A convenient divergent approach to the alkaloids isaindigotone and luotonin A

Article abstract of DOI:10.1055/s-2000-7602

Deoxyvasicinone has been used as the key intermediate to prepare the alkaloids isaindigotone and luotonin A. This intermediate is directly converted into isaindigotone by condensation with 4-acetoxy-3,5-dimethoxybenzaldehyde; alternatively oxidation with SeO₂ afforded the pyrrolo[2,1-b]quinazoline-3,9-dione, a putative precursor of the luotonin A.

Full text of DOI:10.1055/s-2000-7602

SHORT PAPER
1523
A Convenient Divergent Approach to the Alkaloids Isaindigotone and
Luotonin A
Pedro Molina,* Alberto Tárraga,* Antonia González-Tejero
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, E-30071, Murcia, Spain
Fax +34(968)364149; E-mail: pmolina@fcu.um.es
Received May 2000; revised 23 June 2000
methylene group at position 2 of the pyrimidine ring is
able to undergo functionalization either by condensation
with aldehydes9 or by oxidation. 10
Abstract: Deoxyvasicinone has been used as the key intermediate
to prepare the alkaloids isaindigotone and luotonin A. This interme-
diate is directly converted into isaindigotone by condensation with
4-acetoxy-3,5-dimethoxybenzaldehyde; alternatively oxidation
with SeO2 afforded the pyrrolo[2,1-b]quinazoline-3,9-dione, a pu-
tative precursor of the luotonin A.
The first synthesis of isaindigotone (1) begins with deox-
yvasicinone (3) prepared in two steps and 74% overall
yield from o-azidobenzoyl chloride and pyrrolidone.11 Di-
rect conversion of 3 into 1 is accomplished in 64% yield
by condensation with 4-acetoxy-3,5-dimethoxybenzalde-
hyde in acetic acid at reflux temperature followed by basic
treatment with ethanolic NaOH. Spectra of synthetic 1 are
identical to those of the natural product (Scheme). This
two-steps synthesis of isaindigotone (1) from the readily
available deoxyvasicione (3) provides a convenient ac-
cess to 1 and, potentially, its analogs.
Key words: alkaloids, condensation, oxidations, isaindigotone, lu-
otonin A, deoxyvasicinone, o-azidobenzoyl chloride
Isatis indigotica Fort is a biennial herbaceous plant dis-
tributed widely in the Changjiang River valley. The puri-
fied extracts of its root named “Ban-Lan-Gen” in Chinese
are popularly used in clinical practice for treatment of in-
fluenza, epidemic hepatitis, epidemic encephalitis B, car-
bunde, erypsipelas, etc.1 Recently, the new alkaloid
isaindigotone (1) has been isolated from the chloroform/
butanol fraction of the ethanol extracts of the roots, which
was found to be effective for antiendotoxic test using lim-
ulus amebocyte lysate (LAL).2 No synthesis of 1 has been
previously reported to the best of our knowledge.
On the other hand, it has been reported that the oxidation
reaction of deoxyvasicinone (3) employing (1S)-10-cam-
phorsulfonyloxaziridine (Davis reagent) gave vasicinone
in 55% yield,7 which by the conventional oxidation ways
did not give the expected pyrrolo[2,1-b]quinazoline-3,9-
dione (5), a significant precursor leading to luotonin A (2)
in the Kelly synthesis. However, compound 5 has been
prepared in 56% yield by oxidation of the vasicinone us-
ing Jones reagent. 8
Luotonin A (2), the first known natural product to possess
the heteroaromatic pyrroloquinazolinoquinoline ring
system, was isolated in 1997 from the aerial parts of the
Peganum nigellastrum Bunge, a plant indigenous to
northwest China, which showed cytotoxic activity against
mouse leukemia P-388 cells.3 The pentacyclic ring system
presents in luotonin A (2) is strikingly reminiscent of
camptothecin, an inhibitor of topoisomerase I, derivatives
of which are clinically useful anticancer agents.4 The bio-
logical activity of luotonin A (2) and the possibility of ob-
taining camptothecin-like analogs has focused
considerable attention on its synthesis. Three syntheses
have been previously reported. The first one5 (Ganesan
synthesis) is based on the coupling reaction of 3-oxopyr-
roloquinoline with 2-sulfinylaminobenzoyl chloride in the
presence of LiN(TMS)2. In the two others, vasicinone,
prepared in five steps from anthranilic acid and 2-pyrroli-
dinone,6 is converted into 2 either by reaction with anthra-
nyl aldehyde7 (Nomura synthesis) or by oxidation with
Jones reagent followed by Friedländer condensation of
the resulting dione with 2-aminobenzaldehyde8 (Kelly
synthesis).
We have found that deoxyvasicinone (3) does convert into
the pyrrolo[2,1-b]quinazoline-3,9-dione (5) in 42% yield
by oxidation with SeO2 in dioxane at reflux temperature.
An alternative way for the conversion of 3 into 5 involves
the following two-steps sequence: a) condensation of 3
with benzaldehyde in the presence of acetic acid to give 4
in 68% yield and b) ozonolysis of 4 and subsequent addi-
tion of Me2S leading to 5 in 63% yield (Scheme). This
constitutes a formal total synthesis of luotonin A (2) since
5, now available by a shorter route (3 steps) and higher
overall yield (31%) than the reported in the previously
mentioned methods, is the quinazolinone derivative of the
Kelly synthesis of luotonin A (2) and may be converted
into the target molecule in a straighforward manner.
In conclusion, we have achieved for the first time the syn-
thesis of the isaindigotone (1) from deoxyvasicinone (3),
which in turn can be directly converted into the pyrro-
lo[2,1-b]quinazoline-3,9-dione (5), a putative precursor
of the luotonin A (2).
We have devised and improved a reliable divergent ap-
proach to isaindigotone (1) and luotonin A (2) which is
based on the suitable use of the readily available deoxyva-
sicinone (3) as a key common intermediate in which the
All reagents were of commercial quality used from freshly opened
containers. Solvent were dried and purified by conventional
methods prior to use. Preparative column chromatography: Merck
Synthesis 2000, No. 11, 1523–1525 ISSN 0039-7881 © Thieme Stuttgart · New York

1524
P. Molina et al.
SHORT PAPER
O
O
N
O
N
c
N
N
a
OCH3
OH
OCH3
42%
64%
N
N
O
5
3
d
ref. 8
e
68%
b
1
Isaindigotone
63%
O
N
O
N
N
N
N
4
2
Luotonin A
Reagents and conditions: a) i: 4-acetoxy-3,5-dimethoxybenzaldehyde/Ac2O/reflux, ii: NaOH/EtOH, reflux; b) PhCHO/Ac2O, reflux; c) SeO2/
dioxane, reflux; d) O3/CH2Cl2/Me2S; e) o-aminobenzaldehyde/Triton B/EtOH, reflux
Scheme
silica gel 60, particle size 0.040-0.063 mm (230-400 mesh, flash).
Analytical TLC: silica gel 60 F254 plates, Merck, Darmstadt. All
melting points were determined on a Kofler hot-plate melting point
apparatus and are uncorrected. IR spectra were obtained as nujol
emulsions or films on a Nicolet Impact 400 spectrophotometer.
NMR spectra were recorded on a Brucker AC-200 (200 MHz) or a
Varian Unity 300 (300 MHz). Mass spectra were recorded on a
Hewlett-Packard 5993C spectrometer or a Fisons Autospec 500
VG. Microanalyses were performed on a Perkin-Elmer 240 C in-
strument.
(C-7’), 129.7 (C-2’), 130.6 (C-4’), 131.5 (C-3), 134.2 (C-6), 135.4
(C-1’), 149.6 (C-4a), 155.5 (C-3a), 161.2 (C-9, C=O)
MS (EI, 70 eV): m/z (%) = 274 (M+, 100), 228 (19), 185 (18), 128
(23), 115 (51).
Anal. calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.63; H, 5.27; N, 10.12.
Pyrrolo[2,1-b]quinazoline-3,9-dione (5)
Method A: To a solution of SeO2 (120 mg, 1.07 mmol) in H2O (5
mL), was added a solution of deoxyvasicinone (3; 200 mg, 1.07
mmol) in dioxane (10 mL) and the mixture was heated under reflux
temperature for 12 h. After cooling, the solid was removed by filtra-
tion and the filtrate was concentrated under vacuum. The residue
was slurried with Et2O (30 mL) and the resulting brown solid was
recrystallized from acetone to give 5 (90 mg); yield: 42%; mp 165-
170 °C (darkens without melting), (Lit.8 mp 165-170 °C), 205 °C
(chars without melting). Spectroscopic data are identical to those
previously reported.8
Isaindigotone (1)
To a solution of deoxyvasicinone (3; 90 mg, 0.48 mmol) in Ac2O
(11 mL) was added 4-acetoxy-3,5-dimethoxybenzaldehyde (739
mg, 3.3 mmol) and the resultant mixture was heated under reflux for
24 h. After cooling, the solvent was removed under reduced pres-
sure and the crude product was dissolved in 10% NaOH in EtOH
(15 mL). The solution was heated at reflux temperature for 1 h and,
after cooling, was neutralized with 1 N HCl and extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with sat. aq NaHCO3 (20 mL), H2O (20 mL) and dried (MgSO4).
After filtration, the solution was concentrated under vacuum and the
resulting crude product was purified by column chromatography on
silica gel using EtOAc/hexane (2:1) as eluent to give 1 (107 mg);
yield: 64%; mp 249-250 °C (Lit.2 mp 247-248 °C). Spectroscopic
data are identical to those reported for the natural product.
Method B: A stream of O3 was passed throught a solution of com-
pound 4 (500 mg, 1.8 mmol) in CH2Cl2 (100 mL) for 3 min, where-
upon Me2S (0.4 mL) was added. The solution was stirred at r.t. for
30 min and the solvent was removed under reduced pressure. The
resulting crude product was slurried with Et2O (40 mL) and the
brown solid obtained was crystallized as above to give 5 (225 mg);
yield: 63%.
3-Benzylidenepyrrolo[2,1-b]quinazoline-9-one (4)
Acknowledgement
A mixture of deoxyvasicinone (3; 200 mg, 1.07 mmol), benzalde-
hyde (910 mg, 8.56 mmol) and Ac2O (10 mL) was heated at reflux
temperature for 24 h. After cooling, the solvent was removed under
reduced pressure and the crude product was purified by column
chromatography on silica gel using EtOAc/hexane (2:1) as eluent to
give 4 (199 mg); yield: 68%; mp 175-176 °C.
We gratefully acknowledge the financial support of the Dirección
General de Enseñanza Superior (project number PB95- 1019).
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13C NMR (50 MHz, CDCl3/TMS): d = 25.5 (C-2), 44.0 (C-1), 120.8
(C-8a), 126.1 (C-8), 126.3 (C-7), 127.2 (C-5), 128.8 (C-3’), 128.9
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Synthesis 2000, No. 11, 1523–1525 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient Divergent Approach to the Alkaloids Isaindigotone and Luotonin A
1525
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Synthesis 2000, No. 11, 1523–1525 ISSN 0039-7881 © Thieme Stuttgart · New York