Synthesis of iboga alkaloids by Pd-catalyzed heteroannulation of 2-iodoaniline with an internal alkyne as the key step

Article abstract of DOI:10.1016/j.tetlet.2010.01.037

A convenient synthetic route to the iboga-scaffolds is described. Important steps include a Pd-catalyzed regiospecific indole formation between internal alkyne-substituted isoquinuclidine and 2-iodoaniline. The final cyclization was done using Trost's Pd(II)-Ag(I) mixed-metal-mediated cyclization method originally developed for the synthesis of ibogamine. Both exo- (iboga) and endo-isomers (epi-iboga) at C-19 substitution with -CO₂Me have been reported.

Full text of DOI:10.1016/j.tetlet.2010.01.037

Tetrahedron Letters 51 (2010) 1441–1443
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Tetrahedron Letters
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Synthesis of iboga alkaloids by Pd-catalyzed heteroannulation
of 2-iodoaniline with an internal alkyne as the key step
*
Goutam Kumar Jana, Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthetic route to the iboga-scaffolds is described. Important steps include a Pd-catalyzed
regiospecific indole formation between internal alkyne-substituted isoquinuclidine and 2-iodoaniline.
The final cyclization was done using Trost’s Pd(II)–Ag(I) mixed-metal-mediated cyclization method orig-
inally developed for the synthesis of ibogamine. Both exo- (iboga) and endo-isomers (epi-iboga) at C-19
substitution with –CO2Me have been reported.
Received 21 December 2009
Revised 7 January 2010
Accepted 10 January 2010
Available online 15 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Iboga alkaloids comprise a large group of pharmacologically
important indole alkaloids, isolated from the root bark of the Afri-
can shrub Tabernanthe Iboga. Members of this family of alkaloids
have characteristic indole and isoquinuclidine ring fused by a se-
ven-membered indoloazepine ring1 (Fig. 1). A total of 19 iboga-like
alkaloids have been reported2 in which seven have been isolated
recently. These natural products have attracted attention because
of their reported ability to reverse human addiction to multiple
drugs of abuse, including alcohol, heroin, cocaine.3 Apart from
anti-addictive properties, iboga alkaloid congeners show potent
leishmanicide effects against Leishmania amazonensis.4 Although
these alkaloids show important biological activities, natural iboga-
ine 2 causes several side effects such as hallucinations, degenera-
tion of cerebeller purkinje cells,5 whole body tremors and ataxia
in rats6 if the dose is high. Since chemical modifications of the nat-
ural product have been the major means for exploration of the
more potent analogues, a limited number of its analogues have
so far been accessible.7 Thus an efficient synthetic route is neces-
sary for the synthesis of iboga alkaloids and their analogues around
the iboga scaffold that might be useful for the evaluation of phar-
macological profiles and their biological (receptorial) target.8 Büchi
et al. were the first to disclose a successful synthesis of racemic
ibogaine and ibogamine as well as the corresponding unnatural
C(20)-epimers9 and several other syntheses followed.10 Mostly,
the reported syntheses began with b-indolyl acetyl chloride, try-
ptophyl bromide or tryptamine as starting material.
ses (except for a few7a,c) lack the flexibility required to provide ac-
cess to the more elaborate representatives on both indoloazepine
and isoquinuclidine rings 5.
Herein we describe a convenient approach to the synthesis of
iboga 6a and epi-iboga 6b scaffolds (Scheme 1) using Larock het-
eroannulation reaction11 as the key step. As can be seen from our
retrosynthetic analysis of iboga-system 6 if the C2-C16 bond is dis-
connected, the new target molecule will be 2,3-disubstituted in-
dole, 7 (when R = SiMe3) or 3-substituted indole, 8 (when R = H).
Further strategic disconnection of compound 7 shows the pres-
ence of 2-iodoaniline and alkyne-substituted isoquinuclidine 9.
Synthesis of the requisite isoquinuclidine-substituted internal al-
kyne 9 for the palladium-catalyzed 2,3-disubstituted indole forma-
tion is outlined in Scheme 2. The isoquinuclidine ring 9 was
synthesized by heating the mixture of Cbz-protected dihydropyri-
dine12 and methyl acrylate at 160 °C for 40 h in a sealed tube and
this was slightly different from the procedure reported by Büchi
et al.9 Moreover, a single regioisomer 10 was obtained as pyridine
was used as a starting material instead of 3-substituted pyridine.
The separation of the exo- and endo-isomers was difficult at this
stage though its separation was reported13 earlier via the forma-
tion of iodolactone in a multistep process. Here we used the mate-
rial 10 directly in the next step.
Ibogamine (1), R1, R2 = H
N
R1
R2
Ibogaine (2), R1 = OMe and R2 = H
Noribogaine (3), R1 = OH and R2 = H
Ibogaline (4), R1, R2 = OMe
19
20
However, these methods require a prefunctionalized heterocy-
clic indole for the modification of indole sub-system of iboga alka-
loids in order to have heterocyclic analogues 5. But a limited
number of prefunctionalized heterocyclic indoles are commercially
available and are very expensive. In addition, the reported synthe-
18
N
H
n
R1
R2
R3
R4
N
X = O, S, Se; Y = C or N and n = 0,1,2
Iboga analogues and congeners (5)
Y
X
* Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocss5@iacs.res.in (S. Sinha).
Figure 1. Iboga alkaloid family.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.037

1442
G. K. Jana, S. Sinha / Tetrahedron Letters 51 (2010) 1441–1443
Table 1
CO2Me
CO2Me
Trost
Synthesis of 2,3-di-substituted indole 7aa
3
N
N
19
2
16
R
N
H
N
conditions
R
CO2Me
cyclization
N
H
N
CO2Me
base (3 equiv)
I
Iboga scaffold (6)
Isoquinuclidine substituted indole
R
N
P
+
(7), R = SiMe3; (8), R = H
additive (1.5 equiv)
NHP
9a (exo)
Larock's
7a (P = Boc); 7a' (P = H)
heteroannulation
Entry
P
Pd/Ligand
Base
Time (h) Temp (°C) Yieldb (%)
I
Me3Si
N
CO2Me
1c
2c
3d
4d
5d
6d
7d
8d
H
H
H
H
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
Na2CO3 20
K2CO3
16
100
100
100
100
100
100
75
Tracee
Tracee
24
+
NH2
Internal alkyne (9)
2-iodoaniline
16
15
15
Pd(OAc)2/PPh3 K2CO3
36
46
35
73
Scheme 1. Retrosynthetic strategy.
Boc Pd(OAc)2/PPh3 K2CO3
Boc Pd(OAc)2/PPh3 Na2CO3 15
Boc Pd(OAc)2/PPh3 DIPEA
Pd(OAc)2/PPh3 DIPEA
10
12
H
80
41
a
Reactions were carried out in DMF using alkyne 9a 1.2 equiv Pd (5 mol %)/
Cbz
N
HHBr
20% HBr
N
ligand (10 mol %).
in HOAc
b
CO2Me
CO2Me
Isolated yields.
Additive LiCl.
Additive n-Bu4NCl.
Yields not determined.
c
rt, 1h
d
10 (exo + endo)
11
e
K2CO3, CH3CN,
80 ºC, 10h
SiMe3
CO2Me
H
N
N
SiMe3
H
11
CO2Me
N
+
OTs
i) Pd(CH3CN)2Cl2, AgBF4
Et3N, CH3CN, 65 ºC, 12h
CO2Me
Me3Si
endo, 9b (39%)
exo, 9a (35%)
12
7a
N
H
ii) NaBH4, MeOH, 0 ºC, 1h
iii) 20% TFA / CH2Cl2, rt, 3h
Scheme 2. Synthesis of isoquinuclidine substituted alkynes.
Iboga-scaffold, 6a (31%)
Scheme 3. Synthesis of iboga scaffold 6a.
After Cbz-deprotection with 20% HBr/HOAc, the compound 11
was converted to the alkynylated isoquinuclidine 9 and its mixture
of exo- and endo-isomers was then separated by column chroma-
tography on silica gel to give 9a and 9b, respectively, in a 1:1.1 ra-
tio (Scheme 2). These were characterized by 1H NMR. The tosylated
alkyne was in turn synthesized from 3-butyn-1-ol, which was then
converted to the silylated compound 12 in the presence of n-BuLi
with trimethylsilyl chloride. The overall yield was 70% in two steps.
We next investigated the construction of 2,3-disubstituted indole 7
via Larock heteroannulation reaction (Table 1). Initial attempts at
the heteroannulation reaction of 2-iodoaniline with internal al-
kyne 9a under Larock’s condition11 in the presence of LiCl
(1.5 equiv) gave a complex mixture (entries 1 and 2). The reaction
gave 24% isolated yield when n-Bu4NCl (1.5 equiv) was used in-
stead of LiCl (entry 3) and the yield was improved to 36% in the
presence of 10% PPh3 as a ligand (entry 4). Further screening with
Boc-protected-2-iodoaniline and PPh3 as a ligand was performed
and both K2CO3 and Na2CO3 gave moderate yields (entries 5 and
6). We were pleased to find that diisopropylethylamine (DIPEA)
improved the yield to 73% even at low temperature (entry 7).
Unprotected 2-iodoaniline again gave a moderate yield even when
the same base was used (entry 8).
These observations reveal that protecting group as well as base
and additives influenced this Pd-catalyzed reaction. The isoquinu-
clidine bearing 2,3-disubstituted indole 7a, a Trost ibogamine-like
precursor (indole NH was unprotected), was then cyclized using
the Trost mixed-metal-mediated cyclization method10f developed
for the synthesis of ibogamine. After Boc-deprotection, iboga scaf-
fold 6a was obtained in 31% yield (Scheme 3).
The optimized condition of 2,3-disubstituted indole 7a forma-
tion (entry 7, Table 1) was then applied to the coupling of Boc-pro-
tected 2-iodoaniline with endo-isomer 9b, but disappointingly the
reaction gave a complex mixture with very low consumption of 2-
iodoaniline. This is perhaps due to the unfavorable steric and elec-
tronic factors in the transition state by the endo-CO2Me group at
the C-19 position. We have tried several other conditions such as
using a different catalyst [Pd(dppf)2Cl2], and an excess amount of
alkyne 9b (up to 2.5 equiv) but in all these cases the yield was very
poor and it was difficult to purify the product. Then we changed
the protecting group and found that tosyl-protected 2-iodoaniline
gave the coupling products 7b and 7c (regioisomer) as an insepa-
rable mixture in 41% yield. The ratio 7b:7c (2:1) was determined
based on the integration value of (SiMe3) by 1H NMR. The mixture
was then cyclized under Trost’s conditions to give tosylated 6b in
27% yield and an inseparable mixture of desilylated starting mate-
rial and other products. The removal of the tosyl group of Ts-6b by
using Mg metal/NH4Cl in methanol14 at rt afforded epi-iboga scaf-
fold 6b with CO2Me substitution at C-19 in 71% yield (Scheme 4).
N
R
R
Pd(OAc)2 (5 mol %)
PPh3 (10 mol %)
N
N
CO2Me
CO2Me
Ts
7b
+
DIPEA, n-Bu4NCl, DMF,
CO2Me
105 ºC, 48h,
TsN
I
9b (endo)
R = SiMe3
N
R
N
NHTs
7c
7b:7c = 2:1, 41%
H
i) Pd(CH3CN)2Cl2, AgBF4
Et3N, CH3CN, 70 ºC, 40h
CO2Me
7b + 7c
Ts-6b
+
N
ii) NaBH4, MeOH, 0 ºC, 1h
Ts
Ts-6b, (27%)
mixture of
products
Mg/NH4Cl, MeOH, rt, 5h
Epi-iboga-scaffold, 6b (71%)
Scheme 4. Synthesis of epi-iboga scaffold 6b.

G. K. Jana, S. Sinha / Tetrahedron Letters 51 (2010) 1441–1443
1443
mixture of hydrobromide salt 11 (exo + endo) (1.81 g, 100%) which was directly
used in the next step. A suspension of K2CO3 (2.0 g, 14.60 mmol) in anhyd
CH3CN (12 mL) containing the above-mentioned deprotected isoquinuclidine
11 (1.81 g, 7.30 mmol) and alkyne 12 (2.16 g, 7.30 mmol) was refluxed for 10 h
then cooled to room temperature and filtered through a pad of Celite and
washed with EtOAc (10 mL). The combined organic extracts were concentrated
in vacuo and purified by column chromatography on silica gel (3–10% EtOAc in
petroleum ether) to give isoquinuclidine containing alkyne 9a (734 mg, 34.5%),
(RF = 0.48, PE/EtOAc, 9:1) and 9b (820 mg, 38.6%) as a colorless oil (RF = 0.42,
PE/EtOAc, 4:1).
In summary, we have developed a new approach toward the
synthesis of iboga alkaloids using palladium-mediated coupling
reactions as the key steps. Our synthetic approach is extremely
short and flexible and we obtained exo-product 6a15 in high yield
(overall yield 21% from 2-iodoindole) that belongs to the natural
product skeleton and its analogue 6b (endo-product, called epi-
iboga) as well. It is anticipated that minor modifications of the
starting materials and methods presented here should provide ac-
cess to related members and analogues of this alkaloid family 5
(Fig. 1) and could be useful for the total synthesis of some newly
isolated iboga alkaloids.2b Work toward such ends is now under-
way and results will be reported in due course.
Exo 9a. 1H NMR (300 MHz, CDCl3): d 6.43 (t, J = 7.26 Hz, 1H), 6.21 (dd, J = 7.29,
6 Hz, 1H), 3.78 (m, 1H), 3.70 (s, 3H), 3.11–3.07 (dd, J = 9, 2.1 Hz, 1H), 2.65–2.58
(m, 1H), 2.51 (br m, 1H), 2.42–2.36 (dt, J = 11, 3.4 Hz, 1H), 2.4–2.31 (m, 2H),
2.20 (m, 1H), 2.15–2.08 (dt, J = 14.7, 2.9 Hz, 1H), 1.85–1.82 (dt, J = 9, 2.3 Hz,
1H), 1.39–1.31 (ddt, J = 12.7, 9.5, 2.8 Hz, 1H), 0.116 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 174.9, 135.3, 129.9, 105.9, 84.9, 56.8, 54.8, 54.7, 51.9, 45.4, 31.0, 24.3,
19.9, 0.23; IR (neat): m
3045, 2948, 2172, 1738, 1250 cmÀ1; HRMS (ESI): (M+H)+
calcd for C16H25NO2SiH+ 292.1727; found 292.1728.
Acknowledgments
Endo 9b. 1H NMR (300 MHz, CDCl3): d 6.40 (t, J = 7.0 Hz, 1H), 6.15 (ddd, J = 6.8,
5.5, 1 Hz, 1H), 3.79 (ddd, J = 6, 3.3, 1.1 Hz, 1H), 3.61 (s, 3H), 3.08–3.02 (m, 1H),
2.92–2.88 (dd, J = 9.4, 2.0 Hz, 1H), 2.73–2.68 (m, 1H), 2.56 (br. m, 1H), 2.46–
2.40 (m, 1H), 2.35–2.29 (m, 2H), 2.0–1.96 (dt, J = 9.4, 2.3 Hz, 1H), 1.70 (m, 2H),
0.12 (s, 9H); 13C NMR (75 MHz, CDCl3): d 174.4, 134.7, 129.7, 105.6, 85.2, 56.9,
S.S. thanks DST, India, for financial support by a Grant [SR/S1/
OC-38/2007]. G.K.J. is thankful to CSIR for his fellowship.
54.5, 54.2, 51.8, 43.9, 30.7, 26.0, 20.0, 0.19; IR (neat):
m 3047, 2953, 2174, 1739,
1435 cmÀ1; HRMS (ESI): (M+H)+ calcd for C16H25NO2SiH+ 292.1727; found
292.1721.
References and notes
Compound 7a. A dry flask was charged with N-Boc-2-iodoaniline (356 mg,
1.11 mmol), isoquinuclidine containing internal alkyne 9a (389 mg,
1.33 mmol), palladium(II) acetate (12.5 mg, 0.055 mmol), triphenylphosphine
(29.2 mg, 0.11 mmol), n-tetrabutylammonium chloride (463 mg, 1.67 mmol),
diisopropylethylamine (0.75 mL, 4.46 mmol) and DMF (8 mL) under an argon
atmosphere and heated at 75 °C for 10 h. The reaction mixture was cooled to
room temperature and DMF (volatile materials) were removed under reduced
pressure. Then ethyl acetate (5 mL) and water (5 mL) were added to the
residue. The aqueous phase was extracted with ethyl acetate (3 Â 10 mL) and
the combined organic extracts were washed with 5% NaHCO3 (10 mL) and
brine (10 mL) and the solvent was removed in vacuo. The crude product was
purified by column chromatography on silica gel (19:1 PE/EtOAc). The exo-
product 7a was obtained as a light brown sticky material (392 mg, 73%).
RF = 0.49 (PE/EtOAc, 9:1); 1H NMR (300 MHz, CDCl3): d 7.95 (d, J = 8.2 Hz, 1H),
7.53 (dd, J = 7.5, 1 Hz, 1H), 7.32–7.20 (m, 2H), 6.49 (dd, J = 7.35, 7.0 Hz, 1H),
6.26 (dd, J = 6.6, 5.6 Hz, 1H), 3.93 (m, 1H), 3.79 (s, 3H), 3.30–3.27 (dd, J = 9,
2.1 Hz, 1H), 3.05–2.95 (td, J = 13, 5 Hz, 1H), 2.90–2.80 (td, J = 12.5, 5 Hz 1H),
2.65–2.55 (m, 2H), 2.52–2.46 (dt, J = 11, 3.6 Hz, 1H), 2.42–2.33 (m, 1H), 2.28–
2.21 (dt, J = 12.7, 2.9 Hz, 1H), 1.99–1.96 (dt, J = 9, 2.2 Hz, 1H), 1.72 (s, 9H), 1.50–
1.39 (ddt, J = 12.8, 9.5, 2.6 Hz, 1H), 0.44 (s, 9H); 13C NMR (75 MHz, CDCl3): d
175.0, 151.5, 137.1, 136.4, 135.2, 131.9, 130.6, 129.7, 124.6, 122.1, 118.8, 115.3,
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83.5, 59.6, 55.22, 55.0, 51.9, 45.5, 31.1, 28.3, 24.9, 24.3, 2.36; IR (Neat): m 3045,
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argon atmosphere. Silver tetrafluoroborate (275 mg, 1.40 mmol) was added
and the orange heterogeneous mixture immediately became yellow. After
10 min, a solution of dehydroisoquinuclidine 7a (150 mg, 0.35 mmol) in CH3CN
(2.0 mL) was added. The deep red solution was then stirred for 1 h at room
temperature then heated at 65 °C for 12 h. The reaction mixture was cooled to
0 °C, MeOH (1.5 mL) was added, followed by NaBH4 (13 mg, 0.35 mmol) in
portions. The solution was stirred for 1 h at 0 °C, water (1 mL) was added and
the solution was acidified with cold 2 N aq HCl. The mixture was filtered
through a pad of Celite to remove palladium black, extracted with ether
(20 mL) then basified with cold concd aq NH4OH. The basic aq solution was
extracted with ethyl acetate (3 Â 15 mL). The organic extracts were combined,
dried, concentrated in vacuo to give N-Boc protected and deprotected crude
mixture which was used without purification in the next step.
The crude mixture was treated with 20% TFA in CH2Cl2 (2 mL) at 0 °C and then
the reaction mixture was stirred for 3 h at room temperature. CH2Cl2 and
volatiles were removed in vacuo and then saturated aq NaHCO3 solution (3 mL)
and ethyl acetate (5 mL) were added to the residue. The aqueous phase was
extracted with ethyl acetate (3 Â 10 mL); the combined organic extracts were
washed with brine (10 mL) and the solvent was removed by rotary evaporation.
The crude product was purified by silica gel column chromatography (with a
gradual increase of MeOH from 0.5 to 1% in CH2Cl2) to give iboga scaffold 6a
(34 mg, 31%) as a light brown solid. RF = 0.52 (CH2Cl2/MeOH, 16:1); mp 198–
200 °C; 1H NMR (300 MHz, CDCl3): d 7.70 (br s, 1H), 7.47 (dd, J = 6.3, 2.1 Hz, 1H),
7.26 (dd, J = 6.6, 2.4 Hz, 1H), 7.14–7.09 (m, 2H), 3.73 (s, 3H), 3.58 (t, J = 2.1 Hz,
1H), 3.39–3.26 (m, 2H), 3.21–3.15 (dd, J = 14.5, 4 Hz, 1H), 3.02–3.11 (m, 3H),
2.76–2.71 (ddd, J = 10.93, 5.4, 2.2 Hz, 1H, H-16), 2.70–2.62 (m, 1H), 2.40–2.33
(dm, J = 12 Hz, 1H), 2.08 (m, 1H), 1.98 (m, 1H), 1.79–1.67 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 175.3, 141.0, 134.7, 129.8, 121.2, 119.3, 118.0, 110.3, 109.6,
11. (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652; (b)
Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
12. Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46,
5734.
13. Ye, Z.; Guo, L.; Barakat, K. J.; Pollard, P. G.; Palucki, B. L.; Sebhat, I. K.; Bakshi, R.
K.; Tang, R.; Kalyani, R. N.; Vongs, A.; Chen, A. S.; Chen, H. Y.; Rosenblum, C. I.;
MacNeil, T.; Weinberg, D. H.; Peng, Q.; Tamvakopoulos, C.; Miller, R. R.; Stearns,
R. A.; Cashen, D. E.; Martin, W. J.; Metzger, J. M.; Strack, A. M.; MacIntyre, D. E.;
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15. Experimental section and spectral data for some key compounds: Compounds 9a
and 9b. An oil containing mixture of exo- and endo-isomers 10 (2.20 g,
7.30 mmol) was dissolved in 20% hydrogen bromide/acetic acid (15 mL) and
stirred for 1 h. The solution was evaporated in vacuo to dryness to give a
56.9, 54.0, 52.0, 49.3, 45.9, 39.8, 34.4, 26.0, 25.9, 20.4; IR (KBr):
m 3398, 3055,
2926, 2866, 1732, 1614, 1460 cmÀ1; HRMS (ESI) (M+H)+ calcd for C19H22N2O2H+
311.1754; found 311.1753.