Synthesis of the new furo[3,2-h]isoquinoline alkaloid, TMC-120B from Aspergillus ustus

Article abstract of DOI:10.1248/cpb.53.393

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus together with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the appropriate 3,7,8-trisubstituted isoqu

Full text of DOI:10.1248/cpb.53.393

April 2005
Chem. Pharm. Bull. 53(4) 393—397 (2005)
393
Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from
Aspergillus ustus
Teppei KUMEMURA, Tominari CHOSHI, Aki HIRATA, Mitsuko SERA, Yohhei TAKAHASHI,
Junko NOBUHIRO, and Satoshi HIBINO*
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences,
Fukuyama University; Fukuyama, Hiroshima 729–0292, Japan. Received December 7, 2004; accepted January 26, 2005
A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus to-
gether with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the ap-
propriate 3,7,8-trisubstituted isoquinoline framework (23) based on a thermal electrocyclic reaction of the 1-aza
6p-electron system involving the benzene double bond. In addition, the microwave assisted electrocyclic reaction
of this system was newly performed.
Key words furo[3,2-h]isoquinoline; TMC-120B; total synthesis; electrocyclic reaction; 6p-electron system; microwave
In the course of our studies of biologically active con- Results and Discussion
densed heteroaromatic compounds including natural prod-
For the synthesis of the required o-alkenylbenzaldoxime
ucts through the construction of functionalized frameworks (6) and 3,7,8-trisubstituted isoquinoline nucleus (5) (Chart
based on the thermal electrocyclic reaction1—3) of either 6p- 2), reduction of the aldehyde (10) with sodium borohydride
electron4—6) or aza 6p-electron4,5,7) systems incorporating the in ethanol followed by treatment of the resulting alcohol (11)
heteroaromatic or aromatic moiety, we have now selected (90%) with tert-butyldimethylsilyl chloride (TBDMSCl) in
three new furo[3,2-h]isoquinoline alkaloids, TMC-120A (1), the presence of imidazole in DMF gave the TBDMS ether
B (2), and C (3) as target compounds (Fig. 1), which were (12) in 85% yield. The ether (12) was treated with n-BuLi in
isolated from a fermentation broth of Aspergillus ustus TC THF at 0 °C to yield the lithio compound, which was
1118 by Kohno et al. in 1999.8,9) Their structures have been quenched with DMF at the same temperature to afford the
determined by spectroscopic, chemical, and X-ray analyses. benzaldehyde (13) in 75% yield in spite of the restricted po-
TMC-120B (2) shows moderate inhibitory activity against sition of space, according to the procedure reported by Pocci
the interleukin-5 mediated prolongation of eosinophil sur- group.17) The reaction of the aldehyde (13) with hydroxy-
vival (IC50ꢀ2.0 mM).
lamine methyl ether in EtOH gave the oxime methyl ether
We describe here the detailed synthetic work of TMC- (14) in 89% yield, which was treated with tetrabutylammo-
120B (2) as recently reported.10) In a retro-synthetic analysis nium fluoride (TBAF) to afford the benzyl alcohol (15) in
(Chart 1), we planned that TMC-120B (2) would be derived 92% yield. Oxidation of the alcohol (15) with activated man-
from furoisoquinoline (4) prepared firstly by the Dieckmann ganese dioxide (act. MnO2) in CH2Cl2 furnished the ben-
condensation of diester (5). Next, we envisioned that a 3,7,8-
trisubstituted isoquinoline nucleus (5) might be obtained by a
thermal electrocyclic reaction of o-alkenylbenzaldoxime
methyl ether (6) derived from the cleavage of the 2,3-bond of
isoquinoline (5) as an application of the synthesis of iso-
quinoline frameworks by using the 1-azahexatriene sys-
tem.7,11—14) Therefore, we thought that the required 1-aza 6p-
electron system (6) involving the benzene double bond would
be derived from the known 2,4-bismethoxymethyl(bis-
MOM)oxybenzaldehyde (10)15,16) with several steps.
Fig. 1
Chart 1
∗ To whom correspondence should be addressed. e-mail: hibino@fupharm.fukuyama-u.ac.jp
© 2005 Pharmaceutical Society of Japan

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Vol. 53, No. 4
Reagent and conditions: (i) NaBH4, EtOH, rt, 2 h (90%), (ii) TBDMSCl, imidazole, DMF, rt, 12 h (95%), (iii) n-BuLi, THF, 40 min, and then DMF, 0 °C, 20 min (75%), (iv)
MeONH2·HCl, AcONa, EtOH, 80 °C, 12 h (89%), (v) TBAF, THF, rt, 1.5 h (91%), (vi) act. MnO2, CH2Cl2, rt, 24 h (89%), (vii) conc. HCl, MeOH, 0 °C, 3 h (92%), (viii) NaH,
DMF, BrCH2COOMe, rt, 12 h (93%), (ix) AcOH, 90 °C, 12 h (80%), (x) Tf2O, pyridine, CH2Cl2, 0 °C, 4 h (85%), (xi) Me–CHꢀCH–SnBu3, Et4NCl, PdCl2(PPh3)2, DMF, 80 °C, 4 h
(83%), (xii) Table 1.
Chart 2
Table 1
zaldehyde (16) in 89% yield, but a conversion of a formyl
group of 16 into a carboxylic acid (17) with NaClO2 and
H2O2 in acetonitrile18) or a methyl ester (7) with KOH and I2
in MeOH19) both failed. It was difficult to convert the formyl
group of benzaldehyde (16) into an ester group of a supposed
compound 7 in an initial retro-synthetic Chart 1.
We then turned to investigate a synthesis of isoquinoline
(23) having the formyl group in order to achieve a selective
cleavage of MOM-ethers of 2,4-bis(methoxymethyloxy)ben-
zaldehyde (16). The treatment of 16 with conc. hydrochloric
acid (one equivalent) in MeOH at 0 °C successfully produced
the selectively cleavaged 2-hydroxybenzaldehyde (18) in an
excellent yield (92%). The other conditions, such as 12 N
HCl in MeOH at 0 °C,16) conc. HCl (2 drops) in 2-PrOH at
50 °C,20) a trace of HCl in MeOH at 62 °C21) for the cleavage
of MOM-ether, and an aqueous acetic acid in THF at 47 °C22)
for the cleavage of tetrahydropyranyl ether, were not suitable
for selective deprotection. The resulting phenol (18) was then
Temp
(°C)
Time
(min)
Yield
(%)b)
Run
Solvent
MWa)
1
2
3
4
5
6
7
8
o-Dichlorobenzene Without MW
o-Dichlorobenzene Without MW
o-Dichlorobenzene With MW
o-Dichlorobenzene With MW
o-Dichlorobenzene With MW
150
180
130
150
180
150
150
150
30
30
30
20
10
20
20
20
41
44
30
46
45
37
25
32
DMF
With MW
With MW
With MW
2-Methoxyethanol
Bromobenzene
a) MW: microwave. b) %: isolated yields.
converted into the ether (19) by means of methyl bromoac- conventional conditions at 150 °C (run 1) and 180 °C (run 2)
etate with sodium hydride in 93% yield. The cleavage of the to produce the desired 3,7,8-trisubstituted isoquinoline (23).
MOM-ether at the 4-position of 19 in acetic acid at 90 °C In this result, the yield of 23 by run 2 was slightly better than
smoothly provided the 4-hydroxybenzaldehyde (20) in 80% that of run 1. On the other hand, the microwave assisted elec-
yield, and sequential treatment of 20 with trifluoromethane- trocyclic reaction of 22 was performed to study the effect of
sulfonic anhydride (Tf2O) and pyridine at 0 °C gave the tri- the microwave irradiation in the same substrate. The effect of
flate (21) in 85% yield. The palladium-catalyzed cross-cou- the reaction temperature was initially attempted (runs 3—5).
pling reaction of 21 with tributyl 1-propenyltin in the pres- From this experiment, the conditions of 150 °C for 20 min in
ence of PdCl2(PPh3)2 in DMF at 80 °C afforded the appropri- o-dichlorobenzene (run 4) was the best result to complete the
ate o-propenyl benzaldoxime methyl ether (22) in 83% yield reaction. In addition, the effects of the other solvents were
as a 1-aza 6p-electron system (Chart 2).
examined in order to compare with o-dichlorobenzene under
As shown in Table 1, the subsequent thermal electrocyclic the same conditions (runs 6—8). Based on this experiment, it
reaction of 22 was carried out in o-dichlorobenzene under was found that o-dichlorobenzene was the best solvent for

April 2005
395
Reagent and conditions: (i) NaCN, AcOH, MnO2, MeOH, rt, 4 h (83%), (ii) NaOMe, MeOH, 80 °C, 12 h (66%), (iii) LiOH·H2O, DMSO–H2O, 70 °C, 2 h (75%), (iv) LDA,
(CH3)2CO, THF, ꢁ40 °C, 4 h, MeSO2Cl, DMAP, pyridine, 0 °C, 2 h (58%).
Chart 3
were run under an argon atmosphere. Solvents were distilled by normal
methods (THF dried over sodium benzophenone ketyl, CH2Cl2 dried over
CaH2, DMF dried over CaH2). Silica gel 60PF254 (60—100 mesh, Merck Art
7744) was used for column chromatography.
this substrate (run 4). It has been thought that the microwave
irradiated conditions are slightly more effective than the con-
ventional conditions (run 2) for reducing the reaction tem-
perature (run 4) and decreasing the reaction time (runs 4 and
5).
2,4-Bis(methoxymethyloxy)benzyl Alcohol (11) NaBH4 (1.8 g,
48.6 mmol) was added gradually to a stirred solution of benzaldehyde
(10)15,16) (10 g, 44.2 mmol) in EtOH (50 ml) under cooling with ice-water.
After being stirred at room temperature for 2 h, the mixture was concen-
trated under reduced pressure. After addition of water, the residue was ex-
tracted with EtOAc. The organic layer was washed with brine and dried over
Na2SO4. Removal of solvent gave the oily alcohol (11) (9.1 g, 90%), bp
145—147 °C/0.25 torr. 1H-NMR (CDCl3) d: 3.47 (3H, s), 3.48 (3H, s), 4.62
(2H, s), 5.15 (2H, s), 5.20 (2H, s), 6.68 (1H, dd, Jꢀ2.4, 8.2 Hz), 6.80 (1H, d,
Jꢀ2.4 Hz), 7.19 (1H, d, Jꢀ8.2 Hz). MS (CI) m/z: 228 (Mꢂ). HR-MS (CI)
m/z: 228.0994 (Mꢂ) (Calcd for C11H16O5: 228.0998).
For the preparation of the furanone ring, by the Dieck-
mann condensation (Chart 3), 7-formylisoquinoline (23) was
converted into the proposed methyl ester (5) using sodium
cyanide, MnO2, and acetic acid in MeOH according to
Corey’s procedure22,23) in 83% yield. The cyclization of 5
with sodium methoxide in MeOH at 80 °C gave the b-keto
ester (24), which was treated with lithium hydroxide in an
aqueous DMSO at 70 °C24) to produce the furanone (4) in
50% yield from 24. Finally, the carbon–carbon bond forma-
tion of 4 with acetone in the presence of lithium diisopropy-
lamide (LDA) at ꢁ40 °C, followed by treatment with
methanesulfonyl chloride (MsCl) and 4-(dimethylamino)-
pyridine (DMAP) in pyridine25) provided TMC-120B (2)
with the elimination step in 58% yield from 4. Although
this reaction was carried out at ꢁ78 and ꢁ20 °C, the
yields from 4 to 2 were 33 and 35%, respectively, lower
than that at ꢁ40 °C. The physical and spectroscopic data
of synthetic TMC-120B (2) agreed with those of natural
TMC-120B (2) in all respects.
1,3-Bis(methoxymethyloxy)-4-(tert-butyldimethylsilyloxymethyl)ben-
zene (12) A solution of the alcohol (11) (7 g, 30.7 mmol) in DMF (20 ml)
was added to
a solution of tert-butyldimethylsilyl chloride (6.9 g,
46.0 mmol) and imidazole (4.2 g, 61.3 mmol) in DMF (40 ml). After being
stirred at room temperature for 12 h, the reaction mixture was quenched with
an aqueous NaHCO3 solution (saturated), and then the mixture was extracted
with EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, 50 g) using EtOAc–hexane (1 : 9) as an elu-
1
ent to give the oily silyl ether (12) (10 g, 95%). H-NMR (CDCl3) d: 0.10
(6H, s), 0.94 (9H, s), 3.47 (3H, s), 3.47 (3H, s), 4.71 (2H, s), 5.15 (2H, s),
5.17 (2H, s), 6.71 (1H, dd, Jꢀ2.3, 8.4 Hz), 6.77 (1H, d, Jꢀ2.3 Hz), 7.34 (1H,
d, Jꢀ8.4 Hz). MS (CI) m/z: 343 [MꢂH]ꢂ. HR-MS (CI) m/z: 343.1948
[MꢂH]ꢂ (Calcd for C17H31O5Si: 343.1941).
2,6-Bis(methoxymethyloxy)-3-(tert-butyldimethylsilyloxymethyl)benz-
aldehyde (13) A solution of n-BuLi (2.6 M in hexane, 7.9 ml, 20.6 mmol)
was added to a solution of silyl ether (12) (4.7 g, 13.7 mmol) in THF (40 ml)
under cooling with ice-water. After stirring at the same temperature for
40 min, DMF (3.2 ml, 41.2 mmol) was added. The mixture was further
stirred at the same temperature for 20 min, which was quenched with water.
The mixture was extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 50 g) using
EtOAc–hexane (1 : 9) as an eluent to give the oily benzaldehyde (13) (3.8 g,
Conclusion
A total synthesis of new type of furo[3,2-h]isoquinoline
alkaloid TMC-120B (2), isolated from Aspergillus ustus TC
1118 together with TMC-120A (1) and TMC-120C (3), was
established through the construction of the appropriate 3,7,8-
trisubstituted isoquinoline framework based on the thermal
electrocyclic reaction of 1-aza 6p-electron system, followed
by the formation of furanone ring and the introduction of iso-
propylidene moiety in sixteen steps (2.5% overall yield). Fur-
thermore, it was demonstrated that the microwave irradiation
for the thermal electrocyclic reaction of 1-aza 6p-electron
system was a slightly more effective means at least for reduc-
ing the reaction temperature and shortening the time.
1
75%). IR (neat) n: 1693 cmꢁ1. H-NMR (CDCl3) d: 0.11 (6H, s), 0.94 (9H,
s), 3.51 (3H, s), 3.56 (3H, s), 4.81 (2H, s), 5.06 (2H, s), 5.27 (2H, s), 7.02
(1H, d, Jꢀ8.8 Hz), 7.65 (1H, d, Jꢀ8.8 Hz), 10.46 (1H, s). MS (CI) m/z: 371
[MꢂH]ꢂ. HR-MS (CI) m/z: 371.1897 [MꢂH]ꢂ (Calcd for C18H31O6Si:
371.1890).
2-(Methoxyiminomethyl)-1,3-bis(methoxymethyloxy)-4-(tert-butyl-
dimethylsilyloxymethyl)benzene (14) A mixture of benzaldehyde (13)
(5.5 g, 14.9 mmol), MeONH2·HCl (1.9 g, 22.3 mmol), and AcONa (1.8 g,
22.3 mmol) in EtOH (50 ml) was heated at 80 °C for 12 h. After being cooled
to ambient temperature, the mixture was quenched with water. After removal
of solvent under reduced pressure, the residue was extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column chro-
matography (silica gel, 50 g) using EtOAc–hexane (1 : 9) as an eluent to give
Experimental
All melting points were measured with a Yanagimoto micro-melting point
apparatus MP-500D and are uncorrected. IR spectra were recorded with a
Shimadzu FT-IR-8500 spectrophotometer. 1H- and 13C-NMR spectra were
taken with a JEOL AL-300 instrument using tetramethylsilane as an internal
standard. Mass spectra (MS) were determined with a Shimadzu QP5050 (EI)
and JMS-700 (CI with isobutane) spectrometers by direct inlet system, re-
spectively. The microwave assisted reaction was carried out at 180 W and
2450 MHz with “Discover” of CEM corporation. All air sensitive reactions
1
the oily oxime ether (14) (5.3 g, 89%). H-NMR (CDCl3) d: 0.10 (6H, s),
0.94 (9H, s), 3.48 (3H, s), 3.57 (3H, s), 3.98 (3H, s), 4.83 (2H, s), 5.00 (2H,
s), 5.18 (2H, s), 6.95 (1H, d, Jꢀ8.6 Hz), 7.44 (1H, d, Jꢀ8.6 Hz), 8.39 (1H,

396
Vol. 53, No. 4
s). MS (CI) m/z: 400 [MꢂH]ꢂ. HR-MS m/z: 400.2147 [MꢂH]ꢂ (Calcd for
C19H34NO6Si: 400.2155).
The mixture was extracted with CH2Cl2. The organic layer was washed with
water, brine, and dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica gel, 20 g)
using EtOAc–hexane (1 : 9) as an eluent to give the oily triflate (21) (560 mg,
85%). IR (neat) n: 1758, 1697, 1423, 1203, 1137 cmꢁ1. 1H-NMR (CDCl3) d:
3.79 (3H, s), 4.07 (3H, s), 4.70 (2H, s), 7.27 (1H, d, Jꢀ8.2 Hz), 7.95 (1H, d,
Jꢀ8.2 Hz), 8.29 (1H, s), 10.47 (1H, s). MS (EI) m/z: 399 (Mꢂ) and MS (CI)
m/z: 400 [MꢂH]ꢂ. HR-MS (CI) m/z: 400.0305 [MꢂH]ꢂ (Calcd for
C13H13F3NO8S: 400.0314).
3-(Methoxyiminomethyl)-2,4-bis(methoxymethyloxy)benzyl Alcohol
(15) Tetrabutylammonium fluoride (1.0 M in THF, 14.5 ml, 14.5 mmol) was
added to a solution of the oxime ether (14) (5.2 g, 13.0 mmol) in THF
(50 ml). The mixture was stirred at room temperature for 1.5 h, which was
quenched with water. After removal of solvent under reduced pressure, the
residue was extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 50 g) using
EtOAc–hexane (1 : 1) as an eluent to give the oily alcohol (15) (3.4 g, 91%).
1H-NMR (CDCl3) d: 3.47 (3H, s), 3.64 (3H, s), 4.00 (3H, s), 4.57 (2H, s),
5.03 (2H, s), 5.20 (2H, s), 6.95 (1H, d, Jꢀ8.4 Hz), 7.33 (1H, d, Jꢀ8.4 Hz),
8.41 (1H, s). MS (EI) m/z: 285 (Mꢂ); MS (CI) m/z 286 [MꢂH]ꢂ. HR-MS
(CI) m/z: 286.1287 [MꢂH]ꢂ (Calcd for C13H20NO6: 286.1291).
Methyl [6-Formyl-2-(methoxyiminomethyl)-3-(prop-1-en-1-yl)phenyl-
oxy]acetate (22) A mixture of the triflate (21) (84 mg, 0.21 mmol), trib-
utyl(1-propenyl)tin (84 mg, 0.25 mmol), Et4NCl (42 mg, 0.25 mmol) and
PdCl2(PPh3)2 (2 mg, 0.021 mmol) in DMF (4 ml) was heated at 80 °C for 4 h.
After being cooled to ambient temperature, an aqueous KF solution 30%
(8 ml) was added to the reaction mixture. The mixture was stirred at room
temperature for 30 min, which was filtered through a Celite pad, and then the
Celite pad was washed with EtOAc. The combined filtrate was extracted
with EtOAc, which was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column chro-
matography (silica gel, 20 g) using EtOAc–hexane (1 : 9) as an eluent to give
the alkene (22) (51 mg, 83%), mp 49—50 °C (CHCl3–hexane). IR (KBr) n:
1766, 1685 cmꢁ1. 1H-NMR (CDCl3) d: 1.79 (3/3H, dd, Jꢀ1.8, 7.1 Hz), 1.94
(6/3H, dd, Jꢀ1.8, 6.6 Hz), 3.80 (9/3H, s), 3.98 (3/3H, s), 4.01 (6/3H, s), 4.63
(4/3H, s), 4.66 (2/3H, s), 5.96 (1/3H, dq, Jꢀ7.1, 11.7 Hz), 6.31 (2/3H, dq,
Jꢀ6.6, 15.4 Hz), 6.57 (1/3H, dd, Jꢀ1.8, 11.7 Hz), 6.86 (2/3H, dd, Jꢀ1.8,
15.4 Hz), 7.19 (1/3H, d, Jꢀ8.1 Hz), 7.40 (2/3H, d, Jꢀ8.2 Hz), 7.79 (2/3H, d,
Jꢀ8.2 Hz), 7.83 (1/3H, d, Jꢀ8.1 Hz), 8.27 (1/3H, s), 8.37 (2/3H, s), 10.40
(2/3H, s), 10.49 (1/3H, s). MS (EI) m/z: 291 (Mꢂ). Anal. Calcd for
C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 62.07, H, 6.01; N, 4.60.
Methyl [7-Formyl-3-methyl-8-isoquinolyloxy]acetate (23) Without
Microwave Irradiation: A solution of the alkene (22) (191 mg, 0.66 mmol) in
o-dichlorobenzene (7 ml) was heated at 180 °C for 30 min. After being
cooled to ambient temperature, the reaction solution was concentrated under
reduced pressure. The residue was purified by column chromatography (sil-
ica gel, 20 g) using EtOAc–hexane (1 : 1) as an eluent to give the isoquino-
line (23) (74 mg, 44%).
3-(Methoxyiminomethyl)-2,4-bis(methoxymethyloxy)benzaldehyde
(16) A mixture of the alcohol (15) (1.8 g, 6.2 mmol) and activated MnO2
(2.2 g, 21.8 mmol) in CH2Cl2 (30 ml) was stirred at room temperature for
24 h. The reaction mixture was then filtered through a Celite pad, and the
Celite pad was washed with CH2Cl2. The combined CH2Cl2 was concen-
trated under reduced pressure. The residue was purified by column chro-
matography (silica gel, 30 g) using EtOAc–hexane (1 : 9) as an eluent to give
the benzaldehyde (16) (1.6 g, 89%), mp 84—87 °C (AcOEt–hexane). IR
1
(KBr) n: 1673 cmꢁ1. H-NMR (CDCl3) d: 3.49 (3H, s), 3.59 (3H, s), 4.01
(3H, s), 5.12 (2H, s), 5.28 (2H, s), 7.05 (1H, d, Jꢀ8.8 Hz), 7.87 (1H, d,
Jꢀ8.8 Hz), 8.36 (1H, s), 10.29 (1H, s). MS (EI) m/z: 283 (Mꢂ). Anal. Calcd
for C13H17NO6: C, 55.12; H, 6.15; N, 4.94. Found: C, 55.35; H, 6.29; N,
4.72.
2-Hydroxy-3-(methoxyiminomethyl)-4-(methoxymethyloxy)benzalde-
hyde (18) conc. HCl (0.034 ml, 0.35 mmol) was slowly added to a solution
of the benzaldehyde (16) (100 mg, 0.35 mmol) in MeOH (4 ml) under cool-
ing with ice-water. After stirring at the same temperature for 3 h, the mixture
was concentrated. The resulting residue was adjusted to pH 5 with an aque-
ous Na2CO3 solution (10%). The mixture was extracted with EtOAc. The or-
ganic layer was washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column chromatogra-
phy (silica gel, 20 g) using EtOAc–hexane (1 : 9) as an eluent to give the
With Microwave Irradiation: A solution of 22 (22.5 mg, 0.077 mmol) in o-
dichlorobenzene (0.8 ml) was heated at 150 °C for 20 min under microwave
irradiation (180 W), and then the solution was subjected to the same workup
to yield 23 (9.5 mg, 46%), mp 136—138 °C (MeOH). IR (KBr) n: 1759,
phenol (18) (78 mg, 92%), mp 64—67 °C (MeOH). IR (KBr) n: 1674 cmꢁ1
.
1H-NMR (CDCl3) d: 3.49 (3H, s), 4.02 (3H, s), 5.28 (2H, s), 6.73 (1H, d,
Jꢀ8.8 Hz), 7.79 (1H, d, Jꢀ8.8 Hz), 8.61 (1H, s), 10.35 (1H, s), 11.21 (1H,
s). MS (EI) m/z: 239 (Mꢂ). Anal. Calcd for C11H13NO5: C, 55.23; H, 5.48;
N, 5.86. Found: C, 55.42; H, 5.67; N. 5.77.
1
1674 cmꢁ1. H-NMR (CDCl3) d: 2.74 (3H, s), 3.83 (3H, s), 4.91 (2H, s),
7.53 (1H, s), 7.58 (1H, d, Jꢀ8.6 Hz), 8.03 (1H, d, Jꢀ8.6 Hz), 9.61 (1H, s),
10.62 (1H, s). MS (EI) m/z: 259 (Mꢂ). Anal. Calcd for C14H13NO4: C, 64.86;
H, 5.05; N, 5.40. Found: C, 64.99; H, 5.23; N, 5.25.
Methyl
[6-Formyl-2-(methoxyiminomethyl)-3-(methoxymethyloxy)-
phenyloxy]acetate (19) A solution of the phenol (18) (782 mg, 3.3 mmol)
in DMF (8 ml) was added to a suspension of 60% NaH (196 mg, 4.9 mmol)
in DMF (12 ml) under cooling with ice-water. After being stirred at the same
temperature for 30 min, methyl bromoacetate (0.48 ml, 4.9 mmol) was
added. The mixture was stirred at room temperature for 12 h, which was
quenched with an aqueous NH4Cl solution (saturated). The mixture was ex-
tracted with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 20 g) using EtOAc–hexane (3 : 7) as
an eluent to give the ester (19) (942 mg, 93%), mp 98—100 °C (MeOH). IR
Methyl [7-(Methoxycarbonyl)-3-methyl-8-isoquinolyloxy]acetate (5)
AcOH (0.042 ml, 0.73 mmol) was added to a suspension of the isoquinoline
(23) (125 mg, 0.48 mmol), NaCN (118 mg, 2.4 mmol), and activated MnO2
(717 mg, 7.3 mmol) in MeOH (8 ml). After being stirred at room tempera-
ture for 4 h, the mixture was quenched with water. The mixture was then fil-
tered through a Celite pad and the Celite pad was washed with EtOAc. The
combined filtrate was concentrated under reduced pressure and the resulting
residue was extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 20 g) using
EtOAc–hexane (1 : 1) as an eluent to give the methyl ester (5) (116 mg,
1
(KBr) n: 1751, 1678 cmꢁ1. H-NMR (CDCl3) d: 3.49 (3H, s), 3.81 (3H, s),
3.99 (3H, s), 4.69 (2H, s), 5.28 (2H, s), 7.05 (1H, d, Jꢀ8.8 Hz), 7.87 (1H, d,
Jꢀ8.8 Hz), 8.39 (1H, s), 10.42 (1H, s). MS (EI) m/z: 311 (Mꢂ). Anal. Calcd
for C14H17NO7: C, 54.02; H, 5.50; N, 4.50. Found: C, 54.23; H, 5.61; N,
4.45.
83%), mp 92—96 °C (CHCl3). IR (KBr) n: 1716, 1624 cmꢁ1 1H-NMR
.
(CDCl3) d: 2.73 (3H, s), 3.86 (3H, s), 3.97 (3H, s), 4.84 (2H, s), 7.48 (1H,
s), 7.52 (1H, d, Jꢀ8.6 Hz), 8.05 (1H, d, Jꢀ8.6 Hz), 9.73 (1H, s). MS (EI)
m/z: 289 (Mꢂ). Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84.
Found: C, 62.57; H, 5.45; N, 4.68.
Methyl [6-Formyl-3-hydroxy-2-(methoxyiminomethyl)phenyloxy]ac-
etate (20) A solution of the ester (19) (189 mg, 0.61 mmol) in AcOH
(7 ml) was heated at 90 °C for 12 h. After being cooled to ambient tempera-
ture, the reaction mixture was quenched with water. The mixture was stirred
at room temperature for 30 min. The resulting precipitate was filtered to give
the phenol (20) (129 mg, 80%), mp 112—115 °C (AcOEt–hexane). IR (KBr)
Methyl 3-Hydroxy-7-methylfuro[3,2-h]isoquinoline-2-carboxylate (24)
A mixture of methyl ester (5) (300 mg, 1.04 mmol) and NaOMe (280 mg,
5.19 mmol) in MeOH (10 ml) was heated at 80 °C for 12 h. After being
cooled to ambient temperature, the mixture was concentrated under reduced
pressure. The residue was adjusted to pH 4 with 10% HCl solution. The
mixture was extracted with EtOAc, which was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 40 g) using MeOH–CHCl3 (1 : 9) as
an eluent to give the furanone (24) (176 mg, 66%), mp 188—191 °C
1
n: 1751, 1678 cmꢁ1. H-NMR (CDCl3) d: 3.81 (3H, s), 4.03 (3H, s), 4.68
(2H, s), 6.89 (1H, d, Jꢀ8.4 Hz), 7.77 (1H, d, Jꢀ8.4 Hz), 8.82 (1H, s), 10.07
(1H, s), 11.09 (1H, s). MS (EI) m/z: 267 (Mꢂ). Anal. Calcd for C12H13NO6:
C, 53.93; H, 4.90; N, 5.24. Found: C, 54.25; H, 5.18; N, 5.37.
Methyl [6-Formyl-2-(methoxyiminomethyl)-3-(trifluoromethanesul-
fonyloxy)phenyloxy]acetate (21) Trifluoromethanesulfonic anhydride
(0.33 ml, 2.0 mmol) was added to a solution of the phenol (20) (441 mg,
1.7 mmol) and pyridine (0.40 ml, 5.0 mmol) in CH2Cl2 (12 ml) under cooling
with ice-water. After stirring at the same temperature for 4 h, the reaction
mixture was quenched with saturated aqueous NaHCO3 solution (saturated).
1
(CHCl3). IR (KBr) n: 1697 cmꢁ1. H-NMR (CDCl3) d: 2.76 (3H, s), 4.06
(3H, s), 7.55 (1H, d, Jꢀ8.8 Hz), 7.59 (1H, s), 7.87 (1H, d, Jꢀ8.8 Hz), 9.69
(1H, s). MS m/z: 257 (Mꢂ). Anal. Calcd for C14H11NO4: C, 65.37; H, 4.31;
N, 5.44. Found: C, 65.55; H, 4.42; N, 5.40.
7-Methyl-2-hydrofuro[3,2-h]isoquinolin-3-one (4) A solution of the

April 2005
397
furanone (24) (48 mg, 0.19 mmol), LiOH·H2O (39 mg, 0.93 mmol), in
DMSO (3 ml), and H2O (3 ml) was stirred at 70 °C for 1 h. After being
cooled to ambient temperature, the mixture was quenched with an aqueous
NH4Cl solution (saturated). The mixture was extracted with EtOAc. The or-
ganic layer was washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column chromatogra-
phy (silica gel, 20 g) using EtOAc–hexane (1 : 1) as an eluent to give furoiso-
quinoline (4) (28 mg, 75%), mp 119—122 °C (AcOEt–hexane). IR (KBr) n:
Press, New York, 1980.
3) Okamura W. H., de Lera A. R., “Comprehensive Organic Synthesis,”
Vol. 5, eds. by Trost B. M., Fleming I., Paquette L. A., Pergamon
Press, New York, 1991, pp. 699—750.
4) Hibino S., Sugino E., “Advances in Nitrogen Heterocycles,” Vol. 5, ed.
by Moody C. J., JAI Press, Greenwich, CT, 1995, pp. 699—750.
5) Choshi T., Yakugaku Zasshi, 121, 487—495 (2001).
6) Hirayama M., Choshi T., Kumemura T., Tohyama S., Nobuhiro J., Hib-
ino S., Heterocycles, 63, 1765—1770 (2004) and related references
cited therein.
1700 cmꢁ1 1H-NMR (CDCl3) d: 2.76 (3H, s), 4.88 (2H, s), 7.34 (1H, d,
.
Jꢀ8.4 Hz), 7.55 (1H, s), 7.74 (1H, d, Jꢀ8.4 Hz), 9.53 (1H, s). MS (EI) m/z:
199 (Mꢂ). Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.63; H, 4.76; N, 6.84.
7) Kuwabara N., Hayashi H., Hiramatsu N., Choshi T., Kumemura T.,
Nobuhiro J., Hibino S., Tetrahedron, 60, 2943—2952 (2004) and re-
lated references cited therein.
TMC-120B (2)
A solution of the furoisoquinoline (4) (20 mg,
0.10 mmol) in THF (2 ml) was added to a solution of LDA [prepared from
diisopropylamine (0.070 ml, 0.40 mmol) and n-BuLi (2.6 M in hexane,
0.15 ml, 0.40 mmol) in THF (1 ml)] at ꢁ40 °C. After stirring at the same
temperature for 30 min, acetone (0.044 ml, 0.60 mmol) was added. The reac-
tion mixture was slowly warmed to room temperature and stirred for further
4 h. The mixture was quenched with an aqueous NH4Cl solution (saturated),
8) Kohno J., Hiramatsu H., Nishio M., Sakurai M., Okuda T., Komatsub-
ara S., Tetrahedron, 55, 11247—11252 (1999).
9) Kohno J., Sakurai M., Kameda N., Nishio M., Kawano K., Kishi N.,
Okuda T., Komatsubara S., J. Antibiot., 52, 913—916 (1999).
10) Kumemura T., Choshi T., Hirata A., Sera M., Takahashi Y., Nobuhiro
J., Hibino S., Heterocycles, 61, 13—17 (2003).
and then the mixture was extracted with EtOAc. The organic layer was 11) Hibino S., Sugino E., Choshi T., Sato K., J. Chem. Soc. Perkin Trans.
washed with brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The crude alcohol was used for the next step without any further purifi-
cation. Methanesulfonyl chloride (0.017 ml, 0.22 mmol) was added to a solu-
tion of alcohol (19 mg, 0.074 mmol) and DMAP (3 mg, 0.015 mmol) in pyri-
dine (2 ml) under cooling with ice-water. After stirring at room temperature
for 2 h, the mixture was extracted with EtOAc. The organic layer was
1, 1988, 2429—2432.
12) Hibino S., Sugino E., Adachi Y., Nomi K., Sato K., Heterocycles, 28,
275—282 (1989).
13) Sugino E., Hibino S., Heterocycles, 50, 543—559 (1999).
14) Kuwabara N., Hayashi H., Hiramatsu N., Choshi T., Sugino E., Hibino
S., Chem. Pharm. Bull., 47, 1805—1807 (1999).
washed with brine, dried over Na2SO4, and concentrated under reduced pres- 15) Miyake M., Fujimoto Y., Chem. Lett., 1993, 1683—1686.
sure. The residue was purified by column chromatography (silica gel, 10 g) 16) Miyake M., Hanaoka Y., Fujimoto Y., Sato Y., Takemoto N., Yokota I.,
using EtOAc–hexane (4 : 1) as an eluent to give TMC-120B (2) (14 mg,
Yoshiyama Y., Heterocycles, 43, 665—674 (1996).
58%), mp 175—178 °C (MeOH) (lit.,8,9) mp 176—178 °C). IR (KBr) n: 17) Pocci M., Bertini V., Lucchesini F., de Munno A., Picci N., Iemma F.,
1
1693 cmꢁ1. H-NMR (CDCl3) d: 2.26 (3H, s), 2.45 (3H, s), 2.76 (3H, s),
Alfei S., Tetrahedron Lett., 42, 1351—1354 (2001).
18) Dalcanale E., Montanari F., J. Org. Chem., 51, 567—569 (1986).
7.38 (1H, d, Jꢀ8.6 Hz), 7.56 (1H, s), 7.83 (1H, d, Jꢀ8.6 Hz), 9.57 (1H, s).
13C-NMR (CDCl3) d: 182.3, 164.0, 156.7, 146.2, 145.6, 141.4, 133.9, 124.2, 19) Hollinshead S. P., Nichols J. B., Wilson J. W., J. Org. Chem., 59,
120.6, 119.6, 119.4, 114.6, 24.7, 20.4, 17.6. MS m/z: 239 (Mꢂ). Anal. Calcd
for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.54; H, 5.50; N, 20) Hall D. G., Deslongchamps P., J. Org. Chem., 60, 7796—7814 (1995).
6703—6709 (1994).
5.80.
21) Auerbach J., Weinreb S. M., J. Chem. Soc., Chem. Commun., 1974,
298—299.
Acknowledgement This work was supported in part by Grant-in Aid for
Scientific Research (C) (No. 15590033) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
22) Corey E. J., Shaaf T. K., Huber W., Koelliker U., Weinshenker N. M., J.
Am. Chem. Soc., 92, 397—398 (1970).
23) Lai G., Anderson W. K., Synth. Commun., 27, 1281—1283 (1997).
24) Takeuchi Y., Watanabe I., Misumi K., Irea M., Hirose Y., Hirata K.,
Yamato M., Harayama T., Chem. Pharm. Bull., 45, 2011—2015
(1997).
References and Notes
1) Woodward R. B., Hoffmann R., “The Conservation of Orbital Symme-
try,” Chapt. 5, Verlag Chemie, Weinheim, 1970.
25) Danishefsky S., Etheredge S. J., J. Org. Chem., 43, 4604—4605
(1978).
2) Marvel E. N., “Thermal Electrocyclic Reactions,” Chapt. 2, Academic