Transition metals in organic synthesis, Part 95: First total synthesis of the 1,7-dioxygenated carbazole alkaloids clausine Q and clausine R

Article abstract of DOI:10.1055/s-0030-1260972

The sequence of palladium(0)-catalyzed amination and palladium(II)- catalyzed oxidative formation of the biaryl bond provides a direct route to the 1,7-dioxygenated tricyclic carbazole alkaloids clausine Q and clausine R. Georg Thieme Verlag Stuttgart - N

Full text of DOI:10.1055/s-0030-1260972

2056
LETTER
Transition Metals in Organic Synthesis, Part 95:1 First Total Synthesis of the
1,7-Dioxygenated Carbazole Alkaloids Clausine Q and Clausine R
First
Total
Synthesis
o
ü
f
the
A
lkaloi
g
ds Clausine
Q
e
a
nd Clausine
RFuchsenberger, Ronny Forke, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received 6 June 2011
bazoles.11 The aniline 6 served as synthetic precursor for
Abstract: The sequence of palladium(0)-catalyzed amination and
palladium(II)-catalyzed oxidative formation of the biaryl bond pro-
vides a direct route to the 1,7-dioxygenated tricyclic carbazole alka-
loids clausine Q and clausine R.
1,6-dioxygenated carbazoles.9
Palladium(0)-catalyzed coupling of aryl bromide 5 and
aniline 6 afforded the N,N-diarylamine 7 (Scheme 2).13
Using optimized conditions [5 mol% of palladium(II)
acetate in pivalic acid at 130 °C under air],4,11,14,15 the ox-
idative cyclization of 7 provided the carbazole 8 in up to
85% yield.
Key words: alkaloids, catalysis, cyclization, oxidation, palladium
Carbazole alkaloids have attracted a lot of recent interest
because of their large structural variety and promising bi-
ological activities.1–4 3-Methylcarbazole (1), isolated
from Clausena heptaphylla, Clausena indica and Clause-
na anisata, has been recognized as parent compound for
the biogenesis of carbazole alkaloids in terrestrial plants
(Figure 1).3 Oxygenation at the different positions of the
carbazole nucleus, oxidation of the methyl group, preny-
lation (or geranylation) and annulation of further rings oc-
cur in vivo further downstream on the biogenetic
pathway. These transformations provide the structural va-
riety observed for naturally occurring carbazole alkaloids.
For example, the 1,6-dioxygenated carbazole alkaloid 6-
methoxymurrayanine (2) was isolated from the roots of
Clausena lansium (El-Feraly et al., 1991).5 The 1,7-di-
oxygenated carbazole alkaloids clausine Q (3) and
clausine R (4) were extracted from the root bark of
Clausena excavata (Wu et al., 1999).6 We have developed
an efficient access to carbazoles by Buchwald–Hartwig
amination and subsequent palladium(II)-catalyzed oxida-
tive cyclization generating the biaryl bond via double C–
H bond activation.2 This methodology has been success-
fully applied to the total synthesis of 6-oxygenated,7 7-
oxygenated,8 1,6-dioxygenated,9 2,6-dioxygenated,10 and
2,7-dioxygenated tricyclic carbazole alkaloids.11 Alterna-
tively, 2,7-dioxygenated carbazole alkaloids have been
prepared using our iron-mediated approach.12 Herein, we
report the first total synthesis of the 1,7-dioxygenated car-
bazole alkaloids clausine Q (3) and clausine R (4) using
our palladium-catalyzed approach.
Me
MeO
CHO
N
H
N
H
OMe
3-methylcarbazole (1)
6-methoxymurrayanine (2)
CHO
COOMe
HO
HO
N
H
N
H
OMe
OH
clausine Q (3)
clausine R (4)
Figure 1 Some carbazole alkaloids isolated from different plants of
the genus Clausena (family: Rutaceae)
R2
COOMe
[Pd]
(i-Pr)3SiO
+
HO
H2N
Br
N
H
OR1
OMe
5
R1 R2
clausine Q (3) Me CHO
clausine R (4) COOMe
6
H
Scheme 1 Retrosynthetic analysis of clausine Q (3) and clausine R
(4)
Retrosynthetic analysis of clausine Q (3) and clausine R
(4) suggests the 3-bromophenyl triisopropylsilyl ether (5)
and methyl 4-amino-3-methoxybenzoate (6) as precursors
(Scheme 1). The aryl bromide 5 has already been used as
building block for the synthesis of 2,7-dioxygenated car-
Transformation of intermediate 8 into clausine Q (3) was
achieved in three steps: 1) reduction to the corresponding
benzylic alcohol using diisobutylaluminum hydride (92%
yield),16 2) oxidation to aldehyde 9 with manganese diox-
ide (95% yield),17 and 3) removal of the triisopropylsilyl
protecting group using tetrabutylammonium fluoride
(99% yield). This three-step transformation was improved
to 92% overall yield by using the crude products of the
first two reactions for the subsequent conversions and fi-
nal purification by flash chromatography on silica gel
SYNLETT 2011, No. 14, pp 2056–2058
x
x
.x
x
.2
0
1
1
Advanced online publication: 25.07.2011
DOI: 10.1055/s-0030-1260972; Art ID: D17111ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Total Synthesis of the Alkaloids Clausine Q and Clausine R
2057
Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim,
2008, 475. (e) Knölker, H.-J. Chem. Lett. 2009, 38, 8.
(3) Knölker, H.-J.; Reddy, K. R. In The Alkaloids, Vol. 65;
Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008, 1.
(4) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.; Fujii,
N.; Ohno, H. Chem. Commun. 2007, 4516. (c) Liégault, B.;
Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022.
(5) Li, W.-S.; McChesney, J. D.; El-Feraly, F. S.
Phytochemistry 1991, 30, 343.
(6) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Kuoh, C.-S.
Phytochemistry 1999, 52, 523.
COOMe
a
COOMe
+
RO
Br
H2N
RO
N
H
OMe
OMe
5 R = Si(i-Pr)3
6
7
COOMe
c,d
CHO
OMe
b
RO
RO
N
H
8
N
H
9
OMe
(7) Forke, R.; Krahl, M. P.; Krause, T.; Schlechtingen, G.;
Knölker, H.-J. Synlett 2007, 268.
(8) Krahl, M. P.; Jäger, A.; Krause, T.; Knölker, H.-J. Org.
f
e
Biomol. Chem. 2006, 4, 3215.
CHO
OMe
COOMe
(9) Börger, C.; Knölker, H.-J. Synlett 2008, 1698.
(10) Schmidt, M.; Knölker, H.-J. Synlett 2009, 2421.
(11) Forke, R.; Krahl, M. P.; Däbritz, F.; Jäger, A.; Knölker,
H.-J. Synlett 2008, 1870.
(12) Kataeva, O.; Krahl, M. P.; Knölker, H.-J. Org. Biomol.
Chem. 2005, 3, 3099.
HO
HO
N
H
N
H
4
OH
3
(13) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131.
Scheme 2 Synthesis of clausine Q (3) and clausine R (4). Reagents
and conditions: (a) 5 (1.2 equiv), Pd(OAc)2 (5 mol%), S-Phos (10
mol%), Cs2CO3 (1.5 equiv), toluene, 100 °C, 19.5 h (94%); (b)
Pd(OAc)2 (5 mol%), K2CO3 (10 mol%), PivOH, 130 °C, air, 25.5 h
(85%); (c) DIBAL-H (2.3 equiv), Et2O, –78 °C, 2 h (92%); (d) MnO2
(12 equiv), CH2Cl2, r.t., 7.5 h (95%); (e) TBAF (1.5 equiv), THF,
–15 °C to r.t., 10 min (99%); (f) BBr3 (10 equiv), CH2Cl2, –78 °C to
–30 °C, 22 h (72%).
(14) (a) Åkermark, B.; Eberson, L.; Jonsson, E.; Petersson, E.
J. Org. Chem. 1975, 40, 1365. (b) Miller, R. B.; Moock, T.
Tetrahedron Lett. 1980, 21, 3319. (c) Furukawa, H.; Ito, C.;
Yogo, M.; Wu, T.-S. Chem. Pharm. Bull. 1986, 34, 2672.
(d) Knölker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50,
10893. (e) Knölker, H.-J.; Fröhner, W.; Reddy, K. R.
Synthesis 2002, 557. (f) Knölker, H.-J.; Reddy, K. R.
Heterocycles 2003, 60, 1049.
with gradient elution (pentane–ethyl acetate, 3:1 to 1:1).
Treatment of compound 8 with boron tribromide at low
temperature (–78 °C to –30 °C) leads to cleavage of the
triisopropylsilyl and the methyl ether and generates di-
rectly clausine R (4) in 72% yield. Thus, starting from the
commercially available compounds 5 and 6, clausine Q
(3) has been obtained in five steps and 74% overall yield
and clausine R (4) in three steps and 58% overall yield.
The spectroscopic data of both compounds are in full
agreement with those reported by Wu et al. for the natural
products.6 However, the melting points we found for
clausine Q (3) and clausine R (4) are more than 100 °C
higher than those reported.18
(15) Experimental Procedure for the Palladium(II)-
Catalyzed Oxidative Cyclization of 7: The N,N-
diarylamine 7 (301 mg, 0.7 mmol), K2CO3 (9.8 mg, 0.07
mmol), and pivalic acid (680 mg) were heated under air at
130 °C. Freshly recrystallized Pd(OAc)2 (8.0 mg, 0.036
mmol) was added and the reaction mixture was heated under
air at 130 °C with vigorous stirring. After cooling to r.t., the
mixture was taken up in EtOAc and washed first with a sat.
solution of K2CO3 and then with a sat. solution of NaCl. The
aqueous layers were subsequently extracted with EtOAc.
The combined organic layers were dried over Na2SO4 and
the solvent was removed in vacuum. Purification of the
crude product by flash chromatography (pentane–CH2Cl2–
EtOAc, gradient elution from 55:5:1 to 25:5:1) on silica
gel provided methyl 7-triisopropylsilyloxy-1-methoxy-
carbazole-3-carboxylate (8; yield: 255 mg, 85%) as colorless
crystals (mp 164–165 °C). UV (MeOH): lmax = 216, 239,
250, 278 (sh), 283, 305 (sh), 318, 330 nm. IR (ATR): 3351,
2941, 2864, 1685, 1609, 1590, 1504, 1457, 1430, 1396,
1346, 1258, 1218, 1163, 1107, 1035, 997, 968, 921, 881,
851, 839, 823, 800, 754, 707, 672, 623 cm–1. 1H NMR (500
MHz, CDCl3): d = 1.13 (d, J = 7.4 Hz, 18 H), 1.31 (sept, J =
7.4 Hz, 3 H), 3.97 (s, 3 H), 4.04 (s, 3 H), 6.86 (dd, J = 8.5,
2.1 Hz, 1 H), 6.96 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 1.2 Hz, 1
H), 7.89 (d, J = 8.5 Hz, 1 H), 8.31 (br s, 1 H), 8.36 (br s, 1
H). 13C NMR and DEPT (125 MHz, CDCl3): d = 12.71 (3 ×
CH), 17.95 (6 × Me), 51.98 (Me), 55.72 (Me), 101.84 (CH),
105.93 (CH), 114.11 (CH), 115.47 (CH), 117.91 (C), 121.17
(CH), 121.89 (C), 123.85 (C), 132.85 (C), 140.79 (C),
144.84 (C), 155.58 (C), 168.04 (C=O). MS (EI): m/z (%) =
427 (100) [M+], 396 (8), 385 (21), 384 (71), 356 (23), 352
(42), 328 (17), 314 (15), 296 (9), 282 (19). Anal. Calcd for
In conclusion, we have developed a highly efficient syn-
thesis of 1,7-dioxygenated tricyclic carbazole alkaloids
using a sequence of palladium(0)-catalyzed amination
and palladium(II)-catalyzed oxidative cyclization by dou-
ble C–H bond activation. The method has been applied to
the first total synthesis of clausine Q and clausine R which
may be of interest due to their potential anti-TB activity.19
References and Notes
(1) Part 94: Gruner, K. K.; Hopfmann, T.; Matsumoto, K.; Jäger,
A.; Katsuki, T.; Knölker, H.-J. Org. Biomol. Chem. 2011, 9,
2057.
(2) For reviews, see: (a) Knölker, H.-J.; Reddy, K. R. Chem.
Rev. 2002, 102, 4303. (b) Knölker, H.-J. Curr. Org. Synth.
2004, 1, 309. (c) Knölker, H.-J. Top. Curr. Chem. 2005,
244, 115. (d) Knölker, H.-J. In Modern Alkaloids:
Structure, Isolation, Synthesis and Biology; Fattorusso, E.;
Synlett 2011, No. 14, 2056–2058 © Thieme Stuttgart · New York

2058
M. Fuchsenberger et al.
LETTER
C24H33NO4Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.30;
H, 7.94; N, 3.29.
(16) Winterfeldt, E. Synthesis 1975, 617.
Clausine R (4): colorless crystals; mp 293–295 °C (lit.6 178–
181 °C). UV (MeOH): lmax = 214, 240, 251, 282, 305 (sh),
319, 333 nm. IR (ATR): 3439, 3355, 3303, 3011, 2956,
2923, 2852, 1658, 1644, 1631, 1618, 1594, 1490, 1456,
1435, 1390, 1360, 1334, 1311, 1268, 1233, 1169, 1087, 995,
963, 925, 882, 824, 798, 767, 751 cm–1. 1H NMR (500 MHz,
acetone-d6): d = 3.87 (s, 3 H), 6.81 (dd, J = 8.5, 2.1 Hz, 1 H),
7.04 (d, J = 2.1 Hz, 1 H), 7.50 (d, J = 1.1 Hz, 1 H), 7.97 (d,
J = 8.5 Hz, 1 H), 8.24 (d, J = 1.1 Hz, 1 H), 8.47 (s, 1 H), 8.95
(s, 1 H), 10.38 (br s, 1 H). 13C NMR and DEPT (125 MHz,
acetone-d6): d = 51.83 (Me), 98.01 (CH), 110.21 (CH),
110.49 (CH), 114.38 (CH), 117.51 (C), 121.95 (CH), 122.32
(C), 125.46 (C), 133.41 (C), 142.87 (C), 143.01 (C), 157.91
(C), 168.05 (C=O). MS (EI): m/z (%) = 257 (100) [M+], 226
(67), 198 (28), 170 (14). Anal. Calcd for C14H11NO4: C,
65.37; H, 4.31; N, 5.44. Found: C, 65.24; H, 4.95; N, 5.03.
(19) (a) Choi, T. A.; Czerwonka, R.; Fröhner, W.; Krahl, M. P.;
Reddy, K. R.; Franzblau, S. G.; Knölker, H.-J.
(17) Manganese dioxide (precipitated, active) from Merck (art.
805958).
(18) Characteristic Spectroscopic Data of the 1,7-Dioxy-
genated Carbazole Alkaloids 3 and 4: Clausine Q (3):
colorless crystals; mp 189–191 °C (lit.6 85–87 °C). UV
(MeOH): lmax = 202, 242, 285, 295 (sh), 338 nm. IR (ATR):
3438, 3236, 2930, 2844, 1641, 1609, 1570, 1542, 1484,
1368, 1342, 1298, 1241, 1218, 1155, 1131, 1104, 1030, 954,
881, 829, 810, 780, 704, 666 cm–1. 1H NMR (500 MHz,
acetone-d6): d = 4.07 (s, 3 H), 6.85 (dd, J = 8.5, 2.1 Hz, 1 H),
7.08 (d, J = 2.1 Hz, 1 H), 7.39 (d, J = 1.0 Hz, 1 H), 8.01 (d,
J = 8.5 Hz, 1 H), 8.21 (d, J = 1.0 Hz, 1 H), 8.57 (br s, 1 H),
10.02 (s, 1 H), 10.69 (br s, 1 H). 13C NMR and DEPT (125
MHz, acetone-d6): d = 56.01 (Me), 98.25 (CH), 103.37
(CH), 110.82 (CH), 117.35 (C), 119.25 (CH), 122.09 (CH),
125.04 (C), 131.03 (C), 134.74 (C), 142.92 (C), 146.89 (C),
158.09 (C), 191.87 (CHO). MS (EI): m/z (%) = 241 (100)
[M+], 240 (20), 226 (28), 212 (10), 198 (12), 170 (44). Anal.
Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C,
69.20; H, 4.35; N, 5.27.
ChemMedChem 2006, 1, 812. (b) Choi, T. A.; Czerwonka,
R.; Forke, R.; Jäger, A.; Knöll, J.; Krahl, M. P.; Krause, T.;
Reddy, K. R.; Franzblau, S. G.; Knölker, H.-J. Med. Chem.
Res. 2008, 17, 374.
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