Synthesis of indole alkaloid analogues containing the novel hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole skeleton by ring-closing reactions of tryptophan-derived α-amino nitriles

Article abstract of DOI:10.1016/j.tet.2007.06.053

New indole alkaloid analogues, containing a 10b-methyl- or a 10b-hydroxy-1,2,4,5,10b,10c-hexahydropyrrolo[1′,2′,3′:1,9a,9]imidazo[1,2-a]indole skeleton, have been obtained by highly stereoselective electrophile addition-cyclization reactions of a tryptoph

Full text of DOI:10.1016/j.tet.2007.06.053

Tetrahedron 63 (2007) 9229–9234
Synthesis of indole alkaloid analogues containing the novel
hexahydropyrrolo[10,20,30:1,9a,9]imidazo[1,2-a]indole skeleton by
ring-closing reactions of tryptophan-derived a-amino nitriles
*
ꢀ
Juan A. Gonzalez-Vera, M. Teresa Garcıa-Lopez and Rosario Herranz
ꢀ
ꢀ
´
Instituto de Quꢀımica Medica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 14 May 2007; revised 12 June 2007; accepted 14 June 2007
Available online 22 June 2007
Abstract—New indole alkaloid analogues, containing a 10b-methyl- or a 10b-hydroxy-1,2,4,5,10b,10c-hexahydropyrrolo[10,20,30:1,9a,9]-
imidazo[1,2-a]indole skeleton, have been obtained by highly stereoselective electrophile addition–cyclization reactions of a tryptophan-
derived a-amino nitriles.
Ó 2007 Elsevier Ltd. All rights reserved.
(S)
CO2Me
1. Introduction
R3
10b
1
2
Me
3N
10
7
(S)
9
8
MeHNCO2
R1
R2
N
6
4
We have recently described the stereoselective synthesis of
compounds of general formula 1 (Fig. 1), which contain
the novel tetracyclic system 1,2,4,5,10b,10c-hexahydro-
pyrrolo[10,20,30:1,9a,9]imidazo[1,2-a]indole, via an acid-
promoted domino tautomerization of tryptophan-derived
a-amino nitriles.1 This novel ring system could be consid-
ered as a hybrid of 1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-
b]indole and 2,3,9,9a-tetrahydroimidazo[1,2-a]indole, both
present in a growing class of indole alkaloids with a wide
range of biological activities. The hexahydropyrrolo[2,3-
b]indole is present, among others, in the acetylcholinesterase
inhibitor physostigmine (3),2 which has a methyl group at
position 3a, and in diverse alkaloids that possess a hydroxy
group at that position, such as alline (4),3 flustraminol,4
gypsetin,5 okaramins,6 brevianamide E (5),7 and several
peptides, which contain modified tryptophan residues.8 On
the other hand, the 9-hydroxy-tetrahydroimidazo[1,2-a]-
indole is present in the cholecystokinin antagonist asperlicin
(6),9 in the antifungic agents fumiquinazolines,10 or in the
substance P antagonists fiscalins (7).11 In the preparation
of novel indole alkaloid analogues, we have explored and re-
ported herein the synthesis of 1,2,4,5,10b,10c-hexahydro-
pyrrolo-[10,20,30:1,9a,9]imidazo[1,2-a]indole derivatives 2
substituted with a methyl or hydroxy group at the 10b
position, by ring-closing reactions of tryptophan-derived
a-amino nitriles.
(R)
N
Me
N
5
H
NH
Me
1: R3 = H
Physostigmine (3)
2: R3 = Me,OH
O
H
HO
N
HO
(S)
(R)
(S)
(R)
N
(S)
N
(S)
Me
N
H
O
N
H
H
H
Alline (4)
Brevianamide E (5)
O
O
N
(R)
(R)
HN
N
HN (S)
HO
N
H
O
HO
N
O
H
NH
(S)
(S)
NH
(S)
(S)
N
N
(S)
(S)
O
O
Asperlicin (6)
Fiscalin A (7)
Figure 1. General formulas of hexahydropyrroloimidazoindoles and exam-
ples of related indole alkaloids.
2. Results and discussion
The construction of the 10b-methyl-hexahydropyrroloimid-
azoindole system was envisaged by applying a strategy
similar to that reported by the Nakagawa’s group for the
synthesis of physostigmine.12 This strategy involves the
* Corresponding author. Tel.: +34 91 5622900; fax: +34 91 5644853;
e-mail: rosario@iqm.csic.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.053

9230
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 9229–9234
introduction of a methylthiomethyl group in tryptophan
derivatives by a cyclative alkylation with the Corey–Kim
reagent,13 followed by reductive desulfurization of the
methylthiomethyl to a methyl group. The tryptophan- and
cyclohexanone-derived a-amino nitrile 8 was used as a sub-
strate for the study of this methodology. As shown in Scheme
1, the reaction of amino nitrile 8 with 2 equiv of the Corey–
Kim reagent (9) [prepared in situ by reaction of N-chlorosuc-
cinimide with dimethyl sulfide in the presence of 2.4 equiv
of diisopropylethylamine (DIEA)] led to a mixture of 52%
of the 3a-monoalkylated-hexahydropyrrolo[2,3-b]indole
10, along with 20% of the 3a,8-dialkylated product 11.
With the aim of avoiding the formation of this dialkylation
product, the reaction was also performed using only 1 equiv
of the Corey–Kim reagent. However, in this case the conver-
sion was very low, obtaining only 16% of 10, and recovering
53% of the starting amino nitrile. Interestingly, the ring-clos-
ing alkylation proceeded with complete stereoselectivity
toward the 2-exo-diastereoisomer, while the Nakagawa’s
group, under the same reaction conditions, reported a
(z1:1) 2-exo/2-endo diastereoisomeric ratio.12 In the next
step, the treatment of the 3a-monoalkylated compound 10
with 10% solution of trifluoroacetic acid (TFA) in CH2Cl2
quantitatively led to the 5-imino-pyrroloimidazoindole de-
rivative 12, a tautomer of 10, which results from the electro-
philic cyclization of indole NH onto the protonated cyano
group. All attempts of reductive desulfurization of the meth-
ylthiomethyl group of 12, by heating in the presence of
Raney Ni14 or by catalytic hydrogenation in the presence
of this catalyst12 were unsuccessful, recovering the starting
material unchanged. As we had previously observed for the
hydrogenolysis of a benzyloxycarbonyl-protecting group
from a pyrroloimidazoindole containing a N-Z-Ala resi-
due,15 the difficulty of catalytic reductive desulfurization
could be due to catalyst poisoning by the amidine group.
Hence, we turned our attention from the amidine to the lac-
tam analogue 14, which was obtained in 62% yield by alkyl-
ative hydrolysis of the amidine group of 12, carried out by
treatment with MeI and Cs2CO3 in CH3CN at 80 ꢀC for
two days.1a Then, the hydrogenolysis of the methylthio-
methyl group of 14 to the methyl of 15 was successfully
achieved by hydrogenation in the presence of Raney Ni, in
EtOH at 80 ꢀC under 2 atm of H2.
The synthesis of the 10b-hydroxy-hexahydropyrroloimid-
azoindole skeleton was first attempted by applying the Crich’s
methodology of oxidation of hexahydropyrrolo[2,3-b]in-
doles with ceric ammonium nitrate (CAN)16 to the 10b-
unsubstituted hexahydropyrroloimidazoindoles 1. However,
these compounds were recovered unaltered after three days
of treatment with 5 equiv of CAN. Then, the introduction
of the hydroxy group was approached by cyclative oxidation
of the corresponding tryptophan-derived a-amino nitrile. We
decided to try H2O2 as an oxidizer, a commercial, cheap and
environmental friendly reagent. Taking into account that, as
above mentioned, the cyclization to the hexahydropyrrolo-
imidazoindole system requires the cyano activation by pro-
tonation, this oxidation was studied in acid media. As
shown in Scheme 2, the treatment of amino nitrile 8, dis-
solved in a 10% solution of TFA in CH2Cl2, with 4% of
H2O2 (33% solution in H2O) at 0 ꢀC led, after 3 h of reaction,
to the two diastereoisomeric 10b-hydroxy-hexahydropyr-
roloimidazoindoles 16 (54%) and 17 (13%), along with the
2-oxoindolines 18 (11%), traces of the 10b-unsubstituted
hexahydropyrroloimidazoindole 191a (1%) and 21% of H–
Trp–OMe, resulting from the amino nitrile degradation in
CO2Me
HN
N
H
C
N
8
O
Me
iPr2NEt
Cl
S
N
Me
O
9
SMe
SMe
N
+
CO2Me
CO2Me
N
H
N
N
H
N
H
N
MeS
C
C
CO2Me
10 (52%)
11 (20%)
HN
N
H
TFA
C
N
8
SMe
CO2Me
CO2Me
Me
H2O2/H
H
H
H2
N
N
CO2Me
CO2Me
CO2Me
CO2Me
HO
HO
Ni Raney
H
H
N
N
N
N
NH
12 (100%)
MeI/Cs2CO3
NH
13
N
N
NH
16
NH
17
+
H
H
SMe
CO2Me
CO2Me
Me
H
N
H
H
H2
HN
N
N
N
H
O
N
Ni Raney
N
N
C
NH
19
N
O
O
18
14 (62%)
15 (92%)
Scheme 2. H2O2-mediated oxidation of the tryptophan-derived a-amino
nitrile 8.
Scheme 1. Synthesis of 10b-methyl-hexahydropyrroloimidazoindoles.

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 9229–9234
9231
the acid medium. Diastereoisomers 16 and 17 were chro-
matographically resolved; however, the epimeric mixture
of 2-oxoindolines 18 could not be resolved. To minimize
the amino nitrile degradation and the formation of oxoindo-
lines, a reaction condition optimization study was carried
out. The results of this study (Table 1) showed that the in-
crease of the H2O2 concentration lowered the overall yield
of 16 and 17 due to the increase in oxoindolines 18, while
the increase of the TFA concentration or the temperature
led to an increase in degradation products. Finally, the re-
placement of TFA by 85% H3PO4 as acid medium (entry
9) produced a significant increase in the overall yield of
the desired 16 and 17 (86%).
with a 10% solution of TFA in CH2Cl2. This treatment quan-
titatively produced the corresponding 10b-hydroxy-hexahy-
dropyrroloimidazoindoles 16 and 17. The parallel treatment
of amino nitrile 8 with DMDO in the presence of a 10% of
TFA at ꢁ78 ꢀC led directly to 16 and 17, in the same 2-
exo/2-endo diastereomeric ratio (7:1) and in the same overall
yield (85%). Interestingly, both H2O2 and DMDO gave sim-
ilar overall yield of 10b-hydroxy-hexahydropyrroloimid-
azoindoles, although the stereoselectivity of DMDO for the
2-exo-diastereoisomer 16 was higher. This higher stereo-
selectivity is related with the lower reaction temperature,
which favors this kinetic control product. In the case of using
H2O2, the aqueous phase that contains this reagent froze
below 0 ꢀC and the oxidation did not take place.
Table 1. Optimization of reaction conditions for the H2O2-mediated oxida-
tion of 8
The structural assignment of pyrroloimidazoindoles 12 and
14–17 was based on their ES-MS and NMR data. The H
1
Entry Acid
Acid
H2O2
T
t
Yielda (%)
NMR spectra showed the disappearance of the indole NH
and 2-H protons and the appearance of a singlet (dz5.32–
6.77 ppm), corresponding to the 10c-H, while the 13C
NMR spectra showed the conversion of the nitrile carbon
(121.6 ppm) into the amidine or lactam carbon (172–
182 ppm), and the transformation of the aromatic indole
C3 and C2 carbons into two new aliphatic carbons C10b
(49–85 ppm) and C10c (89–94 ppm), respectively. The ste-
reochemistry at these fusion carbons was established on
the basis of the NOE correlations observed in the 1D NO-
ESY spectra (Fig. 2). Furthermore, as it has been described
for hexahydropyrrolo[2,3-b]indole derivatives19 and for un-
substituted pyrroloimidazoindoles 1,1b the 2-endo-10b-
hydroxy-pyrroloimidazoindole 17 showed an upfield shift
concnb concnb (ꢀC) (h)
16 17 18 19 H–Trp–
OMe
(%)
(%)
1
2
3
4
5
6
7
8
9
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
10
10
10
10
10
20
40
40
4
10
20
35
35
10
4
0
0
0
0
25
0
0
25
0
3
2
3
3
1
2
2
1
5
54 13 11 1 21
23 10 19 12 36
30 16 24
32 18 50
8
0
3
22
0
22
23
16
6
6
8
3
3
46
13 12 51
17
8
4
7
1
70
72
4
35
4
10
H3PO4 10
56 30
9
Yields were determined by 1H NMR analysis, except for entries 1 and 9,
where yields are of isolated compounds.
Percentage in CH2Cl2 solution.
a
b
1
of 0.64 ppm for the MeO signal in the H NMR spectrum,
and it was significantly less levorotatory than its respective
2-exo-diastereoisomer 16.
Having in mind that nowadays dimethyldioxirane (DMDO),
due to its good efficacy and selectivity, is the most used
oxidizer of tryptophan derivatives to 3a-hydroxy-pyrrolo-
indoles,17 we decided to study the oxidation of amino nitrile
8 also with this non-commercial reagent, which was freshly
prepared as a 0.05 M solution in acetone.18 Under the reac-
tion conditions reported by the Danishefsky’s group,17a,b
the treatment of 8, dissolved in CH2Cl2, with 1.2 equiv of
the acetone solution of DMDO at ꢁ78 ꢀC gave 85% of
a (7:1) diastereomeric mixture of the 3a-hydroxy-hexahydro-
pyrrolo[2,3-b]indoles 20 and 21 (Scheme 3), which could not
be separated. TLC and 1H NMR analysis showed the instabil-
ity of this mixture and the appearance of degradation prod-
ucts. Therefore, without further purification, it was treated
In conclusion, herein we describe highly stereoselective elec-
trophilic alkylative and oxidative ring-closing reactions of a
tryptophan-derived a-amino nitrile to 10b-methyl- and 10b-
hydroxy-1,2,4,5,10b,10c-hexahydropyrrolo-[10,20,30:1,9a,9]-
imidazo[1,2-a]indoles, respectively, which give easy access
to new indole alkaloid analogues.
Hb
H
NOE
CO2Me
H
Hb
H
Ha
N
Ha
HO
CO2Me
NOE
R
H
N
N
N
X
12, 14-16
NH
17
OH
OH
Figure 2. Configuration assignment of 10b-substituted-hexahydropyrrolo-
imidazoindoles.
CO2Me
CO2Me
CO2Me
CO2Me
N
H
N
+
+
N
H
N
H
N
H
N
C
C
H
20
21
8
3. Experimental
3.1. General
TFA (100%)
HO
HO
H
N
N
All reagents were of commercial quality. Solvents were
dried and purified by standard methods. Analytical TLC
was performed on aluminum sheets coated with 0.2 mm
layer of silica gel 60 F254. Silica gel 60 (230–400 mesh)
was used for flash chromatography. Preparative radial
N
N
NH
16
NH
17
Scheme 3. DMDO-mediated oxidation of a-amino nitrile 8.

9232
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 9229–9234
chromatography was performed on 20 cm diameter glass
plates coated with 1 mm layer of silica gel PF254. Analytical
RP-HPLC was performed on a Novapak C18 (3.9ꢂ150 mm,
4 mm) column, with a flow rate of 1 mL/min, and using a tun-
able UV detector set at 214 nm. Mixtures of CH3CN (solvent
A) and 0.05% TFA in H2O (solvent B) were used as mobile
2.36 (dd, 1H, J¼5 and 13 Hz, 3-H), 2.55 (dd, 1H, J¼8 and
13 Hz, 3-H), 2.61 (m, 1H, 20 or 60-Hec), 3.06 (d, 1H,
J¼12.5 Hz, 3a-CH2), 3.18 (d, 1H, J¼12.5 Hz, 3a-CH2),
3.38 (s, 3H, OCH3), 4.20 (dd, 1H, J¼5 and 8 Hz, 2-H),
4.43 (d, 1H, J¼14 Hz, 8-CH2), 4.69 (d, 1H, J¼14 Hz, 8-
CH2), 5.59 (s, 1H, 8a-H), 6.48 (d, 1H, J¼8 Hz, 7-H), 6.64
(t, 1H, J¼7.5 Hz, 5-H), 7.04 (d, 1H, J¼8 Hz, 4-H), 7.05 (t,
1H, J¼7.5 Hz, 6-H); 13C NMR (100 MHz, CDCl3) d 14.6
[8-(CH2–S–CH3)], 17.1 [3a-(CH2–S–CH3)], 22.9 and 23.0
1
phases. H NMR spectra were recorded at 300, 400, or
500 MHz, using TMS as reference, and 13C NMR spectra
were recorded at 75, 100, or 125 MHz. The NMR spectra as-
signment was based on COSY and HSQC spectra. ESI-MS
spectra were performed, in positive mode, using MeOH as
solvent.
0
0
0
0
0
(C3 and C5 ), 24.5 (C4 ), 36.5 and 37.1 (C2 and C6 ), 41.0
(3a-CH2), 42.4 (C3), 48.2 (8-CH2), 52.0 (OCH3), 57.1
0
(C3a), 60.5 (C1 ), 62.7 (C2), 86.2 (C8a), 106.6 (C7), 117.9
(C5), 122.3 (CN), 122.9 (C4), 128.7 (C6), 130.7 (C3b),
148.1 (C7a), 173.7 (CO2); ES-MS m/z 468.2 (100)
[M+Na]+. Anal. Calcd for C23H31N3O2S2: C, 61.99; H,
7.01; N, 9.43. Found: C, 61.74; H, 7.37; N, 9.79.
3.2. Synthesis of methyl (2S,3aR,8aS)-1-(1-cyanocyclo-
hexyl)-3a-(methylthiomethyl)-1,2,3,3a,8,8a-hexahydro-
pyrrolo[2,3-b]indol-2-yl-carboxylate (10) and methyl
(2S,3aR,8aS)-1-(1-cyanocyclohexyl)-3a,8-bis(methyl-
thiomethyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]-
indol-2-yl-carboxylate (11)
3.3. Synthesis of (2S,10bR,10cR)-5-imino-2-methoxy-
carbonyl-10b-methylthiomethyl-1,2,4,5,10b,10c-hexa-
hydropyrrolo[10,20,30:1,9a,9]imidazo[1,2-a]indole-4-
spirocyclohexane (12)
Dimethyl sulfide (81 mL, 1.11 mmol) was added to a cooled
solution (ꢁ78 ꢀC) of N-chlorosuccinimide (123.2 mg,
0.92 mmol) in CH2Cl2 (3 mL) and the solution was stirred
at that temperature for 1 h. Then, a solution of a-amino nitrile
8 (150.1 mg, 0.46 mmol) in CH2Cl2 (2 mL) and DIEA
(189.5 mL, 1.11 mmol)were added and the stirring was main-
tained at ꢁ78 ꢀC for 2 h. Afterward, the reaction mixture
was brought to room temperature, diluted with CH2Cl2
(20 mL), successively washed with H2O (5 mL), brine
(5 mL), dried over Na2SO4, and evaporated to dryness. The
residue was purified by circular chromatography, using
5–15% EtOAc gradient in hexane as eluant, to give the title
compounds.
TFA (500 mL) was added to a solution of 10 (82.4 mg,
0.21 mmol) in CH2Cl2 (4.5 mL) and the mixture was stirred
at room temperature for 30 min. Then, the mixture was
poured into ice (z10 mg), neutralized with NH4OH, and ex-
tracted with CH2Cl2 (20 mL). The organic extracts were suc-
cessively washed with H2O (5 mL), brine (5 mL), dried over
Na2SO4, and evaporated to dryness. The residue was purified
by circular chromatography, using 30–80% EtOAc gradient
in hexane as eluant, to give the title compound as a foam
(80.9 mg, 100%); [a]2D0 ꢁ109.17 (c 0.9, MeOH); HPLC [No-
vapak C18 (3.9ꢂ150 mm, 4 mm), (A:B, 50:50)] tR 2.54 min;
1H NMR (400 MHz, CDCl3) d 1.26–1.80 and 2.05 (m, 10H,
cyclohexyl), 2.04 [s, 3H, 10b-(CH2–S–CH3)], 2.24 (dd, 1H,
J¼6 and 12 Hz, 1-H), 2.35 (t, 1H, J¼12 Hz, 1-H), 3.01 (d,
1H, J¼12.5 Hz, 10b-CH2), 3.22 (d, 1H, J¼12.5 Hz, 10b-
CH2), 3.24 (dd, 1H, J¼6 and 12 Hz, 2-H), 3.67 (s, 3H,
OMe), 5.65 (s, 1H, 10c-H), 7.07 (dt, 1H, J¼1 and 7.5 Hz,
9-H), 7.24 (d, 1H, J¼7.5 Hz, 10-H), 7.28 (dt, 1H, J¼1 and
7.5 Hz, 8-H), 7.41 (d, 1H, J¼7.5 Hz, 7-H); 13C NMR
(75 MHz, CDCl3) d 17.3 [10b-(CH2–S–CH3)], 21.9, 22.2,
25.4, 29.4, 34.0 (cyclohexyl), 45.0 (C1), 52.2 (OMe), 54.4
(C10b), 61.9 (C2), 72.4 (C4), 91.0 (C10c), 114.9 (C7), 123.5
(C10), 124.1 (C9), 129.0 (C8), 136.4 (C10a), 144.5 (C6a),
173.7 (CO2), 174.0 (C5); ES-MS m/z 386.2 (100) [M+1]+.
Anal. Calcd for C21H27N3O2S: C, 65.42; H, 7.06; N,
10.90. Found: C, 65.63; H, 7.01; N, 10.73.
3.2.1. Methyl (2S,3aR,8aS)-1-(1-cyanocyclohexyl)-3a-
(methylthiomethyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-
b]indol-2-yl-carboxylate (10). Foam (92.1 mg, 52%); [a]D20
ꢁ110.41 (c 0.9, MeOH); HPLC [Novapak C18 (3.9ꢂ
150 mm, 4 mm), (A:B, 50:50)] tR 3.58 min; 1H NMR
(400 MHz, CDCl3) d 1.23–1.86 (m, 9H, cyclohexyl), 2.00
[s, 3H, 3a-(CH2–S–CH3)], 2.18 (dd, 1H, J¼7 and 13 Hz,
3-H), 2.24 (m, 1H, 20or 60-Hec), 2.46 (dd, 1H, J¼8.5 and
13 Hz, 3-H), 3.03 (d, 1H, J¼12.5 Hz, 3a-CH2), 3.08 (d, 1H,
J¼12.5 Hz, 3a-CH2), 3.70 (s, 3H, OCH3), 3.85 (dd, 1H,
J¼7 and 8.5 Hz, 2-H), 4.33 (d, 1H, 8-H), 5.48 (d, 1H, J¼
3.5 Hz, 8a-H), 6.65 (d, 1H, J¼8 Hz, 7-H), 6.75 (t, 1H,
J¼7 Hz, 5-H), 7.07 (t, 1H, J¼8 Hz, 6-H), 7.10 (d, 1H,
J¼7 Hz, 4-H); 13C NMR (100 MHz, CDCl3) d 17.4 [3a-
0
0
0
(CH2–S–CH3)], 22.3 and 22.7 (C3 and C5 ), 24.5 (C4 ),
0
34.9 and 36.7 (C2 y C6 ), 42.0 (3a-CH2), 43.1 (C3), 52.2
0
(OCH3), 56.4 (C3a), 58.5 (C1 ), 60.6 (C2), 84.4 (C8a), 110.3
(C7), 119.4 (C5), 120.9 (CN), 122.6 (C4), 128.7 (C6), 132.5
(C3b), 148.5 (C7a), 175.5 (CO2); ES-MS m/z 386.2 (100)
[M+1]D. Anal. Calcd for C21H27N3O2S: C, 65.42; H, 7.06;
N, 10.90. Found: C, 65.76; H, 7.35; N, 11.23.
0
3.4. Synthesis of (2S,10bR,10cR)-2-methoxycarbonyl-
10b-methylthiomethyl-5-oxo-1,2,4,5,10b,10c-hexahydro-
pyrrolo[10,20,30:1,9a,9]imidazo[1,2-a]indole-4-spiro-
cyclohexane (14)
Cs2CO3 (87.6 mg, 0.27 mmol) and MeI (100.8 mL,
1.62 mmol) were added to a solution of 12 (70.3 mg,
0.18 mmol) in dry CH3CN (3 mL), and this mixture was
stirred at 80 ꢀC in a pressure tube for two days. Afterward,
the solvent was evaporated, the residue was dissolved in
CH2Cl2 (10 mL), and the resulting solution was successively
washed with H2O (3 mL) and brine (3 mL), dried over
Na2SO4, and evaporated to dryness. The residue was purified
by circular chromatography, using 15–25% gradient of
3.2.2. Methyl (2S,3aR,8aR)-1-(1-cyanocyclohexyl)-3a,8-
bis(methylthiomethyl)-1,2,3,3a,8,8a-hexahydropyr-
rolo[2,3-b]indol-2-yl-carboxylate (11). Foam (41.7 mg,
20%); [a]2D0 +96.83 (c 1.1, MeOH); HPLC [Novapak C18
1
(3.9ꢂ150 mm, 4 mm), (A:B, 50:50)] tR 5.76 min; H NMR
(400 MHz, CDCl3) d 1.23–2.04 (m, 9H, cyclohexyl), 2.06
[s, 3H, 8-(CH2–S–CH3)], 2.09 [s, 3H, 3a-(CH2–S–CH3)],

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 9229–9234
9233
EtOAc in hexane as eluant, to yield the title compound as
a foam (45.2 mg, 65%); [a]2D0 ꢁ48.01 (c 0.7, MeOH);
HPLC [Novapak C18 (3.9ꢂ150 mm, 4 mm), (A:B, 50:50)]
tR 14.34 min; 1H NMR (300 MHz, CDCl3) d 1.24–2.02
(m, 10H, cyclohexyl), 2.03 [s, 3H, 10b-(CH2–S–CH3)],
2.30 (d, 2H, J¼9 Hz, 1-H), 3.00 (d, 1H, J¼12.5 Hz, 10b-
CH2), 3.22 (d, 1H, J¼12.5 Hz, 10b-CH2), 3.37 (t, 1H,
J¼9 Hz, 2-H), 3.68 (s, 3H, OMe), 5.77 (s, 1H, 10c-H),
7.11 (t, 1H, J¼7.5 Hz, 9-H), 7.25 (d, 1H, J¼7.5 Hz, 10-H),
7.28 (t, 1H, J¼7.5 Hz, 8-H), 7.45 (d, 1H, J¼7.5 Hz, 7-H);
13C NMR (75 MHz, CDCl3) d 17.8 [10b-(CH2–S–CH3)],
21.9, 22.8, 25.7, 29.4, 33.0 (cyclohexyl), 44.8 (C1), 52.8
(OMe), 55.0 (C10b), 62.3 (C2), 72.2 (C4), 89.2 (C10c),
115.7 (C7), 124.1 (C10), 125.6 (C9), 129.6 (C8),
136.4 (C10a), 142.2 (C6a), 173.4 (CO2), 181.4 (C5); ES-
MS m/z 387.1 (100) [M+1]+. Anal. Calcd for
C21H26N2O3S: C, 65.26; H, 6.78; N, 7.25. Found: C,
65.60; H, 6.89; N, 7.23.
proportions and, in some cases, was purified by circular
chromatography, using 20–60% EtOAc gradient in hexane
as eluant, to give 16–19 and H–Trp–OMe in the yield indi-
cated in Table 1.
3.6.1. (2S,10bR,10cR)-10b-Hydroxy-5-imino-2-methoxy-
carbonyl-1,2,4,5,10b,10c-hexahydropyrrolo[10,20,30:1,9a,9]-
imidazo[1,2-a]indole-4-spirocyclohexane (16). Foam;
[a]2D0 ꢁ124.5 (c 0.6, MeOH); HPLC [Novapak C18
1
(3.9ꢂ150 mm, 4 mm), (A:B, 25:75)] tR 2.88 min; H NMR
(400 MHz, CDCl3) d 1.40–2.01 (m, 10H, cyclohexyl), 2.43
(dd, 1H, J¼6 and 12.5 Hz, 1-H), 2.56 (dd, 1H, J¼10.5 and
12.5 Hz, 1-H), 3.29 (dd, 1H, J¼6 and 10.5 Hz, 2-H), 3.70
(s, 3H, OMe), 5.49 (s, 1H, 10c-H), 7.13 (t, 1H, J¼7 Hz, 9-
H), 7.37 (d, 1H, J¼7 Hz, 10-H), 7.34 (t, 1H, J¼7 Hz, 8-
H), 7.38 (d, 1H, J¼7 Hz, 7-H); 13C NMR (100 MHz,
CDCl3) d 21.8, 22.2, 25.4, 29.1, 34.3 (cyclohexyl), 45.6
(C1), 52.4 (OMe), 61.6 (C2), 71.8 (C4), 85.5 (C10b), 93.4
(C10c), 115.7 (C7), 123.6 (C9), 124.8 (C10), 130.3 (C8),
136.4 (C10a), 143.6 (C6a), 173.4 (CO2), 172.9 (C5); ES-MS
m/z 342.2 (100) [M+1]+. Anal. Calcd for C19H23N3O3:
C, 66.84; H, 6.79; N, 12.31. Found: C, 66.99; H, 7.07;
N, 12.56.
3.5. Synthesis of (2S,10bS,10cR)-2-methoxycarbonyl-
10b-methyl-5-oxo-1,2,4,5,10b,10c-hexahydro-
pyrrolo[10,20,30:1,9a,9]imidazo[1,2-a]indole-4-spiro-
cyclohexane (15)
Ni Raney (125 mg), previously washed with EtOH, was
added to a solution of 14 (29.9 mg, 0.08 mmol) in EtOH
(10 mL) and the reaction mixture was hydrogenated at
80 ꢀC under 2 atm of H2 for 3 h. The catalyst was filtered
off and washed with EtOH (10 mL). The combined filtrates
were evaporated to dryness and the residue was purified by
circular chromatography, using 5–25% gradient of EtOAc
in hexane as eluant, to yield the title compound as a foam
(27.2 mg, 92%); [a]2D0 ꢁ63.20 (c 1, MeOH); HPLC [Nova-
pak C18 (3.9ꢂ150 mm, 4 mm), (A:B, 50:50)] tR 5.85 min;
1H NMR (500 MHz, CDCl3) d 1.40–2.05 (m, 10H, cyclo-
hexyl), 1.61 (s, 3H, 10b-CH3), 2.18 (t, 1H, J¼12 Hz, 1-H),
2.28 (dd, 1H, J¼6 and 12 Hz, 1-H), 3.37 (dd, 1H, J¼6 and
12 Hz, 2-H), 3.69 (s, 3H, OMe), 5.53 (s, 1H, 10c-H), 7.12
(t, 1H, J¼7 Hz, 9-H), 7.17 (d, 1H, J¼7 Hz, 10-H), 7.26 (t,
1H, J¼7 Hz, 8-H), 7.44 (d, 1H, J¼7 Hz, 7-H); 13C NMR
(125 MHz, CDCl3) d 21.4, 22.3, 25.2, 29.0, 32.6 (cyclohex-
yl), 25.5 (10b-CH3), 45.9 (C1), 52.3 (OMe), 49.4 (C10b), 62.2
(C2), 71.9 (C4), 91.1 (C10c), 115.1 (C7), 123.0 (C10), 125.2
(C9), 128.6 (C8), 139.0 (C10a), 140.7 (C6a), 173.3 (CO2),
180.9 (C5); ES-MS m/z 341.2 (100) [M+1]+. Anal. Calcd
for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23. Found: C,
70.49; H, 7.34; N, 7.99.
3.6.2. (2S,10bS,10cS)-10b-Hydroxy-5-imino-2-methoxy-
carbonyl-1,2,4,5,10b,10c-hexahydropyrrolo[10,20,30:1,9a,9]-
imidazo[1,2-a]indole-4-spirocyclohexane (17). Foam;
[a]2D0 +7.99 (c 1.2, MeOH); HPLC [Novapak C18
(3.9ꢂ150 mm, 4 mm), (A:B, 25:75)] tR 3.64 min; H NMR
1
(400 MHz, CDCl3) d 1.24–2.06 (m, 10H, cyclohexyl),
2.39 (d, 1H, J¼13.5 Hz, 1-H), 2.95 (dd, 1H, J¼9.5 and
13.5 Hz, 1-H), 3.06 (s, 3H, OMe), 4.14 (d, 1H, J¼9.5 Hz,
2-H), 5.32 (s, 1H, 10c-H), 7.05 (t, 1H, J¼7 Hz, 9-H),
7.30 (d, 1H, J¼7 Hz, 10-H), 7.33 (t, 1H, J¼7 Hz, 8-H),
7.46 (d, 1H, J¼7 Hz, 7-H); 13C NMR (100 MHz, CDCl3)
d 22.1, 23.1, 25.5, 29.4, 34.6 (cyclohexyl), 44.3 (C1),
51.3 (OMe), 62.6 (C2), 70.4 (C4), 85.7 (C10b), 92.8 (C10c),
114.6 (C7), 123.6 (C9), 123.6 (C10), 130.4 (C8), 136.1
(C10a), 147.8 (C6a), 173.7 (CO2), 176.0 (C5); ES-MS m/z
342.2 (100) [M+1]+; Anal. Calcd for C19H23N3O3:
C, 66.84; H, 6.79; N, 12.31. Found: C, 66.87; H, 6.59;
N, 12.13.
3.6.3. Methyl (2S)-2-(1-cyanocyclohexylamino)-3-[(3RS)-
2-oxoindolin-3-yl]propanoate (18). Foam; HPLC [Nova-
pak C18 (3.9ꢂ150 mm, 4 mm), (A:B, 25:75)] tR 3.55 (68%)
1
and 4.59 (32%) min; H NMR (300 MHz, CDCl3) d 0.77–
1.84 (m, 10H, cyclohexyl), 2.05–2.25 (m, 2H, 3-H), 3.59
[dd, 1H, J¼4 and 8 Hz, 3-H (indoline)], 3.67 and 3.68 (2s,
3H, OCH3), 3.70–3.80 (m, 1H, 2-H), 6.82 [t, 1H,
J¼7.5 Hz, 5-H (indoline)], 6.97 and 6.98 [2t, 1H,
J¼7.5 Hz, 6-H (indoline)], 7.14–7.29 [m, 2H, 4-H and 7-H
(indoline)], 7.98 and 8.13 [2br s, 1H, 1-H (indoline)];
13C NMR (75 MHz, CDCl3) d 21.6, 21.8, 22.3, 22.4,
24.8, 24.9, 34.7, 35.2, 37.0, 37.3, 55.6 and 56.4 (cyclohex-
yl), 33.8 and 34.0 (C3), 42.4 and 42.8 [C3 (indoline)],
52.1 and 52.2 (OCH3), 53.0 (C2), 109.6 and 109.7 [C5 (indo-
line)], 121.3 and 121.5 (CN), 122.4 and 122.5 [C6 (indo-
line)], 124.0 and 124.1 [C4 (indoline)], 128.1 and 128.3
[C7 (indoline)], 129.3 and 129.6 [C3a (indoline)], 141.2
and 141.6 [C7a (indoline)], 174.9 and 175.2 (CO2CH3),
179.5 and 179.8 [C2 (indoline)]; ES-MS m/z 342.2 (100)
[M+1]+.
3.6. General procedure for the H2O2-mediated oxidation
of amino nitrile 8
Aqueous solution of 33% H2O2 (according to the percentage
indicated in Table 1) and the appropriate acid (TFA or 85%
H3PO4 in the percentage indicated in Table 1) were succes-
sively added to a solution of amino nitrile 8 (81.3 mg,
0.25 mmol) in CH2Cl2 (3 mL) and the reaction mixture
was stirred under the reaction conditions indicated in Table
1. Afterward, this mixture was sequentially poured into ice
(z10 mg), neutralized with NH4OH, and extracted with
CH2Cl2 (20 mL). The organic extracts were successively
washed with H2O (5 mL), brine (5 mL), dried over
Na2SO4, and evaporated to dryness. The residue was ana-
lyzed by 1H NMR and HPLC to determine reaction product

9234
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 9229–9234
3.7. General procedure for the DMDO-mediated
oxidation of amino nitrile 8. Method A: synthesis of
methyl (2S,3aRS,8aSR)-1-(1-cyanocyclohexyl)-3a-
hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-
2-yl-carboxylate (20 and 21)
References and notes
ꢀ
1. (a) Gonzalez-Vera, J. A.; Garcıa-Lopez, M. T.; Herranz, R.
Org. Lett. 2004, 6, 2641–2644; (b) Gonzalez-Vera, J. A.;
ꢀ
ꢀ
ꢀ
ꢀ
Garcıa-Lopez, M. T.; Herranz, R. J. Org. Chem. 2005, 70,
8971–8976.
ꢀ
A 0.05 M solution of DMDO18 in acetone (2.4 mL,
0.12 mmol) was added under argon to a cooled solution
(ꢁ78 ꢀC) of amino nitrile 8 (50.1 mg, 0.12 mmol) in
CH2Cl2 (5 mL); the mixture was stirred at that temperature
for 3 h and, then, it was evaporated to dryness. The residue
was purified by circular chromatography, using 20–50%
EtOAc gradient in hexane as eluant, to give the diastereoiso-
meric mixture of 20 and 21 as a foam (34.8 mg, 85%), which
could not be resolved and resulted to be unstable. HPLC
[Novapak C18 (3.9ꢂ150 mm, 4 mm), (A:B, 25:75)] tR
11.22 (74%, 20) and 12.12 (11%, 21) min; 1H NMR
(300 MHz, CDCl3) d 1.21–2.26 (m, 10H, cyclohexyl), 2.26
(dd, 0.88H, J¼1.5 and 14 Hz, 3-H), 2.36 (dd, 0.12H, J¼8
and 13 Hz, 3-H), 2.46 (dd, 0.88H, J¼9 and 14 Hz, 3-H),
2.69 (dd, 0.12H, J¼7.5 and 13 Hz, 3-H), 3.53 and 3.80 (s,
0.37 and 2.63 H, OCH3), 4.08 (dd, 1H, J¼1.5 and 9 Hz, 2-
H), 4.31 (br s, 1H, OH), 4.50 (s, 1H, 8-H), 5.25 (d, 1H,
J¼3 Hz, 8a-H), 6.62 (d, 1H, J¼8 Hz, 7-H), 6.80 (t, 1H, J¼
7.5 Hz, 5-H), 7.12 (t, 1H, J¼8 Hz, 6-H), 7.26 (d, 1H,
J¼7.5 Hz, 4-H); 13C NMR (75 MHz, CDCl3) d 22.9 and
2. Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi,
A. Med. Res. Rev. 1995, 15, 3–31.
3. Tashkhodzhaev, B.; Samikov, K.; Yagudaev, M. R.; Antsupova,
T. P.; Shakirov, R.; Yunusov, S. Y. Khim. Prir. Soedin. 1985,
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8. (a) Leet, J. E.; Schroeder, D. R.; Golik, J.; Matson, J. A.; Doyle,
T. W.; Lam, K. S.; Hill, S. E.; Lee, M. S.; Whitney, J. L.;
Krishnan, B. S. J. Antibiot. 1996, 49, 299–311; (b) Pettit,
G. R.; Tan, R.; Herald, D. L.; Williams, M. D.; Cerny, R. L.
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Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.;
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0
0
0
0
0
23.1 (C3 and C5 ), 24.8 (C4 ), 35.3 and 37.8 (C2 and C6 ),
0
43.0 (C3), 53.2 (OCH3), 59.1 (C1 ), 61.5 (C2), 88.3 (C3a),
€
M.; Scheuer, P. J. Org. Lett. 2003, 5, 1387–1390; (e) Buchel,
89.3 (C8a), 111.3 (C7), 119.8 (C5), 120.5 (CN), 122.6 (C4),
129.5 (C6), 130.9 (C3b), 147.6 (C7a), 177.2 (CO2); ES-MS
m/z 342.2 (100) [M+1]+.
E.; Martini, U.; Mayer, A.; Anke, H.; Sterner, O. Tetrahedron
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3.8. General procedure for the DMDO-mediated oxi-
dation of amino nitrile 8. Method B: synthesis of the
hexahydropyrroloimidazoindole derivatives 16 and 17
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A 0.05 M solution of DMDO18 in acetone (1.8 mL,
0.09 mmol) and TFA (500 mL) were successively added un-
der argon to a cooled solution (ꢁ78 ꢀC) of amino nitrile 8
(30.2 mg, 0.09 mmol) in CH2Cl2 (4.5 mL); the mixture
was stirred at that temperature for 3 h and, then, it was pro-
cessed as indicated for the H2O2-mediated oxidation, to give
the hexahydropyrroloimidazoindoles 16 (19.1 mg, 88%) and
17 (2.9 mg, 12%).
3.9. General procedure for the cyclization of the
hexahydropyrrolo[2,3-b]indoles 20 and 21 to the
hexahydropyrroloimidazoindoles 16 and 17
ꢀ
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5543–5549.
TFA (500 mL) was added to a solution of the epimeric mix-
ture of pyrrolo[2,3-b]indoles 20 and 21 (30 mg, 0.09 mmol)
in CH2Cl2 (4.5 mL) and the reaction mixture was stirred at
room temperature for 30 min. Then, the mixture was pro-
cessed as indicated for the H2O2-mediated oxidation, to
give the hexahydropyrroloimidazoindoles 16 (26.1 mg,
87%) and 17 (3.9 mg, 13%).
17. (a) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem.,
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Acknowledgements
This work was supported by CICYT (SAF2006-01205).
J.A.G.-V. held a postgraduate I3P fellowship from the CSIC.
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(b) Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218–7223.