A Concise Formal Total Synthesis of Mappicine and Nothapodytine B via an Intramolecular Hetero Diels-Alder Reaction

Article abstract of DOI:10.1021/jo000816i

A six-step formal total synthesis of a natural alkaloid, mappicine (3), has been achieved. The highlight of our synthetic strategy is an intramolecular hetero Diels-Alder reaction that was used for the construction of the CD ring system of mappicine (3). In addition, it was demonstrated that the Sonogashira coupling reaction of 2-chloro-3-hydroxymethylquinoline (8c) with trimethylsilylacetylene proceeded at room temperature in excellent yield.

Full text of DOI:10.1021/jo000816i

7110
J . Org. Chem. 2000, 65, 7110-7113
A Con cise F or m a l Tota l Syn th esis of Ma p p icin e a n d
Noth a p od ytin e B via a n In tr a m olecu la r Heter o Diels-Ald er
Rea ction
Masahiro Toyota,* Chiyo Komori, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai, 980-8578, J apan
mihara@mail.pharm.tohoku.ac.jp
Received May 30, 2000
A six-step formal total synthesis of a natural alkaloid, mappicine (3), has been achieved. The
highlight of our synthetic strategy is an intramolecular hetero Diels-Alder reaction that was used
for the construction of the CD ring system of mappicine (3). In addition, it was demonstrated that
the Sonogashira coupling reaction of 2-chloro-3-hydroxymethylquinoline (8c) with trimethylsilyl-
acetylene proceeded at room temperature in excellent yield.
Sch em e 1
In tr od u ction
The E ring decarboxylated camptothecin analogues,
nothapodytines A (1) and B (2), have been recently
isolated from Nothapodytes foetida.1 Nothapodytine B
(mappicine ketone) (2) is an oxidized derivative of natural
alkaloid mappicine (3),2 and both 1 and 2 show significant
cytotoxicity in the human KB cell line.3 Since nothapo-
dytine B (2) has been identified as an antiviral agent with
selective activities against herpes simplex virus-1 (HSV-
1) and HSV-2,4 this family of alkaloids has received
considerable attention by organic chemists.5 Although the
synthesis of nothapodytine B (2) was initially accom-
plished by thermolysis of camptothecin (4)6 and several
other methods for the construction of these types of
alkaloids have also been reported,7 limited supplies of 2
made it necessary to develop novel synthetic methodolo-
gies for nothapodytine B (2). Herein we present a novel
synthetic approach to mappicine (3) employing the in-
tramolecular hetero Diels-Alder reaction as a key step.8
mappicine (3) has been achieved by Kametani et al.,9 the
synthesis of 5 completes the task. The pivotal step of the
synthesis is an intramolecular hetero Diels-Alder reac-
tion of the 1-azadienyne 6. Though a large number of
natural products have been synthesized by using the
hetero Diels-Alder reaction have been reported,10 little
is known about the practical applications of hetero Diels-
Alder reactions of 1-azabutadiene derivatives for the
construction of polycyclic natural alkaloids. The tetra-
cyclic ester 5 could be generated by the intramolecular
hetero Diels-Alder reaction of the 1-azadienyne 6, which
might be formed in situ from the corresponding amide
derivative. The acetylene 7, convertible to 6, would be
synthesized using palladium-catalyzed Sonogashira cou-
pling of the 2-chloroquinoline derivative 8 with trimeth-
ylsilylacetylene.
Resu lts a n d Discu ssion
To introduce an acetylene moiety into the C-2 position
of the 2-chloroquinoline derivatives, palladium-catalyzed
(5) Recent Total Syntheses: (a) Comins, D. L.; Saha, J . K. J . Org.
Chem. 1996, 61, 9623. (b) Boger, D. L.; Homg, J . J . Am. Chem. Soc.
1998, 120, 1218. (c) Yadav, J . S.; Sarkar, S.; Chandrasekhar, S.
Tetrahedron 1999, 55, 5449.
(6) Kingsbury, W. D. Tetrahedron Lett. 1988, 29, 6847.
(7) Saxton, J . E. Monoterpenoid Indole Alkaloids; J ohn Wiley &
Sons: Chichester, New York, Brisbane, Toronto, Singapore, 1994; p
689.
The retrosynthetic analysis for mappicine (3) is shown
in Scheme 1. Since the transformation of the ester 5 into
(1) Wu, T. S.; Chan, Y. Y.; Leu, Y. L.; Chern, C. Y.; Chen, C. F.
Phytochemistry 1996, 42, 907.
(2) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N. J .
Chem. Soc., Perkin Trans. 1 1974, 1215.
(3) Wu, T. S.; Leu, Y. L.; Hsu, H. C.; Ou, L. F.; Chen, C. C.; Chen,
C. F.; Ou, J . C.; Wu, Y. C. Phytochemistry 1995, 39, 383.
(4) (a) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.;
Kingsbury, W. D. J . Org. Chem. 1994, 59, 2623. (b) Pendrak, I.;
Wittrock, R.; Kingsbury, W. D. Ibid. 1995, 60, 2912.
(8) A part of this work was published as preliminary communica-
tion: Toyota, M.; Komori, C.; Ihara, M. Heterocycles 2000, 52, 591.
(9) Kametani, T.; Takeda, H.; Nemoto, H.; Fukumoto, K. J . Chem.
Soc., Perkin Trans. 1 1975, 1825.
(10) Selected reviews: (a) Boger, D. L. Tetrahedron 1983, 39, 2869.
(b) Idem. Chem. Rev. 1986, 86, 781. (c) Idem. J . Heterocycl. Chem. 1996,
33, 1519.
10.1021/jo000816i CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/28/2000

Synthesis of Mappicine and Nothapodytine B
J . Org. Chem., Vol. 65, No. 21, 2000 7111
Sch em e 3
F igu r e 1.
Sch em e 2
in 30% overall yield. Heating of the amide 10 with
chlorotrimethylsilane and triethylamine at 180 °C in the
presence of zinc chloride14 produced the desired tetracy-
clic compound 11 in 79% yield. Desilylation15 of the
vinylsilane 11 with 47% aqueous hydrogen bromide
solution followed by DDQ oxidation16 produced 12 in good
yield.
With the efficient synthesis of the basic carbon frame-
work of mappicine (3) established, our attention was next
focused on the application of this synthetic methodology
to natural alkaloid synthesis. A formal synthesis of
mappicine (3) commenced with compound 7. The amide
formation reaction was carried out in a manner similar
to that described above. Thus, reduction of 7 with wet
triphenylphosphine followed by the condensation with
fumaric acid monoethyl ester in the presence of BOP and
Hu¨nig’s base gave the unsaturated amide 13 in 67%
overall yield (Scheme 3). Intramolecular hetero Diels-
Alder reaction of 13 led to the cycloadduct 14 (76%),
which was treated with aqueous hydrogen bromide to
provide the ester 15 (93% yield) in a single step. As it
turned out, the electron-withdrawing substituent group
(ethyl ester in 13) did not impede the cycloaddition; on
the contrary, it promoted the autoxidation of the corre-
sponding cycloadduct. Finally, compound 15 was sub-
jected to transesterification reaction with methanol in the
presence of concd H2SO4 to afford methyl ester 5. The
structure of 5 was confirmed by HMBC experiments.
Compound 5 had already been transformed into nothapo-
dytine B (2) and mappicine (3) by Kametani and co-
workers.9
Sonogashira coupling reactions11 were investigated as
depicted in Figure 1. The reactions proceeded smoothly
in the presence of 5 mol % of Pd(PPh3)2Cl2 and 5 mol %
of CuI, producing the (trimethylsilyl)acetylene derivative.
It was found that the N-phthalimide moiety in 8d was
not suitable for the Sonogashira coupling process (entry
4).
Having established the efficient synthesis of the acety-
lene derivative 9c, we next examined the transformation
of the primary hydroxyl group of 9c into an azide group.
Treatment of the alcohol 9c with sodium azide, carbon
tetrabromide, and triphenylphosphine afforded the cor-
responding azide (Scheme 2), which was subjected to
reduction12 with triphenylphosphine followed by a con-
densation reaction with methacrylic acid in the presence
of benzotriazolyl-N-oxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP)13 to give rise to the amide
10 in 55% overall yield for two steps. It is worthwhile to
notice that Schotten-Baumann reaction of the corre-
sponding amine and methacryloyl chloride furnished 10
In conclusion, we have developed a novel synthetic
route to nothapodytine B (2) and mappicine (3) by using
intramolecular hetero Diels-Alder reaction as a key step.
(14) (a) Ihara, M.; Kirihara, T.; Fukumoto, K.; Kametani, T.
Heterocycles 1985, 23, 1097. (b) Ihara, M.; Kirihara, T.; Kawaguchi,
A.; Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1984, 25, 4541
(15) J osien, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem. Eur. J . 1998,
4, 67.
(11) Yang, Z.; Barton, D. J . Tetrahedron Lett. 1990, 31, 1369
(12) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 24,
763.
(13) Custro, B.; Dormoy, J . R.; Evin, G.; Celve, C. Tetrahedron Lett.
1975, 1219.
(16) Walker, D.; Hiebert, J . D. Chem. Rev. 1967, 67, 153.

7112 J . Org. Chem., Vol. 65, No. 21, 2000
Toyota et al.
was concentrated to the crude product, which was chromato-
This methodology could be adaptable for the synthesis
of their analogues and camptothecin (4).
graphed. Elution with
a 3:1 mixture of hexanes-EtOAc
afforded the alcohol 9c (1.30 g, 98%) as yellow scales, mp 137-
138 °C. IR (KBr) cm-1: 3225, 2140.1H NMR δ: 0.32 (9H, s),
2.33 (1H, t, J ) 6.0 Hz), 4.99 (2H, d, J ) 6.0 Hz), 7.53 (1H, dd,
J ) 7.0, 1.0 Hz), 7.68 (1H, ddd, J ) 7.0, 7.0, 1.5 Hz), 7.79 (1H,
d, J ) 8.0 Hz), 8.08 (1H, d, J ) 8.0 Hz), 8.19 (1H, s). MS (EI)
m/z: 255 (M+). Anal. Calcd for C15H17NOSi: C, 70.54; H, 6.74;
N, 5.48. Found: C, 70.45; H, 6.80; N, 5.52.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all reactions were per-
formed in oven-dried glassware, sealed with a rubber septum
under an atmosphere of argon. Anhydrous tetrahydrofuran
(THF) and acetonitrile (MeCN) were purchased from Kanto
Chemical Co., Inc. Toluene and diisopropylethylamine (i-Pr2-
NH) were distilled from CaH2. Triethylamine (Et3N) was
distilled from KOH immediately before use. N,N-Dimethyl-
formamide (DMF) was distilled from CaH2 and used im-
mediately. Benzene (C6H6), ethyl acetate (EtOAc), and metha-
nol (MeOH) were distilled under argon immediately prior to
use. Unless otherwise mentioned, materials were obtained
from commercial suppliers and used without further purifica-
tion. Organic extracts were dried by being stirred over
anhydrous Na2SO4, filtered through Celite, and concentrated
under reduced pressure with the aid of a rotary evaporator.
Flash chromatography was carried out using Merck 60 (230-
400 mesh) or Cica 60 (spherical/40-100 µm) silica gel. Reac-
tions and chromatography fractions were analyzed employing
precoated silica gel 60 F254 plates (Merck). Compounds were
visualized using a ultraviolet lamp (254 nm) and/or by staining
with p-anisaldehyde (in EtOH), phosphomolybdic acid (in
EtOH), or ammonium molybdate (in 10% H2SO4). IR spectra
were recorded as KBr pellets unless otherwise noted. Until
otherwise noted, 1H NMR spectra were measured as CDCl3
solutions at 300 MHz, and 13C NMR spectra were recorded as
CDCl3 solution at 75 MHz. Chemical shifts are expressed in
ppm downfield from internal tetramethylsilane or relative
internal CHCl3. J values are in hertz.
2-Ch lor o-3-(h yd r oxyim in om eth yl)qu in olin e (8a ). To a
stirred solution of the aldehyde 8b17 (1.0 g, 5.24 mmol) in
pyridine (5 mL) was added hydroxylamine hydrochloride (372
mg, 5.76 mmol) at room temperature, and then the mixture
was stirred at room temperature for 1 h. After removal of the
solvent, the crude oxime was recrystallized from EtOH to give
8a (946 mg, 88%) as yellow needles, mp 151-152 °C. IR (KBr)
cm-1: 3500, 1615. 1H NMR (300 MHz, acetone-d6) δ: 7.67 (1H,
ddd, J ) 7.0, 7.0, 1.5 Hz), 7.84 (1H, ddd, J ) 6.0, 6.0, 1.5 Hz),
7.95 (1H, d, J ) 7.0 Hz), 8.08 (1H, d, J ) 9.0 Hz), 8.54 (1H, s),
8.73 (1H, s), 11.0 (1H, s). 13C NMR (75 MHz, DMSO-d6) δ:
125.1, 126.9, 127.8, 127.9, 128.8, 131.7, 135.8, 144.2, 147.1,
148.1. HRMS (EI) m/z: Calcd for C10H7ClN2O (M+): 206.0246.
Found: 206.0249.
3-Azidom eth yl-2-[(tr im eth ylsilyl)eth yn yl]qu in olin e (7).
A mixture of the acetylene alcohol 9c (1.0 g, 3.92 mmol),
sodium azide (382 mg, 5.88 mmol), triphenylphosphine (1.54
g, 5.88 mmol), and carbon tetrabromide (1.95 g, 5.88 mmol)
in anhydrous DMF (10 mL) was vigorously stirred at room
temperature for 15 min. After removal of the solvent under
reduced pressure, the residue was chromatographed. Elution
with a 10:1 mixture of hexanes-EtOAc yielded the azide 7
(1.06 g, 97%) as colorless prisms, mp 94-95 °C. IR (neat) cm-1
:
1
2100. H NMR δ: 0.34 (9H, s), 4.75 (2H, s), 7.56(1H, ddd, J
) 7.0, 7.0, 1.0 Hz), 7.74 (1H, ddd, J ) 7.0, 7.0, 1.4 Hz), 7.81-
(1H, d, J ) 7.0 Hz), 8.12 (1H, d, J ) 7.0 Hz), 8.15 (1H, s). 13C
NMR δ: 0.47, 52.1, 100.9, 101.5, 127.1, 127.6, 127.8, 129.3,
130.3, 130.5, 135.0, 142.5, 147.6. HRMS (EI) m/z: Calcd for
C
15H16N4Si (M+): 280.1144. Found: 280.1142.
3-Meth a cr yla m id om eth yl-2-[(tr im eth ylsilyl)eth yn yl]-
qu in olin e (10). To a solution of the azide 7 (406 mg, 1.45
mmol) in THF (15 mL) were added triphenylphosphine (572
mg, 2.18 mmol) and water (0.33 mL) at room temperature,
and then the resulting mixture was heated at 45 °C for 1 h.
After removal of the solvent under reduced pressure, the
residue was diluted with EtOAc (10 mL). The organic layer
was dried over Na2SO4, and then the solvent was evaporated
to furnish the crude amine, which was used in the next step
without purification.
To a stirred solution of the crude amine in anhydrous DMF
(14 mL) were added benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (641 mg,1.45 mmol), meth-
acrylic acid (0.13 mL, 1.53 mmol), and Et3N (0.40 mL, 2.90
mmol) at room temperature, and then the resulting mixture
was stirred at the same temperature for 6 h. After removal of
the solvent under reduced pressure, the residue was chro-
matographed. Elution with a 4:1 mixture of hexanes-EtOAc
gave rise to the amide 10 (256 mg, 55% overall yield for two
steps) as colorless prisms, mp 142-143 °C. IR (neat) cm-1
:
1
3350, 1670, 1627. H NMR δ: 0.33 (9H, s), 1.98 (3H, s), 4.77
(2H, d, J ) 6.0 Hz), 5.38 (1H, s), 5.76 (1H, s), 6.64 (1H, br s),
7.54 (1H, ddd, J ) 7.0, 7.0, 1.0 Hz), 7.70 (1H, ddd, J ) 7.0,
7.0, 1.5 Hz), 7.77 (1H, d, J ) 7.0 Hz), 8.08 (1H, d, J ) 7.0 Hz),
8.12 (1H, s). MS (EI) m/z: 322 (M+). Anal. Calcd for C19H22N2-
OSi: C, 70.77; H, 6.88; N, 8.69. Found: C, 70.49; H, 6.91; N,
8.47.
2-Ch lor o-3-(p h th a lim id om eth yl)qu in olin e (8d ). To a
stirred solution of the alcohol 8c18 (50.0 mg, 0.28 mmol) in
anhydrous THF (3.0 mL) were added phthalimide (41.8 mg,
0.28 mmol), triphenylphosphine (74.5 mg, 0.28 mmol), and
diethyl azodicarboxylate (0.05 mL, 0.28 mmol) at -10 °C, and
then the mixture was allowed to warm to room temperature
and stirred for 5 h. After removal of the solvent, the crude
phthalimide was chromatographed. Elution with a 95:5 mix-
ture of CHCl3-MeOH afforded 8d (153. 4 mg, 75%) as a white
powder, mp 164-166 °C. IR (KBr) cm-1: 1775, 1735. 1H NMR
δ: 5.14 (1H, s), 7.53 (1H, dd, J ) 7.0, 1.0 Hz), 7.68-8.05 (8H,
m). 13C NMR δ: 39.3, 123.8, 127.1 127.4, 127.5, 128.3, 130.6,
132.0, 134.5, 137.1, 147.2, 149.4, 167.9. HRMS (EI) m/z: Calcd
for C18H11ClN2O2 (M+): 322.0508. Found: 322.0479.
11H-7,8-Dih ydr o-8-m eth yl-6-tr im eth ylsilyl-9-oxoin doliz-
in o[1,2-b]qu in olin e (11). A mixture of the amide 10 (62 mg,
0.19 mmol), ZnCl2 (51.8 mg, 0.38 mmol), TMSCl (0.48 mL, 3.8
mmol), and Et3N (0.53 mL, 3.8 mmol) in anhydrous toluene
(3.0 mL) was heated in a sealed tube at 180 °C for 5 h. After
removal of the solvent under reduced pressure, saturated
aqueous NH4Cl solution was added. The resulting mixture was
extracted with EtOAc. The organic layer was washed with
saturated aqueous NaCl solution, dried, and evaporated to
leave the crude product, which was chromatographed. Elution
with a 3:1 mixture of hexanes-EtOAc afforded the cycloadduct
11 (48.4 mg, 79%), as orange needles, mp 222-224 °C. IR
(neat) cm-1: 1675.1H NMR δ: 0.39 (9H, s), 1.30 (3H, d, J )
6.0 Hz), 2.40 (1H, dd, J ) 16.0, 11.0 Hz), 2.58 (1H, m), 2.75
(1H, dd, J ) 16.0, 6.0 Hz), 5.00 (2H, d, J ) 5.0 Hz), 7.54 (1H,
ddd, J ) 7.0, 7.0, 1.0 Hz), 7.71 (1H, ddd, J ) 7.0, 7.0, 1.5 Hz),
7.82 (1H, d, J ) 7.0 Hz), 8.08 (1H, s), 8.09 (1H, d, J ) 7.0 Hz).
MS (EI) m/z: 322 (M+). Anal. Calcd for C19H22N2OSi: C, 70.77;
H, 6.88; N, 8.69. Found: C, 70.72; H, 6.93; N, 8.67.
Rep r esen ta tive P r oced u r e for th e Son oga sh ir a Cou -
p lin g Rea ction .
3-H yd r oxym et h yl-2-[(t r im et h ylsilyl)et h yn yl]q u in o-
lin e (9c). To a stirred solution of the alcohol 8c (1.00 g, 5.18
mmol) in anhydrous DMF (5.0 mL) were added Pd(PPh3)2Cl2
(180 mg, 0.26 mmol), CuI (50.0 mg, 0.26 mmol), Et3N (3.0 mL,
21.5 mmol), and (trimethylsilyl)acetylene (0.81 mL, 5.73 mmol)
at room temperature, and the mixture was stirred at the same
temperature for 1 h. After filtration through Celite, the filtrate
11H-8-Meth yl-9-oxoin d olizin o[1,2-b]qu in olin e (12) To
a stirred solution of the compound 11 (10.0 mg, 0.03 mmol) in
EtOAc (1.5 mL) was added dropwise 47% aqueous HBr
solution (0.3 mL, 2.60 mmol) at room temperature, and then
the resulting mixture was stirred at the same temperature
(17) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J . Chem. Soc., Perkin
Trans. 1 1981, 1520.
(18) Narasimhan, N, S.; Sunder, N. M.; Ammanamanchi, R.; Bonde,
B. D. J . Am. Chem. Soc. 1990, 112, 4431.

Synthesis of Mappicine and Nothapodytine B
J . Org. Chem., Vol. 65, No. 21, 2000 7113
for 5 min. After addition of saturated aqueous NaHCO3
solution, the mixture was extracted with EtOAc. The organic
layer was washed with saturated aqueous NaCl solution, dried
and evaporated to leave the crude product, which was chro-
matographed. Elution with a 1:1 mixture of hexanes-EtOAc
gave the desilylated compound (6.2 mg, 83%), as light yellow
needles, mp 243-245 °C.
and evaporated to give the crude product, which was chro-
matographed. Elution with a 3:1 mixture of hexanes-EtOAc
provided the cycloadduct 14 (24.0 mg, 76%), as a colorless
powder, mp 155-157 °C. IR (neat) cm-1: 1720, 1680. 1H NMR
δ: 0.46 (9H, s), 1.25 (3H, t, J )7.0 Hz), 2.66 (1H, dd, J ) 16.0,
7.0 Hz), 3.05 (1H, dd, J ) 16.0, 1.5 Hz), 3.72 (1H, dd, J ) 7.0,
1.5 Hz), 4.13 (2H, m), 4.90 (1H, d, J ) 15.0 Hz), 5.08 (1H, d,
J ) 15.0 Hz), 7.56 (1H, ddd, J ) 7.0, 7.0, 1.0 Hz), 7.72 (1H,
ddd, J ) 7.0, 7.0, 1.5 Hz), 7.82 (1H, d, J ) 7.0 Hz), 8.08 (1H,
s), 8.10 (1H, d, J ) 7.0 Hz). 13C NMR δ: 0.39, 13.9, 33.0, 41.4,
47.7, 61.1, 109.6, 127.1, 127.5, 127.8, 129.3, 129.4, 129.7, 129.9,
135.8, 145.1, 148.3, 168.1, 172.5. HRMS (EI) m/z: Calcd for
1
IR (KBr) cm-1: 1653. H NMR δ: 1.34 (3H, d, J ) 6.0 Hz),
2.42 (1H, m), 2.73 (2H, m), 5.00 (2H, s), 6.24 (1H, s), 7.56 (1H,
ddd, J ) 7.0, 7.0, 1.0 Hz), 7.73 (1H, ddd, J ) 7.0, 7.0, 1.5 Hz),
7.82 (1H, d, J ) 7.0 Hz), 8.10 (1H, d, J ) 7.0 Hz), 8.11(1H, s).
MS (EI) m/z: 250 (M+). Anal. Calcd for C16H14N2O: C, 76.78;
H, 5.64; N, 11.19. Found: C, 76.59; H, 5.72; N, 11.05.
To a stirred solution of the above product (62.3 mg, 0.25
mmol) in C6H6 (5.0 mL) was added DDQ (86.3 mg, 0.38 mmol)
at room temperature, and the mixture was stirred at room
temperature for 15 min. After addition of saturated aqueous
NaHCO3 solution, the organic layer was separated. The
organic layer was washed with saturated aqueous NaCl
solution, dried, and evaporated to leave the crude product,
which was chromatographed. Elution with a 95:5 mixture of
CHCl3-MeOH gave rise to 12 (48.4 mg, 78%) as light yellow
prisms, mp 230-232 °C. IR (KBr) cm-1: 1654, 1594.1H NMR
δ: 2.31 (3H, s), 5.24 (2H, s), 7.22 (1H, d, J ) 7.0 Hz), 7.53
(1H, d, J ) 7.0 Hz), 7.60 (1H, d, J )7.0 Hz), 7.78 (1H, ddd, J
) 7.0, 7.0, 1.5 Hz), 7.87 (1H, d, J ) 7.0 Hz), 8.17 (1H, d, J )
8.0 Hz), 8.28 (1H, s). 13C NMR δ: 17.0, 49.9, 100.9, 127.5,
128.0, 128.2, 128.8, 129.6, 130.3, 130.6, 130.9, 137.8, 143.7,
148.9, 153.6, 161.9. HRMS (EI) m/z: Calcd for C16H12N2O
(M+): 248.0949. Found: 248.0941.
3-[2(E)-3-Eth oxyca r bon yla cr yla m id om eth yl]-2-[(tr im -
eth ylsilyl)eth yn yl]qu in olin e (13). To a stirred solution of
the azide 7 (549 mg, 1.96 mmol) were added triphenylphos-
phine (514 mg, 1.96 mmol) and H2O (0.40 mL) at room
temperature, and the resulting mixture was heated at 55 °C
for 1 h. After removal of the solvent under reduced pressure,
the residue was dissolved in EtOAc (10 mL). The organic layer
was dried and evaporated to leave the amine, which was used
in the next step without purification.
To a stirred solution of the above product in anhydrous
MeCN (10 mL) were added BOP (867 mg, 1.96 mmol), fumaric
acid monoethyl ester (283 mg, 1.96 mmol), and i-Pr2NEt (0.68
mL, 3.92 mmol) at room temperature, and the resulting
mixture was stirred at the same temperature for 3 h. Evapora-
tion of the solvent yielded the crude product, which was
chromatographed. Elution with a 3:1 mixture of hexanes-
EtOAc provided the amide 13 (501 mg, 67% overall yield for
two steps), as an orange oil. IR (neat) cm-1: 3260, 1718, 1660.
1H NMR δ: 0.33 (9H, s), 1.28 (3H, t, J ) 6.0 Hz), 4.25 (2H, q,
J ) 7.0 Hz), 4.85 (2H, d, J ) 6.0 Hz), 6.40 (1H, br s), 6.87 (1H,
d, J )15.0 Hz), 6.96 (1H, d, 15.0 Hz), 7.54 (1H, dd, J ) 7.0,
7.0 Hz), 7.70 (1H, ddd, J )7.0, 7.0, 1.5 Hz), 7.76 (1H, d, J )
7.0 Hz), 8.08 (1H, d, J ) 7.0 Hz), 8.12(1H, s). MS (EI) m/z:
380 (M+). Anal. Calcd for C21H24N2O3Si: C, 66.29; H, 6.36; N,
7.36. Found: C, 66.41; H, 6.39; N, 7.28.
11H-7,8-Dih yd r o-7-eth oxyca r bon yl-6-tr im eth ylsilyl-9-
oxoin d olizin o[1,2-b]qu in olin e (14) A mixture of the amide
13 (31.4 mg, 0.08 mmol), ZnCl2 (23.2 mg, 0.17 mmol), TMSCl
(0.21 mL, 1.66 mmol), and i-Pr2NEt (0.29 mL, 1.66 mmol) in
anhydrous toluene (3.0 mL) was heated in a sealed tube at
180 °C for 5 h. After removal of the solvent under reduced
pressure, saturated aqueous NH4Cl solution was added. The
resulting mixture was extracted with EtOAc, and the organic
layer was washed with saturated aqueous NaCl solution, dried,
C
21H24N2O3Si (M+): 380.1555. Found: 380.1537.
11H -7-E t h oxyca r b on yl-9-oxoin d olizin o[1,2-b]q u in o-
lin e (15). To a stirred solution of the compound 14 (41.9 mg,
0.11 mmol) in EtOAc (5.0 mL) was added dropwise 47%
aqueous HBr solution at room temperature, and then the
resulting mixture was refluxed for 1 h. The solution was
neutralized with saturated aqueous NaHCO3 solution at 0 °C,
and the mixture was extracted with EtOAc. The organic layer
was washed with saturated aqueous NaCl solution, dried, and
evaporated to leave the crude product, which was chromato-
graphed. Elution with a 95:5 mixture of CHCl3-MeOH gave
15 (31.4 mg, 93%), as a colorless powder, mp 215-217 °C. IR
1
(KBr) cm-1: 1725, 1670, 1610, 1604. H NMR δ: 1.45 (3H, t,
J ) 7.0 Hz), 4.45 (2H, q, J ) 6.0 Hz), 5.31 (2H, s), 7.40 (1H, d,
J ) 1.5 Hz), 7.68 (1H, ddd, J ) 7.0, 7.0, 1.0 Hz), 7.83 (1H, d,
J )1.5 Hz), 7.84 (1H, ddd, J ) 7.0, 7.0, 1.5 Hz), 7.94 (1H, d, J
) 8.0 Hz), 8.25 (1H, d, J ) 8.0 Hz), 8.41 (1H, s). 13C NMR δ:
14.1, 50.1, 62.1, 95.2, 99.7, 122.2, 128.0, 128.2, 128.7, 129.9,
130.7, 131.1, 142.4, 149.1, 161.3, 164.8, 174.2, 212.5. HRMS
(EI) m/z: Calcd for
C
18H14N2O3 (M+): 306.1004. Found:
306.0966.
11H-7-Meth oxyca r bon yl-9-oxoin d olizin o[1,2-b]qu in o-
lin e (5). To a stirred solution of 15 (31.4 mg, 0.10 mmol) in
MeOH (3.0 mL) was added concd H2SO4 (0.1 mL, 1.82 mmol)
at room temperature, and then the resulting mixture was
refluxed for 5 h. The solution was neutralized with saturated
aqueous NaHCO3 solution at 0 °C, and the resulting solution
was extracted with EtOAc. The organic layer was washed with
saturated aqueous NaCl solution, dried, and evaporated to
furnish the crude product, which was chromatographed. Elu-
tion with a 95:5 mixture of CHCl3-MeOH gave rise to 5 (19.6
mg, 67%), as a colorless powder, mp 185-187 °C. IR (KBr)
1
cm-1: 1725, 1669, 1610, 1605. H NMR δ: 3.97 (3H, s), 5.29
(2H, s), 7.36 (1H, d, J ) 1.5 Hz), 7.65 (1H, ddd, J ) 7.0, 7.0,
1.0 Hz), 7.79 (1H, d, J ) 1.5 Hz), 7.81 (1H, ddd, J )7.0, 7.0,
1.5 Hz), 7.93 (1H, d, J ) 8.0 Hz), 8.23 (1H, d, J ) 8.0 Hz),
8.37 (1H, s). 13C NMR δ: 50.2, 53.0, 99.6, 122.1, 128.0, 128.1,
128.2, 128.6, 129.9, 130.6, 131.0. 142.0, 146.7, 149.0, 152.6,
161.1, 165.1. HRMS (EI) m/z: Calcd for C17H12N2O3 (M+): 292,-
0848. Found: 292.0815.
Ack n ow led gm en t. Ack n ow legd m en t. This work
is supported by a Grant-in-Aid (No. 11672097) from the
Ministry of Education, Science, Sports and Culture,
J apan.
Su p p or tin g In for m a tion Ava ila ble: Su p p or tin g In -
for m a tion Ava ila ble: 1H and 13C NMR spectral data for 8a ,
8d , 7, 12, 14, 15, and 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O000816I