Biomimetic total synthesis of (±)-8-oxoerymelanthine

Article abstract of DOI:10.1021/jo9008645

(Chemical Equation Presented) Erymelanthine 1 and 8-oxoerymelanthine 2 are unique erythrina alkaloids containing a pyridine ring. We synthesized (±)-8-oxoerymelanthine 2 in 2.0% overall yield using the following key reactions. The characteristic 6-5-6-6-m

Full text of DOI:10.1021/jo9008645

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Biomimetic Total Synthesis of (()-8-Oxoerymelanthine
Yuki Yoshida,† Kunihiko Mohri,† Kimiaki Isobe,† Toshimasa Itoh,† and
Keiko Yamamoto*,†,‡
†Laboratory of Drug Design and Medicinal Chemistry and ‡High Technology Research Center,
Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
yamamoto@ac.shoyaku.ac.jp
Received April 26, 2009
Erymelanthine 1 and 8-oxoerymelanthine 2 are unique erythrina alkaloids containing a pyridine ring.
We synthesized (()-8-oxoerymelanthine 2 in 2.0% overall yield using the following key reactions.
The characteristic 6-5-6-6-membered ring system was constructed by the stereoselective intermole-
cular Diels-Alder reaction. Oxidative cleavage of the aromatic D-ring was conducted chemo- and
regioselectively by ozonolysis in the presence of BF3-etherate. This cleavage site is identical to the site
cleaved during the biosynthesis of erymelanthine 1. Nitrogen incorporation was achieved by
aminolysis. Conversion of the D-ring pyridone to the corresponding pyridine was efficiently
accomplished by palladium-catalyzed reduction of aryl triflate 21. This is not only the first total
synthesis of (()-8-oxoerymelanthine 2 (where the D-ring is pyridine) but also, more importantly,
a biomimetic total synthesis of an erythrinan D-aza alkaloid.
Introduction
such as the erythroidines3 and erymelanthine.4 These non-
aromatic alkaloids are known to be biologically synthesized
from aromatic alkaloids through oxidative cleavage of the
D-ring, followed by recyclization.1,4
Erythrina alkaloids have attracted much attention, be-
cause in addition to their characteristic polycondensed
structures, they exhibit curare-like and hypnotic activity as
well as pharmacological effects, such as sedation, hypoten-
sion, neuromuscular inhibition, and CNS effects.1,2 This
family of alkaloids is conveniently categorized into aromatic
and non-aromatic alkaloids according to whether the D-ring
is aromatic or non-aromatic.1 The majority of erythrinan
alkaloids belong to the aromatic subclass, and most of the
alkaloids in this subclass have two oxygenated functions, one
at C-15 and one at C-16. These alkaloids are termed “nor-
mal”, since their biosynthesis is believed to use 3,4-dihydrox-
yphenethylamine as the starting material. Non-aromatic
alkaloids consist of ring D-oxa and ring D-aza compounds,1
FIGURE 1. Structures of erymelanthine 1 and 8-oxoerymelanthine 2.
Many methods have been reported for the total synthesis of
erythrina alkaloids having an aromatic D-ring,5 whereas only
a few papers have reported the total synthesis of alkaloids with
a non-aromatic D-ring. The latter reports include the synthesis
of cocculolidine by Kitahara’s group6a and β-erythroidine by
the laboratories of Hatakeyama6b and Funk.6c Cocculolidine7
and β-erythroidine3 are ring D-oxa compounds, with D-rings
that are five-membered and six-membered lactones, respec-
tively. The present paper focuses on the D-aza alkaloids,
erymelanthine 1 and 8-oxoerymelanthine (melanacanthine)
(1) Tsuda, Y.; Sano, T. In The Alkaloids; Academic Press: New York,
1996. Vol. 48, pp 249-337.
(2) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1998,
63, 1144–1155.
(3) Aguilar, M. I.; Giral, F.; Espejo, O. Phytochemistry 1981, 20, 2061–
2062.
(4) (a) Dagne, E.; Steglich, W. Tetrahedron Lett. 1983, 24, 5067–5070.
(b) Jackson, A. H. In The Chemistry and Biology of Isoquinoline Alkaloids;
Phillipson, J. D., Roberts, M. F., Zenk, M. H., Eds.; Springer-Verlag: Berlin, 1985;
pp 62-78.
6010 J. Org. Chem. 2009, 74, 6010–6015
Published on Web 07/08/2009
DOI: 10.1021/jo9008645
r
2009 American Chemical Society

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SCHEME 1
2, which were isolated from Erythrina melanacantha.4 Eryme-
lanthine (1) and 8-oxoerymelanthine (2) are unique com-
pounds because they are the only two erythrina alkaloids
possessing a pyridine ring. During biosynthesis, the D-aza
alkaloid is believed to be produced by aromatic ring cleavage
followed by ammonia incorporation. This biosynthetic path-
way is consistent with the co-isolation of erymelanthine and
aromatic alkaloids such as erysovine and erysodine.4 We
report herein the first total synthesis of 8-oxoerymelanthine
2, a non-aromatic erythrinan D-aza alkaloid. Many 8-oxo
alkaloids have been reported,1,8 and oxidation at C-8, leading
to the 8-oxo-alkaloids, is known to be one step in their
biosynthesis.1,4
aminolysis to give 3. D-oxa compound 4 would be obtained
from muconate 5 by acid treatment, followed by modifica-
tion of the A- and B-rings. D-ring cleavage compound
5 would be obtained from trimethoxybenzene derivative
6 by chemo- and regioselective ozonolysis in the presence
of BF3-etherate, as previously reported.9a,9b Aromatic ery-
thrinan compound 6 would be constructed via dioxopyrro-
line 7 from aryl ethylamine 8 by the method previously
reported by our group, in which a stereoselective intermole-
cular Diels-Alder reaction was used.10 Aryl ethylamine 8 is
available from trimethoxybenzaldehyde.11 It should be
noted that this synthetic strategy is in accord with the
biosynthetic pathway: (1) construction of the 6-5-6-6-mem-
bered ring system using a dopamine derivative as the starting
material, (2) oxidative cleavage of the aromatic D-ring,4a and
(3) nitrogen incorporation into the D-ring.
A retrosynthetic analysis is illustrated in Scheme 1. The
target compound, 8-oxoerymelantine 2, can be derived from
D-aza compound 3 by appropriate reduction. Pyrone 4
would permit nitrogen incorporation by ammonolysis or
Results and Discussion
(5) Recent reports (a) Gu, P. M.; Zhao, Y. M.; Tu, Y. Q.; Wang, M.;
Zhang, S. Y. Chin. Chem. Lett. 2007, 18, 917–919. (b) Gao, S.; Tu, Y. Q.; Hu,
X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.; Zhang, S. Org. Lett.
2006, 8, 2373–6. (c) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601–604. (d) Lee,
H. I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 5067–
5070. (e) References cited by ref 5b.
(6) (a) Kawasaki, T.; Onoda, N.; Watanabe, H.; Kitahara, T. Tetrahe-
dron Lett. 2001, 42, 8003–8006. (b) Fukumoto, H.; Takahashi, K.; Ishihara,
J; Hatakeyama, S. Angew. Chem., Int. Ed. 2006, 45, 2731–2734. (c) He, Y.;
Funk, R. L. Org. Lett. 2006, 8, 3689–3692.
(7) (a) Wada, K.; Marumo, S.; Munakata, K. Tetrahedron Lett. 1966,
5179–5184. (b) Elsohly, M. A.; Knapp, J. E.; Schiff, P. L. Jr.; Slatkin, D. J. J.
Pharm. Sci. 1976, 65, 132–133.
(8) (a) Chawla, A. S.; Jackson, A. H.; Ludgate, P. J. Chem. Soc., Perkin
Trans. 1 1982, 2903–2907. (b) Bhakuni, D. S.; Jain, S. Tetrahedron 1980, 36,
3107–3114. (c) Dagne, E.; Steglich, W. Phytochemistry 1984, 23, 449–451.
(d) Mantle, P. G.; Laws, I.; Widdowson, D. A. Phytochemistry 1984, 23,
1336–1338.
(9) (a) Isobe, K.; Mohri, K.; Tokoro, K.; Fukushima, C.; Higuchi, F.;
Taga, J.; Tsuda, Y. Chem. Pharm. Bull. 1988, 36, 1275–1282. (b) Yoshida, Y.;
Ichikawa, S.; Shinozuka, Y.; Satoh, M.; Mohri, K.; Isobe, K. Heterocycles
2005, 65, 1481–1490. (c) Isobe, K.; Mohri, K.; Itoh, Y.; Toyokawa, Y.;
Takeda, N.; Taga, J.; Hosoi, S.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40,
2632–2638. (d) Isobe, K.; Mohri, K.; Takeda, N.; Suzuki, K.; Hosoi, S.;
Tsuda, Y. Chem. Pharm. Bull. 1994, 42, 197–203. (e) Mohri, K.; Isobe, K.;
Maeda, M.; Takeda, T.; Ohkubo, R.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46,
1872–1877.
Construction of the Tetracyclic Ring System. The charac-
teristic 6-5-6-6-membered ring system of the important
synthetic intermediate 6 was constructed using a method
previously developed for the synthesis of aromatic erythri-
nan alkaloids (Scheme 2).10 Arylethylamine 8, synthesized
from 2,3,4-trimethoxybenzaldehyde using the procedure of
Kubota et al.,11 was condensed with methyl malonyl chloride
by the Schotten-Baumann reaction to yield amide 9. Bis-
chler-Napieralski reaction of 9 using a polyphosphate ester
(PPE)12 produced the C-ring closure product 10, which was
(10) (a) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y.
Chem. Pharm. Bull. 1987, 35, 479–500. (b) Sano, T.; Toda, J.; Maehara, N.;
Tsuda, Y. Can. J. Chem. 1987, 65, 94–98. (c) Sano, T.; Toda, J.; Shoda, M.;
Yamamoto, R.; Ando, H.; Isobe, K.; Hosoi, S.; Tsuda, Y. Chem. Pharm.
Bull. 1992, 40, 3145–3156. (d) Hosoi, S.; Nagao, M.; Tsuda, Y.; Isobe, K.;
Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans. 1 2000, 1505–1511.
(11) Kubota, S.; Masui, T.; Fujita, E.; Kupchan, S. M. J. Org. Chem.
1966, 31, 516–520.
(12) Cava, M. P.; Lakshmikantham, M. V.; Mitchell, M. J. J. Org. Chem.
1969, 34, 2665–2667.
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SCHEME 2
SCHEME 3
then treated with oxalyl chloride to give the desired dioxo-
pyrroline 7 in excellent yield.
The A-ring possessing the desired stereochemistry
was constructed using the Diels-Alder reaction with the
required activated diene. Thus, a solution of pyrroline 7 and
1-methoxy-3-trimethylsilyloxy-butadiene in dioxane/n-hep-
tane was heated in a sealed tube at 130 °C for 1 h to afford
tetracyclic ring products. The crude products, without
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FIGURE 3. Significant HMBC correlation of pyron 14.
BF3-etherate, indicating that BF3 coordinates to the A-ring
enone as well as to the B-ring amide. It is reasonable that
regioselective ozonolysis occurred between C-16 and C-17
since the bond between C-16 and C-17 is less crowded than
that between C-15 and C-16, which lies close to the A-ring
enone that is coordinated by BF3. It is noteworthy that the
oxidative cleavage site is the same as that of biosynthetic
oxidation.4 In the absence of BF3-etherate, ozonolysis of 11
gave a complex mixture containing a trace of muconate 5.
Treatment of muconate 5 in acetic acid at 150 °C for 7 h in a
sealed tube provided a ring-closure product, which was then
treated with diazomethane. HMBC correlation of the product
(Figure 3) indicatedthat the product was pyrone 14 and not its
isomer 16 that would be derived from the C15-C16 cleavage
product 15. Upon treatment of pyrone 14 with MgCl2 and
KI at 110 °C, decarboxylation of the vinylogous β-keto ester,
followed by elimination of mesylate, took place to produce
dienone 17. Dienone 17 was reduced regio- and stereoselec-
tively by NaBH4 in the presence of CeCl3 to afford the alcohol
18 as a single isomer in 91% yield. The stereochemistry at C-3
was determined as a 3R-alcohol by comparison with the NMR
spectra of natural erysotramidine, which is an alkaloid related
to erymelantine.10,13 Allylic alcohol 18 was converted to the
corresponding methyl ether 4 by treatment with diazo-
methane in the presence of neutral silica gel.14
Nitrogen Incorporation. All attempts at ammonolysis to
directly convert pyrone 4 to the corresponding pyridone
3 failed. In contrast, aminolysis was achieved using p-meth-
oxybenzylamine. Upon treatment of 4 with p-methoxyben-
zylamine in methanol, both the pyrone and the methyl
ester were transformed to the corresponding pyridone and
p-methoxybenzyl (PMB) amide, respectively, to afford PMB
amide 19 (Scheme 4). Diamide 19 in TFA was heated at
100 °C for 4 h in a sealed tube to give the deprotected product
20. The amide group at C15 was converted to the correspond-
ing methyl ester by refluxing in methanol in the presence of
TMSCl15 to give ester 3 in excellent yield.
FIGURE 2. Ortep drawing of the mesylate 11.
purification, were reduced with LiBH4 and then treated
with HCl to afford three enones, 6 (80%), 12 (9%), and 13
(4%), whose structures were assigned on the basis of their
spectral data. The Diels-Alder reaction proceeded by en-
dotype addition as reported previously.10 In the H NMR
1
spectrum of enone 6, the methyl protons of the angular ester
at C-6 were observed at δ 3.29, indicating that the methyl
group is considerably shielded. This shielding effect is pre-
sumably caused by anisotropy of the aromatic D-ring,
because the angular methyl ester at C-6 is fixed in the region
just above the aromatic D-ring. X-ray crystallographic
analysis of mesylate 11 described below agreed well with this
theory.
Oxidative Cleavage of the Aromatic D-Ring. Oxidative
cleavage of aromatic rings is widespread in nature but is limited
in the laboratory because of the difficulty in controlling the
reaction. Our group reported that ozonolytic cleavage of
o-dimethoxybenzenes to muconates was satisfactorily con-
trolled by addition of BF3-etherate as a regulator.9 This
oxidation reaction was applied to the aromatic erythrinan
compound 11, which was derived from alcohol 6 by treatment
with methanesulfonyl chloride (Scheme 3). The reaction pro-
ceeded chemo- and regioselectively to afford muconate 5 in
47% yield, and the starting material 11 was recovered in 15%
yield. The enone functionality in the A-ring remained intact,
suggesting that BF3 coordinates to the carbonyl oxygen of the
enone and decreases the electron density of the double bond.
The regioselective C-C bond cleavage of the D-ring is ex-
plained as follows. Following X-ray crystallographic analysis
of compound 11, the ORTEP drawing of 11 showed that the
angular methoxycarbonyl group at C-6 is fixed above the
aromatic D-ring (Figure 2), thus inhibiting the approach of
ozone species from the upper face. The 1H NMR spectrum also
indicated that mesylate 11 adopts a similar conformation in
solution. Thus, the methyl protons of the angular ester at C-6
were observed at δ 3.37, indicating that the methyl group is
shielded and that the methyl ester is fixed in the region above
the aromatic D-ring; therefore, the ozone species is assumed to
approach from the lower face.
To complete the total synthesis of 8-oxoerymelanthine 2,
reduction of pyridone to the corresponding pyridine was
required. After many attempts, this conversion was
achieved via trifluoromethanesulfonate (triflate) 21, which
was obtained from pyridone 3 by treatment with trifluor-
omethanesulfonic anhydride. Appropriate conditions were
found to reduce triflate 21 to provide target compound 2 in
quantitative yield. The present method is a modification
of the strategy reported by Ortar’s group16 and used 1,
On the lower face, the C-17 side is less crowded than the
C-15 side when BF3 coordinates to the A-ring enone. The
1H NMR spectrum of 11, determined in CD2Cl2 in the
presence of BF3-etherate (1.2 equiv), which were the reaction
conditions of ozonolysis, was compared with that in the
absence of BF3-etherate (Supporting Information). The results
demonstrated that the A-ring enone protons at C-1 and C-2
and the B-ring proton at C-7 were deshielded in the presence of
(13) Ito, K.; Furukawa, H.; Haruna, M. Yakugaku Zasshi 1973, 93,
1611–1616.
(14) Ohno, K.; Nishiyama, H.; Nagase, H. Tetrahedron Lett. 1979, 45,
4405–4406.
(15) Xue, C.; Luo, F.-T. J. Chin. Chem. Soc. 2004, 51, 359–362.
(16) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 45, 5541–5544.
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SCHEME 4
3-bis(diphenylphosphino)propane (dppp)17 instead of the
reported phosphine ligands.16 A mixture of triflate 21,
Pd(OAc)2, dppp, triethylamine, and formic acid in DMF
was heated at 60 °C for 1 h in a sealed tube to give (()-8-
oxoerymelanthine 2 in quantitative yield. Thus, palladium-
catalyzed reduction was achieved to provide only the
desired product. The spectral properties of synthetic
(()-2 were identical to those previously reported for the
natural product.4b
1,2-Didehydro-7-hydroxy-15,16,17-trimethoxy-6-methoxycar-
bonyl-3,8-dioxoerythrinan (6). A solution of dioxopyrroline
7 (3.82 g, 11 mmol) and 1-methoxy-3-(trimethylsilyloxy)-1,3-
butadiene (6.33 g, 27.5 mmol) in dry dioxane/dry n-heptane
(42 mL/9.5 mL) was heated at 130 °C for 1 h in a sealed tube. The
reaction mixture was concentrated in vacuo, and the residue was
dissolved in dry THF (100 mL). To this solution at -78 °C was
added a solution of LiBH4 (120 mg, 5.5 mmol) in dry THF
(20 mL), and the mixture was stirred for 1 h. The reaction was
quenched with 5% HCl (76.4 mL) and THF (76.4 mL), and the
resulting mixture was refluxed for 1 h. The mixture was extracted
with CHCl3, washed with brine, dried over Na2SO4, and evapo-
rated. The residue was purified by silica gel column chromatog-
raphy with AcOEt to afford 6 (3.67 g, 80%), 12 (364 mg, 9%),
and 13 (219 mg, 4%). 6: colorless needles; mp 108-122 °C
Conclusions
Total synthesis of (()-8-oxoerymelanthine 2 was accom-
plished in 2.0% overall yield using the regioselective Diels-
Alder reaction, ozonolysis of the aromatic ring, and amino-
lysis as the key reactions. This is the first total synthesis of
an erythrinan alkaloid belonging to the D-aza compound
category. The synthetic route is in accord with the biosyn-
thetic pathway in terms of the construction of the 6-5-6-6-
membered ring system from a dopamine derivative as a
starting material,1,18 oxidative cleavage of the aromatic
D-ring and nitrogen incorporation into the D-ring. The
present work opens a new avenue for the synthesis of non-
aromatic erythrinan D-heteroatom containing alkaloids.
(AcOEt/n-hexane); IR (KBr) 3200, 1735, 1695, 1680 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.57 (1H, d, J=10.6 Hz), 6.45
(1H, d, J=10.6 Hz), 6.30 (1H, s), 4.75 (1H, s), 4.36 (1H, ddd, J=
13.2, 6.1, 1.8 Hz), 4.30 (1H, br s), 3.823, 3.817, and 3.65 (each 3H,
s), 3.29 (3H, s), 3.19 (1H, d, J=15.6 Hz), 3.05 (1H, dt, J=12,1,
4.0 Hz), 2.91 (1H, ddd, J=16.5, 4.0, 1.8 Hz), 2.79 (1H, d, J=
15.6 Hz), 2.61 (1H, ddd, J = 16.5, 12.1, 6.1 Hz); 13C NMR
(75 MHz, CDCl3) δ 194.5, 169.6, 168.4, 152.2, 150.9, 147.2,
141.6, 131.6, 128.1, 119.9, 103.1, 77.2, 63.6, 60.7 (ꢀ2), 59.8, 55.7,
52.5, 50.4, 35.1, 21.3; HR-EIMS m/z calcd for C21H23NO8
417.1424, found 417.1401.
1-(2,3-Dimethoxy-3-oxo-1-propenyl)-3,4,6,7,7a,10,11-heptahy-
dro-7-methanesulfonyloxy-2,7a-dimethoxycarbonyl-6,10-dioxo-
6H-pyrido[2,1-i]indole (5). Ozone was generated with an ozone
generator (ON-1-2 Type, Nihon Ozone Co., Ltd.), using com-
mercial-grade oxygen as a source. The flow rate of oxygen was
50 mL/min, and the voltage was adjusted to 80 V. Ozonized
oxygen was passed into a solution of aromatic erythrinan
Experimental Section
Methyl 7,8,9-Trimethoxy-2,3-dioxo-2,3,5,6-tetrahydropyrrolo-
[2,1-a]-isoquinoline-1-carboxylate (7). A solution of oxalyl chlor-
ide (1.69 g, 13.3 mmol) in dry ether (40 mL) was added dropwise
to a stirred solution of 10 (3.25 g, 11.1 mmol) in dry ether (40 mL)
and dry-n-heptane (40 mL) at 0 °C, and the mixture was stirred
for 1 h. Orange yellow crystals were spontaneously precipitated
and collected by filtration. Dioxopyrroline 7 (3.79 g, 99%) was
obtained as orange yellow prisms by recrystallization from
compound 11 (935 mg, 1.89 mmol) and BF3 Et2O (322 mg,
3
2.27 mmol) in CH2Cl2 (113 mL) at -78 °C for 17 min. After the
excess ozone was removed by suction with an aspirator, 5% Pd/C
(10 mg) was addedto the solution, and the mixturewas allowed to
gradually warm to rt. The reaction mixture was filtrated, and the
filtrate was diluted with CH2Cl2, washed with brine, dried over
Na2SO4, and evaporated. The residue was passed through short
SiO2 column chromatography and then purified by MPLC
(AcOEt/n-hexane, 2:1) to afford 5 (467 mg, 47%) and starting
AcOEt/n-hexane. Mp 149-150 °C; IR (KBr) 1720, 1700 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.08 (1H, s), 4.06, 3.92, 3.877 and
3.875 (each 3H, s), 3.79 (2H, t, J=7.2 Hz), 3.08 (2H, t, J=7.2 Hz);
LR-EIMS m/z 347 (Mþ); HR-EIMS m/z calcd for C17H17NO7
347.1005, found 347.1004.
material 11 (140 mg, 15%). 5: IR (CHCl3) 1740, 1725, 1625 cm-1
;
1H NMR (300 MHz, CDCl3) δ7.24 (1H, d, J=10.7 Hz), 6.32(1H,
d, J=10.7 Hz), 5.47 (1H, s), 5.21 (1H, d, J=3.3 Hz), 4.27 (1H, dd,
J=5.3, 3.2 Hz), 3.78 (6H, s), 3.78 (1H, d, J=16.4 Hz), 3.63 and
3.53 (each 3H, s), 3.37 (3H, s), 3.04 (1H, dt, J=12.5, 4.0 Hz), 2.57
(1H, dd, J=17.6, 4.0 Hz), 2.53 (1H, d, J=16.4 Hz), 2.39-2.22
(1H, m); 13C NMR (75 MHz, CDCl3) δ 192.9, 167.6, 167.4, 164.1,
(17) Kotsuki, H.; Datta, P. K.; Hayakawa, H.; Suenaga, H. Synthesis
1995, 1348–1350.
(18) (a) Barton, D. H. R.; James, R.; Kirby, G. W.; Turner, D. W.;
Widdowson, D. A. J. Chem. Soc. (C) 1968, 1529–1537. (b) Barton, D. H. R.;
Boar, R. B.; Widdowson, D. A. J. Chem. Soc. (C) 1970, 1213–1218. (c)
Barton, D. H. R.; Potter, C. J.; Widdowson, D. A. J. Chem. Soc., Perkin
Trans. 1 1974, 346–348.
6014 J. Org. Chem. Vol. 74, No. 16, 2009

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162.3, 149.7, 142.3, 134.7, 131.9, 130.2, 102.6, 81.6, 64.8, 56.9,
55.8, 53.2, 52.5, 52.1, 45.9, 40.0, 34.1, 25.7; HR-EIMS m/z calcd
for C22H25NO12S 527.1062, found 527.1079.
7.0, 4.0 Hz), 1.71 (1H, dd, J=11.9, 10.4 Hz); 13C NMR (125 MHz,
CDCl3 þ CD3OD) δ 170.1, 163.4, 161.9, 159.3, 159.1, 155.6, 145.0,
140.3, 137.2, 129.7 (ꢀ2), 129.3 (ꢀ2), 128.9 (ꢀ2), 127.4, 124.1, 120.6,
114.2 (ꢀ2), 114.0 (ꢀ2), 103.3, 73.8, 65.1, 56.6, 55.4, 55.3, 46.7, 43.4,
41.1, 34.7, 22.6; HR-FAB-MS (positive-ion mode) m/z 568.2469
[M þ H]þ (calcd for C33H34N3O6 568.2447).
1,2,6,7-Tetradehydro-15-methoxycarbonyl-16(17H)-oxa-3,8,17-
trioxoerythrinan (17). A solution of pyrone 14 (100 mg, 0.2 mmol),
KI (106 mg, 0.62 mmol), and anhydrous MgCl2 (100 mg,
1.04 mmol) in DMSO (8.0 mL) was heated at 110 °C in a sealed
tube for 1 h. After the mixture was cooled to room temperature,
CH3I (5.90 g, 41.58 mmol) was added, and the mixture was stirred
at 50 °C for 17 h. The mixture was diluted with CHCl3, washed
with brine, dried over Na2SO4, and evaporated. The residue was
chromatographed on silica gel (AcOEt/n-hexane, 5:1) to afford 17
(41.5 mg, 61%) and starting material 14 (35.5 mg, 36%). 17:
colorless prisms; mp 248-251 °C (AcOEt); IR (KBr) 1700,
1690 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.73 (1H, dd, J=10.2,
0.6 Hz), 7.19 (1H, s), 6.50 (1H, d, J=10.2 Hz), 6.43 (1H, s), 4.49
(1H, ddd, J=13.8, 5.1, 3.9 Hz), 3.90 (3H, s), 3.24 (1H, d, J=
15.7 Hz), 3.20 (1H, dd, J=13.8, 8.1 Hz), 2.87 (1H, d, J=15.7 Hz),
2.77 (2H, dd, J=8.1, 4.5 Hz); 13C NMR (75 MHz, CDCl3) δ 192.9,
168.5, 159.7, 159.4, 151.5, 147.2, 146.5, 138.0, 132.5, 126.9, 126.8,
106.2, 65.8, 53.3, 49.9, 34.2, 23.6; HR-EIMS m/z calcd for
C17H13NO6 327.0742, found 327.0757.
8-Oxoerymelanthine (2). To a solution of 21 (7.3 mg, 0.0154
mmol), palladium acetate (0.6 mg, 0.0025 mmol, 16 mol %), 1,3-
bis(diphenylphosphino)propane (dppp) (1.0 mg, 0.0025 mmol,
16 mol %), and Et3N (10 μL, 0.0708 mmol) in dry DMF (60 μL)
was added 99% formic acid (2 μL, 0.0508 mmol). The mixture
was heated at 60 °C for 1 h in a sealed tube. The mixture was
poured into brine and extracted with AcOEt. The extract was
washed with brine, dried over Na2SO4 and evaporated. The
residue was passed through short Al2O3 column chromato-
graphy (AcOEt/MeOH, 10:1) to afford 8-oxoerymelanthine
2 (4.9 mg, 98%). 2: pale yellow prisms; mp 164-167 °C
(AcOEt/n-hexane); IR (neat) 1720, 1686 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 8.61 (1H, s), 7.99 (1H, s), 6.95 (1H, dd,
J=10.3, 1.8 Hz), 6.44 (1H, br d, J=10.3 Hz), 6.06 (1H, s), 4.20
(1H, dt, J=13.2, 7.3 Hz), 3.99 (3H, s), 3.85-3.76 (1H, m), 3.64
(1H, quintet), 3.36 (3H, s), 3.21-3.13 (2H, m), 2.79 (1H, dd,
J=12.1, 4.8 Hz), 1.82 (1H, dd, J=12.1, 10.3 Hz); 13C NMR
(75 MHz, CDCl3) δ 170.4, 165.5, 155.6, 150.7, 146.2 (ꢀ2), 136.8,
133.7, 123.8, 120.6, 119.9, 74.1, 65.5, 56.6, 53.0, 40.5, 35.9,
24.6; LR-EIMS m/z 326 (Mþ, 100%), 311 (45%), 294 (75%);
HR-FAB-MS (positive-ion mode) m/z 327.1359 [MþH]þ (calcd
for C18H19N2O4 327.1345). Anal. Calcd for C18H18N2O4 - H2O:
C, 62.78.; H, 5.85; N, 8.13. Found: C, 62.63; H, 5.68 ; N, 7.91.
1,2,6,7-Tetradehydro-3r-methoxy-16-[(4-methoxyphenyl)methyl]-
15-N-[(4-methoxyphenyl)methyl]-16(17H)-aza-8,17-dioxoerythrinan-
15-Carboxamide (19). To a solution of 4 (40 mg, 0.12 mmol) in
MeOH (2 mL) was added 40% 4-methoxybenzylamine (480 mg,
3.5 mmol) in MeOH (910 μL), and the mixture was stirred at rt for
2 h. Furthermore, 40% 4-methoxybenzylamine (320 mg, 2.3 mmol)
in MeOH (607 μL) was added, and the mixture was stirred at rt for 70
h. AcOH (800 μL) was added, the mixture was refluxed for 3 h, and
the residue was diluted with CHCl3,washedwith5%HCl,driedover
Na2SO4, and evaporated. The residue was passed through short SiO2
column chromatography (CHCl3/MeOH, 30:1) and then purified
with MPLC (CHCl3/MeOH, 80:1) to afford 19 (36 mg, 55%) and 4
(26 mg, 39%). 19: colorless powder; mp 181-183 °C (AcOEt/n-
Acknowledgment. We thank Dr. Kitabatake, Permachem
Asia, Ltd. for elemental analysis. Part of this work was
supported by a Grant-in-Aid for High Technology Research
Center Project (no. 19-8) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
1
hexane); IR (KBr) 3427, 1682, 1639 cm-1; H NMR (500 MHz,
CDCl3 þ CD3OD) δ 7.11 (2H, d, J= 8.2 Hz), 7.03 (2H, d, J=
8.2 Hz), 6.83 (2H, d, J=8.2 Hz), 6.77 (1H, dd, J=10.4, 2.4 Hz), 6.73
(2H, d, J=8.2 Hz), 6.28 (1H, br d, J=10.4 Hz), 6.27 (1H, s), 5.92
(1H, s), 5.58 (1H, d, J=14.7 Hz), 5.27 (1H, d, J=14.7 Hz), 4.32 (2H,
dd, J=19.5, 14.7 Hz), 4.30-4.19 (1H, m), 4.02-3.96 (1H, m), 3.80
(3H,s),3.75(3H,s),3.47-3.34(1H,m),3.38(3H,s),3.00(1H,dt,J=
18.5, 8.4 Hz), 2.83 (1H, dd, J=11.9, 5.5 Hz), 2.79 (1H, ddd, J=18.5,
Supporting Information Available: Additional procedures
and spectral data for all new compounds; copies of NMR
spectra of compounds 2-14 and 17-21 and 1H NMR spectra
of compound 11 in CD2Cl2; CIF file for X-ray data of com-
pound 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6015