New synthetic method for indole-2-carboxylate and its application to the total synthesis of duocarmycin SA

Article abstract of DOI:10.1021/ol0489548

(Equation Presented) The sequential coupling and cyclization reactions between aryl halides and methyl propiolate were investigated. The electron-withdrawing groups on the aromatic ring are essential for producing the methyl indole-2-carboxylate derivativ

Full text of DOI:10.1021/ol0489548

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2953-2956
New Synthetic Method for
Indole-2-carboxylate and Its Application
to the Total Synthesis of
Duocarmycin SA
Kou Hiroya,* Shigemitsu Matsumoto, and Takao Sakamoto
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aoba-ku, Sendai 980-8578, Japan
hiroya@mail.tains.tohoku.ac.jp
Received June 5, 2004
ABSTRACT
The sequential coupling and cyclization reactions between aryl halides and methyl propiolate were investigated. The electron-withdrawing
groups on the aromatic ring are essential for producing the methyl indole-2-carboxylate derivatives. On the other hand, the presence of an
extra methyl propiolate and Pd(PPh3)4 were required to provide an efficient catalytic system for the cyclization reactions. This reaction was
used for the total synthesis of duocarmycin SA.
Because compounds containing indole ring systems possess
unique biological activities, the synthetic methods for these
compounds have attracted many organic chemists.1 In our
efforts directed toward the development of a new synthetic
method for heterocyclic compounds, we have already
published the Cu(II) salt catalyzed cyclization reaction of
applied to a wide range of substrates.4 However, it is also
well-known that a major drawback of this reaction is the
difficulty of reaction with electron-deficient alkynes such as
methyl propiolate. In 2001, Anastasia and Negishi published
an elegant breakthrough of this problem using alkynylzinc
derivatives as a counterpart.3 At that time, we had just started
a synthetic study of duocarmycin SA (1) according to the
plan shown in Scheme 1. As we wanted to use the Cu(II)-
catalyzed indole cyclization reaction as a key step for
duocarmycin SA synthesis, we had to synthesize 6 as the
substrate for this reaction. The synthesis of 7 was started
from commercially available 2-amino-5-nitrophenol 8 via the
benzylation of the phenolic hydroxyl group (BnBr, K2CO3,
acetone, reflux, 93%), regioselective iodination (ICl, THF,
reflux, 91%), and bis-mesylation (NaH, MsCl, THF, 0 °C
to rt), followed by the mono-demesylation reaction 5 (TBAF,
2
the 2-ethynylaniline derivatives. Herein, we report a new
synthetic method of the indole-2-carboxylate derivatives
using the sequential coupling and cyclization reaction
between the 2-haloaniline derivatives and methyl propiolate
3
using the modified Negishi’s reaction conditions and its
application to total synthesis of duocarmycin SA.
The palladium-catalyzed cross-coupling reaction between
aryl halides and alkynes (Sonogashira reaction) has been
(1) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
Sundberg, R. J. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Ress, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p 119.
(2) (a) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126.
(b) Hiroya, K.; Itoh, S.; Ozawa, M.; Sakamoto, T. Tetrahedron Lett. 2002,
43, 1277.
(4) (a) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566. (b)
Negishi, E.; Yves, D. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: Hoboken, NJ,
2002; Vol. 1.
(3) Anastasia, L.; Negishi, E. Org. Lett. 2001, 3, 3111.
10.1021/ol0489548 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/23/2004

1, entries 1 and 2). Moreover, in the presence of an electron-
donating group at the R2 position on the ring, a remarkable
drop in the yield of the coupled product 13c was observed
and the indole 14c could not obtained at all (Table 1, entry
3).6
Scheme 1. Synthetic Strategy for Duocarmycin SA (1)
Table 1. Sequential Coupling and Cyclization Reactions
yield (%)
entry
substrate
R1
R2
13
14
1a
2
3
4
5
12a
12b
12c
12d
12e
H
Me
H
H
CN
H
H
OMe
Cl
H
38b
59
20
0
10b
2
0
75b
0
69
a 22% of 12a was recovered. b The yields were calculated by the
integration value of H NMR.
THF, rt, 75% from 10) (Scheme 2). To synthesize the desired
6, iodide 7 was subjected to Negishi’s coupling conditions
(ZnBr2, iPr2NEt, methyl propiolate, Pd(PPh3)4, THF, reflux).3
However, the isolated compound was not the cross-coupled
product 6, but methyl indole-2-carboxylate derivative 5 in
56% yield (Scheme 2). The intermediate alkyne 6 cyclized
to the indole 5 under the reaction conditions. Unfortunately,
the efficiency of both the couplings and the second cycliza-
tion reactions highly depends on the character of the
substituents on the aromatic ring. Namely, the main products
were the coupled acetylenes for the reaction of the com-
pounds having no substituents on the aromatic ring or weak
electron-donating group (methyl) in moderate yields (Table
1
On the other hand, the best results could be obtained for
the substrates possessing electron-withdrawing groups on the
aromatic ring, and all of the coupled products were cyclized
from these substrates (Table 1, entries 4 and 5). Although
these sequential reactions have limitations regarding the
substrates, it is evident that the presence of one electron-
withdrawing group is enough to promote the sequential
cyclization reaction from the result of 7 which has nitro and
benzyloxy groups on the aromatic ring.
We next tried to investigate and identify the true catalyst
for this cyclization reaction using the (2-carbomethoxy)-2-
ethynlyaniline derivative 15 as the substrate (Table 2). It is
apparent that the cyclization reaction is not catalyzed by a
Lewis acid (ZnBr2) (Table 2, entry 1). The reactions in the
presence of Pd(PPh3)4 with or without ZnBr2 did not afford
any indoles at all, which suggested the formation of other
species in the reaction mixture (Table 2, entries 2 and 3).
Surprisingly, in the presence of the extra methyl propiolate,
the indole 14a was isolated in 94% yield. Moreover, a
palladium complex is required (Table 2, entry 5), but ZnBr2
is not necessary for the cyclization process (Table 2, entry
6). Presumably, ZnBr2 may act as an activator in certain
stage(s). Pd2(dba)3 did not efficiently catalyze the reaction
and phenylacetylene did not activate the reaction system
(Table 2, entries 7 and 8). These results suggested that the
phosphine ligand will be crucial, and acetylene as the additive
Scheme 2. Synthesis of Indole 5
(5) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(6) The reason for the low conversion of the electron rich compounds is
not totally clear, but one possibility may be the presence of an undesired
deactivation cycle of the catalyst.
2954
Org. Lett., Vol. 6, No. 17, 2004

quinoline derivative 4, which was synthesized by Natsume
10
et al., as the key intermediate.
Table 2. Requirements for Cyclization Reactions
The nitro group of 5 was reduced by catalytic hydrogena-
tion in the presence of PtO2, and the resulting aniline
derivative was treated with NIS at 0 °C to afford the 4-iodo
derivative (17) (indole number) as the sole product. The
carbamate 18, which was derived from 17 under standard
reaction conditions (ClCO2Me, DMAP, pyridine, 0 °C, 2.5
h, 75% from 5), was coupled with propargyl alcohol under
Sonogashira conditions (PdCl2(PPh3)2, CuI, Et3N, DMF, 50
°C, 2 h, 83%), and the acetylene moiety was converted to
the Z-olefin by catalytic hydrogenation using a poisoned
catalyst (Pd-C, quinoline, MeOH-THF, rt, 8 h). Next, the
alcohol 20 was subjected to the intramolecular Mitsunobu
reaction (DEAD, PPh3, THF, rt, 2 h) to afford the dihydro-
quinoline 21, and the methanesulfonyl group of 21 was
eliminated by solvolysis (K2CO3, MeOH, rt, 12 h) to afford
2210b in almost quantitative yield from 19 (Scheme 3).
ZnBr2
Pd complex
(mol %)
yield
(%)
entry
(equiv)
acetylenea
1
2
3
4
5
6
7
8
9
3
0
0
0
94
0
55
trace
10
0
Pd(PPh3)4 (3)
Pd(PPh3)4 (3)
Pd(PPh3)4 (3)
3
3
3
A
A
A
B
A
Pd(PPh3)4 (3)
Pd(PPh3)4 (3)
Pd2(dba)3 (3)
Pd(OAc)2 (3)
10
PdCl2(MeCN)2 (3)
0
a A: methyl propiolate. B: phenylacetylene.
Scheme 3. Synthesis of Tricyclic Intermediate 22
must be electron deficient for the newly formed active
catalyst. The most frequently used catalysts for the cycliza-
tion of the 2-ethynylaniline derivatives to indoles were the
Pd(II) complexes. Pd(OAc)2 and PdCl2(MeCN)2, which are
typical catalysts for this type cyclization reaction,7 did not
promote any reactions (Table 2, entries 9 and 10). Based on
the results listed above, we currently speculate that the active
catalyst will be formed a combination of Pd(PPh3)4 and
methyl propiolate. Isolation and characterization of the
catalyst are now under investigation.
Duocarmycin SA (1) is an antitumor antibiotic isolated
from Streptomyces sp. DO-113 by Ichimura et al. in 1990.8
The first total synthesis was reported by Boger,9 and the other
three total syntheses were achieved by Natsume’s,10 Tera-
shima’s,11 and Fukuyama’s12 research groups.13 Quite re-
cently, the interesting bioactivities of the seco analogues of
duocarmycin have been reported by Tietze’s group, and the
efficient total synthesis of seco-duocarmycin SA was also
reported.14 All of these syntheses were carried out by
convergent methodology, and we selected the tetrahydro-
(7) For examples, see: (a) Esseveldt, B, C, J.; Delft, F. L.; Gelder, R.;
Rutjes, F. P. J. T. Org. Lett. 2003, 5, 1717. (b) Larock, R. C.; Yum, E. K.;
Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (c) Yu, M. S.; Leon, L. L.;
McGguire, M. A.; Botha, G. Tetrahedron Lett. 1998, 39, 9347.
(8) (a) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawa-
moto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43,
1037. (b) Yasuzawa, T.; Saitoh, Y.; Ichimura, M.; Takahashi, I.; Sano, H.
J. Antibiot. 1991, 44, 445. (c) For review, see: Boger, D. L.; Johnson, D.
S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438.
(9) Boger, D. L.; Machiya, K. J. Am. Chem. Soc. 1992, 114, 10056.
(10) (a) Muratake, H.; Matsumura N. Natsume M. Chem. Pharm. Bull.
1995, 35, 1064. (b) Muratake, H.; Abe, I.; Natsume, M. Chem. Pharm.
Bull. 1996, 44, 67. (c) Muratake, H.; Tonegawa, M.; Natsume, M. Chem.
Pharm. Bull. 1998, 46, 400.
(11) Fukuda, Y.; Terashima, S. Tetrahedron Lett. 1997, 38, 7207.
(12) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am
Chem. Soc. 2003, 125, 6630.
(13) For a review, see: Boger,D. L.; Boyce, C. W.; Garbaccio, R. M.;
Goldberg, J. A. Chem. ReV. 1997, 97, 787.
(14) Tietze, L. F.; Haunert, F.; Feuerstein, T.; Herzig, T. Eur. J. Org.
Chem. 2003, 562 and references therein.
The epoxide 23 was found to be relatively unstable;15 thus
the epoxide 23 was subjected to a regioselective reductive
ring-opening reaction in the same reaction flask to afford
the alcohol 410b,c in 42% yield (m-CPBA, CH2Cl2, 0 °C, 5
min, then Et3SiH, BF3‚OEt2, 0 °C, 5 min) (Scheme 4). The
hydroxyl group of 4 was converted to the corresponding
(15) More than half of the epoxide 23 was decomposed during the
isolation and the purification. Therefore, 23 could not be characterized.
Org. Lett., Vol. 6, No. 17, 2004
2955

In conclusion, we developed the sequential coupling and
cyclization reaction between aryl halides and methyl propio-
late employing Negishi’s reaction conditions 3 and clarified
the scope and limitation of this reaction. Moreover, it was
also clarified that some complexes, which may be formed
between Pd(PPh3)4 and methyl propiolate, are minimum
requirements for the cyclization step. This reaction was
successfully applied to total synthesis of duocarmycin SA
(1). Although the final product of our synthesis is racemic,
but the reaction steps (16 steps from 8) and total yield (3.0%)
are almost comparable those of Fukuyama’s recently pub-
lished elegant asymmetric total synthesis (17 steps, 3.1%
yield).12 In our synthesis, only 11 purifications are necessary
through total synthesis (16 steps). This will be the other
advantage of our synthesis.
Scheme 4. Total Synthesis of Duocarmycin SA (1)
Further applications of the sequential reaction toward the
total synthesis of biologically active compounds and the
identification of the actual catalyst are now in progress in
our laboratory.
Acknowledgment. This work was supported by Grants-
in Aid for Scientific Research (No. 14044007) from the
Ministry of Education, Culture, Sports, Science & Technol-
ogy of Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 2, 4-20,
22, 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
mesylate 24 under standard conditions (MsCl, Et3N, CH2Cl2,
rt, 1 h, 75%), and the benzyl group was eliminated (H2,
Pd(OH)2, MeOH, rt, 1 h). The cyclopropane formation was
carried out according to Natsume’s procedure10b (K2CO3,
OL0489548
10c
MeOH) to afford the tetracyclic intermediate 2
in 83%
yield from 24. Finally, the coupling reaction between 2 and
310b,16 were conducted in the presence of excess K2CO3 in
DMF to furnish total synthesis of duocarmycin SA (1). 9-12
(16) (a) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A., Kitos,
P. A.; Suntornwat, O. J. Am. Chem. Soc. 1990, 112, 8961. (b) Fukuda, Y.;
Itoh, Y.; Nakatani, K.; Terashima, S. Tetrahedron 1994, 50, 2793.
2956
Org. Lett., Vol. 6, No. 17, 2004