Novel domino cyclization of tryptophan-derived amino nitriles: Scope and stereoselectivity

Article abstract of DOI:10.1021/jo051441+

The scope and stereoselectivity of the acid-promoted cyclization of new tryptophan-based α-amino nitriles derived from either ketones or aldehydes to novel hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo-[1,2-a] indoles is described. This cyclization involves th

Full text of DOI:10.1021/jo051441+

Novel Domino Cyclization of Tryptophan-Derived Amino Nitriles:
Scope and Stereoselectivity
Juan A. Gonza´lez-Vera, M. Teresa Garc´ıa-Lo´pez, and Rosario Herranz*
Instituto de Quı´mica Me´dica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
rosario@iqm.csic.es
Received July 12, 2005
The scope and stereoselectivity of the acid-promoted cyclization of new tryptophan-based R-amino
nitriles derived from either ketones or aldehydes to novel hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo-
[1,2-a]indoles is described. This cyclization involves the generation of two or three stereogenic
centers. The time and stereoselectivity of this reaction mostly depended on both the steric volume
of the substituents at the amino nitrile and its stereochemistry. Unhindered amino nitriles gave
exclusively 2-exo-isomers, while hindered amino nitriles, which required higher reaction times,
provided also these isomers under kinetic control. Under thermodynamic control, the 2-endo-isomer
was the main reaction product, except for the benzaldehyde-derived R-amino nitriles, where a
favorable electronic interaction between the phenyl and methoxycarbonyl groups in a relative cis-
disposition might be responsible of the formation of the 2-exo-isomer as the only cyclization product.
Introduction
fused piperazine derivatives (among others: ardeemins6
(2), amauromine,7 roquefortines,8 leptosins,9 breviana-
mide E,10 or okaramines11), and as a modified tryptophan
residue in several peptides such as himastatin,12
chloptosin,13 and the Bacillus subtilis pheromone ComX14
(3). The tetrahydroimidazo[1,2-a]indole is present in
tryptoquivalines,15 asperlicins16 (4),fiscalins17 (5),fumiquin-
azolines,18 and kapakahines, which have an additional
peri-fused piperidone ring.19
We have recently communicated the stereospecific
synthesis of compounds that contain the novel indole-
based tetraheterocyclic system of 1,2,4,5,10b,10c-hexahy-
dropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole (Figure 1,
A), via an acid-promoted domino cyclization of an R-ami-
no nitrile derived from tryptophan and cyclohexanone1
(Scheme 1, a). This novel ring system could be considered
as a hybrid of the 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]-
indole (B) and the 2,3,9,9a-tetrahydroimidazo[1,2-a]in-
dole (C), both present in a growing class of indole
alkaloids. Thus, the 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-
b]indole is present in physostigmine2 (1), flustramines,3
urochordamines,4 mollenines,5 in the numerous group of
(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. Tetra-
hedron 1985, 41, 3037-3048.
(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.
* Corresponding author. Phone: (+34) 91-5622900. Fax: (+34) 91-
5644853.
(1) Gonza´lez-Vera, J. A.; Garc´ıa-Lo´pez, M. T.; Herranz, R. Org. Lett.
2004, 6, 2641-2644.
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H.; Shingu, T.; Ito, T.; Hasegawa, T. J. Antibiot. 1994, 47, 1242-1249.
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(b) Birch, A. J.; Russell, R. A. Tetrahedron 1972, 28, 2999-3008.
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10.1021/jo051441+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/29/2005
J. Org. Chem. 2005, 70, 8971-8976
8971

Gonza´lez-Vera et al.
SCHEME 1. Synthesis of Hexahydropyrrolo-
[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole Derivatives
FIGURE 1. Examples of hexahydropyrrolo[2,3-b]indole and
tetrahydroimidazo[1,2-a]indole alkaloids.
The recurrent presence of indole-based heterocycles in
natural products and in diverse compounds of therapeutic
interest, along with the novelty of the aforementioned
tetracyclic ring system, have pushed us to study, and
report herein, the scope and stereoselectivity of the
cyclization of tryptophan-based R-amino nitriles derived
from other ketones, different from cyclohexanone (7a),
and aldehydes. Among the ketones, we selected N-benzyl-
4-piperidone and acetone (Scheme 1, 7b and 7c, respec-
tively), while among the aldehydes, aliphatic ones of
variable steric volume [acetaldehyde (7d), phenylacetal-
dehyde (7e), and pivalaldehyde (7f)] and benzaldehyde
(7g) were selected. Furthermore, N-Z-L-alaninal (7h) was
also included, as a model, to explore the synthesis
of amino acid-derived hexahydropyrrolo[1′,2′,3′:1,9a,9]-
imidazo[1,2-a]indoles as intermediates in the preparation
of fused piperazine derivatives, which could be analogues
of the aforementioned pyrazino[1′,2′:1,5]pyrrolo[2,3-b]-
indole-containing natural products.6-11
Results and Discussion
Similar to the reaction recently described for the
synthesis of the R-amino nitrile 8a,20 the reaction of
tryptophan methyl ester (6) with the ketones 7b and 7c,
followed by in situ Yb(OTf)3-promoted addition of
TMSCN, yielded the corresponding amino nitriles 8b and
8c, respectively. The application of this methodology to
the reaction of 6 with the aldehydes 7d-h produced
epimeric mixtures of the amino nitriles 8 and 9 in an
∼2:1 ratio, except for the phenylacetaldehyde and piv-
alaldehyde derivatives 8,9e and 8,9f, which were ob-
tained in an ∼3:2 ratio. These epimeric mixtures were
resolved by radial chromatography, except for the piv-
alaldehyde derivatives 8f and 9f, which could not be
chromatographically resolved, but were kinetically re-
solved in the subsequent reaction of cyclization (within
24 h of reaction, 9f cyclized completely, while 70% of 8f
was recovered unchanged). The cyclization was carried
out by treating a CH2Cl2 solution of the corresponding
amino nitrile with a 50% sample of 85% H3PO4, except
for the alanine derivatives 8h and 9h, which were treated
with neat TFA, due to the instability of the Z-protecting
group in H3PO4. In the major and less reactive epimer
(15) (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.
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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.
(17) Wong, S. M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A.
M.; Cooper, R. J. Antibiot. 1993, 46, 545-553.
(18) (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.
(19) (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.
(20) Gonza´lez-Vera, J. A.; Garc´ıa-Lo´pez, M. T.; Herranz, R. J. Org.
Chem. 2005, 70, 3660-3666.
8972 J. Org. Chem., Vol. 70, No. 22, 2005

Tryptophan-Derived Amino Nitrile Cyclization
TABLE 1. Stereoselectivity of the Cyclization of
SCHEME 2. Epimerization Mechanism
Tryptophan-Derived r-Amino Nitriles
starting
pyrroloimidazoindole
R-amino nitrilea
(%)b
time
(h)
entry
No.
8ac
R1
R2
10
11
13
1
(CH2)5
(CH2)5
[(CH2)2]2NBn
[(CH2)2]2NBn
Me
1
192
3
192
1
2
2
100c
100c
74c
19c
95c
71
0
0
2
8ac
8bc
8bc
8cc
8d
9d
9d
8e
8e
8e
9e
9e
9e
8f
3
26
81
0
4
5
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6
Me
0
72
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
within 3 h of reaction (entry 3), the 2-exo-isomer 10b was
the major reaction product in a 3:1 ratio, while after 8
days (entry 4) the thermodynamic-controlled product 13b
was major in a 10b/13b ratio of 1:4.
7
Me
Me
0
0
8
24
24
96
360
10
24
360
24
48
192
360
24
2
24
192
2
3
144
3
100
72
0
9
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
tBu
21
34
72
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
64
25
With respect to the aldehyde derivatives, the cycliza-
tion of each isolated acetaldehyde-derived epimer 8d and
9d was completely stereoselective toward the correspond-
ing 2-exo-isomer 10d and 11d, respectively, with reten-
tion of the stereochemistry at the R-amino nitrile chiral
center. This result allowed the assignment of the absolute
configuration at that chiral center of 8d and 9d by
correlation. In the other amino nitriles 8,9e-h, that
configuration was tentatively assigned by comparison of
96
90
7
74
6
26
7
7
8f
tBu
13
72
84
7d
0
8f
tBu
25
13
8f
tBu
8f+9f tBu
41d
100
100
80
8g
8g
8g
9g
8h
8h
9h
Ph
Ph
0
Ph
0
1
their respective H NMR and HPLC data with those of
Ph
100
18
0
70
0
8d and 9d. Thus, in the major isomers 8 (S), the Trp 2-H,
3-H, and indole protons 1-H and 2-H appeared at a higher
field than in the corresponding (R)-epimers 9. Further-
more, the major isomers 8 showed higher tR (Novapak
C18) than the minor ones 9.
(S)-CH(Me)-NHZ
(S)-CH(Me)-NHZ
(S)-CH(Me)-NHZ
12
48e
0
a The 8/9 ratio was determined as ∼2:1 by 1H NMR or HPLC
analysis of the crude amino nitrile mixture, except for 8,9e and
8,9f, where it was determined as ∼3:2. b Isolated yields (%), except
for entries 8-10, 13, 15-17, and 24, where the ratio was
determined in the HPLC analysis of the reaction mixture. c As R1
) R2, 8 ) 9 and 10 ) 11. d 70% of 8f was recovered. e This low
yield was due to the partial replacement (38%) of the Z protecting
group of 13h by a trifluoroacetyl group.
Interestingly, both isolated acetaldehyde-derived
epimers 10d and 11d exchanged slowly, and at room
temperature in CDCl3 solution, the equilibrium of this
exchange was achieved after 94 days with a 10d/11d
ratio of 4:1. Under the acid medium of the cyclization
reaction, after 24 h, the epimerization of 11d to 10d was
complete (Table 1, entry 8). As shown in Scheme 2, this
epimerization must proceed through the enamine tau-
tomer 14d, although this isomer was not detected,
probably due to its short lifetime. In the case of the other
aldehyde derivatives bearing higher volume groups (8,9e-
h), the epimer 11, with the R1 group toward the endo-
face, was not obtained, and neither this isomer nor the
corresponding enamine tautomer 14 was detected in the
reaction mixture.
In most cases of the aldehyde-derived amino nitriles
(8 and 9d-f and h), the steric volume of the R1 substit-
uents and their configuration affected their cyclization
reaction time, and this had an important influence on
the stereoselectivity. Thus, the (R)-amino nitriles 9, after
the shorter reaction times required for their complete
conversion (entries 7, 12, 19, and 26), yielded exclusively
the kinetic controlled 2-exo-isomers 10 (or 11d in the case
of the acetaldehyde derivatives). However, the increase
in the reaction time in more constrained amino nitriles
favored the formation of the 2-endo-isomer, such as in
the phenylacetaldehyde derivative 9e, where after 15
days, isomer 13e was the major isomer in a 3:1 ratio
(entry 14). The (S)-amino nitriles 8, which, except for the
acetaldehyde and benzaldehyde derivatives 8d and 8g,
required considerable higher reaction times, also gave the
2-exo-isomer 10 as major product of short reaction times
(entries 9, 15, and 24), although with low % of cyclization.
However, within higher reaction times, the thermody-
namic controlled 2-endo-isomer 13 was the main reaction
product (entries 11, 18, and 25), except for the acetalde-
8h the TFA treatment produced, in addition to the
cyclization to its tautomer 13h (48%), partial replacement
of the Z group of this cyclized compound by a trifluoro-
acetyl group (38%).
The literature precedents on the synthesis of tetrahy-
dropyrrolo[2,3-b]indoles have demonstrated the high
preference for cis versus trans fusion in the pyrroloindole
junction and that the 2-endo-carboxylate isomers are
thermodynamically more stable, while the 2-exo-isomers
are the kinetically controlled products.21 Bearing in mind
these precedents, two stereoisomers might be expected
from the cyclization of the amino nitriles derived from
symmetrical ketones (8a-c), while in the case of the
amino nitriles derived from aldehydes (8 and 9d-h), due
to the additional stereogenic center generated at position
4, the four stereosisomers 10-13, shown in Scheme 1,
might be formed. As shown in Table 1, the results
depended mostly upon the steric volume of the amino
nitrile R1 and R2 substituents and upon the reaction time.
Thus, in the ketone derivatives 8a and 8c (entries 1, 2,
and 5), independent on the reaction time, the cyclization
was stereospecific toward the respective 2-exo-isomer 10a
and 10c. However, in the N-benzyl-4-piperidone deriva-
tive 8b, the results depended on the reaction time. Thus,
(21) (a) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487-1494.
(b) Caballero, E.; Avendan˜o, C.; Mene´ndez, J. C. Tetrahedron: Asym-
metry 1998, 9, 967-981. (c) 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. (d) Crich, D.;
Huang, X. J. Org. Chem. 1999, 64, 7218-7223 and references therein.
J. Org. Chem, Vol. 70, No. 22, 2005 8973

Gonza´lez-Vera et al.
FIGURE 2. NOE effects observed in the 1H NOESY 1D
spectra.
hyde- and benzaldehyde-derived amino nitriles, which
gave only the 2-exo-isomer (10d and 10g, respectively).
Interestingly, the epimer of 13 at position 4, 12, was not
obtained in any case.
We also studied the configurational stability of the
2-exo-hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]in-
doles 10a-c and 10d-g. At room temperature in CH3-
CN solution, conditions of the HPLC analysis, samples
of all of these compounds remained unaltered after more
than 15 days. After 8 days under the cyclization reaction
conditions (a solution of each compound in CH2Cl2 was
stirred at room temperature with a 50% of 85% H3PO4),
the ketone derivatives 10a-c and the acetaldehyde and
benzaldehyde derivatives 10d and 10g retained their
2-exo-configuration. However, the phenylacetaldehyde
and pivalaldehyde derivatives 10e and 10f isomerized
slowly to the 2-endo-isomers 13e and 13f, which after
20 days reached a 10/13 ratio of 1:4 and 2:3, respectively.
In all cases, traces of the corresponding amino nitriles 8
and 9, in a time-independent ratio (3-10%), were de-
tected in the HPLC analysis of the reaction mixtures.
This indicated that, in the acid medium, the R-amino
nitriles were in equilibrium with their respective pyrro-
loimidazoindole derivatives, and, therefore, the cycliza-
tion could be considered as an acid-promoted tautomer-
ization reaction. Interestingly, the 2-exo (10) to 2-endo
(13) isomerization requires both the opening of the fused
pyrroloimidazo system and the epimerization at position
4. Although we have not identified any intermediate of
this isomerization, we think that it is more probable that
the epimerization happens at the pyrroloimidazoindol
state, via an enamine intermediate similar to 14, than
at the amino nitrile state. In our previous wide experi-
ence in amino acid-derived R-amino nitriles,20 we have
not observed epimerizations, in either basic or acid
media.
The configurational assignment of the hexahydropyr-
rolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indoles 10-13 was based
on the NOE effects observed in their 1H NOESY 1D
spectra, shown in Figure 2. Furthermore, as has been
previously described for tetrahydropyrrolo[2,3-b]indole
derivatives,21a,d the endo-isomers 13 showed an upfield
shift of the MeO signal in their 1H NMR spectra,
appearing at 3.02-3.29 ppm, and their coupling constant
between 2-H and the 1-endo-H (Ha) was 0-2.5 Hz.
Additionally, comparatively, the 2-exo-isomers 10 were
significantly more levorotatory than their respective
2-endo-isomers 13.21d
The overall results of the above cyclization and con-
figuration stability studies show that the 2-exo-methoxy-
carbonyl tautomer 10 was the most stable in the ben-
zaldehyde derivatives (g) and in the less hindered
compounds (those derived from cyclohexanone (a), ac-
etone (c), and acetaldehyde (d)), while in those more
FIGURE 3. Chem 3D models of the 2-methoxycarbonyl-exo-
and -endo-isomers of the pyrroloimidazoindol derivatives of
acetaldehyde (10d and 13d) and benzaldehyde (10g and 13g).
hindered compounds, such as those derived from N-ben-
zyl-4-piperidone (b), phenylacetaldehyde (e), pivalalde-
hyde (f), and N-Z-alaninal (h), the 2-endo-methoxycar-
bonyl isomer was the most stable. In the case of the
aldehyde derivatives, the results could be explained in
terms of the 3D molecular models for the four pyrro-
loimidazoindoles 10-13. Thus, in any case, the 2-endo-
isomer 12 would be the less stable, as both the methoxy-
carbonyl and the R1 moieties would project toward the
more constrained concave endo-face. The relative stability
between 10, 11, and 13 would depend mostly on the steric
volume of the R1 substituent, which, except for very small
groups as Me (acetaldehyde derivatives (d)), would have
a high preference for an orientation toward the less
hindered exo-face of the pyrroloimidazoindol framework,
as in 10 or 13. Finally, with the increase in volume of
R1, a destabilizing steric interaction of this group with
the 2-methoxycarbonyl moiety, in a relative cis-disposi-
tion in the 2-exo-isomer 10, would displace the equilib-
rium toward the 2-endo-isomer 13, in which those groups
would be in a relative trans-disposition. Although the
steric volume of the phenyl group is higher than that of
the phenylmethyl group,22 the higher stability of the exo-
tautomer 10g versus the endo 13g might be attributed
to a possible nonbonding secondary orbital interaction,
possibly of the π-stacking type,23 between the ester
moiety and the 4-phenyl group, which would adopt a
parallel cis-disposition, as shown in Figure 3.
In the case of the ketone derivatives (a-c), the
stabilization of the 2-endo-isomer in the N-benzyl-4-
(22) MacPhee, J. A.; Panaye, A.; Dubois, J.-E. Tetrahedron 1978,
34, 3553-3562.
(23) Crich, D.; Chan, C.; Davies, J. W.; Natarajan, S.; Vinter, J. G.
J. Chem. Soc., Perkin Trans. 2 1992, 2233-2240.
8974 J. Org. Chem., Vol. 70, No. 22, 2005

Tryptophan-Derived Amino Nitrile Cyclization
TABLE 2. Analytical Data of the Hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole Derivatives 10b-h, 11d, and
13b-i
RP HPLCc
ESI-MS
compda
R1
R2
formulab
yield (%)
[M + 1]
[R]20
tR (min)
(A:B)
D
10b
13b
10c
10d
11d
10e
13e
10f
[(CH2)2]2N-Bn
C25H28N4O2
C25H28N4O2
94
81
95
71
72
96
74
86
84
100
70
48
34
417.3
417.3
286.2
272.1
272.1
348.3
348.3
314.3
314.3
334.2
435.3
435.3
397.0
-158.45 (c 1.1, MeOH)
-14.76 (c 1.1, MeOH)
-133.92 (c 1.1, MeOH)
-127.69 (c 1.3, MeOH)
-104.86 (c 0.9, MeOH)
-114.29 (c 1.0, MeOH)
-5.31 (c 0.4, MeOH)
-148.31 (c 1, MeOH)
+12.04 (c 1, MeOH)
-98.41 (c 0.9, MeOH)
-119.07 (c 1.3, MeOH)
+15.02 (c 0.8, MeOH)
-13.72 (c 0.7, MeOH)
2.68
2.81
2.00
2.17
2.36
2.07
2.49
2.02
2.31
2.02
10.25
8.16
3.44
(25:75)
(25:75)
(25:75)
(25:75)
(25:75)
(50:50)
(50:50)
(50:50)
(50:50)
(50:50)
(30:70)
(30:70)
(30:70)
[(CH2)2]2N-Bn
Me
Me
H
C16H19N3O2
C15H17N3O2
C15H17N3O2
C21H21N3O2
C21H21N3O2
Me
H
Me
H
PhCH2
PhCH2
H
tBu
H
C18H23N3O2
C18H23N3O2
13f
tBu
H
10g
10h
13h
13id
Ph
H
C20H19N3O2
C24H26N4O4
C24H26N4O4
C18H19F3N4O3
(S)-CH(Me)NHZ
(S)-CH(Me)NHZ
(S)-CH(Me)NHCOCF3
H
H
H
a Foams. b Satisfactory analysis for C, H, N. c Novapak C18 (3.9 × 150 mm, 4 µm). A ) CH3CN, B ) 0.05% TFA in H2O. d Resulting
from the partial replacement of the Z-protecting group of 13h by a trifluoroacelyl group.
TABLE 3. Significant 1H NMR Data of the Hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole Derivatives 10b-h, 11d,
and 13b-ia
compd
1-H
2-H
3.23
7-H
7.36
8-H
7.23
9-H
10-H
10b-H
3.80
10c-H OMe
R1
R2
J1,2
J1,10b
J10b,10c
10b
2.12,
2.48
7.02 7.14
5.84
3.65 1.72-2.19,
2.53-2.73,
6 and 11.5 0 and 8
7
3.50, 7.21-7.31
13b
10c
2.13,
4.01
7.42
7.20
6.94 7.08
3.81
5.65
3.02 1.44-2.16,
2.45, 2.76-2.85,
3.47, 3.53
3.67 1.54
0 and 9
0 and 8.5 7.5
2.76-2.85
2.15,
2.37
3.21
3.18
3.09
7.37
7.36
7.36
7.23
7.23
7.20
7.23
7.21
7.23
7.22
7.02 7.15
7.04 7.17
6.99 7.13
7.04 7.16
7.00 7.14
7.03 7.14
6.99 7.12
3.79
3.78
3.76
3.77
3.78
3.76
3.77
5.84
5.86
5.66
5.71
5.59
5.73
5.64
1.25 6 and 12
0 and 8
7
7
7
7
10d 2.15,
3.69 1.53
3.65 1.24
3.52 3.07,
3.74 6 and 11.5 0 and 8
4.15 6 and 11.5 0 and 8
2.45
11d 2.04,
2.28
2.10,
2.49
2.25,
2.62
2.08,
2.49
2.18,
2.65
2.23,
2.53
10e
13e
10f
13f
10g
3.15-3.22 7.40
3.90 6 and 12
4.10 0 and 8
0 and 8
3.15-3.22
3.96
3.19
4.06
3.44
3.28
7.37
7.44
7.46
7.64
7.39
3.13 3.05,
0 and 8.5 7.5
3.12
3.67 1.12
3.27 6 and 11.5 1 and 8
7
3.16 1.10
3.31 2.5 and 8.5 2 and 7.5 7.5
7.20-7.49 7.09 7.20-7.49 3.70-3.75 5.67
3.75 7.20-7.49
4.92 6 and 11
0 and 8
7
10h 2.21,
7.24
7.06 7.17
3.79
5.71
5.67
5.65
3.64 1.36,
4.10,
3.71 6 and 11.5 0 and 8
7.5
2.42
5.98
13h 2.15,
4.09
4.15
7.29-7.36 7.22
7.17-7.20 7.26
7.04 7.15
3.71
3.29 1.34,
3.83 4 and 8
3.93 5 and 8
4 and 8
5 and 8
7.5
7.5
2.56
4.16,
5.35
13i
2.10,
2.59
7.07 7.17-7.20 3.70
3.40 1.39,
4.38,
8.00
a Spectra registered at 400 or 500 MHz in CDCl3, assigned with the help of COSY spectra.
piperidone derivatives (b), with respect to the cyclohex-
anone (a) and acetone (c) derivatives, might also be due
to the increase in steric hindrance, but some stabilizing
electronic interaction of the N-benzyl group with the
aromatic part of the pyrroloimidazoindol system cannot
be ruled out.
Studies on the synthesis of hexahydropyrrolo[1′,2′,3′:
1,9a,9]imidazo[1,2-a]indole derivatives with an additional
J. Org. Chem, Vol. 70, No. 22, 2005 8975

Gonza´lez-Vera et al.
room temperature for a variable time, as specified in Table 1.
Afterward, the reaction mixture was sequentially poured into
ice, neutralized with NH4OH, and extracted with CH2Cl2 (20
mL). The organic extracts were successively washed with H2O
(5 mL) and brine (5 mL), dried over Na2SO4, and evaporated
to dryness. The residue was purified by circular chromatog-
raphy, using 30-100% gradient of EtOAc in hexane as eluant.
fused piperazine ring from the alanine derivatives 10h
and 13h, via N-Z removal followed by lactamization, are
in progress and will be communicated in due time.
The hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]in-
dole derivatives herein described 10-13 were evaluated
as cytotoxics in human lung carcinoma (A549) and
human colon carcinoma (HT-29) cell lines. However, none
of them showed significant cytotoxicity at concentrations
below 10-6 M.
In conclusion, the results herein described show the
wide scope of the acid-promoted domino cyclization of
tryptophan-based R-amino nitriles derived from either
ketones or aldehydes to hexahydropyrrolo[1′,2′,3′:1,9a,9]-
imidazo[1,2-a]indoles. The reaction time and the stereo-
selectivity mostly depended on both the steric volume of
the substituents at the amino nitrile and its stereochem-
istry. Unhindered R-amino nitriles gave exclusively the
isomer with the 2-CO2Me group toward the exo-face (10)
as the kinetic and thermodynamic controlled product,
while more hindered R-amino nitriles, which required
higher conversion times, under kinetic control, gave also
the 2-exo-isomer, but under thermodynamic control,
provided the 2-endo-isomer 13 as main reaction product.
The absolute preference of the 2-exo-stereochemistry of
the benzaldehyde derivative 10g versus the 2-endo 13g
might be due to some stabilizing electronic interaction
between the 4-phenyl and the 2-methoxycarbonyl groups
in a relative parallel cis-disposition.
1
Significant analytical and H NMR spectroscopic data of the
resulting hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole
derivatives 10b-g, 12d, and 13b-g are summarized in the
Tables 2 and 3. 13C NMR spectroscopic data are summarized
in Table 4 of the Supporting Information.
Acid-Promoted Cyclization of r-Amino Nitriles 8 and
9. Method B: Synthesis of the Hexahydropyrrolo[1′,2′,3′:
1,9a,9]imidazo[1,2-a]indole Derivatives 10h, 13h, and 13i.
The corresponding R-amino nitriles 8h and 9h (1.5 mmol) were
dissolved in neat TFA (2 mL), and the solution was stirred at
room temperature for a variable time, as specified in Table 1.
Afterward, the reaction mixture was processed and purified
as above for method A. Amino nitrile 9h gave exclusively the
tautomer 10h, while 8h gave a mixture of the tautomer 13h
and the analogue with a trifluoroacetyl group replacing the
Z-protecting group 13i, which were resolved in the chromato-
graphic purification. Significant analytical and 1H NMR
spectroscopic data of the resulting hexahydropyrrolo[1′,2′,3′:
1,9a,9]-imidazo[1,2-a]indole derivatives 10h, 13h, and 13i are
summarized in the Tables 2 and 3, respectively. 13C NMR
spectroscopic data are summarized in Table 4 of the Support-
ing Information.
Acknowledgment. This work was supported by
CICYT (SAF2000-0147). The antitumoral evaluation
was carried out by the company Pharma Mar, S. A.
Experimental Section
Supporting Information Available: General methods,
experimental procedure for the synthesis, characterization
data of R-amino nitriles 8 and 9, and the 13C NMR data of the
pyrroloimidazoindol derivatives 10-13. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Acid-Promoted Cyclization of r-Amino Nitriles 8 and
9. Method A: Synthesis of the Hexahydropyrrolo[1′,2′,3′:
1,9a,9]imidazo[1,2-a]indole Derivatives 10b-g, 11d, and
13b-g. H3PO4 (85%, 3 mL) was added to a solution of the
corresponding Trp-derived R-amino nitrile (8b-g and 9d-g)
(1.5 mmol) in CH2Cl2 (6 mL), and the mixture was stirred at
JO051441+
8976 J. Org. Chem., Vol. 70, No. 22, 2005