Fischer indolization of octahydroindol-6-one derivatives revisited: diastereoisomerization and racemization processes

Article abstract of DOI:10.1016/j.tetasy.2008.09.009

Fischer indolization of enantiopure 2-methoxycarbonyl-cis-octahydroindol-6-ones using AcOH as a catalyst induces racemization of the octahydropyrrolocarbazoles obtained. Conversely, when using TsOH, the α-amino ester moiety preserves its configuration, although the other stereogenic centers show a partial or total stereolability according to the constitutional framework.

Full text of DOI:10.1016/j.tetasy.2008.09.009

Tetrahedron: Asymmetry 19 (2008) 2130–2134
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Fischer indolization of octahydroindol-6-one derivatives revisited:
diastereoisomerization and racemization processes
*
Mar Borregán, Ben Bradshaw, Nativitat Valls, Josep Bonjoch
Laboratori de Química Orgànica, Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII s/n 08028-Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2008
Accepted 15 September 2008
Available online 10 October 2008
Fischer indolization of enantiopure 2-methoxycarbonyl-cis-octahydroindol-6-ones using AcOH as a
catalyst induces racemization of the octahydropyrrolocarbazoles obtained. Conversely, when using TsOH,
the
partial or total stereolability according to the constitutional framework.
Ó 2008 Elsevier Ltd. All rights reserved.
a-amino ester moiety preserves its configuration, although the other stereogenic centers show a
1. Introduction
Our group has previously studied the Fischer indolization of
cis-octahydroindol-6-ones to achieve a synthetic entry to pyrroloc-
arbazoles as precursors to ibophyllidine alkaloids.4,8 In the unsub-
stituted racemic series (R = H, Scheme 1), the process was
regioselective, leading to a octahydropyrrolo[3,2-c]carbazole as
the only compound.7 Conversely, using an enantiopure 2-ethyl
substituted derivative resulted in the formation of both the linear
and angular isomers and, interestingly, diastereoisomerization
processes were observed when acetic acid was used to promote
the indolization8 (Scheme 1).
The Fischer indolization of b-amino ketones has been reported
in the field of indole alkaloid synthesis, either as a crucial step in
total syntheses (e.g., aspidopermidine1 and ibogamine2) or in
synthetic approaches to dasycarpidan,3 ibophyllidine,4 strychnos,5
or aspidospermane alkaloids.6 A drawback of this annulation
process can be the regioselectivity of the reaction.7 Another, less
reported, problem is the loss of the absolute stereochemistry in
the resulting indole compounds, when enantiopure b-amino
ketones are used.
There are two reasons why we decided to revisit this process
and to study, in the work reported here, the Fischer indolization
of the exo- and endo-isomers of enantiopure methyl 6-oxo-
H
octahydroindole-2-carboxylate
1 and 2: (i) to evaluate the
influence of a sterically less demanding substituent at C(2) on
the regioselectivity by replacing the ethyl group with a methoxy-
carbonyl group; (ii) to gain insight into the stereolability of pyrro-
locarbazoles obtained from b-amino ketones.
R
C6H5
O
N
H
i) PhNHNH2
ii) AcOH
2. Results and discussion
C6H5
R
N
H
Enantiopure octahydroindolones 1 and 2 were synthesized from
O-methyltyrosine in three steps according to our described proce-
dure.9 The Fischer indolization of the phenylhydrazone of ketone
(ꢀ)-1 in acetic acid gave a complex mixture of pyrrolocarbazoles
3–8 in 60% overall yield (Scheme 2), which was characterized after
careful purification of the reaction mixture. Firstly, three com-
pounds with an exo-relationship between the ester at C-2 and
the tetracyclic skeleton were eluted: the linear trans-isomer 3,
the linear cis-isomer 4, and the angular pyrrolocarbazole 5. Three
other pyrrolocarbazoles were then isolated, this time with an
endo-relationship: the linear cis-isomer 6, the trans-linear isomer
7, and the angular pyrrolocarbazole 8. The ratio of the exo/endo iso-
mers was 1:3, with the linear pyrrolocarbazole 7 (22%) and the
angular pyrrolocarbazole 8 (14%) being the main compounds of
H
H
+
H
R
N
H
N
N
H
R
C6H5
55%
8%
+ 8% diast.
H; racemic
Et; enantiopure
ref. 4
ref. 8
none
16%
+ 16% diast.
Scheme 1. Previous results in the Fischer indolization of cis-octahydroindol-6-
ones.
* Corresponding author. Tel.: +34 934024540; fax: +34 934024539.
E-mail address: josep.bonjoch@ub.edu (J. Bonjoch).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.009

M. Borregán et al. / Tetrahedron: Asymmetry 19 (2008) 2130–2134
2131
H
H
or
CO2Me
CO2Me
O
N
O
N
H
H
Ph
Ph
i) PhNHNH2
ii) AcOH
2
(-)-
(-)-1
Ph
CO2Me
H
H
H
N
H
+
+
H
CO2Me
CO2Me
N
H
N
N
H
N
N
H
H
Ph
Ph
3 (5%)
4 (4%)
5 (6%)
Ph
CO2Me
H
H
N
H
+
+
CO2Me
H
CO2Me
N
H
N
N
H
N
H
N
H
H
Ph
Ph
7 (22%)
6 (4%)
8 (16%)
Scheme 2. Racemization in the Fischer indole synthesis (the depicted compounds 3–8 are racemic).
the indolization process. The same result was obtained starting
from the phenylhydrazone of ketone (ꢀ)-2. It is noteworthy that
the compounds isolated were racemic (see Section 4), in spite of
the enantiopure character of the starting amino ketones 1 or 2.
Thus, acetic acid not only promoted the expected equilibration of
the ring-fused system but also two previously unreported pro-
cesses: the racemization of the stereogenic methine carbon of
observed, but in these compounds, the racemization was only
partial (Table 1), indicating that it is more difficult to change the
configuration at the carbon-fused atoms in b-amino ketones than
in their corresponding phenylhydrazones or pyrrolocarbazole
derivatives.
After these results (generation of twelve compounds, six race-
mic pairs, from a unique compound, 1 or 2), we decided to examine
the Fischer indolization using TsOH as the acid catalyst. Initially,
we checked the stereochemical behavior of ketones 1 and 2 in
the presence of TsOH. b-Amino ketone 1 suffered from a partial
transformation to 2, but in this case the (S)-configuration at C-2
of both ketones remained stable (Table 1). As expected, in the light
of our previous studies of the equilibration of both compounds,9 b-
amino ketone 2 was more stable than 1 under these reaction con-
ditions. When the phenylhydazone of exo-ketone 1 was heated in
an ethanol solution containing TsOH, a Fischer indolization took
place to give a mixture of three compounds 4, 7, and 8 (Scheme
3). We assumed that these compounds were enantiopure, since
the a-amino ester unit and the formation of trans-pyrrolocarbazole
derivatives. Indeed, although the methoxycarbonyl group at C-2 in-
duces a slightly better regioselectivity in the indolization process
of octahydroindol-6-ones than that observed in the 2-ethyl deriv-
ative (at 2:3 instead of the 1:2 ratio), the stereolability of the inter-
mediates under these reaction conditions does not permit the
synthesis of enantiopure pyrrolocarbazoles.10–12 Although it is well
known that N-benzylidene-protected amino acid derivatives are
liable to be racemized due to the high acidity of the
a-proton of
the ester,13 it is notable that we were unable to find a precedent
for the epimerization of N-alkylproline derivatives.14,15
At this point, we evaluated the stereochemical behavior of the
the stereogenic center of the a-amino ester moiety is stereostable
starting
a
-amino ketones 1 and 2 in acetic acid at 80 °C for 3 h
under these reaction conditions, maintaining the (S)-configuration,
(the same reaction conditions as used for the indolization). A total
loss of the stereochemistry of the amino ester unit was once again
H
i) PhNHNH2
Table 1
(—)-4
+
7
+
(—)-8
Isomerization of octahydroindoles 1 and 2a
CO2Me
O
N
ii) TsOH
Reaction conditionsb
Enantiomeric excessc
Ratio
H
(34%)
(18%)
(7%)
Ar
(ꢀ)-1
(ꢀ)-2
(ꢀ)-1
AcOH neat, 90 °C, 3 h
AcOH neat, 90 °C, 3 h
TsOHꢁH2O (1 equiv),
benzene, 80 °C, 4 h
TsOHꢁH2O (1 equiv),
benzene, 80 °C, 4 h
5 M HCl in MeOH,
65 °C, overnight
(+)-1, 50% ee; (ꢀ)-2, 87% ee
(+)-2, 52% ee; (ꢀ)-1, 64% ee
(ꢀ)-1, >99% ee; (ꢀ)-2, >99%
1:1
1:1
1.2:1
(-)-1
H
i) PhNHNH2
ii) TsOH
(ꢀ)-2
(ꢀ)-1
(ꢀ)-2, >99% ee; (ꢀ)-1
(ꢀ)-2, >99% ee; (ꢀ)-1
7:1
(—)-8
(+)-6 +
(—)-3
+
CO2Me
O
N
7:1 Ref. 9
H
(15%)
(20%)
(8%)
Ar
a
(-)-2
The reactions were performed on a 0.2 mmol scale.
Compounds isolated after column chromatography.
b
c
Determined by comparison of the optical rotation with the literature value.9
Scheme 3. Fischer indolization of 1 and 2 using TsOH as promoter.

2132
M. Borregán et al. / Tetrahedron: Asymmetry 19 (2008) 2130–2134
Ph
Ph
H
Ph
H
Ph
Ph
R
+
CO2Me
+
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
H
N
(—)-1
H
H
H
H
+
N
H
N
H
N
H
N
(— )-8
H
Scheme 4. Diastereoisomerization of pyrrolo[3,2-c]carbazole 5.
H
H
H
H
H
H
H
H
H
6
(+)-
+
R
CO2Me
R
R
N
N
N
H
N
N
HN
N
H
N
H
H
R = CO2Me
Ph
Ph
Ph
Ph
(—)-3
Scheme 5. Epimerization of pyrrolo[2,3-b]carbazole 4.
according to the results reported in Table 1. Interestingly, an epi-
merization occurred at C-10a, the trans pyrrolocarbazole 7 being
isolated. The formation of indole 8 would have required a double
configurational change. A similar result was observed with endo-
ketone 2, which produced a mixture of trans- and cis-linear pyrro-
locarbazoles 3 and 6, respectively, and again the angular pyrroloc-
arbazole 8 (Scheme 3). Thus, although enantiopure compounds
were isolated using TsOH as the catalyst, the regioselectivity (5:1
from 1 and 2:1 from 2) once again favored the linear pyrrolocar-
bazoles over the angular fused compound 8.
In the linear compounds, the cis-isomers 4 and 6 were distin-
guished from trans-isomers 3 and 7 on the basis of the chemical
shifts and multiplicity of the ring junction proton H-10a. The H-
10a of 3 and 7 appeared upfield at d 3.38 (td, J = 10, 5 Hz) and d
2.74, respectively, relative to that of 4 and 6 (d 3.60 and 3.22). In
the 13C NMR spectra, ring junction carbons C-3a (d 34.3 and
35.9) and C-10a (d 58.8 and 61.8) of cis isomers 4 and 6 appeared
upfield relative to C-3a (d 42.6 and 41.4) and C-10a (d 64.1 and
65.6) of trans isomers 3 and 7.
The epimerization of stereogenic centers linked to the indole
nucleus at either the
a- or b-carbon, when bonded to a nitrogen
atom, has been reported with particularly exhaustive studies on
indoloquinolizidines.16,17 This stereolability has also been de-
trans-linear derivatives
scribed in compounds bearing units of 3-(a
-aminomethyl)indole.18
2.35
δ
δ 3.38 (10,10,5)
A plausible mechanism for the diastereosiomerization, leading to
pyrrolocarbazole (ꢀ)-8 from (ꢀ)-1, is depicted in Scheme 4. It
involves a Grob-type fragmentation of the protonated indole 5 (a
retro Pictet-Spengler process), followed by an epimerization at
the b-amino carbon through a tautomeric equilibrium of the ini-
tially formed iminium salt and a later reprotonation. The same tan-
dem ring-opening/ring-closure mechanism could operate in the
racemization processes using AcOH as reported above (Scheme 2).
More interesting was the epimerization in linear pyrrolocarbaz-
ole derivatives to give the previously unreported trans-octahydro-
pyrrolo[2,3-b]carbazole compounds. A possible pathway, in which
H
H
3a
2.19
δ
3a
CO2Me
N
10a
CO2Me
10a
N
H
H
H
H
2.74
δ
C6H5
C6H5
(10,9,5)
7
3
cis-linear derivatives
H
2.95
δ
MeO2C
H
3a
the protonated indole undergoes
a retro-imino aza-Michael
N
C6H5
δ 3.6
process followed by an intramolecular conjugate addition of the
resulting secondary amine upon the vinylindole system, as
depicted in Scheme 5, could be considered.
H
10a
3a
10a
H
δ 3.22 (6,6,6)
CO2Me
N
H
H
The constitutional and strereochemical arrangement of cis-4
and 6 and trans-linear 3 and 7 isomers, and cis-angular isomers 5
and 8 were assigned by 1H and 13C NMR spectroscopic analyses
aided by COSY and HSQC experiments (Fig. 1 and Table 2). The dif-
ferentiation between linear and angular isomers was made on the
basis that H-10c of the angular isomers 5 and 8, which corresponds
to H-10a of 4-7, appeared downfield at d 4.63 and 3.99 relative to
H-10a of the linear isomers (d 3.20–3.55). For the cis-derivatives,
the chemical shifts of the methine protons H-3a and H-10a (for 4
and 6) or H-10c (for 5 and 8) are more deshielded in the exo- than
in the endo-compounds due to the syn-relationship of the
methoxycarbonyl group with both protons.19 In the 13C NMR spec-
tra, the chemical shift of the benzylic methylene carbon of endo
(d ꢂ 58–59) and exo isomers (d ꢂ 52–53) was also characteristic.
δ 2.50 (12,5,5,5)
C6H5
6
4
C6H5
H
N
N
H
2.30
CO2Me
H
10c
H
δ 3.99 (2)
3a
H
10c
C6H5
4.63 (4)
δ
3a
MeO2C
N
H
δ 2.35
5
H
8
Figure 1. Preferred conformations of compounds 3–8.

M. Borregán et al. / Tetrahedron: Asymmetry 19 (2008) 2130–2134
2133
Table 2
13C NMR data of pyrrolocarbazoles 3–8
Carbon
3 (exo/trans)
4 (exo/cis)
6 (endo/cis)
7 (endo/trans)
Carbon
5 (exo)
8 (endo)
C-2
C-3
62.5
34.2
62.6
35.9
65.1
35.1
65.6
33.7
C-2
C-3
59.9
34.2
66.0
34.6
C-3a
C-4
42.6
25.9
34.3
22.0
35.9
23.1
41.4
25.9
C-3a
C-4
37.1
27.6
37.2
26.3
C-4a
C-4b
C-5
C-6
C-7
110.5
127.2
117.8
119.3
121.2
110.8
136.5
133.0
30.2
64.1
51.8
175.1
51.2
107.9
127.0
117.7
119.2
121.1
110.5
136.2
131.6
22.2
58.8
53.6
175.0
51.6
108.1
127.0
117.7
119.0
120.9
110.4
136.1
131.8
26.1
61.8
58.0
175.0
51.8
110.3
127.0
117.8
119.2
121.1
110.5
136.4
132.9
30.0
67.3
57.7
175.0
51.8
C-10b
C-10a
C-10
C-9
C-8
C-7
C-6a
C-5a
C-5
C-10c
NCH2
CO2Me
CH3
109.6
128.1
118.5
119.6
121.1
110.5
136.5
135.9
23.0
56.8
52.8
175.5
51.0
109.7
128.2
118.4
119.5
121.0
110.5
136.5
135.9
23.0
61.8
59.6
175.4
51.1
C-8
C-8a
C-9a
C-10
C-10a
NCH2
CO2Me
CH3
The numbering of angular derivatives 5 and 8 has been arranged for an easier comparison of their data with those of the other pyrrolocarbazoles.
between CH2Cl2 and saturated Na2CO3 solution. After additional
extractions of the aqueous phase, the dried organic extracts were
concentrated and purified by chromatography (hexane/EtOAc 1:4
increasing to 1:1) to give, in order of elution the exo-isomers 3
(12 mg, 5%), 4 (10 mg, 4%), and 5 (16 mg, 6%) and the endo isomers
6 (10 mg, 4%), 7 (54 mg, 22%), and 8 (40 mg, 16%). Overall yield was
3. Conclusion
In conclusion, the a-carbon of the amino ester in polycyclic pro-
line analogues 1–8 reported here has shown its stereolability in an
acetic medium at 80–90 °C. Moreover, attention should be paid to
the possibility of epimerization (or racemization) in pyrrolo[3,2-c]-
and pyrrolo[2,3-b]carbazoles working, in either acetic or p-tolu-
enesulfonic acid, since these compounds are prone to suffering ret-
ro-Pictet Spengler and fragmentation processes, which promotes
the loss of their stereochemical integrity.
57%. Compound 7: ½a D22
ꢃ
¼ 0 (c 1, CHCl3); Compound 8: ½a D22
¼ 0 (c
ꢃ
1, CHCl3). For analytical data see below. An analogous result was
found using the endo (ꢀ)-ketone 2.
4.2.2. Fischer indolization of exo ketone 1 using TsOH
To a solution of ketone 1 (97 mg, 0.34 mmol) in EtOH (4 mL)
were added phenylhydrazine (50 mg, 0.34 mmol) and Na2CO3
(39 mg, 0.37 mmol). The mixture was heated at reflux for 3 h (until
the disappearance of the ketone carbonyl absorption in the IR spec-
trum), filtered, and concentrated. TsOHꢁH2O (129 mg, 0.68 mmol)
was added to a solution of the crude hydrazone in EtOH (3.5 mL).
The reaction mixture was heated at reflux temperature for 3 h,
quenched with Et2O (8 mL) and saturated NaHCO3 solution
(8 mL). The aqueous phase was extracted with Et2O, and the com-
bined organic extracts were washed with brine, dried, concen-
trated, and the residue was purified by chromatography. On
elution with hexane/EtOAc (1:1) were successively isolated (ꢀ)-4
(39 mg, 34%), 7 (21 mg, 18%), and (ꢀ) 8 (8 mg, 7%). Overall yield
was 59%.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in a CDCl3 solution at
400 MHz, and 75 or 100 MHz, respectively. In addition, chemical
shifts are reported as d values (ppm) relative to internal Me4Si.
Infrared spectra were recorded on a Nicolet 205 FT-IR spectropho-
tometer. HRMS were determined on an Autospec-VG apparatus.
Optical rotations were taken on a Perkin–Elmer 241 polarimeter
with a 1 ml (L = 1 dm) cell. TLC was performed on SiO2 (silica gel
60 F254, Merck). The spots were located by UV light and a 1%
KMnO4 solution. Column chromatography was carried out on
SiO2 (silica gel 60, SDS, 230–400 mesh). All reactions were carried
out under an argon atmosphere with dry, freshly distilled solvents
4.2.3. Fischer indolization of endo ketone 2 using TsOH
Operating as above, using ketone 1 (130 mg, 0.45 mmol), the
reaction mixture resulting from the indolization process was puri-
fied by chromatography. On elution with hexane/EtOAc (4:1) (ꢀ)-3
(21 mg, 12%), (+)-6 (28 mg, 16%), and (ꢀ)-8 (26 mg, 15%) were
isolated successively. Overall yield: 43%.
under anhydrous conditions. As a chiral starting material
was used.
L-tyrosine
4.2. Fischer indolization of 1 and 2
4.2.1. Fischer indolization of exo ketone 1 using AcOH
4.3. Analytical data for pyrrolocarbazole 3–8
To a solution of ketone 1 (200 mg, 0.69 mmol) in EtOH (5 mL)
were added phenylhydrazine (103 mg, 0.7 mmol) and Na2CO3
(81 mg, 0.75 mmol). The mixture was heated at reflux for 2 h (until
disappearance of ketone carbonyl absorption in IR spectum), fil-
tered, and concentrated: 13C NMR (100 MHz, CDCl3, DEPT) d 23.1
(CH2), 25.0 (CH2), 33.9 (CH2), 35.1 (CH2), 35.2 (CH), 50.9 (CH3),
52.5 (CH2), 59.7 (CH), 62.0 (CH), 112.9 (CH), 119.5 (CH), 126.8
(CH), 128.1 (CH), 128.7 (CH), 129.0 (CH), 139.3 (C), 145.8 (C),
148.0 (C), 174.5 (C). The residue was dissolved in glacial AcOH
(8 mL), and the solution was heated at 90 °C for 2 h. The reaction
mixture was concentrated and the residue was partitioned
4.3.1. (2S,3aS,10aR)-1-Benzyl-2-methoxycarbonyl-
1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazole 3
½
a 2D2
ꢃ
¼ ꢀ102 (c 1.25, CHCl3); 1H NMR (gCOSY, 400 MHz) 1.72
(ddd, J = 12.8, 10.4, 5.6 Hz, H-3), 2.19 (m, H-3a), 2.45–2.57 (m, H-
3, H-4, H-10), 2.97 (dd, J = 13.6, 4.8 Hz, H-10eq), 3.02 (dd, J = 14,
5.2 Hz, H-4eq), 3.38 (td, J = 10, 5 Hz, H-10a), 3.63 (s, 3H, OMe),
3.85 and 4.05 (2d, J = 13.6, 1H each, NCH2Ar), 3.93 (dd, J = 8.8,
6 Hz, H-2), 7.04 and 7.07 (2t, J = 7.5 Hz each, H-7 and H-6), 7.20–
7.30 (m, 6H, ArH), 7.40 (d, J = 7.5 Hz, 1H, H-5), 7.75 (br s, 1H,

2134
M. Borregán et al. / Tetrahedron: Asymmetry 19 (2008) 2130–2134
NH); 13C NMR (HSQC), see Table 2. HRMS (ESI-TOF) calcd for
C23H25N2O2: 361.1910 (M++1), found 361.1918.
HRMS (ESI-TOF) calcd for C23H25N2O2: 361.1910 (M++1), found
361.1912.
4.3.2. (2S,3aR,10aR)-1-Benzyl-2-methoxycarbonyl-
1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazole 4
Acknowledgments
½
a 2D2
ꢃ
¼ ꢀ129:3 (c 2.14, CHCl3); 1H NMR (gCOSY, 400 MHz) 1.95–
This research was supported by the MEC (Spain)-FEDER through
project CTQ2007-61338/BQU. Thanks are also due to the DURSI
(Catalonia) for Grant 2005SGR-00442. M.B. was a recipient of a
doctoral fellowship from MEC (Spain).
2-05 (m, 2H, H-3), 2.60–2.80 (m, 4H, H-4 and H-10), 2.95 (m, H-3a),
3.55 (dd, J = 9.0, 1.2 Hz, H-2), 3.60 (masked, 1H, H-10a) 3.61 (s, 3H,
OCH3), 3.87 and 3.96 (2d, J = 13 Hz, 1H each, NCH2Ar), 7.00–7.05
(m, 2H, ArH), 7.20–7.30 (m, 6H, ArH), 7.40 (d, J = 7.5 Hz, H-5),
7.60 (s, 1H, NH); 13C NMR (100 MHz, gHSQC), see Table 2. HRMS
(ESI-TOF) calcd for C23H25N2O2: 361.1910 (M++1), found 361.1915.
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10645–10652; (f) Coldham, I.; Burrell, A. J. M.; White, L. E.; Adams, H.; Oram, N.
Angew. Chem., Int. Ed. 2007, 46, 6159–6162; (g) Callier-Dublanchet, A.-C.;
Cassayre, J.; Gagosz, F.; Quiclet-Sire, B.; Sharp, L. A.; Zard, S. Z. Tetrahedron 2008,
64, 4803–4816.
2. (a) Sallay, S. I. J. Am. Chem. Soc. 1967, 89, 6762–6763; (b) White, J. D.; Choi, Y.
Org. Lett. 2000, 2, 2373–2376; (c) White, J. D.; Choi, Y. Helv. Chim. Acta 2003, 85,
4306–4327.
3. Bonjoch, J.; Casamitjana, N.; Gràcia, J.; Ubeda, M.-C.; Bosch, J. Tetrahedron Lett.
1990, 31, 2449–2452.
4.3.3. rac-(2S,3aR,10cS)-1-Benzyl-2-methoxycarbonyl-
1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,2-c]carbazole 5
1H NMR (400 MHz, CDCl3) 1.60 (m, 1H, H-4), 1.95 (m, 1H, H-3),
2.15 (m, 1H, H-3 and H-4), 2.35 (m, 1H, H-3a), 2.80 (m, 2H, H-5),
3.60 (masked, H-2), 3.63 (s, 3H, OMe), 3.92 and 4.23 (2d,
J = 13 Hz, 1H each, NCH2Ar), 4.63 (d, J = 4 Hz, H-10c), 7.05–7.30
(m, 8H, ArH), 7.65 (d, J = 7.5 Hz, 1H, H-10), 7.95 (br s, 1H, NH);
13C NMR (HSQC, 75 MHz, CDCl3), see Table 2. HRMS (ESI-TOF) calcd
for C23H25N2O2: 361.1910 (M++1), found 361.1913.
4. Bonjoch, J.; Catena, J.; Valls, N. J. Org. Chem. 1996, 61, 7106–7115.
5. Bonjoch, J.; Casamitjana, N.; Quirante, J.; Rodríguez, M.; Bosch, J. J. Org. Chem.
1987, 52, 267–275.
6. Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
4628–4641.
4.3.4. (2S,3aS,10aS)-1-Benzyl-2-methoxycarbonyl-
1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazole 6
½
a 2D2
ꢃ
¼ þ3 (c 0.5, CHCl3); 1H NMR (gCOSY, 400 MHz) 1.93 (dt,
J = 12.4, 7.2 Hz, H-3), 2.30 (ddd, J = 12.4, 8.8, 7.2 Hz, 1H), 2.50 (dq,
J = 12, 5,4 Hz, H-3a), 2.75-2.94 (m, 4H, H-4 and H-10), 3.22 (q,
J = 6 Hz, H-10a), 3.54 (dd, J = 8.8, 7.2 Hz, H-2), 3.56 (s, 3H, OCH3),
3.92 (s, 2H, NCH2Ar), 7.00–7.05 (m, 2H, ArH), 7.20–7.30 (m, 6H,
ArH), 7.40 (d, J = 7.5 Hz, H-5), 7.60 (br s, 1H, NH); 13C NMR
(100 MHz, gHSQC), see Table 2. HRMS (ESI-TOF) calcd for
C23H25N2O2: 361.1910 (M++1), found 361.1918.
7. For seminal work in this field, see: (a) Ban, Y.; Iijima, I. Tetrahedron Lett. 1969,
2523–2525; (b) Inoue, I.; Ban, Y. J. Chem. Soc. (C) 1970, 602–610; (c) Lawton, G.;
Saxton, J. E.; Smith, A. J. Tetrahedron 1977, 33, 1641–1653.
8. Bonjoch, J.; Catena, J.; Terricabras, D.; Fernàndez, J.-C.; López-Canet, M.; Valls,
N. Tetrahedron: Asymmetry 1997, 8, 3143–3151.
9. Valls, N.; López-Canet, M.; Vallribera, M.; Bonjoch, J. Chem. Eur. J. 2001, 7, 3446–
3460.
10. For previous syntheses of racemic octahydropyrrolo[3,2-c]carbazoles, see: (a)
Magnus, P. D.; Exon, C.; Sear, N. L. Tetrahedron 1983, 39, 3725–3729; (b) Padwa,
A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure, M. S.; Wang, Q. J. Org. Chem. 2002,
67, 5928–5937; (c) Coldham, I.; Dobson, B. C.; Fletcher, S. R.; Franklin, A. I. Eur.
J. Org. Chem. 2007, 2676–2686. See also Refs. 4 and 8.
11. Apart from our studies (Ref. 4 and 8), only an incidental reference was found
with regards to octahydropyrrolo[2,3-b]carbazoles: Bennasar, M.-L.; Zulaica,
E.; Ramírez, A.; Bosch, J. Tetrahedron 1999, 55, 3128–3317.
12. It is noteworthy that regioisomeric pyrrolo[2,3-a]carbazoles have been
reported as potential cyclin dependent kinase 1 inhibitors: Fousteris, M. A.;
Papakyriakou, A.; Koutsourea, A.; Manioudaki, M.; Lampropoulou, E.;
Papadimitriou, E.; Spyroulias, G. A.; Nikolaropoulos, S. S. J. Med. Chem. 2008,
51, 1048–1052.
13. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J. Org. Chem. 1983, 48, 843–846;
See also: Sayago, F. J.; Calaza, M. I.; Jiménez, A. I.; Cativiela, C. Tetrahedron 2008,
64, 84–91.
4.3.5. (2S,3aR,10aS)-1-Benzyl-2-methoxycarbonyl-
1,2,3,3a,4,9,10,10a-octahydropyrrolo[2,3-b]carbazole 7
1H NMR (COSY, 500 MHz, CDCl3) 1.89 (dt, J = 12, 11 Hz, 1H, H-3),
2.24 (ddd, J = 12, 7.5, 3.5 Hz, 1H, H-3), 2.33–2.38 (m, 1H, H-3a),
2.36 (dd, J = 10, 1.5 Hz, 1H, H-4), 2.61 (dd, J = 14.5, 9.5 Hz, 1H, H-
10), 2.74 (ddd, J = 10, 9, 5 Hz, 1H, H-10a), 2.80 (dd, J = 15, 5 Hz,
1H, H-10), 2.99 (ddd, J = 10, 9, 1.5 Hz, 1H, H-4), 3.57 (s, 3H, OMe),
3.57 (dd, J = 11, 3.5 Hz, 1H, H-2), 3.89 and 3.94 (2d, J = 13.5 Hz,
1H each, NCH2Ar), 7.04 (t, J = 7.5 Hz, 1H, H-7), 7.09 (t, J = 7.5 Hz,
1H, H-6), 7.21–7.33 (m, 6H, ArH), 7.41 (d, J = 7.5 Hz, H-5), 7.65
(br s, 1H, NH); 13C NMR (HSQC, 75 MHz, CDCl3), see Table 2. HRMS
(ESI-TOF) calcd for C23H25N2O2: 361.1910 (M++1), found 361.1913.
14. The epimerization of N-unsubstituted proline derivatives has been reported
using acetic acid and acetic anhydride: (a) Robinson, D. S.; Greenstein, J. P. J.
Biol. Chem. 1952, 383–388; (b) Baker, G. L.; Fritschel, S. J.; Stille, J. R.; Stille, J. K.
J. Org. Chem. 1981, 46, 2954–2960.
15. For a brief comment about the possibility of epimerization of an
a-amino ester
4.3.6. (2S,3aS,10cR)-Benzyl-2-methoxycarbonyl-
at reflux in glacial acetic acid by formation of mixed anhydride, see:
a
1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,2-c]carbazole 8
Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org. Chem. 1981, 46, 4914–4920.
16. Lounasmaa, M.; Berner, M.; Brunner, M.; Suomalainen, H.; Tolvanen, A.
Tetrahedron 1998, 54, 10205–10216 and references therein.
½
a 2D2
ꢃ
¼ ꢀ13 (c 1.4, CHCl3); IR (film) 3340, 1739; 1H NMR (COSY,
500 MHz, CDCl3) 1.69–1.75 (m, 2H, H-3 and H-4), 2.26–2.32 (m,
1H, H-3a), 2.42–2.52 (m, 1H, H-3), 2.52–2,59 (m, 1H, H-4), 2.70
(dd, J = 16, 11, 5.5 Hz, 1H. H-5), 2.77 (ddd, J = 16.5, 6, 3 Hz, H-5),
3.10 (s, 3H, OMe), 3.43 (dd, J = 7, 3.5 Hz, 1H, H-2), 3.61 (d,
J = 12 Hz, 1H, NCH2Ar), 3.99 (d, J = 2 Hz, 1H, H-10c), 4.59 (d,
J = 12 Hz, 1H, NCH2Ar), 7.04 (t, J = 8 Hz, 1H, H-8), 7.08 (t, J = 8 Hz,
1H, H-9), 7.15–7.30 (m, 6H, ArH), 7.61 (d, J = 7.5 Hz, 1H, H-10),
8.1 (br s, 1H, NH); 13C NMR (HMQC, 75 MHz, CDCl3), see Table 2.
17. For other epimerizations reported in 2-(a-aminomethyl)indole derivatives,
see: Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797–1842.
18. (a) Amat, M.; Hadida, S.; Llor, N.; Sathyanarayana, S.; Bosch, J. J. Org. Chem.
1996, 61, 3878–3882; (b) Kalaus, G.; Juhász, I.; Éles, J.; Greiner, I.; Kajtár-
Peredy, M.; Brlik, J.; Szabó, L.; Szántay, C. J. Heterocycl. Chem. 2000, 37, 245–251.
19. For detailed NMR studies on octahydroindole-2-carboxylic acid derivatives, see
Ref. 9. See also: (a) Valls, N.; Vallribera, M.; Carmeli, S.; Bonjoch, J. Org. Lett.
2003, 5, 447–450; (b) Valls, N.; Vallribera, M.; Font-Bardía, M.; Solans, X.;
Bonjoch, J. Tetrahedron: Asymmetry 2003, 14, 1241–1244.