A synthesis of the tetracyclic carboskeleton of isaindigotidione

Article abstract of DOI:10.1016/j.tetlet.2004.02.052

An efficient synthesis of the unique indolizino[7,6-c]quinoline carboskeleton of isaindigotidione has been achieved. This strategy employed L-proline and isatin as the main building blocks in the construction of the framework. Four transformations occurred in a one-pot operation to furnish the tetracyclic nucleus.

Full text of DOI:10.1016/j.tetlet.2004.02.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2985–2988
A synthesis of the tetracyclic carboskeleton of isaindigotidione
Ch Yan Poon and Pauline Chiu*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology
for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
Received 20 November 2003; revised 23 January 2004; accepted 3 February 2004
Abstract—An efficient synthesis of the unique indolizino[7,6-c]quinoline carboskeleton of isaindigotidione has been achieved. This
strategy employed L-proline and isatin as the main building blocks in the construction of the framework. Four transformations
occurred in a one-pot operation to furnish the tetracyclic nucleus.
Ó 2004 Elsevier Ltd. All rights reserved.
The root of Isatis indigotica Fort., an herbaceous bien-
nial plant found in the Changjiang river valley, is a
traditional Chinese medicinal herbal drug named ban-
langen, commonly used to treat ailments such as influ-
enza,1 and even prescribed recently in Hong Kong for
bolstering immunity against the SARS virus. Indirubin,
one of the compounds extracted from this root, has
proven to be an anticancer agent, which has been used in
the clinic for chronic granulocytic leukemia.2
have yet been reported. Thus, we have undertaken a
synthetic study of isaindigotidione and its analogues.
Herein, we report an efficient approach toward the novel
tetracyclic skeleton of isaindigotidione 2, which may be
amenable for generating analogues with variation at C7.
Our initial retrosynthesis is shown in Scheme 1. In this
route toward the tetracyclic framework of isaindigo-
tidione, ring D would originate from L-proline deriva-
tive 3, and ring A would be provided by methyl
anthranilate 4. The intervening ring B was envisioned to
arise from a Dieckmann type cyclization and ring C was
to be constructed by the carbonylation of an enol triflate
intermediate, followed by intramolecular amide forma-
tion.
Isolated along with indirubin is another interesting
alkaloid, isaindigotidione 1, a novel derivative of indo-
lizino[7,6-c]quinoline 2, which has been found in natural
products for the first time (Fig. 1).1 The biological effects
of isaindigotidione 1 have not been ascertained, but the
butanol fractions of the root ethanolic extracts, from
which isaindigotidione was obtained, were found to be
effective in anti-endotoxic tests.1 To our knowledge, no
synthetic studies of this compound or its derivatives
The synthetic approach as outlined in Scheme 1 was
successful up to a point. Boc-L-proline 3 was converted
to Boc- -prolinal by borane reduction and PDC oxi-
L
dation (Scheme 2).3 Homologation using the stabilized
Wittig reagent carbomethoxymethylenetriphenylphos-
phorane gave enoate 5 in good yield. Catalytic hydro-
genation produced saturated ester 6.4 Hydrolysis
afforded acid 7, which was condensed with methyl
anthranilate 4. Acylations of aryl amines are known to
be rather sluggish,5 and our attempts to optimize the
9
10
11
D
8
O
N
C
O
12
N
7a
7
H
H
1
4
OMe
OH
2
A
B
N
H
6
5
3
O
N
O
H
OMe
1
2
D
Carbonylation
O
N
C
N
BOC
H
Figure 1. Isaindigotidione 1 and indolizino[7,6-c]quinoline 2.
COOMe
COOH
3
A
B
Wittig
O
NH2
N
homologation
H
4
Keywords: Alkaloid; Indolizine; Quinoline.
* Corresponding author. Tel.: +852-2859-8949; fax: +852-2857-1586;
e-mail: pchiu@hku.hk
2
Scheme 1. Initial retrosynthesis of indolizino[7,6-c]quinoline 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.052

2986
C. Y. Poon, P. Chiu / Tetrahedron Letters 45 (2004) 2985–2988
CO2Me
d
a-c
O
N
O
3
N
CO2Me
H2N
N
b
a
c
BOC
5
6
BOC
CO2Me
-
6
5
CF3CO2
NH
BOC
15
CO2Me
P
N
CO2Me
CO2H
f
e
h
14
N
N
O
BOC
BOC
7
O
N
O
HO
N
8
9
P= H
P= BOC
g
H
d
H
CO2Me
NH
BOC
N
H
O
TfO
HO
X
2
N
N
N
BOC
N
BOC
16
BOC
O
BOC
O
Scheme 4. Reagents and conditions: (a) H2, Pd–C, MeOH, (b) TFA,
CH2Cl2, 96% over two steps, (c) 13, i-Pr2NEt, THF, 90%, (d) NaOMe,
MeOH, 96%.
11
10
Scheme 2. Reagents and conditions: (a) BH3–THF, (b) PDC 92% over
two steps, (c) MeO2CCH@PPh3, CH2Cl2, 96%, (d) H2, Pd–C, 100%,
(e) NaOH, MeOH, 90%, (f) BOP, Et3N, CH2Cl2, 4, 67%, (g) (Boc)2O,
95%, (h) LDA, THF, 68%.
pling between proline ester 12 and a protected isatin
derivative 13.
conditions of this coupling did not result in significant
improvements in the yield. The use of either BOP or
DCC to promote amide formation with methyl anthra-
nilate 4 generated aryl amide 8 in moderate yields.
Protection of the amide by (Boc)2O afforded substrate 9
for the construction of ring B. The Dieckmann-type
condensation between the enolate of the amide and the
aryl ester proceeded to give b-ketoamide 10, which
existed predominantly in its enol form.
Thus ester 5 was reduced to 6 and deprotected to give
proline derivative 12 as its trifluoroacetate salt 14
(Scheme 4). The crude salt was treated with Boc-pro-
tected isatin 1310 in the presence of excess HunigÕs base
€
to give compound 15 in excellent yield. The coupling
occurred at room temperature and was surprisingly
facile compared to previous acylations of isatin, which
required refluxing conditions.9
The intramolecular aldol of substrate 15 was only
marginally successful upon treatment with excess LDA.
The condensation product was formed as a mixture of
diastereomeric aldols 16 with large amounts of recov-
ered 15. Treatment with sodium methoxide in methanol
at room temperature generated aldol and dehydrated
aldol products, along with tetracyclic compounds in
which the final ring closure had also occurred sponta-
neously. Finally, under refluxing conditions, quinolone
2 was isolated in 96% yield after 5 h.11 Notably, a total
of four transformations, that is, aldol cyclization,
dehydration, acylation, and Boc-deprotection occurred
in a one-pot operation with great efficiency.
Compound 10 was to be carbonylated via its enol triflate
11. Triflation using conventional reagents such as Tf2O/
Et3N,6 Ph2NTf/Et3N,7 and CominsÕ reagent8 were tried,
but none of these conditions were successful, in most
cases returning only starting material after reaction. It
may be that substrate 10 is too sterically congested for
triflation to proceed efficiently.
Since the carbonylation step proved problematic, we
considered another synthetic strategy, which would
avoid the need for carbonylation at this critical stage.
We identified isatin as a carbonylated analogue of
anthranilate 4. The retroanalysis toward the tetracyclic
skeleton of 2 was redesigned as shown in Scheme 3. Ring
C could be furnished by the ring opening reaction of
isatin with proline derivative 12,9 followed by intramo-
lecular aldol cyclization. Ring B could be formed via a
more facile intramolecular version of the previous lac-
tamization. This approach hinged on the effective cou-
The structure of tetracyclic quinolone 2 was confirmed
1
by standard analytical methods including H, 13C 1-D,
and 2-D NMR, IR, and HRMS.12
Derivatives of 2, including isaindigotidione 1, having the
skeletal framework of 2 and bearing substituents at C7,
should be accessible through substituted analogues of 6.
Thus a methylated analogue was synthesized in a similar
manner based on the strategy for the assembly of 2
(Scheme 5). Methylation via the addition of the Gilman
reagent afforded 17a in excellent yield, as a 2:1 mixture
of diastereomers.13 The mixture of 17a was deprotected
to give 18a, and treated with isatin 13 as done previously
to afford intermediate 19a. Bis-cyclization using base
afforded the methylated derivatives 20a and 21a as a 3:1
mixture of diastereomers under more vigorous condi-
tions (8 h).
CO2Me
N
H
D
O
N
C
O
N
O
12
O
O
N
BOC
A
B
CO2Me
N
H
O
NH
P
2
13
Scheme 3. Second retrosynthetic plan toward quinolone 2.

C. Y. Poon, P. Chiu / Tetrahedron Letters 45 (2004) 2985–2988
2987
products 20b/21b in 11:1 ratio in 90% overall yield. The
structures of the diastereomeric products were deter-
mined again by the value of the coupling constant
H2N
R
c
N
R
a
b
-
BOC
CF3CO2
5
J
H7–H7a, being 4.0 Hz for 20b, and 12.3 Hz for 21b. The
CO2Me
CO2Me
DFT calculations of diastereomers 20b and 21b also
showed that the thermo- dynamically more stable iso-
mer was 20b by about 3.3 kcal/mol. Attempts to invert
the stereochemistry of isomer 20b at C7 by a low-
temperature, kinetic protonation were as yet unsuc-
cessful.
17a
17b
18a
18b
R= Me
R= Ph
R= Me
R= Ph
O
7a
7
7a
O
N
O
N
N
d
H
R
H
R
7
+
O
NH
BOC
R
CO2Me
N
H
O
N
H
O
We herein disclose an efficient strategy toward the syn-
thesis of the unique tetracyclic and pentacyclic frame-
work of isaindigotidione 1. We are continuing our
investigations to append the final ring to compound 2,
as well as other strategies, to complete the total synthesis
of 1.
19a R= Me
19b R= Ph
20a R= Me
20b R= Ph
21a R=Me
21b R= Ph
Scheme 5. Reagents and conditions: (a) Me2CuLi, 96% for 17a; PhBr,
cat. Pd(PPh3)4, then H2/Pd/C, 57% over two steps for 17b, (b) TFA,
quantitative for 18a and 18b, (c) 13, i-Pr2NEt, 86% for 19a, 85% for
19b, (d) NaOMe, MeOH reflux, 92% for 20a/21a, 90% for 20b/21b.
The structures of the major and minor tetracyclic iso-
mers were deduced as follows. Comparing the coupling
constants of the protons at C7 for both diastereomeric
products, JH7–H7a in the minor isomer was 12.0 Hz, while
that in the major isomer was smaller, with a value of
4.2 Hz. Structures 20a and 21a were both optimized
computationally by DFT calculations using the B3LYP/
6-31G(d) model. In the minimum energy conformation
of 21a, the dihedral angle defined by H7a–C7a–C7–H7
was found to be 167°, that is, nearly anti, while that in
the major isomer 20a was 45°. Thus a larger value for
JH7–H7a was expected for the isomer with structure 21a.
This stereochemical assignment was further confirmed
by JH7–H7a in the natural product 1, which also has a
value of 12.0 Hz.1 Therefore the minor isomer 21a pos-
sessed the same relative stereochemistry as isaindigo-
tidione 1.
Acknowledgements
Miss Lihong Hu and Dr. G. H. Chen of the Department
of Chemistry at The University of Hong Kong are
thanked for their help in performing the computations.
Financial support from a Research Initiation Grant
from the CRCG of The University of Hong Kong and
the Areas of Excellence Scheme established under the
University Grants Committee of the Hong Kong SAR,
China (Project AoE/P-10/01) are gratefully acknowl-
edged. C.Y.P. thanks the Swire Group and Robert
Black College for a Swire Scholarship and conference
travel grant support.
References and notes
Since the ratio of diastereomers changed from 2:1 in
17a, to 3:1 in 20a/21a, the bis-cyclization reaction con-
ditions were obviously equilibrating. This was also
confirmed by the DFT calculations, which showed that
the minimized structure of 20a to be 5.8 kcal/mol more
stable than isomer 21a. Thus 20a predominated under
these reaction conditions because it is the thermody-
namically more stable epimer.
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The synthesis of the phenylated analogue of 2, which
possesses the full pentacyclic framework of 1, was also
synthesized in a similar manner. Although the addition
of methyl cuprate to proline ester derivative 5 was facile,
addition of Ph2CuLi, Ph2CuCNLi2, PhMgBr, and
PhMgBr/CuI gave only 10–20% yield of 17b.14 Thus the
phenyl group was appended by an alternative two-step
strategy. A palladium-catalyzed Heck arylation of ester
5 generated the phenylated alkenoate, which was then
reduced by catalytic hydrogenation. The reduction
was nonselective and a 1:1 ratio of diastereomers of
17b was obtained. The mixture of the diastereomers
of 17b was carried forward using the same strategy of
deprotection to give 18b, and acylation to afford 19b
without incident. Base-induced cyclization required over
12 h for complete reaction, and afforded pentacyclic
5. Miyazawa, T.; Otomatsu, T.; Yamada, T.; Kuwata, S.
Tetrahedron Lett. 1984, 25, 771–772.
ꢀ
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Bosch, J. J. Org. Chem. 1999, 64, 9605–9612.
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J. Org. Chem. 1990, 55, 906–910.
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6299–6302.
9. Albrecht, F. Liebigs Ann. Chem. 1982, 794–807.
10. Wille, G.; Steglich, W. Synthesis 2001, 759–762.
11. Preparation of 2. To a solution of 15 (44.5 mg, 0.11 mmol)
in MeOH (2 mL) was added NaOMe (35.6 mg,
0.66 mmol). The mixture was heated to a gentle reflux
for 5 h under Ar until the reaction was deemed complete
by TLC. After removal of volatiles, the residue was
suspended in water, and extracted with EtOAc. The
organics were separated, dried (anhydrous Na2SO4), and

2988
C. Y. Poon, P. Chiu / Tetrahedron Letters 45 (2004) 2985–2988
161.8, 162.2; HRMS-EI (m=z): Mþ calcd for C15H14N2O2,
concentrated in vacuo. The crude material was purified by
flash chromatography (35% EtOAc/hexane) to afford 2
(26.8 mg, 96%) as a milky white solid.
254.1055; found, 254.1053.
13. Le Coz, S.; Mann, A.; Thareau, F.; Taddei, M. Hetero-
cycles 1993, 36, 2073–2080.
D
12. Characterization of 2. Mp 231 °C; ½aꢀ þ 53:6 (c 0.43,
20
CHCl3); IR (CHCl3): 3023, 3017, 2888, 2350, 1645, 1448,
14. Most alkylations of proline derivatives at this site were
intramolecular, see: (a) Moriwake, T.; Hamano, S.; Saito,
S. Heterocycles 1988, 27, 1135–1139; (b) Exceptions: Ref.
13, also: Hanessian, S.; Buckle, R.; Bayrakdarian, M.
J. Org. Chem. 2002, 67, 3387–3397; (c) However, Ph2CuLi
added to the closely related ester derived from Garner
aldehyde with good diastereoselectivity but diminished
yield: Jako, I.; Uiber, P.; Mann, A.; Taddei, M.; Wermuth,
C. G. Tetrahedron Lett. 1990, 31, 1011–1014.
789, 760, 733, 728 cmꢁ1 1H NMR (600 MHz, CDCl3) d
;
1.78–1.85 (m, 1H), 1.88–1.96 (m, 1H), 2.13–2.17 (m, 1H),
2.38 (m, 1H), 2.45 (dd, J ¼ 16:8, 13.8 Hz, 1H), 3.52 (dd,
J ¼ 16:80, 4.2 Hz, 1H), 3.69–3.75 (m, 1H), 3.77–3.86 (m,
2H), 7.29 (t, J ¼ 7:7 Hz, 1H), 7.35 (d, J ¼ 8:1 Hz, 1H),
7.51 (t, J ¼ 7:6 Hz, 1H), 9.02 (d, J ¼ 8:3 Hz, 1H), 11.49 (s,
1H); 13C NMR (150 MHz, CDCl3) d 23.4, 28.8, 33.7, 45.4,
55.9, 115.7, 117.7, 123.4, 127.8, 130.2, 131.6, 136.3, 137.4,