Transition Metal Complexes in Organic Synthesis, Part 71:1 First Total Synthesis of Furoclausine-A

Article abstract of DOI:10.1055/s-2004-815417

The first total synthesis of the furo[3,2-a]carbazole alkaloid furoclausine-A is described using an iron-mediated construction of the carbazole framework and an acid-catalyzed annulation of the furan ring as key steps.

Full text of DOI:10.1055/s-2004-815417

528
LETTER
Transition Metal Complexes in Organic Synthesis, Part 71:1 First Total
Synthesis of Furoclausine-A
First
Total
S
ynthes
a
is of Furoc
n
lausine-A s-Joachim Knölker,* Micha P. Krahl
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@chemie.tu-dresden.de
Received 28 October 2003
(1) based on a palladium-catalyzed cross-coupling and
subsequent regioselective insertion of a nitrene.11 More
recently, Yasuhara has described the fifth approach via an
oxidative photocyclization of 3-(indol-2-yl)-2-(isopro-
penyl)furan.12 Total syntheses of the other furocarbazole
alkaloids have not been reported yet.
Abstract: The first total synthesis of the furo[3,2-a]carbazole alka-
loid furoclausine-A is described using an iron-mediated construc-
tion of the carbazole framework and an acid-catalyzed annulation of
the furan ring as key steps.
Key words: alkaloids, cyclizations, furans, iron, oxidations
Until now only four members of the relatively young class
of furocarbazole alkaloids (1–4) have been discovered
(Figure 1).1–5 In 1990, Furukawa described the isolation
and structural elucidation of furostifoline (1) and eustifo-
line-D (2).6 Both alkaloids were obtained from the root
bark of Murraya euchrestifolia, a shrub growing in
Taiwan. Seven years later, Wu isolated furoclausine-A (3)
and furoclausine-B (4) from the acetone extract of the root
bark of Clausena excavata.7
O
Me
O
Me
N
H
N
H
Figure 2 Clausena excavata (courtesy of Professor Pei-Fen Lee,
National Taiwan University, Taipei, Nature Conservation Network)
Furostifoline (1)
Eustifoline-D (2)
In the present paper, we describe the first total synthesis
of furoclausine-A (3). Using the iron-mediated oxidative
coupling of arylamines and cyclohexadienes a wide range
of biologically active carbazole alkaloids has been synthe-
sized previously.13 However, this method was not utilized
for the total synthesis of a 7-oxygenated carbazole natural
product, as present in furoclausine-A (3). Such a substitu-
tion pattern requires a 2-methoxy-substituted tricarbon-
yl(h5-cyclohexadienyl)iron cation as a building block.
Our approach to furoclausine-A (3) envisaged the iron-
mediated formation of the carbazole skeleton followed by
an acid-catalyzed annulation of the furan ring as key steps.
The retrosynthetic analysis of furoclausine-A (3) based on
this strategy leads to 1-methoxycyclohexa-1,4-diene (5)
and the arylamine 6 as precursors (Scheme 1).
CHO
CHO
O
HO
O
HO
N
H
N
H
OH
Furoclausine-A (3)
Furoclausine-B (4)
Figure 1 Furocarbazole alkaloids
The extracts of the plant Clausena excavata are used in
traditional folk medicine in China for the treatment of var-
ious infections and poisonous snakebites (Figure 2). Be-
cause of their pharmacological potential the furocarbazole
alkaloids have attracted a lot of interest among synthetic
chemists.8–12 The first total synthesis of furostifoline (1)
was described by us in 1996, by an iron-mediated con-
struction of the carbazole framework.8 Two years later,
Hibino and Beccalli reported two further total syntheses
using an electrocyclic ring closure reaction as key step.9,10
In 1999, Timári developed a novel route to furostifoline
Alkylation of commercial 2-methyl-5-nitrophenol (7)
with 2-bromo-1,1-diethoxyethane to compound 8 and
subsequent catalytic hydrogenation using palladium on
activated carbon afforded the arylamine 6 (Scheme 2).
Tricarbonyl(h5-2-methoxycyclohexadienylium)iron tet-
rafluoroborate (9) is readily prepared on a large scale by
the azadiene-catalyzed complexation of 1-methoxycyclo-
hexa-1,4-diene (5),14 followed by hydride abstraction and
hydrolytic separation of the 1-methoxy and 2-methoxy re-
SYNLETT 2004, No. 3, pp 0528–0530
Advanced online publication: 12.01.2004
DOI: 10.1055/s-2004-815417; Art ID: G29203ST
© Georg Thieme Verlag Stuttgart · New York
1
8.
0
2.
2
0
0
4

LETTER
First Total Synthesis of Furoclausine-A
529
CHO
O
gioisomers.15 Electrophilic substitution of the arylamine 6
by reaction with the iron complex salt 9 led regioselec-
tively to the iron complex 10.16 Oxidative cyclization of
complex 10 using iodine in pyridine provided the carba-
zole 11.16,17 The annulation of the furan ring, by heating
the carbazole 11 with catalytic amounts of amberlyst 15 in
chlorobenzene at 120 °C,18,19 afforded 8-methoxy-4-me-
thyl-10H-furo[3,2-a]carbazole (12).16 Oxidation of 12
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
gave O-methylfuroclausine-A (13).16 Finally, cleavage of
the methyl ether using BBr3 provided furoclausine-A (3)
(Scheme 3).20
[Fe(CO)3]
HO
N
H
Furoclausine-A (3)
Me
O
+
OEt
OEt
Scheme 1 Retrosynthetic analysis of furoclausine-A (3)
MeO
H2N
5
6
In conclusion, a convergent five-step synthesis leading to
furoclausine-A (3) in 9% overall yield has been devel-
oped. We obtained furoclausine-A (3) as crystals (decom-
position 110 °C),20 whereas the natural product was
described as an oil.7 All spectral data (UV, IR, 1H NMR,
13C NMR, and MS) of our synthetic furoclausine-A (3)20
are in good agreement with those reported for the natural
product.7 The method described above can be used to pro-
vide access to furoclausine-A and a variety of structural
analogues in sufficient quantities for biological screening.
Me
Me
OEt
OEt
OH
O
BrCH2CH(OEt)2
K2CO3, DMF, 153°C
81%
NO2
NO2
7
8
Me
OEt
OEt
O
H2, Pd/C
Acknowledgment
MeOH, 25°C
99%
This work was supported by the Fonds der Chemischen Industrie.
We thank the BASF AG, Ludwigshafen, for a gift of penta-
carbonyliron.
NH2
6
Scheme 2 Synthesis of the arylamine 6
References
(1) Part 70: Knölker, H.-J. Curr. Org. Synthesis 2004, 1, in print.
(2) Chakraborty, D. P. In The Alkaloids, Vol. 44; Cordell, G. A.,
Ed.; Academic Press: New York, 1993, 257.
MeO
Me
OEt
OEt
+
Fe(CO)3
O
(OC)3Fe
iodine, pyridine
Me
MeO
MeCN
+
25 °C, 23 h
87%
air, 90 °C, 6 h
OEt
BF4
H2N
10
O
71%
NH2
OEt
9
6
Me
Me
O
O
Et
amberlyst 15, PhCl
DDQ, MeOH/H2O
O
MeO
MeO
O
120 °C, 20 h
82%
25 °C, 55 min
43%
Et
N
H
N
H
11
12
CHO
O
CHO
O
2 equiv. BBr3, CH2Cl2
MeO
HO
–78 °C to –20 °C, 3 d
41%
N
H
N
H
13
Furoclausine-A (3)
Scheme 3 Iron-mediated total synthesis of furoclausine-A (3)
Synlett 2004, No. 3, 528–530 © Thieme Stuttgart · New York

530
H.-J. Knölker, M. P. Krahl
LETTER
(3) Kirsch, G. H. Curr. Org. Chem. 2001, 5, 507.
(4) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(5) Chakraborty, D. P.; Roy, S. In Prog. Chem. Org. Nat. Prod.,
Vol. 85; Herz, W.; Grisebach, H.; Kirby, G. W.; Steglich,
W.; Tamm, C., Eds.; Springer: Wien, 2003, 125.
(6) Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1990, 38, 1548.
(7) Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Heterocycles 1997, 45,
969.
(8) (a) Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1996, 37,
9183. (b) Knölker, H.-J.; Fröhner, W. Synthesis 2000, 2131.
(9) (a) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.;
Hibino, S. Chem. Pharm. Bull. 1998, 46, 1948.
(b) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.;
Hibino, S. Chem. Pharm. Bull. 2001, 49, 881.
(10) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron
1998, 54, 11675.
(11) Soós, T.; Timári, G.; Hajós, G. Tetrahedron Lett. 1999, 40,
8607.
(12) Yasuhara, A.; Suzuki, N.; Sakamoto, T. Chem. Pharm. Bull.
2002, 50, 143.
12: 13C NMR (125 MHz, CDCl3): d = 15.42 (CH3), 55.67
(CH3), 95.18 (CH), 103.54 (CH), 108.12 (CH), 111.37 (C),
114.11 (C), 116.06 (CH), 117.94 (C), 118.00 (C), 120.16
(CH), 130.69 (C), 140.01 (C), 143.72 (CH), 153.35 (C),
157.96 (C). Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21;
N, 5.57. Found: C, 76.27; H, 5.31; N, 5.74.
O-Methylfuroclausine-A (13): 13C NMR (125 MHz,
acetone-d6): d = 55.82 (CH3), 96.40 (CH), 104.73 (CH),
110.14 (CH), 113.56 (C), 116.30 (C), 118.31 (C), 119.11
(C), 120.11 (CH), 121.58 (CH), 137.80 (C), 142.31 (C),
146.06 (CH), 154.11 (C), 159.99 (C), 187.79 (CHO). Anal.
Calcd for C16H11NO3: 72.45; H, 4.18; N, 5.28. Found: C,
72.31; H, 4.20; N, 5.49.
(17) Experimental Procedure for the Oxidative Cyclization to
the Carbazole 11: Iodine (1.18 g, 4.65 mmol) was added to
a solution of the iron complex 10 (713 mg, 1.46 mmol) in
anhyd pyridine (20 mL) at 90 °C. After stirring for 6 h at 90
°C in the air, the reaction mixture was cooled to r.t., a
solution of sodium thiosulfate (2.4 g) and citric acid (1.3 g)
in water (24 mL) was added, and the resulting mixture was
extracted with Et2O several times. The combined organic
layers were washed with water (3 × 30 mL) and dried over
MgSO4. Removal of the solvent and purification of the
residue by flash chromatography (EtOAc–hexane, 1:1) on
silica gel provided the carbazole 11 as colorless crystals;
yield: 356 mg (71%); mp: 195–196 °C.
(13) (a) Knölker, H.-J. Synlett 1992, 371. (b) Knölker, H.-J. In
Transition Metals for Organic Synthesis, Vol. 1; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, 534.
(c) Knölker, H.-J. Chem. Soc. Rev. 1999, 28, 151.
(14) (a) Knölker, H.-J.; Ahrens, B.; Gonser, P.; Heininger, M.;
Jones, P. G. Tetrahedron 2000, 56, 2259. (b) Knölker, H.-J.
Chem. Rev. 2000, 100, 2941.
(18) Röhrkasten, R.; Konrad, M. In Methoden der Organischen
Chemie (Houben-Weyl), Vol. E6b; Kreher, R. P., Ed.;
Thieme: Stuttgart, 1994, 94.
(15) Birch, A. J.; Cross, P. E.; Lewis, J.; White, D. A.; Wild, S.
B. J. Chem. Soc. A 1968, 332.
(16) All new compounds have been fully characterized (UV, IR,
1H NMR, 13C NMR, MS, and elemental analysis).
13C NMR and DEPT spectral data, and elemental analyses.
10: 13C NMR (125 MHz, CDCl3): d = 15.34 (2 × CH3), 15.57
(CH3), 32.62 (CH2), 37.58 (CH), 53.10 (CH), 54.01 (CH),
54.39 (CH3), 62.70 (2 × CH2), 66.98 (CH), 68.99 (CH2),
100.14 (CH), 100.73 (CH), 116.93 (C), 122.74 (C), 128.50
(CH), 139.93 (C), 142.10 (C), 155.53 (C), 211.25 (3 × CO).
Anal. Calcd for C23H29FeNO7: C, 56.69; H, 6.00; N, 2.87.
Found: C, 56.77; H, 6.12; N, 2.91.
(19) Amberlyst 15 from Fluka (art. 06423).
(20) Furoclausine-A (3): Light yellow crystals; mp: 110 °C
(dec.). IR (ATR): n = 3302, 1703, 1670, 1619, 1590, 1444,
1350, 1325, 1302, 1276, 1258, 1228, 1165, 1149, 1114,
1070, 1040, 993, 956, 856, 830, 810, 799, 775, 750, 730,
686, 629, 591, 549 cm–1. 1H NMR (500 MHz, acetone-d6): d
= 6.92 (dd, J = 8.4, 2.1 Hz, 1 H), 7.09 (d, J = 2.1 Hz, 1 H),
7.32 (d, J = 2.2 Hz, 1 H), 8.05 (d, J = 2.2 Hz, 1 H), 8.10 (d,
J = 8.4 Hz, 1 H), 8.51 (s, 1 H), 8.54 (s, 1 H), 10.47 (s, 1 H),
11.16 (br s, 1 H). 13C NMR (125 MHz, acetone-d6): d = 98.22
(CH), 104.67 (CH), 110.73 (CH), 113.43 (C), 116.16 (C),
117.64 (C), 119.36 (C), 119.85 (CH), 121.62 (CH), 137.75
(C), 142.57 (C), 146.02 (CH), 154.09 (C), 157.49 (C),
187.75 (CHO). UV (MeOH): l = 220, 235, 287(sh), 300, 345
nm. MS (150 °C): m/z (%) = 251(100) [M+], 250 (74), 222
(26), 194 (11), 139 (3). HRMS: m/z [M+] calcd for
C15H9NO3: 251.0582; found: 251.0568.
11: 13C NMR (75 MHz, CDCl3): d = 15.39 (2 × CH3), 16.68
(CH3), 55.64 (CH3), 62.92 (2 × CH2), 69.36 (CH2), 93.81
(CH), 94.90 (CH), 100.90 (CH), 107.68 (CH), 116.75 (C),
117.41 (C), 119.37 (C), 119.98 (CH), 120.82 (CH), 138.89
(C), 140.56 (C), 155.33 (C), 157.95 (C). Anal. Calcd for
C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 70.03; H,
7.48; N, 4.15.
Synlett 2004, No. 3, 528–530 © Thieme Stuttgart · New York