Synthesis of isocoumarin compounds, 8-Hydroxy-6-Methoxy-3-Pentyl-1H-Isochromen-1-One and Fusariumin analog using palladium-Catalyzed carbonylation trapping with O-enolate

Article abstract of DOI:10.3987/COM-17-13746

Concise synthesis of 6,8-dialkoxyisocoumarin framework was achieved using Pd-catalyzed carbonylation trapping with O-enolate. This methodology was applied to the synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one isolated from Tessmannia densiflora and fusariumin analog.

Full text of DOI:10.3987/COM-17-13746

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HETEROCYCLES, Vol. 94, No. 8, 2017
HETEROCYCLES, Vol. 94, No. 8, 2017, pp. 1542 - 1553. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 17th May, 2017, Accepted, 14th June, 2017, Published online, 19th June, 2017
DOI: 10.3987/COM-17-13746
SYNTHESIS
8-HYDROXY-6-METHOXY-3-PENTYL-1H-ISOCHROMEN-1-ONE AND
FUSARIUMIN ANALOG USING PALLADIUM-CATALYZED
OF
ISOCOUMARIN
COMPOUNDS,
CARBONYLATION TRAPPING WITH O-ENOLATE
Masaki Asai,a Yasunao Hattori,b and Hidefumi Makabea*
aGraduate School of Science and Technology, Department of Agriculture,
Division of Food Science and Biotechnology, Shinshu University, 8304
Minami-minowa, Kami-ina, Nagano 399-4598, Japan
bCenter for Instrumental Analysis, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8412, Japan
*E-mail: makabeh@shinshu-u.ac.jp
Abstract – Concise synthesis of 6,8-dialkoxyisocoumarin framework was
achieved using Pd-catalyzed carbonylation trapping with O-enolate. This
methodology
was
applied
to
the
synthesis
of
8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one isolated from Tessmannia
densiflora and fusariumin analog.
INTRODUCTION
Isocoumarin compounds are natural products which are isolated from wide range of natural sources such
as microorganism, plants and insects and so on. These compounds have significant biological activities
such as cytotoxic, antifungal, antiallergic and antimararial activities.1 Most of natural isocoumarin
compounds have 3-alkyl side chain and 6,8-dioxygenated functional groups. In 1962, Huneck isolated
8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) from dried powder of Lecidea confluens after
treatment with CH2N2.2 This compound was also isolated by Nkunya and co-workers from Tessmannia
densiflora in 2009.3 Compound 1 showed insecticidal activity against mosquito larvae. In 2011, Laatsch
and co-workers isolated fusariumin (2) which showed significant growth inhibitory activity against the
brine shrimp from Fusarium sp.4 As to the examples of the synthesis of isocoumarin compounds, heating
of homophthalic acid5 and preparation from homophthalic anhydride6 were reported. These methods often
suffered from low yield. In 2009, Willis and co-workers synthesized isocoumarin compound thunberginol
A using Pd-catalyzed carbonylation-intramolecular O-enolate acylation.7 We also reported concise

HETEROCYCLES, Vol. 94, No. 8, 2017
1543
synthesis of legioliulin using this strategy and Heck reaction.8 Here, we wish to report the synthesis of
8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) and 6,8-dimethylfusariumin (3), the analog of
fusariumin (2), using Pd-catalyzed carbonylation trapping with O-enolate as a key step (Figure 1).
OH
8
O
OH
O
OMe O
1
O 2
O
OH
O
OH
7
1'
6
3
MeO
HO
MeO
8'
5
4
8-hydroxy-6-methoxy 3-pentyl-1H-isochromen-1-one (1)
fusariumin (2)
6,8-dimethylfusariumin (3)
Figure 1. Structure of isocoumarins
RESULTS AND DISCUSSION
The synthetic strategy is shown in Scheme 1. As to the synthetic strategy of 1, isocoumarin ring would be
constructed using Pd-catalyzed carbonylation trapping with O-enolate 9-13 from iodoketone 5. Iodoketone
5 would be synthesized ortho iodination followed by oxidation of alcohol 6. Compound 6 would be
prepared from aldehyde 714 and pentylmagnesium bromide. Aldehyde 7 would be synthesized from
commercially available 3,5-dimethoxyphenylacetic acid. As to the synthetic strategy of 3, isocoumarin
ring would be constructed from iodoketone 8. Iodoketone 8 would be prepared ortho iodination followed
by oxidation of alcohol 9. Alcohol 9 would be synthesized from aldehyde 7 and organolithium compound
10. Compound 10 would be prepared from 5-hexyn-1-ol.
OH
O
OMe O
O
O
OH
MeO
MeO
8-hydroxy-6-methoxy 3-pentyl-1H-isochromen-1-one (1)
6,8-dimethylfusariumin (3)
Pd-catalyzed carabonylation
Pd-catalyzed carabonylation
trapping with O-enolate
trapping with O-enolate
OMe O
OMe
OMe
I
O
O
OTBDPS
MeO
MeO
4
8
OMe
I
O
OH
OTBDPS
MeO
MeO
OMe
7
5
9
OMe
OH
OTBDPS
+
Li
CHO
MeO
MeO
10
6
OMe
OMe
HO
BrMg
+
CHO
MeO
CO2H
MeO
3,5-dimethoxyphenylacetic acid
7
5-hexyn-1-ol
Scheme 1. Synthetic strategy of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) and
6,8-dimethylfusariumin (3)

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HETEROCYCLES, Vol. 94, No. 8, 2017
Scheme 2 shows the synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) (Scheme 2).2,3
Grignard reaction of pentylmagnesium bromide with aldehyde 714 afforded alcohol 6. Iodination at C-2
position of the benzene ring using NIS in the presence of p-TsOH gave 11. Oxidation of the secondary
hydroxy group of 11 using Dess-Martin periodinane afforded 5. Pd-Catalyzed carbonylation trapping
with O-enolate of 5 using Cl2Pd(PPh3)2 as a catalyst and AcONa as a base under the 1 atm of CO
atmosphere at 80 oC furnished isocoumarin 4 in 72% yield.6 When this reaction was performed at 50 oC,
o
the yield was almost same as that of 80 C. By comparison with mono-oxygenated isocoumarin, which
was synthesized by us before,8 the chemical yield was much higher. The reason might be that the
additional methoxy group enhanced the reactivity of oxidative addition of the Pd catalyst due to electron
donating effect. Finally, selective deprotection of the C-8 methyl group due to the coordination of BCl3 at
the ortho carbonyl group gave 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) in good yield.15
The lactone carbonyl absorption in the IR spectrum showed 1672 cm-1 by forming hydrogen bond with
C-8 hydroxy group.16 The spectral data of synthetic 1 were in good agreement with those of the reported
o
values.3 As to the melting point value, our synthetic sample (57-58 C) was consistent with that of the
o
reported value (57-57.5 C) by Huneck et al.,2 although Nkunya and co-workers reported much higher
value (79-80 oC).3
OMe
OMe
OMe
OH
THF
78%
NIS, p-TsOH, CCl4
BrMg
+
CHO
OH
MeO
MeO
MeO
MeO
MeO
80%
pentylmagnesium bromide
7
6
OMe
I
Cl2Pd(PPh3)2, CO (1 atm),
AcONa, DMF, 80 oC
I
Dess-Martin periodinane, CH2Cl2
74%
O
72%
11
5
OMe O
C
OMe O
O
OH
O
PdI
OH
BCl3, CH2Cl2
87%
O
MeO
MeO
4
8-hydroxy-6-methoxy 3-pentyl-1H-isochromen-1-one (1)
Scheme 2. Synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1) isolated from
Tessmannia densiflora
Next, we began to synthesize 6,8-dimethylfusariumin (3) (Scheme 3). Scheme 3 shows the preparation of
cyclization precursor 8 of the 6,8-dimethylfusariumin (3). Protection of the hydroxy group as a THP ether
of 5-hexyn-1-ol afforded 12.17 Reaction of lithium acetylide of 12 with (S)-2-methyloxirane in the
presence of BF3·Et2O gave alcohol 13.18 Reduction of the triple bond to E-double bond using LiAlH4
under reflux in THF afforded 14. Protection of the secondary hydroxy group of 14 with TBDPSCl in the
presence of imidazole afforded 15. Selective deprotection of the THP group of 15 using PPTS gave 16

HETEROCYCLES, Vol. 94, No. 8, 2017
1545
followed by iodination using I2 and PPh3 in the presence of imidazole furnished primary iodide 17 in good
yield. Lithium-halogen exchange of 17 using t-BuLi followed by reaction with aldehyde 7 afforded 9.
Regioselective iodination of 9 using NIS in the presence of p-TsOH gave 18. Oxidation of the secondary
hydroxy group using Dess-Martin periodinane afforded cyclization precursor 8.
.
n-BuLi, BF3 Et2O
HO
DHP, PPTS
THPO
OH
THPO
OH
O
CH2Cl2
94%
5-hexyn-1-ol
THF, −78 oC
13
12
81%
OTBDPS
LiAlH4
TBDPSCl, ImH
PPTS
THPO
THPO
THF, reflux
77%
DMF
98%
MeOH
90%
15
14
OTBDPS
OTBDPS
t-BuLi, Et2O, −78 oC
I2, PPh3, ImH
I
HO
toluene
93%
OMe
17
16
CHO
MeO
7
41%
OMe
OMe
I
OH
OTBDPS
NIS, p-TsOH
OH
OTBDPS
MeO
CCl4
57% (71% brsm)
MeO
9
18
OMe
I
Dess-Martin periodinane
O
OTBDPS
CH2Cl2
89%
MeO
8
Scheme 3. Synthesis of cyclization precursor 8 of 6,8-dimethylfusariumin (3)
The cyclization precursor 8 was in hand, we investigated Pd-catalyzed carbonylation trapping with
O-enolate to construct isocoumarin ring (Table 1). As shown in Table 1, the reaction temperature was
important. We found that 50 oC was optimized reaction temperature.
Table 1. Pd-catalyzed carbonylation trapping with O-enolate 8
OMe
OMe O
10 mol% of Cl2Pd(PPh3)2
CO (1 atm), AcONa (2.0 eq)
DMF
I
O
OTBDPS
O
OTBDPS
MeO
MeO
Table 1
8
19
Entry
Temp (oC)
Time (h)
96
Yield of 19 (%)
50
89
1
2
80
24
3
76
55
100
3

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HETEROCYCLES, Vol. 94, No. 8, 2017
As whole carbon skeleton of 3 was constructed, we deprotected the TBDPS group of 19 using TBAF to
afford 6,8-dimethylfusariumin (3) in good yield. As to the absolute configuration at C-8’ position of
natural fusariumin (2), Laatsch and co-workers determined to be S by comparison of the positive sign of
the optical rotation of the known compounds, (+)-(S)-3-hydroxybutyl benzoate and
(+)-(S)-dichlorodiaportin, respectively. However, because the specific rotation value of natural 2 is very
small {[α]D + 1.01 (c 0.2, MeOH)},4 it is difficult to determine the absolute configuration by specific
rotation. The specific rotation value of our synthetic 6,8-dimethylfusariumin (3) showed −6.60 (c 2.05,
CHCl3). If 6,8-dimethylfusariumin (3) could be prepared from natural fusariumin (2), the absolute
configuration at C-8’ position would be determined definitely by comparison with our synthetic 3.
OMe O
OMe O
O
OTBDPS
O
OH
TBAF, THF
85%
MeO
MeO
19
6,8-dimethylfusariumin (3)
Scheme 4. Synthesis of 6,8-dimethylfusariumin (3)
CONCLUSION
Concise synthesis of 6,8-dialkoxyisocoumarin frame work was achieved using Pd-catalyzed
carbonylation trapping with O-enolate. This methodology was applied to the synthesis of natural products,
8-hydroxy-6-methyl-3-pentyl-1H-isochromen-1-one (1) isolated from Tessmannia densiflora and
6,8-dimethylfurariumin (3) which is an analog of furariumin (2).
EXPERIMENTAL
1
13
General. H and C NMR spectra were measured with a Bruker DRX 500 FT-NMR spectrometer in
CDCl3 at 500 and 125 MHz, respectively. Chemical shifts were relative to tetramethylsilane as an internal
standard. The coupling constants were given in Hz. Mass spectra were obtained on JEOL GC-mate II and
Shimadzu LCMS-IT-TOF mass spectrometer. IR spectra were recorded with JASCO FT-IR 480 Plus
infrared spectrometer. Optical rotations were determined with a JASCO DIP-1000 polarimeter.
1-(3,5-Dimethoxyphenyl)heptan-2-ol (6). To a suspension of Mg (122 mg, 5.0 mmol) was added small
amount of I2 and one drop of 1,2-dibromoethane in THF (1.0 mL) under an argon atmosphere. To the
mixture prepared as described above, 1-bromoheptane (516 µL, 4.17 mmol) was added. The mixture was
diluted with THF (7.0 mL) and aldehyde 7 (250 mg, 1.39 mmol) was added. After being stirred for 30
o
min at 0 C, the reaction was quenched with 1M HCl (5.0 mL). The mixture was extracted with EtOAc
(5.0 mL x 3), and the organic layer was washed with water, brine, dried over Na2SO4, filtered, and

HETEROCYCLES, Vol. 94, No. 8, 2017
1547
concentrated. The residue was purified with silica gel column chromatography (hexane:EtOAc = 5:1) to
afford 6 (274 mg, 78%) as a colorless oil; IR (film ) νmax cm-1: 3423, 2998, 2931, 2858, 1596, 1463, 1429,
1343, 1322, 1294, 1206, 1150, 1069, 935, 829, 701; 1H NMR (500 MHz, CDCl3) δ: 6.37 (2H, d, J = 2.0
Hz), 6.34 (1H, d, J = 2.0 Hz), 3.82-3.74 (1H, m), 3.79 (3H, s), 3.78 (3H, s), 2.77 (1H, dd, J = 13.5, 4.0
Hz), 2.57 (1H, dd, J = 13.5, 9.0 Hz), 1.63 (1H, br., -OH), 1.54-1.42 (3H, m), 1.40-1.25 (5H, m), 0.90 (3H,
t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ: 160.8, 141.0, 107.3, 98.3, 72.5, 55.2, 44.4, 36.8, 31.9, 25.4,
22.6, 14.0 ppm. HRMS-EI [M]+: Calcd for C15H24O3 252.1726, Found 252.1721.
1-(2-Iodo-3,5-dimethoxyphenyl)heptan-2-ol (11). To a solution of 6 (240 mg, 0.95 mmol) in CCl4 was
added NIS (214 mg, 0.95 mmol) and small amount of p-TsOH·H2O. After the resulting mixture had been
stirred for 1 h, the reaction was quenched with saturated aqueous NaHCO3 (5 mL) and aqueous Na2S2O3
(5 mL). The mixture was extracted with EtOAc (20 mL x 2), and the organic layer was washed with water
and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with silica gel column
chromatography (hexane : EtOAc = 5:1) to give 11 (289 mg, 80%) as a colorless solid. Mp 46-47 oC; IR
(KBr) νmax cm-1: 3415, 3001, 2953, 2929, 2856, 1580, 1454, 1413, 1375, 1324, 1280, 1205, 1162, 1081,
1
1010, 939, 828, 720 cm-1; H NMR (500 MHz, CDCl3) δ: 6.49 (1H, d, J = 2.5 Hz), 6.33 (1H, d, J = 2.5
Hz), 3.93-3.90 (1H, m), 3.88 (3H, s), 3.80 (3H, s), 3.06 (1H, dd, J = 13.5, 4.0 Hz), 2.77 (1H, dd, J = 13.5,
9.0 Hz), 1.60-1.51 (4H, m), 1.43-1.25 (5H, m), 0.90 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ:
160.7, 159.0, 143.6, 107.8, 97.1, 82.2, 71.2, 56.4, 55.5, 48.7, 37.0, 31.8, 25.3, 22.6, 14.1 ppm. HRMS-EI:
m/z [M]+: Calcd for C15H23IO3; 378.0692, Found 378.0695.
1-(2-Iodo-3,5-dimethoxyphenyl)heptan-2-one (5). To a solution of 11 (245 mg, 0.65 mmol) in CH2Cl2
(2.0 mL) was added Dess-Martin periodinane (331 mg, 0.78 mmol) at 0 oC. After being stirred for 30 min
at room temperature, the reaction was quenched with saturated aqueous NaHCO3 (5 mL) and aqueous
Na2S2O3 (5 mL) at 0 oC and the mixture had been stirred until the organic layer was cleared. The mixture
was extracted with EtOAc (20 mL x 2), and the organic layer was washed with water and brine, dried
over Na2SO4, filtered, and concentrated. The residue was purified with silica gel column chromatography
(hexane : EtOAc = 7:1) to give 5 (182 mg, 74%) as a colorless oil. IR (film) νmax cm-1: 3002, 2955, 2932,
1
2870, 1716, 1581, 1454, 1434, 1418, 1334, 1281, 1205, 1163, 1080, 1011, 932, 830, 730 cm-1; H NMR
(500 MHz, CDCl3) δ: 6.43 (1H, d, J = 2.5 Hz), 6.34 (1H, d, J = 2.5 Hz), 3.94 (2H, s), 3.87 (3H, s), 3.81
(3H, s), 2.49 (2H, t, J = 7.0 Hz), 1.64-1.58 (2H, m), 1.34-1.23 (4H, m), 0.88 (3H, t, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3) δ: 207.4, 160.9, 159.1, 140.3, 107.6, 97.5, 82.6, 56.4, 55.4, 55.0, 42.6, 31.3, 23.4, 22.4,
13.9 ppm. HRMS-EI: m/z [M]+: Calcd for C15H21IO3; 376.0536, Found 376.0532.

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HETEROCYCLES, Vol. 94, No. 8, 2017
6,8-Dimethoxy-3-pentylisocoumarin (4). To a solution of 5 (125 mg, 0.33 mmol) in DMF (7.0 mL) was
added AcONa (54 mg, 0.66 mmol) and Cl2Pd(PPh3)2 (23 mg, 33 µmol) under 1 atm of CO atmosphere.
o
After the resulting mixture had been stirred for 20 h at 80 C, the reaction was quenched with saturated
aqueous NH4Cl at room temperature. The mixture was extracted with EtOAc (20 mL x 3) and the organic
layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was
purified with preparative TLC (hexane : EtOAc = 3:1) to afford 4 (65 mg, 72%) as a colorless solid. Mp
83-84 oC, IR (KBr) νmax cm-1: 3088, 2931, 2859, 1725, 1664, 1599, 1570, 1511, 1456, 1426, 1374, 1243,
1
1214, 1164, 1120, 1102, 1057, 996, 837 cm-1; H NMR (500 MHz, CDCl3) δ: 6.42 (1H, d, J = 2.0 Hz),
6.32 (1H, d, J = 2.0 Hz), 6.09 (1H, s), 3.96 (3H, s), 3.89 (3H, s), 2.46 (2H, t, J = 7.5 Hz), 1.69-1.65 (2H,
13
m), 1.35-1.29 (4H, m), 0.90 (3H, t, J = 7.0 Hz); C NMR (125 MHz, CDCl3) δ: 165.2, 163.1, 159.7,
159.1, 142.4, 102.9, 99.4, 98.1, 56.2, 55.5, 33.2, 31.1, 26.4, 22.3, 13.9 ppm. These NMR spectra were
identified with those of the reported values.6
8-Hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one (1). To a solution of 4 (60 mg, 0.22 mmol) in
CH2Cl2 (4.4 mL) was added BCl3 (1.0 M in heptane, 330 µL, 0.33 mmol) at 0 oC. After being stirred for
20 h at 0 oC, the reaction was quenched with saturated aqueous NaHCO3. The mixture was extracted with
EtOAc (20 mL x 2), and the organic layer was washed with water, brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified with preparative TLC (hexane : EtOAc = 4:1) to afford 1 (50 mg,
o
o
o
87%) as a colorless solid. Mp 56-57 C (lit, 57-57.5 C,2 79-80 C3). IR (KBr) νmax cm-1: 3079, 3001,
2945, 2867, 1672, 1637, 1568, 1511, 1454, 1391, 1346, 1294, 1249, 1207, 1196, 1159, 1077, 953, 880,
761 cm-1; 1H NMR (500 MHz, CDCl3) δ: 11.12 (1H, s), 6.44 (1H, d, J = 2.0 Hz), 6.30 (1H, d, J = 2.0 Hz),
6.17 (1H, s), 3.86 (3H, s), 2.48 (2H, t, J = 7.0 Hz), 1.71-1.65 (2H, m), 1.36-1.31 (4H, m), 0.91 (3H, t, J =
13
6.5 Hz); C NMR (125 MHz, CDCl3) δ: 166.7, 166.4, 163.5, 158.0, 139.4, 103.8, 100.9, 100.1, 99.9,
55.6, 33.2, 31.1, 26.4, 22.3, 13.9 ppm. HRMS-EI: m/z [M]+: Calcd for C15H18O4; 262.1205, Found
262.1207. These NMR spectra were identified with those of the reported values.3
(S)-9-[(Tetrahydro-2H-pyran-2-yl)oxy]-4-nonyn-2-ol (13). To a solution of 12 (2.0 g, 11.0 mmol) in
o
THF (44 mL) was added n-BuLi (2.5 mol/L in hexane, 2.9 mL, 7.3 mmol) at −78 C. Then, BF3·OEt2
(0.92 mL, 7.3 mmol) was added to the solution. After being stirred for 10 min, (S)-2-methyloxirane (0.51
mL, 7.3 mmol) was added. After being stirred for 1 h, the reaction was quenched with saturated aqueous
NaHCO3. The mixture was extracted with EtOAc (100 mL x 3), and the organic layer was washed with
water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with silica gel
column chromatography (hexane : EtOAc = 3:1) to afford 13 (1.42 g, 81%) as a colorless oil. IR (film)

HETEROCYCLES, Vol. 94, No. 8, 2017
1549
νmax cm-1: 3420, 2941, 2869, 2658, 1454, 1441, 1372, 1352, 1323, 1284, 1261, 1201, 1137, 1119, 1076,
1
1034, 941, 905, 868, 814; H NMR (500 MHz, CDCl3) δ: 4.59-4.57 (1H, m), 3.93-3.84 (2H, m),
3.79-3.74 (1H, m), 3.52-3.48 (1H, m), 3.43-3.39 (1H, m), 2.42-2.21 (4H, m), 2.08 (1H, br., -OH),
1.85-1.51 (10H, m), 1.24 (3H, d, J = 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ: 98.9, 82.9, 76.4, 67.0, 66.5,
62.3, 30.7, 29.4, 28.9, 25.8, 25.5, 22.2, 19.6, 18.6 ppm. HRMS-EI: m/z [M]+: Calcd for C14H24O3;
240.1726, Found: 240.1721.
(2S,4E)-9-[(Tetrahydro-2H-pyran-2-yl)oxy]-4-nonen-2-ol (14). To a suspension of LiAlH4 (420 mg,
o
11.1 mmol) in THF (74 mL) was added 13 (888 mg, 3.70 mmol) in THF (10 mL) at 0 C. The mixture
was then heated to reflux and stirred for 36 h. After the reaction had been completed, the mixture was
cooled to 0 oC and H2O (20 mL) in THF (20 mL) was added. After being stirred for 30 min, the mixture
was filtered through a pad of Celite with EtOAc. The filtrate was concentrated and the residue was
purified with silica gel column chromatography (hexane : EtOAc = 3:1) to afford 14 (689 mg, 77%) as a
colorless oil. IR (film) νmax cm-1: 3419, 2939, 2869, 1454, 1441, 1370, 1353, 1323, 1261, 1200, 1137,
1
1119, 1077, 1034, 971, 942, 905, 869, 814; H NMR (500 MHz, CDCl3) δ: 5.57-5.51(1H, m), 5.45-5.39
(1H, m), 4.58-4.57 (1H, m), 3.89-3.84 (1H, m), 3.81-3.72 (2H, m), 3.51-3.48 (1H, m), 3.42-3.37 (1H, m),
2.25-2.17 (1H, m), 2.12-2.04 (3H, m), 1.74-1.42 (11H, m), 1.18 (3H, d, J = 6.0 Hz); 13C NMR (125 MHz,
CDCl3) δ: 134.2, 126.1. 98.8, 67.4, 67.1, 62.3, 42.5, 32.4, 30.7, 29.2, 26.1, 25.4, 22.6, 19.6 ppm.
HRMS-EI: m/z [M]+: Calcd for C14H26O3; 242.1882, Found: 242.1879.
(2S,4E)-2-tert-Butyldiphenylsilyloxy-8-tetrahydropyranyloxynon-4-ene (15). To a solution of 14 (647
mg, 2.67 mmol) in DMF (30 mL) was added imidazole (273 mg, 4.0 mmol) and TBDPSCl (0.77 mL,
2.94 mmol) at 0 oC. After the resulting mixture had been stirred for 39 h, the reaction mixture was diluted
with Et2O. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified with silica gel column chromatography (hexane : EtOAc = 10:1) to afford 15
(1.26 g, 98%) as a colorless oil. IR (film) νmax cm-1: 3071, 3048, 2932, 2857, 1590, 1472, 1428, 1376,
1
1353, 1323, 1260, 1200, 1112, 1078, 1035, 1005, 971, 905, 869, 822; H NMR (500 MHz, CDCl3) δ:
7.68-7.67 (4H, m), 7.43-7.35 (6H, m), 5.38-5.29 (2H, m), 4.58-4.56 (1H, m), 3.88-3.81 (2H, m),
3.74-3.70 (1H, m), 3.50-3.47 (1H, m), 3.39-3.34 (1H, m), 2.19-2.06 (2H, m), 2.00-1.96 (2H, m),
1.85-1.79 (1H, m), 1.73-1.68 (1H, m), 1.62-1.50 (6H, m), 1.44-1.36 (2H, m), 1.09 (9H, s), 1.04 (3H, d, J
13
= 6.0 Hz); C NMR (125 MHz, CDCl3) δ: 135.9, 134.8, 134.6, 132.6, 129.5, 129.4, 127.4, 126.7. 98.8,
69.6, 67.4, 62.3, 42.7, 32.4, 30.7, 29.2, 27.0, 26.1, 25.5, 22.9, 19.7, 19.3 ppm. HRMS-EI: m/z [M]+: Calcd
for C30H44O3Si; 480.3060, Found: 480.3058.

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HETEROCYCLES, Vol. 94, No. 8, 2017
(5E,8S)-8-tert-Butyldiphenylsilyloxynon-5-en-1-ol (16). To a solution of 15 (1.25 g, 2.60 mmol) in
MeOH (26 mL) was added PPTS (65 mg, 0.26 mmol). After the resulting mixture had been stirred for 44
h, the reaction was quenched with saturated aqueous NaHCO3 (10 mL). The mixture was extracted with
EtOAc (50 mL x 2), and the combined organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated. The residue was purified with silica gel column chromatography (hexane : EtOAc =
5:1) to furnish 16 (929 mg, 90%) as a colorless oil. [α]19 −21.1 (c 1.03, CHCl3); IR (film) νmax cm-1:
D
3337, 3071, 3048, 2930, 2857, 1590, 1487, 1462, 1390, 1362, 1131, 1111, 1076, 1006, 971, 939, 892, 869,
822; 1H NMR (500 MHz, CDCl3) δ: 7.69-7.67 (4H, m), 7.43-7.35 (6H, m), 5.35-5.33 (2H, m), 3.86-3.82
(1H, m), 3.62 (2H, t, J = 6.5 Hz), 2.19-2.07 (2H, m), 2.00-1.96 (2H, m), 1.57-1.50 (2H, m), 1.41-1.35 (2H,
13
m), 1.17 (1H, brs), 1.09 (9H, s), 1.04 (3H, d, J = 6.0 Hz); C NMR (125 MHz, CDCl3) δ: 135.9, 135.7,
134.8, 134.6, 132.4, 129.4, 127.4, 126.8, 69.6, 62.9, 42.8, 32.3, 27.2, 27.0, 25.5, 22.9, 19.3 ppm.
HRMS-ESI: m/z [M+Na]+: Calcd for C25H36O2SiNa; 419.2377, Found: 419.2381.
(2S,4E)-9-Iodonon-4-ene-2-tert-butyldiphenyloxysilane (17). To a solution of 16 (929 mg, 2.34 mmol)
in toluene (23 mL) were added imidazole (207 mg, 3.0 mmol), PPh3 (797 mg, 3.0 mmol), and I2 (652 mg,
2.57 mmol). After the resulting mixture had been stirred for 15 h, the reaction was quenched with
o
aqueous Na2S2O3 (20 mL) at 0 C. The mixture was extracted with pentane and the organic layer was
washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with
silica gel column chromatography (hexane) to afford 17 (1.10 g, 93%) as a pale yellow oil. This
compound was used immediately for the next step. [α]19 −19.9 (c 1.23, CHCl3); IR (film) νmax cm-1:
D
3070, 3047, 2962, 2856, 1472, 1461, 1427, 1389, 1376, 1362, 1203, 1128, 1111, 1081, 997, 970, 892, 866,
822; 1H NMR (500 MHz, CDCl3) δ: 7.69-7.67 (4H, m), 7.43-7.35 (6H, m), 5.43-5.25 (2H, m), 3.87-3.81
(1H, m), 3.15 (2H, t, J = 7.0 Hz), 2.18-2.07 (2H, m), 2.04-1.96 (2H, m), 1.84-1.72 (2H, m), 1.44-1.34 (2H,
13
m), 1.09 (9H, s), 1.04 (3H, d, J = 5.5 Hz); C NMR (125 MHz, CDCl3) δ: 136.1, 135.9, 134.8, 134.5,
131.9, 129.5, 127.5, 127.2, 69.6, 53.5, 42.7, 33.0, 31.5, 30.2, 27.1, 23.0, 19.3 ppm.
(7E,10S)-1-(3,5-Dimethoxyphenyl)-10-tert-butyldiphenylsilyloxyundec-7-en-2-ol (9). To a solution of
17 (82 mg, 0.16 mmol) in Et2O (2.0 mL) was added t-BuLi (1.7 mol/L in pentane, 0.19 mL, 0.32 mmol)
at −78 oC. After the mixture had been stirred for 30 min, aldehyde 7 (15 mg, 83 µmol) in Et2O (2.0 mL)
was added to the mixture. After the resulting mixture had been stirred for 1 h, the reaction was quenched
o
with saturated aqueous NH4Cl (5.0 mL) at −78 C. The mixture was extracted with EtOAc (10 mL x 3)
and the organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified with preparative TLC (toluene : EtOAc = 5:1) to afford 9 (19 mg, 41%) as a pale

HETEROCYCLES, Vol. 94, No. 8, 2017
1551
yellow oil. IR (film) νmax cm-1: 3428, 3070, 2930, 2856, 1606, 1596, 1462, 1428, 1376, 1361, 1345, 1323,
1
1294, 1206, 1151, 1111, 1072, 998, 971, 823; H NMR (500 MHz, CDCl3) δ: 7.69-7.67 (4H, m),
7.42-7.34 (6H, m), 6.37 (2H, d, J = 2.0 Hz), 6.35 (1H, d, J = 2.0 Hz), 5.38-5.29 (2H, m), 3.92-3.81 (2H,
m), 3.78 (6H, s), 2.76 (1H, dd, J = 13.5, 4.0 Hz), 2.55 (1H, dd, J = 13.5, 9.0 Hz), 2.19-2.07 (2H, m),
1.97-1.93 (2H, m), 1.60-1.34 (7H, m), 1.09 (9H, s), 1.04 (3H, d, J = 6.0 Hz); 13C NMR (125 MHz,
CDCl3) δ: 160.9, 140.9, 135.9, 134.8, 134.6, 132.6, 129.4, 127.4, 126.5, 107.3, 98.4, 72.4, 69.6, 55.3,
44.4, 42.8, 36.7, 32.6, 29.5, 27.0, 25.3, 22.9, 19.2 ppm. HRMS-EI: m/z [M]+: Calcd for C35H48OSi;
560.3322, Found: 560.3320.
(7E,10S)-1-(2-Iodo-3,5-dimethoxyphenyl)-10-tert-butyldiphenylsilyloxyundec-7-en-2-ol (18). To a
solution of 9 (49 mg, 87 µmol) in CCl4 (1.7 mL) was added NIS (20 mg, 87 µmol). After the resulting
mixture had been stirred for 1 h, the reaction was quenched with aqueous Na2S2O3. The mixture was
extracted with EtOAc (20 mL x 2) and the organic layer was washed with water, brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified with preparative TLC (toluene : EtOAc = 10:1) to
afford 18 (34 mg, 57%) as a colorless oil. IR (film) νmax cm-1: 3422, 3070, 2929, 2856, 1580, 1455, 1428,
1413, 1325, 1280, 1205, 1163, 1111, 1080, 1010, 971, 823; 1H NMR (500 MHz, CDCl3) δ: 7.69-7.67 (4H,
m), 7.42-7.35 (6H, m), 6.48 (1H, d, J = 2.5 Hz), 6.33 (1H, d, J = 2.5 Hz), 5.37-5.30 (2H, m), 3.94-3.76
(2H, m), 3.86 (3H, s), 3.80 (3H, s), 3.05 (1H, dd, J = 13.8, 4.0 Hz), 2.76 (1H, dd, J = 13.8, 9.0 Hz),
2.19-2.07 (2H, m), 1.98-1.97 (2H, m), 1.68-1.31 (7H, m), 1.09 (9H, s), 1.04 (3H, d, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3) δ: 160.8, 159.1, 143.6, 135.9, 134.8, 134.6, 132.7, 129.4, 127.4, 126.5, 107.9, 97.1,
82.2, 71.1, 69.6, 56.4, 55.5, 48.8, 42.7, 36.9, 32.6, 29.5, 27.0, 25.2, 22.9, 19.2 ppm. HRMS-EI: m/z [M]+:
Calcd for C35H47IOSi; 686.2289, Found: 686.2284.
(7E,10S)-1-(2-Iodo-3,5-dimethoxyphenyl)-10-tert-butyldiphenylsilyloxyundec-7-en-2-one (8). To a
solution of 18 (86 mg, 0.125 mmol) in CH2Cl2 (2.0 mL) was added Dess-Martin periodinane (68 mg, 0.16
o
mmol) at 0 C. After being stirred for 30 min at room temperature, the reaction was quenched with
o
aqueous NaHCO3/Na2S2O3 (1:1, 10 mL) at 0 C and the mixture had been stirred until the organic layer
was cleared. The mixture was extracted with EtOAc (20 mL x 2) and the organic layer was washed with
water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with preparative
TLC (toluene : EtOAc = 10:1) to afford 8 (76 mg, 89%) as a colorless oil. [α]19D −13.7 (c 0.760, CHCl3);
IR (film) νmax cm-1: 3070, 2961, 2930, 2856, 1717, 1581, 1455, 1428, 1375, 1362, 1335, 1306, 1281,
1
1205, 1163, 1111, 971, 823; H NMR (500 MHz, CDCl3) δ: 7.68-7.66 (4H, m), 7.42-7.34 (6H, m), 6.38
(1H, d, J = 2.5 Hz), 6.33 (1H, d, J = 2.5 Hz), 5.34-5.30 (2H, m), 3.88 (2H, s), 3.84 (3H, s), 3.83-3.79 (1H,

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HETEROCYCLES, Vol. 94, No. 8, 2017
m), 3.78 (3H, s), 2.47 (2H, t, J = 7.5 Hz), 2.17-2.05 (2H, m), 1.95-1.92 (2H, m), 1.62-1.55 (2H, m),
13
1.34-1.26 (2H, m), 1.08 (9H, s), 1.04 (3H, d, J = 7.5 Hz); C NMR (125 MHz, CDCl3) δ: 207.1, 160.9,
159.1, 140.3, 135.8, 134.7, 134.5, 132.2, 129.4, 127.4, 126.7, 107.7, 97.5, 82.6, 69.6, 56.4, 55.4, 54.9,
42.7, 42.4, 32.4, 28.9, 27.0, 23.1, 22.8, 19.2 ppm. HRMS-ESI: m/z [M+Na]+: Calcd for C35H45IOSiNa;
707.2024, Found: 707.2026.
(5’E,8’S)-8’-tert-Butyldiphenylsilyloxynon-5’-enyl-6,8-dimethoxy-1H-2-benzopyran-1-one (19). To a
solution of 8 (54 mg, 0.079 mmol) in DMF (5.0 mL) was added AcONa (13 mg, 0.16 mmol) and
Cl2Pd(PPh3)2 (5.5 mg, 7.9 µmol) under 1 atm of CO atmosphere. After the resulting mixture had been
o
stirred for 96 h at 50 C, the reaction was quenched with saturated aqueous NH4Cl at room temperature.
The mixture was extracted with EtOAc (20 mL x 3) and the organic layer was washed with water, brine,
dried over Na2SO4, filtered and concentrated. The residue was purified with preparative TLC (hexane :
EtOAc = 2:1) to afford 19 (41 mg, 89%) as a colorless oil. [α]19 −17.8 (c 2.05, CHCl3); IR (film) νmax
D
cm-1: 3070, 3047, 2962, 2930, 2856, 1731, 1664, 1600, 1571, 1458, 1427, 1375, 1240, 1213, 1164, 1111,
1
1075, 997, 823; H NMR (500 MHz, CDCl3) δ: 7.68-7.66 (4H, m), 7.42-7.34 (6H, m), 6.42 (1H, d, J =
2.5 Hz), 6.30 (1H, d, J = 2.5 Hz), 6.06 (1H, s), 5.38-5.29 (2H, m), 3.96 (3H, s), 3.87 (3H, s), 3.86-3.83
(1H, m), 2.44 (2H, t, J = 7.5 Hz), 2.18-2.05 (2H, m), 2.00-1.96 (2H, m), 1.68-1.62 (2H, m), 1.41-1.37 (2H,
13
m), 1.09 (9H, s), 1.04 (3H, d, J = 5.5 Hz); C NMR (125 MHz, CDCl3) δ: 165.3, 163.2, 159.7, 159.0,
142.4, 135.8, 134.8, 134.5, 132.2, 129.4, 127.4, 126.9, 103.0, 99.4, 98.1, 69.6, 56.2, 55.5, 42.7, 33.1, 32.3,
28.7, 27.0, 26.2, 22.9, 19.2 ppm. HRMS-ESI: m/z [M+Na]+: Calcd for C36H44O5SiNa; 607.2850, Found:
607.2845.
6,8-Dimethylfusariumin (3). To a solution of 19 (10 mg, 17 µmol) in THF (1.7 mL) was added TBAF
(1.0 mol/L, 30 µL, 0.030 mmol) at 0 oC. After being stirred for 67 h at room temperature, the reaction was
quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc (20 mL x 3) and the
organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue
was purified with preparative TLC (hexane : EtOAc = 1:3) to afford 3 (5 mg, 85%) as a colorless solid.
Mp 114-115 oC; [α]19 −6.60 (c 2.05, CHCl3); IR (KBr) νmax cm-1: 3460, 2917, 2849, 1715, 1663, 1600,
D
1570, 1457, 1426, 1374, 1242, 1165, 1120, 1060, 993, 977, 846; 1H NMR (500 MHz, CDCl3) δ: 6.43 (1H,
d, J = 2.0 Hz), 6.32 (1H, d, J = 2.0 Hz), 6.13 (1H, s), 5.55-5.40 (2H, m), 3.96 (3H, s), 3.89 (3H, s),
3.82-3.76 (1H, m), 2.47 (2H, t, J = 7.5 Hz), 2.23-2.02 (2H, m), 2.12-2.05 (3H, m), 1.72-1.55 (2H, m),
1.47-1.41 (2H, m), 1.06 (3H, d, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ: 165.3, 163.2, 159.7, 158.9,
142.4, 133.9, 126.4, 103.1, 103.0, 99.5, 98.2, 67.2, 56.3, 55.6, 42.5, 33.1, 32.3, 28.7, 26.2, 22.7 ppm.

HETEROCYCLES, Vol. 94, No. 8, 2017
1553
HRMS-EI: m/z [M]+: Calcd for C20H26O5; 346.1780, Found: 346.1782.
SUPPORTING INFORMATION
1H and 13C NMR spectra of 1 and 3.
ACKNOWLEDGEMENTS
This work was supported in part by JSPS KAKENHI Grant Number 15K07408 to H. M.
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