An expedient synthesis of ellipticine via Suzuki-Miyaura coupling

Article abstract of DOI:10.1016/j.tetlet.2010.02.125

A simple and efficient total synthesis of ellipticine was developed via the Suzuki-Miyaura coupling of sterically sensitive 2-hydroxybenzeneboronic acid with a multifunctional aryl halide using Pd(OAc)₂ as a catalyst and Cu(OAc)₂·H₂O as an additive in DMSO/H₂O as a key step followed by double N-arylation and cyclization.

Full text of DOI:10.1016/j.tetlet.2010.02.125

Tetrahedron Letters 51 (2010) 2335–2338
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Tetrahedron Letters
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An expedient synthesis of ellipticine via Suzuki–Miyaura coupling
a
a
Takeo Konakahara a,b,c, , Y. B. Kiran , Yuri Okuno , Reiko Ikeda a,b,c, Norio Sakai a,b
*
a Department of Pure and Applied Chemistry, Faculty of Science & Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
b Research Institute for Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
c Center for Technologies against Cancer, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient total synthesis of ellipticine was developed via the Suzuki–Miyaura coupling of ste-
rically sensitive 2-hydroxybenzeneboronic acid with a multifunctional aryl halide using Pd(OAc)2 as a
catalyst and Cu(OAc)2ÁH2O as an additive in DMSO/H2O as a key step followed by double N-arylation
and cyclization.
Received 23 December 2009
Revised 17 February 2010
Accepted 22 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ellipticine
Suzuki–Miyaura coupling
Formylation
Steric sensitivity
Double N-arylation
Ellipticine (1), first isolated from the leaves of Ochrosia elliptica
Labill in 1959, is a member of the pyrido[4,3-b]carbazole family.
Ellipticine and its derivatives display potent antitumor and anti-
cancer properties. These compounds are good DNA intercalating
molecules, and their high DNA binding affinity is thought to be
responsible in part for these pharmacological properties.1 More re-
cent studies have also indicated that ellipticine and its derivatives
are active against HIV.2 The unique structural features, limited
toxic side effects, and complete lack of hematological toxicity of
these compounds has prompted chemists to develop synthetic
strategies for the preparation of ellipticine and several of its ana-
logues for pharmacological evaluation.1,3
and efficient approach for the synthesis of this compound is
desirable.
A retro synthetic strategy for the synthesis of 1 is outlined in
Scheme 1. The compound 1 could be readily prepared by a selec-
tive coupling of multifunctional aryl halide 2 with 2-hydroxyben-
zeneboronic acid (3) using Suzuki–Miyaura coupling followed by
double N-arylation of biphenyl triflate 4 and cyclization of the
formylated carbazole derivative 5.3
The complete synthetic sequence of 1 via Suzuki–Miyaura
coupling is shown in Scheme 2. Initially, the formylation of 2,5-
dimethylphenol (6) was examined. Using the Reimer–Tiemann
A wide variety of synthetic studies and total syntheses of ellip-
ticine have been reported by many groups,4 which includes our
own work in this area.5 The most convenient synthesis starts with
indole.4a–f Gribble and Moody have reported useful procedures for
the synthesis of ellipticine using the Diels–Alder approach.4g–i All
these procedures, however, involve protection/deprotection prob-
lems4b–h and a large number of steps,4j and some require triazene,
which is a potential carcinogen.4i,k While recognizing these limita-
tions, it must be noted that the Gribble and Moody procedures
have improved the yields and regioselectivity.4l Recently, a radical
cascade protocol was applied to the synthesis of ellipticine, but the
reaction intermediates need a toxic phosgene solution for their
preparation.4m In light of all the afore-mentioned problems, and
considering the interesting biological activities of 1, a general
CHO
ref. 3
N
N
H
N
H
5
1
CHO
OTf
HO OH
B
OH
X
OH
+
OTf
CHO
3
2
4
* Corresponding author. Tel.: +81 04 7122 9502; fax: +81 04 7123 9326.
E-mail address: konaka@rs.noda.tus.ac.jp (T. Konakahara).
Scheme 1. Retro synthesis of ellipticine.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.125

2336
T. Konakahara et al. / Tetrahedron Letters 51 (2010) 2335–2338
HO OH
CHO
B
CHO
OTf
OH
OH
OH
OH
I
3
D
B
A
OH
C
OTf
OH
CHO
CHO
6
7 (70%)
8 (73%)
9 (69%)
4 (92%)
E
CHO
Ns
N
N
G
F
N
R
N
H
N
H
OEt
OEt
10: R = tBuCO2
5: R = H (62%)
1 (79%)
11 (67%)
Scheme 2. Reagents and conditions: (A) dichloromethyl methyl ether (1.1 equiv), AlCl3 (1.5 equiv), 0 °C, 5 min; (B) NaOAc (1 equiv), I2 (1 equiv), 1:1 MeOH/H2O, rt, 12 h; (C)
Pd(OAc)2, Cu(OAc)2ÁH2O, Na2CO3, DMSO/H2O, 130 °C, 3 h; (D) Tf2O, Et3N, CH2Cl2, rt, 20 min; (E) tBuCO2NH2, Pd(OAc)2, Xantphos, K3PO4, xylene, 130 °C, 18 h [compound 10
(not detected); compound 5]; (F) (i) aminoacetal, benzene, reflux; (ii) MeOH, NaBH4, rt, 1 h; (iii) Ns–Cl, pyridine, MeCN, rt, 6 h; (G) 6 M HCl–dioxane, reflux, 3 h.
reaction, 4-hydroxy-2,5-dimethylbenzaldehyde (7) was obtained
from 6 in only 16% yield. Due to this low yield, formylation of 6 un-
der Vilsmeier–Haack conditions was attempted, resulting in the
formation of 2,5-dimethylphenyl formate (12) in moderate yield.6,7
We overcame the problem of low yield with the synthesis of 7 by
changing the reagent combination and reducing the quantity, as
reported by Gross et al.8 We observed the formation of 7 (70%),
2-hydroxy-3,6-dimethylbenzaldehyde (7a, 22%), and 4-hydroxy-
2,5-dimethylisophthaldehyde (7b, 3%) from 6 using our modified
conditions.7,9 From 7, we prepared 4-hydroxy-3-iodo-2,5-dimeth-
ylbenzaldehyde (8) using iodinating reagent I2/NaOAc (1:1 equiv)
in aq MeOH.7,10 From 2-bromophenol (13), we prepared
2-hydroxybenzeneboronic acid (3) in high yields by modifying
the Gilman et al. procedure.7,11,12
of 9 improved when DMSO was employed, but the formation of
some byproducts was observed (entries 9 and 10). In addition,
we improved the reaction conditions for the preparation of 9 by
reducing both the amount of Pd-catalyst (2 mol %) and the dura-
tion of exposure to 5 mol % of Cu(OAc)2ÁH2O (entries 11 and 12).
Reportedly, a formyl group will not react with arylboronic acid 3
under our developed conditions.15,16 The use of DMF/H2O with
3 mol % of palladium catalysts resulted in the formation of
unidentified products (entries 13–15).
The non-reactivity of compound 3 with 8, as shown in Table 1
(entries 1, 2, and 8), was due, in many cases, only to the poor reac-
tivity of ortho-substituted arylboronic acid 3, presumably because
of steric sensitivity.13b,c We overcame this problem when using a
Pd-catalyst by using MeOH/H2O and DMSO/H2O as a solvent (en-
tries 6, 7, and 9–12). This reveals that the aryl–aryl exchange be-
tween the palladium(II) complex may be enhanced in high polar
solvents. In general, the synthesis of a biphenyl substance with
electron-donating groups results in contamination of the coupling
product (entries 3–5, 13–15), which may be due to competitive
hydrolytic deiodination in aqueous conditions.17 This problem
was overcome by our newly developed conditions (entries 9–12).
The use of a base as a suspension in DMF or dioxane produced
no significant results.
Copper and its salts have been used in Suzuki–Miyaura coupling
by some groups.13e,18 Li et al. reported the use of Cu(OAc)2ÁH2O/1,4-
diaza-bicyclo[2.2.2]octane for the Suzuki–Miyaura coupling of ben-
zeneboronic acid with 1-iodo-4-methoxybenzene using Cs2CO3 as a
base and DMF as a solvent.18d Mao et al., obtained the Suzuki–Miya-
ura coupling product 4-methyl-benzeneboronic acid with iodoben-
zene in low yields in the presence of Cu(OAc)2ÁH2O as a catalyst,
K2CO3 as a base, and DMF as a solvent.18f Gros et al. reported Cu salts
as an additive along with Pd-catalyst to minimize the formation of
byproducts in a Suzuki reaction.18c Thus, we selected Cu(OAc)2ÁH2O
as an additive to reduce the formation of byproducts in our Suzuki–
Miyaura coupling of 3 with 8 for the preparation of 9, and we
succeeded (entries 11 and 12).
The obtained biphenyl derivative 9 was converted into the
corresponding ditriflate 4,7 which was then subjected to double
N-arylation19 with O-tert-butyl carbamate19c to get tert-butyl-3-for-
myl-1,4-dimethyl-9H-9-carbazolecarboxylate (10). Under our
reaction conditions, 1,4-dimethyl-9H-carbazole-3-carbaldehyde
(5) was formed instead of the expected 10.7 It is possible that 5 is
formed from 10 by in situ thermolysis.20 Furthermore, the elec-
In the synthesis of 1 via Suzuki–Miyaura coupling, it is neces-
sary to prepare the unsymmetrical biphenyl compound
9
(Scheme 1). Suzuki–Miyaura coupling is one of the most general
and powerful methods for the synthesis of unsymmetrical biphe-
nyl derivatives by the coupling of aryl halide derivatives with
arylboronic acid.13 Morris and Nguyen14 reported the expected
coupling of arylboronic acid with halosalicylaldehyde derivatives
in the presence of Pd(dppf)Cl2 or Pd(PPh3)4, both of which are
expensive compounds. However, Lee et al.15 unsuccessfully at-
tempted a similar type of coupling using the conditions reported
by Morris and Nguyen.14 In addition, the nature of both the sol-
vent and the catalytic system greatly impact the arylboronic acid
coupling reactions;16 for example, the addition of chloroform
turns a conventional palladium compound into a catalyst for
the 1,2 addition of arylboronic acids to aldehydes in the presence
of a base16a and further phosphine-free Suzuki–Miyaura coupling
conditions are favorable.13d,e Therefore, we re-examined the reac-
tion conditions for the selective preparation of 9 by the reaction
of 3 with 8 in polar and non-polar solvents using various Pd-cat-
alysts under phosphine-free conditions (Table 1; entries 1–15).7
The Suzuki–Miyaura coupling of compounds 3 with 8 was not
successful even after 24 h in a DME/H2O system containing
3 mol % of Pd(PPh3)4 or PdCl2 (entries 1 and 2). In a toluene/
H2O system, the deiodination of 8 was observed, which led to
the formation of 7 from 8 in the presence of 3 mol % of palladium
catalysts (entries 3–5). On the other hand, the reaction in the
MeOH/H2O system resulted in the formation of the expected
product 9 in low yield along with 7 and unidentified byproducts
(entries 6 and 7), but no reaction using Pd/C (entry 8). The yield

T. Konakahara et al. / Tetrahedron Letters 51 (2010) 2335–2338
2337
Table 1
Examination of the Suzuki–Miyaura coupling of 3 with 8 to afford 9
Entry
Pd-catalyst (3 mol %)
Additive (5 mol %)
Solvent
Temp (°C)
Time (h)
9b (%)
a
b
b
c
c
c
1
2
3
4
5
6
7
8
9
10
11e
12
13
14
15
Pd(PPh3)4
PdCl2
Pd(PPh3)4
PdCl2
Pd(OAc)2
Pd(PPh3)4
PdCl2
—
—
—
—
—
—
—
DME/H2O
DME/H2O
80
80
24
24
12
12
12
12
12
12
12
12
3
—
—
—
—
—
a
a
Toluene/H2O
Toluene/H2O
Toluene/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMF/H2O
100
100
100
100
100
50
130
130
130
130
100
100
100
a
a
a
12
14
a
a
b
Pd/C
—
—
a
Pd(OAc)2
PdCl2
—
—
57
50
69
63
a
f
Pd(OAc)2
Cu(OAc)2ÁH2O
e
PdCl2
Cu(OAc)2ÁH2O
3
a
d
Pd(PPh3)4
PdCl2
Pd(OAc)2
—
—
—
12
12
12
—
—
—
a
d
DMF/H2O
DMF/H2O
a
d
a
b
c
d
e
f
With no additive.
No reaction; starting materials were recovered quantitatively.
Formation of 7 by deiodination of 8 was observed.
Unidentified byproducts were observed.
Conditions to get the highest yield of 9.
2 mol % of Pd catalyst used.
tron-withdrawing group (–CHO) on the heteroarenes activates
deprotonation of the tert-butyl group in mildly basic conditions.21
Finally, the synthesis of ellipticine (1) was accomplished simply
from compound 5, in contrast to previous reports.22 Compound 5
was condensed with aminoacetaldehyde diethyl acetal to provide
the imine quantitatively.22 Next, we reduced the imine to its amine
with NaBH4 in MeOH; then we converted the formed amine into the
corresponding N-nocyl (Ns) derivative with 2-nitrobenzenesulfonyl
chloride in the presence of pyridine in rt of 6 h. These three steps can
be performed on a large scale without purification to provide 11 in
67% overall yield.7 The compound 11 was then refluxed for 3 h in
6 M HCl–dioxane and was purified by column chromatography to
give ellipticine (1) as the sole product in 79% yield. The mechanism
of the reaction probably involves ring closure and then solvolysis of
sulfonamide. Theelectronic effects of thesubstituentat the orthopo-
sition of the sulfonamides probably dramatically influence their sta-
bility against solvolysis. In a previous report,22 hydrogenation of the
imine at a pressure of 5 atm provided an amine that was then tosy-
lated (three days reaction at 20 °C) with toluene-p-sulfonyl chloride
in pyridine; this was then subjected to cyclization with aq HCl–diox-
ane to obtain ellipticine (1) along with N-tosyl-3,4-dihydroellipti-
cine, which also afforded ellipticine (1) following further alkaline
hydrolysis. Our new protocol was an improvement over that found
in previous reports because of its simplicity4c–g and ease of
handling.4f,j
MEXT 2009–2011 (No. 21590025); Program for Development of
Strategic Research Center in Private Universities supported by
MEXT, 2009–2013. Y.B.K. is grateful for the financial support of a
postdoctoral fellowship from the Tokyo University of Science.
Supplementary data
Supplementary data (experimental procedures and NMR spec-
tra) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.02.125.
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This work was partially supported by a Grant-in-Aid for Scien-
tific Research from MEXT, a matching fund subsidy from MEXT
2004–2006 (No. 16550148); a grant for the High-Tech Research
Central Project for Private Universities: a matching fund subsidy
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12
6
7. The details of the experiment given in Supplementary data.
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9. Gross et al.,8 in their experiments
a combination of SnCl4 (2.0 equiv)/
dichloromethyl methyl ether (1.65 equiv) or AlCl3 (1.5–3.0 equiv)/triethyl
orthoformate (excess) was used for formylation of phenols (1 equiv). They
7 (40%) and 7a (20%) from 6 by using SnCl4/
dichloromethyl methyl ether for formylation.
reported the formation of
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trimethyl borate as reported.11 Further our simple workup improves the yield
(85%; lit.11 47%) and purity of 3.7
OH
OLi
OH
OH
n-BuLi
B OH
Li
Br
i) B(OCH3)3
ether
-90 0C to rt
ii) Acid hydrolysis
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13a
3 (85%)
13