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 Fax 515-294-0105; e-mail: gakraus@iastate.edu

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 has increased rapidly since the first compound was isolated in 1986.¹ Among these compounds, the makaluvamines² and the batzellines³ contain the trisubstituted iminoquinone unit 1, while veiutamine,⁴ the discorhabdins⁵ and wakayin⁶ have the fully-substituted iminoquinone unit 2. Veiutamine (2, R=H, G= p-hydroxybenzyl) group, exhibited activity against solid tumors and was more active (IC₅₀ 0.3 mg/mL) than makaluvamine D (1, R=H, X=p-hydroxyphenethyl) against human colon tumor cell line HCT 116. The makaluvamines are topoisomerase II inhibitors.

Syntheses and several approaches have been reported.⁷ 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.

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 beginning with succinimide 7⁸ 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.

With quantities of 6 now readily available, the intramolecular nucleophilic addition reaction was investigated using various bases (LDA, t-BuOK) in aprotic solvents.⁹ 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 lactam 9 in 55% yield on a five millimole scale.¹⁰ 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% yield.¹¹ Reduction of the nitro groups using catalytic hydrogenation in ethyl acetate over 12 hours provided indole 12 in 42% yield.¹² Catalytic hydrogenation in acetic anhydride with sodium acetate afforded diacetate 13.

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.
References
(1) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(2) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.; 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.
(4) Venables, D. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M. Tetrahedron Lett. 1997, 38, 721.
(5) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Higa, T.; Sakai, R. J. Org. Chem. 1988, 53, 4621.
(6) Copp, B. R.; Ireland, C. M.; Barrows, L. R. J. Org. Chem. 1991, 56, 4596.
(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.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992, 114, 2175.
(8) Compound 7 was produced from 4 and succinic anhydride with continuous removal of water. Piutti, A. Chem. Ber. 1896, 29, 84.
(9) Nucleophilic aromatic substitution: Terrier, F. Chem. Rev. 1982, 82, 77.
(10) A 2D COSY experiment on compound 10 confirmed the tetrahydroquinoline structure.
(11) Fewer equivalents produced an inseparable mixture of starting material, aldehyde and alcohol. The ratio of aldehyde to alcohol was 4:1.
(12) Compound 12: 300 MHz NMR (CDCl₃) d 2.94 (t, J=5.7 Hz, 2 H), 3.43 (t, J=5.7 Hz, 2 H), 3.84 (s, 3 H), 5.79 (s, 1 H), 6.58 (s, 1 H), 7.66 (brs, 1 H). 75 MHz ¹³C NMR (CDCl₃ + CD₃COCD₃) d 23.0, 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 (CDCl₃) d 2.22 (s, 3 H), 2.46 (s, 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 C₁₅H₁₇N₃O₃: 287, 230, 188. HRMS m/z for C₁₅H₁₇N₃O₃: calcd. 287.1270; found 287.1267. Mp 217 °C with decomp.