Transition metals in organic synthesis. Part 108: First total synthesis of ekeberginine

Article abstract of DOI:10.1016/j.tetlet.2012.11.093

Using a palladium(II)-catalyzed oxidative cyclization and a regioselective nickel-mediated prenylation as key steps, the first total synthesis of the 1-oxygenated carbazole alkaloid ekeberginine has been achieved in six steps and in 63% overall yield.

Full text of DOI:10.1016/j.tetlet.2012.11.093

Tetrahedron Letters 54 (2013) 591–593
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Tetrahedron Letters
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Transition metals in organic synthesis. Part 108: first total synthesis of
ekeberginine q
⇑
Claudia Thomas, Hans-Joachim Knölker
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a palladium(II)-catalyzed oxidative cyclization and a regioselective nickel-mediated prenylation as
key steps, the first total synthesis of the 1-oxygenated carbazole alkaloid ekeberginine has been achieved
in six steps and in 63% overall yield.
Received 18 October 2012
Revised 12 November 2012
Accepted 22 November 2012
Available online 29 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Catalysis
Cyclizations
Oxidation
Palladium
Over the past two decades, carbazole alkaloids have been exten-
sively studied due to their broad range of useful biological activi-
ties and several novel synthetic methodologies for their synthesis
have been developed.1,2 The 1-oxygenated carbazole alkaloids re-
present a prominent sub-group and have been mostly isolated
from plants of the genera Murraya and Clausena of the Rutaceae
family. A particular exception is ekeberginine (1-methoxy-4-
prenyl-9H-carbazole-3-carbaldehyde) (1), which has been isolated
from the stem bark of Ekebergia senegalensis, which belongs to a
different family, Meliaceae (Fig. 1).3
(Rutaceae).4 Ekeberginine (1) is the 4-prenyl derivative of mur-
rayanine (2b) and thus, we thought that 1 could be prepared from
the structurally more simple 1-methoxycarbazoles 2. We have pre-
viously described two efficient routes to mukonine (2a).5 The first
process employs an iron-mediated carbazole synthesis and the
Br
CHO
CHO
Only several years later, ekeberginine (1) was also obtained
from the combined stem bark and root extracts of Clausena anisata
[Ni]
Br
N
H
N
H
4
OMe
OMe
3
1
ekeberginine
R
Me
COOMe
CHO
N
H
OMe
N
H
N
H
N
H
OMe
OMe
2a mukonine
2a
mukonine
2b murrayanine
2c
R = COOMe
R = CHO
OMe
2c
murrayafoline A
murrayafoline A R = Me
1 ekeberginine
COOMe
Figure 1. Naturally occurring 1-methoxycarbazole alkaloids.
[Pd]
+
H2N
Br
q
OMe
6
For part 107, see: Agarwal, S.; Kataeva, O.; Schmidt, U.; Knölker, H.-J. RSC Adv.
2013, 3. http://dx.doi.org/10.1039/c2ra22823h.
5
⇑
Corresponding author. Fax: +49 351 463 37030.
E-mail address: hans-joachim.knoelker@tu-dresden.de (H.-J. Knölker).
Scheme 1. Retrosynthetic analysis of ekeberginine (1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.093

592
C. Thomas, H.-J. Knölker / Tetrahedron Letters 54 (2013) 591–593
COOMe
COOMe
The regioselective introduction of the prenyl group should be
feasible by the reaction of an appropriate bromocarbazole with
bis[ -bromo(
3-prenyl)nickel] (8) (Scheme 3). Complex 8 was
COOMe
a
+
l
g
H2N
Br
N
H
7
OMe
6
easily prepared by treatment of prenyl bromide (3) with 3 equiv
of tetracarbonylnickel in benzene at 60 °C following the procedure
described by Wilke et al.10 The dimeric prenylnickel bromide com-
plex 8 has proven to be very useful for the prenylation of alkyl and
aryl halides.11 Previously, we applied the nickel-mediated prenyla-
tion to the synthesis of carquinostatin A and neocarazostatin B.12,13
Moreover, our synthesis of lavanduquinocin has demonstrated that
even structurally more complex allyl moieties can be introduced
by this procedure.14
OMe
5
Me
b
c
N
H
N
H
OMe
OMe
2a
2c
murrayafoline A
mukonine
Bromination of murrayafoline A (2c) afforded exclusively 4-bro-
momurrayafoline A (9), a result which was in agreement with ear-
lier observations by our group on the regioselectivity of
electrophilic substitutions of carbazoles (Scheme 4).1d,9 Oxidation
of 9 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) led
to 4-bromomurrayanine (4).15 Finally, coupling with prenyl bro-
mide via the reaction of 4-bromomurrayanine (4) with an excess
of complex 8 in N,N-dimethylformamide at an elevated tempera-
ture provided ekeberginine (1) in 86% yield. The spectroscopic data
(UV, IR, 1H NMR, 13C NMR, MS)16 of our synthetic ekeberginine (1)
were in good agreement with those reported for the natural
product.3,4
In conclusion, we have achieved the first total synthesis of
ekeberginine (1) and thus confirmed the structural assignment.
Our palladium-catalyzed route leads to the natural product in
six steps and 63% overall yield based on commercially available
methyl 4-amino-3-methoxybenzoate (6) and provides sufficient
quantities in order to investigate the biological activities of 1.
These studies and further applications of the present method
are ongoing.
Scheme 2. Palladium-catalyzed synthesis of murrayafoline A (2c). Reagents and
conditions: (a) 6 mol % Pd(OAc)2, 12 mol % SPhos, 1.1 equiv 5, 1.4 equiv Cs2CO3,
toluene, reflux, 40 h, 100%; (b) 0.1 equiv Pd(OAc)2, 0.1 equiv K2CO3, PivOH, 115 °C,
14 h, 91%; (c) 3 equiv LiAlH4, Et2O/CH2Cl2 (1:1), rt, 4.5 h, 87%.
second utilizes a palladium-catalyzed approach.5–7 Moreover, the
oxidation state of the C1-substituent at C-3 of the carbazole is eas-
ily modified by the reduction of 2a to murrayafoline A (2c) and by
the oxidation of 2c to murrayanine (2b). Therefore, we have de-
vised the following synthetic plan for ekeberginine (1) (Scheme 1).
A nickel-mediated prenylation of 4-bromomurrayanine (4-bro-
mo-1-methoxy-9H-carbazole-3-carbaldehyde) (4) as the ultimate
precursor of ekeberginine (1) should provide the natural product.
4-Bromomurrayanine (4) could be derived in three steps from
mukonine (2a) via reduction to murrayafoline A (2c), regioselective
bromination, and subsequent oxidation of the methyl group. Muk-
onine (2a) is accessible from bromobenzene (5) and methyl 4-ami-
no-3-methoxybenzoate
(6)
using
a
palladium-catalyzed
approach.5,7 Alternatively, mukonine (2a) can be prepared via an
iron-mediated carbazole synthesis.5,6
Buchwald–Hartwig coupling of bromobenzene (5) with aryl-
amine 6 and subsequent palladium(II)-catalyzed oxidative cycliza-
tion via double C–H bond activation provided mukonine (2a) in
91% yield over two steps (Scheme 2).5,7 Reduction of 2a using lith-
ium aluminum hydride then afforded murrayafoline A (2c).8,9
Supplementary data
Supplementary data (1H and 13C NMR spectra of 4-bromomur-
rayanine (4) and ekeberginine (1)) associated with this article
can be found in the online version at http://dx.doi.org/10.1016/
j.tetlet.2012.11.093.
Br
Ni Ni
Br
Br
a
References and notes
1. (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427; (b) Knölker, H.-
J. Curr. Org. Synth. 2004, 1, 309–331; (c) Knölker, H.-J.; Reddy, K. R. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008; Vol. 65, pp 1–
430; (d) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev. 2012, 112, 3193–
3328.
3
8
Scheme 3. Synthesis of bis[
l-bromo(
g
3-prenyl)nickel] (8). Reagents and condi-
tions: (a) 3 equiv Ni(CO)4, benzene, 60 °C, 30 min.
2. (a) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115–148; (b) Knölker, H.-J. Chem.
Lett. 2009, 38, 8–13; (c) Bauer, I.; Knölker, H.-J. Top. Curr. Chem. 2012, 309, 203–
253.
3. Lontsi, D.; Ayafor, J. F.; Sondengam, B. L.; Conolly, J. D.; Rycroft, D. S. Tetrahedron
Lett. 1985, 26, 4249–4252.
Br
Me
Me
a
b
4. Ngadjui, B. T.; Ayafor, J. F.; Sondengam, B. L.; Conolly, J. D. Phytochemistry 1989,
28, 1517–1519.
5. Börger, C.; Krahl, M. P.; Gruner, M.; Kataeva, O.; Knölker, H.-J. Org. Biomol. Chem.
2012, 10, 5189–5193.
N
H
N
H
OMe
OMe
6. (a) Knölker, H.-J.; Bauermeister, M. J. Chem. Soc., Chem. Commun. 1990, 664–
665; (b) Knölker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49, 11221–11236;
(c) Knölker, H.-J.; Wolpert, M. Tetrahedron Lett. 1997, 38, 533–536; (d) Knölker,
H.-J.; Wolpert, M. Tetrahedron 2003, 59, 5317–5322; For reviews, see: (e)
Knölker, H.-J. Synlett 1992, 371–387; (f) Knölker, H.-J. Chem. Soc. Rev. 1999, 28,
151–157.
7. (a) Krahl, M. P. Ph.D. Dissertation, Technical University of Dresden, 2006; (b)
Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008,
73, 5022–5028.
2c murrayafoline A
9
Br
CHO
CHO
c
8. (a) Chakraborty, D. P.; Roy, S.; Dutta, A. K. J. Indian Chem. Soc. 1987, 64, 215–
217; (b) Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters, E.-M. Synthesis
1998, 1501–1505; (c) Bringmann, G.; Tasler, S. Tetrahedron 2001, 57, 2337–
2343.
9. Börger, C.; Kataeva, O.; Knölker, H.-J. Org. Biomol. Chem. 2012, 10, 7269–7273.
10. Wilke, G.; Bogdanovic´, B.; Hardt, P.; Heimbach, P.; Keim, W.; Kröner, M.;
Oberkirch, W.; Tanaka, K.; Steinrücke, E.; Walter, D.; Zimmermann, H. Angew.
Chem. 1966, 78, 157–172. Angew. Chem., Int. Ed. Engl. 1966, 5, 151–164.
N
H
4
N
H
OMe
OMe
1 ekeberginine
Scheme 4. Synthesis of ekeberginine (1). Reagents and conditions: (a) 1.03 equiv
NBS, MeCN, rt, 4 h, 99%; (b) 6.0 equiv DDQ, MeOH/H2O/THF (16:4:1), rt, 2 h, 93%; (c)
excess complex 8, DMF, 55 °C, 2 h, 86%.

C. Thomas, H.-J. Knölker / Tetrahedron Letters 54 (2013) 591–593
593
11. (a) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89, 2755–2757; (b)
Plieninger, H.; Sirowej, H. Chem. Ber. 1971, 104, 2027–2029; (c) Inoue, S.;
Yamaguchi, R.; Saito, K.; Sato, K. Bull. Chem. Soc. Jpn. 1974, 47, 3098–3101; For a
review, see: (d) Billington, D. C. Chem. Soc. Rev. 1985, 14, 93–120.
12. Synthesis of carquinostatin A: (a) Knölker, H.-J.; Fröhner, W. Synlett 1997,
1108–1110; (b) Knölker, H.-J.; Reddy, K. R. Synlett 1999, 596–598; (c) Knölker,
H.-J.; Baum, E.; Reddy, K. R. Tetrahedron Lett. 2000, 41, 1171–1174; (d) Fröhner,
W.; Reddy, K. R.; Knölker, H.-J. Heterocycles 2007, 74, 895–912.
10.48 (s, 1H), 11.25 (br s, 1H); 13C NMR (125 MHz, acetone-d6): d = 56.45 (CH3),
105.83 (CH), 112.97 (CH), 116.44 (C), 121.09 (CH), 123.19 (C), 123.58 (CH),
124.37 (C), 126.49 (C), 127.80 (CH), 135.89 (C), 141.40 (C), 146.38 (C), 191.03
(CHO).
16. Ekeberginine (1): Colorless crystals, mp: 227.5–229 °C (Ref. 3: 230–231 °C); UV
(MeOH): kmax = 224, 240, 251, 274, 287, 344 nm; IR (ATR):
m = 3141, 3089,
2995, 2959, 2910, 2850, 1699, 1642, 1607, 1580, 1501, 1488, 1462, 1425, 1372,
1333, 1302, 1262, 1216, 1180, 1150, 1116, 1079, 1015, 965, 922, 850, 798, 728,
13. Synthesis of neocarazostatin B: (a) Knölker, H.-J.; Fröhner, W.; Wagner, A.
Tetrahedron Lett. 1998, 39, 2947–2950; (b) Czerwonka, R.; Reddy, K. R.; Baum,
E.; Knölker, H.-J. Chem. Commun. 2006, 711–713.
655, 597, 553 cmÀ1 1H NMR (500 MHz, CDCl3): d = 1.71 (d, J = 1.3 Hz, 3H), 1.91
;
(s, 3H), 4.05 (s, 3H), 4.32 (d, J = 6.0 Hz, 2H), 5.33 (m, 1H), 7.31 (ddd, J = 8.0, 7.1,
1.1 Hz, 1H), 7.47 (dt, J = 1.0, 8.1 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H),
8.15 (d, J = 8.0 Hz, 1H), 8.63 (br s, 1H), 10.46 (s, 1H); 13C NMR (125 MHz,
CDCl3): d = 18.52 (CH3), 25.79 (CH3), 26.97 (CH2), 55.91 (CH3), 104.76 (CH),
111.56 (CH), 120.84 (CH), 122.42 (CH), 122.71 (C), 123.18 (CH), 123.96 (C),
126.08 (CH), 126.59 (C), 132.94 (C), 134.36 (C), 136.75 (C), 139.61 (C), 144.22
(C), 190.68 (CHO); MS (EI): m/z (%) = 293 (100, M+), 278 (34), 264 (13), 250
(45), 237 (39), 235 (14), 209 (99); HRMS: m/z calcd for C19H19NO2: 293.1416,
found: 293.1406.
14. Synthesis of lavanduquinocin: (a) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett.
1998, 39, 2537–2540; (b) Knölker, H.-J.; Baum, E.; Reddy, K. R. Chirality 2000,
12, 526–528; (c) Fröhner, W.; Kethiri, K. R.; Knölker, H.-J. Arkivoc 2012, iii, 330–
342.
15. 4-Bromomurrayanine (4): Light brown crystals, mp: 231–232 °C; 1H NMR
(500 MHz, acetone-d6): d = 4.10 (s, 3H), 7.36 (dt, J = 0.9, 8.1 Hz, 1H), 7.47 (s,
1H), 7.56 (dt, J = 1.0, 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 8.81 (d, J = 8.1 Hz, 1H),