Synthesis of the Pyrano[3,2- a ]carbazole Alkaloids Koenine, Koenimbine, Koenigine, Koenigicine, and Structural Reassignment of Mukonicine

Article abstract of DOI:10.1055/s-0035-1560359

Using the palladium(II)-catalyzed oxidative cyclization of a diarylamine and the annulation of a dimethylpyran ring by Lewis acid promoted reaction with prenal as key steps, the total syntheses of the 6-oxygenated pyrano[3,2-a]carbazole alkaloids koenine and koenimbine, and of the 6,7-dioxygenated pyrano[3,2-a]carbazole alkaloids koenigine and koenigicine (koenimbidine, koenidine) were achieved. Moreover, these studies led to an improved synthetic route to the 2,6-dioxygenated carbazole alkaloid glycozolidol. Mukonicine, originally published as 6,8-dimethoxypyrano[3,2-a]carbazole, was found to be identical with koenigicine.

Full text of DOI:10.1055/s-0035-1560359

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 150–160
paper
150
C. Schuster et al.
Paper
Synthesis
Synthesis of the Pyrano[3,2-a]carbazole Alkaloids Koenine,
Koenimbine, Koenigine, Koenigicine, and Structural Reassignment
of Mukonicine
Christian Schuster
Marika Rönnefahrt
Konstanze K. Julich-Gruner
Anne Jäger
MeO
MeO
MeO
H
+
+
HO
O
MeO
O
N
H
N
H
TIPSO
Br
H2N
O
OBn
koenigine
koenigicine (koenimbidine,
koenidine, mukonicine)
Arndt W. Schmidt
Hans-Joachim Knölker*
Department of Chemistry, Technische Universität Dresden,
Bergstraße 66, 01069 Dresden, Germany
hans-joachim.knoelker@tu-dresden.de
Received: 30.09.2015
RO
Accepted: 01.10.2015
6
Published online: 08.10.2015
DOI: 10.1055/s-0035-1560359; Art ID: ss-2015-z0560-op
O
O
N
H
N
H
Abstract Using the palladium(II)-catalyzed oxidative cyclization of a
diarylamine and the annulation of a dimethylpyran ring by Lewis acid
promoted reaction with prenal as key steps, the total syntheses of the
6-oxygenated pyrano[3,2-a]carbazole alkaloids koenine and koenim-
bine, and of the 6,7-dioxygenated pyrano[3,2-a]carbazole alkaloids
koenigine and koenigicine (koenimbidine, koenidine) were achieved.
Moreover, these studies led to an improved synthetic route to the 2,6-
dioxygenated carbazole alkaloid glycozolidol. Mukonicine, originally
published as 6,8-dimethoxypyrano[3,2-a]carbazole, was found to be
identical with koenigicine.
1 girinimbine
2a R = H
2b R = Me
koenine
koenimbine
MeO
MeO
6
6
O
RO
O
7
8
N
N
H
MeO
H
3 6,8-dimethoxygirinimbine
koenigine
4a R = H
(structure proposed
for mukonicine)
4b R = Me
koenigicine
(koenimbidine,
koenidine)
Key words alkaloids, catalysis, cyclization, natural products, palladi-
um
Figure 1 Oxygenated pyrano[3,2-a]carbazole alkaloids
Carbazole alkaloids are intriguing because of their
structural variety and their broad range of useful biological
activities.1–3 One important structural family are the pyra-
no[3,2-a]carbazoles featuring girinimbine (1) as the parent
compound (Figure 1).4 Several oxygenated pyrano[3,2-a]-
carbazole alkaloids have been isolated from various plant
sources. Koenine (2a), a 6-hydroxygirinimbine, was isolated
by Narasimhan et al. from the leaves of Murraya koenigii.5,6
Koenimbine (2b) was obtained by Narasimhan et al.6,7 from
the fruits of M. koenigii and by Kapil et al. from the leaves of
the same plant.8 Koenimbine (2b) was found to have a sig-
nificant antidiarrhoeal activity.9
Mukonicine, which has been assigned as 6,8-dimethoxy-
girinimbine (3), was isolated from the leaves of M. koe-
nigii.10 The 6,7-dioxygenated pyrano[3,2-a]carbazole alka-
loid koenigine (4a) was isolated by Narasimhan et al. from
the same natural source.5,6 The corresponding 6,7-di-
methoxygirinimbine (4b) was obtained from the leaves of
M. koenigii first in 1969 by Kapil et al. (named koenigicine),8
and one year later by Joshi et al. (named koenimbidine),11
and by Narasimhan et al. (named koenidine).5,6
Over the past two decades, we have developed four dif-
ferent synthetic routes to girinimbine (1).12–15 The palladi-
um-catalyzed synthesis of 2-hydroxy-3-methylcarbazole
followed by annulation of the pyran ring in a Lewis acid
promoted reaction with prenal provided the best access to
1 (4 steps, 69% overall yield).15 Our palladium-catalyzed
route provides an efficient access to a broad range of carba-
zoles16 and has been applied to the total syntheses of 2,6-
dioxygenated carbazole alkaloids,17 and 7- and 8-oxygenated
pyrano[3,2-a]carbazole alkaloids.18–22 In the present work,22
we describe the application of our methodology to the syn-
thesis of the pyrano[3,2-a]carbazoles 2–4.
Buchwald–Hartwig coupling of the bromoarene 5 and
the arylamine 6 in the presence of DavePhos23 as ligand af-
forded the N,N-diarylamine 7 (Scheme 1). The palladi-
um(II)-catalyzed oxidative cyclization24 of 7 led to the or-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 150–160

151
C. Schuster et al.
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Synthesis
thogonally diprotected 2,6-dioxygenated carbazole 8 in 67%
yield over both steps. Removal of the silyl protecting group
with tetrabutylammonium fluoride (TBAF) afforded glyco-
zolidol (9) via an improved route (3 steps, 54% overall
yield).25 Cleavage of the methyl ether of compound 8 by
treatment with boron tribromide provided the 2-hydroxy-
carbazole 10. Annulation of the pyran ring following Casir-
aghi’s method (reaction with prenal in the presence of tita-
nium tetraisopropoxide in toluene at r.t.)15,26 afforded the
pyrano[3,2-a]carbazole 11. Desilylation using TBAF provided
koenine (2a), which was obtained in five steps and 35%
overall yield. Finally O-methylation of koenine (2a) led to
koenimbine (2b). The spectroscopic data of our products 2a
and 2b are in full agreement with those reported in the
literature for the corresponding compounds isolated from
natural sources.5–8 The approach depicted in Scheme 1 pro-
vided koenimbine (2b) in six steps and only 20% overall
yield. Therefore, we sought a shorter route that would pro-
vide this natural product in a better overall yield.
For the alternative approach to koenimbine (2b), the
N,N-diarylamine 14 was prepared by Buchwald–Hartwig
coupling of p-bromoanisole (12) and the arylamine 13
(Scheme 2). Palladium(II)-catalyzed oxidative cyclization of
14 afforded the 2,6-dioxygenated carbazole 15 in 65% yield
over both steps. Cleavage of the silyl ether with TBAF led to
carbalexin C (16).17,27 Annulation of the pyran ring afforded
koenimbine (2b) in four steps and 39% overall yield based
on compound 12. Our approach to koenine (2a) and
koenimbine (2b) is much superior to the previous synthe-
ses reported by Kapil et al.28
MeO
MeO
a
+
N
H
OR
Br
H2N
OR
12
13
14
(R = SiPh2t-Bu)
MeO
MeO
b
c
OR
OH
RO
N
N
RO
a
H
H
+
N
H
7
OMe
Br
H2N
OMe
15
carbalexin C (16)
MeO
5
6
d
(R = SiPh2t-Bu)
O
N
RO
HO
H
koenimbine (2b)
b
c
OMe
OMe
N
H
N
H
Scheme 2 Synthesis of carbalexin C (16) and koenimbine (2b).
Reagents and conditions: a) 13 (1.2 equiv), Pd(OAc)2 (6 mol%), BINAP
(6 mol%), Cs2CO3 (1.2 equiv), toluene, reflux, 1 d (86%); b) Pd(OAc)2
(10 mol%), Cu(OAc)2 (2.5 equiv), AcOH, air, 130 °C (MW, 300 W), 2 h
(76%); c) TBAF (1.6 equiv, 1 M in THF), DMF, 0 °C to r.t., 1 h (90%);
d) Ti(Oi-Pr)4 (4 equiv), prenal (2 equiv), toluene, r.t., 16 h (67%).
8
glycozolidol (9)
d
RO
RO
e
OH
O
Mukonicine has been described as 6,8-dimethoxygirin-
imbine (3).10 Based on this structural assignment, our ret-
rosynthetic analysis led to 2-hydroxy-6,8-dimethoxy-3-
methylcarbazole (17) (Scheme 3). Using carbazole 17 as
precursor, annulation of the pyran ring by reaction with an
appropriate C5-building block would lead directly to 6,8-di-
methoxygirinimbine (3). Carbazole 17 should be accessible
from the bromoarene 18 and the arylamine 19 following
our palladium-catalyzed route.
N
H
N
H
10
11
HO
MeO
f
g
O
O
N
H
N
H
koenine (2a)
koenimbine (2b)
Scheme 1 Synthesis of glycozolidol (9), koenine (2a), and koenimbine
(2b). Reagents and conditions: a) 6 (1.1 equiv), Pd2(dba)3 (6 mol%), Dave-
Phos (12 mol%), NaOt-Bu (1.4 equiv), toluene, reflux, 24 h (quant.); b)
Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.5 equiv), DMF (3 drops), 130 °C (MW,
300 W), 45 min (67%); c) TBAF (1.5 equiv, 1 M in THF), DMF, 0 °C, 20
min (81%); d) BBr3 (2.1 equiv), CH2Cl2, –78 °C (30 min), –10 to 0 °C (2
h), r.t. (16 h) (85%); e) Ti(Oi-Pr)4 (4 equiv), prenal (2 equiv), toluene, r.t.,
16 h (70%); f) TBAF (1.2 equiv, 1 M in THF), DMF, 0 °C, 10 min (87%); g)
MeI (1.1 equiv), NaH (1.8 equiv), THF, 0 °C to r.t., 24 h (57%).
MeO
MeO
O
OH + C5 moiety
N
N
MeO
MeO
H
H
17
3
MeO
+
Br
H2N
OBn
OMe
18
19
Scheme 3 Retrosynthetic analysis of 6,8-dimethoxygirinimbine (3)
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C. Schuster et al.
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Synthesis
We have demonstrated previously that our approach to
carbazoles can be efficiently applied to the synthesis of tri-
oxygenated derivatives.29 Thus, palladium(0)-catalyzed
coupling of 2,4-dimethoxybromobenzene (18) with the
arylamine 19 to the N,N-diarylamine 20 and subsequent
palladium(II)-catalyzed oxidative cyclization provided the
carbazole 21 (Scheme 4). Removal of the benzyl protecting
group by hydrogenolysis afforded 2-hydroxy-6,8-dime-
thoxy-3-methylcarbazole (17). Preparation of the dimethyl-
propargyl ether 22 using Godfrey’s procedure30 followed by
thermally induced rearrangement31 provided 6,8-dime-
thoxygirinimbine (3). Since the yield for the annulation of
the pyran ring at carbazole 17 was only 40% over both steps,
we also tested an alternative procedure (Scheme 5).
the presence of 20 mol% phenylboronic acid in propanoic
acid–toluene and obtained 6,8-dimethoxygirinimbine (3) in
69% yield (Scheme 5).
1
However, a careful comparison of the H NMR spectro-
scopic data of compound 3 with those which have been re-
ported for the natural product mukonicine showed that the
data are not in agreement (Table 1). There are significant
differences especially in the chemical shifts observed for
the protons at C5 and C7. Also the melting points for both
compounds differ by more than 60 °C. Thus, we concluded
that the structure of mukonicine may be isomeric to 6,8-di-
methoxygirinimbine (3) and focused on our next synthetic
target, koenigicine (4b), which in fact represents a regioiso-
mer of compound 3.
MeO
MeO
Table 1 Comparison of the 1H NMR Data (Solvent: CDCl3) and Melting
Point of Mukonicine with Those of Compound 3
a
+
N
H
OBn
OH
Br
H2N
OBn
MeO
MeO
Mukonicine10
Compound 3
18
19
20
C3-CH3
C4-H
2.30 (s)
2.31 (s)
MeO
MeO
b
c
7.56 (s)
7.59 (s)
OBn
C5-H
7.40 (s)
6.99 (br s)
N
H
N
H
MeO
MeO
C6-OCH3
C7-H
3.90 (s)
3.90 (s)
21
17
6.88 (s)
6.49 (d, J = 2.1 Hz)
3.96 (s)
MeO
MeO
C8-OCH3
NH
3.90 (s)
d
e
7.81 (br s)
1.44 (s)
7.88 (br s)
O
O
N
H
N
C2′-CH3 (2 ×)
C3′-H
1.47 (s)
MeO
MeO
H
5.65 (d, J = 9 Hz)
6.55 (d, J = 9 Hz)
233–234 °C
5.67 (d, J = 9.7 Hz)
6.63 (d, J = 9.7 Hz)
165–170 °C
22
3
C4′-H
Scheme 4 Synthesis of 6,8-dimethoxygirinimbine (3) via Godfrey’s
method. Reagents and conditions: a) 19 (1.2 equiv), Pd(OAc)2 (20 mol%),
XPhos (40 mol%), Cs2CO3 (1.4 equiv), toluene, reflux, 16 h (92%); b)
Pd(OAc)2 (10 mol%), K2CO3 (10 mol%), PivOH, 85 °C, 24 h (67%); c) 20%
Pd(OH)2/C, H2, MeOH–CH2Cl2 (4:1), r.t., 2 d (88%); d) 1. 2-methylbut-3-
yn-2-ol (1.15 equiv), (CF3CO)2O (1.15 equiv), DBU (1.5 equiv), MeCN, –5 °C,
20 min, 2. 17 (1.0 equiv), DBU (1.3 equiv), CuCl2·H2O (1 mol%), MeCN,
0 °C, 18 h; e) toluene, reflux, 24 h (40% over 2 steps).
mp
Buchwald–Hartwig coupling of the bromoarene 23 and
the arylamine 19 in the presence of XPhos as ligand to the
N,N-diarylamine 24 followed by palladium(II)-catalyzed
oxidative cyclization gave the orthogonally protected 2,6,7-
trioxygenated carbazole 25 in 66% yield over both steps
(Scheme 6). Debenzylation of 25 to the 2-hydroxycarbazole
26 and subsequent Lewis acid promoted annulation of the
pyran ring led to the pyrano[3,2-a]carbazole 27. Removal of
the silyl protecting group using TBAF afforded koenigine
(4a). The O-methylation of koenigine (4a) provided koenigi-
cine (4b) in six steps and 33% overall yield based on the bro-
moarene 23. Thus, we have achieved the first total synthe-
sis of koenigine (4a) and a novel considerably improved to-
tal synthesis of koenigicine (koenimbidine, koenidine)
(4b).33
The boronic acid catalyzed pyran ring annulation was
recently applied by us to the synthesis of pyranocarbazole
alkaloids.19,32 Thus, we treated compound 17 with prenal in
MeO
MeO
a
OH
O
N
H
N
H
MeO
MeO
17
3
Scheme 5 Synthesis of 6,8-dimethoxygirinimbine (3) via the boronic
acid catalyzed pyran annulation. Reagents and conditions: a) prenal
(1.5 equiv), PhB(OH)2 (20 mol%), EtCO2H (110 equiv), toluene, reflux,
46 h (69%).
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Synthesis
MeO
MeO
TIPSO
23
a
TIPSO
N
H
OBn
Br
24
MeO
b
c
TIPSO
OBn
N
H
25
Figure 2 Molecular structure of koenigicine (koenimbidine, koenidine)
(4b) in the crystal (orthorhombic, P212121); ORTEP plot showing ther-
mal ellipsoids at the 50% probability level.
MeO
MeO
d
TIPSO
OH
TIPSO
O
N
H
N
H
A comparison of the 1H NMR data and the melting point
of our synthetic compound 4b with those reported for koe-
nigicine (4b), as well as with the corresponding data reported
on the other isolations of this alkaloid, koenimbidine (4b),
and koenidine (4b) confirmed a very good agreement (Ta-
ble 2). Moreover, we found that the data of our compound
4b also matched those reported for mukonicine. Therefore,
we concluded that the structure for mukonicine must be re-
assigned as 4b and that mukonicine is in fact identical with
koenigicine (koenimbidine, koenidine).
In conclusion, we have developed an efficient route to
the oxygenated pyrano[3,2-a]carbazole alkaloids 2–4. Key
steps of our approach are the palladium(0)-catalyzed C–N
bond formation followed by a palladium(II)-catalyzed oxi-
dative cyclization of the corresponding N,N-diarylamine to
generate the carbazole framework. Thus, koenine (2a) was
obtained in five steps and 35% overall yield and koenimbine
(2b) in four steps and 39% overall yield. In the course of this
work, we also developed an improved synthesis of the 2,6-
dioxygenated carbazole alkaloid glycozolidol (9), which be-
26
27
MeO
MeO
e
f
HO
O
MeO
O
N
H
N
H
koenigine (4a)
koenigicine (4b)
Scheme 6 Synthesis of koenigine (4a) and koenigicine (4b). Reagents
and conditions: a) 3-benzyloxy-4-methylaniline (19) (1.2 equiv),
Pd(OAc)2 (6 mol%), XPhos (12 mol%), Cs2CO3 (1.2 equiv), toluene, re-
flux, 19.5 h (93%); b) Pd(OAc)2 (15 mol%), Cu(OAc)2 (2.5 equiv), AcOH,
130 °C (MW, 300 W), 1 h (71%); c) 10% Pd/C, H2, EtOAc, r.t., 19 h (89%);
d) Ti(Oi-Pr)4 (4 equiv), prenal (2 equiv), toluene, r.t., 15.5 h (65%); e)
TBAF (1.5 equiv, 1 M in THF), THF, 0 °C, 10 min (94%); f) Me2SO4 (5
equiv), K2CO3 (2 equiv), acetone, 56 °C, 18.5 h (93%).
An unequivocal confirmation of our structural assign-
ment of compound 4b was achieved by the X-ray analysis of
a single crystal (Figure 2).
Table 2 Comparison of the 1H NMR Data (Solvent: CDCl3) and the Melting Points of Koenigicine, Koenimbidine, Koenidine, and Mukonicine with Those
of Synthetic 4b
Koenigicine (4b)8
Koenimbidine (4b)11
Koenidine (4b)5,6
Mukonicine
Synthetic 4b
C3-CH3
C4-H
2.33 (s)
2.30 (s)
7.53 (s)
7.40 (s)
3.90 (s)
3.90 (s)
6.90 (s)
2.30 (s)
2.33 (s)
7.50 (s)
7.52 (s)
7.36 (s)
7.56 (s)
7.55 (br s)
7.38 (s)
C5-H
7.40 (s)
7.40 (s)
C6-OCH3
C7-OCH3
C8-H
3.86 (s)
3.90 (s)
3.93 (s)
3.96 (s)
3.90 (s)
3.98 (s)
6.83 (s)
6.87 (s)
6.88 (s)
6.90 (s)
NH
7.81 (br s)
1.50 (s)
7.81 (br s)
1.44 (s)
7.74 (br s)
1.48 (s)
C2′-CH3 (2 ×)
C3′-H
1.49
5.63 (d, J = 10 Hz)
6.58 (d, J = 10 Hz)
224–225 °C
5.63 (d, J = 10 Hz)
6.78 (d, J = 10 Hz)
225 °C
5.65
5.65 (d, J = 9 Hz)
6.55 (d, J = 9 Hz)
233–234 °C
5.68 (d, J = 9.7 Hz)
6.60 (d, J = 9.7 Hz)
223–224 °C
C4′-H
6.58
mp
224–225 °C
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 150–160

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C. Schuster et al.
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Synthesis
came available in three steps and 54% overall yield. 6,8-Di-
methoxygirinimbine (3) was synthesized in four steps and
37% overall yield and was found not to be identical with
mukonicine. Finally, we have completed the first total syn-
thesis of koenigine (4a) in five steps and 36% overall yield
and an improved synthesis of koenigicine (koenimbidine,
koenidine) (4b) in six steps and 33% overall yield. Moreover,
by comparison of the H NMR data and the melting points,
we concluded that mukonicine has to be reassigned and is
identical with koenigicine (koenimbidine, koenidine) (4b).
N-[4-(tert-Butyldiphenylsilyloxy)phenyl]-3-methoxy-4-methyl-
aniline (7)
A solution of the bromoarene 5 (1.00 g, 2.43 mmol) in toluene (15 mL)
was added dropwise over a period of 2 h to a solution of 3-methoxy-
4-methylaniline (6) (366 mg, 2.67 mmol), Pd2(dba)3 (134 mg, 0.146
mmol), DavePhos (115 mg, 0.292 mmol), and NaOt-Bu (321 mg, 3.34
mmol) in toluene (35 mL) at reflux. The reaction mixture was heated
at reflux for 24 h, cooled to r.t., and the solvent was removed under
vacuum. Flash chromatography (silica gel, PE–EtOAc, 30:1) of the
crude product provided 7 as a red-brown viscous oil; yield: 1.13 g
(quant.).
1
IR (ATR): 3395, 3068, 2952, 2931, 2857, 1609, 1591, 1570, 1558, 1542,
1501, 1458, 1426, 1392, 1250, 1230, 1161, 1128, 1110, 1038, 995,
915, 823, 742, 700, 637, 610 cm–1
.
All reactions were carried out in oven-dried glassware using anhy-
drous solvents under an argon atmosphere, unless stated otherwise.
CH2Cl2, THF, and toluene were dried using a solvent purification sys-
tem (MBraun-SPS). Petroleum ether (PE) used refers to the hydrocar-
bon mixture with a boiling range of 40–65 °C. Pd(OAc)2 was recrystal-
lized from glacial AcOH. All other chemicals were used as received
from commercial sources. Flash chromatography was performed on a
Büchi Sepacore system equipped with an UV monitor using silica gel
from Acros Organics (0.035–0.070 mm). TLC was performed with TLC
plates from Merck (60 F254) using UV light for visualization. Melting
points were measured on a Gallenkamp MPD 350 melting point appa-
ratus. Ultraviolet spectra were recorded on a PerkinElmer 25 UV/Vis
spectrometer. IR spectra were recorded on a Thermo Nicolet Avatar
360 FT-IR spectrometer using the ATR method (Attenuated Total Re-
flectance). NMR spectra were recorded on Bruker DRX 500 and
Avance III 600 spectrometers. Chemical shifts δ are reported in parts
per million with the solvent signal as internal standard. Standard ab-
breviations were used to denote the multiplicities of the signals. Mass
spectra were recorded on a Finnigan MAT-95 spectrometer (electron
impact, 70 eV) or by GC/MS-coupling using an Agilent Technologies
6890 N GC System equipped with a 5973 Mass Selective Detector
(electron impact, 70 eV). ESI-MS spectra were recorded on an Esquire
LC with an ion trap detector from Bruker. Positive and negative ions
were detected. Elemental analyses were measured on an EuroVector
EuroEA3000 elemental analyzer.
1H NMR (500 MHz, CDCl3): δ = 1.13 (s, 9 H), 2.14 (s, 3 H), 3.73 (s, 3 H),
5.55 (br s, 1 H), 6.42–6.43 (m, 2 H), 6.70–6.72 (m, 2 H), 6.85 (d, J = 8.7
Hz, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.37–7.45 (m, 6 H), 7.74–7.76 (m, 4
H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 15.44 (CH3), 19.42 (C), 26.52
(3 CH3), 55.13 (CH3), 99.75 (CH), 108.27 (CH), 118.15 (C), 120.23 (2
CH), 120.63 (2 CH), 127.69 (4 CH), 129.80 (2 CH), 130.82 (CH), 133.06
(2 C), 135.53 (4 CH), 136.58 (C), 143.66 (C), 150.49 (C), 158.28 (C).
MS (EI): m/z (%) = 467 (100, [M+]), 410 (48).
HRMS: m/z [M+] calcd for C30H33NO2Si: 467.2281; found: 467.2275.
6-(tert-Butyldiphenylsilyloxy)-2-methoxy-3-methyl-9H-carba-
zole (8)
DMF (3 drops) was added to a mixture of the diarylamine 7 (60.0 mg,
0.128 mmol), Pd(OAc)2 (2.9 mg, 13 μmol), and Cu(OAc)2 (58.0 mg,
0.319 mmol), and the mixture was heated at 130 °C by microwave ir-
radiation (300 W) for 45 min. Removal of the solvent under vacuum
and flash chromatography (silica gel, PE–EtOAc, 20:1) of the crude
product provided 8 as a light brown solid; yield: 40.0 mg (67%); mp
110–112 °C.
IR (ATR): 3406, 3048, 2995, 2932, 2857, 1631, 1583, 1485, 1458, 1427,
1392, 1319, 1271, 1194, 1130, 1110, 1037, 1003, 917, 871, 821, 810,
737, 699, 626, 606 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.14 (s, 9 H), 2.30 (s, 3 H), 3.88 (s, 3 H),
6.76 (dd, J = 8.6, 2.4 Hz, 1 H), 6.77 (s, 1 H), 7.04 (d, J = 8.6 Hz, 1 H),
7.33–7.42 (m, 7 H), 7.54 (s, 1 H), 7.64 (br s, 1 H), 7.77–7.79 (m, 4 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.61 (CH3), 19.56 (C), 26.64
(3 CH3), 55.49 (CH3), 92.32 (CH), 109.35 (CH), 110.19 (CH), 116.18 (C),
116.85 (CH), 118.79 (C), 121.46 (CH), 124.08 (C), 127.66 (4 CH),
129.70 (2 CH), 133.51 (2 C), 134.27 (C), 135.63 (4 CH), 139.96 (C),
149.21 (C), 157.34 (C).
4-Bromphenyl tert-Butyldiphenylsilyl Ether (5)
Imidazole (3.94 g, 57.8 mmol) was added to a solution of 4-bro-
mophenol (5.00 g, 28.9 mmol) in DMF (60 mL). The mixture was
stirred for 15 min at r.t., t-BuPh2SiCl (11.2 mL, 43.3 mmol) was added,
and stirring was continued for 3 h at r.t. H2O (30 mL) and aq 1 M HCl
(50 mL) were added and the reaction mixture was extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were washed with
brine and sat. aq NH4Cl, and dried (MgSO4). Removal of the solvent
and flash chromatography (silica gel, PE–EtOAc, 15:1) of the crude
product provided 5 as a colorless solid; yield: 11.5 g (97%); mp 50 °C
(Lit.34 43.5–45 °C).
MS (EI): m/z (%) = 465 (63, [M+]), 408 (100), 204 (11).
HRMS: m/z [M+] calcd for C30H31NO2Si: 465.2124; found: 465.2126.
UV (MeOH): λ = 219 (sh), 238, 259, 297 (sh), 310, 332 (sh), 346 (sh)
nm.
IR (ATR): 3055, 2959, 2929, 2890, 2856, 1517, 1481, 1459, 1427, 1390,
1362, 1272, 1254, 1191, 1166, 1112, 1067, 1004, 918, 823, 736, 694,
Fluorescence (MeOH): λex = 310 nm, λem = 375 nm.
630, 613 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 9 H), 6.63–6.65 (m, 2 H), 7.17–
7.20 (m, 2 H), 7.37–7.40 (m, 4 H), 7.43–46 (m, 2 H), 7.69–7.71 (m, 4 H).
Glycozolidol (6-Hydroxy-2-methoxy-3-methyl-9H-carbazole; 9)
A 1 M solution of TBAF in THF (1.15 mL, 1.15 mmol) was added to a
solution of the carbazole 8 (355 mg, 0.762 mmol) in DMF (15 mL) at
0 °C. After stirring for 20 min at 0 °C, H2O (10 mL) was added, and the
mixture was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with sat. aq NH4Cl and dried (MgSO4). Removal of
13C NMR and DEPT (125 MHz, CDCl3): δ = 19.40 (C), 26.41 (3 CH3),
113.31 (C), 121.45 (2 CH), 127.84 (4 CH), 130.03 (2 CH), 132.05 (2 CH),
132.38 (2 C), 135.43 (4 CH), 154.71 (C).
MS (EI): m/z (%) = 412 (4), 410 (4, [M+]), 355 (100), 353 (96), 273 (18).
HRMS: m/z [M+] calcd for C22H23BrOSi: 410.0702; found: 410.0715.
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the solvent under vacuum and flash chromatography (silica gel, PE–
EtOAc, 5:1) of the crude product provided 9 as a light yellow solid;
yield: 140 mg (81%); mp 245–250 °C (Lit.25a 240 °C).
layers were dried (MgSO4). Removal of the solvent under vacuum and
flash chromatography (silica gel, PE–EtOAc, 20:1) of the crude
product provided 11 as an orange viscous oil; yield: 43.5 mg (70%).
IR (ATR): 3520, 3387, 2959, 2940, 2917, 2848, 1629, 1585, 1485, 1457,
1434, 1373, 1347, 1310, 1281, 1220, 1195, 1158, 1135, 1113, 1032,
IR (ATR): 3428, 3068, 3045, 2955, 2925, 2855, 1643, 1458, 1427, 1392,
1360, 1334, 1280, 1205, 1138, 1110, 1057, 1026, 972, 892, 857, 821,
998, 908, 881, 853, 818, 789, 754, 614 cm–1
.
802, 742, 699, 664, 608 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 2.25 (s, 3 H), 3.85 (s, 3 H), 6.75 (dd,
J = 8.6, 2.4 Hz, 1 H), 6.87 (s, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 7.25 (d,
J = 2.4 Hz, 1 H), 7.68 (s, 1 H), 8.78 (br s, 1 H), 10.62 (br s, 1 H).
13C NMR and DEPT (125 MHz, DMSO-d6): δ = 16.63 (CH3), 55.25 (CH3),
92.53 (CH), 104.13 (CH), 110.85 (CH), 112.94 (CH), 115.20 (C), 116.57
(C), 121.10 (CH), 123.30 (C), 133.54 (C), 140.27 (C), 150.32 (C), 156.61
(C).
1H NMR (500 MHz, acetone-d6): δ = 1.16 (s, 9 H), 1.47 (s, 6 H), 2.26 (s,
3 H), 5.76 (d, J = 9.8 Hz, 1 H), 6.80 (dd, J = 8.6, 2.4 Hz, 1 H), 6.88 (d,
J = 9.8 Hz, 1 H), 7.16 (d, J = 8.6 Hz, 1 H), 7.42–7.51 (m, 8 H), 7.84–7.86
(m, 4 H), 10.07 (br s, 1 H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.16 (CH3), 20.03 (C),
27.03 (3 CH3), 27.83 (2 CH3), 76.48 (C), 105.36 (C), 109.83 (CH), 111.40
(CH), 117.37 (C), 117.56 (CH), 118.01 (C), 118.60 (CH), 121.68 (CH),
124.98 (C), 128.66 (4 CH), 129.66 (CH), 130.78 (2 CH), 134.25 (2 C),
135.99 (C), 136.35 (4 CH), 137.17 (C), 149.75 (C), 150.52 (C).
MS (EI): m/z (%) = 227 (100, [M+]), 212 (70), 184 (19), 183 (19), 154
(10).
MS (EI): m/z (%) = 517 (100, [M+]), 502 (48), 460 (65), 223 (29).
HRMS: m/z [M+] calcd for C34H35NO2Si: 517.2437; found: 517.2425.
UV (MeOH): λ = 216, 232, 262, 311 nm.
Fluorescence (MeOH): λex = 311 nm, λem = 384 nm.
UV (MeOH): λ = 224, 238, 252 (sh), 272 (sh), 287 (sh), 296, 336, 352,
367 nm.
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.74;
H, 5.89; N, 6.17.
Fluorescence (MeOH): λex = 296 nm, λem = 391 nm.
6-(tert-Butyldiphenylsilyloxy)-2-hydroxy-3-methyl-9H-carbazole
(10)
Koenine (2a)
A 1 M solution of BBr3 in CH2Cl2 (0.16 mL, 0.16 mmol) was added
slowly to a stirred solution of carbazole 8 (35 mg, 0.075 mmol) in
CH2Cl2 (5 mL) at –78 °C. The mixture was stirred for 30 min at –78 °C,
for 2 h at –10 to 0 °C, warmed to r.t., and stirred overnight at r.t.
MeOH–H2O (1:15, 16 mL) was added, the aqueous layer was extracted
with CH2Cl2 (3 × 8 mL), and the combined organic layers were dried
(MgSO4). Removal of the solvent under vacuum and flash chroma-
tography (silica gel, PE–EtOAc, 4:1) of the crude product provided 10
as a yellow viscous oil, which solidified on standing; yield: 28 mg
(85%); mp 93 °C.
A 1 M solution of TBAF in THF (0.20 mL, 0.20 mmol) was added slowly
to a solution of the pyrano[3,2-a]carbazole 11 (85 mg, 0.164 mmol) in
DMF (5 mL) at 0 °C and the mixture was stirred for 10 min at 0 °C. H2O
(5 mL) was added and the mixture was extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with sat. aq NH4Cl
and dried (MgSO4). Removal of the solvent under vacuum and flash
chromatography (silica gel, PE–EtOAc, 2:1) of the crude product pro-
vided koenine (2a) as a light yellow solid; yield: 40 mg (87%); mp
244–247 °C (Lit.5,6 250–252 °C).
IR (ATR): 3457, 3327, 2970, 2922, 1703, 1643, 1492, 1466, 1402, 1362,
1324, 1210, 1177, 1130, 1110, 1052, 978, 887, 849, 802, 779, 745,
IR (ATR): 3410, 3068, 2929, 2857, 1634, 1578, 1484, 1458, 1427, 1391,
1274, 1203, 1108, 1037, 1012, 933, 874, 821, 738, 699, 605 cm–1
.
722, 688, 655, 603 cm–1
.
1H NMR (600 MHz, acetone-d6): δ = 1.16 (s, 9 H), 2.31 (s, 3 H), 6.77
(dd, J = 8.6, 2.3 Hz, 1 H), 6.91 (s, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 7.41 (d,
J = 2.3 Hz, 1 H), 7.44–7.49 (m, 7 H), 7.55 (s, 1 H), 7.84–7.86 (m, 4 H),
9.72 (s, 1 H).
1H NMR (500 MHz, acetone-d6): δ = 1.49 (s, 6 H), 2.31 (s, 3 H), 5.78 (d,
J = 9.8 Hz, 1 H), 6.88 (dd, J = 8.5, 2.0 Hz, 1 H), 6.91 (d, J = 9.8 Hz, 1 H),
7.26 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 1.5 Hz, 1 H), 7.65 (s, 1 H), 7.87 (br s,
1 H), 9.99 (br s, 1 H).
13C NMR and DEPT (150 MHz, acetone-d6): δ = 16.63 (CH3), 20.05 (C),
27.06 (3 CH3), 96.87 (CH), 109.66 (CH), 111.17 (CH), 116.86 (C),
117.10 (CH), 117.28 (C), 122.08 (CH), 124.97 (C), 128.66 (4 CH),
130.77 (2 CH), 134.36 (2 C), 135.97 (C), 136.43 (4 CH), 141.81 (C),
149.54 (C), 155.58 (C).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.16 (CH3), 27.83 (2
CH3), 76.40 (C), 105.06 (CH), 105.28 (C), 111.66 (CH), 113.86 (CH),
117.49 (C), 117.67 (C), 118.66 (CH), 121.72 (CH), 125.16 (C), 129.50
(CH), 135.13 (C), 137.04 (C), 150.35 (C), 151.62 (C).
MS (EI): m/z (%) = 279 (29, [M+]), 264 (100), 132 (11).
MS (EI): m/z (%) = 451 (53, [M+]), 394 (100), 197 (14).
HRMS: m/z [M+] calcd for C29H29NO2Si: 451.1968; found: 451.1961.
UV (MeOH): λ = 216, 240, 264, 311, 333 (sh), 349 (sh) nm.
Fluorescence (MeOH): λex = 311 nm, λem = 375 nm.
HRMS: m/z [M+] calcd for C18H17NO2: 279.1259; found: 279.1255.
UV (MeOH): λ = 227, 233, 252 (sh), 272 (sh), 297, 336, 356, 368 (sh)
nm.
Fluorescence (MeOH): λex = 297 nm, λem = 392 nm.
8-(tert-Butyldiphenylsilyloxy)-3,3,5-trimethyl-3,11-dihydropyra-
no[3,2-a]carbazole (11)
Koenimbine (2b)
NaH (3.9 mg, 0.163 mmol) (60% suspension in oil) was added to a
solution of koenine (2a) (25 mg, 90 μmol) in THF (4 mL) at 0 °C. MeI (6
μL, 96 μmol) was added and the reaction mixture was stirred at r.t. for
24 h. H2O (5 mL) was added and the mixture was extracted with EtO-
Ac (3 × 10 mL). The combined organic layers were washed with brine
3-Methylbut-2-enal (prenal) (23 μL, 0.240 mmol) and Ti(Oi-Pr)4 (0.14
mL, 0.473 mmol) were added to a solution of the 2-hydroxycarbazole
10 (54.0 mg, 0.120 mmol) in toluene (5 mL). The solution was stirred
at r.t. for 16 h, H2O (5 mL) and aq 1 M HCl (5 mL) were added, the mix-
ture was extracted with EtOAc (3 × 15 mL), and the combined organic
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and dried (MgSO4). Removal of the solvent under vacuum and flash
chromatography (silica gel, PE–EtOAc, 20:1) of the crude product pro-
vided koenimbine (2b) as a colorless solid; yield: 15 mg (57%).
3-(tert-Butyldiphenylsilyloxy)-N-(4-methoxyphenyl)-4-meth-
ylaniline (14)
A solution of 4-bromoanisole (12) (1.32 mL, 10.5 mmol) in toluene
(15 mL) was added over a period of 2 h to a solution of Pd(OAc)2 (144
mg, 0.641 mmol), rac-BINAP (400 mg, 0.642 mmol), Cs2CO3 (4.00 g,
12.3 mmol), and aniline 13 (4.50 g, 12.4 mmol) in toluene (70 mL) at
reflux temperature. The reaction mixture was heated at reflux for 24
h and then cooled to r.t. The solvent was removed under vacuum.
Flash chromatography (silica gel, PE–EtOAc, 40:1) of the crude prod-
uct provided 14 as a brown solid; yield: 4.25 g (86%); mp 89–91 °C.
For spectroscopic data, see below.
2-(tert-Butyldiphenylsilyloxy)-4-nitrotoluene
Imidazole (4.44 g, 65.2 mmol) was added to a solution of 2-methyl-5-
nitrophenol (5.00 g, 32.7 mmol) in DMF (60 mL). The mixture was
stirred for 10 min at r.t., t-BuPh2SiCl (12.8 mL, 49.2 mmol) was added,
and stirring at r.t. was continued for additional 4 h. H2O (50 mL) and
aq 1 M HCl (50 mL) were added and the mixture was extracted with
EtOAc (3 × 100 mL). The combined organic layers were washed with
brine and sat. aq NH4Cl, and then dried (MgSO4). Removal of the sol-
vent under vacuum and flash chromatography (silica gel, hexane–
Et2O, 20:1) of the crude product provided the title compound as
colorless crystals; yield: 12.8 g (quant.); mp 119–123 °C.
IR (ATR): 3396, 3070, 2959, 2929, 2853, 1606, 1580, 1510, 1466, 1425,
1391, 1339, 1283, 1240, 1183, 1169, 1128, 1112, 1039, 1001, 983,
880, 816, 769, 744, 697, 683, 631, 611 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 1.12 (s, 9 H), 2.34 (s, 3 H), 3.72 (s,
3 H), 6.31 (d, J = 1.9 Hz, 1 H), 6.43 (dd, J = 8.1, 1.9 Hz, 1 H), 6.57 (m, 4
H), 6.81 (br s, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 7.45–7.48 (m, 4 H), 7.51–
7.54 (m, 2 H), 7.77–7.78 (m, 4 H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.48 (CH3), 19.93 (C),
26.84 (3 CH3), 55.53 (CH3), 106.96 (CH), 110.39 (CH), 114.99 (2 CH),
118.88 (C), 120.02 (CH), 120.09 (CH), 128.71 (4 CH), 130.81 (2 CH),
131.88 (CH), 133.47 (2 C), 136.18 (4 CH), 137.32 (C), 144.52 (C),
154.66 (C), 154.81 (C).
IR (ATR): 3074, 3030, 2953, 2932, 2855, 1588, 1516, 1492, 1427, 1409,
1341, 1320, 1278, 1256, 1191, 1115, 1087, 998, 963, 870, 854, 737,
699, 687, 637, 615 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.14 (s, 9 H), 2.45 (s, 3 H), 7.22 (d,
J = 2.1 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.37–7.47 (m, 6 H), 7.64 (dd,
J = 8.3, 2.1 Hz, 1 H), 7.68–7.70 (m, 4 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 17.48 (CH3), 19.61 (C), 26.58
(3 CH3), 113.12 (CH), 116.02 (CH), 128.08 (4 CH), 130.40 (2 CH),
130.73 (CH), 131.57 (2 C), 135.38 (4 CH), 136.77 (C), 146.58 (C),
153.95 (C).
MS (EI): m/z (%) = 467 (100, [M+]), 410 (48), 332 (30), 205 (16), 181
(8), 166 (10), 158 (15).
Anal. Calcd for C30H33NO2Si: C, 77.05; H, 7.11; N, 2.99. Found: C,
77.04; H, 7.09; N, 3.01.
MS (EI): m/z (%) = 391 (6, [M+]), 335 (74), 334 (100), 287 (30), 257 (8),
227 (15), 210 (10), 197 (11).
2-(tert-Butyldiphenylsilyloxy)-6-methoxy-3-methyl-9H-carba-
zole (15)
HRMS: m/z [M+] calcd for C23H25NO3Si: 391.1604; found: 391.1620.
AcOH (1.5 mL) was added to a mixture of the diarylamine 14 (132 mg,
0.282 mmol), Pd(OAc)2 (6.3 mg, 28 μmol), and Cu(OAc)2 (128 mg,
0.705 mmol), and the mixture was heated at 130 °C under air by mi-
crowave irradiation (300 W) for 2 h. Removal of the solvent under
vacuum and flash chromatography (silica gel, PE–EtOAc, 20:1) of the
crude product provided 15 as a yellow solid; yield: 100 mg (76%); mp
66 °C.
UV (MeOH): λ = 223 (sh), 241 (sh), 273, 279, 327 nm.
Anal. Calcd for C23H25NO3Si: C, 70.56; H, 6.44; N, 3.58. Found: C,
70.62; H, 6.59; N, 3.55.
3-(tert-Butyldiphenylsilyloxy)-4-methylaniline (13)
A mixture of 2-(tert-butyldiphenylsilyloxy)-4-nitrotoluene (12.8 g,
32.7 mmol) and 10% Pd/C (1.28 g) in CH2Cl2 (200 mL) was stirred at r.t.
for 24 h under a H2 atmosphere at 5 bar. The mixture was filtered over
Celite which was subsequently washed with EtOAc. Removal of the
solvent from the combined filtrates and flash chromatography (silica
gel, PE–EtOAc, 15:1) of the crude product provided 13 as an orange
solid; yield: 11.8 g (quant.); mp 90–92 °C.
IR (ATR): 3420, 3070, 2930, 2856, 1635, 1587, 1485, 1468, 1428, 1389,
1361, 1329, 1294, 1275, 1216, 1173, 1135, 1109, 1032, 1017, 914,
860, 821, 801, 778, 743, 700, 686, 613 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.13 (s, 9 H), 2.55 (s, 3 H), 3.88 (s, 3 H),
6.40 (s, 1 H), 6.87 (dd, J = 8.7, 2.4 Hz, 1 H), 7.08 (d, J = 8.7 Hz, 1 H), 7.28
(br s, 1 H), 7.34–7.43 (m, 7 H), 7.76–7.78 (m, 5 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 17.70 (CH3), 19.60 (C), 26.50
(3 CH3), 56.02 (CH3), 100.55 (CH), 102.54 (CH), 110.71 (CH), 113.02
(CH), 117.06 (C), 120.70 (C), 121.29 (CH), 123.73 (C), 127.83 (4 CH),
129.86 (2 CH), 132.90 (2 C), 134.22 (C), 135.45 (4 CH), 139.38 (C),
152.96 (C), 153.69 (C).
MS (EI): m/z (%) = 465 (100, [M+]), 408 (36), 330 (43), 204 (13).
MS (ESI, +10 V): m/z = 466.2 [(M + H)+].
HRMS: m/z [M+] calcd for C30H31NO2Si: 465.2124; found: 465.2114.
IR (ATR): 3419, 3337, 3030, 2931, 2857, 1609, 1588, 1508, 1463, 1428,
1389, 1360, 1314, 1277, 1208, 1176, 1116, 1000, 970, 861, 838, 823,
811, 794, 742, 711, 699, 683, 613 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.08 (s, 9 H), 2.27 (s, 3 H), 3.15 (br s, 2
H), 5.80 (d, J = 2.1 Hz, 1 H), 6.15 (dd, J = 7.9, 2.1 Hz, 1 H), 6.90 (d, J = 7.9
Hz, 1 H), 7.35–7.43 (m, 6 H), 7.72 (dd, J = 7.9, 1.2 Hz, 4 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.32 (CH3), 19.60 (C), 26.54
(3 CH3), 106.4 (CH), 107.95 (CH), 118.40 (C), 127.77 (4 CH), 129.80 (2
CH), 131.02 (CH), 133.09 (2 C), 135.43 (4 CH), 144.84 (C), 154.33 (C).
MS (EI): m/z (%) = 361 (89, [M+]), 305 (60), 304 (100), 302 (27), 226
UV (MeOH): λ = 218, 240 (sh), 270 (sh), 311 nm.
(82).
Fluorescence (MeOH): λex = 311 nm, λem = 379 nm.
HRMS: m/z calcd [M+] for C23H27NOSi: 361.1862; found: 361.1867.
Carbalexin C (2-Hydroxy-6-methoxy-3-methyl-9H-carbazole; 16)
UV (MeOH): λ = 213, 243 (sh), 265, 272, 291 nm.
A 1 M solution of TBAF in THF (0.31 mL, 0.31 mmol) was added to a
solution of the carbazole 15 (89.9 mg, 0.193 mmol) in DMF (6 mL) at
0 °C. The reaction mixture was stirred and warmed to r.t. over a period
of 1 h. After the addition of H2O (4 mL), the mixture was extracted
Anal. Calcd for C23H27NOSi: C, 76.41; H, 7.53; N, 3.87. Found: C, 76.74;
H, 7.62; N, 3.80.
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with Et2O (3 × 10 mL). The combined organic layers were washed
with brine and dried (MgSO4). Removal of the solvent under vacuum
and flash chromatography (silica gel, PE–EtOAc, 2:1) of the crude
product provided 16 as a light yellow solid; yield: 39.4 mg (90%); mp
187–191 °C (Lit.27 colorless oil).
of 16 h at reflux, the mixture was allowed to cool to r.t. Removal of the
solvent under vacuum and flash chromatography (silica gel, PE–
EtOAc, 7:1) of the crude product provided 20 as a brownish oil; yield:
159 mg (92%).
IR (ATR): 3403, 3058, 3026, 2998, 2934, 2832, 1611, 1588, 1558, 1512,
1452, 1437, 1400, 1281, 1253, 1205, 1157, 1123, 1028, 918, 824, 795,
IR (ATR): 3392, 3293, 2922, 2840, 1632, 1580, 1460, 1437, 1326, 1293,
1262, 1209, 1135, 1110, 1027, 1010, 981, 885, 864, 838, 822, 793,
736, 696 cm–1
.
768, 721, 641, 609 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.22 (s, 3 H), 3.80 (s, 3 H), 3.83 (s, 3 H),
5.03 (s, 2 H), 5.69 (br s, 1 H), 6.39 (dd, J = 8.7, 2.7 Hz, 1 H), 6.52 (d,
J = 2.7 Hz, 1 H), 6.54 (dd, J = 8.0, 2.1 Hz, 1 H), 6.61 (d, J = 2.1 Hz, 1 H),
7.01 (d, J = 8.0 Hz, 1 H), 7.05 (d, J = 8.7 Hz, 1 H), 7.32 (m, 1 H), 7.37–
7.43 (m, 4 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 15.67 (CH3), 55.58 (CH3),
55.63 (CH3), 69.65 (CH2), 99.33 (CH), 101.80 (CH), 103.73 (CH), 109.28
(CH), 117.64 (CH), 118.74 (C), 126.40 (C), 127.03 (2 CH), 127.62 (CH),
128.45 (2 CH), 130.92 (CH), 137.48 (C), 143.21 (C), 150.38 (C), 154.44
(C), 157.32 (C).
1H NMR (500 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.90 (s, 3 H), 4.83 (br s, 1
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).
13C NMR and DEPT (125 MHz, CDCl3): δ = 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).
MS (EI): m/z (%) = 227 (100, [M+]), 212 (78), 184 (45), 154 (10).
UV (MeOH): λ = 215, 232, 262, 312 nm.
MS (EI): m/z (%) = 349 (100, [M+]), 230 (51), 91 (34).
HRMS: m/z [M+] calcd for C22H23NO3: 349.1678; found: 349.1687.
Fluorescence (MeOH): λex = 312 nm, λem = 374 nm.
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.32;
H, 5.97; N, 6.26.
2-Benzyloxy-6,8-dimethoxy-3-methyl-9H-carbazole (21)
A mixture of the diarylamine 20 (114 mg, 0.325 mmol), Pd(OAc)2 (7.3
mg, 32.5 μmol), K2CO3 (4.5 mg, 32.5 μmol), and pivalic acid (418 mg)
was heated at 85 °C under air by microwave irradiation (300 W) for 24
h. Subsequently, EtOAc was added and the mixture was washed
several times with sat. aq K2CO3. The organic layer was dried (MgSO4).
Removal of the solvent under vacuum and flash chromatography (sili-
ca gel, PE–EtOAc, 15:1) of the crude product provided 21 as a yellow
solid; yield: 75.7 mg (67%); mp 59–63 °C.
Koenimbine (2b)
3-Methylbut-2-enal (prenal) (0.050 mL, 0.521 mmol) and Ti(Oi-Pr)4
(0.31 mL, 1.02 mmol) were added to a solution of carbalexin C (16)
(58.0 mg, 0.255 mmol) in toluene (5 mL). After stirring the solution at
r.t. for 16 h, H2O (5 mL) and aq 1 M HCl (5 mL) were added. The mix-
ture was extracted with EtOAc (3 × 15 mL) and the combined organic
layers were dried (MgSO4). Removal of the solvent under vacuum
and flash chromatography (silica gel, PE–EtOAc, 20:1) of the crude
product provided koenimbine (2b) as a colorless solid; yield: 50.0 mg
(67%); mp 194–195 °C (Lit.6–8 194–195 °C).
IR (ATR): 3430, 3068, 3028, 2924, 2850, 1735, 1634, 1591, 1506, 1452,
1424, 1388, 1326, 1304, 1277, 1234, 1204, 1165, 1142, 1102, 1043,
1016, 998, 929, 904, 874, 812, 733, 694, 621 cm–1
.
IR (ATR): 3403, 2955, 2920, 2851, 1724, 1643, 1457, 1436, 1401, 1380,
1335, 1294, 1246, 1209, 1139, 1124, 1110, 1057, 1025, 979, 894, 877,
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.90 (s, 3 H), 3.95 (s, 3 H),
5.15 (s, 2 H), 6.50 (d, J = 2.0 Hz, 1 H), 6.89 (s, 1 H), 7.02 (d, J = 2.0 Hz, 1
H), 7.32 (m, 1 H), 7.40 (m, 2 H), 7.48 (m, 2 H), 7.74 (s, 1 H), 7.90 (br s, 1
H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.93 (CH3), 55.51 (CH3),
56.01 (CH3), 70.05 (CH2), 93.60 (CH), 94.18 (CH), 96.02 (CH), 116.97
(C), 119.40 (C), 121.48 (CH), 123.78 (C), 124.38 (C), 127.08 (2 CH),
127.72 (CH), 128.52 (2 CH), 137.46 (C), 139.12 (C), 145.86 (C), 154.64
(C), 156.31 (C).
845, 807, 768, 745, 717, 684, 664, 606 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.32 (s, 3 H), 3.90 (s, 3 H),
5.67 (d, J = 9.7 Hz, 1 H), 6.59 (d, J = 9.7 Hz, 1 H), 6.93 (dd, J = 8.7, 2.4
Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.62 (s, 1 H),
7.72 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.07 (CH3), 27.57 (2 CH3),
56.01 (CH3), 75.84 (C), 102.58 (CH), 104.48 (C), 111.00 (CH), 113.01
(CH), 116.83 (C), 117.22 (CH), 118.33 (C), 121.03 (CH), 124.43 (C),
129.26 (CH), 134.32 (C), 135.69 (C), 149.82 (C), 153.94 (C).
MS (EI): m/z (%) = 347 (48, [M+]), 256 (100), 228 (13), 198 (19), 91
(96).
HRMS: m/z [M+] calcd for C22H21NO3: 347.1521; found: 347.1515.
MS (EI): m/z (%) = 293 (16, [M+]), 278 (100), 263 (10), 235 (11).
MS (ESI, +10 V): m/z = 294.1 [(M + H)+].
UV (MeOH): λ = 236, 256 (sh), 268 (sh), 305 nm.
UV (MeOH): λ = 230, 238, 251 (sh), 271 (sh), 282 (sh), 295, 336, 363
(sh) nm.
Fluorescence (MeOH): λex = 305 nm, λem = 394 nm.
Fluorescence (MeOH): λex = 295 nm, λem = 407 nm.
2-Hydroxy-6,8-dimethoxy-3-methyl-9H-carbazole (17)
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.68;
H, 6.74; N, 4.57.
A mixture of carbazole 21 (156 mg, 0.450 mmol) and Pd(OH)2/C (20%
Pd; 31 mg) in MeOH–CH2Cl2 (15 mL, 4:1) was stirred at r.t. for 2 d un-
der a H2 atmosphere at normal pressure. The mixture was filtered
over Celite (Et2O) and the solvent was removed under vacuum to af-
ford 17 as a colorless solid; yield: 102 mg (88%); mp 145–150 °C.
3-Benzyloxy-N-(2,4-dimethoxyphenyl)-4-methylaniline (20)
A solution of 2,4-dimethoxybromobenzene (18; 107 mg, 0.495 mmol)
in toluene (5 mL) was added over a period of 3 h to a mixture of 3-
benzyloxy-4-methylaniline (19)15 (127 mg, 0.595 mmol), Cs2CO3 (245
mg, 0.693 mmol), Pd(OAc)2 (22.2 mg, 99 μmol), and XPhos (94.4 mg,
0.198 mmol) in toluene (10 mL) at reflux. After a total reaction time
IR (ATR): 3511, 3412, 3339, 2992, 2921, 2832, 2138, 2055, 2030, 2009,
1975, 1771, 1734, 1716, 1699, 1684, 1638, 1588, 1555, 1541, 1508,
1472, 1455, 1428, 1403, 1360, 1304, 1273, 1239, 1206, 1137, 1093,
1044, 991, 930, 868, 808, 751, 696, 619 cm–1
.
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1H NMR (500 MHz, acetone-d6): δ = 2.36 (s, 3 H), 3.88 (s, 3 H), 3.96 (s,
3 H), 6.53 (d, J = 2.1 Hz, 1 H), 7.01 (s, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 7.73
(s, 1 H), 8.24 (s, 1 H), 9.74 (br s, 1 H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.72 (CH3), 55.72
(CH3), 55.98 (CH3), 94.38 (CH), 96.40 (CH), 97.28 (CH), 117.38 (C),
117.48 (C), 122.06 (CH), 124.84 (C), 125.34 (C), 141.10 (C), 146.83 (C),
155.37 (C), 155.41 (C).
MS (EI): m/z (%) = 257 (100, [M+]), 242 (37), 214 (11), 199 (22).
HRMS: m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1040.
UV (MeOH): λ = 235, 255 (sh), 267 (sh), 306, 329 (sh) 343 (sh) nm.
Fluorescence (MeOH): λex = 306 nm, λem = 389 nm.
3-Benzyloxy-N-[4-methoxy-3-(triisopropylsilyloxy)phenyl]-4-
methylaniline (24)
A solution of bromoanisole 23 (818 mg, 2.28 mmol) in toluene (8 mL)
was added over a period of 2 h to a mixture of 3-benzyloxy-4-meth-
ylaniline (19)15 (583 mg, 2.73 mmol), Cs2CO3 (890 mg, 2.73 mmol),
Pd(OAc)2 (30.7 mg, 0.137 mmol), and XPhos (130 mg, 0.273 mmol) in
toluene (15 mL) at reflux. After a total reaction time of 19.5 h at reflux
temperature, the mixture was filtered over a small path of Celite. Sub-
sequent purification of the crude product by flash chromatography
(silica gel, isohexane–EtOAc, 20:1) provided 24 as a brownish oil;
yield: 1.04 g (93%).
IR (ATR): 3391, 3061, 3028, 2943, 2865, 1604, 1557, 1542, 1502, 1461,
1386, 1269, 1222, 1193, 1160, 1126, 1029, 998, 919, 882, 844, 800,
776, 735, 681 cm–1
.
6,8-Dimethoxygirinimbine (3)
1H NMR (600 MHz, CDCl3): δ = 1.10 (d, J = 7.4 Hz, 18 H), 1.22–1.30 (m,
3 H), 2.21 (s, 3 H), 3.79 (s, 3 H), 4.99 (s, 2 H), 5.38 (br s, 1 H), 6.47 (br d,
J = 7.5 Hz, 1 H), 6.54 (s, 1 H), 6.58 (br d, J = 7.9 Hz, 1 H), 6.68 (d, J = 1.9
Hz, 1 H), 6.76 (d, J = 8.6 Hz, 1 H), 6.99 (d, J = 7.9 Hz, 1 H), 7.31–7.33 (m,
1 H), 7.37–7.40 (m, 2 H), 7.42–7.43 (m, 2 H).
13C NMR and DEPT (150 MHz, CDCl3): δ = 12.87 (3 CH), 15.62 (CH3),
17.91 (6 CH3), 56.11 (CH3), 69.73 (CH2), 100.94 (CH), 108.51 (CH),
112.64 (CH), 113.31 (2 CH), 118.43 (C), 127.09 (2 CH), 127.66 (CH),
128.45 (2 CH), 130.96 (CH), 136.66 (C), 137.44 (C), 143.90 (C), 146.21
(C), 146.36 (C), 157.52 (C).
Propanoic acid (1.30 mL, 17.6 mmol) and prenal (24.6 μL, 0.240
mmol) were added to a solution of carbazole 17 (41.2 mg, 0.160
mmol) and phenylboronic acid (3.9 mg, 30 μmol) in toluene (6 mL).
The mixture was heated at reflux for 46 h and then cooled to r.t. Re-
moval of the solvent under vacuum and flash chromatography (silica
gel, PE–EtOAc, 9:1) of the crude product provided 3 as a colorless
solid; yield: 35.5 mg (69%); mp 165–170 °C.
IR (ATR): 3388, 3006, 2920, 2851, 2056, 2030, 1733, 1715, 1670, 1642,
1592, 1502, 1448, 1438, 1420, 1403, 1357, 1299, 1281, 1214, 1202,
1183, 1141, 1121, 1102, 1042, 977, 934, 879, 809, 779, 724, 688, 624,
604 cm–1
.
MS (EI): m/z (%) = 491 (41, [M+]), 433 (57), 342 (14), 327 (17), 314
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 6 H), 2.31 (s, 3 H), 3.90 (s, 3 H),
3.96 (s, 3 H), 5.67 (d, J = 9.7 Hz, 1 H), 6.49 (d, J = 2.1 Hz, 1 H), 6.63 (d,
J = 9.7 Hz, 1 H), 6.99 (br s, 1 H), 7.59 (s, 1 H), 7.88 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.10 (CH3), 27.58 (2 CH3),
55.53 (CH3), 55.99 (CH3), 75.82 (C), 93.65 (CH), 96.07 (CH), 104.74 (C),
117.26 (C), 117.33 (CH), 118.39 (C), 121.04 (CH), 124.27 (C), 124.44
(C), 129.18 (CH), 135.07 (C), 145.90 (C), 149.69 (C), 154.73 (C).
MS (EI): m/z (%) = 323 (74, [M+]), 308 (100), 293 (16).
HRMS: m/z [M+] calcd for C20H21NO3: 323.1521; found: 323.1532.
UV (EtOH): λ = 239, 242, 255 (sh), 280 (sh), 291, 348 nm.
Fluorescence (EtOH): λex = 348 nm, λem = 424 nm.
(11), 91 (100).
UV (MeOH): λ = 285 nm.
Anal. Calcd for C30H41NO3Si: C, 73.28; H, 8.40; N, 2.85. Found: C,
73.34; H, 8.61; N, 2.93.
2-Benzyloxy-6-methoxy-3-methyl-7-(triisopropylsilyloxy)-9H-
carbazole (25)
A mixture of the diarylamine 24 (100 mg, 0.203 mmol), Pd(OAc)2
(6.80 mg, 30.5 μmol), Cu(OAc)2 (92.3 mg, 0.508 mmol), and AcOH (1
mL) was heated at 130 °C under air by microwave irradiation (300 W)
for 1 h. The mixture was cooled to r.t., diluted with EtOAc, and washed
with sat. aq K2CO3 and brine several times. The aqueous layers were
extracted with EtOAc and the combined organic layers were dried
(MgSO4). Removal of the solvent under vacuum and flash chromatog-
raphy (silica gel, isohexane–EtOAc, 20:1) of the crude product provided
25 as a colorless solid; yield: 70.5 mg (71%); mp 154–156 °C.
4-Bromo-2-(triisopropylsilyloxy)anisole (23)
Imidazole (671 mg, 9.85 mmol) and chlorotriisopropylsilane (1.60
mL, 7.39 mmol) were added to a solution of 5-bromo-2-methoxyphe-
nol (1 g, 4.93 mmol) in CH2Cl2 (10 mL). The mixture was stirred for 2 h
at r.t. and then washed with H2O. The aqueous layer was extracted
with CH2Cl2 and the combined organic layers were dried (MgSO4). Re-
moval of the solvent under vacuum and flash chromatography (silica
gel, isohexane–EtOAc, 25:1) of the crude product provided 23 as a
colorless oil; yield: 1.78 g (quant.).
IR (ATR): 3367, 3061, 3031, 2942, 2864, 1624, 1478, 1454, 1432, 1390,
1361, 1283, 1222, 1164, 1122, 1074, 1042, 1005, 978, 919, 881, 837,
818, 780, 737, 683, 652, 626 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.13 (d, J = 7.6 Hz, 18 H), 1.27–1.35 (m,
3 H), 2.43 (s, 3 H), 3.90 (s, 3 H), 5.13 (s, 2 H), 6.84 (s, 1 H), 6.91 (s, 1 H),
7.32–7.34 (m, 1 H), 7.39–7.41 (m, 3 H), 7.48–7.49 (m, 2 H), 7.63 (br s,
1 H), 7.69 (s, 1 H).
13C NMR and DEPT (150 MHz, CDCl3): δ = 12.89 (3 CH), 16.85 (CH3),
17.96 (6 CH3), 56.32 (CH3), 70.20 (CH2), 94.30 (CH), 102.50 (CH),
102.78 (CH), 116.69 (C), 117.08 (C), 119.20 (C), 120.61 (CH), 127.04 (2
CH), 127.67 (CH), 128.48 (2 CH), 134.08 (C), 137.59 (C), 139.05 (C),
144.41 (C), 146.20 (C), 155.30 (C).
IR (ATR): 2943, 2866, 1557, 1495, 1464, 1443, 1400, 1268, 1224, 1180,
1132, 1071, 1032, 1015, 996, 931, 881, 861, 793, 706, 679, 623 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.09 (d, J = 7.4 Hz, 18 H), 1.20–1.29 (m,
3 H), 3.77 (s, 3 H) 6.69–6.70 (m, 1 H) 6.99–7.01 (m, 2 H).
13C NMR and DEPT (150 MHz, CDCl3): δ = 12.82 (3 CH), 17.84 (6 CH3),
55.55 (CH3), 112.18 (C), 113.15 (CH), 123.53 (CH), 124.01 (CH), 146.43
(C), 150.32 (C).
MS (EI): m/z (%) = 489 (37, [M+]), 431 (100), 345 (13), 78 (12), 43 (12).
UV (MeOH): λ = 212, 237, 267, 316, 328 (sh), 341 (sh) nm.
Fluorescence (MeOH): λex = 267 nm, λem = 371 nm.
MS (EI): m/z (%) = 317 (83), 315 (81, [M+ − CHMe2]), 302 (100), 300
(94), 260 (16), 258 (16), 231 (39), 229 (36), 216 (28), 214 (26).
Anal. Calcd for C16H27BrO2Si: C, 53.47; H, 7.57. Found: C, 53.73; H,
7.55.
Anal. Calcd for C30H39NO3Si: C, 73.58; H, 8.03; N, 2.86. Found: C,
73.30; H, 8.15; N, 2.93.
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2-Hydroxy-6-methoxy-3-methyl-7-triisopropylsilyloxy-9H-carba-
zole (26)
and the combined organic layers were dried (MgSO4). Removal of the
solvent under vacuum and flash chromatography (silica gel, isohex-
ane–EtOAc, 3:1) of the crude product provided koenigine (4a) as a
light yellow solid; yield: 126 mg (94%); mp 182–183 °C (Lit.5,6 183–
185 °C).
A mixture of carbazole 25 (679 mg, 1.39 mmol) and 10% Pd/C (204
mg) in EtOAc (35 mL) was stirred at r.t. for 19 h under a H2 atmo-
sphere at normal pressure. The mixture was filtered over Celite
(EtOAc) and the solvent was removed under vacuum to afford 26 as a
colorless-light pink solid; yield: 492 mg (89%); mp 177–178 °C.
IR (ATR): 3501, 3410, 3309, 3041, 2973, 2930, 2050, 1727, 1629, 1593,
1557, 1542, 1474, 1458, 1430, 1374, 1357, 1342, 1279, 1248, 1204,
1159, 1126, 1056, 1030, 1012, 980, 941, 882, 844, 767, 738, 716, 694,
IR (ATR): 3701, 3626, 3571, 3339, 2942, 2865, 1698, 1623, 1479, 1435,
1388, 1358 1296, 1225, 1206, 1177, 1154, 1140, 1116, 1071, 1004,
652, 621 cm–1
.
974, 921, 869, 832, 767, 724, 708, 685, 644 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.32 (s, 3 H), 3.99 (s, 3 H),
5.69 (d, J = 9.7 Hz, 1 H), 5.80 (s, 1 H), 6.60 (dd, J = 9.7, 1.5 Hz, 1 H), 6.96
(s, 1 H), 7.35 (s, 1 H), 7.53 (s, 1 H), 7.66 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.05 (CH3), 27.52 (2 CH3),
56.63 (CH3), 75.66 (C), 96.68 (CH), 101.27 (CH), 104.60 (C), 115.91 (C),
117.23 (C), 117.28 (CH), 118.17 (C), 119.94 (CH), 129.45 (CH), 134.35
(C), 134.66 (C), 141.89 (C), 144.45 (C), 148.63 (C).
MS (EI): m/z (%) = 309 (37, [M+]), 294 (100), 279 (39).
UV (MeOH): λ = 223, 237 (sh), 289 (sh), 300, 344, 359 (sh) nm.
Fluorescence (MeOH): λex = 300 nm, λem = 376 nm.
1H NMR (600 MHz, CDCl3): δ = 1.12 (d, J = 7.5 Hz, 18 H), 1.25–1.34 (m,
3 H), 2.39 (s, 3 H), 3.90 (s, 3 H), 4.78 (br s, 1 H), 6.77 (s, 1 H), 6.89 (s, 1
H), 7.37 (s, 1 H), 7.59 (br s, 1 H), 7.64 (s, 1 H).
13C NMR and DEPT (150 MHz, CDCl3): δ = 12.89 (3 CH), 16.11 (CH3),
17.95 (6 CH3), 56.39 (CH3), 96.59 (CH), 102.50 (CH), 102.90 (CH),
115.76 (C), 116.62 (C), 117.82 (C), 120.73 (CH), 134.24 (C), 139.39 (C),
144.57 (C), 146.20 (C), 151.94 (C).
MS (EI): m/z (%) = 399 (21, [M+]), 341 (100), 255 (25), 43 (22).
UV (MeOH): λ = 213, 235, 267, 318, 329 (sh), 342 (sh) nm.
Fluorescence (MeOH): λex = 267 nm, λem = 367 nm.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.76;
H, 5.94; N, 4.61.
Anal. Calcd for C23H33NO3Si: C, 69.13; H, 8.32; N, 3.51. Found: C,
69.00; H, 8.31; N, 3.49.
Koenigicine (Koenimbidine, Koenidine, 4b)
8-Methoxy-3,3,5-trimethyl-9-(triisopropylsilyloxy)pyrano[3,2-
a]carbazole (27)
Me2SO4 (63 μL, 0.663 mmol) was added to a solution of koenigine (4a;
41.0 mg, 0.133 mmol) and K2CO3 powder (36.6 mg, 0.266 mmol) in
acetone (3.5 mL) at 56 °C. The mixture was stirred for 18.5 h at 56 °C
and H2O was added. The mixture was extracted with EtOAc (2 ×) and
the combined organic layers were dried (MgSO4). Removal of the sol-
vent under vacuum and flash chromatography (silica gel, isohexane–
EtOAc, 3:1) of the crude product provided koenigicine (4b) as a light
brown solid; yield: 40 mg (93%); mp 223–224 °C (Lit.5,6 [koenidine]
224–225 °C, Lit.8 [koenigicine] 224–225 °C, Lit.11 [koenimbidine]
225 °C).
Prenal (48.3 μL, 0.500 mmol) was added to a solution of the carbazole
26 (100 mg, 0.250 mmol) in toluene (5 mL) and then, Ti(Oi-Pr)4 (0.30
mL, 1.00 mmol) was added in one portion. The reaction mixture was
stirred at r.t. for 15.5 h. Removal of the solvent under vacuum and
flash chromatography (silica gel, isohexane–EtOAc, 25:1) of the crude
product afforded 27 as a colorless solid; yield: 76.0 mg (65%); mp
135–137 °C.
IR (ATR): 3347, 2942, 2865, 2056, 1629, 1577, 1559, 1541, 1491, 1471,
1459, 1433, 1400, 1357, 1283, 1233, 1207, 1165, 1127, 1057, 1015,
IR (ATR): 3424, 2977, 2939, 2833, 1734, 1697, 1626, 1492, 1471, 1443,
1400, 1375, 1359, 1274, 1241, 1207, 1192, 1158, 1116, 1056, 1029,
941, 915, 884, 843, 797, 769, 738, 681, 616 cm–1
.
994, 945, 871, 826, 780, 767, 740, 722, 699, 682, 662, 614 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 1.12 (d, J = 7.5 Hz, 18 H), 1.26–1.35 (m,
3 H), 1.47 (s, 6 H), 2.32 (s, 3 H), 3.89 (s, 3 H), 5.68 (d, J = 9.7 Hz, 1 H),
6.59 (d, J = 9.7 Hz, 1 H), 6.93 (s, 1 H), 7.34 (s, 1 H), 7.54 (br s, 1 H), 7.61
(br s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 1.48 (s, 6 H), 2.33 (s, 3 H), 3.93 (s, 3 H),
3.98 (s, 3 H), 5.68 (d, J = 9.7 Hz, 1 H), 6.60 (d, J = 9.7 Hz, 1 H), 6.90 (s, 1
H), 7.38 (s, 1 H), 7.55 (br s, 1 H), 7.74 (br s, 1 H).
1H NMR (500 MHz, CD2Cl2): δ = 1.47 (s, 6 H), 2.30 (s, 3 H), 3.90 (s, 3 H),
3.91 (s, 3 H), 5.72 (d, J = 9.7 Hz, 1 H), 6.64 (d, J = 9.7 Hz, 1 H), 6.95 (s, 1
H), 7.38 (s, 1 H), 7.54 (br s, 1 H), 7.85 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.07 (CH3), 27.52 (2 CH3),
56.16 (CH3), 56.51 (CH3), 75.67 (C), 94.58 (CH), 102.10 (CH), 104.61
(C), 115.99 (C), 117.20 (C), 117.26 (CH), 118.29 (C), 120.10 (CH),
129.45 (CH), 133.97 (C), 134.66 (C), 144.29 (C), 148.07 (C), 148.63 (C).
13C NMR and DEPT (150 MHz, CDCl3): δ = 12.87 (3 CH), 16.02 (CH3),
17.95 (6 CH3), 27.46 (2 CH3), 56.33 (CH3), 75.62 (C), 102.68 (CH),
102.79 (CH), 104.62 (C), 117.14 (C), 117.32 (C, CH), 118.13 (C), 120.14
(CH), 129.41 (CH), 134.14 (C), 134.90 (C), 144.40 (C), 146.31 (C),
148.66 (C).
MS (EI): m/z (%) = 465 (18, [M+]), 450 (100), 392 (24), 306 (29), 43
(19).
13C NMR and DEPT (125 MHz, CD2Cl2): δ = 16.15 (CH3), 27.64 (2 CH3),
56.44 (CH3), 56.85 (CH3), 76.08 (C), 95.19 (CH), 102.84 (CH), 105.01
(C), 116.17 (C), 117.49 (C), 117.53 (CH), 118.53 (C), 120.32 (CH),
129.89 (CH), 134.45 (C), 135.06 (C), 144.92 (C), 148.85 (C), 149.01 (C).
MS (EI): m/z (%) = 323 (42, [M+]), 308 (100), 292 (23), 154 (11).
UV (MeOH): λ = 223, 237, 289 (sh), 298, 341, 357 (sh) nm.
Fluorescence (MeOH): λex = 298 nm, λem = 376 nm.
UV (MeOH): λ = 223, 238 (sh), 290 (sh), 300, 329, 360 (sh) nm.
Fluorescence (MeOH): λex = 300 nm, λem = 370 nm.
Anal. Calcd for C28H39NO3Si: C, 72.21; H, 8.44; N, 3.01. Found: C,
72.07; H, 8.49; N, 3.34.
Koenigine (4a)
A 1 M solution of TBAF in THF (0.650 mL, 0.650 mmol) was added
slowly to a solution of the pyrano[3,2-a]carbazole 27 (202 mg, 0.434
mmol) in THF (12 mL) at 0 °C. The solution was stirred for 10 min at
0 °C and H2O was added. The mixture was extracted with EtOAc (2 ×)
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.23;
H, 6.79; N, 4.47.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 150–160

160
C. Schuster et al.
Paper
Synthesis
X-ray Crystallographic Data35
(18) Hesse, R.; Jäger, A.; Schmidt, A. W.; Knölker, H.-J. Org. Biomol.
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(22) Part 126 of Transition Metals in Organic Synthesis; for Part 125,
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C20H21NO3, M = 323.38 g mol–1, crystal size: 0.37 × 0.10 × 0.09 mm3,
orthorhombic, space group: P212121, a = 7.496(2), b = 10.345(2),
c = 21.658(4) Å, V = 1679.5(6) Å3, Z = 4, ρcalcd = 1.279 g cm–3, μ = 0.086
mm–1, λ = 0.71073 Å, T = 198(2) K, θ range = 3.31–28.99°, reflections
collected: 63725, independent reflections: 4461 (Rint = 0.0465), 226
parameters. The structure was solved by direct methods and refined
by full-matrix least squares on F2; final
R indices [I >2σ(I)]:
R1 = 0.0379; wR2 = 0.0868; max. residual electron density: 0.203 e Å–3
.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560359.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(35) CCDC-1014932 contains the supplementary crystallographic
data for 4b. These data can be obtained free of charge from
The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 150–160