An efficient Au-catalyzed synthesis of isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine v from propadienyl methyl ether

Article abstract of DOI:10.1039/c2ob27432a

Naturally occurring carbazole alkaloids such as isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V have been synthesized through a gold-catalyzed cyclization reaction of 1-(indol-2-yl)-2-methoxy-2,3-allenols, which are readily available from indolecarbaldehydes and methoxypropadiene. Compared to the reported procedures, our approach is general, atom economic, highly selective, and the starting materials are easily available.

Full text of DOI:10.1039/c2ob27432a

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An Efficient Au-Catalyzed Synthesis of Isomukonidine, Clausine L,
Mukonidine, Glycosinine, Mukonal, and Clausine V from Propadienyl
Methyl Ether
Youai Qiu, Dengke Ma, Chunling Fu,* and Shengming Ma*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Naturally occurring carbazole alkaloids such as isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V have been
synthesized through a goldꢀcatalyzed cyclization reaction of 1ꢀ(indolꢀ2ꢀyl)ꢀ2ꢀmethoxyꢀ2,3ꢀallenols, which are readily available from
indolecarbaldehydes and methoxypropadiene. Compared to the reported procedures, our approach is general, atom economic, highly
10 selective, and the starting materials are easily available.
Introduction
Carbazole alkaloids have received considerable interest because
of their existence in nature and unnatural compounds with
promising biological activities. For example, many 2ꢀoxygenated
15 carbazole alkaloids have been isolated from different parts of
Murraya, which grows in southern Asia. Some of these
compounds (Fig. 1) show useful biological activities:1 Mukonal
was isolated from the stem bark of this plant by Bhattacharyya in
1984;2 Wu and coꢀworkers described the isolation of mukonidine
20 and its Oꢀmethyl derivative (clausine L) from Chinese medicinal
plant Clausena excavate during studies on antiplatelet
aggregation activity in 1993.3 Chakraborty et al. isolated
mukonidine from the stem bark of Murraya koenigii in 1978,4
however, the physical and spectroscopic data were not in full
25 agreement with those of Wu’s synthesized sample. Finally, the
data of Knölker’s synthetic mukonidine confirmed that the
structure of Wu’s mukonidine is correct;5 Bhattacharyya et al.
obtained clausine L from the stem bark of Murraya koenigii in
1994;6 Lange et al. reported the isolation of Oꢀmethylmukonal
30 from Murraya siamensis in 1990.7a Two years later,
Bhattacharyya and coꢀworkers also obtained Oꢀmethylmukonal
from the root bark of a different natural source, Glycosmis
pentaphylla collected in Thailand, and named glycosinine.7b
Glycosinine was also isolated by Kongkathip and coꢀworkers
35 from the rhizomes and roots of Claysena excavate, and shows
interesting antiꢀHIV activity;7c in 1999, Wu and coꢀworkers
reported the isolation of clausine V from the acetone extract of
the root bark of Clausena excavate.8
50 Fig. 1 Naturally occurring 2ꢀoxygenated and 2,7ꢀdioxgenated carbazole
alkaloids
Knölker et al. reported the synthesis of mukonidine based on
the oxidation of the tricarbonyl [η4ꢀ4a,9aꢀdihydroꢀ9Hꢀcarbazole]
55 iron complex with pꢀchloranil (tetrachloroꢀ1,4ꢀbenzoquinone)
providing the desired product in very low yield (22%) together
with the undesired 21% biaryl derivative;9 the same group
subsequently described a remarkable approach for the preparation
of clausine L, mukonidine, glycosinine, and clausine V via
60 palladium(Ⅱ)ꢀcatalyzed oxidative cyclization of N, Nꢀ
diarylamines, which was prepared via BuchwaldꢀHartwig
coupling of iodobenzene and 3ꢀmethoxyꢀ4ꢀmethylaniline.5a
However, large amounts of oxidants (2.5 equiv of Cu(OAc)2, 2.2
equiv of DDQ, 25 equiv of MnO2) and highly toxic reagent (5
65 equiv of KCN) limit large scale synthesis. In the same year,
clausine L and mukonidine were synthesized by an improved
palladium(Ⅱ)ꢀcatalyzed route via CꢀH activation of N,Nꢀ
diarylamines, which was synthesized by palladium(0)ꢀcatalyzed
BuchwaldꢀHartwig amination of iodobenzene and methyl 4ꢀ
70 aminoꢀ2ꢀmethoxybenzoate.5b Even before the isolation of the
naturally occurring clausine V, Hsieh and Litt reported the
synthesis of this compound via Cadogan’s reductive cyclization
of 2ꢀnitrobiphenyl derivative with triethyl phosphite.10a In
40 Laboratory of Molecular Recognition and synthesis, Department of
Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of
China. E-mail: masm@sioc.ac.cn; Fax: +86-21-64167510.
† Electronic Supplementary Information (ESI) available: [details of any
45 supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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analogy to Heish and Litt’s procedure, clausine V was also
prepared by Keuethe and Childers. The difference is that the 2ꢀ
nitrobiphenyl derivative was synthesized by SuzukiꢀMiyaura
crossꢀcoupling of the 4ꢀmethoxyꢀ2ꢀnitrobenzenediazonium
tetrafluoroborate salt with 4ꢀmethoxyphenylboronic acid.10b
However, this approach was not environmentalꢀfriendly due to
the employment of large amounts of organophosphorous reagents
yielding two equivalents of phosphorous oxide. Thus, a general
and efficient route to these compounds is still desirable. In 2009,
hydride, bromideꢀlithium exchange and addition of
dimethylformamide afforded glycosinine in 60% yield. Mukonal
was afforded by demethylation with treatment of BBr3 in CH2Cl2.
5
10 we have described an approach to the carbazole skeleton through
a Ptꢀcatalyzed cyclization of 1ꢀ(indolꢀ2ꢀyl)ꢀ2,3ꢀallenols.11 Two
years later, we developed an Auꢀcatalyzed route to 2ꢀoxygenated
carbazoles, which was applied to the synthesis of naturally
occurring carbazole alkaloids such as siamenol, clausineꢀN,
15 clausineꢀC, clauszolineꢀK, and clausineꢀM.12 Herein, we wish to
report further application of this methodology to the general
synthesis of isomukonidine, clausine L, mukonidine, glycosinine,
mukonal, and clausine V.
Results and discussion
20
By retrosynthetic analysis of these carbazoles, the goldꢀ
catalyzed cyclization of indolyꢀ2,3ꢀallenols would be the key step
for synthesis of these natural carbazoles. Firstly, we considered
that using readily available methoxypropadiene13 and indoleꢀ2ꢀ
carbaldehyde as the starting materials for the synthesis of indolyꢀ
55
A similar approach may also be used for the synthesis of
25 2,3ꢀallenols.12 Then, regioselective bromination at Cꢀ3 with Nꢀ
bromosuccinimide, debenzylation, and necessary final
transformations would afford these natural carbazoles listed in
Fig.1 (Scheme 1).
allenol 2b, which undergoes
cyclization under the standard reaction conditions to afford
60 exclusively carbazole 3b in 74% yield from 1b to 3b. Then,
clausine V was obtained by deprotection of the Nꢀbenzyl group
with potassium tertꢀbutoxide in dimethylsulfoxide under oxygen
atmosphere (Scheme 3).
a smoothly AuClꢀcatalyzed
R1
OCH3
R3
OCH3
OR2
R3
Au
N
H
R3
N
N
OH
Bn
Bn
natural carbazoles
listed in Fig. 1
Li
CHO
R3
N
OCH3
Bn
30
Scheme 1 Retrosynthetic analysis of carbazoles listed in Fig. 1
Addition of 1ꢀmethoypropadienyllithium to the 1ꢀbenzylꢀ1Hꢀ
35 indoleꢀ2ꢀcarbaldehyde 1a, afforded the required methoxyꢀ
substituted allenol 2a, which was used without further
purification in the next step. Luckily, 9ꢀbenzylꢀ2ꢀmethoxyꢀ9Hꢀ
carbazole was formed exclusively in 77% yield from 1a to 3a
with a catalytic amount of gold (Ⅰ) chloride. Regioselective
40 electrophilic bromination at Cꢀ3 with Nꢀbromosuccinimide,
provided 9ꢀbenzylꢀ3ꢀbromoꢀ2ꢀmethoxyꢀ9Hꢀcarbazole 4a in 93%
yield. Then, debenzylation by treatment with potassium tertꢀ
butoxide in dimethylsulfoxide under oxygen atmosphere provided
the carbazole 5a in 81% yield.14 Gladly, isomukonidine was
45 synthesized by deprotonation of 5a with potassium hydride, BrꢀLi
exchange with nꢀBuLi, and carboxylation with gaseous carbon
dioxide in a moderate yield (50%). Clausine L was obtained by
methylation of 6a functionality with MeI in 90% yield with
NaHCO3 as base. Then, removal of the methyl group in clausine
50 L by treatment with BBr3 in CH2Cl2 led to mukonidine. For the
synthesis of glycosinine, deprotonation of 5a with potassium
65
Total yields of naturally occurring carbazole alkaloids from the
readily available methoxypropadiene are: isomukonidine (5 steps
with 29% overall yield), clausine L (6 steps with 26% overall
70 yield), mukonidine (7 steps with 17% overall yield), glycosinine
(5 steps with 34% overall yield), mukonal (6 steps with 30%
overall yield), clausine V (3 steps with 61% overall yield). The
spectroscopic data of our synthetic compounds are in full
agreement with those reported for the corresponding natural
75 products.
Conclusions
In conclusion, we have realized the highly efficient synthesis
of isomukonidine, clausine L, mukonidine, glycosinine, mukonal,
and clausine V via AuClꢀcatalyzed cyclization of indolyꢀ2,3ꢀ
2
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allenols 2a and 2b from the easily available indolecarbaldehydes
and methoxypropadiene with an excellent regioselectivity. Due to
the easy availability of the starting materials, excellent selectivity,
smooth reaction conditions, these routes will have a wide range
of application in organic synthesis and industrial production.
Further studies including biological activity studies of the
derivatives are being carried out in our laboratory.
5
Typical procedure Ⅱ: To a dry Schlenk tube were added
50 sequentially AuCl (23.0 mg, 0.1 mmol), 2a (prepared in the
previous step) and toluene (20 mL) under nitrogen atmosphere.
After stirring for 12 h at rt, the reaction was complete as
monitored by TLC. Filtration, evaporation and column
chromatography on silica gel (petroleum ether/ethyl acetate =
55 40/l) afforded 3a (443.2 mg, 77%, from 1a to 3a): solid; m.p.
143ꢀ144 °C (n-hexane/ethyl acetate); 1H NMR (300 MHz,
CDCl3) δ 8.06ꢀ7.88 (m, 2H, ArH), 7.38ꢀ7.04 (m, 8H, ArH), 6.90ꢀ
6.72 (m, 2H, ArH), 5.38 (s, 2H, CH2), 3.81 (s, 3H, CH3); 13C
NMR (75 MHz, CDCl3) δ 159.1, 142.0, 140.7, 137.0, 128.7,
60 127.4, 126.4, 124.5, 123.2, 121.1, 119.5, 119.3, 116.9, 108.6,
107.5, 93.4, 55.6, 46.5; IR (KBr) ν (cmꢀ1) 3086, 3060, 3031,
3009, 2962, 2936, 2833, 1625, 1603, 1575, 1496, 1464, 1451,
1358, 1334, 1248, 1200, 1173, 1119, 1055, 1033; MS (70 ev, EI)
m/z (%) 288 (M++1, 21.55), 287 (M+, 100); Elemental analysis
65 calcd for C20H17NO: C, 83.59; H, 5.96; N, 4.87; Found: C, 83.50,
H, 5.92; N, 4.92.
Acknowledgements
Financial support from the National Basic Research Program
10 of China (2009CB825300) and the National Natural Science
Foundation for China (21232006) is greatly appreciated. S. Ma. is
a Qiu shi Ajunct professor at Zhejiang University. We thank Ms.
Nan Wang in our group for reproducing the results of 9a
(glycosinine) and 10a (mukonal) in Scheme 2.
15 Experimental Section
General information：1H and 13C NMR spectra were recorded
with a Bruker AM 300 MHz spectrometer. IR spectra were
recorded with a Perkin–Elmer 983G instrument. Elemental
analyses were measured with a CarloꢀErba EA1110 elementary
20 analysis instrument. Mass spectrometry was performed with a HP
5989A system. Highꢀresolution mass spectrometry was
determined with a Finnigan MAT 8430 or Bruker APEXIII
instrument. Toluene, THF, Et2O, and CH2Cl2 were distilled from
Na/benzophenone before use. KH and dimethylformamide were
25 purchased from Acros, BBr3 (1.0 M in CH2Cl2) was purchased
from TCI. Unless otherwise indicated, chemicals and solvents
were purchased from commercial suppliers.
3. Synthesis of 1-(1-benzyl-6-methoxy-1H-indol-2-yl)-2-
methoxybuta-2,3-dien-1-ol (2b)
1. Synthesis of 1-(1-benzyl-1H-indol-2-yl)-2-methoxybuta-2,3-
dien-1-ol (2a)
30
70
Following typical procedure Ⅰ : The reaction of 1ꢀ
methoxypropaꢀ1,2ꢀdiene (382.0 mg, 5.46 mmol)/THF (20 mL),
n-BuLi (2.0 mL, 2.5 M in hexane, 5 mmol), and 1ꢀbenzylꢀ6ꢀ
methoxyꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (1069.0 mg, 4 mmol)/THF (5
75 mL) afforded 2b, the crude product 2b was then submitted to the
next step without further purification.
Typical procedure Ⅰ: To a solution of 1ꢀmethoxypropaꢀ1,2ꢀ
4. Synthesis of 9-benzyl-2,7-dimethoxy-9H-carbazole (3b)
diene (180.1 mg, 2.57 mmol) in THF (13 mL) was added
◦
dropwise n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) at ꢀ40 C
35 with stirring under a nitrogen atmosphere within 5 min. After
◦
being stirred for 30 min at ꢀ40 C, a solution of 1ꢀbenzylꢀ1Hꢀ
indoleꢀ2ꢀcarbaldehyde (470.1 mg, 2.0 mmol) in THF (3 mL) was
added dropwise at this temperature within 20 min. Then the
mixture was allowed to warm up to room temperature, after 1 h,
40 the reaction was complete as monitored by TLC. The mixture
was quenched with a saturated aqueous solution of NH4Cl (10
mL), and extracted with diethyl ether (20 mL×3). The combined
organic layer was washed with water and dried over anhydrous
K2CO3. After filtration and evaporation, the crude product 2a was
45 then submitted to the next step without further purification.
80
Following typical procedure Ⅱ. The reaction of AuCl (53.5 mg,
0.23 mmol) and 2b (prepared in the previous step) in toluene (20
mL) at rt for 11.5 h afforded 3b (943.7 mg, 74%) (petroleum
ether/ethyl acetate = 30/l~20/1): solid; m.p. 146ꢀ147 °C (n-
hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J =
85 8.4 Hz, 2H, ArH), 7.31ꢀ7.20 (m, 3H, ArH), 7.18ꢀ7.08 (m, 2H,
ArH), 6.88ꢀ6.74 (m, 4H, ArH), 5.37 (s, 2H, CH2), 3.84 (s, 6H, 2 ×
CH3); 13C NMR (75 MHz, CDCl3) δ 158.2, 142.1, 136.9, 128.8,
127.4, 126.4, 120.1, 117.1, 107.1, 93.6, 55.6, 46.5; IR (KBr) ν
2. Synthesis of 9-benzyl-2-methoxy-9H-carbazole (3a)
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Elemental analysis calcd for C13H10BrNO: C, 56.55; H, 3.65; N,
5.07; Found: C, 56.71; H, 3.68; N, 5.05.
(cmꢀ1) 3087, 3063, 3027, 2999, 2953, 2937, 2833, 1601, 1575,
1484, 1470, 1453, 1358, 1332, 1257, 1241, 1195, 1167, 1120,
1051, 1026; MS (70 ev, EI) m/z (%) 318 (M++1, 24.01), 317 (M+,
100); Elemental analysis calcd for C21H19NO2: C, 79.47; H, 6.03;
N, 4.41; Found: C, 79.54, H, 6.09; N, 4.53.
7. Synthesis of 2-methoxy-9H-carbazole-3-carboxylic acid
(Isomukonidine)
5
5. Synthesis of 9-benzyl-3-bromo-2-methoxy-9H-carbazole
(4a)
50
To a suspension of freshly washed and dried potassium hydride
(321.0 mg, 25%, 2.0 mmol) in THF (25 mL) was added 5a (275.6
mg, 1.0 mmol). After being stirred for 35 min at rt, the resulting
A suspension of 3a (715.1 mg, 2.49 mmol) and NBS (447.6
mixture was cooled to ꢀ78 oC, nꢀBuLi (0.44 mL, 2.5 M in hexane,
10 mg, 2.51 mmol) in CCl4 (25 mL) was stirred at rt for 30 min. The
reaction was complete as monitored by TLC. Evaporation and
column chromatography on silica gel (petroleum ether/ethyl
acetate = 40/l) afforded 4a (848.5 mg, 93%): solid; m.p. 140ꢀ141
o
55 1.1 mmol) was added within 5 min. After being stirred at ꢀ78 C
for additional 30 min, CO2 (dried by passing through
concentrated H2SO4) was bubbled through the mixture for 40
min. The resulting mixture was then allowed warm up to room
temperature. After 4 h, the reaction was complete as monitored
60 by TLC. The mixture was diluted with 30 mL of ethyl acetate,
acidified with dilute hydrochloric acid (aq. 10%) to PH < 4,
extracted with ethyl acetate (20 mL×3), washed with water (10
mL), and dried over anhydrous Na2SO4. After filtration and
evaporation, the residue was purified by column chromatography
65 on silica gel (petroleum ether/ethyl acetate = 1/1~1/2 for the first
round, dichloromethane/ethyl acetate = 3/1 for the second round
(impure part)) to give isomukonidine 6a (combined weight: 121.3
mg, 50%): solid; m.p. 224ꢀ226 oC (n-hexane/ethyl acetate) (lit.5a:
1
°C (n-hexane/ethyl acetate); H NMR (300 MHz, CDCl3) δ 8.19
15 (s, 1H, ArH), 7.93 (d, J = 7.2 Hz, 1H, ArH), 7.37ꢀ7.00 (m, 8H,
ArH), 6.70 (s, 1H, ArH), 5.32 (s, 2H, CH2), 3.82 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3) δ 154.5, 140.7, 140.6, 136.5, 128.8,
127.5, 126.2, 125.0, 124.5, 122.1, 119.7, 119.6, 117.5, 108.8,
103.2, 92.5, 56.3, 46.5; IR (KBr) ν (cmꢀ1) 3061, 3028, 3004,
20 2929, 1630, 1601, 1494, 1463, 1454, 1421, 1353, 1314, 1256,
1194, 1174, 1123, 1043, 1028; MS (70 ev, EI) m/z (%) 367
(M+(81Br), 69.63), 365 (M+(79Br), 70.80), 91 (100); Elemental
analysis calcd for C20H16BrNO: C, 65.59; H, 4.40; N, 3.82;
Found: C, 65.54; H, 4.36; N, 3.84.
o
226 C (decomp.)); 1H NMR (300 MHz, acetoneꢀd6) δ 10.88 (bs,
70 1H, COOH), 10.65 (bs, 1H, NH), 8.81 (s, 1H, ArH), 8.20 (d, J =
8.1 Hz, 1H, ArH), 7.56 (d, J = 8.1 Hz, 1H, ArH), 7.43 (t, J = 7.5
Hz, 1H, ArH), 7.33ꢀ7.24 (m, 2H, ArH), 4.17 (s, 3H, CH3); 13C
NMR (75 MHz, acetoneꢀd6) δ 167.4, 159.7, 145.9, 142.4, 127.2,
127.0, 124.8, 121.7, 121.5, 119.0, 112.7, 112.6, 95.5, 58.0; IR
75 (KBr) ν (cmꢀ1) 3240, 1706, 1626, 1609, 1577, 1495, 1460, 1439,
1402, 1343, 1327, 1224, 1163, 1028; MS (70 ev, EI) m/z (%) 242
(M++ 1, 15.98), 241 (M+, 100).
25 6. Synthesis of 3-bromo-2-methoxy-9H-carbazole (5a)
A solution of 4a (909.4 mg, 2.48 mmol) and tꢀBuOK (2780.4
mg, 24.8 mmol) in THF (15 mL) and DMSO (15 mL) with a O2
balloon was stirred at rt. After 4 h, the reaction was complete as
30 monitored by TLC. The resulting mixture was diluted with 20 mL
of ethyl acetate, and quenched with water (10 mL). The aqueous
layer was extracted with ethyl acetate (20 mL×3), the combined
organic layer was washed with water (10 mL×2) and dried over
anhydrous Na2SO4. After filtration and evaporation, the residue
35 was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 10/l~5/1~2/1) afforded 5a (556.0 mg, 81%),
8. Synthesis of methyl 2-methoxy-9H-carbazole-3-carboxylate
(Clausine L)
COOCH3
COOH
MeI, NaHCO3
OCH3
OCH3
DMF, rt, 16 h
90%
N
N
H
H
7a
Clausine L
6a
80
To a Schlenk tube was added 6a (159.8 mg, 0.66 mmol),
NaHCO3 (201.9 mg, 2.4 mmol), DMF (12 mL), and MeI (0.17
mL, d=2.28 g/mL, 2.7 mmol) sequentially. After being stirred for
16 h, the reaction was complete as monitored by TLC. The
1
solid; m.p. 190ꢀ191 °C (n-hexane/ethyl acetate); H NMR (300
MHz, acetoneꢀd6) δ 10.39 (bs, 1H, NH), 8.32 (s, 1H, ArH), 8.09
(d, J = 7.8 Hz, 1H, ArH), 7.51 (d, J = 7.8 Hz, 1H, ArH), 7.37 (t, J
40 = 7.7 Hz, 1H, ArH), 7.29ꢀ7.10 (m, 2H, ArH), 3.99 (s, 3H, CH3);
13C NMR (75 MHz, acetoneꢀd6) δ 156.1, 142.1, 141.9, 126.5,
125.8, 124.0, 121.1, 120.9, 119.4, 112.4, 104.2, 96.2, 57.4; IR
(KBr) ν (cmꢀ1) 3412, 3017, 2981, 2943, 1607, 1573, 1481, 1461,
1444, 1369, 1310, 1252, 1230, 1195, 1165, 1037, 1025; MS (70
45 ev, EI) m/z (%) 277 (M+(81Br), 96.66), 275 (M+(79Br), 100);
85 resulting mixture was quenched with water (20 mL). The aqueous
layer was extracted with ethyl acetate (20 mL×3), the combined
organic layer was washed with water (5 mL×2) and dried over
anhydrous Na2SO4. After filtration and evaporation, the residue
was purified by column chromatography on silica gel (petroleum
90 ether/ethyl acetate = 1/1) to give Clausine L 7a (151.7 mg, 90%):
o
solid; m.p. 174ꢀ175 C (n-hexane/ethyl acetate) (lit.5a: 172ꢀ173
4
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room temperature (10 min). The resulting mixture was quenched
with water (10 mL) at 0 C and extracted with ethyl acetate (20
oC); δ 10.52 (bs, 1H, NH), 8.61 (s, 1H, ArH), 8.13 (d, J = 7.8 Hz,
1H, ArH), 7.53 (d, J = 8.1 Hz, 1H, ArH), 7.40 (t, J = 7.4 Hz, 1H,
ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 7.18 (s, 1H, ArH), 3.94 (s,
o
mL×3). The organic layer was washed with dilute hydrochloric
3H, CH3), 3.90 (s, 3H, CH3); 13C NMR (75 MHz, acetoneꢀd6) δ 50 acid (5%), and dried over anhydrous Na2SO4. After filtration and
5
168.2, 160.5, 145.4, 142.2, 126.7, 125.7, 124.9, 121.4, 121.2,
117.7, 114.4, 112.5, 95.5, 57.1, 52.5; IR (KBr) ν (cmꢀ1) 3271,
3005, 2980, 2954, 1704, 1634, 1609, 1580, 1463, 1428, 1393,
1349, 1314, 1279, 1247, 1203, 1165, 1086, 1036; MS (70 ev, EI)
m/z (%) 256 (M+ + 1, 17.35), 255 (M+, 98.43), 224 (100);
evaporation, the residue was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 5/1~3/1 for the first
round, petroleum ether/ethyl acetate = 5/1~3/1 for the second
round (impure part)) to give Glycosinine 9a (combined weight:
55 133.8 mg, 60%): solid; m.p. 192ꢀ194 oC (n-hexane/ethyl acetate),
(lit.5a 196ꢀ198 C); H NMR (300 MHz, acetoneꢀd6) δ 10.64 (bs,
1H, NH), 10.47 (s, 1H, CHO), 8.52 (s, 1H, ArH), 8.14 (d, J = 7.8
Hz, 1H, ArH), 7.51 (d, J = 8.1 Hz, 1H, ArH), 7.38 (t, J = 7.8 Hz,
1H, ArH), 7.23 (t, J = 7.5 Hz, 1H, ArH), 7.16 (s, 1H, ArH), 4.02
60 (s, 3H, CH3); 13C NMR (75 MHz, acetoneꢀd6) δ 189.4, 163.2,
147.2, 142.4, 127.2, 125.2, 122.2, 121.8, 121.5, 120.4, 118.8,
112.7, 94.6, 57.1; IR (KBr) ν (cmꢀ1) 3408, 3310, 2865, 1666,
1601, 1579, 1463, 1435, 1328, 1259, 1243, 1201, 1157, 1034;
MS (70 ev, EI) m/z (%) 226 (M+ + 1, 15.14), 225 (M+, 100).
o
1
10 9. Synthesis of methyl 2-hydroxy-9H-carbazole-3-carboxylate
( Mukonidine)
To a solution of 7a (144.1 mg, 0.57 mmol) in CH2Cl2 (10 mL)
15 was added a solution of BBr3 (2.2 mL, 1.0 M in CH2Cl2, 2.2
mmol) at ꢀ78 oC within 10 min under N2. The mixture was stirred
65 11. Synthesis of 2-hydroxy-9H-carbazole-3-carbaldehyde
(Mukonal)
o
o
at ꢀ78 C (1 h), ꢀ20 C (2.6 h), and room temperature (1 h), the
reaction was complete as monitored by TLC. The mixture then
was quenched with 15 mL of a saturated aqueous solution of
20 NaHCO3 at 0 oC, the aqueous layer was extracted with ethyl
acetate (20 mL×3). The organic layer was washed with water and
dried over anhydrous Na2SO4. After filtration and evaporation,
the residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 3/1) to give Mukonidine 8a (88.9
25 mg, 65%): solid; m.p. 192ꢀ193 oC (n-hexane/ethyl acetate) (lit.5a:
To a solution of 9a (113.1 mg, 0.5 mmol) in CH2Cl2 (10 mL)
70 was added a solution of BBr3 (2.0 mL, 1.0 M in CH2Cl2, 2.0
mmol) at ꢀ78 oC within 10 min under N2. The mixture was stirred
at ꢀ78 C (40 min) and ꢀ20 C (22 h). The reaction was complete
as monitored by TLC. The resulting mixture was quenched with
20 mL of a saturated aqueous solution of NaHCO3 at ꢀ20 oC, then
o
189 C); 1H NMR (300 MHz, acetoneꢀd6) δ 11.13 (s, 1H, OH),
o
o
10.54 (bs, 1H, NH), 8.64 (s, 1H, ArH), 8.11 (d, J = 7.8 Hz, 1H,
ArH), 7.50 (d, J = 8.1 Hz, 1H, ArH), 7.40 (t, J = 7.5 Hz, 1H,
ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 6.97 (s, 1H, ArH), 4.03 (s, 75 diluted with 30 mL of ethyl acetate. The aqueous layer was
30 3H, CH3) ; 13C NMR (75 MHz, acetoneꢀd6) δ 172.9, 162.3, 147.3,
extracted with ethyl acetate (20 mL×3). The organic layer was
142.6, 127.2, 125.0, 124.1, 121.6, 121.3, 118.5, 112.5, 106.6,
98.4, 53.3; IR (KBr) ν (cmꢀ1) 3355, 2951, 1647, 1631, 1466,
1434, 1374, 1330, 1261, 1239, 1167, 1095; MS (70 ev, EI) m/z
(%) 242 (M+ + 1, 8.02), 241 (M+, 52.69), 209 (100);
washed with water and dried over anhydrous Na2SO4. After
filtration and evaporation, the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate =
80 5/1) to give Mukonal 10a (90.7 mg, 86%): solid; m.p. 239ꢀ240 oC
(n-hexane/ethyl acetate) (lit.2 238 °C); 1H NMR (300 MHz,
acetoneꢀd6) δ 11.52 (s, 1H, OH), 10.75 (bs, 1H, NH), 10.03 (s,
1H, CHO), 8.48 (s, 1H, ArH), 8.12 (d, J = 7.5 Hz, 1H, ArH), 7.54
(d, J = 8.4 Hz, 1H, ArH), 7.43 (t, J = 7.5 Hz, 1H, ArH), 7.27 (t, J
85 = 7.5 Hz, 1H, ArH), 6.94 (s, 1H, ArH); 13C NMR (75 MHz,
acetoneꢀd6) δ 197.4, 162.7, 147.8, 142.7, 129.3, 127.5, 125.0,
122.0, 121.4, 119.3, 117.0, 112.8, 98.1; IR (KBr) ν (cmꢀ1) 3375,
2961, 2941, 2855, 1640, 1610, 1477, 1455, 1363, 1326, 1249,
1205, 1167; MS (70 ev, EI) m/z (%) 212 (M+ + 1, 14.33), 211
90 (M+, 100).
35 10. Synthesis of 2-methoxy-9H-carbazole-3-carbaldehyde
(Glycosinine)
To a suspension of freshly washed and dried potassium hydride
40 (321.6 mg, 25%, 2.0 mmol) in THF (25 mL) was added 5a (275.5
mg, 1.0 mmol). After being stirred for additional 30 min at rt, the
mixture was cooled to ꢀ78 oC, nꢀBuLi (0.44 mL, 2.5 M in hexane,
1.1 mmol) was added to the mixture within 5 min. After being
12. Synthesis of 2,7-dimethoxy-9H-carbazole (5b) (Clausine
V)
o
stirred at ꢀ78 C for 30 min, a mixture of anhydrous DMF (0.39
45 mL, d = 0.9445 g/mL, 5.0 mmol)/THF (2 mL) was added
dropwise for 5 min. The mixture was stirred at ꢀ30 oC (0.5 h), and
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Bhattacharyya, P. Bhattacharyya, A. Chakraborty, B. K.
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dried over anhydrous Na2SO4. After filtration and evaporation,
10 the residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 2/1~1/1, it shoud be noted that
the column packed with silica gel was eluted with a mixture of
petroleum ether and triethylamine (100:1) before loading the
sample) afforded clausine V 5b (193.6 mg, 83%), solid; m.p.
15 279ꢀ280 °C (n-hexane/ethyl acetate) (lit.10a 272ꢀ274 °C); 1H
NMR (300 MHz, acetoneꢀd6) δ 10.11 (bs, 1H, NH), 7.89 (d, J =
8.4 Hz, 2H, ArH), 7.02 (d, J = 2.2 Hz, 2H, ArH), 6.80 (dd, J1 =
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20 56.5; IR (KBr) ν (cmꢀ1) 3383, 2836, 1609, 1573, 1504, 1456,
1323, 1265, 1233, 1198, 1160, 1120, 1027; MS (70 ev, EI) m/z
(%) 228 (M++ 1, 15.75), 227 (M+, 100).
70
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