Reductive Heck coupling: An efficient approach toward the iboga alkaloids. Synthesis of ibogamine, epiibogamine and iboga analogs

Article abstract of DOI:10.1016/j.tetlet.2012.01.097

A mild and efficient synthetic route to the iboga scaffold by employing reductive-Heck type annulation is described. The utility of this process is demonstrated by the direct access to the ibogamine, epiibogamine and iboga-analogs. The cyclization precursors were readily obtained from 2-iodoaniline by heteroannulation reaction with suitable alkynes followed by iodination.

Full text of DOI:10.1016/j.tetlet.2012.01.097

Tetrahedron Letters 53 (2012) 1671–1674
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Tetrahedron Letters
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Reductive Heck coupling: an efficient approach toward the iboga
alkaloids. Synthesis of ibogamine, epiibogamine and iboga analogs
⇑
Goutam Kumar Jana, Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient synthetic route to the iboga scaffold by employing reductive-Heck type annulation is
described. The utility of this process is demonstrated by the direct access to the ibogamine, epiibogamine
and iboga-analogs. The cyclization precursors were readily obtained from 2-iodoaniline by heteroannu-
lation reaction with suitable alkynes followed by iodination.
Received 15 December 2011
Revised 18 January 2012
Accepted 22 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Reductive-Heck coupling
Iboga alkaloids
Indoloazepine
Heteroannulation
Palladium catalyst
Iboga alkaloids are pharmacologically important indole alka-
loids, consist of seven membered indoloazepine ring fused with a
rigid isoquinuclidine ring (Fig. 1).1 Such indoloazepine ring system
is also present in several other bioactive natural products2 and
medicinally important molecules.3 Pharmacological properties of
iboga-alkaloids have been reviewed many times.4 Iboga modified
structures exhibit many interesting pharmacological properties5
such as anti-addictive, antifungal or antilipase, anti-HIV-1, anti-
cholinesterasic, anti-leishmanicide activities. Iboga-alkaloids, par-
ticularly catharanthine (3) is known to involve in the biochemical
pathways for the generation of structurally more complex vinca
alkaloids vinblastine and vincristine, two drugs used in the treat-
ment of a number of human cancers.6
synthesis of iboga analogs. Though, the method involved direct
C–H bond activation, the yield was low and not economical as it re-
quired 1–2 equiv of palladium catalyst and 2–4 equiv of AgBF4.
It is therefore highly desirable to develop new efficient and
economical methods for the construction of the indoloazepine core
structure of the iboga-scaffold. Herein, we describe a catalytic, mild
and efficient method to achieve this transformation for the synthe-
sis of ibogamine and iboga analogs.
Conceptually b-H elimination is prohibited in the Pd-catalyzed
Heck type C–C bond forming reaction, where rigid double bond is
involved.12 Accordingly, we envisioned that reductive-Heck type
Construction of seven membered indoloazepine ring is the cru-
cial step in the synthesis of iboga alkaloids.1 Several methods are
available in the literature such as electrocyclic ring closure,7
mixed-metal-mediated cyclization,8 Fischer indolization9 and
reductive amination10 for the creation of this ring system to access
the total synthesis of ibogaine or ibogamine. Other syntheses1 have
followed these approaches for the construction of indoloazepine
ring leading to the synthesis of iboga alkaloids. However, most of
these strategies suffer from several limitations concerning flexibil-
ity, yields and reaction conditions. In the Büchi’s method, synthesis
of cyclization precursor is a multistep process and cyclization in
hot acetic acid results in rearranged product formation.7 Our
earlier strategy11a involved Trost’s cyclization method8 for the
N
N
R
N
H
N
H
CO2Me
R = H; Ibogamine (1)
R = OMe; Ibogaine (2)
3
Catharanthine ( )
Figure 1. Iboga-family alkaloids.
R
R
N
N
Reductive
I
N
Heck coupling
N
H
H
5
4
⇑
Corresponding author.
E-mail address: ocss5@iacs.res.in (S. Sinha).
Scheme 1. Synthetic strategy for reductive-Heck coupling.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.097

1672
G. K. Jana, S. Sinha / Tetrahedron Letters 53 (2012) 1671–1674
R
N
N
ICl, AgBF4
DCM:MeOH (1:1)
R
N
ICl, AgBF4
N
R
R
N
DCM:MeOH
(1:1), rt, 8 h
I
N
Ts
-10 oC, 15 min
84 %
I
N
SiEt3
Ts
N
P
SiMe3
74 %
5c R = CO2Me
P
8
5a
6
N
P = Boc, R = CO2Me
R
Pd(OAc)2, PPh3, HCO2Na
DMF:CH3CN(3:1), 55 oC
Scheme 2. Synthesis of cyclization precursor 5a.
N
Ts
7b
57%
Table 1
Mg(0), MeOH
NH4Cl, rt
71 %
Optimization of reductive-Heck coupling conditiona
R
10 mol % [Pd]
20 mol % PPh3
N
R
N
N
+
5a
CO2Me
reducing agent,
solvent, temp
N
H
N
Boc
Boc
R = CO2Me
N
H
7a
5b
TFA,DCM
91 %
4b
X-ray crystal structure of 4b
Scheme 3. Synthesis of C-19 endo-substituted Iboga-scaffold 4b.
R
N
N
H
4a
CO2Et
N
X-ray crrystal sstructuure of 4a
i) NaBH4, THF:MeOH (1:1)
ii) NaH, THF, CS2, MeI
R = CO2Me
O
iii) TBTH, AIBN, Toluene
70 %
Entry
Conditions (reducing agent, solvent, temp, time)
Yieldd (%)
10
9
7a
5b
1b
2c
3
4
5
6
7
8
HCO2H, piperidine, DMF, 80 °C, 2 h
HCO2H, piperidine, DMF, 80 °C, 2 h
HCO2H, piperidine, DMF, 80 °C, 2 h
HCO2H, piperidine, DMF, rt, 10 h
HCO2H, piperidine, DMF, 50 °C, 4 h
HCO2Na, DMF, 50 °C, 5 h
20
15
25
15
40
50
68
51
66
60
60
12
45
36
15
11
i) TMSI, DCM, 0 oC - rt, 3 h
ii) CH3CN, K2CO3, 70 oC, 10 h
N
SiEt3
OTs
Et3Si
12a
12b
(exo Et); (24 %)
(endo Et); (32 %)
11
HCO2Na, DMF/CH3CN (3:1), 55 °C, 6 h
HCO2H, DMF/CH3CN (3:1), 55 °C, 8 h
N
12a (exo Et)
Larock's
heteroannulation
+
I
a
All reactions were carried out using 10 mol % of Pd(OAc)2 and 20 mol % of
ligand(PPh3).
N
b
Pd(PPh3)4(10 mol %).
Without ligand.
Isolated yields.
SiEt3
P
NHP
c
13
d
Scheme 4. Synthesis of cyclization precursor for Ibogamine.
annulation could be a useful method to the indoloazepine ring
system containing a fused isoquinuclidine ring, since Heck cou-
pling or oxidative-Heck coupling would lead to a highly strained
bridgehead olefinic system (Scheme 1).
ded the expected product 7a in a 68% yield (Table 1, entry 7). We
failed to achieve this conversion when 5 mol % of the catalyst
and 10 mol % of the ligand were used. Under this condition, about
60% of the starting material was consumed and the reaction did not
proceed further even after prolonged stirring. The X-ray crystal
structure of 4a which was obtained after Boc deprotection of 7a
showed the desired connectivity.
Then we turned our attention to the synthesis of C-19 epimer of
4a using the optimized reductive-Heck coupling condition. The
synthesis of 8 from Ts-protected 2-iodoaniline gave better yield
when TES connected alkyne was used.11a Iodination of 2-triethylsi-
lyl substituted indole 8 required room temperature and longer
reaction time in comparison to 2-trimethylsilyl substituted indole
6 (Scheme 3). Under the optimized coupling condition, the cyclized
product was obtained in a 57% yield which after Ts-deprotection by
Mg(0) in methanol furnished C-19 epimeric iboga scaffold 4b.
With this success, our next aim was the synthesis of ibogamine
(1)1 to demonstrate a suitable application of this transformation.
For the synthesis of ibogamine and epiibogamine, we initially fol-
lowed convergent protocol to access the cyclization precursors
(Scheme 4). Compound 9 was obtained by the Diels–Alder reaction
between dihydropyridine and methyl vinyl ketone as an insepara-
ble epimeric mixture (3:4).16 After reduction with NaBH4, the
resulting mixture of diastereoisomeric alcohols was converted into
To check the feasibility of the reductive-Heck type annulation
reaction, initially we took 5a, a cyclization precursor which directly
would lead to the C-19 exo-substituted iboga-scaffold. The cycliza-
tion precursor 5a was prepared from Boc-protected 2-iodoaniline
by heteroannulation reaction11 followed by iodination using ICl
in the presence of AgBF4 (Scheme 2). Initially, we had used NIS
for iodionation but the yield was not satisfactory. After several
experimentations, we found that mixed solvent system in the pres-
ence of AgBF4 was suitable to afford the cyclization precursor 5a in
very good yield.
Initial attempt of the reductive-Heck type annulation using
Pd(PPh3)4 as catalyst and formic acid–piperidine as reducing sys-
tem in DMF at 80 °C resulted mostly in the deiodinated compound
5b (Table 1, entries 1–3).13
Performing the reaction at 50 °C by using Pd(OAc)2 in the pres-
ence of PPh3 afforded the desire product 7a in a 40% yield14 (Table
1, entry 5). When formic acid and piperidine were replaced with
sodium formate,15 a less effective reducing agent, the yield of de-
sired product was increased by upto 50%. We were pleased to find
that a mix solvent system, DMF and acetonitrile in 3:1 ratio affor-

G. K. Jana, S. Sinha / Tetrahedron Letters 53 (2012) 1671–1674
1673
OR
also involve Pd-catalyzed heteroannulation reaction. The applica-
tion of this protocol for the synthesis of other iboga alkaloids and
their analogs will be reported shortly.
Pd(OAc)2, Na2CO3,
DMF, 90 oC
I
OSiEt3
Et3Si
N
H
SiEt3
NH2
14
Acknowledgments
15a; R = SiEt3 (51%)
TESCl,
Imidazole
15b
; R = H (25%)
96 %
We thank Dr. N.N. Adarsh for crystal structure and DST, India,
for financial support. G.K.J. is thankful to CSIR, India for fellowship.
i) NIS, DCM, 0 oC
I2, PPh3, Imidazole
OH
N
H
I
ii) TBAF, THF
78 %
Supplementary data
DCM
81 %
16
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.097.
N
CH3CN, K2CO3
70 oC, 10 h
I
H.HI
N
N
I
N
H
17
I
References and notes
H
18a (exo); 27 %
18b (endo); 35 %
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N
Pd(OAc)2, PPh3,
18a (exo Et)
HCOONa
18b
(endo Et)
N
DMF:CH3CN (3:1)
H
Ibogamine (1, exo Et; 68 % )
Epiibogamine ( , endo Et; 51 %)
1a
Scheme 6. Final step for the synthesis of ibogamine and epiibogamine.
6. (a) Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 420; (b)
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137; (c) Scott, A. I.; Gueritte, F.; Lee,
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E. K. J. Am. Chem. Soc. 1991, 113, 6689.
the corresponding xanthates. Without separation, the mixture of
xanthates on radical deoxygenation17 afforded inseparable exo
and endo mixture of dehydroisoquinuclidine 10 with some TBTH
byproducts in a 70% overall yield from 9. Deprotection of dehy-
droisoquinuclidine 10 and N-alkylation with tosylated alkyne 11
afforded isoquinuclidine containing alkynes 12a and 12b (3:4) in
moderate yields. Attempted heteroannulation reaction of alkyne
12a with 2-iodoaniline was disappointing though it worked well
previously11a when CO2Me substituted (instead of ethyl) dehy-
droisoquinuclidine containing alkyne was used. We tried several
conditions, but in all the cases complex mixture was obtained with
very low amount of expected product which was inseparable from
the alkyne 12a.
So we turned our attention toward an alternative route for the
efficient synthesis of cyclization precursors 18a and 18b (Scheme
5). To avoid these problems, we considered initial construction of
indole part from 2-iodoaniline by use of a simple disilylated alkyne
14 prior to the connection with isoquinuclidine ring 10a. The het-
eroannulation reaction of 2-iodoaniline with alkyne 14 gave the
expected product 15a and mono-desilylated compound 15b in
good yields. Iodination of 15a by NIS followed by silyl deprotection
using TBAF afforded 2-iodotryptol 16 which was not quite stable.
The compound 16 was immediately iodinated and purified to ob-
tain tryptoyl iodide 17 in a 63% yield from 15a. Compound 15b
was converted to 15a as iodination of 15b using NIS was not clean.
Reaction of 10a with 2-iodo tryptoyl iodide 17 in acetonitrile affor-
ded separable cyclization precursors 18a and 18b in good yields.
With the cyclization precursors 18a and 18b in hand, we then
applied optimized reductive-Heck cyclization condition separately
to obtain ibogamine (1) and epiibogamine (1a) in 68% and 51%
yields, respectively (Scheme 6).
12. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
13. (a) Malpass, J. R.; Cox, C. D. Tetrahedron Lett. 1999, 40, 1419; (b) Cox, C. D.;
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Takahashi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2004, 126, 16553.
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404; (c) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am.
Chem. Soc. 2008, 130, 5368; (d) Brieaddy, L. E.; Mascarella, S. W.; Navarro, H. A.;
Atkinson, R. N.; Damaj, M. I.; Martin, B. R.; Carrol, F. I. Tetrahedron Lett. 2001, 42,
3795; (e) Carroll, F. I.; Robinson, T. P.; Brieaddy, L. E.; Atkinson, R. N.;
Mascarella, S. W.; Damaj, M. I.; Martin, B. R.; Navarro, H. A. J. Med. Chem. 2007,
50, 6383.
16. Mariano, P. S.; Dunaway Mariano, S.; Huesmann, P. L. J. Org. Chem. 1979, 44,
124.
17. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc. Perkin Trans. 1 1975, 1574.
18. Experimental procedure and spectral data of some key compounds:
Cyclization precursor 5a:
To a cooled solution (À15 °C) of compound 6 (500 mg, 1.16 mmol) in DCM and
MeOH (1:1, 4 mL) was added silver tetrafluoroborate (230 mg, 0.83 mmol)
followed by the dropwise addition of ICl (1.4 mL, 1 M) under argon
atmosphere. After 15 min of stirring the ice-salt bath was removed and
10 mL of DCM was added to the reaction mixture. The organic layer was
washed with aq Na2S2O3 solution, brine and dried over anhydrous Na2SO4. The
organic part was concentrated in vacuo, purified by silica gel column
chromatography using EtOAc in petroleum ether (PE/EtOAc 9:1) as eluent to
get the compound 5a (520 mg, 84%) as a light brown foam. Rf = 0.23 (PE/EtOAc
9:1). 1H NMR (500 MHz, CDCl3, d): 8.05 (dd, J = 6.5, 2.5 Hz, 1H), 7.45 (dd, J = 6.0,
2.5 Hz, 1H), 7.21 (m, 2H), 6.46 (t, J = 7.5 Hz, 1H), 6.25 (t, J = 6.5 Hz, 1H), 3.93
(dd, J = 4.0, 1.5 Hz, 1H), 3.69 (s, 3H), 3.27 (dd, J = 9.5, 2.0 Hz, 1H), 2.86–2.81
(ddd, J = 13.5, 11.0, 6.0 Hz, 1H), 2.77–2.71 (ddd, J = 13.0, 11.0, 5.0 Hz, 1H), 2.60
(m, 2H), 2.45 (dt, J = 10.5, 5.0 Hz, 1H), 2.30 (td, J = 11.5, 5.0 Hz, 1H), 2.20 (dt,
J = 14.0, 3.5 Hz, 1H), 1.98 (dt, J = 9.0, 2.5 Hz, 1H), 1.70 (s, 9H), 1.42 (m, 1H); 13C
NMR (125 MHz, CDCl3, d): 174.97, 149.51, 138.22, 135.23, 130.03, 129.85,
128.22, 124.32, 122.66,118.37, 115.60, 85.00, 78.64, 57.07, 55.15, 55.12, 51.82,
45.45, 31.19, 28.44, 27.27, 24.44; IR (neat): 2947, 1732, 1444 cmÀ1. HRMS (ESI)
In summary, we have described a novel entry to direct construc-
tion of iboga skeleton18 based on reductive-Heck type cyclization.
The cyclization step is catalytic, mild, and efficient. With this
cyclization as the key step, total synthesis of ibogamine18 and epii-
bogamine18 has been achieved. Syntheses of cyclization precursors
(M+H)+ calcd for C24H30IN2O4 537.1245, found 537.1246.
+

1674
Iboga scaffold 7a:
G. K. Jana, S. Sinha / Tetrahedron Letters 53 (2012) 1671–1674
(DCM/MeOH as eluent with gradual increase in conc. of MeOH from 0.5–1.5%)
to give 18a (109 mg, 27%) and 18b (142 mg, 35%) as light yellow foam.
Compound 18a: 1H NMR (500 MHz, CDCl3, d): 8.04 (br s, 1H), 7.55 (d, J = 8.0 Hz,
1H), 7.28 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.31
(m, 2H), 3.28 (br s, 1H), 3.20 (d, J = 9.0 Hz, 1H), 2.84–2.69 (m, 2H and 1H), 2.45
(m, 2H), 2.02 (d, J = 8.5 Hz, 1H), 1.55 (m, 2H), 1.46 (m, 1H), 1.32 (m, 1H), 0.96
(m, 1H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3, d): 139.04, 132.97,
132.86, 127.70, 123.38, 122.23, 120.90, 119.73, 118.27, 110.04, 58.74, 56.45,
56.33, 41.24, 31.77, 29.85, 27.20, 26.40, 12.62; IR (Neat, cmÀ1): 3206, 2957,
Optimized reductive-Heck coupling condition: Dry DMF (1.50 mL) and CH3CN
(0.50 mL) were added to a flask containing compound 5a (150 mg, 0.28 mmol)
under argon atmosphere followed by the addition of HCOONa (38 mg,
0.56 mmol). The mixture was degassed and finally back-filled with argon
then Pd(OAc)2 (6 mg, 10 mol %) and PPh3 (14.5 mg, 20 mol %) were added with
stirring. The mixture was heated for 6 h at 55 °C. Solvents were removed in
vacuo then H2O (2 mL) and ethyl acetate (4 mL) were added to the residue. The
aqueous phase was extracted with ethyl acetate (2 Â 4 mL), the combined
organic layers were washed with brine (4 mL), dried (Na2SO4). The solvent was
removed in vacuo and the crude material was purified by column
chromatography (silica gel, gradient of PE/EtOAc from 7:1 to 5:1) to give
deiodinated compound 5b (17 mg, 15%) and the title compound 7a (78 mg,
68%) as light yellow solid. Compound 7a: Rf = 0.21 (PE/EtOAc 5:1). mp 159–
161 °C. 1H NMR (500 MHz, CDCl3, d): 7.98 (dd, J = 7.0, 2.0 Hz, 1H), 7.40 (dd,
J = 7.0, 2.5 Hz, 1H), 7.23 (m, 2H), 3.95 (dd, J = 11.0, 6.0 Hz, 1H), 3.71 (s, 3H), 3.52
(s, 1H), 3.28–3.20 (m, 1H), 3.14 (m, 2H), 3.12 (dt, J = 9.5, 2.5 Hz, 1H), 3.00 (d,
J = 9.5 Hz, 1H), 2.77 (ddd, J = 11.0, 5.0, 2.5 Hz, 1H), 2.68 (dt, J = 16.0, 2.5 Hz, 1H),
2.35 (m, 1H), 2.26 (m, 1H), 2.00 (m, 1H), 1.74 (m, 1H), 1.68 (s, 9H), 1.66 (m, 1H);
13C NMR (125 MHz, CDCl3, d): 175.41, 150.71, 143.19, 135.24, 130.58, 123.56,
122.46, 117.92, 117.27, 115.45, 83.82, 56.81, 53.63, 51.99, 50.78, 46.76, 37.86,
34.36, 28.50, 26.25, 25.68, 20.70; IR (KBr, cmÀ1): 2976, 1729, 1724, 1458, 1155,
1653, 1448, 746; HRMS (ESI) (M+H)+ calcd for C19H24IN2 407.0979, found
407.0977.
+
Compound 18b: 1H NMR (500 MHz, CDCl3, d): 8.60 (br s, 1H), 7.92 (d, J = 6.5 Hz,
1H), 7.33 (d, J = 7.0 Hz, 1H), 7.08 (m, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.40 (t,
J = 7.0 Hz, 1H), 4.23 (br s, 1H), 4.07 (br d, J = 9.0 Hz, 1H), 3.54 (br t, J = 10.0 Hz,
1H), 3.21 (br t, J = 8.0 Hz, 1H), 3.12 (dt, J = 12.0, 5.0 Hz, 1H), 2.85 (br s, 1H), 2.77
(br t, J = 7.0 Hz, 1H), 2.22 (br d, J = 10.5 Hz, 1H), 2.11 (br m, 1H), 2.03 (m, 1H),
1.72–1.68 (m, 2H), 1.28 (d, J = 11.5 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3, d): 138.91, 137.96, 127.99, 127.04, 124.35, 122.77, 120.58,
119.20, 115.99, 110.67, 56.64, 55.91, 55.61, 38.44, 29.11, 27.21, 27.08, 17.78,
12.58; IR (Neat, cmÀ1): 3206, 2957, 1653, 746; HRMS (ESI) (M+H)+ calcd for
+
C19H24IN2 407.0979, found 407.0975.
Ibogamine (1):
754; HRMS (ESI) (M+H)+ calcd for C24H31N2O4 411.2278, found 411.2276.
The procedure was same as described for the cyclization of compound 5a
(above), ibogamine (1) was obtained as a pale brown oil (68%), which was
crystallized upon standing; Rf = 0.34 (DCM/MeOH 20:1), mp 137–139 °C. 1H
NMR (500 MHz, CDCl3, d): 7.82 (br s,1H), 7.47 (d, J = 7.5 Hz, 1H), 7.27 (d,
J = 9.0 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 3.51 (br d,
J = 15.5 Hz, 1H), 3.34–3.19 (m, 3H), 3.09 (d, J = 10,0 Hz, 1H), 3.03 (d, J = 6.0 Hz,
2H), 2.82 (d, J = 14.5 Hz, 1H), 2.10 (t, J = 12.5 Hz, 1H), 1.93 (s, 1H), 1.86 (td,
J = 10.0, 2.5 Hz, 1H), 1.69–1.52 (m, 4H), 1.31 (m, 1H), 0.91 (t, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3, d): 141.97, 134.84, 129.91, 121.12, 119.27, 118.05,
110.22, 109.41, 57.73, 54.34, 50.12, 42.15, 41.67, 34.37, 32.30, 27.96, 26.70,
20.83, 12.06; IR (KBr, cmÀ1): 3394, 2924, 1612, 1461; HRMS (ESI) (M+H)+ calcd
+
Compound 17: To a stirred solution of 16 (400 mg, 1.39 mmol) in DCM (5 mL)
were added imidazole (189 mg, 2.78 mmol), PPh3 (366 mg, 1.4 mmol) and I2
(355 mg, 1.4 mmol) at 0 °C. Stirring was continued for 4 h at 0 °C. DCM (5 mL)
was added to the reaction mixture. The organic layer was washed with aq
Na2S2O3 solution and brine. The organic part was dried over anhydrous Na2SO4,
concentrated in vacuo, and the crude material was purified by silica gel column
chromatography (EtOAc/PE 19:1) to give compound 17 (447 mg, 81%) as light
yellow crystalline solid. Rf = 0.51 (PE/EtOAc 9:1), mp 107–109 °C. 1H NMR
(500 MHz, CDCl3, d): 8.05 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.15 (m, 2H), 3.33 (m, 4H); 13C NMR (125 MHz, CDCl3, d): 138.97, 127.05,
122.73, 121.73, 120.29, 117.85, 110.63, 31.85, 4.21; IR (KBr, cmÀ1): 3364, 2957,
1445, 1169, 741; (ESI) (M+Na)+ calcd for C10H9I2NNa+ 419.8717, found
419.8713.
+
for C19H25N2 281.2012, found 281.2011.
Epiibogamine (1a):
Rf = 0.33 (DCM/MeOH 12:1), mp 185–188 °C. 1H NMR (500 MHz, CDCl3, d): 8.08
(br s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14 (m, 2H), 3.52 (br
m, 2H), 3.30 (br s, 1H), 3.24 (m, 2H), 3.11–3.01 (m, 2H), 2.40 (br s, 1H), 2.21 (m,
1H), 2.07 (m, 3H), 1.67 (m, 1H), 1.43 (m, 2H), 1.10 (m, 1H), 0.94 (t, J = 6.0 Hz,
3H); 13C NMR (125 MHz, CDCl3, d): 134.46, 129.68, 127.96, 121.13, 119.40,
117.92, 110.35, 110.09, 60.79, 57.37, 54.76, 49.73, 35.13, 31.77, 29.84, 28.47,
26.40, 20.31, 12.25; IR (KBr, cmÀ1): 3401, 2923, 1611, 1463; HRMS (ESI)
(M+H)+ calcd for C19H25N2+: 281.2012, found 281.2012.
Cyclization precursors 18a and 18b:
A
suspension of K2CO3 (333 mg, 2.4 mmol) in anhydrous CH3CN (6 mL)
containing deprotected isoquinuclidine 10a (319 mg, 1.2 mmol) and 2-iodo
compound 17 (400 mg, 1.0 mmol) was heated at 70 °C for 10 h then the
reaction mixture was 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