Asymmetric total synthesis of fusarentin 6-methyl ether and its biomimetic transformation into fusarentin 6,7-dimethyl ether, 7-O-demethylmonocerin, and (+)-monocerin

Article abstract of DOI:10.1021/jo400760q

A concise asymmetric total synthesis of a fusarentin ether (1) with sequential biomimetic transformation to its analogues fusarentin 6,7-dimethyl ether (2), 7-O-demethylmonocerin (3), and (+)-monocerin (4) has been accomplished. The cis-fused furobenzopyranones of 7-O-demethylmonocerin (3) and (+)-monocerin (4) were efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of fusarentin 6-methyl ether (1) using hypervalent iodine reagent.

Full text of DOI:10.1021/jo400760q

Note
pubs.acs.org/joc
Asymmetric Total Synthesis of Fusarentin 6‑Methyl Ether and Its
Biomimetic Transformation into Fusarentin 6,7-Dimethyl Ether,
7‑O‑Demethylmonocerin, and (+)-Monocerin
Bowen Fang,† Xingang Xie,† Changgui Zhao,† Peng Jing,† Huilin Li,† Zhengshen Wang,† Jixiang Gu,†
and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
Gansu 730000, People’s Republic of China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, Gansu 730000, People’s Republic of China
S
* Supporting Information
ABSTRACT: A concise asymmetric total synthesis of a
fusarentin ether (1) with sequential biomimetic transformation
to its analogues fusarentin 6,7-dimethyl ether (2), 7-O-
demethylmonocerin (3), and (+)-monocerin (4) has been
accomplished. The cis-fused furobenzopyranones of 7-O-
demethylmonocerin (3) and (+)-monocerin (4) were
efficiently constructed via an intramolecular nucleophilic
trapping of a quinonemethide intermediate, which was
obtained by benzylic oxidation of fusarentin 6-methyl ether
(1) using hypervalent iodine reagent.
and monocerin (4) is depicted in Scheme 1. We envisioned
he fusarentin ethers 1 and 2 were originally isolated along
Twith 7-O-demethylmonocerin (3) and (+)-monocerin (4) that monocerin (4) could be readily obtained from 7-O-
from Fusarium larvarum in 1979.1 Since then, monocerin and a
demethylmonocerin (3), which contains two phenolic hydroxyl
substituents, but since the reactivity of one of them is
attenuated by hydrogen bonding to adjacent carbomethoxy
groups, 3 can be selectively monomethylated to 4.17 As for 3,
on the basis of a previous biosynthetic hypothesis of
monocerin3,16 and Simpson and co-workers’ elegant biomi-
metic total synthesis of monocerin,12 we envisioned that it
could be accomplished via an intramolecular conjugate addition
of the 10-hydroxyl group to C-4 of the quinonemethide
intermediate 7, which could be obtained by an oxidation of the
arene in fusarentin 6-methyl ether (1). Fusarentin 6-methyl
ether (1) could be synthesized from δ-valerolactone 8, which in
turn could be prepared from homobenzylic alcohol 9 via an
oxa-Pictet−Spengler cyclization followed by a proper oxidation.
The C-3 stereogenic center in alcohol 9 would be established
by a SmI2-promoted Evans−Tishchenko reduction. In addition,
the requisite chiral β-hydroxy ketone 10 could be easily
accessed by several steps from the known 4-isopropoxy-3,5-
dimethoxybenzaldehyde (11).
series of its analogues have been isolated from several fungal
species (Figure 1).2−7 The structural features of monocerin and
its analogues include a 4-oxyisochroman-1-one skeleton and a
2,3,5-trisubstituted tetrahydrofuran, which are embedded with
all-cis stereochemistry. The fusarentin ethers 1 and 2 are the
ring-opened derivatives of 7-O-demethylmonocerin (3) and
(+)-monocerin (4). Along with the elucidation of structures,
studies regarding their biological properties have also been
performed, showing various antifungal, insecticidal, and plant
pathogenic properties and phytotoxic activity.6−9 Due to their
potential for application in the pharmaceutical industry, these
natural products attracted the attention of synthetic chemists,
and several total syntheses of fusarentin ethers 1 and 210 and
monocerin (4)11−15 have been reported. One elegant synthetic
study was reported by Simpson, who employed a radical
benzylic bromination to initiate the formation of cis-
tetrahydrofuran.12 Biosynthetically, monocerin was found to
be of heptaketide origin, and 13C labeling studies suggested the
cis-fused furobenzopyranones arose by intramolecular nucleo-
philic trapping of a quinonemethide intermediate by a pendant
alcohol.3,16 Herein, we describe a concise asymmetric total
synthesis of fusarentin 6-methyl ether (1) and its sequential
biomimetic transformation into fusarentin 6,7-dimethyl ether
(2), 7-O-demethylmonocerin (3), and monocerin (4).
The synthesis of fusarentin 6-methyl ether (1) commenced
from the known 4-isopropoxy-3,5-dimethoxybenzaldehyde
(11)18 (Scheme 2). Homologation of 11 was performed via a
Wittig reaction, and the resulting enol ether was directly
subjected to 1,3-propanedithiol and BF3·OEt2 to give dithiane
The retrosynthetic pathway of fusarentin 6-methyl ether (1),
fusarentin 6,7-dimethyl ether (2), 7-O-demethylmonocerin (3),
Received: April 10, 2013
© XXXX American Chemical Society
A
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Figure 1. The fusarentin ethers 1 and 2 and monocerin (4) and its analogues.
Scheme 1. Retrosynthetic Plan for Synthesis of (+)-Monocerin (4) and Isocoumarin Derivatives
12 (76% yield over two steps). Treatment of 12 with t-BuLi in
THF was followed by the ring opening of (S)-2-propyloxirane
(13)19 to afford β-hydroxydithiane 14 in 75% yield. Removal of
the 1,3-dithiane group was achieved under mild conditions by I2
and CaCO3 to give β-hydroxy ketone 10. Then an SmI2-
promoted Evans−Tishchenko reduction20 was employed with
ketone 10, generating the desired homobenzylic alcohol 9 with
high diastereoselectivity (the diastereoselectivity is calculated
on the basis of 1H NMR integration of the crude mixture, dr >
15:1). Moreover, the hydroxy group of C-10 was protected as a
propionate. Subsequently, treatment of alcohol 9 with trimethyl
orthoformate and TMSOTf, the oxa-Pictet−Spengler reac-
tion,21 was found to be reliable and the resulting cyclic acetal
was directly treated with Jones reagent22 to afford δ-
valerolactone 8 in 85% yield in two consecutive steps. Finally,
removal of the propionyl group was readily accomplished under
slightly basic conditions to give the alcohol δ-valerolactone 15,
which was converted into fusarentin 6-methyl ether (1) upon
deisopropylation23 and partial demethylation24 with boron
trichloride in 60% overall yield. The deisopropylation is favored
over demethylation probably because isopropyl ether is less
stable with the Lewis acid. The C-8 methoxy group is
attenuated by hydrogen bonding to adjacent carbomethoxy
groups, which can be selectively demethylated. The yield of the
last step, a dealkylation reaction, was moderate, probably due to
B
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Scheme 2. Synthesis of Fusarentin 6-Methyl Ether (1)
Scheme 3. Synthesis of Fusarentin 6,7-Dimethyl Ether (2), 7-O-Demethylmonocerin (3), and Monocerin (4)
a
Table 1. Synthesis of 7-O-Demethylmonocerin (3) from Fusarentin 6-Methyl Ether (1)
b
entry
reagent (amt (equiv))
solvent
CH3CN
temp
reflux
time (h)
yield (%)
c
1
2
3
4
5
K2S2O8 (2)
1
8
0
d
Ce(NH4)2(NO3)6 (1.5)
K3Fe(CN)6 (10)
DDQ (1.1)
CH3CN/H2O
CHCl3
reflux
10
e
room temp
room temp
room temp
24
1
0
1,4-dioxane
60
63
PhI(OAc)2 (1.1)
DCM
1
a
b
c
d
1 (30 mg, 0.1 mmol) and 1 mL of solvent were mixed. Isolated yield. Starting material decomposition. Recovery of most of the starting material.
e
Quantitative recovery of the starting material.
the fact that fusarentin 6-methyl ether (1) was unstable during
the column chromatography purification process.
With fusarentin 6-methyl ether (1) in hand, we set out to
investigate its biomimetic transformation to fusarentin 6,7-
C
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Note
1
(3.15 g, 76% yield for two steps) as a colorless oil: H NMR (400
MHz, CDCl3) δ 6.44 (s, 2H), 4.31 (dt, J = 12.4, 6.2 Hz, 1H), 4.23 (t, J
= 7.2 Hz, 1H), 3.82 (s, 6H), 2.94 (d, J = 7.2 Hz, 2H), 2.91−2.78 (m,
4H), 2.16−2.08 (m, 1H), 1.92−1.81 (m, 1H), 1.29 (s, 3H), 1.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 153.4, 135.0, 132.4, 106.2, 75.1,
55.9, 48.4, 42.2, 30.5, 25.6, 22.4; HRMS (ESI) calcd for C16H25O3S2
[M + H]+ 329.1240, found 329.1245.
dimethyl ether (2), 7-O-demethylmonocerin (3), and mono-
cerin (4) (Scheme 3). It was found that selective mono-
methylation of 1 with iodomethane in the presence of
anhydrous potassium carbonate in acetone at room temper-
ature17 gave a 58% yield of fusarentin 6,7-dimethyl ether (2)
and a 32% yield of the dimethyl ether 16. The desired product
2 could be easily isolated by silica-based column chromatog-
raphy, and regioselective demethylation of 16 also generated
fusarentin 6,7-dimethyl ether (2) in 72% yield.
Subsequent oxidation of fusarentin 6-methyl ether (1) was
tested using various conditions, and the results are summarized
in Table 1. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
and PhI(OAc)2 were found to be the most effective reagents.
The 7-hydroxyl group of phenol 1 was oxidized as carbonyl,
along with intramolecular nucleophilic trapping of the
quinonemethide intermediate 7 by conjugate addition of the
10-hydroxyl group to C-4, which afforded 7-O-demethylmono-
cerin (3). The isolated yield was moderate, probably due to the
product’s instability against column chromatography. The
structure of 3 was characterized by X-ray diffraction analysis,
confirming the cis-fused furobenzopyranones (see the Support-
ing Information).
Regioselective methylation of 7-O-demethylmonocerin (3)
afforded a 56% yield of monocerin (4), along with a 29% yield
of the diprotected product 17, which also could be converted
into 4 in 60% yield (Scheme 3). Treatment of fusarentin 6-
methyl ether (1) with PhI(OAc)2, followed by regioselective
methylation, smoothly furnished monocerin (4) and compound
17 in 73% combined yield (4:17 = 1:1.2) for two consecutive
steps. Monocerin (4) was obtained in 61% yield in these
procedures.
In summary, we have achieved a concise asymmetric total
synthesis of fusarentin 6-methyl ether with an overall yield of
20.5% over nine steps. Utilizing this compound as the key
intermediate, we have achieved biomimetic total syntheses of
fusarentin 6,7-dimethyl ether (2), 7-O-demethylmonocerin (3),
and monocerin (4) with an overall yield of 16.5% over 11 steps,
12.9% over 10 steps, and 12.5% over 12 steps.
Synthesis of (S)-1-(2-(4-Isopropoxy-3,5-dimethoxybenzyl)-
1,3-dithian-2-yl)pentan-2-ol (14). To a solution of 1,3-dithiane
12 (1.97 g, 6 mmol) in anhydrous THF (20 mL) was added t-BuLi
(1.3 M in pentane, 6 mL, 7.8 mmol) at −40 °C under Ar, and the
mixture was stirred for 0.5 h at −40 °C. A solution of (S)-2-
propyloxirane (13; 725 mg, 8.4 mmol) in THF (10 mL) was added
dropwise. After it was stirred for 1 h at −40 °C, the reaction mixture
was warmed to room temperature and stirred overnight. The reaction
mixture was quenched with saturated aqueous NH4Cl (10 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification by column chromatography (petroleum ether/EtOAc 8/
1) gave β-hydroxydithiane 14 (1.86 g, 75% yield) as a pale yellow oil:
[α]20 = +16.0° (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
1
D
6.52 (s, 2H), 4.32 (dt, J = 12.4, 6.2 Hz, 1H), 4.05 (s, 1H), 3.80 (s, 6H),
3.50 (s, 1H), 3.25 (d, J = 14.1 Hz, 1H), 3.15 (d, J = 14.1 Hz, 1H), 3.06
(ddd, J = 13.8, 10.7, 2.8 Hz, 1H), 2.91 (dd, J = 10.6, 3.0 Hz, 1H),
2.83−2.73 (m, 2H), 2.24 (dd, J = 15.2, 9.4 Hz, 1H), 2.12−1.99 (m,
1H), 1.97−1.75 (m, 2H), 1.52−1.40 (m, 2H), 1.39−1.29 (m, 2H),
1.28 (s, 3H), 1.27 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 153.0, 135.2, 130.1, 108.3, 75.1, 68.5, 55.9, 52.5, 46.5,
43.5, 39.7, 26.8, 26.3, 24.6, 22.4, 22.4, 18.6, 14.0; HRMS (ESI) calcd
for C21H35O4S2 [M + H]+ 415.1971, found 415.1977.
Synthesis of (S)-4-Hydroxy-1-(4-isopropoxy-3,5-
dimethoxyphenyl)heptan-2-one (10). To a solution of β-
hydroxydithiane 14 (1.86 g, 4.5 mmol) in THF/H2O (4/1, 45 mL)
was added CaCO3 (4.5 g, 45.0 mmol) at 0 °C, and then iodine (4.5 g,
18 mmol) was added portionwise. The mixture was stirred for 0.5 h
and quenched with saturated aqueous Na2S2O3 (20 mL). The aqueous
phase was separated and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 3/1) gave β-hydroxy ketone 10 (1.16 g,
80% yield) as a colorless oil: [α]20 = +44.0° (c = 1.0, CHCl3); H
1
D
NMR (400 MHz, CDCl3) δ 6.38 (s, 2H), 4.35−4.27 (m, 1H), 4.01
(dd, J = 7.5, 3.7 Hz, 1H), 3.80 (s, 6H), 3.62 (s, 2H), 2.97 (d, J = 3.3
Hz, 1H), 2.59 (qd, J = 17.6, 5.9 Hz, 2H), 1.48−1.36 (m, 2H), 1.35−
1.21 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 209.6, 153.9, 135.2, 128.6, 106.3, 75.1,
67.3, 55.9, 50.9, 48.0, 38.4, 22.3, 18.5, 13.8; HRMS (ESI) calcd for
C18H29O5 [M + H]+ 325.2010, found 325.2014.
EXPERIMENTAL SECTION
■
Synthesis of 2-(4-Isopropoxy-3,5-dimethoxybenzyl)-1,3-di-
thiane (12). To a suspension of methoxymethylphosphonium
chloride (6.5 g, 19 mmol) in anhydrous THF (50 mL) was added
LDA (2.0 M, 9.4 mL, 18.8 mmol) at 0 °C under Ar, and the mixture
was stirred for 0.5 h at 0 °C. A solution of 4-isopropoxy-3,5-
dimethoxybenzaldehyde (11; 2.82 g, 12.6 mmol) in THF (30 mL) was
added dropwise. After it was stirred for 2 h, the mixture was quenched
with saturated aqueous NH4Cl (15 mL) at 0 °C, and the resulting
mixture was diluted with Et2O (20 mL). The organic layers were
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
dissolved in petroleum ether, after removal of triphenylphosphine
oxide by filtration; the filtrate was concentrated in vacuo to give the
crude product, which was used immediately without further
purification.
Synthesis of (2S,4S)-2-Hydroxy-1-(4-isopropoxy-3,5-
dimethoxyphenyl)heptan-4-yl Propionate (9). To a solution of
β-hydroxy ketone 10 (1.16 g, 3.6 mmol) in anhydrous THF (8 mL)
were added propionaldehyde (2.1 mL, 28.8 mmol) and SmI2 (0.1 M,
18 mL, 1.8 mmol) at −10 °C under Ar. After it was stirred for 4 h at
−10 °C, the mixture was quenched with saturated aqueous NaHCO3
(10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated in
vacuo. Purification by column chromatography (petroleum ether/
EtOAc 3/1) gave alcohol 9 (1.24 g, 90% yield) as a colorless oil:
[α]20D = −3.0° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.41
(s, 2H), 5.13 (ddd, J = 12.6, 8.1, 4.2 Hz, 1H), 4.30 (dt, J = 12.3, 6.2
Hz, 1H), 3.80 (s, 6H), 3.72 (s, 1H), 2.88 (d, J = 3.4 Hz, 1H), 2.67 (qd,
J = 13.7, 6.4 Hz, 2H), 2.34 (q, J = 7.6 Hz, 2H), 1.72−1.44 (m, 4H),
1.39−1.31 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.14 (t, J = 7.6 Hz,
3H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4,
153.6, 134.6, 133.7, 106.3, 75.1, 71.2, 68.3, 55.9, 43.9, 42.1, 36.9, 27.7,
22.4, 18.6, 13.7, 9.2; HRMS (ESI) calcd for C21H34O6Na [M + Na]+
405.2248, found 405.2252.
The crude residue was dissolved in CH2Cl2 (50 mL), and 1,3-
propanedithiol (1.5 mL, 15 mmol) was added at −10 °C. To the
resultant solution was added BF3·Et2O (3.2 mL, 25 mmol) dropwise
and the solution stirred at −10 °C for 2 h. Saturated aqueous
NaHCO3 was added slowly at −10 °C to quench the excess BF3·Et2O.
After it was warmed to room temperature, the mixture was extracted
with Et2O (3 × 15 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification by column
chromatography (petroleum ether/EtOAc 20/1) gave dithiane 12
Synthesis of (S)-1-((S)-7-Isopropoxy-6,8-dimethoxy-1-oxoi-
sochroman-3-yl)pentan-2-yl Propionate (8). To a solution of
alcohol 9 (1.24 g, 3.2 mmol) and trimethyl orthoformate (8.3 mL) in
D
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Note
CH2Cl2 (20 mL) was added TMSOTf (0.06 mL, 0.35 mmol) at 0 °C.
After it was stirred for 1 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate
(3 × 10 mL). The combined organic layers were washed with brine
and dried over anhydrous Na2SO4. Concentration in vacuo gave the
crude product as an oil, which was used immediately without further
purification.
(58%) of fusarentin 6,7-dimethyl ether (2) and 9 mg of (32%) (S)-3-
((S)-2-hydroxypentyl)-6,7,8-trimethoxyisochroman-1-one (16).
Fusarentin 6,7-dimethyl ether (2): white solid: mp 102−104 °C;
[α]20 = −25.0° (c = 1.0, CHCl3) (lit.1 mp 103 °C; [α]20 = −29°);
D
D
1H NMR (400 MHz, CDCl3) δ 11.04 (s, 1H), 6.26 (s, 1H), 4.85−4.77
(m, 1H), 4.00 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.85 (qd, J = 16.3,
7.6 Hz, 2H), 2.43 (s, 1H), 1.92 (ddd, J = 14.4, 9.7, 2.0 Hz, 1H), 1.72−
1.60 (m, 1H), 1.51−1.27 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.7, 158.3, 155.9, 135.6, 135.1, 102.7, 102.0,
76.5, 66.7, 60.5, 56.0, 42.2, 40.0, 33.4, 18.5, 13.9; HRMS (ESI) calcd
for C16H23O6 [M + H]+ 311.1489, found 311.1485.
The crude product was dissolved in acetone (18 mL), and Jones
oxidant (3.0 M, 3.2 mL, 9.6 mmol) was added at 0 °C. After it was
stirred for 1 h, the mixture was quenched with saturated aqueous
NaHCO3 (10 mL) and extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 2/1) gave δ-valerolactone 8 (1.11 g, 85%
yield) as a pale yellow oil: [α]20D = −68.0° (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 6.46 (s, 1H), 5.12 (t, J = 3.2 Hz, 1H), 4.46−4.35
(m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 2.81 (ddd, J = 18.8, 16.0, 7.3 Hz,
2H), 2.29 (q, J = 7.6 Hz, 2H), 2.04 (ddd, J = 14.5, 8.3, 3.8 Hz, 1H),
1.87 (ddd, J = 14.6, 8.4, 3.9 Hz, 1H), 1.67−1.48 (m, 2H), 1.40−1.29
(m, 2H), 1.28 (d, J = 2.8 Hz, 3H), 1.26 (d, J = 2.8 Hz, 3H), 1.10 (t, J =
7.6 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.8, 161.7, 158.1, 156.6, 140.1, 136.3, 111.8, 105.5, 76.0, 74.4, 70.4,
61.3, 55.9, 39.5, 36.7, 34.6, 27.6, 22.4, 22.3, 18.2, 13.8, 9.0; HRMS
(ESI) calcd for C22H33O7 [M + H]+ 409.2221, found 409.2226.
Synthesis of (S)-3-((S)-2-Hydroxypentyl)-7-isopropoxy-6,8-
dimethoxyisochroman-1-one (15). To a solution of δ-valerolac-
tone 8 (1.11 g, 2.71 mmol) in CH3OH (10 mL) was added anhydrous
K2CO3 (1.12 g, 8.1 mmol) at room temperature. After it was stirred
for 3 h, the reaction mixture was quenched with H2O (10 mL) and the
mixture was extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 1.5/1) gave alcohol 15 (936 mg, 98% yield)
as a pale yellow oil: [α]20D = −85.0° (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 6.47 (s, 1H), 4.70 (t, J = 10.3 Hz, 1H), 4.39 (dt, J =
12.2, 6.0 Hz, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 2.83 (dt, J =
15.9, 14.8 Hz, 2H), 2.25 (s, 1H), 1.97−1.86 (m, 1H), 1.64 (dd, J =
17.7, 6.5 Hz, 1H), 1.52−1.31 (m, 4H), 1.27 (t, J = 6.1 Hz, 6H), 0.91
(t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 158.1,
156.6, 140.0, 136.9, 111.7, 105.5, 76.0, 74.7, 66.9, 61.2, 55.9, 42.2, 40.1,
34.8, 22.4, 22.3, 18.6, 13.9; HRMS (ESI) calcd for C19H29O6 [M + H]+
353.1959, found 353.1954.
(S)-3-((S)-2-Hydroxypentyl)-6,7,8-trimethoxyisochroman-1-one
1
(16): colorless oil; [α]20 = −65.0° (c = 1.0, CHCl3); H NMR (400
D
MHz, CDCl3) δ 6.47 (s, 1H), 4.75−4.62 (m, 1H), 4.02 (s, 1H), 3.91
(s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 2.82 (ddd, J = 19.2, 16.1, 7.3 Hz,
2H), 2.26 (s, 1H), 1.90 (ddd, J = 14.2, 9.5, 1.9 Hz, 1H), 1.68−1.59 (m,
1H), 1.68−1.59 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.2, 157.4, 156.1, 141.9, 137.2, 111.6, 105.6, 74.7,
66.9, 61.6, 60.9, 56.0, 42.1, 40.1, 34.8, 18.6, 13.9; HRMS (ESI) calcd
for C17H25O6 [M + H]+ 325.1646, found 325.1643.
Synthesis of Fusarentin 6,7-Dimethyl Ether (2) from 16. To a
solution of alcohol 16 (9 mg, 0.028 mmol) in dry CH2Cl2 (0.5 mL)
was added BCl3 (1.0 M, 31 μL, 0.031 mmol) at −10 °C under Ar. The
mixture was stirred at −10 °C for 1 h and quenched with saturated
aqueous NaHCO3 (0.5 mL). The mixture was extracted with ethyl
acetate (10 mL), and the organic layer was washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. Purification by
column chromatography (petroleum ether/EtOAc 2/1) gave fusar-
entin 6,7-dimethyl ether (2; 6 mg, 72% yield). The characterization
data of 2 are consistent with those reported previously.
Synthesis of 7-O-Demethylmonocerin (3). To a solution of
fusarentin 6-methyl ether (1; 36 mg, 0.12 mmol) in CH2Cl2 (3 mL)
was added PhI(OAc)2 (45 mg, 0.13 mmol) at room temperature. The
mixture was stirred for 1 h and quenched with saturated aqueous
Na2S2O3 (1 mL). The mixture was extracted with ethyl acetate (10
mL), and the organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification by column
chromatography (CH2Cl2/CH3OH, 30/1) yielded 22 mg (63%) of 7-
O-demethylmonocerin (3) as a white solid: mp 173−175 °C; [α]20
=
D
+33.0° (c = 1.0, CHCl3) (lit.1 mp 172−175 °C); 1H NMR (400 MHz,
CDCl3) δ 11.15 (s, 1H), 6.62 (s, 1H), 5.60 (s, 1H), 5.07 (dd, J = 5.5,
3.0 Hz, 1H), 4.56 (d, J = 3.1 Hz, 1H), 4.12 (dq, J = 12.7, 6.4 Hz, 1H),
3.98 (s, 3H), 2.60 (ddd, J = 14.6, 8.5, 6.3 Hz, 1H), 2.16 (dd, J = 14.4,
5.8 Hz, 1H), 1.77−1.64 (m, 1H), 1.64−1.52 (m, 1H), 1.49−1.29 (m,
2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.7,
152.1, 149.4, 134.1, 126.9, 104.0, 101.7, 81.5, 78.5, 74.4, 56.3, 39.0,
38.0, 19.0, 13.9; HRMS (ESI) calcd for C15H19O6 [M + H]+ 295.1176,
found 295.1172.
Synthesis of Fusarentin 6-Methyl Ether (1). To a solution of
alcohol 15 (353 mg, 1.0 mmol) in dry CH2Cl2 (10 mL) was added
BCl3 (1.0 M, 2.1 mL, 2.1 mmol) at −10 °C under Ar. After it was
stirred for 3 h, the reaction mixture was quenched with saturated
aqueous NaHCO3 (3 mL) and extracted with ethyl acetate (3 × 10
mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification by column
chromatography (petroleum ether/EtOAc 1/1) gave fusarentin 6-
methyl ether (1; 177 mg, 60% yield) as a white solid: mp 139−140 °C;
[α]20 = −35.0° (c = 1.0, CHCl3) (lit.1 mp 137 °C; [α]20 = −30°);
Synthesis of (+)-Monocerin (4) and (2S,3aR,9bR)-6,7,8-
Trimethoxy-2-propyl-3,3a-dihydro-2H-furo[3,2-c]isochromen-
5(9bH)-one (17). Following the procedure described for the
preparation of 2 and 16, (+)-monocerin (4; 13 mg, 56%) and 17 (7
mg, 29%) were obtained as colorless oils.
D
D
1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 6.27 (s, 1H), 5.74 (s,
(+)-Monocerin (4): [α]25D = +53° (c = 1, CHCl3), [α]25D = +60° (c
= 0.2, CH3OH) (lit.1 [α]24D = +53°); 1H NMR (400 MHz, CDCl3) δ
11.29 (s, 1H), 6.60 (s, 1H), 5.06 (dd, J = 5.3, 3.0 Hz, 1H), 4.55 (d, J =
3.0 Hz, 1H), 4.13 (dt, J = 14.8, 6.3 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H),
2.60 (ddd, J = 14.6, 8.5, 6.2 Hz, 1H), 2.17 (dd, J = 14.5, 5.8 Hz, 1H),
1.74−1.66 (m, 1H), 1.64−1.52 (m, 1H), 1.50−1.29 (m, 2H), 0.92 (t, J
= 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.7, 158.6, 156.2,
137.2, 131.1, 104.3, 102.0, 81.2, 78.7, 74.4, 60.7, 56.2, 38.9, 38.0, 19.1,
13.9; HRMS (ESI) calcd for C16H21O6 [M + H]+ 309.1333, found
309.1328.
1H), 4.83 (t, J = 10.4 Hz, 1H), 4.03 (s, 1H), 3.90 (s, 3H), 2.84 (qd, J =
16.2, 7.6 Hz, 2H), 2.39 (s, 1H), 1.94 (ddd, J = 14.2, 9.8, 1.8 Hz, 1H),
1.72−1.64 (m, 1H), 1.55−1.30 (m, 4H), 0.92 (t, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.8, 152.1, 149.3, 132.0, 131.2, 102.4,
101.7, 76.9, 66.9, 56.1, 42.1, 40.0, 33.1, 18.6, 13.9; HRMS (ESI) calcd
for C15H21O6 [M + H]+ 297.1333, found 297.1330.
Synthesis of Fusarentin 6,7-Dimethyl Ether (2) and (S)-3-((S)-
2-Hydroxypentyl)-6,7,8-trimethoxyisochroman-1-one (16). To
a solution of fusarentin 6-methyl ether (1; 26 mg, 0.088 mmol) in
acetone (1.5 mL) were added anhydrous K2CO3 (14 mg, 0.1 mmol)
and MeI (44 μL, 0.7 mmol) at room temperature under Ar. After it
was stirred for 3 days in the dark, the reaction mixture was quenched
with H2O (1 mL) and the mixture was extracted with ethyl acetate (3
× 2 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. Purification by
column chromatography (petroleum ether/EtOAc 2/1) yielded 16 mg
Compound 17: [α]25D = +45° (c = 1, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 6.78 (s, 1H), 4.94 (dd, J = 5.3, 2.8 Hz, 1H), 4.52 (d, J = 2.8
Hz, 1H), 4.17−4.10 (m, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H),
2.51 (ddd, J = 14.4, 8.8, 5.8 Hz, 1H), 2.15 (dd, J = 14.2, 5.4 Hz, 1H),
1.75−1.65 (m, 1H), 1.64−1.52 (m, 1H), 1.48−1.28 (m, 2H), 0.90 (t, J
= 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 157.9, 156.5,
144.2, 132.5, 111.2, 108.1, 79.5, 78.9, 75.1, 61.8, 61.1, 56.2, 39.0, 38.1,
E
dx.doi.org/10.1021/jo400760q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
19.2, 13.9; HRMS (ESI) calcd for C17H23O6 [M + H]+ 323.1489,
found 323.1493. Following the procedure described for the
preparation of 2 from 16, 4 mg of (+)-monocerin (4; 60%) was
obtained from 17. The characterization data of 4 are consistent with
those reported previously.
(11) Mori, K.; Takaishi, H. Tetrahedron 1989, 45, 1639−1646.
(12) Dillon, M. P.; Simpson, T. J.; Sweeney, J. B. Tetrahedron Lett.
1992, 33, 7569−7572.
(13) Cassidy, J. H.; Farthing, C. N.; Marsden, S. P.; Pedersen, A.;
Slater, M.; Stemp, G. Org. Biomol. Chem. 2006, 4, 4118−4126.
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Am. Chem. Soc. 1988, 110, 6471−6480.
Synthesis of (+)-Monocerin (4) and (2S,3aR,9bR)-6,7,8-
Trimethoxy-2-propyl-3,3a-dihydro-2H-furo[3,2-c]isochromen-
5(9bH)-one (17) from Fusarentin 6-Methyl Ether (1). To a
solution of fusarentin 6-methyl ether (1; 44 mg, 0.148 mmol) in
CH2Cl2 (3 mL) was added PhI(OAc)2 (55 mg, 0.16 mmol) at room
temperature. The mixture was stirred for 1 h and quenched with
saturated aqueous Na2S2O3 (1 mL). The mixture was extracted with
ethyl acetate (10 mL), and the organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was dissolved in acetone (2 mL), and anhydrous K2CO3 (22
mg, 0.16 mmol) and MeI (68 μL, 1.1 mmol) were added at room
temperature under Ar. After it was stirred for 3 days in the dark, the
reaction mixture was quenched with H2O (1 mL) and extracted with
ethyl acetate (3 × 2 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification by column chromatography (petroleum ether/EtOAc 3/
1) yielded 19 mg (41%) of (+)-monocerin (4) and 15 mg (32%) of
17. Following the procedure described for the preparation of 2 from
16, 9 mg of (+)-monocerin (4; 64%) was obtained from 15 mg of 17.
The characterization data of 17 and 4 are consistent with those
reported previously.
(18) For the synthesis of 4-isopropoxy-3,5-dimethoxybenzaldehyde
(11), see: Shirali, A.; Sriram, M.; Hall, J. J.; Nguyen, B. L.;
Guddneppanavar, R.; Hadimani, M. B.; Ackley, J. F.; Siles, R.;
Jelinek, C. J.; Arthasery, P.; Brown, R. C.; Murrell, V. L.; McMordie,
A.; Sharma, S.; Chaplin, D. J.; Pinney, K. G. J. Nat. Prod. 2009, 72,
414−421.
(19) For the synthesis of (S)-2-propyloxirane (13), see: Bates, R. W.;
Lu, Y. J. Org. Chem. 2009, 74, 9460−9465.
(20) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447−6449.
(21) For intramolecular oxa-Pictet−Spengler cyclizations, see: Zheng,
H.; Zhao, C.; Fang, B.; Jing, P.; Yang, J.; Xie, X.; She, X. J. Org. Chem.
2012, 77, 9460−9465.
(22) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. J.
Chem. Soc. 1946, 39−45.
ASSOCIATED CONTENT
* Supporting Information
(23) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Org. Lett. 2011, 13, 312−
315.
■
S
(24) Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.;
Morton, R. B.; Parton, B.; Price, A. W.; Somvichien, N. Tetrahedron
Lett. 1966, 7, 4153−4159.
Text, tables, figures, and a CIF file giving crystallographic data
for 3 and 1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for X.S.: shexg@lzu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research was provide by the NSFC
(21125207, 21102062, 21072086), the MOST
(2010CB833203), PCSIRT (IRT1138), the FRFCU (lzujbky-
2013-49,lzujbky-2013-ct02), and Program 111.
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