A new synthetic route to the 1-oxygenated carbazole alkaloids, mukonine and clausine e (clauzoline I)

Article abstract of DOI:10.3987/COM-08-S(D)71

A new synthesis of the 1-oxygenated 1,3-disubstituted carbazole alkaloids, mukonine (1a) and clausine (1f) is described. The construction of the carbazole framework is based on an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 1

Full text of DOI:10.3987/COM-08-S(D)71

HETEROCYCLES, Vol. 79, 2009
955
HETEROCYCLES, Vol. 79, 2009, pp. 955 - 965. © The Japan Institute of Heterocyclic Chemistry
Received, 16th October, 2008, Accepted, 27th November, 2008, Published online, 11th December, 2008.
DOI: 10.3987/COM-08-S(D)71
A NEW SYNTHETIC ROUTE TO THE 1-OXYGENATED CARBAZOLE
ALKALOIDS, MUKONINE AND CLAUSINE E (CLAUZOLINE I)
Shigeo Tohyama, Tominari Choshi, Shuhei Azuma, Haruto Fujioka, and
Satoshi Hibino*
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy
and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima
729-0292, Japan
E-mail: hibino@fupharm.fukuyama-u.ac.jp
This paper is dedicated to the late Dr. John W. Daly
Abstract – A new synthesis of the 1-oxygenated 1,3-disubstituted carbazole
alkaloids, mukonine (1a) and clausine (1f) is described. The construction of the
carbazole framework is based on an allene-mediated electrocyclic reaction
involving the indole 2,3-bond. The 1,3-disubstituted 1-oxygenated carbazoles 1a
and 1f are derived from the 1,2,3-trisubstituted carbazole.
INTRODUCTION
Naturally occurring carbazole alkaloids display a wide variety of biological activities, such as antitumor,
antibacterial, antimicrobial, and anti-inflammatory activities. An intensive effort has been directed toward
their isolation, and total synthesis.1 The search for the biologically active compounds of Murraya and
Clausena led to the discovery of a broad variety of carbazole alkaloids, including the 1-oxygenated
3-substituted carbazoles and 2-oxygenated 3-substituted carbazoles. Among them, the simple
1-oxygenated 3-substituted carbazole alkaloids, mukonine (1a) and clausine E (clauzoline I: 1f) have
been isolated from Murraya koenigii1a,2 and Clausena excavata1,3,4 (and anisata), together with 1b~1e, 1g,
and 1h (Scheme 1). Several excellent synthetic routes for their preparation have been reported.1,5
We have been working to develop the synthesis of a biologically active condensed heterocyclic
compound based on a thermal electrocyclic reaction of either the 6π-electron system or the aza
6π-electron system.6 Recently, the total synthesis of 3-oxygenated or 3,4-dioxygenated polyfunctionalized
carbazole alkaloids was developed by an allene-mediated electrocyclic reaction involving the indole
2,3-bond.7 Initially, we planned a short-step sequence toward a 1-oxyganated carbazole 1 based on a

956
HETEROCYCLES, Vol. 79, 2009
thermal electrocyclic reaction of 2,3-bisalkenylindole 2 6 (Scheme 1). However, it was difficult to prepare
the precursor 2. Taking advantage of our recent efforts,7 we applied this methodology for the syntheses of
mukonine (1a) and clausine (1f).
R2
R2
R1
R2
Me
Me
Me
Me
Me
H
CO2Me
CO2H
CHO
1a
1b
1c
1d
1e
1f
N
H
N
H
1
OR1
OR1
2
CH2OH
Me
R2
R2
CO2Me
CHO
OR3
OR3
H
1g
1h
H
Me
N
N
H
OR1
OR1
H
3
4
Scheme 1
CO2R1
CO2R1
OR2
1) n-BuLi, Et2NH
2) CH2ClCH2(OR2)2
CHO
THF
0oC, 1.5 h
N
N
OH
MOM
MOM
5a : R1=Me
5b : R1=Et
6a : R1=R2=Me (48%)
6b: R1=R2=Et (87%)
CO2R1
CO2R1
OR2
MOMCl
iPr2NEt
OR2
base
CH2Cl2
50oC, 3 h
N
N
OMOM
OMOM
MOM
MOM
7a : R1=R2=Me (40%)
7b : R1=R2=Et (88%)
1) DDQ
CH2Cl2
50oC, 24 h
CO2R1
OR2
CO2Me
CHO
2) 6M HCl
ethylene glycol
N
N
H
OMOM
OH
MOM
THF
60oC, 7 h
9: 57%
8a: R1=R2=Me (52%)
8b: R1=R2=Et (88%)
8c: R1=H, R2=Et (98%)
8d: R1=Me, R2=Et (99%)
MeI, NaOH
HMPA
rt, 1 h
Scheme 2

HETEROCYCLES, Vol. 79, 2009
957
RESULTS AND DISCUSSION
In the present paper, we describe a new synthesis of the 1-oxygenated 3-substituted carbazoles, mukonine
(1a) and clausine (1f), based on an alle4ne-mediated electrocyclic reaction of the 6π-electron system
involving the indole 2,3-bond (Scheme 2). We chose methyl 3-[2-formyl-N-(methoxymethyl)-
indole-3-yl]acrylate (5a) and ethyl 3-[2-formyl-N-(methoxymethyl)indole-3-yl]acrylate (5b) as starting
materials.8 Nucleophilic addition reaction of 5a and 5b with lithium methoxyacetylide or ethoxyacetylide,
(prepared from chloroacetaldehyde dimethyl acetal or chloroacetaldehyde diethyl acetal with lithium
diethylamide in in situ),9 gave the propargyl alcohol 6a and 6b, respectively. Subsequent treatment of 6a
and 6b with chloromethyl methyl ether (MOMCl) in CH2Cl2 at 50 o C afforded the propargyl ether 7a and
7b, respectively. An allene-mediated electrocyclic reaction of the propargyl ether 7a was carried out by
tetrahydroammonium fluoride (TBAF) according to the reported procedure7b to give the
1,2,3-trisubstituted carbazole-3-methyl ester 8a in somewhat low yield.
Table 1. Synthesis of 1,2,3-Trisubstituted Carbazoles by Allene-mediated Electrocyclic Reaction
CO2Et
OEt
CO2H
OEt
CO2Et
OEt
base
+
N
N
N
OMOM
OMOM
OMOM
MOM
8b
MOM
8c
MOM
7b
run
time (min)
yield (%) of 8c
base
base (eq.)
yield (%) of 8b
1
2
3
4
5
TBAF
5
5
5
5
3
10
15
60
60
60
88
76
64
!
!
!
9
TBAF
TBAF
18
98
89
t-BuOK
t-BuOK
As shown in Table 1, the propargyl ether 7b was subjected to a similar reaction using TBAF to yield the
cyclized carbazoles 8b in moderate to good yields, together with the carbazole-3-carboxylic acid 8c (run
1-3). On the other hand, the same reaction of 7b using t-BuOk7 gave the exclusively
carbazole-3-carboxylic acid 8c through a cyclization followed by a hydrolysis of the ester 8c (run 4, 5).
The carbazole-3-carboxylic acid 8c was treated with MeI in the presence of hexamethylphosphoramide
(HMPA) to proceed to the carbazole-3-methyl ester 8d. Oxidation of the alkoxymethyl group at the
2-position of carbazoles 8a and 8d with dichlorodicyanoquinone (DDQ) in CH2Cl2 provided the
2-formyl-1-hydroxycarbazole 9, derived from both compounds. The allover yield (42%) of 1-oxygenated

958
HETEROCYCLES, Vol. 79, 2009
carbazole 9 from 5b was greater than that of the methyl ester series 5a (5%).
For the synthesis of 1a and 1f (Scheme 3), alkylation of the 1-hydroxycarbazole 9 was carried out by MeI
o
or benzyl bromide in the presence of K2CO3 at 0 C to yield 1-methoxycarbazole 10a and
1-benzyloxycarbazole 10b, respectively. Baeyer-Villiger reaction of 10a and 10b with
m-chloroperbenzoic acid (mCPBA) in the presence of potassium fluoride (KF)10 in CH2Cl2 afforded
2-hydroxycarbazoles 11a and 11b, respectively. Subsequent treatment of 11a and 11b with N-phenyl
bistrifluoromethanesulfonylamide (Tf2NPh) in the presence of NaH gave triflates 12a and 12b, which
were subjected to hydrogenolysis11 with 10% Pd-C and hydrogen gas to produce mukonine (1a) and
clausine E (1f) along with debenzylation. The spectral and physical data of the obtained mukonine (1a)
and clausine E (1f) were identified by comparison with those reported previously.12
CO2Me
CHO
CO2Me
CHO
MeI or BnBr
K2CO3
mCPBA, KF
CH2Cl2
rt, 1 h
DMF
0oC, 12 h
N
N
OR
OH
H
H
10a : R=Me (51%)
10b: R=Bn (78%)
9
CO2Me
CO2Me
OH
CO2Me
H2
Tf2NPh
NaH
10% Pd-C
OTf
EtOH
rt, 4 h
THF
-30oC, 3 h
N
N
N
H
OR
OR
OR
H
H
11a: R=Me
11b: R=Bn
12a: R=Me (48% from 10a)
12b: R=Bn
1a : R=Me (73%)
1f : R=H (28% from 10b)
Scheme 3
CONCLUSION
In summary, 1,3-disubstituted 1-oxygenated carbazole alkaloids, mukonine (1a) and clausine E (1f) were
newly synthesized by the construction of 1,2,3-trisubstituted 1-oxygenated carbazoles 8a and 8c based on
an allene-mediated electrocyclic reaction involving the indole 2,3-bond, followed by removal of the
alkoxymethyl group at the 2-position of 8a and 8c in four-steps. Although this synthetic route is a long
process, this scheme can be applied to a synthesis of the other carbazole alkaloids 1b-1e, 1g, and 1h. In
addition, we demonstrated that 2,3-disubstituted 2-oxygenated carbazole alkaloids such as mukonal and
mukonidine1,3,5 can be derived from 1,2,3-trisubstituted carbazole 9.
EXPERIMENTAL
All melting points were measured with a Yanagimoto micro-melting point apparatus MP-500D and are
uncorrected. IR spectra were recorded with ATR method using a Shimadzu FTIR-8000
1
spectrophotometer and Technologies DuraScop. H-NMR and 13C-NMR spectra were taken with a JEOL

HETEROCYCLES, Vol. 79, 2009
959
AL-300 instrument using tetramethylsilane as an internal standard. Mass spectra (MS) were determined
with a Shimadzu QP5050 (EI) and JMS-700 (CI with isobutane) spectrometers by direct inlet system,
respectively. Solvents were distilled by normal methods (THF dried over sodium benzophenone ketyl,
CH2Cl2 dried over CaH2, DMF dried over CaH2). Silica gel 60PF254 (60-100 mesh, Merck Art 7744) was
used for column chromatography.
Methyl 3-[2-formyl-N-(methoxymethyl)indol-3-yl]acrylate (5a)
A stirred mixture of 3-iodoindole (1 g, 3.17 mmol), methyl acrylate (0.57 mL, 6.3 mmol), Et3N (0.87 mL,
6.3 mmol), PPh3 (26 mg, 0.1 mmol), and Pd(OAc)2 (13.5 mg, 0.06 mmol) in DMF (45 mL) were heated
o
at 100 C for 1 h under Ar. After being cooled to ambient temperature, the reaction mixture was diluted
with water, and the mixture was extracted with EtOAc. The EtOAc was washed with water and brine,
dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel 20 g) using EtOAc-hexane (1:4 v/v) as an eluent to give the N-MOM-indole
o
1
5a8 (734 mg, 85%). mp 104-106 C (EtOAc); IR (ATR)ν: 1697, 1647 cm-1; H-NMR (CDCl3)δ: 3.32
(3H, s), 3.86 (3H, s), 6.01 (2H, s), 6.69 (1H, d, J=16.0 Hz), 7.35 (1H, t, J=7.3 Hz), 7.52 (1H, t, J=7.3 Hz),
7.61 (1H, d, J=7.3 Hz), 8.01 (1H, d, J=7.3 Hz), 8.32 (1H, d, J=16.0 Hz), 10.38 (1H, s); MS m/z: 273 (M+).
Ethyl 3-[2-formyl-N-(methoxymethyl)indol-3-yl]acrylate (5b)
The same procedure as above was carried out using 3-iodoindole (1 g, 3.17 mmol) and ethyl acrylate (697
µL, 6.4 mmol) to give the N-MOM-indole 5b (830 mg, 91%). mp 83-85oC (EtOAc); IR (ATR)ν: 1709,
1631 cm-1; 1H-NMR (CDCl3)δ: 1.38 (3H, t, J=7.1 Hz), 3.31 (3H, s), 4.32 (2H, q, J=7.1 Hz), 6.01 (2H, s),
6.68 (1H, d, J=15.8 Hz), 7.43 (1H, t, J=7.3 Hz), 7.51 (1H, t, J=7.3 Hz), 7.54 (1H, d, J=7.3 Hz), 8.02 (1H,
d, J=7.3 Hz), 8.31 (1H, d, J=15.8 Hz), 10.38 (1H, s); MS m/z: 287 (M+).
Methyl 3-[2-(1-hydroxy-3-methoxyprop-2-yn-1-yl)-N-(methoxymethyl)indol-3-yl]acrylate (6a)
Et2NH (3.59 mL, 34.69 mmol) was added to a solution of n-BuLi (2.59 mol/L in hexane, 12.1 mL, 31.22
mmol) in THF (27 mL) under cooling with ice-water. After stirring at the same temperature for 10 min,
chloroacetaldehyde dimethyl acetal (1.19 mL, 10.41 mmol) was added to the reaction mixture at the same
temperature for further 1.5 h. A solution of N-MOM-indole 5a (474 mg, 1.73 mmol) in THF (15 mL) was
added to the reaction mixture at same temperature for further 1.5 h. The reaction mixture was quenched
with saturated aqueous NH4Cl solution, and then extracted with EtOAc. The EtOAc was washed with
water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel 15 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the oily
1
propargyl alcohol 6a (274 mg, 48%). IR (ATR)ν: 2271, 1712 cm-1; H-NMR (CDCl3)δ: 3.35 (3H, s),
3.64 (1H, d, J=7.5 Hz), 3.82 (3H, s), 3.91 (3H, s), 5.63 (1H, d, J=11.0 Hz), 6.09 (1H, d, J=7.5 Hz), 6.13
(1H, d, J=11.0 Hz), 6.57 (1H, d, J=15.8 Hz), 7.27 (1H, t, J=7.2 Hz), 7.34 (1H, t, J=7.2 Hz), 7.52 (1H, d,

960
HETEROCYCLES, Vol. 79, 2009
J=7.2 Hz), 7.93 (1H, d, J=7.2 Hz), 8.09 (1H, d, J=15.8 Hz), MS m/z: 329 (M+). HR-MS m/z: 329.1270
(Calcd for C18H19NO5: 329.1263)
Ethyl 3-[2-(3-ethoxy-1-hydroxyprop-2-yn-1-yl)-N-(methoxymethyl)indol-3-yl]acrylate (6b)
The same procedure as above was carried out using N-MOM-indole 5b (753 mg, 2.62 mmol) and
chloroacetaldehyde diethyl acetal (3.34 mL, 22.57 mmol) to give the oily propargyl alcohol 6b (817 mg,
87%). IR (ATR)ν: 2264, 1697 cm-1; 1H-NMR (CDCl3)δ: 1.33 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz),
3.33 (3H, s), 3.90 (1H, d, J=5.9 Hz), 4.12 (2H, q, J=7.1 Hz), 4.25 (2H, q, J=7.1 Hz), 5.65 (1H, d, J=11.0
Hz), 6.09 (1H, d, J=11.0 Hz), 6.11 (1H, d, J=5.9 Hz), 6.52 (1H, d, J=16.0 Hz), 7.25 (1H, t, J=7.6 Hz),
7.31 (1H, t, J=7.6 Hz), 7.51 (1H, d, J=7.6 Hz), 7.92 (1H, d, J=7.6 Hz), 8.08 (1H, d, J=16.0 Hz), MS m/z:
357 (M+). HR-MS m/z: 357.1585 (Calcd for C20H23NO5 : 357.1576).
Methyl
3-{2-[3-methoxy-1-(methoxymethyloxy)prop-2-yn-1-yl]-N-(methoxymethyl)indol-3-yl}
acrylate (7a)
A solution of propargyl alcohol 6a (548 mg, 1.66 mmol), MOMCl (0.76 mL, 9.98 mmol), and i-Pr2NEt
o
(2.29 mL, 13.31 mmol) in CH2Cl2 (15 mL) were heated at 50 C for 3 h. After being cooled to ambient
temperature, the reaction mixture was quenched with water, and then was extracted with CH2Cl2. The
organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography (silica gel 15 g) using EtOAc-hexane (3:7
v/v) as an eluent to give the oily propargyl ether 7a (264 mg, 40%). IR (ATR)ν: 2268, 1709 cm-1;
1H-NMR (CDCl3)δ: 3.34 (3H, s), 3.39 (3H, s), 3.82 (3H, s), 3.90 (3H, s), 4.58 (1H, d, J=6.6 Hz), 4.93
(1H, d, J=6.6 Hz), 5.75 (2H, s), 6.07 (1H, s), 6.55 (1H, d, J=15.8 Hz), 7.26 (1H, td, J=7.0, 1.2 Hz), 7.32
(1H, td, J=7.0, 1.2 Hz), 7.58 (1H, dd, J=7.0, 1.2 Hz), 7.92 (1H, dd, J=7.0, 1.2 Hz), 8.10 (1H, d, J=15.8
Hz), MS m/z: 373 (M+). HR-MS m/z: 373.1550 (Calcd for C20H23NO6 : 373.1525).
Ethyl 3-{2-[3-ethoxy-1-(methoxymethyloxy)prop-2-yn-1-yl]-N-(methoxymethyl)indol-3-yl}acrylate
(7b)
The same procedure as above was carried out using propargyl alcohol 6b (595 mg, 1.67 mmol) to give the
oily propargyl ether 7b (590 mg, 88%). IR (ATR)ν: 2264, 1716 cm-1; 1H-NMR (CDCl3)δ: 1.35 (3H×2,
t, J=7.1 Hz), 3.34 (3H, s), 3.39, (3H, s), 4.13 (2H, q, J=7.1 Hz), 4.28 (2H, q, J=7.1 Hz), 4.58 (1H, d,
J=7.0 Hz), 4.94 (1H, d, J=7.0 Hz), 5.77 (2H, d, J=1.8 Hz), 6.09 (1H, s), 6.55 (1H, d, J=16.0 Hz), 7.26
(1H, t, J=7.6 Hz), 7.32 (1H, t, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz), 8.10 (1H, d,
J=16.0 Hz), MS m/z: 401 (M+). HR-MS m/z: 401.1811 (Calcd for C22H27NO6 : 401.1838).
Methyl 2-(methoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3- carboxylate (8a)

HETEROCYCLES, Vol. 79, 2009
961
TBAF (1M in THF, 3.29 mL, 3.29 mmol) was added to a solution of the propargyl ether 7a (246 mg, 0.66
o
mmol) in THF (10 mL), and then heated at 90 C for 10 min. After being cooled to an ambient
temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution, and then
extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 10
g) using EtOAc-hexane (3:7 v/v) as an eluent to give the 2-methoxymethylcarbazole 8a (128 mg, 52%).
o
1
mp 58-60 C (Et2O-hexane); IR (ATR)ν: 1720 cm-1; H-NMR (CDCl3)δ: 3.30 (3H, s), 3.48 (3H, s),
3.60 (3H, s), 3.97, (3H, s), 4.97 (2H, s), 5.26 (2H, s), 6.07 (2H, s), 7.32 (1H, t, J=7.7 Hz), 7.52 (1H, t,
J=7.7 Hz), 7.60 (1H, d, J=7.7 Hz), 8.08 (1H, d, J=7.7 Hz), 8.49 (1H, s), MS m/z: 373 (M+). HR-MS m/z:
373.1543 (Calcd for C20H23NO6 : 373.1525).
Ethyl 2-(ethoxymethyl)-N-(methoxymethyl)-1-(methoxy-methyloxy)carbazole-3-carboxylate (8b)
The same procedure as above was carried out using propargyl ether 7b (600 mg, 1.49 mmol) to give the
o
2-ethoxymethylcarbazole 8b (525 mg, 88%). mp 56-57 C (Et2O-hexane); IR (ATR)ν: 1712 cm-1;
1H-NMR (CDCl3)δ: 1.25 (3H, t, J=7.0 Hz), 1.45 (3H, t, J=7.1 Hz), 3.28 (3H, s), 3.60, (3H, s), 3.64 (2H,
q, J=7.0 Hz), 4.43 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.26 (2H, s), 6.05 (2H, s), 7.30 (1H, t, J=7.2 Hz), 7.50
(1H, t, J=7.2 Hz), 7.58 (1H, d, J=7.2 Hz), 8.07 (1H, d, J=7.2 Hz), 8.43 (1H, s), MS m/z: 401 (M+).
HR-MS m/z: 401.1824 (Calcd for C22H27NO6 : 401.1838).
2-(Ethoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3-carboxylic acid (8c)
A solution of propargyl ether 7b (57 mg, 0.15 mmol) in THF (3 mL) was added to a solution of t-BuOK
(86 mg, 0.76 mmol) in t-BuOH (3 mL), and then heated at 90 oC for 1 h. After being cooled to an ambient
temperature, the reaction mixture was adjusted to pH 5 with AcOH, and then extracted with EtOAc. The
organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was recrystallized from CHCl3-hexane to give the carbazole-3-carboxylic acid 8c
(52 mg, 98%). mp 138-139 oC (CHCl3-hexane) IR (ATR)ν: 2924, 1682 cm-1; 1H-NMR (CDCl3)δ: 1.33
(3H, t, J=7.1 Hz), 3.32 (3H, s), 3.61, (3H, s), 3.79 (2H, q, J=7.1 Hz), 4.99 (2H, s), 5.25 (2H, s), 6.03 (2H,
s), 7.34 (1H, t, J=7.1 Hz), 7.54 (1H, t, J=7.1 Hz), 7.60 (1H, d, J=7.1 Hz), 8.10 (1H, d, J=7.1 Hz), 8.62
(1H, s), MS m/z: 373 (M+). HR-MS m/z: 373.1509 (Calcd for C20H23NO6 : 373.1525).
Methyl 2-(ethoxymethyl)-N-(methoxymethyl)-1-(methoxymethyloxy)carbazole-3-carboxylate (8d)
25% aqueous NaOH (1.1 mL, 6.74 mmol) solution was added to a solution of the carbazole-3-carboxylic
acid 8c (629 mg, 1.68 mmol) in HMPA (15 mL) at rt, and then stirred at same temperature for 30 min.
MeI (0.84 mL, 13.48 mmol) was added to a reaction mixture, and then stirred at the same temperature for
further 1 h. The reaction mixture was adjusted to pH 5 with AcOH, and then extracted with EtOAc. The

962
HETEROCYCLES, Vol. 79, 2009
organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography (silica gel 20 g) using EtOAc-hexane (1:4
v/v) as an eluent to give the oily 2-ethoxymethylcarbazole 8d (647 mg, 99%). IR (ATR)ν: 1726 cm-1;
1H-NMR (CDCl3)δ: 1.25 (3H, t, J=7.0 Hz), 3.29 (3H, s), 3.60 (3H, s), 3.65 (2H, q, J=7.0 Hz), 3.96, (3H,
s), 5.00 (2H, s), 5.26 (2H, s), 6.05 (2H, s), 7.30 (1H, t, J=7.5 Hz), 7.50 (1H, t, J=7.5 Hz), 7.58 (1H, d,
J=7.5 Hz), 8.06 (1H, d, J=7.5 Hz), 8.44 (1H, s), MS m/z: 387 (M+). HR-MS m/z: 387.1702 (Calcd for
C21H25NO6 : 387.1682).
Methyl 2-formyl-1-hydroxycarbazole-3-carboxylate (9)
A solution of 2-methoxymethylcarbazole 8a (100 mg, 0.27 mmol), DDQ (122 mg, 0.54 mmol), and
o
LiClO4 (28 mg, 0.27 mmol) in CH2Cl2/H2O (18:1) (10 mL) were heated at 60 C for 24 h. After being
cooled to ambient temperature, the reaction mixture was filtered though Celite pad. The filtrate was
extracted with CH2Cl2. The organic layer was washed water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was used without purification. 6 M HCl (0.5 mL) and
ethylene glycol (0.5 mL) were added to a solution of the residue in THF (4 mL), and then heated at 60oC
for 7 h. After being cooled to ambient temperature, the reaction mixture was added water and then
extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 5 g)
using EtOAc-hexane (3:17 v/v) as an eluent to give the 2-formylcarbazole 9 (32 mg, 46%). mp 204-205
oC (Et2O-hexane); IR (ATR)ν: 3355, 1682, 1647 cm-1; 1H-NMR (CDCl3)δ: 4.01 (3H, s), 7.31-7.36 (1H,
m), 7.55 (2H, br d, J=4.0 Hz), 8.11 (1H, d, J=7.3 Hz), 8.34 (1H, s), 8.85 (1H, br s), 10.84 (1H, s), 13.22
(1H, s), MS m/z: 269 (M+). HR-MS m/z: 269.0697 (Calcd for C15H11NO4 : 269.0688).
Methyl 2-formyl-1-hydroxycarbazole-3-carboxylate (9)
The same procedure as above was carried out using 2-ethoxymethylcarbazole 8d (200 mg, 0.52 mmol) to
give the 2-formylcarbazole 9 (79 mg, 57%).
Methyl 2-formyl-1-methoxycarbazole-3-carboxylate (10a)
A mixture of 2-formylcarbazole 9 (39 mg, 0.14 mmol), MeI (9 µL, 0.14 mmol), and K2CO3 (20 mg, 0.14
mmol) in DMF (5 mL) was stirred at rt for 12 h. The reaction mixture was quenched with aqueous NH4Cl
solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography
(silica gel 5 g) using EtOAc-hexane (1:4 v/v) as an eluent to give the 1-methoxycarbazole 10a (21 mg,
51%). mp 204-205 oC (EtOAc-hexane); IR (ATR)ν: 3240, 1682 cm-1; 1H-NMR (CDCl3)δ: 3.99 (3H, s),
4.10 (3H, s), 7.30-7.36 (1H, m), 7.53-7.55 (2H, m), 8.11 (1H, d, J=7.3 Hz), 8.42 (1H, s), 8.67 (1H, br s),

HETEROCYCLES, Vol. 79, 2009
963
10.59 (1H, s), MS m/z: 283 (M+). HR-MS m/z: 283.0849 (Calcd for C16H13NO4 : 283.0845).
Methyl 1-benzyloxy-2-formylcarbazole-3-carboxylate (10b)
The same procedure as above was carried out using 2-formylcarbazole 9 (57 mg, 0.21 mmol) and benzyl
o
bromide (25 µL, 0.21 mmol) to give the 1-benzyloxycarbazole 10b (59 mg, 78%). mp 128-129 C
(Et2O-hexane); IR (ATR)ν: 3545, 1678 cm-1; 1H-NMR (CDCl3)δ: 3.98 (3H, s), 5.23 (2H, s), 7.28 (1H, t,
J=7.5 Hz), 7.35-7.50 (7H, m), 8.05 (1H, d, J=7.5 Hz), 8.30 (1H, br s), 8.39 (1H, s), 10.49 (1H, s), MS
m/z: 359 (M+). HR-MS m/z: (Calcd for C22H17NO4 : 359.1158).
Methyl 1-methoxy-2-(trifluoromethanesulfonyloxy)carbazole-3-carboxylate (12a)
A solution of 1-methoxycarbazole 10a (47 mg, 0.17 mmol), mCPBA (382 mg, 1.66 mmol), and KF (193
mg, 3.32 mmol) in CH2Cl2 (10 mL) was stirred at rt for 1 h. The reaction mixture was purified by column
chromatography (silica gel 5 g) using EtOAc-hexane (3:17 v/v) as an eluent to give crude
2-hydroxycarbazole 11a. A solution of 2-hydroxycarnazole in THF (3 mL) was added to a suspension of
o
60%NaH (11 mg, 0.28 mmol) in THF (3 mL) at -30 C. After stirred at the same temperature for 0.5 h,
the reaction mixture which was added Tf2NPh (47 mg, 0.13 mmol), was stirred at the same temperature
for further 3 h. The reaction mixture was quenched with aqueous NH4Cl solution, and then extracted with
EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography (silica gel 3 g) using
EtOAc-hexane (3:17 v/v) as an eluent to give the oily triflate 12a (32 mg, 48%). IR (ATR)ν: 3320, 1709,
1358, 1120 cm-1; 1H-NMR (CDCl3)δ: 4.00 (3H, s), 4.09 (3H, s), 7.31-7.37 (1H, m), 7.52 (2H, br d, J=3.7
Hz), 8.10 (1H, d, J=7.7 Hz), 8.56 (1H, s), 8.58 (1H, br s), MS m/z: 403 (M+). HR-MS m/z: 403.0318
(Calcd for C16H12F3NO6S : 403.0337).
Mukonine (1a)
A suspension of triflate 11a (28 mg, 0.069 mmol) and 10%Pd-C (30 mg) in EtOH (2 mL) was stirred at rt
for 6 h under hydrogen atmosphere. The reaction mixture was filtrated through Celite pad, and the Celite
pad was washed EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel 3 g) using EtOAc-hexane (3:17 v/v) as an eluent to give
o
the mukonine (1a) (13 mg, 73%). mp 197-198 ℃ (Et2O-hexane) (Lit.,5a mp 197-198 C, Lit.,11a mp 195
oC and Lit.,11b mp 201 oC) ; IR (ATR)ν: 3316, 1693 cm-1; 1H-NMR (CDCl3)δ: 3.92 (3H, s), 4.07 (3H, s),
7.26 (1H, t, J=7.8 Hz), 7.45 (1H, t, J=7.8 Hz), 7.58 (1H, s), 7.63 (1H, d, J=7.8 Hz), 8.21 (1H, d, J=7.8
Hz), 8.47 (1H, s), 10.78 (1H, br s), MS m/z: 255 (M+). HR-MS m/z: 255.0876 (Calcd for C15H13NO3 :
255.0895).

964
HETEROCYCLES, Vol. 79, 2009
Clausine E (1f)
A solution of 1-benzyloxycarbazole 10b (79 mg, 0.22 mmol), mCPBA (509 mg, 2.20 mmol), and KF
(255 mg, 4.40 mmol) in CH2Cl2 (5 mL) was stirred at rt for 1 h. The reaction mixture was purified by
column chromatography (silica gel 5 g) using EtOAc-hexane (1:19 v/v) as an eluent to give crude
2-hydroxycarbazole 11b. A solution of 2-hydroxycarbazole 11b in THF (3 mL) was added to a
o
suspension of 60%NaH (18 mg, 0.44 mmol) in THF (3 mL) at -30 C. After stirred at the same
temperature for 0.5 h, the reaction mixture which was added Tf2NPh (79 mg, 0.22 mmol), was stirred at
the same temperature for further 3 h. The reaction mixture was quenched with aqueous NH4Cl solution,
and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel
3 g) using EtOAc-hexane (1:9 v/v) as an eluent to give the crude triflate 12b. A suspension of the crude
triflate 12b and 10%Pd-C (50 mg) in EtOH (2 mL) was stirred at rt for 6 h under hydrogen atmosphere.
The reaction mixture was filtrated through Celite pad, and the Celite pad was washed with EtOAc. The
combined filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel 3 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the clausine E (1f) (15
o
o
o
mg, 28%). mp 190-191 C (Et2O-hexane) (Lit.,3a mp 218-220 C and Lit.,11b mp 203 C) ; IR (ATR)ν:
1
3347, 1655, 1631, 1601 cm-1; H-NMR (acetone-d6)δ: 3.88 (3H, s), 7.23 (1H, td, J=7.4, 1.1 Hz), 7.43
(1H, td, J=7.4, 1.1 Hz), 7.56 (1H, d, J=1.1 Hz), 7.61 (1H, dd, J=7.4, 1.1 Hz), 8.18 (1H, dd, J=7.4, 1.1 Hz),
8.38 (1H, d, J=1.1 Hz), 9.07 (1H, s), 10.64 (1H, br s), MS m/z: 241 (M+). HR-MS m/z: 241.0756 (Calcd
for C14H11NO3 : 241.0739).
REFERENCES
1. (a) D. P. Chakraborty, Prog. Chem. Org. Nat. Prod., ed. by W. Herz, H. Grisebach, and G. W. Kirby,
Springer, Wien, 1977, Vol. 34, p. 299; (b) P. Bhattacharyya and D. P. Chakraborty, Prog. Chem. Org.
Nat. Prod., ed. by W. Herz, H. Grisebach, and G. W. Kirby, Springer, Wien, 1987, Vol. 52, p. 159;
(c) D. P. Chakraborty and S. Roy, Prog. Chem. Org. Nat. Prod., ed. by W. Herz, H. Grisebach, and G.
W. Kirby, Springer, Wien, 1991, Vol. 57, p. 71; (d) D. P. Chakraborty, The Alkaloids, ed. by G. A.
Cordell, Academic Press, New York, 1993, Vol. 44, p. 257; (e) H.-J. Knölker, Chem. Soc. Rev., 1999,
28, 151; (f) H.-J. Knölker and K. R. Reddy, Chem. Rev., 2002, 102, 4303; (g) H.-J. Knölker, Top.
Curr. Chem., 2005, 244, 115.
2. (a) B. K. Chowdhury and D. P. Chakraborty, Chem. Ind., (London), 1969, 549; (b) B. K. Chowdhury
and D. P. Chakraborty, Phytochemistry, 1971, 10, 481; (c) D. P. Chakraborty, P. Bhattacharyya, S.
Roy, S. P. Bhattacharyya, and A. K. Biswas, Phytochemistry, 1978, 17, 834.
3. (a) T.-S. Wu, S.-C. Huang, P.-L. Wu, and C.-M. Teng, Phytochemistry, 1996, 43, 133; (b) T.-S. Wu,
S.-C. Huang, P.-L. Wu, and C.-S. Kuoh, Phytochemistry, 1999, 52, 523.

HETEROCYCLES, Vol. 79, 2009
965
4. (a) C. Ito, S. Katsuno, H. Ohta, M. Omura, I. Kajiura, and H. Furukawa, Chem. Pharm. Bull., 1997,
45, 48; (b) C. Ito, S. Katsuno, M. Itoigawa, N. Ruangrungsi, T. Mukainaka, M. Okuda, Y. Kitagawa,
H. Tokuda, H. Nishino, and H. Furukawa, J. Nat. Prod., 2000, 63, 125.
5. (a) A. Zempoalteca and J. Tamariz, Heterocycles, 2002, 57, 259; (b) H.-J. Knölker and M. Wolpert,
Tetrahedron, 2003, 59, 5317; (c) A. Kuwahara, K. Nakano, and K. Nozaki, J. Org. Chem., 2005, 70,
413; (d) L.-C. Campeau, M. Parisien, A. Jean, and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581; (e)
Z. Liu and R. C. Larock, Tetrahedron, 2007, 63, 347; (f) B. Liegault, D. Lee, M. P. Huestis, D. R.
Stuart, and K. Fagnou, J. Org. Chem., 2008, 73, 5022.
6. (a) S. Hibino and E. Sugino, In Advances in Nitrogen Heterocycles, ed. by C. J. Moody, JAI Press,
Greenwich, CT, 1995, Vol. 5, p. 699; (b) T. Kawasaki and M. Sakamoto, J. Indian Chem. Soc., 1994,
71, 443; (c) T. Choshi, Yakugaku Zasshi, 2001, 121, 487; (d) T. Choshi, T. Kumemura, J. Nobuhiro,
and S. Hibino, Tetrahedron Lett., 2008, 49, 3725 and related references cited therein.
7. (a) T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino, and S. Hibino, Tetrahedron Lett., 1996,
37, 2593; (b) T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Heterocycles, 1996, 43, 1847; (c) T.
Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino, and S. Hibino, J. Org. Chem., 1997, 62,
2535; (d) H. Hagiwara, T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Chem. Pharm. Bull., 1998,
46, 1948; (e) H. Hagiwara, T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Tetrahedron, 2000, 56,
5807; (f) H. Hagiwara, T. Choshi, H. J. Nobuhiro, H. Fujimoto, and S. Hibino, Chem. Pharm. Bull.,
2001, 49, 881; (g) M. Hirayama, T. Choshi, T. Kumemura, S. Tohyama, J. Nobuhiro, and S. Hibino,
Heterocycles, 2004, 63, 1765; (h) J. Nobuhiro, M. Hirayama, T. Choshi, K. Kamoshita, S. Maruyama,
Y. Sukenaga, T. Ishizu, H. Fujioka, and S. Hibino, Heterocycles, 2006, 70, 491; (i) S. Tohyama, T.
Choshi, K. Matsumoto, A. Yamabuki, K. Ikegata, J. Nobuhiro, and S. Hibino, Tetrahedron Lett.,
2005, 46, 5263; (j) A. Yamabuki, H. Fujinawa, T. Choshi, S. Tohyama, K. Matsumoto, K. Ohmura, J.
Nobuhiro, and S. Hibino, Tetrahedron Lett., 2006, 47, 5859.
8. K. Ohmura, T. Choshi, S. Watanabe, Y. Satoh, J. Nobuhiro, and S. Hibino, Chem. Pharm. Bull., 2008,
56, 237.
9. S. Raucher and B. L. Bray, J. Org. Chem., 1987, 52, 2332.
10. (a) E. Lee-Ruff and F. J. Ablenas, Can. J. Chem., 1987, 65, 1663; (b) B.-P. Ying, B. G. Trogden, D.
T. Kohlman, S.-X. Liang, and Y.-C. Xu, Org. Lett., 2004, 6, 1523.
11. J. P. Horwitz, V. K. Iyer, H. B. Vardhan, J. Corombos, and S. C. Brooks, J. Med. Chem., 1986, 29,
692.
12. (a) D. P. Chakraborty, P. Bhattacharyya, S. Roy, S. P. Bhattacharyya, and A. K. Biswas,
Phytochemistry, 1978, 17, 834; (b) G. Bringmann, S. Tasler, H. Endress, and K. Peters, and E.-M.
Peters, Synthesis, 1998, 1501.