Synthetic studies about strychnopivotine: synthesis of the bridged azatricyclic fragment

Article abstract of DOI:10.1016/j.tet.2007.07.098

Pd(0)-promoted coupling of an amino-tethered vinyl iodide and ketone enolate is the key step to synthesize the CDE ring system of the indole alkaloid strychnopivotine. Attempts to induce the same process in a compound bearing an o-nitrophenyl group as a l

Full text of DOI:10.1016/j.tet.2007.07.098

Tetrahedron 63 (2007) 10177–10184
Synthetic studies about strychnopivotine:
synthesis of the bridged azatricyclic fragment
*
Daniel Sole, Xavier Urbaneja, Alejandro Cordero-Vargas and Josep Bonjoch
*
ꢀ
Laboratori de Quꢀımica Orgaꢁnica, Facultat de Farmaꢁcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Received 19 June 2007; revised 24 July 2007; accepted 26 July 2007
Available online 1 August 2007
Abstract—Pd(0)-promoted coupling of an amino-tethered vinyl iodide and ketone enolate is the key step to synthesize the CDE ring system
of the indole alkaloid strychnopivotine. Attempts to induce the same process in a compound bearing an o-nitrophenyl group as a latent indole
moiety failed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
incorporation of the nitrophenyl group and formation of
the quaternary center, the crucial steps would be: (i)
closure of the pyrrolidine ring through a one-pot procedure
involving ozonolysis of the allyl group and a double (inter-
and intramolecular) reductive amination;6 (ii) closure of
the piperidine D ring by an a-alkenation of the remaining
ketone group, using the Pd-mediated intramolecular cou-
pling of vinyl halides and ketone enolates;7,8 and (iii) for-
mation of the indoline ring either by reductive cyclization
of a-(2-nitrophenyl)ketones9 or through the Smalley
reaction.10
Strychnopivotine, isolated in 1980 from the root bark of
Strychnos variabilis,1 is the only Strychnos alkaloid2 bearing
a 2-acylindoline moiety in its pentacyclic framework. No to-
tal synthesis of this natural product has been published to
date.3,4 We wish to explain here our results5 in developing
a Pd-catalyzed intramolecular cyclization approach toward
the CDE azatricyclic fragment of strychnopivotine as the
key step in the search for a synthetic entry to this alkaloid.
We envisioned a synthetic approach to strychnopivotine im-
plying the use of a non-indolic advanced intermediate, with
the crucial quaternary center already constructed, and the B
ring present in a latent form (Scheme 1). After the
2. Results and discussion
Beginning with a model compound without the aryl group,
such as the amino-tethered vinyl iodide ketone 1, we initially
studied the Pd-catalyzed coupling of this ketone to check the
constitutional stability of the resulting bridged azatricyclic
compound 2, since we have previously observed the ten-
dency of some related 4-alkylidene-2-azabicyclo[3.3.1]-
nonan-6-ones (DE strychnopivotine ring) to undergo
isomerization to the corresponding enamines.7b
C
H
N
D
H
N
A
B
E
N
Ac
H
H
H
NO2
Me
O
O
Strychnopivotine
N
O
H
I
Taking the known a-allylcyclohexanedione 411 as a starting
material, the required azabicyclic compound 5 was prepared
by the tandem process of ozonolysis and double reductive
amination, using (Z)-2-iodo-2-butenylamine,12–14 to elabo-
rate the octahydroindole ring (31%). Hydrolysis of 5 pro-
vided the amino-tethered vinyl halide 1, which was
subjected to Pd-promoted cyclization in the presence of
KOPh. This ring formation led to the azatricyclic compound
2 in 52% yield (Scheme 2).
NO2
O
O
NO2
NO
2 O
O
O
O
Scheme 1. Synthetic strategy toward strychnopivotine.
Keywords: Alkaloids; Alkenation; Nitro compounds; Nitrogen heterocycles;
Palladium.
* Corresponding authors. Tel.: +34 934024540; fax: +34 934024539 (J.B.);
e-mail: josep.bonjoch@ub.edu
Having successfully achieved the strychnopivotine azatricy-
clic ring core formation, we decided to extend the synthetic
pathway using as starting material a cyclohexanedione
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.098

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10178
moiety in a double reductive amination process: firstly in
O
O
i) Me2CO3, NaH
ii) , NaH
an intermolecular way upon the aldehyde obtained by ozo-
nolysis, and then in an intramolecular manner way upon
the ketone carbonyl group. Thus, ozonolysis of the allyl
group of 8, followed by reaction of the ozonide intermediate
with (Z)-2-iodo-2-butenylamine hydrochloride12–14 and
sodium cyanoborohydride gave cis-octahydroindole 9 in
36% overall yield. In addition, trans-9 was isolated as a mi-
nor product (9%). The amino-tethered ketone vinyl iodide 11
required for the Pd-catalyzed cyclization was obtained by
acid hydrolysis of 9. In an alternative path, when methyl-
amine hydrochloride was used as the aminocyclization
agent, octahydroindole 10 was isolated in 59% yield to-
gether with small amounts (12%) of trans-10. Unfortunately,
treatment of 10 with a-(chloroethyl) chloroformate and sub-
sequent heating in a methanol solution of the carbamate in-
termediate furnished the corresponding secondary amine in
poor yield. Finally, when the latter was alkylated with (Z)-1-
bromo-2-iodo-2-butene14 the required 9 was rendered in
only 20% overall yield. Because of these disappointing
yields, the protocol (8/10/9) was discarded and we
decided to use the original route for the preparation of 9.
i) O3
ClH N
Br
ii)
3
iii) LiI, 135 °C
O
O
O
O
I
(70% for three steps)
NaBH3CN
4
3
(31%)
Me
N
Me
N
O
H
O
H
I
I
10% aq HCl
(95%)
H
H
O
1
5
H
PhOK
Pd(PPh3)4
N
H
THF
H
(52%)
O
2
Scheme 2. Synthesis of the CDE ring system of strychnopivotine.
incorporating the o-nitrophenyl group as a latent form of the
indole nucleus.
The stereochemistry of the synthesized azabicyclic com-
pounds was elucidated by 2D NMR spectra (COSY,
HSQC). The key evidence for the relative configuration,
1
Our approach to the synthesis of strychnopivotine com-
menced with o-nitroarylation of the 1,4-cyclohexanedione
monoethylene acetal (3). Among the three procedures
reported in the literature for the synthesis of 2-(o-nitrophe-
nyl)cyclohexanone,15 we decided to use the Rawal’s proto-
col15b,16 to prepare the undescribed aryl ketone 6. The
starting ketone 3 was transformed into its silyl enol ether
(not shown) and then treated with o-nitrophenylphenyliodo-
nium fluoride (NPIF) to furnish 6 in 82% overall yield
(Scheme 3). The elaboration of the quaternary center was
accomplished by O-allylation and a subsequent Claisen rear-
rangement. Thus, treatment of nitrophenyl ketone 6 with
allyl bromide and Cs2CO3 provided allyl vinyl ether 7,
which, on heating at 185 ꢀC, was converted to the a,a-disub-
stituted cyclohexanedione 8 in 95% yield (70% overall yield
for the three initial steps). The next step involved the elabo-
ration of the pyrrolidine ring by introducing the amino
cis or trans, was the H NMR chemical shift of the most
deshielded aromatic proton, which appears as a doublet at
d >8.60 in trans-3a-(o-nitrophenyl)octahydroindol-5-one
derivatives, but at d <7.60 in the cis series. The cis stereo-
chemistry and its preferred conformation were apparent
from the 7a-methine proton multiplicity, since it appeared
as a broad singlet, which is consistent only with an equatorial
disposition of H-7a with respect to the cyclohexane ring
(Fig. 1). The 13C NMR chemical shifts of C-4, C-6, and
R
H
N
R
3a
7a
3a
N
H
O
O
NO2
5
NO2
O 5
O
Figure 1. cis- and trans-Octahydroindoles 9 and 10.
O
O
O
O
Br
Cs2CO3
(i) LDA, TMSCl
(ii) NPIF
185 °C
Toluene
NO2
NO2
(80% for two steps)
(90%)
(95%)
O
O
O
O
O
O
NO2
O
O
3
6
7
8
R
Me
N
O
N
H
H
N
H
I
Pd(PPh3)4
(i) O3
10% aq HCl
(89%)
(ii) MeNH3Cl,
NaBH3CN
t-BuOK
H
NO2
NO2
NO2
O
O
O
11
CH2
(36%)
(59%)
9, R =
R = H
(55%) RX
I
ACECl;
MeOH
(25%)
10, R = Me
Scheme 3. Synthesis of cis-3a-(o-nitrophenyl)octahydroindol-5-ones.

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10179
Table 1. 13C NMR data for octahydroindol-5-ones
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
NCH2
CHI
]CH
CH3
1b
51.7
51.1
50.1
50.9
54.1
54.1
51.2
50.4
50.1
50.6
51.1
50.6
31.1
31.1
38.6
39.0
39.2
39.0
37.1
29.4
29.3
34.9
34.6
34-0
36.6
37.6
48.8
48.6
48.5
48.4
51.6
48.0
48.9
50.9
50.8
51.1
43.4
29.1
39.8
44.2
40.9
44.3
50.2
38.1
40.7
50.4
49.7
50.9
213.6
109.5
108.3
108.5
108.2
108.3
210.5
108.9
109.6
212.7
212.4
212.2
35.7
28.6
29.4
35.0
29.1
35.0
34.7
37.4
38.5
37.9
38.4
38.4
24.6
23.6
21.7
20.7
21.4
20.4
23.1
22.1
22.4
23.1
33.8
23.1
59.7
60.5
63.1
74.3
66.5
77.3
64.5
64.7
63.1
65.6
62.9
65.6
65.7
65.4
65.1
66.8
40.0
41.6
64.7
64.7
65.7
65.5
40.5
55.3
109.9
111.1
110.0
110.0
130.9
129.8
131.0
132.1
21.7
21.6
21.8
21.8
5b
9c
trans-9c
10a
trans-10b
11b
108.3
109.4
110.7
109.6
73.9
131.6
131.1
130.1
130.8
80.3
21.6
21.7
21.7
21.8
3.3
12b
14c
15c
16c
17a
143.9
128.0
17.8
The assignments were aided by HSQC experiments for compounds 10 and 17, and DEPT in all cases.
All spectra were recorded in CDCl3 at 100 MHz.
a
b
All spectra were recorded in CDCl3 at 75 MHz.
All spectra were recorded in CDCl3 at 50 MHz.
c
C-7a are strongly shielded in cis compounds in comparison
with those of trans derivatives (see Table 1 in Section 3).
Me
N
H
HCHO,
NaBH3CN
I
12
(74%)
Attempts to induce the cyclization of vinyl iodide 11 failed.
Decomposition of the starting material was always observed
when using t-BuOK as the base and Pd(PPh3)4 as the catalyst
in a THF solution at reflux temperature, the root of the prob-
lem probably being the known instability of nitrophenyl
derivatives in a basic medium.17
14 X = (OCH2)2
15 X = O
aq HCl
(95%)
NMe
2 X
N
H
Me
N
O
Me
H
Since we were concerned that the nitro group might be inter-
fering with the coupling step, a simpler compound with a
reduced group was prepared. Reduction of the nitro com-
pound 9 with SnCl2$2H2O gave aniline 12 (95%), which
was hydrolyzed to give hemiaminal 13a. When the aniline
12 was acetylated, a hemiaminal 13b was again formed after
acetal hydrolysis (Scheme 4). To avoid this undesired reac-
tivity and to obtain a 3a-aryloctahydroindole with which to
attempt the Pd-catalyzed cyclization, the amino group was
blocked. The resulting dimethylamino derivative 1418 was
of course inadequate for the total synthesis but it was useful
for evaluating the scope of the synthetic methodology
(Scheme 5). Efforts to synthesize other diprotected amino
derivatives were unsuccessful. After hydrolysis of 14, ketone
15 was isolated, but disappointingly, a cyclized product was
NMe2
NMe2
O
16
17
Scheme 5.
never observed from this substrate. Using t-BuOK as the
base, alkyne 16 was isolated from an elimination process,
while using KPhO led to the reduced alkene 17.
As a result of our inability to obtain the desired cyclization,
we turned our attention to the formation of the correspond-
ing allylic nitro derivatives of ketones 11 and 15. In 2004,
we described that vinyl halides undergo intramolecular cou-
pling with amino-tethered allylic nitro moieties in the pres-
ence of a palladium catalyst and base.19 Interestingly, neither
ketone 11 nor ketone 15 on treatment with nitromethane us-
ing a catalytic amount of N,N-dimethylethylenediamine as
a base in benzene solution20 gave the corresponding allylic
nitro compound, but cyclized compounds 18 and 19 were
isolated, respectively (Scheme 6). In these reaction condi-
tions, ketone 11 was transformed into an a-activated species,
which evolved through an addition to the nitrophenyl group
to give the corresponding nitrone 18. On the other hand, tet-
racyclic pyrrolocarbazole 19 was formed through an initial
allylic nitro compound, which experimented an allylic sub-
stitution,21 the aniline being the nucleophilic species. In
this way, the strychnopivotine B ring was achieved. Finally,
the generated ammonium salt underwent a dealkylation pro-
cess to give 19 in 42% overall yield. Although compounds
18 and 19 embodied the tetracyclic pyrrolocarbazole frag-
ment of strychnopivotine, the low yield in which the com-
pounds were isolated as well as their functionalization
induced us to close this synthetic approach using 3a-nitro-
phenyl octahydroindol-5-ones as intermediates.
Me
N
H
I
SnCl2.2H2O
(95%)
9
O
O
NH2
12
10% aq HCl
(99%)
1) Ac
2O
(95%)
2) 10% aq HCl
Me
Me
N
N
H
I
H
I
N
H
OH
N
Ac
OH
13b
13a
Scheme 4. Hemiaminal derivatives.

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10180
MeOH (26 mL). To this solution were added first 2-iodo-
Me
CH3NO2
Me
Me
Me
N
N
but-2-enylamine hydrochloride12 (3.77 g, 16.16 mmol) and
then NaBH3CN (350 mg, 5.29 mmol). After being stirred
for 30 min, an additional portion of NaBH3CN (370 mg,
5.59 mmol) was added and stirring was continued for 1 h.
At this time, an additional portion of NaBH3CN (960 mg,
14.51 mmol) was added. The reaction mixture was stirred
overnight, and then the MeOH was evaporated. The crude
was dissolved in CH2Cl2 and washed with saturated aqueous
NaHCO3. Concentration of the dried organic extracts give
H
H
H
H
I
I
N
O
N
H2N
NO2
11
18
O
N
O
N
C6H6, rfx
(21%)
Me
CH3NO2
H
I
I
N
Me
a
residue, which was purified by chromatography
H2N
N
N
15
19
1
O
N
(CH2Cl2) to give 5 (862 mg, 31%): H NMR (200 MHz,
CDCl3) 1.32–1.75 (m, 5H), 1.77 (dd, J¼6.6, 1.5 Hz, CH3),
1.80–2.30 (m, 5H), 2.54 (q, J¼3 Hz, H-7a), 2.88 (d,
J¼14 Hz, 1H, NCH2), 3.12 (td, J¼9.2, 6 Hz, 1H, H-2),
3.58 (dt, J¼14, 1.8 Hz, 1H, NCH2), 3.94 (s, 4H, OCH2),
5.82 (q, J¼7 Hz, 1H); 13C NMR (75 MHz, CDCl3, DEPT),
see Table 1.
C6H6, rfx
(42%)
Me
N
H
I
I
+
N
N
Me
NO2
Me
Scheme 6. Pyrrolo[2,3-d]carbazoles 18 and 19.
3.3. cis-1-[(Z)-2-Iodo-2-butenyl]octahydroindol-5-one
(1)
In summary, although it was not possible to carry out the
intramolecular coupling using 3a-(o-nitro or dimethylami-
no)phenyl substituted octahydroindolone derivatives, a
synthetic entry to the functionalized CDE ring of strychno-
pivotine was achieved when the octahydroindolone was
unsubstituted at C-3a. Further studies of this methodology
are needed to determine if another o-substituted phenyl
derivative in the Pd-catalyzed a-alkenation of ketone
enolates could allow the key bond formation. It would also
be useful to explore the potential of azatricyclic ketone 2
to achieve the pentacyclic strychnopivotine with a Japp–
Klingemann indolization.22
To a solution of compound 5 (0.55 g, 1.51 mmol) in THF
(60 mL) was added 10% aqueous HCl (60 mL). After stir-
ring at room temperature overnight, the mixture was basified
with Na2CO3 and extracted with CH2Cl2. The organic
extracts were dried and concentrated to give 1 (468 mg,
95%), which was used without purification in the next
1
step: H NMR (300 MHz, CDCl3) 1.40 (m, 1H), 1.78 (dd,
J¼6.6, 1.5 Hz, CH3), 1.80–2.0 (m, 3H), 2.1–2.2 (m, 2H),
2.32 (dd, J¼15, 6.6 Hz, H-4), 2.42 (dd, J¼15, 6.6 Hz, H-
4), 2.60 (m, 1H), 2.72 (m, 1H), 2.78 (ddd, J¼8.5, 8.1,
3.6 Hz, H-2), 3.03 (td, J¼8.5, 2.1 Hz, H-2), 3.06 (d,
J¼13.8 Hz, 1H, NCH2), 3.58 (dt, J¼13.8, 1.8 Hz, 1H,
NCH2), 5.84 (q, J¼6.4 Hz, ]CH); 13C NMR (75 MHz,
CDCl3, DEPT), see Table 1.
3. Experimental
3.1. General
3.4. (1RS,7RS,8RS)-2-(E)-Ethylidene-4-azatricyclo-
[5.2.2.04,8]undecan-10-one (2)
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous condi-
tions. Analytical TLC was performed on SiO2 (silica gel
60 F254, Merck) and the spots were located with iodoplati-
nate reagent or 1% aqueous KMnO4. Chromatography refers
to flash chromatography and was carried out on SiO2 (silica
gel 60, SDS, 230–240 mesh ASTM). Drying of organic
extracts during workup of reactions was performed over an-
To a stirred solution of ketone 1 (75 mg, 0.232 mmol) and
phenol (69 mg, 0.729 mmol) in THF (30 mL) were added
under argon t-BuOK (0.58 mL of a 1 M solution in tert-butyl
alcohol) and Pd(PPh3)4 (17 mg, 0.015 mmol). The solution
was heated at reflux overnight. After being cooled to room
temperature, the reaction mixture was diluted with CH2Cl2
and washed with saturated aqueous NaHCO3 and 1 M aque-
ous NaOH. The organic layer was dried and concentrated.
The residue was purified by chromatography (CH2Cl2/
MeOH 98:2 to CH2Cl2/DEA 90:10) to give ketone 2
1
hydrous Na2SO4. H and 13C NMR spectra were recorded
with a Varian Gemini 200 or 300, or a Varian Mercury 400
instrument. Chemical shifts are reported in parts per million
downfield (d) from Me4Si. All new compounds were deter-
mined to be >95% pure by 1H NMR spectroscopy.
1
(23 mg, 52%): H NMR (400 MHz, CDCl3, gCOSY) 1.63
(d, J¼7 Hz, 3H, CH3), 1.65 (m, 2H, H-6), 2.00 (br d,
J¼14 Hz, H-9), 2.14 (m, 1H, H-11), 2.42 (m, 1H, H-9),
2.55 (m, H-7), 2.60 (m, 1H, H-11), 2.79 (td, J¼11.2, 6 Hz,
1H, H-5), 2.95 (d, J¼15.5 Hz, 1H, H-3), 3.15 (m, 1H,
H-5), 3.38 (m, 1H, H-1), 3.63 (br s, 1H, H-8), 3.78 (d,
J¼15.5 Hz, 1H, H-3), 5.49 (q, J¼7 Hz, 1H, ]CH); 13C
NMR (100 MHz, CDCl3, DEPT, gHSQC) 13.1 (CH3), 25.9
(C-9), 32.4 (C-6), 38.8 (C-7), 41.4 (C-11), 45.5 (C-1), 51.2
(C-5), 52.6 (C-3), 55.8 (C-8), 125.0 (]CH), 211.2 (C-10).
Anal. Calcd for C12H17NO: C, 75.35; H, 8.98; N, 7.32.
Found: C, 74.98; H, 9.28; N, 7.05.
3.2. cis-1-[(Z)-2-Iodo-2-butenyl]octahydroindol-5-one
ethylene acetal (5)
A stirred solution of 2-allyl-1,4-cyclohexanedione mono-
ethylene acetal11 (4, 1.50 g, 7.64 mmol) in CH2Cl2
(120 mL) at ꢁ78 ꢀC was charged with a constant stream of
ozone. After 25 min, the solution turned characteristic pale
blue and was purged with oxygen. The solvent was evapo-
rated without warming, and the residue was dissolved in

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10181
3.5. 2-(2-Nitrophenyl)-1,4-cyclohexanedione
monoethylene acetal (6)
12 h. After the solvent was evaporated, the residue was crys-
tallized (1% EtOAc in hexane) affording 8 (6.17 g, 95%) as
1
pale brown crystals: IR (KBr) 1701, 1519, 1359 cmꢁ1; H
A solution of 1,4-cyclohexanedione monoethylene acetal (3,
5.06 g, 31.4 mmol) in THF (20 mL) was added to a cooled so-
lution(ꢁ78 ꢀC) ofLDA (26 mL, 1.5 M in cyclohexane)in THF
(80 mL) over 10 min. After stirring for 1 h, TMSCl (7.2 mL,
55.60 mmol) was slowly added over 5 min. The solution was
allowed to warm-up to room temperature and, after stirring
for 1 h, the solvent was evaporated. Dry pentane (100 mL)
was added and the LiCl removed by filtration. Concentration
of the filtrate gave the corresponding silyl enol ether (6.82 g,
95%), which was used without purification in the next step.
NMR (200 MHz, CDCl3) 2.03 (d, J¼13 Hz, 1H), 2.41–
2.60 (m, 3H), 2.79 (m, 1H), 2.84 (d, J¼13.5 Hz, 1H), 2.97
(dd, J¼16.5, 6 Hz, 1H), 3.39 (dd, J¼16.5, 7.2 Hz, 1H),
3.95 and 4.12 (AA0BB0 system, 4H), 4.93 (dd, J¼10,
1.5 Hz, 1H), 5.06 (dd, J¼17, 1.5 Hz, 1H), 5.36 (dddd,
J¼17, 10, 7, 6 Hz, 1H), 7.39 (td, J¼8, 1.5 Hz, 1H), 7.44–
7.62 (m, 2H), 7.87 (dd, J¼8, 1.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3, DEPT) 32.4 (CH2), 36.1 (CH2), 40.3
(CH2), 47.4 (CH2), 56.1 (C), 64.1 (CH2), 64.8 (CH2),
107.1 (C), 117.9 (CH2), 125.7 (CH), 127.6 (CH), 129.3
(CH), 132.6 (C), 132.8 (CH), 136.4 (C), 149.0 (C), 206.2
(CO). Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N,
4.28. Found: C, 64.19; H, 6.09; N, 4.31.
To a stirred solution of NPIF15b (6.06 g, 17.56 mmol) in dry
DMSO/CH2Cl2 (25/37 mL) was added the above silyl enol
ether (4.15 g, 18.17 mmol) dropwise at ꢁ40 ꢀC. The mixture
was stirred for 2 h at this temperature and allowed to warm to
room temperature gradually over 2–3 h. The reaction mixture
was poured into H2O (50 mL), and the whole was extracted
with ether. Theextractswerewashed with brine, dried, andcon-
centrated. The residue was purified by chromatography (hex-
ane to hexane/EtOAc 1:1) to give 6 (4.03 g, 83%): IR (NaCl)
3.8. cis-1-[(Z)-2-Iodo-2-butenyl]-3a-(2-nitrophenyl)-
octahydroindol-5-one ethylene acetal (9)
Following the above procedure for the aminocyclization of 4
to 5, from ketone 8 (940 mg, 2.97 mmol) and 2-iodobut-2-
enamine hydrochloride (1.18 g, 5.04 mmol), 9 (517 mg,
36%) and trans-9 (129 mg, 9%) were obtained after chroma-
tography (hexane to hexane/EtOAc 1:1).
1
1716, 1523, 1339 cmꢁ1; H NMR (300 MHz, CDCl3) 2.12
(dm, J¼13.2 Hz, 1H), 2.22 (td, J¼13.8, 5.1 Hz, 1H), 2.30
(ddd, J¼13, 6, 3.6 Hz, 1H), 2.48 (t, J¼13 Hz, 1H), 2.53
(ddd, J¼15, 4.8, 2.7 Hz, 1H), 2.85 (tdd, J¼14.5, 7.2, 0.8 Hz,
1H), 4.02–4.13 (m, 4H), 4.54 (dd, J¼10.5, 6 Hz, 1H), 7.29
(dd, J¼7.8, 1.2 Hz, 1H), 7.44 (td, J¼8, 1.5 Hz, 1H), 7.60 (td,
J¼8, 1.2 Hz, 1H), 8.03 (dd, J¼8.1, 1.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3, DEPT) 33.9 (CH2), 38.1 (CH2), 40.3
(CH2), 50.3 (CH), 64.7 (CH2), 64.8 (CH2), 107.1 (C), 125.1
(CH), 128.0 (CH), 130.6 (CH), 133.0 (C), 133.3 (CH), 148.9
(C), 206.3 (CO). Anal. Calcd for C12H15NO5: C, 60.65; H,
5.45; N, 5.05. Found: C, 60.22; H, 5.50; N 4.92.
Data for 9: 1H NMR (200 MHz, CDCl3) 1.38 (dm,
J¼11.4 Hz, 1H), 1.79 (dd, J¼6.4, 1.8 Hz, CH3), 1.90–2.29
(m, 7H), 2.90 (d, J¼14 Hz, 1H), 3.13 (m, 1H), 3.56–3.70
(m, 3H), 3.76–3.89 (m, 4H), 5.88 (q, J¼6.6 Hz, 1H), 7.26–
7.48 (m, 4H, ArH); 13C NMR (50 MHz, CDCl3, DEPT),
see Table 1.
1
Compound trans-9: H NMR (300 MHz, CDCl3) 0.95 (m,
1H), 1.58 (m, 2H), 1.80 (dd, J¼6.5, 1.5 Hz, CH3), 1.88 (m,
1H), 2.05 (qd, J¼12.6, 4.5 Hz, H-7ax), 2.17 (m, 1H),
2.28–2.41 (m, 2H), 2.57 (ddd, J¼12.5, 8, 2.1 Hz, H-7a),
2.71 (dd, J¼13.5, 1.5 Hz, 1H, NCH2), 3.01 (q, J¼8.5 Hz,
H-2), 3.05 (d, J¼13.5 Hz, 1H, NCH2), 3.58 (m, 1H), 3.77
(m, 4H, OCH2), 5.86 (q, J¼6.5 Hz, ]CH), 7.26 (td, J¼8,
1.5 Hz, 1H, ArH), 7.47 (m, 2H, ArH), 8.91 (d, J¼8 Hz,
1H, ArH); 13C NMR (50 MHz, CDCl3, DEPT), see Table 1.
3.6. 4-Allyloxy-3-(2-nitrophenyl)-3-cyclohexenone
ethylene acetal (7)
A mixture of ketone 6 (6.3 g, 22.8 mmol), allyl bromide
(5.2 mL, 60.2 mmol), and anhydrous Cs2CO3 (23.5 g,
70.6 mmol) in acetone (125 mL) was stirred at reflux
temperature overnight. The solvent was removed, and the res-
iduewasdissolvedinCH2Cl2 and washedwithsaturatedaque-
ous NaHCO3 and brine. The organic layer was dried and
concentrated to giveenolether 7 (6.50 g, 90%)asanoil, which
was usedinthe nextstep without further purification:1H NMR
(200 MHz, CDCl3) 1.95 (m, 2H), 2.40 (m, 2H), 2.65 (m, 2H),
2.59 (s, 2H), 4.03 (s, 2H), 4.06 (m, 4H), 5.00 (ddt, J¼10.5, 2.5,
1.5 Hz, 1H), 5.05 (ddt, J¼17.2, 2.5, 1.5 Hz, 1H), 5.65 (ddt,
J¼17.2, 10.5, 5.4 Hz, 1H), 7.35 (ddd, J¼8.2, 7.3, 1.5 Hz,
1H, H-40), 7.40 (dd, J¼7.8, 1.5 Hz, 1H, H-60), 7.55 (ddd,
J¼7.8, 7.3, 1.2 Hz, 1H, H-50), 7.85 (dd, J¼8.2, 1.2 Hz, 1H,
H-30); 13C NMR (50 MHz, CDCl3, DEPT) 24.1 (CH2), 31.1
(CH2), 39.0 (CH2), 64.5 (OCH2), 68.6 (CH2), 107.2 (C),
116.5 (CH2), 123.8 (CH), 127.1 (CH), 128.0 (C), 131.0
(CH), 132.4 (CH), 133.8 (CH), 148.0 (C).
3.9. 2-Methyl-3a-(2-nitrophenyl)octahydroindol-5-one
ethylene acetal (10)
A stirred solution of ketone 8 (520 mg, 1.64 mmol) in
CH2Cl2 (30 mL) at ꢁ78 ꢀC was treated with a constant
stream of ozone. After 15 min, the solution turned character-
istic pale blue and was purged with oxygen. The solvent was
removed with a rotatory evaporator without warming, and
the residue was dissolved in MeOH (15 mL). To this solution
were added first methylamine hydrochloride (1.72 g,
25.0 mmol) and then sodium cyanoborohydride (74 mg,
1.12 mmol). After being stirred for 30 min, an additional
portion of sodium cyanoborohydride (88 mg, 1.33 mmol)
was added and stirring was continued for 1 h. At this time,
a third portion of sodium cyanoborohydride (203 mg,
3.1 mmol) was added, and stirring was continued overnight.
After removal of the methanol under reduced pressure,
CH2Cl2 was added and the resulting organic solution was
washed with saturated aqueous NaHCO3 solution, dried,
and concentrated. The resulting oil was purified by
3.7. 2-Allyl-2-(2-nitrophenyl)-1,4-cyclohexanedione
monoethylene acetal (8)
A solution of enol ether 7 (6.50 g, 20.5 mmol) in toluene
(60 mL) was stirred at 180–190 ꢀC in a sealed tube for

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10182
chromatography (CH2Cl2) to give 356 mg (59%) of 10 and
72 mg (12%) of trans-10.
washed with brine. The organic layers were dried and con-
centrated to give 12 (782 mg, 95%), which was used without
purification in the next step: H NMR (300 MHz, CDCl3)
1
1
Compound 10: H NMR (400 MHz, CDCl3, gCOSY) 1.38
1.46 (dm, J¼9 Hz, 1H), 1.80 (dd, J¼6.3, 1.2 Hz, CH3),
1.95 (m, 3H), 2.07–2.27 (m, 4H), 2.72 (dd, J¼13.8,
1.5 Hz, 1H), 2.92 (d, J¼13.5 Hz, 1H), 3.08–3.16 (m, 2H),
3.57 (q, J¼8 Hz, 1H), 3.68–3.90 (m, 5H), 5.88 (q,
J¼6.6 Hz, ]CH), 6.64 (dd, J¼7.5, 1.5 Hz, 1H, ArH), 6.73
(td, J¼7.5, 1.5 Hz, 1H, ArH), 7.02 (td, J¼7.5, 1.5 Hz, 1H,
ArH), 7.18 (dd, J¼7.5, 1.5 Hz, 1H, ArH); 13C NMR
(75 MHz, CDCl3, DEPT), see Table 1.
(ddd, J¼12, 6, 3.2 Hz, H-6eq), 1.89 (td, J¼12, 6 Hz, H-
6ax), 1.97 (m, 1H, H-3), 1.99–2.05 (m, 2H, H-7), 2.02 (d,
J¼14.4 Hz, H-4), 2.10 (dd, J¼14, 4, 1.6 Hz, H-4), 2.24
(m, 2H, H-2 and H-3), 2.30 (s, NCH3), 2.69 (br s, H-7a),
3.18 (ddd, J¼10.5, 7, 7 Hz, H-2), 3.57 and 3.82 (2 m, 2H
each, OCH2), 7.30 (ddd, J¼7, 6.8, 2 Hz, 1H, ArH), 7.42–
7.50 (m, 3H, ArH); 13C NMR (100 MHz, CDCl3, DEPT,
gHSQC), see Table 1. Anal. Calcd for C17H22N2O4: C,
64.13; H, 6.97; N, 8.80. Found: C, 64.02; H, 7.22; N, 8.51.
3.13. Hydrolysis of acetal 12
1
Compound trans-10: H NMR (300 MHz, CDCl3) 1.56–
To a solution of compound 12 (47 mg, 0.103 mmol) in THF
(2 mL) was added 10% aqueous HCl (2 mL). After stirring
at room temperature overnight, the reaction mixture was ba-
sified with Na2CO3 and extracted with CH2Cl2. The organic
extracts were dried and concentrated to give quantitatively
13a: 13C NMR (50 MHz, CDCl3, DEPT) 21.6 (CH3), 21.7
(CH2), 30.8 (CH2), 35.1 (CH2), 40.3 (CH2), 47.0 (C), 50.3
(CH2), 65.4 (CH2), 68.5 (CH), 81.5 (C), 110.9 (C), 113.4
(CH), 117.1 (CH), 123.9 (CH), 124.6 (C), 127.6 (CH),
130.2 (CH), 144.5 (C).
1.67 (m, 4H), 1.80–2.05 (m, 3H), 2.27–2.42 (m, 2H), 2.38
(s, NCH3), 2.52 (ddd, J¼12.5, 8.1, 3 Hz, 1H), 3.16 (dt,
J¼10, 8 Hz, H-2), 3.56 (m, 1H), 3.77 (m, 4H, OCH2), 7.25
(td, J¼8, 1.5 Hz, 1H, ArH), 7.43 (td, J¼8, 1.5 Hz, 1H,
ArH), 7.49 (dd, J¼8, 1.5 Hz, 1H, ArH), 8.58 (dd, J¼8,
1.5 Hz, 1H, ArH); 13C NMR (75 MHz, CDCl3, DEPT), see
Table 1.
3.10. cis-1-[(Z)-2-Iodo-2-butenyl]-3a-(2-nitrophenyl)-
octahydroindol-5-one (11)
Acetylation of aniline 12 (Ac2O) followed by acid treatment
of the resulting amido acetal gave tetracyclic hemiaminal
13b: 13C NMR (75 MHz, CDCl3, DEPT) 21.7 (CH3), 23.9
(CH2), 25.6 (NAc), 30.7 (CH2), 32.2 (CH2), 41.4 (CH2),
46.1 (C), 49.6 (CH2), 65.3 (CH2), 66.2 (CH), 89.7 (C),
110.3 (C), 123.6 (CH), 124.1 (CH), 124.3 (CH), 126.3
(CH), 130.4 (CH), 135.1 (C), 138.7 (C), 175.6 (C).
To a solution of 9 (531 mg, 1.10 mmol) in THF (10 mL) was
added 10% aqueous HCl (15 mL). After being stirred over-
night, the mixture was basified with Na2CO3 and extracted
with CH2Cl2. The organic extracts were dried and concen-
trated to give ketone 11 (444 mg, 92%), which was used
without purification in the next step. An analytical sample
was obtained by chromatography (CH2Cl2): 1H NMR
(300 MHz, CDCl3) 1.79 (dd, J¼6.3, 1.2 Hz, CH3), 1.91–
2.06 (m, 2H), 2.11–2.31 (m, 4H), 2.79 (d, J¼15 Hz, 1H,
H-4ax), 2.82 (ddd, J¼17, 12, 6 Hz, 1H, H-6ax), 2.96 (dd,
J¼15, 0.6 Hz, 1H, H-4eq), 3.02 (d, J¼13.5 Hz, 1H,
NCH2), 3.11 (m, 1H), 3.27 (t, J¼3 Hz, 1H, H-7a), 3.65 (dt,
J¼13.5, 1.8 Hz, 1H, NCH2), 5.85 (qd, J¼6.3, 1.8 Hz,
]CH), 7.37 (m, 1H, ArH), 7.49–7.52 (m, 3H, ArH); 13C
NMR (75 MHz, CDCl3, DEPT), see Table 1. Anal. Calcd
for C18H21IN2O3: C, 49.10; H, 4.81; N, 6.36. Found: C,
49.19; H, 4.79; N, 6.32.
3.14. cis-1-[(Z)-2-Iodo-2-butenyl]-3a-[2-(N,N-dimethyl-
amino)phenyl]octahydroindol-5-one ethylene acetal (14)
To a stirred solution of 12 (782 mg, 1.72 mmol) and 37%
aqueous formaldehyde (1.6 mL) in acetonitrile (7 mL) was
added NaBH3CN (0.41 g, 6.20 mmol). Glacial acetic acid
(0.180 mL) was added over 10 min, and the reaction mixture
was stirred at room temperature for 2 h. An additional
amount of glacial acetic acid (0.180 mL) was added, and
stirring was continued for further 30 min. The reaction mix-
ture was poured into CH2Cl2, basified with 1 N NaOH, and
washed with brine. The organic layers were dried and con-
centrated. The residue was purified by chromatography
(CH2Cl2 to CH2Cl2/MeOH 98:2) to give 14 (613 mg,
74%): 1H NMR (200 MHz, CDCl3) 1.44 (dm, J¼8 Hz,
1H), 1.68 (m, 1H), 1.79 (dd, J¼6.3, 1.2 Hz, CH3), 1.97–
2.27 (m, 5H), 2.56 and 2.58 (2s, 6H, NMe), 2.77 (dd,
J¼14, 2 Hz, 1H), 2.94 (d, J¼14 Hz, 1H), 3.07 (br, 1H),
3.15 (ddd, J¼9.2, 9.2, 6.4 Hz, 1H), 3.50 (m, 1H), 3.60
(m, 1H), 3.75–3.90 (m, 4H), 5.88 (q, J¼6.2 Hz, ]CH),
7.07–7.35 (m, 4H); 13C NMR (50 MHz, CDCl3, DEPT),
see Table 1.
3.11. Attempts of cyclization of 11
To a stirred solution of ketone 11 (77 mg, 0.175 mmol) in
freshly distilled THF (5 mL) were added under argon
t-BuOK (0.180 mL of 1 M solution in tert-butyl alcohol)
and Pd(PPh3)4 (47 mg, 0.041 mmol). The solution was
heated at reflux for 45 min. After being cooled to room tem-
perature, the reaction mixture was diluted with Et2O and
washed with brine. The organic layer was dried and concen-
trated to give a residue resulting in decomposition of the
starting material.
3.12. cis-1-[(Z)-2-Iodo-2-butenyl]-3a-(2-aminophenyl)-
octahydroindol-5-one ethylene acetal (12)
3.15. cis-1-[(Z)-2-Iodo-2-butenyl]-3a-[2-(N,N-dimethyl-
amino)phenyl]octahydroindol-5-one (15)
To a solution of 11 (877 mg, 1.81 mmol) in DMF (20 mL)
was added SnCl2$2H2O (4.30 g, 18.68 mmol). After stirring
at room temperature for 24 h, the reaction mixture was basi-
fied with 50% aqueous NaOH, extracted with CH2Cl2, and
To a solution of compound 14 (1.16 g, 2.41 mmol) in THF
(10 mL) was added 10% aqueous HCl (30 mL). After stir-
ring at room temperature for 23 h, the reaction mixture
was basified with Na2CO3 and extracted with CH2Cl2. The

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10183
organic extracts were dried and concentrated to give 15
(1.00 g, 95%), which was used without purification in the
next step: H NMR (300 MHz, CDCl3) 1.58 (m, 1H), 1.79
2.05 (dm, J¼14.5 Hz, 1H), 2.41 (td, J¼12.3, 3.6 Hz, H-4),
2.51 (dm, J¼16 Hz, 1H), 2.79 (ddd, J¼12, 9.3, 5.1 Hz,
1H), 3.11 (ddd, J¼16, 14.5, 3.6 Hz, 1H), 3.26 (dd, J¼9,
6.6 Hz, 1H), 3.37 (br s, 1H, H-3a), 3.40 (d, J¼12 Hz, 1H,
NCH2), 3.66 (dt, J¼12, 1.5 Hz, 1H, NCH2), 5.95 (q,
J¼6.3 Hz, 1H, ]CH), 7.47–7.59 (m, 3H, ArH), 7.86 (d,
J¼8 Hz, 1H, ArH); 13C NMR (50 MHz, CDCl3, DEPT)
21.8 (CH3), 27.0 (CH2), 36.9 (CH2), 37.0 (CH2), 51.7
(CH2), 55.9 (C), 65.2 (CH), 65.5 (CH2), 109.0 (C), 116.9
(CH), 122.2 (CH), 128.8 (CH), 132.1 (CH), 131.6 (CH),
141.6 (C), 142.4 (C), 145.9 (C), 190.3 (C).
1
(dd, J¼6.3, 1.8 Hz, CH3), 1.95–2.06 (m, 2H), 2.10–2.19
(m, 2H), 2.28–2.39 (m, 2H), 2.55 and 2.58 (2s, 3H each,
NMe), 2.72–2.82 (m, 2H), 3.02–3.18 (m, 3H), 3.64 (d,
J¼13.5 Hz, 1H, NCH2), 5.84 (q, J¼6.3 Hz, ]CH), 7.24
(td, J¼8, 1.5 Hz, 1H, ArH), 7.23–7.30 (m, 2H, ArH), 7.39
(dd, J¼8, 1.5 Hz, 1H, ArH); 13C NMR (50 MHz, CDCl3,
DEPT), see Table 1. Anal. Calcd for C20H27IN2O: C,
54.80; H, 6.21; N, 6.39. Found: C, 54.46; H, 6.50; N, 6.12.
3.16. Attempts of cyclization of 15
3.18. Treatment of ketone 15 with nitromethane in basic
medium
(a) To a stirred solution of ketone 15 (65 mg, 0.148 mmol) in
freshly distilled THF (5 mL) were added under argon
t-BuOK (0.230 mL of 1 M solution in tert-butyl alcohol)
and Pd(PPh3)4 (35 mg, 0.030 mmol). The solution was
heated at reflux for 45 min. After being cooled to room tem-
perature, the reaction mixture was diluted with Et2O and
washed with brine. The organic layer was dried and concen-
trated. The residue was purified by chromatography (CH2Cl2
to CH2Cl2/MeOH 92:8) to give alkyne 16 (40 mg, 87%): 1H
NMR (200 MHz, CDCl3) 1.71 (s, CH3), 2.0–2.5 (m, 6H),
2.58 (s, 6H, NMe), 2.65–3.15 (m, 4H), 3.30–3.55 (m, 3H);
13C NMR (50 MHz, CDCl3, DEPT), see Table 1.
In a round-bottomed flask fitted with a Dean–Stark
trap were placed 15 (444 mg, 1.01 mmol), nitromethane
(1.3 mL, 22.80 mmol), N,N-dimethylethylenediamine
(54 mL, 0.467 mmol), and benzene (5 mL), and the solution
was refluxed for 8 h. The benzene solution was cooled,
washed with saturated aqueous NaHCO3 solution and brine,
dried, and concentrated. The residue was purified by
chromatography (CH2Cl2) to give 3-[(Z)-2-iodo-2-butenyl]-
7-methyl-6-methylene-1,2,3,3a,4,5,6a,7-octahydropyrrolo-
1
[2,3-d]carbazole (19, 180 mg, 42%): H NMR (200 MHz,
CDCl3) 1.37 (m, 1H), 1.71 (m, 1H), 1.75 (d, J¼6.6 Hz,
CH3), 1.85 (m, 1H), 2.11–2.30 (m, 2H), 2.37 (m, 1H),
2.52 (m, 1H), 2.60 (s, 3H, NMe), 2.70 (m, 1H), 2.80 (m,
1H), 3.17 and 3.39 (2d, J¼14 Hz, 1H each, NCH2), 3.23
(s, H-6a), 4.99 and 5.08 (2s, 1H each, ]CH2), 5.82 (q,
J¼6.6 Hz, ]CH), 6.49 (d, J¼8 Hz, 1H, ArH), 6.74 (t,
J¼8 Hz, 1H, ArH), 7.12 (t, J¼8 Hz, 1H, ArH), 7.24 (d,
J¼8 Hz, 1H, ArH); 13C NMR (50 MHz, CDCl3, DEPT)
21.7 (CH3), 26.1 (CH2), 30.3 (CH3), 33.5 (CH), 34.8
(CH2), 50.4 (CH2), 54.4 (C), 63.6 (CH2), 67.3 (CH), 79.1
(CH), 107.5 (CH), 109.9 (C),114.6 (CH2), 118.3 (CH),
123.5 (CH), 127.6 (CH), 130.3 (CH), 137.7 (C), 143.8
(C), 151.7 (C). Anal. Calcd for C20H25IN2: C, 57.15; H,
5.99; N, 6.66. Found: C, 56.79; H, 6.29; N, 6.44.
(b) To a stirred solution of ketone 15 (300 mg, 0.685 mmol)
and phenol (194 mg, 2.05 mmol) in freshly distilled THF
(5 mL) were added under argon t-BuOK (1.70 mL of 1 M
solution in tert-butyl alcohol) and Pd(PPh3)4 (81 mg,
0.069 mmol). The solution was heated at reflux for 2 h. After
being cooled to room temperature, the reaction mixture was
diluted with CH2Cl2 and washed with saturated aqueous
NaHCO3 and 1 N aqueous NaOH. The organic layer was
dried and concentrated. The residue was purified by chroma-
tography (CH2Cl2 to CH2Cl2/MeOH 84:16) to give 17
1
(41 mg, 19%): H NMR (400 MHz, CDCl3, gCOSY) 1.68
(d, J¼6 Hz, CH3), 2.05 (m, 2H, H-6 and H-7), 2.10 (m,
2H, H-3 and H-7), 2.20 (m, 1H, H-6), 2.30 (m, 1H, H-2),
2.45 (masked, 1H, H-3), 2.50 (br s, 6H, NMe), 2.82 (d,
J¼15 Hz, H-4), 2.83 (masked, 1H, NCH2), 2.99 (d,
J¼15 Hz, H-4), 3.15 (br, 1H, H-7a), 3.20 (m, 1H, H-2),
3.39 (dd, J¼13.2, 4.8 Hz, 1H, NCH2), 5.55 (m, ]CH),
5.60 (m, ]CH), 7.14 (td, J¼8, 1.5 Hz, 1H, ArH), 7.25 (m,
2H, ArH), 7.38 (dd, J¼8, 1.5 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3, DEPT, gHSQC), see Table 1.
Acknowledgements
This research was supported by the MEC (Spain)-FEDER
through project CTQ2004-04701/BQU. Thanks are also
due to the DURSI (Catalonia) for Grant 2005SGR-
00442. A.C.-V. is a recipient of a fellowship from MEC
(Spain).
3.17. Treatment of ketone 11 with nitromethane in basic
medium
References and notes
In a round-bottomed flask fitted with a Dean–Stark trap were
placed 11 (444 mg, 1.01 mmol), nitromethane (1.0 mL,
1. Tits, T.; Tavernier, D.; Angenot, L. Phytochemistry 1980, 19,
1531–1534.
17.54 mmol),
N,N-dimethylethylenediamine
(40 mL,
0.346 mmol), and benzene (10 mL), and the solution was re-
fluxed for 8 h. The benzene solution was cooled, washed
with saturated aqueous NaHCO3 solution and brine, dried,
and concentrated. The residue was purified by chromato-
graphy (CH2Cl2 to CH2Cl2/MeOH 98:2) to give tetracyclic
keto nitrone 3-[(Z)-2-iodo-2-butenyl]-7-oxide-1,2,3,3a,4,5-
hexahydropyrrolo[2,3-d]carbazol-6-one (18, 89 mg, 21%):
1H NMR (300 MHz, CDCl3) 1.56 (tt, J¼14.1, 3.5 Hz,
H-5), 1.81 (dd, J¼6.3, 1.2 Hz, CH3), 1.82 (masked, 1H),
2. Bosch, J.; Bonjoch, J.; Amat, M. The Alkaloids; Cordell, G. A.,
Ed.; Academic: New York, NY, 1996; Vol. 48, pp 75–189.
3. Professor Padwa (Emory University), however, has mentioned
achieving the total synthesis of strychnopivotine in Ref. 22 of
his communication about the strychnine synthesis, see:
Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9,
279–282.
4. For studies toward a synthetic route to strychnopivotine, lead-
ing to methanoazocino[4,3-b]indol-6-one derivatives (ABDE

´
D. Sole et al. / Tetrahedron 63 (2007) 10177–10184
10184
framework), see: (a) Teuber, H.-J.; Tsaklakidis, C.; Bats, J. W.
LiebigsAnn. Chem. 1992, 461–466; For other approaches to this
ꢁ
tetracyclic 2-acylindole motif, see: (b) Gracia, J.; Casamitjana,
N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 3939–3951
temperature and then treatment with an HCl/H2O/EtOH
mixture at room temperature to precipitate the corresponding
hydrochloride, which was isolated in 80% overall yield.
13. For another synthetic procedure, see: Takasu, K.; Ohsato, H.;
Kuroyanagi, J.; Ihara, M. J. Org. Chem. 2002, 67, 6001–6007.
14. (a) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982,
47, 404–408; (b) Rawal, V. H.; Michoud, C. Tetrahedron Lett.
€
and references therein; (c) Patir, S.; Rosenmund, P.; Gotz, P. H.
Heterocycles 1996, 43, 15–22.
5. Results were taken from the Ph.D. Thesis of X. Urbaneja,
University of Barcelona, February 2006.
6. For the synthetic approach of 3a-(o-nitrophenyl)octahydroin-
dole derivatives and related azabicyclic compounds, see: (a)
ꢀ
ꢀ
1991, 32, 1695–1698; (c) Bonjoch, J.; Sole, D.; Garcıa-Rubio,
S.; Bosch, J. J. Am. Chem. Soc. 1997, 119, 7230–7240.
15. (a) RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. J. Am. Chem.
Soc. 1985, 107, 5473–5483; (b) Iwama, T.; Birman, V. B.;
Kozmin, S. A.; Rawal, V. H. Org. Lett. 1999, 1, 673–676; (c)
Ryba, T. D.; Harran, P. G. Org. Lett. 2000, 2, 851–853.
16. For synthetic applications of this nitroarylation process in nat-
ural product synthesis, see: Kozmin, S. A.; Iwama, T.; Huang,
Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628–4641; (b)
Aggarwal, V. K.; Olofsson, B. Angew. Chem., Int. Ed. 2005, 44,
5516–5519.
ꢀ
Sole, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996, 52, 4013–
4028; (b) Bonjoch, J.; Sole, D.; Cuesta, X. Heterocycles
ꢀ
ꢀ
1997, 45, 315–322; (c) Bonjoch, J.; Sole, D.; Carrillo, R.;
Peidro, E.; Bosch, J. Tetrahedron 2001, 57, 6011–6017.
ꢀ
ꢀ
7. (a) Sole, D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225–
2228; (b) Sole, D.; Diaba, F.; Bonjoch, J. J. Org. Chem.
ꢀ
ꢀ
ꢀ
2003, 68, 5746–5749; (c) Bonjoch, J.; Diaba, F.; Puigbo, G.;
Peidro, E.; Sole, D. Tetrahedron Lett. 2003, 44, 8387–8390;
ꢀ
ꢀ
ꢀ
(d) Sole, D.; Urbaneja, X.; Bonjoch, J. Adv. Synth. Catal.
2004, 346, 1646–1650; (e) Diaba, F.; Ricou, E.; Sole, D.;
17. The high reactivity of nitrophenyl derivatives in basic media is
well-known, see: (a) Muth, C.; Abraham, N.; Linfield, M. L.;
Wotring, R. B.; Pacofsky, E. A. J. Org. Chem. 1960, 25, 736–
739; (b) Collins, P. A.; McFarlane, M. D.; Mackie, R. K.;
Smith, D. M. Tetrahedron 1992, 48, 7887–7898; (c)
Moskalev, N.; Makosza, M. Chem. Commun. 2001, 1248–
1249; (d) Ricci, A.; Fochi, M. Angew. Chem., Int. Ed. 2003,
42, 1444–1446.
ꢀ
ꢀ
Teixido, E.; Valls, N.; Bonjoch, J. ARKIVOC 2007, iv, 320–330.
8. For other applications of this methodology in alkaloid synthe-
sis, see: (a) Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. J. Org. Chem.
2006, 71, 8884–8890 and references therein; (b) See Ref. 3; (c)
Asari, A.; Angelov, P.; Auty, J. M.; Hayes, C. J. Tetrahedron
Lett. 2007, 48, 2631–2634.
ꢀ
9. (a) Sole, D.; Pares, A.; Bonjoch, J. Tetrahedron 1994, 50, 9769–
9774; (b) Sole, D.; Garcıa-Rubio, S.; Vallverdu, L.; Bonjoch, J.
ꢀ
18. The transformation was carried out using HCHO and
NaCNBH3 in acid medium, see: (a) Borch, R. F.; Hassid,
A. I. J. Org. Chem. 1972, 37, 1673–1674; (b) Manabe, K.;
Okamura, K.; Tadamasa, D.; Koga, K. J. Org. Chem. 1993,
58, 6692–6700.
ꢀ
ꢀ
ꢀ
J. Org. Chem. 2001, 66, 5266–5268.
10. (a) Azadi-Ardakani, M.; Alkhader, M. A.; Lippiatt, J. H.; Patel,
D. I.; Smalley, R. K.; Higson, S. J. Chem. Soc., Perkin Trans. 1
1986, 1107–1111; (b) Alonso, D.; Caballero, E.; Medarde, M.;
ꢀ
19. Sole, D.; Urbaneja, X.; Bonjoch, J. Tetrahedron Lett. 2004, 45,
3131–3135.
ꢀ
Tome, F. Tetrahedron Lett. 2005, 46, 4839–4841; (c) Butin,
A. V.; Smirnov, S. K. Tetrahedron Lett. 2005, 46, 8443–8445
and references therein.
11. Zhou, G.-C.; Zhu, D.-Y. Synth. Commun. 2002, 32, 37–44; For
20. (a) Barton, D. H. R.; Motherwell, W. B.; Zard, S. Z. J. Chem.
Soc., Chem. Commun. 1982, 551–552; (b) Tamura, R.; Sato,
M.; Oda, D. J. Org. Chem. 1986, 51, 4368–4375.
21. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, NY, 2001; Chapter 7.
ꢀ
a straightforward synthesis, see: Ibrahem, I.; Cordova, A.
Angew. Chem., Int. Ed. 2006, 45, 1952–1956.
12. This amine was synthesized from (Z)-1-bromo-2-iodo-2-bu-
tene (Ref. 14) by reaction with HMTA in CHCl3 at reflux
22. Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534–
3538.