Transition metals in organic synthesis, part 91:1 palladium-catalyzed approach to 2,6-dioxygenated carbazole alkaloids - First total synthesis of the phytoalexin carbalexin C

Article abstract of DOI:10.1055/s-0029-1217810

The palladium(0)-catalyzed C-N bond formation and palladium(II)-catalyzed oxidative cyclization provide an efficient route to a series of 2,6-dioxygenated carbazole alkaloids including the first total synthesis of the phytoalexin carbalexin C.

Full text of DOI:10.1055/s-0029-1217810

LETTER
2421
Transition Metals in Organic Synthesis, Part 91:1 Palladium-Catalyzed
Approach to 2,6-Dioxygenated Carbazole Alkaloids – First Total Synthesis
of the Phytoalexin Carbalexin C
Synthesis of the
Phytoa
ralexin Cika Schmidt, 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 5 June 2009
Herein, we describe an efficient palladium-catalyzed
route to 2,6-dioxygenated carbazole alkaloids including
the first total synthesis of the phytoalexin carbalexin C (4).
Abstract: The palladium(0)-catalyzed C–N bond formation and
palladium(II)-catalyzed oxidative cyclization provide an efficient
route to a series of 2,6-dioxygenated carbazole alkaloids including
the first total synthesis of the phytoalexin carbalexin C.
Glycozolidine (1, Figure 1), the first 2,6-dioxygenated
Key words: alkaloids, antibiotics, catalysis, cyclization, palladium carbazole from natural sources, was isolated by
Chakraborty et al. from the root bark of Glycosmis penta-
phylla (Rutaceae) in 1966.11 In traditional folk medicine,
extracts of this plant are used for the treatment of fever.
Glycozolidal (2) and glycozolidol (3) have been obtained
much later from the same natural source by Bhattacharyya
et al.12,13 Glycozolidine (1) was also isolated from the
roots of Glycosmis arborea by Chakravarty et al.14 In
2001, Greger et al. observed that wounding, UV irradia-
tion, or treatment with the fungus Botrytis cinerea in-
duced the generation of a series of carbazole alkaloids in
the leaves of Glycosmis pentaphylla and Glycosmis parvi-
flora.15 Among these stress-induced carbazole phytoalex-
ins were the novel carbalexins, for example, carbalexin C
(4). Lansine (5) was isolated by Kapil et al. from the
leaves of Clausena lansium.16 Moreover, glycozolidal (2)
and lansine (5) were obtained by Wu et al. from the stem
bark of the Chinese medicinal plant Clausena excavata.17
Carbazole alkaloids, especially those which are highly
substituted, are attracting a lot of interest because of their
broad range of useful biological activities.1–5 Their bio-
genesis in terrestrial plants starts from 3-methylcarbazole
as parent compound.2,3 Further biogenetic transformations
are oxygenation at different positions, oxidation of the
methyl group, prenylation, and annelation of additional
rings. The in vivo conversion leads to the large structural
variety found for naturally occurring carbazoles. Based on
the oxygenation pattern of tricyclic carbazole alkaloids,
we have introduced a novel classification system for these
natural products.3
MeO
R
HO
Me
OMe
OMe
Our interest in the natural products described above was
induced by the carbalexins, described as the first carba-
zole-containing phytoalexins,15 as well as the pharmaco-
logical potential of these compounds. In 2005, Franzblau
et al. isolated lansine (5) from Micromelum hirsutum and
found that it inhibits the growth of Mycobacterium tuber-
culosis (strain H37Rv).18 In a cooperation with the Franz-
blau group, we could identify several carbazoles with
promising anti-TB activity.19 Thus, we had a strong inter-
est to develop a general access to 2,6-dioxygenated carba-
zoles. A few individual syntheses of the natural products
N
H
N
H
glycozolidine (1) R = Me
glycozolidal (2) R = CHO
glycozolidol (3)
MeO
CHO
OH
MeO
Me
OH
N
H
N
H
carbalexin C (4)
lansine (5)
Figure 1 Naturally occurring 2,6-dioxygenated carbazole alkaloids 1–3 and also one synthesis of lansine (5) have been report-
ed.20 However, no synthesis has been reported so far for
carbalexin C (4). In the present paper, we describe a flex-
We have developed efficient routes to highly oxygenated
ible modular approach to the 2,6-dioxygenated carbazole
carbazoles which are sensitive to oxidation. Recently, we
alkaloids 1–5 using the palladium-catalyzed route devel-
have reported a short iron-mediated synthesis for 2,7-di-
oxygenated carbazole alkaloids.6 Our palladium-cata-
lyzed approach has been applied to the synthesis of 7-
oxygenated,7 6-oxygenated,8 1,6-dioxygenated,9 2-oxy-
genated, and 2,7-dioxygenated carbazole alkaloids.10
oped by our group.
Palladium(0)-catalyzed Buchwald–Hartwig coupling of
4-bromoanisole (6) and 3-methoxy-4-methylaniline (7)
afforded the diarylamine 8 (Scheme 1).21 The palladi-
um(II)-catalyzed oxidative cyclization to the carbazole
framework was achieved by reoxidation of palladium(0)
to palladium(II) with cupric acetate, using the reaction
conditions developed previously by our group.4d,7–10,22
SYNLETT 2009, No. 15, pp 2421–2424
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217810; Art ID: G16809ST
© Georg Thieme Verlag Stuttgart · New York

2422
M. Schmidt, H.-J. Knölker
LETTER
Thus, reaction of the diarylamine 8 in the presence of 10 For the synthesis of the phytoalexin carbalexin C (4) and
mol% of palladium(II) acetate and 2.5 equivalents of cu- lansine (5), we prepared the silyl-protected arylamine 13
pric acetate with microwave heating at 130 °C23 provided quantitatively in two steps from 2-methyl-5-nitrophenol.26
glycozolidine (1).24 Oxidation of 1 using 2,3-dichloro- Buchwald–Hartwig coupling of 4-bromoanisole (6) and
5,6-dicyano-1,4-benzoquinone (DDQ) led to glycozolidal arylamine 13 led to the diarylamine 14 (Scheme 3). Palla-
(2). Cleavage of both methyl ether groups of glycozoli- dium(II)-catalyzed cyclization of 14 provided the carba-
dine (1) afforded 2,3-dihydroxy-3-methylcarbazole (9), zole 15, a crucial precursor for both natural products.27
which was known by degradation of the natural prod- Desilylation of 15 using tetrabutylammonium fluoride
uct.11b,20a The spectroscopic data for the carbazole alka- (TBAF) afforded carbalexin C (4). Although, carbalexin
loids were in good agreement with those reported in the C (4) has been described as an oil,15 we obtained this com-
literature.24
pound in solid form (mp 187–191 °C).24 Oxidation of 15
with DDQ to the 3-formyl derivative 16 and subsequent
removal of the silyl group with TBAF provided lansine
(5).
MeO
Me
Me
MeO
a
+
N
H
OMe
H2N
OMe
Br
6
7
MeO
Me
8
Me
MeO
a
+
N
H
OTPS
MeO
Me
H2N
OTPS
MeO
CHO
Br
b
c
6
13
OMe
OMe
14
N
H
N
H
MeO
Me
MeO
Me
glycozolidine (1)
glycozolidal (2)
b
c
OTPS
OH
d
N
H
N
H
HO
Me
15
carbalexin C (4)
OH
d
N
H
9
MeO
CHO
MeO
CHO
OH
e
OTPS
Scheme 1 Palladium-catalyzed synthesis of glycozolidine (1) and
glycozolidal (2). Reagents and conditions: a) 7 (1.1 equiv), Pd(OAc)2
(6 mol%), BINAP (6 mol%), Cs2CO3 (1.2 equiv), toluene, 111 °C, 1
d, Ar (75%); b) Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.5 equiv), AcOH,
air, MW, 130 °C, 2 h (68%); c) DDQ (2.2 equiv), MeOH–THF–H2O
(10:3:1), r.t., 1.5 h (75%); d) BBr3 (2 equiv), CH2Cl2, –78 °C (30 min)
to 0 °C (1 h) to r.t. (20 h), Ar (99%).
N
H
N
H
16
lansine (5)
Scheme 3 Palladium-catalyzed synthesis of carbalexin C (4) and
lansine (5); TPS = tert-BuPh2Si. Reagents and conditions: a) 13 (1.1
equiv), Pd(OAc)2 (6 mol%), BINAP (6 mol%), Cs2CO3 (1.2 equiv),
toluene, 111 °C, 1 d, Ar (86%); b) Pd(OAc)2 (10 mol%), Cu(OAc)2
(2.5 equiv), AcOH, air, MW, 130 °C, 2 h (76%); c) TBAF (1.6 equiv),
DMF, 0 °C to r.t., 1 h, Ar (90%); d) DDQ (2.2 equiv), MeOH–THF–
H2O (10:3:1), r.t., 80 min (77%); e) TBAF (1.6 equiv), DMF, 0 °C to
r.t., 1 h, Ar (65%).
4-(Benzyloxybromo)benzene (10)25 was chosen as pre-
cursor for glycozolidol (3). Buchwald–Hartwig amination
of 10 with the arylamine 7 afforded the diarylamine 11
(Scheme 2). Palladium(II)-catalyzed oxidative cycliza-
tion of 11 to the carbazole 12 followed by cleavage of the
benzyl ether provided glycozolidol (3).24
In conclusion, we have developed an efficient access to
2,6-dioxygenated carbazole alkaloids using a sequence of
palladium(0)-catalyzed amination and palladium(II)-cata-
lyzed cyclization via double C–H bond activation. The
present work reports the first total synthesis of the novel
phytoalexin carbalexin C (4) in 5 steps and 59% overall
yield based on 2-methyl-5-nitrophenol.
BnO
Me
Me
BnO
a
+
N
H
OMe
H2N
OMe
Br
10
7
11
BnO
Me
HO
Me
References and Notes
b
c
OMe
OMe
(1) Part 90: Knott, K. E.; Auschill, S.; Jäger, A.; Knölker, H.-J.
Chem. Commun. 2009, 1467.
N
H
N
H
(2) (a) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry
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4303. (b) Knölker, H.-J.; Reddy, K. R. In The Alkaloids, Vol.
65; Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008, 1.
12
glycozolidol (3)
Scheme 2 Palladium-catalyzed synthesis of glycozolidol (3).
Reagents and conditions: a) 7 (1.1 equiv), Pd(OAc)2 (6 mol%),
BINAP (6 mol%), Cs2CO3 (1.2 equiv), toluene, 111 °C, 2 d, Ar
(83%); b) Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.5 equiv), AcOH, air,
MW, 130 °C, 3 h (60%); c) 10% Pd/C, H2, CH2Cl2–THF (1:2), r.t., 4
d (91%).
Synlett 2009, No. 15, 2421–2424 © Thieme Stuttgart · New York

LETTER
Synthesis of the Phytoalexin Carbalexin C
2423
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(24) Characteristic Spectroscopic Data of the 2,6-Dioxy-
genated Carbazole Alkaloids 1–5 and 9
Glycozolidine (1): light yellow solid; mp 158–161 °C. 1H
NMR (500 MHz, CDCl3): d = 2.35 (s, 3 H), 3.88 (s, 3 H),
3.91 (s, 3 H), 6.78 (s, 1 H), 6.95 (dd, J = 8.7, 2.5 Hz, 1 H),
7.23 (d, J = 8.7 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.70 (br
s, 1 H), 7.74 (s, 1 H). 13C NMR and DEPT (125 MHz,
CDCl3): d = 16.70 (CH3), 55.47 (CH3), 56.03 (CH3), 92.42
(CH), 102.51 (CH), 110.88 (CH), 112.95 (CH), 116.20 (C),
118.94 (C), 121.37 (CH), 123.98 (C), 134.13 (C), 140.00
(C), 153.84 (C), 157.42 (C). Anal. Calcd (%) for C15H15NO2:
C, 74.67; H, 6.27; N, 5.81. Found: C, 74.81; H, 6.33; N, 5.71.
Glycozolidal (2): yellow solid; mp 188–193 °C. 1H NMR
(500 MHz, CDCl3): d = 3.90 (s, 3 H), 3.98 (s, 3 H), 6.83 (s,
1 H), 7.00 (dd, J = 8.7, 2.5 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1
H), 7.49 (d, J = 2.5 Hz, 1 H), 8.12 (br s, 1 H), 8.52 (s, 1 H),
10.47 (s, 1 H). 13C NMR and DEPT (125 MHz, CDCl3):
d = 55.83 (CH3), 55.92 (CH3), 92.35 (CH), 103.14 (CH),
111.34 (CH), 114.64 (CH), 117.47 (C), 118.76 (C), 121.85
(CH), 124.34 (C), 134.42 (C), 145.51 (C), 154.84 (C),
161.51 (C), 189.44 (CHO). Anal. Calcd (%) for C15H13NO3:
C, 70.58; H, 5.13; N, 5.49. Found: C, 70.71; H, 5.29; N, 5.39.
2,6-Dihydroxy-3-methylcarbazole (9): colorless solid;
mp >250 °C (decomp.). 1H NMR (500 MHz, acetone-d6):
d = 2.35 (s, 3 H), 6.84 (dd, J = 8.5, 2.4 Hz, 1 H), 6.93 (s, 1
H), 7.23 (d, J = 8.5 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.70
(s, 1 H), 7.80 (br s, 1 H), 8.21 (br s, 1 H), 9.65 (br s, 1 H).
13C NMR and DEPT (125 MHz, acetone-d6): d = 16.65
(CH3), 96.84 (C), 96.89 (CH), 105.02 (CH), 111.40 (CH),
113.44 (CH), 116.90 (C), 122.08 (CH), 125.15 (C), 135.08
(C), 141.76 (C), 151.47 (C), 155.48 (C).
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Glycozolidol (3): yellow solid; mp 245–250 °C. 1H NMR
(500 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.82 (s, 3 H), 6.72
(dd, J = 8.5, 2.4 Hz, 1 H), 6.84 (s, 1 H), 7.16 (d, J = 8.5 Hz,
1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.65 (s, 1 H), 8.75 (br s, 1 H),
10.60 (br s, 1 H). 13C NMR and DEPT (125 MHz, DMSO-
d6): d = 16.62 (CH3), 55.24 (CH3), 92.51 (CH), 104.11 (CH),
110.83 (CH), 112.93 (CH), 115.18 (C), 116.56 (C), 121.08
(CH), 123.28 (C), 133.52 (C), 140.26 (C), 150.30 (C),
156.60 (C). Anal. Calcd (%) for C14H13NO2: C, 73.99; H,
5.77; N, 6.16. Found: C, 73.74; H, 5.89; N, 6.17.
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Heterocycles 1993, 36, 1483. (f) Bedford, R. B.; Betham,
M. J. Org. Chem. 2006, 71, 9403.
Carbalexin C (4): light yellow solid; mp 187–191 °C. 1H
NMR (500 MHz, CDCl3): d = 2.39 (s, 3 H), 3.90 (s, 3 H),
6.81 (s, 1 H), 6.94 (dd, J = 8.7, 2.5 Hz, 1 H), 7.24 (d, J = 8.7
Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.70 (br s, 1 H), 7.73 (s,
1 H), 7.89 (br s, 1 H). 13C NMR and DEPT (125 MHz,
CDCl3): d = 16.14 (CH3), 56.07 (CH3), 96.52 (CH), 102.71
(CH), 110.88 (CH), 113.20 (CH), 116.03 (C), 117.40 (C),
121.70 (CH), 123.97 (C), 134.36 (C), 140.15 (C), 153.16
(C), 153.89 (C). Anal. Calcd (%) for C14H13NO2: C, 73.99;
H, 5.77; N, 6.16. Found: C, 73.32; H, 5.97; N, 6.26.
Lansine (5): yellow solid; mp 202–204 °C. 1H NMR (500
MHz, CDCl3): d = 3.91 (s, 3 H), 6.82 (s, 1 H), 7.02 (dd,
J = 8.7, 2.4 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.47 (d,
J = 2.4 Hz, 1 H), 8.11 (br s, 1 H), 8.12 (s, 1 H), 9.91 (s, 1 H),
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Synlett 2009, No. 15, 2421–2424 © Thieme Stuttgart · New York

2424
M. Schmidt, H.-J. Knölker
LETTER
(27) Experimental Procedure for the Palladium(II)-
11.43 (s, 1 H). 13C NMR and DEPT (125 MHz, CDCl3):
d = 56.01 (CH3), 96.79 (CH), 103.36 (CH), 111.41 (CH),
114.48 (CH), 115.30 (C), 117.81 (C), 123.96 (C), 127.49
(CH), 134.68 (C), 146.11 (C), 154.96 (C), 161.10 (C),
195.12 (CHO). Anal. Calcd (%) for C14H11NO3: C, 69.70; H,
4.60; N, 5.81. Found: C, 69.75; H, 4.70; N, 5.69.
Catalyzed Oxidative Cyclization
The diarylamine 14 (132 mg, 283 mmol), Pd(OAc)2 (6.3 mg,
28 mmol), Cu(OAc)2 (128 mg, 705 mmol), and AcOH (1.5
mL) were heated in a 10 mL microwave vessel for 2 h at
130 °C. Removal of the solvent in vacuum and flash chro-
matography (PE–EtOAc, 15:1) of the crude product on
Celite/silica gel provided O-tert-butyldiphenylsilylcarba-
lexin C (15; 100 mg, 76%) as a yellow oil. 13C NMR and
DEPT (125 MHz, CDCl3): d = 17.70 (CH3), 19.61 (C), 26.50
(3 CH3), 56.02 (CH3), 100.55 (CH), 102.55 (CH), 110.71
(CH), 113.03 (CH), 117.07 (C), 120.70 (C), 121.30 (CH),
123.73 (C), 127.84 (4 CH), 129.86 (2 CH), 132.91 (2 C),
134.23 (C), 135.45 (4 CH), 139.39 (C), 152.96 (C), 153.69
(C).
(25) Kim, J.; Kim, Y. K.; Park, N.; Hahn, J. H.; Ahn, K. H. J. Org.
Chem. 2005, 70, 7087.
(26) Synthesis of 3-(tert-butyldiphenylsilyloxy)-4-methyl-
aniline (13): 1. commercial 2-methyl-5-nitrophenol (1.0
equiv), t-BuPh2SiCl (1.5 equiv), imidazole (2 equiv), DMF,
r.t., 4 h; 2. 10% Pd/C, H2 (5 bar), CH2Cl2, r.t., 24 h (100%
overall yield).
Synlett 2009, No. 15, 2421–2424 © Thieme Stuttgart · New York

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