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

Article abstract of DOI:10.1021/ol049222i

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 α-amino nitrile. Charac

Full text of DOI:10.1021/ol049222i

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2641-2644
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
Juan A. Gonza´lez-Vera, M. Teresa Garc´ıa-Lo´pez, and Rosario Herranz*
Instituto de Qu´ımica Me´dica (CSIC), Juan de la CierVa 3, E-28006 Madrid, Spain
rosario@iqm.csic.es
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 dike-
topiperazine derivatives (among others, ardeemins,6 amau-
romine,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-
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.
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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,
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10.1021/ol049222i CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/14/2004

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.
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.
1
With respect to 1, the H NMR spectra of the tetracyclic
tautomer 2a showed the disappearance of the signals corre-
sponding 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.
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 pipera-
zine,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
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 tetrahy-
dropyrrolo[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.; Garc´ıa-Lo´pez, M. T.; Cenarruzabeitia, E.; Del R´ıo,
J.; Herranz, R. Tetrahedron 2003, 59, 4491-4499. (b) Herrero, S.; Garc´ıa-
Lo´pez, M. T.; Herranz, R. J. Org. Chem. 2003, 68, 4582-4585.
(20) Herrero, S.; Salgado, A.; Garc´ıa-Lo´pez, M. T.; Herranz, R.
Tetrahedron Lett. 2002, 43, 4899-4902.
a starting material for the synthesis of spirocyclic compounds.
The access to this carboxamide was planned via acid-
(21) (a) Herranz, R.; Sua´rez-Gea, M. L.; Vinuesa, S.; Garc´ıa-Lo´pez, M.
T. J. Org. Chem. 1993, 58, 5186-5191. (b) Gonza´lez-Mun˜iz, R.; Garc´ıa-
Lo´pez, M. T.; Go´mez-Monterrey, I.; Herranz, R.; Jimeno, M. L.; Sua´rez-
Gea, 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.; Garc´ıa-Lo´pez, M. T.; Herranz, R.; Ballaz, S.; Barber,
A.; Fortun˜o, A.; Del R´ıo, 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, 5564-
5565. (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, 675-
678.
(15) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.; Kawai,
K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu, T. Tetra-
hedron 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.; Kelly-
Borges, 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, 1387-
1390.
(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.; Garc´ıa-Lo´pez, M. T.; Latorre, M.; Cenarruzabeitia, E.;
Del R´ıo, J.; Herranz, R. J. Org. Chem. 2002, 67, 3866-3873.
2642
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,
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
Table 1. Influence of Reaction Conditions on the Result of
Treatment of Amino Nitrile 1 with Acids
yield (%)a
acid (%) in
CH2Cl2
acid
T °C
t
1
2a 2b
3
4
concentrated H2SO4
concentrated H2SO4
concentrated H2SO4
concentrated H2SO4
85% H3PO4
TFA
TFA
TFA
TFA
50
33
25
10
33
100
50
25
25
25
25
25
25
2 h
2 h
2 h
3 h 34
2 h
0
0
0
85
85
100
66
100
100
75
60
23
44
7
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
Scheme 3. Reactivity of Amidine Derivative 2a
0
0
0
25 48 h
0
25
25
25
4 d
4 d 11
8 d 13
18
24
64
10
85
10
TFA
TFA
100
50 24 h 40
50 8 d
0
0
10b
9
a Yields were determined by integration of characteristic signals in the
1H NMR spectra of the crude reaction mixture. b 10% TFA in CHCl3.
without carboxamide 3, by decreasing the amount of con-
centrated 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-â-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
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
Scheme 2. Proposed Mechanism for Synthesis of
Hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole
Derivatives 2
1
comparison of the pattern of H 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.
Org. Lett., Vol. 6, No. 16, 2004
2643

5 by acid hydrolysis with 1 N HCl, 2a was stable at room
temperature, but after 2 days of refluxing at 100 °C, the 2,6-
dioxopiperazine derivative 7 was isolated (74%) without
detection of the formation of 5.
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 tetrahy-
droimidazo[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 com-
pounds. 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.
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.
Acknowledgment. This work was supported by CICYT
(SAF2000-0147).
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
1-10. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, the acid-mediated stereospecific domino
tautomerization of the tryptophan-derived R-amino nitrile 1
OL049222I
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Org. Lett., Vol. 6, No. 16, 2004