ORGANIC LETTERS
Unprecedented Stereospecific Synthesis of a Novel Tetracyclic Ring System, a Hybrid of Tetrahydropyrrolo[2,3-b]indole and Tetrahydroimidazo[1,2-a]indole, via a Domino Reaction upon a Tryptophan-Derived Amino Nitrile
2004 Vol. 6, No. 16 2641-2644
Juan A. Gonza´lez-Vera, M. Teresa Garcı´a-Lo´pez, and Rosario Herranz* Instituto de Quı´mica Me´ dica (CSIC), Juan de la CierVa 3, E-28006 Madrid, Spain
[email protected] Received April 28, 2004
ABSTRACT
Compounds containing a novel tetracyclic ring system, a hybrid of tetrahydropyrrolo[2,3-b]indole and tetrahydroimidazo[1,2-a]indole, are synthesized via an acid-mediated stereospecific domino tautomerization of a tryptophan-derived r-amino nitrile. Characterization of these new compounds and preliminary studies on the reactivity of the tetracyclic heterocyclic system are reported.
The tetrahydropyrrolo[2,3-b]indole heterocyclic system (A) is present in a growing class of alkaloid natural products, for example, physostigmine,1 flustramines,2 urochordamines,3 mollenines,4 himastatin,5 and the numerous group of diketopiperazine derivatives (among others, ardeemins,6 amauromine,7 roquefortines,8 leptosins,9 brevianamides,10 or okaramines11). The tetrahydroimidazo[1,2-a]indole system (B) is also present in some natural products, such as tryptoquivalines,12 asperlicins,13 fiscalins,14 fumiquinazo(1) (a) Takano, S.; Ogasawara, K. In The Alkaloids. Chemistry and Pharmacology; Brosi, A., Ed.; Academic Press: San Diego, 1989; Vol. 36, pp 225-251. (b) Pharmacology review: Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. ReV. 1995, 15, 3-31. (2) Carle, J. S.; Christophersen, C. J. Org. Chem. 1980, 45, 1586-1589. (3) Tsukamoto, S.; Hirota, H.; Kato, H.; Fusetani, N. Tetrahedron Lett. 1993, 34, 4819-4822. (4) Wang, H.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod. 1998, 61, 804-807. (5) Kamenecka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 4163. (6) Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine, J. B. J. Antibiot. 1993, 46, 380-386. (7) Takase, S.; Kawai, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1985, 41, 3037-3048. 10.1021/ol049222i CCC: $27.50 Published on Web 07/14/2004
© 2004 American Chemical Society
lines,15 and kapakahines, which have an additional peri-fused piperidone ring.16 Herein we present an easy and efficient synthesis of compounds that present the novel indole-based (8) (a) Ohmomo, S.; Sato, T.; Utagawa, T.; Abe, M. Agric. Biol. Chem. 1975, 39, 1333-1334. (b) Scott, P. M.; Merrien, M.-A.; Polonsky, J. Experientia 1976, 32, 140-141. (c) Scott, P. M.; Kennedy, P. C. J. Agric. Food Chem. 1976, 24, 865-868. (d) Ohmomo, S.; Utagawa, S.; Abe, M. Agric. Biol. Chem. 1977, 41, 2097-2098. (9) Takahashi, C.; Numata, A.; Matsumura, E.; Minoura, K.; Eto, H.; Shingu, T.; Ito, T.; Hasegawa, T. J. Antibiot. 1994, 47, 1242-1249. (10) (a) Birch, A. J.; Wright, J. J. Tetrahedron 1970, 26, 2329-2344. (b) Birch, A. J.; Russell, R. A. Tetrahedron 1972, 28, 2999-3008. (11) (a) Murao, S.; Hayashi, H.; Takiuchi, K.; Arai, M. Agric. Biol. Chem. 1988, 52, 885-886. (b) Hayashi, H.; Furutsuka, K.; Shiono, Y. J. Nat. Prod. 1999, 62, 315-317. (c) Shiono, Y.; Akiyama, K.; Hayashi, H. Biosci. Biotechnol. Biochem. 2000, 64, 1519-1521. (12) (a) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Tetrahedron Lett. 1976, 17, 2861-2864. (b) Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843-1848. (13) (a) Chang, R. S.; Lotti, V. J.; Monaghan, R. L.; Birnbaum, J.; Stapley, E. O.; Goetz, M. A.; Albers-Schonberg, G.; Patchett, A. A.; Liesch, J. M.; Hensens, O. D.; Springer, J. P. Science 1985, 230, 177-179. (b) Liesch, J. M.; Hensens, O. D.; Zink, D. L.; Goetz, M. A. J. Antibiot. 1988, 41, 878-881. (14) Wong, S. M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A. M.; Cooper, R. J. Antibiot. 1993, 46, 545-553.
tetracyclic ring system C. This heterocyclic system could be considered as an hybrid of tetrahydropyrrolo[2,3-b]indole and tetrahydroimidazo[1,2-a]indole.
As part of a wide program to develop methodologies for generating peptidomimetics, we have focused our attention on the potential of amino acid derived R-amino nitriles as a source of diversity of privileged scaffolds,17 such as piperazine,18 1,4-benzodiazepine,19 and pyrazino[1,2-c]pyrimidine20 derivatives, via (cyano-methylene)amino pseudopeptides.21 In the course of this research, we were interested in the tryptophan-derived R-amino carboxamide 3 (Scheme 1) as
Scheme 1. Reactivity of Trp-Derived Amino Nitrile 1 in Acid Media; Yield of Products 2-4 Shown in Table 1
a starting material for the synthesis of spirocyclic compounds. The access to this carboxamide was planned via acid(15) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu, T. Tetrahedron Lett. 1992, 33, 1621-1624. (b) Belofsky, G. N.; Anguera, M.; Jensen, P. R.; Fenical, W.; Kock, M. Chem. Eur. J. 2000, 6, 1355-1360. (16) (a) Nakao, Y.; Yeung, B. K.; Yoshida, W. Y.; Scheuer, P. J.; KellyBorges, M. J. Am. Chem. Soc. 1995, 117, 8271-8272. (b) Yeung, B. K.; Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer, P. J.; Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168-7173. (c) Nakao, Y.; Kuo, J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5, 13871390. (17) (a) Patchett, A. A.; Nargund, R. P. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic Press: San Diego, 2000; Vol. 35, pp 289-298. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (18) Herrero, S.; Garcı´a-Lo´pez, M. T.; Latorre, M.; Cenarruzabeitia, E.; Del Rı´o, J.; Herranz, R. J. Org. Chem. 2002, 67, 3866-3873. 2642
mediated hydration of the L-Trp-derived amino nitrile 1.22 However, the treatment of a CH2Cl2 solution of this nitrile with concentrated H2SO4 [(1:1) H2SO4/CH2Cl2] yielded the carboxamide 3 as a minor product (15%) along with the unexpected compound 2a (85%), tautomer of aminonitrile 1, which includes the hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole ring system C. The mass of the [M + 1] ion of the new compound 2a in FAB-HRMS (m/z 326.1884) corresponded to the same molecular formula as that of the amino nitrile 1, indicating that both compounds were isomers. With respect to 1, the 1H NMR spectra of the tetracyclic tautomer 2a showed the disappearance of the signals corresponding to the indole NH and 2-H protons and the appearance of a doublet at 5.82 ppm and a triplet at 3.76 ppm for 10c-H and 10b-H protons, respectively. Accordingly, the 13C NMR spectrum of 2a showed the disappearance of the indole C2 and C3 signals and the appearance of the corresponding fusion carbons C10c and C10b at 87.3 and 43.0 ppm, as well as the disappearance of the nitrile carbon (121.6 ppm) of 1, and the presence of the amidine carbon of 2a at 173.9 ppm. The amidine NH did not appear in the 1H NMR, probably because of a very fast exchange with the solvent. However, the IR spectrum showed a narrow band at 3311 cm-1 corresponding to the stretching vibration of this NH. The stereochemistry at the fusion positions C10b and C10c was established on the basis of the NOE correlations observed in the 1D NOESY spectra of 2a. Thus, 10c-H showed a NOE effect with 10b-H, and this proton demonstrated NOE with the 1-H proton, which did not show NOE with 2-H. Searching the literature for precedents on the synthesis of tetrahydropyrrolo[2,3-b]indole derivatives, we found the Taniguchi and Hino’s reports on the formation of tryptophan and tryptamine cyclic tautomers by treatment with acids,23 and several posterior reports on the building of the tetrahydropyrrolo[2,3-b]indole ring system on tryptophan and tryptamine derivatives by reaction with electrophiles.24 In these cases, mixtures of diastereoisomers at the pyrroloindole fusion stereogenic centers are usually obtained for tryptophan derivatives, in which the product with the endo carboxylate group is the thermodynamically more stable and the isomer (19) (a) Herrero, S.; Garcı´a-Lo´pez, M. T.; Cenarruzabeitia, E.; Del Rı´o, J.; Herranz, R. Tetrahedron 2003, 59, 4491-4499. (b) Herrero, S.; Garcı´aLo´pez, M. T.; Herranz, R. J. Org. Chem. 2003, 68, 4582-4585. (20) Herrero, S.; Salgado, A.; Garcı´a-Lo´pez, M. T.; Herranz, R. Tetrahedron Lett. 2002, 43, 4899-4902. (21) (a) Herranz, R.; Sua´rez-Gea, M. L.; Vinuesa, S.; Garcı´a-Lo´pez, M. T. J. Org. Chem. 1993, 58, 5186-5191. (b) Gonza´lez-Mun˜iz, R.; Garcı´aLo´pez, M. T.; Go´mez-Monterrey, I.; Herranz, R.; Jimeno, M. L.; Sua´rezGea, M. L.; Johansen, N. L.; Madsen, K.; Thøgersen, H.; Suzdak, P. J. Med. Chem. 1995, 38, 1015-1021. (d) Herrero, S.; Sua´rez-Gea, M. L.; Gonza´lez-Mun˜iz, R.; Garcı´a-Lo´pez, M. T.; Herranz, R.; Ballaz, S.; Barber, A.; Fortun˜o, A.; Del Rı´o, J. Bioorg. Med. Chem. Lett. 1997, 7, 855-860. (22) Prepared applying a modification of our methodology for the synthesis of (cyanomethylene)amino pseudopeptides described in ref 21a. (23) (a) Hino, T.; Taniguchi, M. J. Am. Chem. Soc. 1978, 100, 55645565. (b) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487-1494. (24) (a) Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218-7223 and references therein. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953-11963 and references therein. (c) Caballero, E.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 2003, 68, 6944-6951 and references therein. (d) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675678. Org. Lett., Vol. 6, No. 16, 2004
with the exo carboxylate group (as in 2a) is the kinetically controlled product. In our case, because compound 2a had been initially obtained as one single isomer, we studied the possibility of controlling the stereochemistry by modifying the reaction conditions (acid, temperature, and time). As summarized in Table 1, 2a was quantitatively obtained,
Table 1. Influence of Reaction Conditions on the Result of Treatment of Amino Nitrile 1 with Acids acid concentrated H2SO4 concentrated H2SO4 concentrated H2SO4 concentrated H2SO4 85% H3PO4 TFA TFA TFA TFA TFA TFA
acid (%) in CH2Cl2 T °C 50 33 25 10 33 100 50 25 10 100 10b
25 25 25 25 25 25 25 25 25 50 50
yield (%)a t 2h 2h 2h 3h 2h 48 h 4d 4d 8d 24 h 8d
1
2a
0 85 0 85 0 100 34 66 0 100 0 100 0 75 11 60 13 23 40 44 9 7
2b
3
4
0 0 0 0 0 0 7 5 0 6 0
15 15 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 18 24 64 10 85
the enantiomer of amino nitrile 1 (1c, derived from D-Trp) led to the enantiomer of 2a (2c). We tried the unequivocal structural assignment of 2a, including that of the E/Z configuration at the amidino group, by X-ray analysis. However, we could not obtain good crystals for that analysis. Then, we attempted the assignment of the E/Z configuration by methylation of the amidine group. This was initially attempted by treatment with MeI at 80 °C in the presence of Cs2CO3. Under these conditions, the reaction was very slow (3 days) and led to only hydrolysis at the amidine group, providing the lactam analogue 5 (Scheme 3). When the methylation was attempted by
Scheme 3.
Reactivity of Amidine Derivative 2a
a 1H
Yields were determined by integration of characteristic signals in the NMR spectra of the crude reaction mixture. b 10% TFA in CHCl3.
without carboxamide 3, by decreasing the amount of concentrated H2SO4 or replacing it by 85% H3PO4 or neat TFA. When we decreased the TFA concentration or increased the temperature, the formation of a minor isomer 2b (less than 7%) was also observed, along with the tetrahydro-β-carboline derivative 4.25 The resulting mixture was chromatographically resolved, and the NOE correlations observed for 2b showed the same relative disposition for 2-H, 10b-H, and 10c-H protons as in the major isomer 2a. Therefore, we assumed that 2a and 2b should be isomers at the amidine group. The formation of the endo isomer of 2a, as well as the formation of intermediates of partial reaction (pyrroloindole-cycled nitrile or carboxamide or indole-amidine derivatives), were not detected in any case. The acid-catalyzed domino26 synthesis of 2a could be initiated by the nitrile protonation, as shown in Scheme 2. This reaction was stereospecific, as
Scheme 2. Proposed Mechanism for Synthesis of Hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole Derivatives 2
treatment with Me2SO4 at room temperature (10 days), using K2CO3 as base, a 54% yield of the lactam derivative 5 was obtained, along with a (5:1) mixture of the methyl derivatives 6a/6b (37%). To avoid the hydrolysis of the amidine group, the methylation was performed without base, by treatment with MeI (6 equiv) at 80 °C for 24 h, yielding the (5:1) 6a,b mixture (89%), which could not be resolved. The NOE correlation observed in its 1D NOESY spectrum between the methyl group and the 7-H proton of the major isomer 6a allowed the assignment of a Z-configuration to this isomer. Interestingly, the amidine derivative 2a was stable after 6 days of treatment with Cs2CO3 at 80 °C. The comparison of the pattern of 1H and 13C NMR signals corresponding to 6a and 6b with those of 2a and 2b showed a higher similarity of 2a with 6a than with 6b. Although this result does not allow an unequivocal assignment, it suggests that 6a and 2a have the same configuration at the amidino group. When we tried to obtain the lactam analogue (25) Gatta, F.; Misiti, D. J. Heterocycl. Chem. 1987, 1183-1187. (26) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
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5 by acid hydrolysis with 1 N HCl, 2a was stable at room temperature, but after 2 days of refluxing at 100 °C, the 2,6dioxopiperazine derivative 7 was isolated (74%) without detection of the formation of 5. Finally, the protection of the amidine group and the saponification of the carboxylate group were studied as a means to facilitate the future chemical manipulation of the tetracyclic ring system. As shown in Scheme 3, the reaction of 2a with acetyl chloride or benzyl chloroformate, in the presence of propylene oxide, yielded the corresponding N-acetyl and N-benzyloxycarbonyl derivatives 8 (65%) and 9 (100%), respectively. However, 2a was recovered unaltered after treatment with di(tert-butyl)dicarbonate in the presence of TEA and a catalytic amount of 4-(dimethyl)aminopyridine. With regard to the saponification, it required treatment with an excess of NaOH [in (1:2) H2O/MeOH] for 10 h, and the resulting acid was unstable, being isolated as the sodium salt 10, with ∼10% of the sodium salt of L-Trp. When this salt was treated with acid resin Dowex 50 X 4, to liberate the free acid, it decomposed into a complex mixture. In conclusion, the acid-mediated stereospecific domino tautomerization of the tryptophan-derived R-amino nitrile 1
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herein described gives access to novel tetracyclic amidine and lactam derivatives. These new compounds contain a novel tetracyclic ring system that could be considered a hybrid of the tetrahydropyrrolo[2,3-b]indole and tetrahydroimidazo[1,2-a]indole ring systems. The recurrent presence of these heterocyclic systems in natural products stimulates interest in the structural manipulation of these new compounds. Therefore, studies to explore the extension of this domino reaction to other tryptophan-derived R-amino nitriles, as well as the introduction of additional substituents into this novel heterocyclic system, are in progress. Acknowledgment. This work was supported by CICYT (SAF2000-0147). Supporting Information Available: Experimental procedures and characterization data for the new compounds 1-10. This material is available free of charge via the Internet at http://pubs.acs.org. OL049222I
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