyldimethylsilyl)oxy]propyl}-5-methoxy-4-
oxo-4H-pyran-3-ylcarbonyl)-3,5-dimethoxybenzoate (21): The carb-
onylative Stille cross-coupling was carried out according to GP1.
Two ground palladium(II) acetate/X-Phos ChemDose® tablets
(2 μmol loading per tablet, Pd/P = 1:2), 2-{1-[(tert-butyldimethylsil-
yl)oxy]propyl}-3-methoxy-5-(trimethylstannyl)-4H-pyran-4-one
(20; 12.0 mg, 0.03 mmol, 1.0 equiv.), methyl 2-iodo-3,5-dimeth-
oxybenzoate (5; 13.0 mg, 0.04 mmol, 1.5 equiv.), and dry caesium
pyran-4-one (10; 390 mg, 54%) as a yellow oil. nd = 1.59. Rf (iHex/
1
EtOAc = 4:1) = 0.28. H NMR (300 MHz, CDCl3): δ = 8.07 (s, 1 fluoride (8.00 mg, 0.06 mmol, 2.2 equiv.) were dissolved in degassed
H), 3.87 (s, 3 H), 2.70 (q, J = 7.6 Hz, 2 H), 1.22 (t, J = 7.6 Hz, 3 dioxane (5 mL). The reactor was heated at 95 °C for 120 h with an
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.4, 163.6, 156.2,
internal carbon monoxide pressure of 5 bar. The resulting reaction
mixture was concentrated and purified by column chromatography
141.9, 92.2, 60.5, 21.9, 11.5 ppm. IR: ν = 2978 (w), 1650 (s), 1561
˜
(m), 1460 (m), 1442 (m), 1320 (m), 1233 (s), 1170 (s), 1133 (s), 1009 on silica gel (iHex/EtOAc = 5:1) to afford methyl 2-(6-{1-[(tert-
(s), 971 (s), 937 (m), 847 (s), 781 (m), 709 (m) cm–1. HRMS (EI+):
calcd. for [C8H9IO3]+· 279.9591; found 279.9591 [M]+·.
butyldimethylsilyl)oxy]propyl}-5-methoxy-4-oxo-4H-pyran-3-yl-
carbonyl)-3,5-dimethoxybenzoate (21; 9 mg, 67%) as a colorless
resin. Rf (iHex/EtOAc = 2:1) = 0.43. 1H NMR (300 MHz, CDCl3):
δ = 8.51 (s, 1 H), 7.07 (d, J = 2.3 Hz, 1 H), 6.63 (d, J = 2.2 Hz, 1
H), 4.88 (dd, J = 7.4, 6.4 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.77
(s, 3 H), 3.73 (s, 3 H), 1.75 (m, 2 H), 0.93 (t, J = 7.5 Hz, 3 H), 0.88
(s, 9 H), 0.09 (s, 3 H), –0.01 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 191.7, 172.4, 166.7, 161.1, 160.1, 159.8, 157.7, 145.6,
130.4, 127.1, 126.0, 105.7, 103.1, 68.2, 60.6, 56.2, 55.8, 52.5, 28.8,
Methyl 2-(6-Ethyl-5-methoxy-4-oxo-4H-pyran-3-ylcarbonyl)-3,5-di-
methoxybenzoate (12): The carbonylative Stille cross-coupling reac-
tion was carried out according to GP1. Five ground palladium(II)
acetate/X-Phos ChemDose® tablets (2 μmol loading per tablet, Pd/
P = 1:2), 2-ethyl-3-methoxy-5-(trimethylstannyl)-4H-pyran-4-one
(11; 122 mg, 0.38 mmol, 1.0 equiv.), methyl 2-iodo-3,5-dimeth-
oxybenzoate (5; 223 mg, 0.69 mmol, 1.8 equiv.), and dry caesium
fluoride (129 mg, 0.84 mmol, 2.2 equiv.) were dissolved in degassed
dioxane (8 mL). The reaction was heated at 95 °C for 120 h with an
internal carbon monoxide pressure of 5 bar. The resulting reaction
mixture was concentrated and purified by column chromatography
on silica gel (iHex/EtOAc = 3:1) to afford methyl 2-(6-ethyl-5-meth-
25.9, 18.3, 10.1, –4.8, –4.9 ppm. IR: ν = 2955 (w), 2918 (w), 2850
˜
(m), 1722 (w), 1681 (m), 1649 (s), 1603 (s), 1580 (w), 1566 (w), 1463
(w), 1443 (w), 1407 (w), 1330 (s), 1294 (w), 1249 (s), 1214 (s), 1144
(s), 1100 (m), 1063 (s), 1012 (m), 972 (w), 953 (m), 896 (m), 855
(w), 836 (s), 804 (w), 777 (s), 729 (w), 680 (w) cm–1. HRMS (ESI+):
calcd. for [C26H37O9Si]+ 521.2201; found 521.2206 [M + H]+.
oxy-4-oxo-4H-pyran-3-ylcarbonyl)-3,5-dimethoxybenzoate
(12;
93 mg, 64%) as a colorless solid, m.p. 148–152 °C. Rf (iHex/EtOAc
3-O-Methylfunicone (1): Methyl 2-(6-{1-[(tert-butyldimethylsil-
= 2:1) = 0.16. 1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1 H), 7.08 yl)oxy]propyl}-5-methoxy-4-oxo-4H-pyran-3-ylcarbonyl)-3,5-di-
(d, J = 2.2 Hz, 1 H), 6.64 (d, J = 2.2 Hz, 1 H), 3.86 (s, 3 H), 3.79
(s, 3 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 2.70 (q, J = 7.6 Hz, 2 H), 1.24
(t, J = 7.6 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 192.2,
172.3, 166.7, 162.8, 161.0, 159.8, 157.6, 146.34, 130.0, 126.8, 126.5,
methoxybenzoate (21; 35.0 mg, 67.0 μmol, 1.0 equiv.) and p-tolu-
enesulfonic acid (13 mg, 67.0 μmol, 1.0 equiv.) were dissolved in
toluene (4 mL) and heated at reflux for 12 h. Afterwards the sol-
vent was removed under reduced pressure and the crude product
was purified by column chromatography on silica (iHex/EtOAc =
105.4, 103.3, 60.7, 56.3, 55.8, 52.6, 22.0, 11.6 ppm. IR: ν = 2943
˜
(w), 1719 (m), 1677 (m), 1640 (s), 1601 (s), 1442 (m), 1328 (s), 1249 2:1) to afford 3-O-methylfunicone (1; 13 mg, 50%) as a colorless
(s), 1214 (s), 1142 (s), 1080 (s), 1034 (s), 953 (m), 850 (s), 788 (m), solid, m.p. 185–187 °C. Rf (iHex/EtOAc = 1:1) = 0.34. 1H NMR
727 (m) cm–1. HRMS (ESI+): calcd. for [C19H21O8]+ 377.1231;
found 377.1229 [M + H]+.
(600 MHz, CDCl3): δ = 8.48 (s, 1 H), 7.08 (d, J = 2.2 Hz, 1 H),
6.64 (d, J = 2.3 Hz, 1 H), 6.61 (dq, J = 15.8, 6.7 Hz, 1 H), 6.55
(dq, J = 15.8, 1.5 Hz, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.78 (s, 3
H), 3.73 (s, 3 H), 1.97 (dd, J = 6.7, 1.5 Hz, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 192.1, 172.7, 166.7, 161.0, 159.3, 157.6,
154.8, 144.4, 135.1, 130.0, 126.6, 126.4, 118.7, 105.5, 103.3, 60.8,
2-{1-[(tert-Butyldimethylsilyl)oxy]propyl}-5-iodo-3-methoxy-4H-pyr-
an-4-one (19): In a dry, argon-flushed Schlenk flask equipped with
a magnetic stirring bar and a septum, 2-{1-[(tert-butyldimethylsil-
yl)oxy]propyl}-3-methoxy-4H-pyran-4-one
(18;
99.0 mg,
56.3, 55.8, 52.6, 19.2 ppm. IR: ν = 2920 (m), 2850 (w), 2357 (m),
˜
0.33 mmol, 1.0 equiv.) was dissolved in THF (5 mL) and
TMPZnCl·LiCl (0.44 mL, 0.49 mmol, 1.5 equiv.) was added drop-
wise at room temperature and stirred for 30 min. Iodine (126 mg,
0.50 mmol, 1.5 equiv.) was added to this solution and the dark-
brown reaction mixture was stirred for 90 min and then concen-
trated. The resulting residue was purified by column chromatog-
raphy on silica gel (iHex/EtOAc = 3:1) to afford 2-{1-[(tert-butyldi-
2339 (w), 1717 (m), 1675 (w), 1635 (m), 1602 (m), 1558 (m), 1456
(m), 1330 (m), 1295 (m), 1247 (m), 1213 (s), 1140 (s), 1062 (s),
953 (m), 857 (m), 788 (m), 668 (m) cm–1. HRMS (ESI+): calcd. for
[C20H21O8]+ 389.1231; found 389.1233 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic and biochemical experimental details, NMR spectra
and primer extension assays for 3 and 12.
methylsilyl)oxy]propyl}-5-iodo-3-methoxy-4H-pyran-4-one
(19;
139 mg, 99%) as a colorless oil. nD = 1.60. Rf (iHex/EtOAc = 9:1)
1
= 0.60. H NMR (600 MHz, CDCl3): δ = 8.14 (s, 1 H), 4.92 (dd,
Acknowledgments
J = 7.4, 6.5 Hz, 1 H), 3.92 (s, 3 H), 1.75 (m, 2 H), 0.91 (t, J =
7.4 Hz, 3 H), 0.87 (s, 9 H), 0.09 (s, 3 H), –0.02 (s, 3 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 171.6, 161.0, 156.5, 141.0, 92.1, 68.1,
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (SFB749 and CA275/8-4). We thank Nina Wichlein for syn-
60.5, 29.0, 25.8, 18.3, 10.1, –4.8, –4.9 ppm. IR: ν = 3066 (w), 2955
˜
82
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Eur. J. Org. Chem. 2013, 77–83

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Received: September 20, 2012
Published Online: November 19, 2012
Eur. J. Org. Chem. 2013, 77–83
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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