Preparation of a key tricyclic intermediate for the synthesis of pyrroloiminoquinone natural products

Article abstract of DOI:10.1055/s-1998-867117

Indole 12 was prepared in seven steps from para-anisidine. The key step was an intramolecular nucleophilic aromatic substitution reaction.

Full text of DOI:10.1055/s-1998-867117

August 1998
SYNLETT
845
Preparation of a Key Tricyclic Intermediate for the Synthesis of Pyrroloiminoquinone Natural
Products
George A. Kraus* and Natesan Selvakumar
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax 515-294-0105; e-mail: gakraus@iastate.edu
Received 5 June 1998
Summary: Indole 12 was prepared in seven steps from para-anisidine.
The key step was an intramolecular nucleophilic aromatic substitution
reaction.
The group of natural products bearing a pyrroloiminoquinone subunit
1
has increased rapidly since the first compound was isolated in 1986.
2
3
Among these compounds, the makaluvamines and the batzellines
4
contain the trisubstituted iminoquinone unit 1, while veiutamine, the
discorhabdins and wakayin have the fully-substituted iminoquinone
5
6
unit 2. Veiutamine (2, R=H, G= p-hydroxybenzyl) group, exhibited
activity against solid tumors and was more active (IC 0.3 µg/mL) than
50
With quantities of
nucleophilic addition reaction was investigated using various bases
(LDA, t-BuOK) in aprotic solvents. To the best of our knowledge,
intramolecular aromatic nucleophilic addition reactions similar to this
one in aprotic solvents have not been reported. Using three equivalents
of potassium tert-butoxide in THF at -35 °C followed by oxidative
workup with one equivalent of ceric ammonium nitrate (CAN) afforded
6 now readily available, the intramolecular
makaluvamine D (1, R=H, X=p-hydroxyphenethyl) against human
colon tumor cell line HCT 116. The makaluvamines are topoisomerase
II inhibitors.
9
10
lactam 9 in 55% yield on a five millimole scale. Selective reduction of
the lactam using borane in THF from 0 °C to ambient temperature
provided amine 10 in 84% yield. Partial reduction of the ester with
DIBAL (13 equiv. in toluene at -78 °C) afforded aldehyde 11 in 92%
11
yield. Reduction of the nitro groups using catalytic hydrogenation in
ethyl acetate over 12 hours provided indole 12 in 42% yield. Catalytic
7
12
Syntheses and several approaches have been reported. With the
exception of the route of Alvarez, Joule and coworkers (which begins
with a quinoline), most of the existing syntheses proceed by appending
the B ring onto a bicyclic indole ring system. In our approach the C ring
is appended onto a tetrahydroquinoline ring system which in turn is
made using a novel intramolecular nucleophilic aromatic substitution
reaction. Our synthesis proceeds via intermediate 3 and is applicable to
the preparation of both 1 and 2.
hydrogenation in acetic anhydride with sodium acetate afforded
diacetate 13.
The initial synthesis of ester 6 began with the reaction of succinic
anhydride with para-anisidine (4). Nitration of the resulting amido acid
5 using fuming nitric acid and sulfuric acid followed by esterification
provided 6 along with a variable amount of mono-nitration product
which made purification of 6 difficult. However, a modified route
8
beginning with succinimide 7 permitted a convenient large scale
synthesis of 6. Imide 7 underwent dinitration with fuming nitric acid and
sulfuric acid in 86% yield, affording 8 as a yellow solid with mp 174 °C.
The reaction of 8 with sodium methoxide (1.2 equiv. in 6:1 THF:MeOH)
provided amido ester 6 in 96% yield.
Tricyclic intermediate 12 can be prepared in only seven steps from para-
anisidine. The route is flexible and will make available quantities of
compounds for further biological evaluation. Interestingly, intermediate
9
should permit an additional nucleophilic addition, providing
convenient access to both makaluvamine and veiutamine analogs.

846
LETTERS
SYNLETT
References
Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chem.
Soc. 1992, 114, 2175.
(1) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(2) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
(8) Compound 7 was produced from 4 and succinic anhydride with
continuous removal of water. Piutti, A. Chem. Ber. 1896, 29, 84.
Kramer, R. A.; Ireland, C. M. J. Am. Chem. Soc. 1993, 115, 1632.
(3) Sun, H. H.; Sakemi, S.; Burres, N.; McCarthy, P. J. Org. Chem.
1990, 55, 4964.
(9) Nucleophilic aromatic substitution: Terrier, F. Chem. Rev. 1982,
82, 77.
(4) Venables, D. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M.
(10) A 2D COSY experiment on compound 10 confirmed the
Tetrahedron Lett. 1997, 38, 721.
tetrahydroquinoline structure.
(5) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Higa, T.; Sakai, R. J.
Org. Chem. 1988, 53, 4621.
(11) Fewer equivalents produced an inseparable mixture of starting
material, aldehyde and alcohol. The ratio of aldehyde to alcohol
was 4:1.
(6) Copp, B. R.; Ireland, C. M.; Barrows, L. R. J. Org. Chem. 1991,
56, 4596.
(12) Compound 12: 300 MHz NMR (CDCl ) δ 2.94 (t, J=5.7 Hz, 2 H),
3
(7) White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc. 1994,
116, 1831. Roberts, D.; Joule, J. A.; Bros, M. A.; Alvarez, M. J.
Org. Chem. 1997, 62, 568. Yamada, F.; Hamabuchi, S.; Shimizu,
A.; Somei, M. Heterocycles 1995, 41, 1905. Peat, A. J.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028. Sadanandan,
E. V.; Pillai, S. K.; Lakshmikantham, M. V.; Billimoria, A. D.;
Culpepper, J. S.; Cava, M. P. J. Org. Chem. 1995, 60, 1800. Zhao,
R.; Lown, W. Synth. Comm. 1997, 27, 2103. Makoza, M.;
Stalewski, J.; Maslennikova, O. S. Synthesis 1997, 1131. Kita, Y.;
3.43 (t, J=5.7 Hz, 2 H), 3.84 (s, 3 H), 5.79 (s, 1 H), 6.58 (s, 1 H),
13
7.66 (brs, 1 H). 75 MHz C NMR (CDCl + CD COCD ) δ 23.0,
3
3
3
43.7, 59.8, 92.0, 111.2, 113.2, 113.5, 125.4, 128.1, 135.2, 137.6.
Compound 13: 300 MHz NMR (CDCl ) δ 2.22 (s, 3 H), 2.46 (s, 3
3
H), 2.89-3.00 (m, 2 H), 3.98 (s, 3 H), 4.08-4.20 (m, 2 H), 6.84 (s, 1
H), 7.70 (bs, 1 H), 7.87 (bs, 1 H), 8.21 (bs, 1 H). MS m/z for
C
H N O : 287, 230, 188. HRMS m/z for C H N O : calcd.
15 17 3 3 15 17 3 3
287.1270; found 287.1267. Mp 217 °C with decomp.