Synthesis of Methylene-Bridged Biscarbazole Alkaloids by using an Ullmann-type Coupling: First Total Synthesis of Murrastifoline-C and Murrafoline-E

Article abstract of DOI:10.1002/chem.201504680

We describe the total synthesis of methylene-bridged biscarbazole alkaloids by using a late-stage Ullmann-type coupling of fully functionalised carbazole subunits. The carbazole derivatives were synthesised via a sequence of palladium(0)- and palladium(II

Full text of DOI:10.1002/chem.201504680

DOI: 10.1002/chem.201504680
Full Paper
&
Natural-Products Synthesis
Synthesis of Methylene-Bridged Biscarbazole Alkaloids by using
an Ullmann-type Coupling: First Total Synthesis of Murrastifoline-
C and Murrafoline-E**
[
a]
Sebastian K. Kutz, Carsten Bçrger, Arndt W. Schmidt, and Hans-Joachim Knçlker*
Abstract: We describe the total synthesis of methylene-
bridged biscarbazole alkaloids by using a late-stage Ull-
mann-type coupling of fully functionalised carbazole subu-
nits. The carbazole derivatives were synthesised via a se-
quence of palladium(0)- and palladium(II)-catalysed coupling
reactions. Our approach has provided bismurrayafoline-A,
bismurrayafolinol, chrestifolines B–D, and the first total syn-
thesis of murrastifoline-C and murrafoline-E.
Introduction
Carbazole alkaloids have been isolated from various organisms,
such as algae, moulds, and bacteria, but the main natural sour-
ces are terrestrial plants of the genera Murraya, Clausena, and
[
1]
Glycosmis. A broad range of biological activities has been de-
scribed for carbazoles, and some derivatives show promising
pharmacological potential. In biscarbazole alkaloids, two carba-
zole ring systems are connected, either by direct linkage, an
ether bridge, or a methylene unit. Most biscarbazole alkaloids
have been isolated from the same plants as their monomeric
[
2]
carbazole subunits. Only recently, these compounds have
[3]
also been obtained from microorganisms. The biological ac-
tivities of biscarbazole alkaloids have only rarely been studied,
which can be attributed to the scarce amounts available from
natural sources. For the past decades, carbazoles have been
a focus of synthetic organic chemistry and a variety of classical
and transition-metal-dependent syntheses have been de-
[
1]
scribed. Only few methodologies are known for the target-
[4]
oriented synthesis of biscarbazoles. Recently, we described
the total syntheses of several members of this class of alkaloids
by using the late-stage coupling of appropriately substituted
Figure 1. The methylene-bridged biscarbazole alkaloids: bismurrayafoline-A
[5]
monomeric carbazole subunits. These carbazole derivatives
(
1), bismurrayafolinol (2), chrestifoline-B (4), chrestifolineC (5), chrestifoline D
[
6a–e]
are accessible by applying our iron-mediated
or palladiu-
(3), murrafoline E (6), and murrastifoline C (7).
[6f–t]
m(II)-catalysed approaches.
Herein, we describe the synthe-
sis of the methylene-bridged biscarbazole alkaloids bismurraya-
foline-A (1), bismurrayafolinol (2), chrestifoline-D (3), chrestifo-
line-B (4), chrestifoline-C (5), and the first total synthesis of
their regioisomers murrafoline-E (6) and murrastifoline-C
Bismurrayafoline-A (1) was isolated in 1983 by Furukawa
et al. from an extract of the root bark of Murraya euchrestifolia
[
7]
(
7) (Figure 1).
Hayata in ethanol. In 2000, Lee and co-workers described the
[
8]
weak activity of 1 against some cancer-cell lines. In 2001,
Bringmann and Tasler observed that the reduction of mukoeic
acid ethyl ester with lithium aluminium hydride in the pres-
ence of murrayafoline-A (8a) (Figure 2) leads to the formation
[
a] S. K. Kutz, Dr. C. Bçrger, Dr. A. W. Schmidt, Prof. Dr. H.-J. Knçlker
Department Chemie, Technische Universität Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax: (+49)351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
[
9]
of 1 in up to 19% yield. Recently, we described the synthesis
of 1 by coupling 8a and a protected 4-bromomurrayafoline-A
under Ullmann conditions by using an unprecedented isomeri-
[
**] Transition Metals in Organic Synthesis, Part 127. For Part 126, see: ref. [6t].
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504680.
[
5b]
sation (six steps and 28% overall yield). Bismurrayafolinol (2)
Chem. Eur. J. 2016, 22, 2487 – 2500
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[
1g]
ous natural sources. An efficient synthesis of 9b was ach-
[
6l]
ieved by using our palladium-catalysed approach.
Results and Discussion
Our retrosynthetic analysis of the methylene-bridged carba-
zoles 1–7 suggested the unprotected carbazoles 10 and the ni-
trogen-protected carbazoles 11 with a leaving group X at the
(
carbazol-3-yl)methyl group as precursors (Scheme 1). An Ull-
Figure 2. Monomeric 1-methoxycarbazole alkaloids 8a–e and pyrano[3,2-
a]carbazole alkaloids girinimbine (9a) and mahanimbine (9b).
[17]
[18]
mann-type coupling or a Buchwald–Hartwig amination of
0 and 11 would lead to the biscarbazoles 1–7. Compound 11
1
could be synthesised from mukonine (8e) by N-protection, re-
duction of the ester group to a hydroxymethyl substituent,
and transformation of the hydroxy group into a suitable leav-
ing group. Coupling of 11 with murrayafoline-A (8a) would
afford bismurrayafoline-A (1). Bismurrayafolinol (2) and chresti-
foline-D (3) would be obtained from the same koenoline deriv-
ative 11 and mukonine (8e) followed by adjustment of the oxi-
was isolated by Furukawa and co-workers from the root bark
[10]
of Murraya euchrestifolia Hayata in 1987. In 2001, Bringmann
et al. described the formation of 2 in up to 6% yield by the re-
duction of mukoeic acid ethyl ester with lithium aluminium hy-
[9]
dride (3% overall yield over seven steps). Chrestifoline-D (3)
was isolated by Furukawa, Wu, and co-workers in 1992 from
an extract of the root bark of Murraya euchrestifolia Hayata in
dation state of the C -substituent. Coupling of girinimbine (9a)
1
[
11]
or mahanimbine (9b) with the protected koenoline derivative
acetone. Together with the isolation, Furukawa and Wu also
described the oxidation of 1 to 3 by using DDQ (30% yield).
In 1990, Furukawa and co-workers isolated chrestifoline-B (4)
and chrestifoline-C (5) from an extract of the root bark of Mur-
11 would lead to chrestifoline-B (4) or chrestifoline-C (5). For
the synthesis of murrafoline-E (6) and murrastifoline-C (7),
either a 2-oxygenated carbazole derivative 11 or appropriately
substituted pyrano[3,2-a]carbazoles would be potential precur-
sors. Coupling with murrayafoline-A (8a) would lead to the bis-
carbazoles 6 and 7.
[12]
raya euchrestifolia Hayata in acetone. Compound 5 was iso-
lated from nature as an optically active compound ([a] =
D
À5.6, c=0.054 in CHCl ); however, the absolute configuration
3
was not assigned. Biscarbazoles 1–5 share the same (carbazol-
3
-yl)methyl subunit, which is derived from 8a. The N-alkylated
carbazol-9-yl subunit is either derived from 8a, koenoline
(
(
8b), murrayanine (8c), girinimbine (9a), or mahanimbine
9b) (Figure 2).
For the synthesis of murrafoline-E (6) and murrastifoline-C
7), an N-substituted murrayafoline-A derivative constitutes the
(
carbazol-9-yl subunit and girinimbine (9a) or mahanimbine
9b) should serve as the (carbazol-3-yl)methyl subunit. Com-
(
pound 6 was isolated in 1988 by Furukawa and co-workers
from an extract of the root bark of Murraya euchrestifolia
[
13]
Hayata in acetone. Two years later, Furukawa et al. described
the isolation of murrastifoline-C (7) along with chrestifoline-B
(
4) and chrestifoline-C (5) from an extract of the root bark of
[12]
the same plant in acetone. Surprisingly, murrastifoline-C (7)
did not show any optical activity ([a] =0, c=0.10 in CHCl ),
[
12]
D
3
although optically active 5, which also has a chiral mahanim-
bine-derived subunit, was isolated from the same compart-
ment of the same plant.
All the monomeric carbazole subunits of biscarbazoles 1–7
have been isolated from nature, in some cases from the same
Scheme 1. Retrosynthesis for the methylene-bridged biscarbazoles 1–7
(PG=protecting group).
[1g]
plant as the corresponding biscarbazoles.
Compound 9a
14]
[
was isolated first in 1964 by Chakraborty et al. Subsequently,
the same alkaloid was also obtained by others and several syn-
thetic approaches have been developed. We applied a molyb-
denum-mediated, an iron-mediated, and our palladium-cata-
Recently, we described an improved route to 8e by using
the Buchwald–Hartwig coupling of bromobenzene and methyl
4-amino-3-methoxybenzoate (12) and a subsequent palladi-
um(II)-catalysed oxidative cyclisation in pivalic acid
[6c,g,15]
lysed route to the synthesis of 9a.
(+)-Mahanimbine
[
5a,19]
(
(+)-9b) was isolated for the first time in 1966 by Chakraborty
(Scheme 2).
This approach leads to 8e in two steps and
[16]
et al. from Murraya koenigii Spreng. Later, others reported
the isolation of the (À)-enantiomer and racemic 9b from vari-
91% yield. For the synthesis of biscarbazoles 1–5, we first
transformed 8e into the activated N-protected koenoline deriv-
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Scheme 3. Coupling of mukonine (8e) with the koenoline derivatives 14.
Scheme 2. Synthesis of mukonine (8e) and the koenoline derivatives 14. Re-
agents and conditions: a) Pd(OAc) (0.06 equiv), SPhos (0.12 equiv), PhBr
(1.4 equiv), PhMe, reflux, 40 h (100%); b) Pd(OAc)
(0.1 equiv), PivOH, air, 1158C, 14 h (91%); c) Boc
2.0 equiv), DMAP (1.0 equiv), MeCN, RT, 24 h (96%); d) DIBAL-H (3.2 equiv),
O, À788C, 3.5 h (100%); e) 14a: PNB-Cl (1.5 equiv), DMAP (1.5 equiv),
CH Cl , RT, 1.5 h (99%); 14b: Ac O (1.5 equiv), DMAP (1.5 equiv), CH Cl , RT,
5 min (99%); 14c: MsCl (1.2 equiv), iPr NEt (2.9 equiv), CH Cl , 08C, 6.5 h
99%). DIBAL-H=diisobutylaluminium hydride, DMAP=4-(dimethylamino)-
2
Table 1. Results and conditions for the coupling of mukonine (8e) with
the koenoline derivatives 14.
(
(
(
1.1 equiv), Cs
2
CO
3
2
0.1 equiv), K CO
2
3
2
O
Koenoline
derivative
Conditions
Products Yield
[%]
Et
2
2
2
2
2
2
1
1
4c
8e (0.8 equiv), NaH (7.0 equiv), THF,
15b
15a
34
29
4
(
2
2
2
0
8C!RT, 15 h
4b
8e (1.3 equiv), Pd(OAc)
2
(0.1 equiv),
CO (1.4 equiv),
pyridine, MsCl=methanesulfonyl chloride, PivOH=pivalic acid, PNB-
Cl=para-nitrobenzoyl chloride.
rac-BINAP (0.1 equiv), Cs
2
3
PhMe, reflux, 14 days
1
1
4a
4a
8e (1.3 equiv), Pd(OAc)
rac-BINAP (0.1 equiv), Cs
PhMe, reflux, 4 days
2
(0.1 equiv),
CO (1.4 equiv),
15a
15b
35
27
2
3
atives 14. Thus, the nitrogen atom of carbazole 8e was pro-
tected as a tert-butyl carbamate and the methoxycarbonyl sub-
stituent at C3 was reduced to a hydroxymethyl group with di-
isobutylaluminium hydride (DIBAL-H). The resulting protected
koenoline derivative 13 has already served as an intermediate
in our approach to the ether-linked biscarbazole oxydimurraya-
8e (2.0 equiv), CuI (0.2 equiv), pyrrole-2-
carboxylic acid (0.4 equiv), K PO
4.0 equiv) DMSO, 110 8C, 6 days
8e (1.3 equiv), CuBr (0.2 equiv), pyrrole-2- 15a
carboxylic acid (0.4 equiv), K PO
4.0 equiv), DMSO, 1108C, 40 h
15a
59
63
3
4
(
14a
3
4
(
[
5a]
foline. We then examined several leaving groups at the (car-
bazol-3-yl)methyl group for the projected N-alkylation of 8e.
The transformation of the hydroxy group of 13 into the corre-
sponding mesylate, triflate, trifluoroacetate, and bromide
groups failed, probably due to the high reactivity of the result-
ing products. The treatment of 13 with methanesulfonic anhy-
dride induced homoetherification to provide a protected oxy-
tives 14. After establishing a reliable protocol, the reaction
conditions should be applicable to other coupling partners, for
example, 8a. Nucleophilic substitution of benzylic chloride 14c
by treatment with deprotonated 8e afforded the desired pro-
tected biscarbazole 15b in only low yields. The reaction of
14b and 8e under Buchwald–Hartwig conditions was extreme-
ly slow and afforded the deprotected biscarbazole 15a after
stirring for 14 days in toluene at reflux. Obviously, prolonged
exposure of the Boc-protected compounds to elevated tem-
peratures leads to cleavage of the Boc group, although the
temperatures in our case were not as high as those reported
[5a]
dimurrayafoline derivative (56% yield). The treatment of 13
with trifluoroacetic anhydride led to the same product, albeit
in much lower yield (23%). Attempts to form the triflate or
bromide derivatives mostly led to decomposition. The treat-
ment of 13 with methanesulfonyl chloride led quantitatively to
the corresponding chloromethyl derivative 14c (Scheme 2).
The acetate 14b was obtained from 13 in one step and quan-
titative yield by treatment with acetic anhydride under stan-
dard conditions. However, 14b and 14c showed low reactivity
in the desired coupling reaction (see below). Finally, a suitable
substrate for our coupling reaction was found to be para-nitro-
benzoate 14a, which was obtained almost quantitatively by
the treatment of 13 with PNB-Cl and stoichiometric amounts
of DMAP.
[
20]
by Rawal and Cava. The para-nitrobenzoate derivative 14a
was consumed much more quickly under the same conditions,
and we obtained the deprotected biscarbazole 15a in 35%
yield and the biscarbazole 15b in 27% yield after heating for
4 days in toluene at reflux. Finally, coupling of 14a and 8e
[
21]
under modified Ullmann conditions provided the deprotect-
ed biscarbazole 15a as the sole product in 63% yield. Appa-
rently, cleavage of the Boc group is facilitated by using the Ull-
mann-type protocol.
With the activated carbazoles 14 in hand, we turned our ef-
forts to establishing suitable conditions for the coupling to the
desired methylene-bridged biscarbazoles (Scheme 3 and
Table 1).
The non-natural biscarbazole 15a, which may be of further
interest for biological studies, was then transformed into bis-
murrayafolinol (2), chrestifoline-D (3), and the non-natural free
acid 16 (Scheme 4). The reduction of 15a with DIBAL-H led to
2 in quantitative yield. Thus, 2 was obtained by our approach
Because 8e is easily available in large amounts, we first opti-
mised the coupling of 8e with the activated koenoline deriva-
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Scheme 5. Synthesis of murrayafoline-A (8a). Reagents and conditions:
a) LiAlH (3.0 equiv), Et O/CH Cl (1:1), RT, 4.5 h (87%).
4 2 2 2
potassium phosphate as base, which are the Ullmann condi-
tions that were most successful for the coupling of 8e and
14a, finally provided 1 in 46% yield (Scheme 6). As observed
before, the Boc group of 14a was cleaved under the reaction
conditions. The present approach afforded 1 in six steps and
4
0% overall yield, which is superior to our previous route (six
[
5b]
steps, 28% overall yield). We then applied the same strategy
to the synthesis of 4 and 5. The Ullmann coupling of 14a and
9
a led to 4 (41% yield) and the reaction of 14a and 9b pro-
vided 5 (31% yield). Thus, chrestifoline-B (4) was obtained in
six steps and 35% overall yield and chrestifoline-C (5) in six
steps and 27% overall yield based on commercially available
compounds.
Scheme 4. Synthesis of bismurrayafolinol (2) and chrestifoline-D (3). Re-
agents and conditions: a) DIBAL-H (3.2 equiv), Et
O, À788C, 4 h (100%);
b) MnO (5.0 equiv), CH Cl , RT, 20 h (78%); c) excess KOH, H O, EtOH, RT,
4 h (99%).
2
2
2
2
2
6
in seven steps and 54% overall yield based on commercially
available compounds. The oxidation of 2 with manganese(IV)
[
22]
oxide afforded 3 in 78% yield. This outcome represents a tre-
mendous improvement relative to the procedure developed
[11]
by Furukawa, Wu, and co-workers . In their case, the oxida-
tion of 2 with DDQ as the oxidation agent provided 3 in only
3
0% yield. Our approach provided 3 in eight steps and 42%
overall yield. Finally, the saponification of 15a with aqueous
potassium hydroxide in ethanol led quantitatively to the bis-
carbazole carboxylic acid 16, which is available in seven steps
and 54% overall yield (Scheme 4). In future investigations of
the Murraya plants, compound 16 may be identified as a natu-
ral product. Unfortunately, 15a could not be converted into
1
by complete reduction of the ester group of 15a to
a methyl group, although it has long been known that methyl
carbazole-3-carboxylates can be reduced to the corresponding
3
-methylcarbazoles with lithium aluminium hydride as the re-
[
6k,9,21,23]
ducing agent.
However, that reduction has only been
reported for carbazoles that are unsubstituted at the carbazole
nitrogen atom. The treatment of biscarbazole 15a with lithium
aluminium hydride only led to 2 (90% yield), without any trace
of the desired bismurrayafoline-A (1).
Scheme 6. Synthesis of bismurrayafoline-A (1), chrestifoline-B (4), and chres-
tifoline-C (5). Reagents and conditions: a) 8a (1.5 equiv), CuBr (0.4 equiv),
pyrrole-2-carboxylic acid (0.8 equiv), K
3
PO
46%); b) 9a (1.3 equiv), CuBr (0.2 equiv), pyrrole-2-carboxylic acid
0.4 equiv), K PO (4.2 equiv), DMSO, 1258C, 40 h (41% 4); c) 9b (1.3 equiv),
4
(4.1 equiv), DMSO, 110 8C, 40 h
(
(
3
4
Based on that observation, we decided to synthesise bismur-
rayafoline-A (1) by applying a direct coupling of murrayafoline-
A (8a) and the para-nitrobenzoate 14a. Thus, the ester group
of 8e was first reduced with lithium aluminium hydride to pro-
3 4
CuBr (0.2 equiv), pyrrole-2-carboxylic acid (0.4 equiv), K PO (4.2 equiv),
DMSO, 1208C, 40 h (31% 5).
[9,24]
vide 8a in high yield (Scheme 5).
Notably, this approach
For the synthesis of murrafoline-E (6) and murrastifoline-C
(7), we explored two different synthetic strategies (Scheme 7).
The first route features a late-stage common intermediate as
the precursor for both compounds. Coupling of the protected
2-oxygenated carbazoles 17 and 8a would lead to intermedi-
led to the natural product 8a in three steps and 79% overall
yield, which is the highest yield reported for the synthesis of
murrayafoline-A (8a) so far. The reaction of 8a and 14a in the
presence of copper(I) bromide, pyrrole-2-carboxylic acid, and
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Scheme 8. Route 1: Synthesis of clausine-L (21) and 1-methoxy-9-[(2-meth-
oxycarbazol-3-yl)methyl]-3-methylcarbazole (23). Reagents and conditions:
a) 20 (1.1 equiv), PhI (1.0 equiv), Pd(OAc)
2
(0.05 equiv), rac-BINAP
(1.6 equiv), PhMe, reflux, 2 days (99%); b) Pd(OAc)
(0.25 equiv), K CO (0.25 equiv), PivOH, air, 1038C,
O (1.8 equiv), DMAP (1.1 equiv), MeCN, RT, 3 days
98%); d) DIBAL-H (3.8 equiv), Et
O, À788C, 5 h (96%); e) PNB-Cl (1.5 equiv),
, RT, 5 days (95%). BINAP=2,2’-bis(diphenylphosphi-
(
(
4
0.06 equiv), Cs
0.1 equiv), Cu(OAc)
days (81%); c) Boc
2
CO
3
2
2
2
3
2
(
2
2 2
DMAP (1.5 equiv), CH Cl
no)-1,1’-binaphthyl.
low yield and insufficient purity. Therefore, we decided to
follow the alternative synthetic route.
This second approach started with the oxidation of 9a by
using DDQ to obtain the corresponding aldehyde murrayacine
[
29]
[6c,l]
Scheme 7. Synthetic routes to murrafoline-E (6) and murrastifoline-C (7).
(24) in 96% yield (Scheme 9).
Boc-Protection of the carba-
zole nitrogen atom of 24 followed by reduction of the carbal-
dehyde to a hydroxymethyl group and activation of the latter
as para-nitrobenzoate provided 25 in 87% yield over three
steps. Coupling of para-nitrobenzoate 25 and 8a by applica-
tion of the conditions described above directly provided 6;
thus, biscarbazole 6 was obtained in nine steps and 15% over-
all yield based on commercially available compounds.
ate 18. Biscarbazoles 6 and 7 would then become available by
deprotection and pyran-ring annulation by using either a C or
5
a C10 building block. Various methods have been developed
for this type of annulation, for example, the copper-catalysed
reaction with 2-methyl-3-butyn-2-yl trifluoroacetate (the God-
[
6l,26]
frey procedure)
or the treatment of a phenol with prenal
[6n,27]
[6p,28]
and titanium(IV) isopropoxide
or phenylboronic acid.
The second route requires individual transformations of 9a
and 9b to the protected derivatives 19. An Ullmann-type cou-
pling of 19 and 8a would provide 6 and 7.
For the first route, clausine-L (methyl 2-methoxycarbazole-3-
carboxylate) (21) was transformed into carbazole 22, which
possesses a para-nitrobenzoyloxy leaving group at the C3 sub-
stituent (Scheme 8). Clausine-L (21) was isolated in 1993 by Wu
et al. from an extract of the leaves of Clausena excavata in
[
25]
methanol. Various approaches to this natural product have
[
1g]
been developed.
We described the synthesis of clausine-L
(
21) as an intermediate in our approach to the indol-2-ylcarba-
[
6h]
zole pityriazol. A Buchwald–Hartwig coupling of methyl 4-
amino-2-methoxybenzoate (20) and iodobenzene followed by
a palladium(II)-catalysed oxidative cyclisation provided 21 in
8
0% yield over two steps. Compound 21 was transformed into
Scheme 9. Synthesis of murrafoline-E (6). Reagents and conditions: a) DDQ
the (para-nitrobenzoyloxy)methyl-substituted carbazole 22 by
using the same three-step sequence as described for the syn-
thesis of 14a; that is, N-Boc protection, reduction, and O-acyla-
tion (89% yield over three steps). Attempts to achieve an Ull-
mann-type coupling of 22 and 8a provided biscarbazole 23 in
(2.2 equiv), MeOH/THF/H
b) Boc O (2.1 equiv), DMAP (1.0 equiv), MeCN, RT, 24 h (88%); c) NaBH
3.0 equiv), MeOH, 08C, 4 h (100%); d) PNB-Cl (1.5 equiv), DMAP (1.5 equiv),
CH Cl , RT, 4 days (99%); e) 8a (1.6 equiv), CuBr (0.3 equiv), pyrrole-2-carbox-
ylic acid (0.7 equiv), K PO (6.3 equiv), DMSO, 110 8C, 24 h (26%). DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
2
O (10:3:1), RT, 90 min (96%; see refs. [6c,l];
2
4
(
2
2
3
4
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The same sequence of steps was then applied to the total
synthesis of 7 (Scheme 10). The treatment of 2-hydroxy-3-
[6l]
[30]
methylcarbazole (26), which is also a natural product, with
citral and titanium(IV) isopropoxide provided (Æ)-9b, which
was subjected to oxidation with DDQ to provide the naturally
[6l,31]
occurring aldehyde murrayacinine (27).
Compound 27 was
converted into N-Boc-murrayacinine (28), which was reduced
to the corresponding alcohol. Esterification with para-nitroben-
zoyl chloride provided the building block 29 desired for the
Ullmann-type coupling. The reaction of 29 with 8a in the pres-
ence of catalytic amounts of copper(I) bromide, pyrrole-2-car-
boxylic acid, and potassium phosphate provided 7. The spectra
of our synthetic 7 were in agreement with the original spectra
1
(
i.e., UV, IR, and H NMR) of the isolated natural product, kindly
Figure 3. HPLC separation of the enantiomers of murrastifoline C (7) on
a chiral phase (nucleocel d-RP from Macherey–Nagel).
provided by Professor C. Ito. Our synthesis leads to murrastifo-
line-C (7) in nine steps and 8% yield based on commercially
available compounds.
the small value of optical rotation for the pure enantiomer and
the only small amounts of 7 available by isolation from
[
12]
nature, the question whether the natural product is racemic
or not cannot be answered at this point.
Conclusion
We have developed an efficient method for the synthesis of
methylene-bridged biscarbazole alkaloids. Our approach led to
the total synthesis of bismurrayafoline-A (1), bismurrayafolinol
(
2), chrestifoline-D (3), chrestifoline-B (4), chrestifoline-C (5),
murrafoline-E (6), and murrastifoline-C (7), of which 6 and 7
have been obtained by total synthesis for the first time. The
spectroscopic data of the natural products obtained by synthe-
sis are in good agreement with those isolated from natural
[
7,10–13]
sources.
Moreover, we have achieved the separation of
the enantiomers of 7 and determined the value of their optical
rotation. The present chemistry also has provided access to
novel synthetic methylene-bridged biscarbazoles, which are
being investigated for their pharmacological potential. The
studies on the bioactivity of the biscarbazole derivatives are
ongoing and will be reported elsewhere.
Scheme 10. Synthesis of murrastifoline-C (7). Reagents and conditions:
a) citral (1.9 equiv), Ti(OiPr)
b) DDQ (2.2 equiv), MeOH/THF/H
c) Boc O (2.0 equiv), DMAP (1.1 equiv), MeCN, RT, 25 h (85%); d) NaBH
6.1 equiv) THF, 08C, 5.5 h (100%); e) PNB-Cl (1.5 equiv), DMAP (1.5 equiv),
CH Cl , RT, 76 h (99%); f) 8a (1.5 equiv), CuBr (0.2 equiv), pyrrole-2-carboxylic
acid (0.4 equiv), K PO (4.2 equiv), DMSO, 1108C, 25 h (20%).
4
(3.9 equiv) PhMe, À788C!RT, 15 h (82%);
2
O (10:2:3), RT, 1 h (70%; see ref. [6l]);
2
4
(
2
2
3
4
Experimental Section
General: All the reactions were carried out in oven-dried glassware
with dry solvents in an argon atmosphere unless stated otherwise.
Acetonitrile, dichloromethane, THF, diethyl ether, and toluene were
dried by using a solvent-purification system (MBraun-SPS). Palladiu-
m(II) acetate was recrystallised from glacial acetic acid. All the
other chemicals were used as received from commercial sources.
Manganese(IV) oxide (precipitated active) was obtained from
Merck (art. 805958). Flash chromatography was performed on
a Büchi Sepacore system equipped with an UV monitor on silica
gel (Acros Organics; 0.035–0.070 mm). TLC analysis was performed
on TLC plates from Merck (60 F254) with UV light for visualisation.
Melting points were measured on a Gallenkamp MPD 350 melting-
point apparatus. UV spectra were recorded on a PerkinElmer 25
UV/Vis spectrometer, shoulders are labelled with sh. IR spectra
were recorded on a Thermo Nicolet Avatar 360 FTIR spectrometer
Because chrestifoline-C (5) was obtained from nature in an
optically active form, whereas murrastifoline-C (7) was not, we
were interested in separating the enantiomers of 7. In some
cases, chiral natural products exhibit only very low optical ac-
tivity, and thus enantiomerically pure natural compounds are
easily mistaken for racemates. The enantiomers of 7 were sep-
arated by means of preparative HPLC on a Nucleocel Delta-RP
column from Macherey–Nagel (see Figure 3 and the Experi-
mental Section). The specific optical rotation was determined
20
to be [a]D = +0.23 (c=0.1 in MeOH) for the first enantiomer
2
0
(
tR =13.3 min) and [a]D =À0.22 (c=0.1 in MeOH) for the
second enantiomer (t =19.2 min), respectively. Considering
R
Chem. Eur. J. 2016, 22, 2487 – 2500
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2492
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
by using the attenuated total reflectance (ATR) method. NMR spec-
tra were recorded on Bruker DRX 500 and Avance III 600 spectrom-
eters. Chemical shifts d are reported in parts per million with the
solvent signal as an internal standard. The following abbreviations
have been used: s=singlet, d=doublet, t=triplet, q=quartet,
quin=quintet, m=multiplet, and br=broad. Mass spectra were
recorded on a Finnigan MAT-95 spectrometer (electron impact=
N-Boc-mukonine (9-tert-butyl 3-methyl 1-methoxycarbazole-3,9-
dicarboxylate): A solution of Boc O (298 mg, 1.37 mmol) in aceto-
2
nitrile (9 mL) and DMAP (83.5 mg, 0.683 mmol) was added to a so-
lution of 8e (175 mg, 0.686 mmol) in acetonitrile (10 mL) and the
mixture was stirred at room temperature for 24 h. Evaporation of
the solvent and purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 4:1) provided the
7
0 eV) or by GC-MS coupling on an Agilent Technologies 6890 N
product (235 mg, 96%) as a colourless solid. M.p. 130–1318C;
1
GC system equipped with a 5973 mass-selective detector (electron
impact=70 eV). ESI mass spectra were recorded on a Bruker Es-
quire LC with an ion-trap detector. Positive and negative ions were
detected. Elemental analyses were measured on an EuroVector
EuroEA3000 elemental analyser. HPLC analysis was carried out on
an Agilent Model 1100 with UV (G1315B UV-DAD, detection at l=
H NMR (500 MHz, CDCl ): d=1.66 (s, 9H), 3.99 (s, 3H), 4.05 (s, 3H),
3
7.37 (ddd, J=7.9, 7.1, 0.9 Hz, 1H), 7.50 (ddd, J=8.3, 7.3, 1.2 Hz,
1H), 7.67 (d, J=1.3 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 8.08 (d, J=
13
8.3 Hz, 1H), 8.35 ppm (d, J=1.3 Hz, 1H); C NMR and DEPT
(125 MHz, CDCl ): d=28.05 (3CH ), 52.39 (CH ), 55.94 (CH ), 83.89
3
3
3
3
(C), 109.96 (CH), 114.37 (CH), 114.83 (CH), 120.25 (CH), 123.15 (CH),
125.20 (C), 125.91 (C), 127.74 (CH), 127.91 (C), 131.15 (C), 140.57
(C), 148.19 (C), 150.41 (C=O), 167.44 ppm (C=O); IR (ATR): n=3013,
2974, 2933, 1732, 1712, 1587, 1493, 1443, 1366, 1345, 1301, 1279,
1235, 1213, 1155, 1140, 1099, 1036, 1019, 992, 940, 895, 881, 843,
2
15, 260, and 560 nm), fluorescence (G1321A), and evaporative
light-scattering detection (ELS 1000, Polymer Laboratories);
column: Vydac 208TP104 (reverse-phase C , 4.6”250 mm) with
a flow rate of 1.0 mLmin (eluent A: H O+0.1% CF COOH, eluent
B: MeCN+0.1% CF COOH; gradient from 20 to 90% B in 35 min).
8
À1
2
3
À1
754, 744, 729, 679, 640, 613 cm ; UV (MeOH): lmax =239, 247 (sh),
3
For chiral HPLC, a Nucleocel Delta-RP column (reversed phase,
260, 273 (sh), 313, 327 nm; fluorescence (MeOH): l =260, l =
ex em
+
4
9
.6”250 mm; Macherey–Nagel) was used for isocratic elution with
360 nm; MS (EI): m/z (%): 255 (100, [MÀBoc] ), 240 (42), 224 (34),
À1
5% MeCN in H O with a flow rate of 0.8 mLmin at 308C.
212 (8), 196 (10), 181 (14), 153 (18), 126 (12), 112 (10); MS (ESI;
2
+
1
0 V): m/z: 728 [2M+NH ] ; elemental analysis (%) calcd for
4
Methyl 3-methoxy-4-(phenylamino)benzoate: Bromobenzene
728 mL, 6.83 mmol) was slowly added at reflux temperature to a so-
lution of methyl 4-amino-3-methoxybenzoate (12) (1.14 g,
.29 mmol), palladium(II) acetate (84.6 mg, 0.377 mmol), 2-dicyclo-
hexylphosphino-2’,6’-dimethoxybiphenyl (SPhos) (309 mg,
.754 mmol), and caesium carbonate (2.87 g, 8.79 mmol) in toluene
45 mL). The mixture was heated at reflux for 40 h and filtered over
C H NO : C 67.59, H 5.96, N 3.94; found: C 67.71, H 6.02, N 3.91.
20
21
5
(
N-Boc-3-(hydroxymethyl)-1-methoxycarbazole (13): A 1.5m solu-
tion of DIBAL-H in toluene (0.79 mL, 1.2 mmol) was added to a solu-
tion of N-Boc-mukonine (234 mg, 0.658 mmol) in diethyl ether
(22 mL) at À788C within 5 min and the mixture was stirred for
90 min. A further portion of DIBAL-H (1.5 m in toluene, 0.62 mL,
0.93 mmol) was added and the mixture was stirred for 2 h at
À788C. Ethyl acetate (2 mL) was added and the mixture was stirred
for 15 min. After addition of water (2 mL), the mixture was warmed
to room temperature and diluted with water. The layers were sepa-
rated, the aqueous layer was extracted with diethyl ether (4”), and
the combined organic layers were dried over magnesium sulfate.
Evaporation of the solvent and purification of the residue by flash
chromatography on silica gel (petroleum ether/ethyl acetate 2:1)
6
0
(
a short pad of celite with ethyl acetate. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl ace-
tate 4:1) to provide the product (1.62 g, 100%) as a colourless
1
solid. M.p. 114–1158C; H NMR (500 MHz, CDCl ): d=3.88 (s, 3H),
3
3
8
1
.97 (s, 3H), 6.54 (brs, 1H), 7.06 (tt, J=7.4, 1.3 Hz, 1H), 7.21 (d, J=
.4 Hz, 1H), 7.22 (dd, J=8.5, 1.3 Hz, 2H), 7.34 (m, 2H), 7.52 (d, J=
.8 Hz, 1H), 7.59 ppm (dd, J=8.4, 1.8 Hz, 1H); C NMR and DEPT
1
3
(
(
(
(
125 MHz, CDCl ): d=51.94 (CH ), 55.94 (CH ), 110.97 (CH), 111.03
3 3 3
CH), 120.11 (C), 120.92 (2CH), 123.15 (CH), 123.98 (CH), 129.58
2CH), 138.32 (C), 140.78 (C), 146.62 (C), 167.30 ppm (C=O); IR
ATR): n=3342, 3004, 2955, 2845, 1687, 1588, 1520, 1500, 1464,
provided 13 (216 mg, 100%) as a colourless solid. M.p. 127–1288C;
1
H NMR (500 MHz, CDCl ): d=1.65 (s, 9H), 1.79 (brs, 1H), 3.99 (s,
3
3H), 4.84 (s, 2H), 7.01 (d, J=0.8 Hz, 1H), 7.33 (ddd, J=7.8, 7.0,
0.9 Hz, 1H), 7.46 (ddd, J=8.3, 7.2, 1.2 Hz, 1H), 7.58 (s, 1H), 7.93 (d,
J=7.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.35 ppm (d, J=1.3 Hz, 1H);
1
9
2
452, 1433, 1415, 1351, 1293, 1280, 1229, 1178, 1136, 1107, 1027,
À1
90, 948, 883, 844, 787, 749, 695, 661, 626 cm ; UV (MeOH): l
=
max
+
13
97 (sh), 330 nm; MS (EI): m/z (%): 257 (100, [M ]), 242 (47), 226
C NMR and DEPT (125 MHz, CDCl ): d=28.10 (3CH ), 55.75 (CH ),
3
3
3
(
15), 183 (23), 182 (11), 154 (36), 77 (10); elemental analysis (%)
65.91 (CH ), 83.33 (C), 108.53 (CH), 110.73 (CH), 114.58 (CH), 119.97
2
calcd for C H NO : C 70.02, H 5.88, N 5.44; found: C 69.96, H 5.87,
(CH), 122.80 (CH), 125.58 (C), 127.29 (CH), 127.70 (C), 128.46 (C),
1
5
15
3
N 5.31.
137.20 (C), 140.59 (C), 148.84 (C), 150.86 ppm (C=O); IR (ATR): n=
3
1
9
511, 2978, 2932, 2879, 1710, 1592, 1497, 1467, 1443, 1393, 1369,
339, 1295, 1278, 1251, 1214, 1137, 1108, 1063, 1047, 1016, 958,
29, 862, 837, 768, 754, 734, 684, 655, 621, 608 cm ; UV (MeOH):
Mukonine (methyl 1-methoxycarbazole-3-carboxylate) (8e):
A
mixture of methyl 3-methoxy-4-(phenylamino)benzoate (125 mg,
.486 mmol), palladium(II) acetate (10.9 mg, 48.4 mmol), potassium
À1
0
lmax =232, 264 (sh), 275, 285, 310, 322 nm; fluorescence (MeOH):
carbonate (6.7 mg, 49 mmol), and pivalic acid (450 mg) was heated
at 115 8C for 14 h under air. After cooling to room temperature, di-
chloromethane was added and the mixture was washed twice with
a saturated aqueous solution of potassium carbonate. The com-
bined aqueous layers were extracted with dichloromethane (3”).
The combined organic layers were washed with a saturated aque-
ous solution of sodium chloride and dried over magnesium sulfate.
Evaporation of the solvent and purification of the residue by flash
chromatography on silica gel (petroleum ether/ethyl acetate 4:1)
provided 8e (113 mg, 91%) as colourless crystals. M.p. 199–2008C
+
lex =285, lem =350 nm; MS (EI): m/z (%): 227 (100, [MÀBoc] ), 210
(
51), 198 (17), 184 (11), 183 (13), 167 (30), 154 (22), 139 (9); MS (ESI;
À
À50 V): m/z: 326 [MÀH] ; elemental analysis (%) calcd for
C H NO : C 69.71, H 6.47, N 4.28; found: C 69.85, H 6.56, N 4.24.
19
21
4
N-Boc-1-methoxy-3-(4-(nitrobenzoyloxy)methyl)carbazole (14a):
DMAP (41.5 mg, 0.340 mmol) and 4-nitrobenzoyl chloride (63.1 mg,
0.340 mmol) were added to a solution of the N-Boc-carbazol-3-yl-
methanol 13 (74.2 mg, 0.227 mmol) in dichloromethane (10 mL)
and the mixture was stirred at room temperature for 90 min. A sa-
turated aqueous solution of sodium bicarbonate was added and
the layers were separated. The aqueous layer was extracted with
dichloromethane (3”) and the combined organic layers were dried
over magnesium sulfate. Evaporation of the solvent and purifica-
(
ref. [33]: 1958C); fluorescence (MeOH): l =276, l =392 nm; ele-
ex em
mental analysis (%) calcd for C H NO : C 70.58, H 5.13, N 5.49;
1
5
13
3
found: C 70.31, H 5.36, N 5.39; see ref. [5a] for further spectroscop-
ic data.
Chem. Eur. J. 2016, 22, 2487 – 2500
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2493
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tion of the residue by flash chromatography on silica gel (petrole-
(CH), 122.89 (CH), 125.30 (C), 127.48 (CH), 128.14 (C), 128.43 (C),
133.49 (C), 140.60 (C), 148.82 (C), 150.72 ppm (C=O); IR (ATR): n=
3058, 2975, 2922, 2851, 2057, 1721, 1652, 1588, 1500, 1443, 1418,
um ether/ethyl acetate 4:1 to 0:1) provided 14a (107 mg, 99%) as
1
yellow crystals. M.p. 184–1858C; H NMR (500 MHz, CDCl ): d=1.66
3
(
s, 9H), 4.01 (s, 3H), 5.54 (s, 2H), 7.06 (d, J=1.2 Hz, 1H), 7.34 (ddd,
1396, 1355, 1339, 1280, 1249, 1215, 1152, 1137, 1106, 1040, 1018,
À1
J=7.9, 7.1, 0.8 Hz, 1H), 7.48 (ddd, J=8.3, 7.3, 1.1 Hz, 1H), 7.70 (d,
J=1.2 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H),
8
2
(
(
1
1
1
964, 930, 840, 818, 767, 750, 698, 657, 626 cm ; UV (MeOH): lmax
=
236, 256 (sh), 276 (sh), 286, 311, 323 nm; fluorescence (MeOH):
lex =286, lem =349 nm.
1
3
.25–8.30 ppm (m, 4H); C NMR and DEPT (125 MHz, CDCl ): d=
3
8.11 (3CH ), 55.89 (CH ), 68.34 (CH ), 83.57 (C), 110.10 (CH), 113.05
3
3
2
Methyl 1-methoxy-9-[(1-methoxycarbazol-3-yl)methyl]carbazole-
CH), 114.60 (CH), 120.05 (CH), 122.92 (CH), 123.72 (2CH), 125.29
C), 127.56 (CH), 128.31 (C), 128.54 (C), 131.01 (2CH), 131.20 (C),
35.73 (C), 140.57 (C), 148.79 (C), 150.68 and 150.72 (C and C=O),
64.80 ppm (C=O); IR (ATR): n=3115, 3087, 2986, 2962, 2931, 2850,
3
(
-carboxylate (15a): A mixture of the activated carbazole 14a
66.6 mg, 0.140 mmol), 8e (46.4 mg, 0.182 mmol), copper(I) bro-
mide (4.0 mg, 28 mmol), freshly dried potassium phosphate
120 mg, 0.565 mmol), and pyrrole-2-carboxylic acid (6.2 mg,
6 mmol) in DMSO (1 mL) was heated at 110 8C for 40 h. A saturat-
ed aqueous solution of ammonium chloride (3 mL) and water
1.5 mL) was added and the mixture was extracted with ethyl ace-
(
5
720, 1590, 1522, 1446, 1343, 1304, 1274, 1247, 1222, 1156, 1140,
À1
1
107, 1043, 1019, 969, 868, 845, 830, 767, 757, 712, 685, 654 cm
;
UV (MeOH): l =230, 257, 284, 308, 321 nm; MS (ESI; 10 V): m/z:
4
sis (%) calcd for C H N O : C 65.54, H 5.08, N 5.88; found: C 65.75,
H 5.12, N 5.66.
max
+
(
+
+
99 [M+Na] , 970 [2M+NH ] , 975 [2M+Na] ; elemental analy-
4
tate (4”). The combined organic layers were dried over magnesi-
um sulfate and the solvent was evaporated. Purification of the resi-
due by flash chromatography on silica gel (petroleum ether/ethyl
2
6
24
2
7
N-Boc-3-(acetoxymethyl)-1-methoxycarbazole (14b): Acetic anhy-
dride (24 mL, 0.25 mmol) and DMAP (31.3 mg, 0.256 mmol) were
acetate 19:1!7:3) provided biscarbazole 15a (40.9 mg, 63%) as
1
a colourless solid. M.p. 152–1538C; H NMR (500 MHz, CDCl ): d=
3
added to
a
solution of the N-Boc-carbazol-3-ylmethanol 13
3.81 (s, 3H), 3.99 (s, 3H), 4.02 (s, 3H), 6.05 (s, 2H), 6.76 (d, J=
0.8 Hz, 1H), 7.17 (ddd, J=7.9, 6.9, 1.1 Hz, 1H), 7.27 (ddd J=7.8, 7.0,
0.8 Hz, 1H), 7.37 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.40–7.44 (m, 2H),
7.497 (d, J=8.1 Hz, 1H), 7.500 (s, 1H), 7.66 (d, J=1.3 Hz, 1H), 7.93
(d, J=7.8 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.20 (brs, 1H), 8.54 ppm
(
55.9 mg, 0.171 mmol) in dichloromethane (5 mL) and the mixture
was stirred at room temperature for 45 min. A saturated aqueous
solution of sodium bicarbonate was added and the layers were
separated. The aqueous layer was extracted with dichloromethane
13
(
3”) and the combined organic layers were dried over magnesium
(d, J=1.3 Hz, 1H); C NMR and DEPT (125 MHz, CDCl ): d=49.76
3
sulfate. Evaporation of the solvent and purification of the residue
by flash chromatography on silica gel (petroleum ether/ethyl ace-
(CH ), 52.18 (CH ), 55.51 (CH ), 56.08 (CH ), 104.89 (CH), 108.20 (CH),
2
3
3
3
110.38 (CH), 110.99 (CH), 111.09 (CH), 116.38 (CH), 119.46 (CH),
120.23 (CH), 120.56 (CH), 120.66 (CH), 121.50 (C) 123.51 (C), 123.65
(C), 124.17 (C), 124.55 (C), 125.88 (CH), 126.48 (CH), 129.13 (C),
130.65 (C), 133.19 (C), 139.49 (C), 141.76 (C), 145.87 (C), 146.57 (C),
168.03 ppm (C=O); IR (ATR): n=3360, 3055, 2992, 2949, 2933, 2836,
1771, 1734, 1716, 1692, 1653, 1625, 1582, 1542, 1503, 1489, 1448,
1401, 1358, 1338, 1306, 1266, 1251, 1200, 1167, 1134, 1103, 1037,
tate 4:1!2:1) provided 14b (62.7 mg, 99%) as a colourless solid.
1
M.p. 129–1308C; H NMR (500 MHz, CDCl ): d=1.65 (s, 9H), 2.14 (s,
3
3
8
0
H), 4.00 (s, 3H), 5.25 (s, 2H), 6.98 (d, J=0.8 Hz, 1H), 7.33 (ddd, J=
.2, 7.3, 0.9 Hz, 1H), 7.47 (ddd, J=8.5, 7.3, 1.3 Hz, 1H), 7.61 (d, J=
.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.10 ppm (d, J=8.2 Hz, 1H);
C NMR and DEPT (125 MHz, CDCl ): d=21.31 (CH ), 28.10 (3CH ),
1
3
3
3
3
À1
5
5.79 (CH ), 66.92 (CH ), 83.42 (C), 109.89 (CH), 112.67 (CH), 114.55
1011, 991, 947, 906, 861, 837, 764, 729, 694, 665, 613 cm ; UV
3
2
(
CH), 120.05 (CH), 122.85 (CH), 125.41 (C), 127.40 (CH), 128.08 (C),
(MeOH): lmax =240 (sh), 252 (sh), 270, 292 (sh), 325 nm; fluores-
cence (MeOH): l =270, l =393 nm; MS (EI): m/z (%): 464 (26,
1
1
1
28.44 (C), 131.95 (C), 140.56 (C), 148.69 (C), 150.77 (C=O)
71.14 ppm (C=O); IR (ATR): n=3003, 2990, 2963, 2941, 1734, 1716,
588, 1463, 1446, 1366, 1346, 1307, 1277, 1250, 1226, 1216, 1151,
ex
em
+
[M ]), 255 (32), 240 (8), 224 (8), 210 (100), 167 (11); MS (ESI; 50 V):
+
À
m/z: 487 [M+Na] ; MS (ESI; À100 V): m/z: 463 [MÀH] ; HRMS:
1
139, 1112, 1043, 1024, 976, 962, 929, 853, 844, 825, 773, 756, 743,
m/z calcd for C H N O : 464.1736; found: 464.1741; occasionally,
29
24
2
4
À1
7
2
3
1
11, 663, 625, 606 cm ; UV (MeOH): lmax =233, 255 (sh), 260 (sh),
74, 285, 310, 321 nm; fluorescence (MeOH): l =287, l
the Boc-protected biscarbazole methyl 9-[(9-(tert-butoxycarbonyl)-
=
em
1-methoxycarbazol-3-yl)methyl]-1-methoxycarbazole-3-carboxylate
ex
+
1
44 nm; MS (EI): m/z (%): 269 (68, [MÀBoc] ), 227 (10), 210 (100),
(15b) was obtained as a byproduct: H NMR (500 MHz, CDCl ): d=
3
+
98 (10), 167 (35); MS (ESI; 10 V): m/z: 392 [M+Na] , 756 [2M+
1.61 (s, 9H), 3.78 (s, 3H), 3.99 (s, 3H), 4.00 (s, 3H), 6.03 (s, 2H), 6.80
(d, J=1.0 Hz, 1H), 7.24–7.30 (m, 2H), 7.36 (d, J=1.1 Hz, 1H), 7.40–
7.46 (m, 3H), 7.65 (d, J=1.4 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 8.05
+
NH ] ; elemental analysis (%) calcd for C H NO : C 68.28, H 6.28,
N 3.79; found: C 68.42, H 6.22, N 3.79.
4
21 23
5
(
1
(
1
d, J=8.4 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.54 ppm (d, J=1.4 Hz,
H); C NMR and DEPT (125 MHz, CDCl ): d=28.10 (3CH ), 49.32
3 3
CH ), 52.21 (CH ), 55.65 (CH ), 56.10 (CH ), 83.33 (C), 107.99 (CH),
2 3 3 3
08.24 (CH), 110.13 (CH), 110.21 (CH), 114.57 (CH), 116.39 (CH),
N-Boc-3-Chloromethyl-1-methoxycarbazole (14c): Ethyldiisopro-
pylamine (76 mL, 0.44 mmol) and methanesulfonyl chloride (14 mL,
13
0
.18 mmol) were added to a solution of the N-Boc-carbazol-3-ylme-
thanol 13 (49.9 mg, 0.152 mmol) in dichloromethane (10 mL) at
8C and the mixture was stirred at that temperature for 6.5 h. A sa-
1
19.98 (CH), 120.38 (CH), 120.65 (CH), 120.86 (C), 121.70 (C), 122.68
0
(
CH), 123.64 (C), 124.57 (C), 125.45 (C), 126.57 (CH), 127.27 (CH),
turated aqueous solution of sodium bicarbonate was added and
the layers were separated. The aqueous layer was extracted with
dichloromethane (3”) and the combined organic layers were dried
over magnesium sulfate. Evaporation of the solvent and purifica-
tion of the residue by flash chromatography on silica gel (petrole-
1
1
28.51 (C), 133.12 (C), 135.01 (C), 140.49 (C), 141.70 (C), 146.57 (C),
48.84 (C), 150.78 (C=O), 167.99 ppm (C=O).
Bismurrayafolinol ({1-methoxy-9-[(1-methoxycarbazol-3-yl)meth-
yl]carbazol-3-yl}methanol) (2): A 1.5m solution of DIBAL-H in tolu-
ene (0.08 mL, 0.1 mmol) was slowly added to a solution of biscar-
bazole 15a (29.9 mg, 64.4 mmol) in diethyl ether (10 mL). The mix-
ture was stirred for 90 min at À788C and a further portion of
DIBAL-H (1.5 m in toluene, 0.06 mL, 0.09 mmol) was added. The
mixture was stirred for further 2.5 h at À788C. Ethyl acetate (1 mL)
was added, the mixture was stirred for 15 min, and the reaction
was quenched with water (2 mL). After warming to room tempera-
um ether/ethyl acetate 4:1!2:1) provided 14c (52.0 mg, 99%) as
1
a colourless solid. M.p. 118–1198C; H NMR (500 MHz, CDCl ): d=
3
1
.65 (s, 9H), 4.01 (s, 3H), 4.77 (s, 2H), 7.00 (d, J=1.2 Hz, 1H), 7.34
(
t, J=7.5 Hz, 1H), 7.47 (ddd, J=8.3, 7.3, 1.1 Hz, 1H), 7.62 (d, J=
1
.2 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.10 ppm (d, J=8.3 Hz, 1H);
C NMR and DEPT (125 MHz, CDCl ): d=28.10 (3CH ), 47.17 (CH ),
1
3
3
3
2
5
5.82 (CH ), 83.50 (C), 109.86 (CH), 112.62 (CH), 114.57 (CH), 120.03
3
Chem. Eur. J. 2016, 22, 2487 – 2500
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2494
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ture, more water was added and the layers were separated. The
aqueous layer was extracted with diethyl ether (4”). The combined
organic layers were dried over magnesium sulfate and the solvent
was evaporated. Purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 2:1!1:1) provided
2H), 7.00 (d, J=0.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 7.24 (t, J=
7.4 Hz, 1H), 7.31 (ddd, J=8.1, 7.1, 1.0 Hz, 1H), 7.41 (d, J=8.1 Hz,
1H), 7.47 (ddd, J=8.2, 7.3, 0.9 Hz, 1H), 7.56 (s, 1H), 7.63 (d, J=
1.1 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 8.25 (d,
J=7.8 Hz, 1H), 8.47 (d, J=1.3 Hz, 1H), 11.28 (s, 1H), 12.72 ppm
13
2
(28.7 mg, 100%) as a colourless solid. M.p. 120–1218C (ref. [10]:
(brs, 1H); C NMR and DEPT (125 MHz, [D ]DMSO): d=48.85 (CH ),
6 2
55.31 (CH ), 55.98 (CH ), 105.70 (CH), 108.10 (C), 110.86 (CH), 111.18
3 3
1
colourless oil, ref. [9]: 117 8C); H NMR (500 MHz, CDCl ): d=3.83 (s,
3
3
7
1
1
1
H), 3.97 (s, 3H), 4.86 (s, 2H), 6.02 (s, 2H), 6.79 (d, J=0.8 Hz, 1H),
.01 (d, J=1.1 Hz, 1H), 7.16 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 7.21 (m,
H), 7.35–7.41 (m, 3H), 7.46 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.74 (s,
H), 7.92 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.17 ppm (brs,
(CH), 111.50 (CH), 113.66 (C), 115.84 (CH), 118.61 (CH), 120.11 (CH),
120.15 (CH), 120.67 (CH), 122.37 (C), 122.90 (C), 123.19 (C), 123.83
(C), 125.48 (CH), 126.43 (CH), 128.87 (C), 129.78 (C), 132.01 (C),
139.87 (C), 141.09 (C), 145.56 (C), 146.16 (C), 168.00 ppm (C=O); IR
(ATR): n=3421, 3055 3008, 2925, 2852, 2542, 2214, 2074, 1734,
1644, 1583, 1506, 1490, 1473, 1445, 1421, 1378, 1344, 1287, 1254,
1232, 1203, 1166, 1144, 1105, 1032, 1014, 938, 877, 839, 787, 764,
1
3
H); C NMR and DEPT (125 MHz, CDCl ): d=49.64 (CH ), 55.55
3
2
(
(
1
(
1
CH ), 55.94 (CH ), 66.47 (CH ), 105.04 (CH), 107.23 (CH), 110.05
3 3 2
CH), 110.94 (CH), 111.06 (CH), 112.02 (CH), 119.34 (CH), 119.41 (CH),
20.34 (CH), 120.69 (CH), 123.36 (C), 123.59 (C), 124.18 (C), 124.95
C), 125.81 (CH), 125.96 (CH), 129.06 (C), 129.92 (C), 131.24 (C),
32.56 (C), 139.49 (C), 141.59 (C), 145.80 (C), 147.29 ppm (C); IR
ATR): n=3495, 3253, 3053, 2992, 2924, 2853, 1584, 1501, 1450,
À1
744, 730, 690, 661, 617 cm ; UV (MeOH): lmax =224, 244, 249 (sh),
258 (sh), 271, 290, 314, 326, 341 nm; fluorescence (MeOH): l =
ex
+
290, lem =368 nm; MS (ESI; 50 V): m/z: 473 [M+Na] ; MS (ESI;
À
(
À75 V): m/z: 449 [MÀH] .
1
9
2
401, 1356, 1335, 1305, 1288, 1265, 1231, 1200, 1137, 1103, 1034,
Murrayafoline-A (1-methoxy-3-methylcarbazole) (8a): Lithium
aluminium hydride (93.6 mg, 2.47 mmol) was added at room tem-
perature to a solution of 8e (210 mg, 0.821 mmol) in dichlorome-
thane (8 mL) and diethyl ether (8 mL) and the mixture was stirred
for 4.5 h. Water was added, the layers were separated, and the
aqueous layer was extracted with dichloromethane (3”). The com-
bined organic layers were dried over magnesium sulfate and the
solvent was evaporated. Purification of the residue by flash chro-
matography on silica gel (petroleum ether/ethyl acetate 4:1) pro-
vided 8a (151 mg, 87%) as a colourless solid. M.p. 54–558C
À1
85, 940, 907, 861, 834, 767, 728, 694, 665 cm ; UV (MeOH): lmax
=
25, 243, 252, 261 (sh), 281, 292, 331, 343 (sh) nm; fluorescence
+
(
MeOH): l =292, l =373 nm; MS (EI): m/z (%): 436 (12, [M ]),
ex em
4
34 (5), 420 (5), 210 (100), 167 (10), 149 (5), 84 (9); HRMS: m/z
calcd for C H N O : 436.1787; found: 436.1781.
2
8
24
2
3
Chrestifoline-D (1-methoxy-9-[(1-methoxycarbazol-3-yl)methyl]-
carbazole-3-carbaldehyde) (3): Manganese(IV) oxide (21.2 mg,
2
chloromethane (7 mL) and the mixture was stirred at room temper-
ature for 20 h. Filtration over a short pad of silica gel with dichloro-
methane, evaporation of the solvent, and purification by flash
chromatography on silica gel (petroleum ether/ethyl acetate 2:1)
44 mmol) was added to a solution of 2 (21.3 mg, 48.8 mmol) in di-
(
ref. [32]: 52–538C); elemental analysis (%) calcd for C H NO: C
14 13
7
9.59, H 6.20, N 6.63; found: C 79.73, H 6.48, N 6.75; see ref. [5b]
for the spectroscopic data.
provided 3 (16.6 mg, 78%) as a colourless solid. M.p. 163–1648C
Bismurrayafoline-A
(1-methoxy-9-[(1-methoxycarbazol-3-yl)-
1
(
ref. [11]: colourless oil); H NMR (500 MHz, CDCl ): d=3.83 (s, 3H),
3
methyl]-3-methylcarbazole) (1): A mixture of the activated carba-
zole 14a (66.6 mg, 0.140 mmol), 8a (44.3 mg, 0.210 mmol), cop-
per(I) bromide (8.0 mg, 56 mmol), freshly dried potassium phos-
phate (122 mg, 0.575 mmol), and pyrrole-2-carboxylic acid
4
6
7
7
.04 (s, 3H), 6.07 (s, 2H), 6.77 (d, J=0.8 Hz, 1H), 7.17 (ddd, J=7.8,
.9, 1.1 Hz, 1H), 7.31 (m, 1H), 7.37 (ddd, J=8.1, 7.0, 1.1 Hz, 1H)
.41 (m, 1H), 7.45 (ddd, J=8.2, 7.2, 1.1 Hz, 1H), 7.49 (s, 1H), 7.52–
.54 (m, 2H), 7.92 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.21
(
4
12.4 mg, 0.112 mmol) in DMSO (1 mL) was heated at 110 8C for
0 h. A saturated aqueous solution of ammonium chloride (3 mL)
1
3
(
brs, 1H), 8.27 (d, J=1.3 Hz, 1H), 10.07 ppm (s, 1H); C NMR and
DEPT (125 MHz, CDCl ): d=49.86 (CH ), 55.53 (CH ), 56.06 (CH ),
3
2
3
3
and water (1.5 mL) was added and the mixture was extracted with
ethyl acetate (4”). The combined organic layers were dried over
magnesium sulfate and the solvent was evaporated. Purification of
the residue by flash chromatography on silica gel (petroleum
ether/ethyl acetate 49:1!7:3) provided 1 (27.0 mg, 46%) as
a light-red–brown solid. M.p. 209–2108C (ref. [7]: 176–1778C); see
ref. [5b] for the spectroscopic data.
1
1
1
(
04.84 (CH), 105.01 (CH), 110.71 (CH), 111.01 (CH), 111.13 (CH),
19.51 (CH), 120.34 (CH), 120.49 (CH), 120.64 (CH), 120.72 (CH),
23.46 (C), 123.56 (C), 124.20 (C), 124.64 (C), 125.95 (CH), 126.75
CH), 129.17 (C), 129.67 (C), 130.33 (C), 134.20 (C), 139.49 (C),
1
3
1
1
7
41.76 (C), 145.91 (C), 147.60 (C), 191.82 ppm (CHO); IR (ATR): n=
253, 3055, 2934, 2836, 2056, 2030, 1844, 1772, 1735, 1717, 1698,
675, 1655, 1635, 1621, 1583, 1504, 1488, 1451, 1399, 1335, 1299,
264, 1242, 1199, 1179, 1134, 1104, 1035, 1012, 906, 861, 832, 767,
Chrestifoline-B
(11-[(1-methoxycarbazol-3-yl)methyl]-3,3,5-tri-
methyl-3,11-dihydropyrano[3,2-a]carbazole) (4): A mixture of the
activated carbazole 14a (33.3 mg, 69.9 mmol), girinimbine (9a;
À1
32, 665 cm ; UV (MeOH): lmax =222, 242, 251, 275, 291, 338, 346
(
(
sh) nm; fluorescence (MeOH): l =275, l =376 nm; MS (EI): m/z
ex em
%): 434 (22, [M ]), 210 (100), 167 (12); HRMS: m/z calcd for
2
3.5 mg, 89. mmol), copper(I) bromide (2.0 mg, 14 mmol), freshly
+
dried potassium phosphate (61.9 mg, 0.292 mmol), and pyrrole-2-
carboxylic acid (3.1 mg, 28 mmol) in DMSO (1 mL) was heated at
1258C for 40 h. A saturated aqueous solution of ammonium chlo-
ride (2 mL) and water (1 mL) was added and the mixture was ex-
tracted with ethyl acetate (4”). The combined organic layers were
dried over magnesium sulfate. Evaporation of the solvent and pu-
rification of the residue by flash chromatography on silica gel (pe-
troleum ether/ethyl acetate 49:1!7:3) provided 4 (13.5 mg, 41%)
C H N O : 434.1630; found: 434.1616.
28
22
2
3
1
-Methoxy-9-[(1-methoxycarbazol-3-yl)methyl]carbazole-3-car-
boxylic acid (16): An aqueous solution of potassium hydroxide
50 wt%, 2 mL) and water (1 mL) was added to a solution of biscar-
(
bazole 15a (45.9 mg, 98.8 mmol) in ethanol (5 mL). The mixture
was stirred at room temperature for 40 h and additional aqueous
potassium hydroxide (50 wt%, 1 mL) was added. The mixture was
stirred for a further 24 h and acidified with diluted hydrochloric
acid. The aqueous layer was extracted with dichloromethane (4”)
and the combined organic layers were dried over magnesium sul-
fate. Evaporation of the solvent provided biscarbazole 16 in suffi-
as a light-red–brown solid. M.p. 106–1078C (ref. [12]: colourless oil).
1
H NMR (500 MHz, CDCl ): d=1.44 (s, 6H), 2.37 (s, 3H), 3.88 (s, 3H),
3
5.48 (d, J=9.9 Hz, 1H), 5.75 (s, 2H), 6.76 (s, 1H), 6.81 (d, J=9.9 Hz,
1H), 7.15 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 7.21 (ddd, J=7.8, 5.9,
2.0 Hz, 1H), 7.28–7.31 (m, 2H), 7.37 (ddd, J=8.1, 7.1, 1.1 Hz, 1H),
7.43 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.80 (s, 1H), 7.89 (d, J=7.9 Hz,
cient purity (44.1 mg, 99%) as a light-beige solid. M.p. 248–2498C;
1
H NMR (500 MHz, [D ]DMSO): d=3.84 (s, 3H), 4.09 (s, 3H), 6.04 (s,
6
Chem. Eur. J. 2016, 22, 2487 – 2500
www.chemeurj.org
2495
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
3
+
1
H), 8.00 (d, J=7.7 Hz, 1H), 8.23 ppm (brs, 1H); C NMR and DEPT
541 [M+H] ; HRMS: m/z calcd for C H N O : 540.2777; found:
37 36 2 2
(
(
1
(
1
(
(
1
9
2
2
125 MHz, CDCl ): d=16.47 (CH ), 27.19 (2CH ), 49.98 (CH ), 55.71
540.2760.
3
3
3
2
CH ), 74.96 (C), 103.87 (CH), 106.03 (C), 109.05 (CH), 110.03 (CH),
3
Methyl 2-methoxy-4-(phenylamino)benzoate: In a Schlenk flask,
iodobenzene (3.38 g, 16.6 mmol) was added at reflux temperature
to a solution of methyl 4-amino-2-methoxybenzoate (20) (3.15 g,
11.07 (CH), 117.39 (C), 118.85 (C), 119.03 (CH), 119.14 (CH), 119.52
CH), 119.60 (CH), 120.89 (CH), 121.46 (CH), 123.45 (C), 123.62 (C),
24.59 (CH), 124.65 (C), 125.96 (CH), 128.70 (CH), 129.20 (C), 130.12
C), 136.56 (C), 139.52 (C), 142.20 (C), 146.23 (C), 150.98 ppm (C); IR
ATR): n=3325, 2922, 2852, 2048, 1704, 1634, 1582, 1501, 1450,
1
7.4 mmol), palladium(II) acetate (183 mg, 0.817 mmol), rac-BINAP
(
621 mg, 0.998 mmol), and caesium carbonate (8.55 g, 26.2 mmol)
in toluene (80 mL) within 6 h, and the mixture was heated at reflux
for 2 days. The solvent was evaporated and the residue was puri-
fied by flash chromatography on silica gel/celite (petroleum ether/
396, 1345, 1309, 1253, 1230, 1186, 1130, 1104, 1073, 1035, 1012,
À1
83, 836, 737, 664 cm ; UV (MeOH): lmax =227 (sh), 239, 251 (sh),
58 (sh), 290, 325, 338, 358 (sh) nm; fluorescence (MeOH): l =
ex
acetone 10:1!4:1) to provide the product (4.23 g, 99%) as a col-
+
90, lem =372 nm; MS (EI): m/z (%): 472 (33, [M ]), 263 (52), 248
1
ourless solid. M.p. 1058C; H NMR (500 MHz, [D ]acetone): d=3.74
6
À
(
100), 210 (95), 167 (26); MS (ESI; À10 V): m/z: 471 [MÀH] ; HRMS:
(
s, 3H), 3.78 (s, 3H), 6.67 (dt, J=8.6, 2.1 Hz, 1H), 6.73 (t, J=1.8 Hz,
m/z calcd for C H N O : 472.2151; found: 472.2122.
3
2
28
2
2
1
2
H), 7.01 (td, J=7.3, 0.8 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.33 (m,
H), 7.71 (d, J=8.6 Hz, 1H), 7.92 ppm (brs, 1H); C NMR and DEPT
1
3
Chrestifoline-C (11-[(1-methoxycarbazol-3-yl)methyl]-3,5-dimeth-
yl-3-(4-methylpent-3-en-1-yl)-3,11-dihydropyrano[3,2-a]carba-
zole) (5): A mixture of the activated carbazole 14a (33.3 mg,
(
125 MHz, [D ]acetone): d=51.34 (CH ), 55.85 (CH ), 99.32 (CH),
6 3 3
1
1
07.32 (CH), 111.02 (C), 120.70 (CH), 123.06 (CH), 130.19 (2CH),
34.41 (2CH), 142.56 (C), 150.58 (C), 162.24 (C), 166.31 ppm (C=O);
6
9.9 mmol), mahanimbine (9b) (30.1 mg, 90.8 mmol), copper(I) bro-
mide (2.0 mg, 14 mmol), freshly dried potassium phosphate
62.0 mg, 0.292 mmol), and pyrrole-2-carboxylic acid (3.1 mg,
8 mmol) in DMSO (1 mL) was heated at 1208C for 40 h. A saturat-
ed aqueous solution of ammonium chloride (2 mL) and water
IR (ATR): n=3332, 3185, 3009, 2956, 2831, 1695, 1613, 1587, 1576,
521, 1496, 1456, 1434, 1399, 1344, 1322, 1294, 1241, 1206, 1181,
1
(
2
1149, 1086, 1031, 994, 976, 959, 890, 847, 833, 778, 744, 703, 692,
À1
6
69, 633, 612 cm ; UV (MeOH): l =211, 242, 289, 322 nm; MS
max
+
(
EI): m/z (%): 257 (78, [M ]), 226 (100), 167 (15), 154 (17), 77 (8); ele-
(
(
1 mL) was added and the mixture was extracted with ethyl acetate
4”). The combined organic layers were dried over magnesium sul-
mental analysis (%) calcd for C H NO : C 70.02, H 5.88, N 5.44;
found: C 70.13, H 5.79, N 5.31.
15
15
3
fate. Evaporation of the solvent and purification of the residue by
flash chromatography on silica gel (petroleum ether/ethyl acetate
9
M.p. 89–908C (ref. [12]: colourless oil); H NMR (500 MHz, CDCl ):
d=1.40 (s, 3H), 1.54 (s, 3H), 1.63 (s, 3H), 1.70–1.76 (m, 2H), 2.05–
2
5
(
J=7.8, 6.0, 1.9 Hz, 1H), 7.30 (m, 2H), 7.37 (ddd, J=8.1, 7.1, 1.0 Hz,
1
7
[
(
7
7
Clausine-L (21): A mixture of methyl 2-methoxy-4-(phenylamino)-
benzoate (200 mg, 0.777 mmol), palladium(II) acetate (18.6 mg,
82.8 mmol), copper(II) acetate (35.1 mg, 0.193 mmol), potassium
carbonate (29.3 mg, 212 mmol), and pivalic acid (1.00 g) was heated
at 1038C for 4 days under air. After cooling to room temperature,
diethyl ether was added. The organic layer was washed with a satu-
rated aqueous solution of potassium carbonate (2”), then the
combined aqueous layers were extracted with diethyl ether (3”).
The combined organic layers were washed with a saturated aque-
ous solution of sodium chloride (2”) and subsequently dried over
sodium sulfate. Evaporation of the solvent and purification of the
residue by flash chromatography on silica gel (petroleum ether/
ethyl acetate 10:1!2:3) provided 21 (160 mg, 81%) as a yellow
solid. M.p. 172–1738C (ref. [25]: 133–1358C); see ref. [6h] for spec-
troscopic data.
9:1!6:3) provided 5 (11.8 mg, 31%) as a light-red–brown solid.
1
3
.18 (m, 2H), 2.37 (s, 3H), 3.89 (s, 3H), 5.07 (tt, J=7.1, 1.3 Hz, 1H),
.45 (d, J=10.0 Hz, 1H), 5.74 (s, 2H), 6.76 (d, J=0.7 Hz, 1H), 6.83
d, J=10.0 Hz, 1H), 7.15 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 7.21 (ddd,
H), 7.43 (m, 1H), 7.48 (s, 1H), 7.79 (s, 1H), 7.90 (d, J=7.8 Hz, 1H),
1
.99 (d, J=7.7 Hz, 1H), 8.23 ppm (s, 1H); H NMR (600 MHz,
D ]acetone): d=1.39 (s, 3H), 1.50 (s, 3H), 1.58 (s, 3H), 1.68–1.77
6
m, 2H), 2.06–2.07 (m, 2H), 2.34 (s, 3H), 3.90 (s, 3H), 5.05 (tt, J=
.2, 1.3 Hz, 1H), 5.59 (d, J=10.0 Hz, 1H), 5.85 (s, 2H), 6.96 (s, 1H),
.00 (d, J=10.0 Hz, 1H), 7.06 (ddd, J=7.8, 7.2, 0.6 Hz, 1H), 7.18 (t,
J=7.4 Hz, 1H), 7.29–7.34 (m, 2H), 7.42–7.45 (m, 2H), 7.53 (d, J=
8
1
1
.1 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.86 (s, 1H), 8.04 (d, J=7.7 Hz,
N-Boc-clausine-L (9-tert-butyl 3-methyl 2-methoxycarbazole-3,9-
1
3
H), 10.38 ppm (brs, 1H); C NMR and DEPT (125 MHz, CDCl ): d=
dicarboxylate): A solution of Boc O (583 mg, 2.67 mmol) in aceto-
3
2
6.48 (CH ), 17.68 (CH ), 22.84 (CH ), 25.13 (CH ), 25.79 (CH ), 40.20
nitrile (12 mL) was added to a solution of 21 (372 mg, 1.46 mmol)
in acetonitrile (15 mL) and then DMAP (195 mg, 1.60 mmol) was
added to the mixture, which was stirred at room temperature for
3 days. Evaporation of the solvent and purification of the residue
by flash chromatography on silica gel (petroleum ether/ethyl ace-
3
3
2
3
3
(
CH ), 50.01 (CH ), 55.72 (CH ), 77.37 (C, overlap with the signal of
2 2 3
CDCl ), 103.88 (CH), 105.93 (C), 109.03 (CH), 110.04 (CH), 111.06
3
(
1
(
CH), 117.32 (C), 118.72 (C), 119.12 (CH), 119.29 (CH), 119.53 (CH),
19.60 (CH), 120.91 (CH), 121.50 (CH), 123.46 (C), 123.65 (C), 124.33
CH), 124.55 (CH), 124.66 (C), 125.97 (CH), 127.96 (CH), 129.21 (C),
tate 4:1) provided the product (510 mg, 98%) as a colourless solid.
1
1
1
1
30.13 (C), 131.78 (C), 136.60 (C), 139.53 (C), 142.22 (C), 146.23 (C),
M.p. 137–1388C; H NMR (500 MHz, CDCl ): d=1.77 (s, 9H), 3.96 (s,
3
1
3
50.98 ppm (C); C NMR and DEPT (150 MHz, [D ]acetone): d=
3H), 4.04 (s, 3H), 7.35 (td, J=7.4, 0.8, 1H), 7.42 (ddd, J=8.5, 7.2,
1.3 Hz, 1H), 7.92 (dd, J=7.6, 0.5 Hz, 1H), 8.02 (s, 1H), 8.23 (d, J=
6
6.47 (CH ), 17.55 (CH ), 23.39 (CH ), 25.31 (CH ), 25.75 (CH ), 40.71
3
3
2
3
3
13
(
CH ), 50.04 (CH ), 55.92 (CH ), 77.82 (C), 101.79 (C), 105.06 (CH),
8.3 Hz, 1H), 8.46 ppm (s, 1H); C NMR and DEPT (125 MHz, CDCl3):
2
2
3
1
06.73 (C), 109.93 (CH), 110.42 (CH), 112.24 (CH), 118.19 (C), 118.92
d=28.51 (3CH ), 52.22 (CH ), 56.50 (CH ), 84.60 (C), 100.21 (CH),
3
3
3
(
1
(
1
3
1
7
2
C), 119.71 (CH), 119.79 (CH), 119.98 (CH), 120.29 (CH), 120.96 (CH),
22.19 (CH), 123.92 (C), 124.23 (C), 125.09 (CH), 125.33 (CH), 126.37
CH), 128.76 (CH), 130.26 (C), 130.76 (C), 131.89 (C), 137.00 (C),
115.62 (C), 116.39 (CH), 118.60 (C), 119.31 (CH), 123.51 (CH), 123.69
(CH), 125.57 (C), 126.56 (CH), 138.88 (C), 142.49 (C), 151.00 (C=O),
159.57 (C), 166.77 ppm (C=O); IR (ATR): n=3157, 2990, 2949, 2835,
2057, 1771, 1717, 1682, 1653, 1630, 1605, 1576, 1492, 1446, 1433,
1393, 1344, 1284, 1239, 1205, 1153, 1090, 1044, 970, 890, 841, 787,
41.07 (C), 142.93 (C), 147.28 (C), 151.67 ppm (C); IR (ATR): n=
416, 3048, 2962, 2922, 2852, 2054, 1635, 1586, 1503, 1450, 1397,
346, 1274, 1230, 1180, 1132, 1104, 1074, 1035, 1011, 979, 879, 831,
À1
761, 740, 714, 693, 655 cm ; UV (MeOH): lmax =235, 243, 260, 281
À1
67, 738, 664, 621 cm ; UV (MeOH): lmax =228 (sh), 242, 251 (sh),
(sh), 292 (sh), 301, 322 nm; fluorescence (MeOH): l =260, l =
ex em
+
82 (sh), 290, 327, 340, 360 nm; fluorescence (MeOH): l =290,
377 nm; MS (EI): m/z (%): 255 (100, [MÀBoc] ), 224 (93), 209 (18),
ex
+
lem =368 nm; MS (EI): m/z (%): 540 (13, [M ]), 457 (14), 347 (10),
3
194 (9), 181 (8), 166 (14), 153 (15), 139 (11), 126 (7), 112 (8), 104 (5),
+
31 (19), 248 (100), 225 (19), 209 (58), 167 (16); MS (ESI; 10 V): m/z:
90 (6), 76 (5), 63 (5); MS (ESI; 10 V): m/z: 356 [M+H] ; elemental
Chem. Eur. J. 2016, 22, 2487 – 2500
www.chemeurj.org 2496
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
analysis (%) calcd for C H NO : C 67.59, H 5.96, N 3.94; found: C
N-Boc-murrayacine: A solution of Boc O (226 mg, 1.04 mmol) in
2
0
21
5
2
6
7.53, H 6.15, N 3.98.
acetonitrile (5 mL) and DMAP (62.2 mg, 0.509 mmol) was added to
a solution of 24 (139 mg, 0.501 mmol) in acetonitrile (10 mL) and
the mixture was stirred at room temperature for 24 h. Evaporation
of the solvent and purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 8:1!4:1) provided
N-Boc-3-(hydroxymethyl)-2-methoxycarbazole: A 1.5m solution
of DIBAL-H in toluene (0.92 mL, 1.4 mmol) was slowly added to
a solution of 9-tert-butyl 3-methyl 2-methoxycarbazole-3,9-dicar-
boxylate (246 mg, 0.692 mmol) in diethyl ether (19 mL) at À788C.
After stirring at the same temperature for 60 min, a 1.5m solution
of DIBAL-H in toluene (0.83 mL, 1.2 mmol) was added. The mixture
was stirred at À788C for 4 h, ethyl acetate (2 mL) was added, and
the mixture was stirred for 15 min. Water (2 mL) was added to the
reaction mixture, which was then warmed to room temperature
and diluted with water. The layers were separated and the aqueous
layer was extracted with diethyl ether (4”). The organic layers
were combined, washed with a saturated aqueous solution of
sodium chloride, and dried over magnesium sulfate. Evaporation of
the solvent and purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 2:1!1:1) provided
the product (166 mg, 88%) as a light-yellow solid. M.p. 124–1268C;
1
H NMR (500 MHz, CDCl ): d=1.60 (s, 6H), 1.68 (s, 9H), 5.75 (d, J=
3
9.9 Hz, 1H), 6.62 (d, J=9.9 Hz, 1H), 7.35 (td, J=7.4, 0.9 Hz, 1H),
7.41 (ddd, J=8.4, 7.3, 1.2 Hz, 1H), 7.89 (dd, J=7.6, 0.6 Hz, 1H), 8.09
13
(d, J=8.3 Hz, 1H), 8.32 ppm (s, 1H), 10.54 (s, 1H); C NMR and
DEPT (125 MHz, CDCl ): d=27.42 (2CH ), 28.28 (3CH ), 76.72 (C),
3
3
3
85.09 (C), 110.80 (C), 115.54 (CH), 118.77 (CH), 119.57 (CH), 121.08
(C), 121.26 (CH), 121.33 (C), 123.97 (CH), 125.90 (C), 126.96 (CH),
127.29 (CH), 139.80 (C), 140.56 (C), 150.86 (C=O), 156.38 (C),
189.60 ppm (CHO); IR (ATR): n=3051, 2970, 2868, 2056, 2030,
2009, 1918, 1870, 1844, 1771, 1734, 1699, 1673, 1653, 1639, 1590,
1509, 1474, 1458, 1436, 1408, 1368, 1320, 1297, 1266, 1220, 1189,
1150, 1121, 1071, 1045, 1022, 947, 918, 891, 843, 813, 786, 756,
the product (217 mg, 96%) as a colourless solid. M.p. 133–1348C;
1
À1
H NMR (500 MHz, CDCl ): d=1.77 (s, 9H), 4.00 (s, 3H), 4.82 (s, 2H),
724, 681, 633 cm ; UV (MeOH): lmax =228, 265, 278 (sh), 292, 310
3
7
.33 (td, J=7.4, 0.8 Hz, 1H), 7.39 (ddd, J=8.4, 7.1, 1.3 Hz, 1H), 7.86
(sh), 324 (sh), 379 nm; fluorescence (MeOH): lex =292, lem =
498 nm; MS (ESI; 25 V): m/z: 378 [M+H] , 777 [2M+Na] ; ele-
+
+
(
s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 8.23 ppm (d, J=8.2 Hz,
1
3
1
H); C NMR and DEPT (125 MHz, CDCl ): d=28.55 (3CH ), 55.80
mental analysis (%) calcd for C23
found: C 73.54, H 6.51, N 3.71.
H23NO : C 73.19, H 6.14, N 3.71;
4
3
3
(
CH ), 62.54 (CH ), 84.05 (C), 99.18 (CH), 116.31 (CH), 118.67 (C),
3 2
1
1
18.99 (CH), 119.61 (CH), 123.30 (CH), 125.21 (C), 125.86 (CH),
26.04 (C), 138.40 (C), 139.48 (C), 151.25 (C=O), 157.54 ppm (C); UV
N-Boc-5-(hydroxymethyl)-3,3-dimethylpyrano[3,2-a]carbazole:
Sodium borohydride (68.8 mg, 1.82 mmol) was added to a solution
of N-Boc-murrayacine (227 mg, 0.601 mmol) in methanol (10 mL) at
(
MeOH): lmax =234, 241, 260, 280 (sh), 302, 321, 338 (sh) nm; fluo-
rescence (MeOH): l =260, lem =378 nm; IR (ATR): n=3513, 3161,
ex
0
8C and the mixture was stirred for 4 h. The solvent was evaporat-
2
1
1
6
1
977, 2933, 2862, 2836, 2057, 2030, 1844, 1792, 1771, 1734, 1717,
696, 1653, 1627, 1476, 1453, 1423, 1373, 1353, 1305, 1274, 1235,
201, 1172, 1146, 1115, 1036, 982, 934, 890, 830, 789, 760, 718, 649,
ed, diethyl ether was added, and the mixture was washed with
a saturated aqueous solution of ammonium chloride. The aqueous
layer was extracted with diethyl ether (3”) and the combined or-
ganic layers were dried over magnesium sulfate. Evaporation of
the solvent and purification of the residue by flash chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 4:1) provided the
product (227 mg, 100%) as colourless crystals. M.p. 135–1378C;
À1
+
05 cm ; MS (EI): m/z (%): 227 (100, [MÀBoc] ), 210 (59), 198 (22),
84 (18), 183 (18), 180 (24), 167 (25), 166 (19), 154 (16), 139 (10);
+
+
MS (ESI; 10 V): m/z: 310 [MÀOH] , 677 [2M+Na] ; elemental anal-
ysis (%) calcd for C H NO : C 69.71, H 6.47, N 4.28; found: C
1
9
21
4
6
9.77, H 6.49, N 4.26.
H NMR (500 MHz, CDCl ): d=1.55 (s, 6H), 1.67 (s, 9H), 2.41 (brs,
3
1
9
1
H), 4.80 (d, J=3.9 Hz, 2H), 5.67 (d, J=9.9 Hz, 1H), 6.68 (d, J=
.9 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.37 (ddd, J=8.4, 7.1,
.4 Hz, 1H), 7.75 (s, 1H), 7.84 (dd, J=7.5, 0.6 Hz, 1H), 8.12 ppm (d,
N-Boc-2-methoxy-3-{[(4-nitrobenzoyl)oxy]methyl}carbazole (22):
DMAP (101 mg, 0.829 mmol) and 4-nitrobenzoyl chloride (154 mg,
0
2
.830 mmol) were added to a solution of N-Boc-3-(hydroxymethyl)-
-methoxycarbazole (181 mg, 0.553 mmol) in dichloromethane
13
J=8.2 Hz, 1H); C NMR and DEPT (125 MHz, CDCl ): d=27.45
3
(
2CH ), 28.32 (3CH ), 62.41 (CH ), 75.98 (C), 84.35 (C), 110.77 (C),
3 3 2
(
15 mL). After stirring at room temperature for 5 days, a saturated
115.66 (CH), 118.90 (CH), 119.35 (CH), 120.36 (C), 121.94 (CH),
aqueous solution of sodium bicarbonate was added and the layers
were separated. The aqueous layer was extracted with dichlorome-
thane (3”). The organic layers were combined and dried over mag-
nesium sulfate. Evaporation of the solvent and purification of the
residue by flash chromatography on silica gel (petroleum ether/
1
23.41 (CH), 125.13 (C), 125.97 (CH), 126.40 (C), 126.62 (CH), 135.47
(
C), 140.14 (C), 151.13 and 151.38 ppm (C and C=O); IR (ATR): n=
3
1
1
7
544, 3426, 3051, 2978, 2926, 2866, 2056, 2030, 2009, 1917, 1868,
844, 1792, 1771, 1726, 1649, 1593, 1464, 1422, 1366, 1332, 1296,
248, 1184, 1149, 1122, 1073, 1045, 992, 957, 929, 880, 853, 813,
ethyl acetate 2:1) provided 22 (250 mg, 95%) as a yellow solid.
À1
83, 756, 744, 651, 621 cm ; UV (MeOH): lmax =236, 258 (sh), 267
1
M.p. 170–1728C; H NMR (500 MHz, CDCl ): d=1.78 (s, 9H), 3.99 (s,
3
(
sh), 276, 300, 310 nm; fluorescence (MeOH): l =300, l =
ex em
3
1
8
2
H), 5.58 (s, 2H), 7.34 (t, J=7.4 Hz, 1H), 7.41 (ddd, J=8.3, 7.3,
.2 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.98 (s, 1H), 8.00 (brs, 1H),
+
+
3
32 nm; MS (ESI; 10 V): m/z: 776 [2M+NH ] , 781 [2M+Na] ; ele-
4
mental analysis (%) calcd for C H NO : C 72.80, H 6.64, N 3.69;
found: C 72.98, H 6.81, N 3.71.
1
3
23 25
4
.23–8.28 ppm (m, 5H); C NMR and DEPT (125 MHz, CDCl ): d=
3
8.54 (3CH ), 56.03 (CH ), 63.88 (CH ), 84.25 (C), 99.47 (CH), 116.36
3
3
2
(
1
(
CH), 118.67 (C), 119.03 (CH), 119.55 (C), 121.53 (CH), 123.40 (CH),
23.67 (2CH), 125.76 (C), 126.12 (CH), 130.98 (2CH and C), 136.06
C), 138.49 (C), 150.63 and 151.19 and 157.98 (2C and C=O),
N-Boc-3,3-dimethyl-5-{[(4-nitrobenzoyl)oxy]methyl}pyrano[3,2-
a]carbazole (25): DMAP (108 mg, 0.884 mmol) and 4-nitrobenzoyl
chloride (164 mg, 0.884 mmol) were added to a solution of N-Boc-
1
1
1
1
64.93 ppm (C=O); IR (ATR): n=3055, 3005, 2949, 2925, 2823, 2053,
917, 1721, 1684, 1651, 1635, 1604, 1558, 1527, 1486, 1451, 1422,
395, 1359, 1322, 1280, 1253, 1219, 1192, 1153, 1127, 1103, 1044,
5-(hydroxymethyl)-3,3-dimethylpyrano[3,2-a]carbazole
(224 mg,
0.590 mmol) in dichloromethane (20 mL) and the mixture was
stirred at room temperature for 4 days. A saturated aqueous solu-
tion of sodium bicarbonate was added and the layers were sepa-
rated. The aqueous layer was extracted with dichloromethane (3”)
and the combined organic layers were dried over magnesium sul-
fate. Evaporation of the solvent and purification of the residue by
flash chromatography on silica gel (petroleum ether/ethyl acetate/
À1
014, 999, 918, 871, 850, 837, 787, 764, 745, 714, 665, 613 cm ; UV
(
(
MeOH): lmax =233, 252 (sh), 263, 291, 303 nm; fluorescence
MeOH): l =270, l =363 nm; MS (ESI; 10 V): m/z: 970 [2M+
ex
em
+
+
NH ] , 975 [2M+Na] ; elemental analysis (%) calcd for C H N O :
C 65.54, H 5.08, N 5.88; found: C 65.62, H 5.17, N 5.50.
4
26 24
2
7
Chem. Eur. J. 2016, 22, 2487 – 2500
www.chemeurj.org
2497
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ethanol 79:20:1) provided 25 (309 mg, 99%) as a yellow solid.
(17), 211 (62), 196 (32), 180 (15), 168 (30), 167 (26); HRMS: m/z
1
M.p. 161–1638C; H NMR (500 MHz, CDCl ): d=1.50 (s, 6H), 1.67 (s,
calcd for C H N O : 472.2151; found: 472.2127.
3
32 28
2
2
9
7
7
8
H), 5.56 (s, 2H), 5.68 (d, J=9.8 Hz, 1H), 6.68 (d, J=9.8 Hz, 1H),
.32 (td, J=7.4, 0.9 Hz, 1H), 7.39 (ddd, J=8.4, 7.1, 1.3 Hz, 1H),
.85–7.87 (m, 1H), 7.87 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.24–
N-Boc-murrayacinine (28):
A
solution of Boc O (270 mg,
2
1
.24 mmol) in acetonitrile (5 mL) and DMAP (80.0 mg, 0.655 mmol)
was added to
a solution of murrayacinine (27; 210 mg,
1
3
.30 ppm (m, 4H); C NMR and DEPT (125 MHz, CDCl ): d=27.41
3
0
.608 mmol) in acetonitrile (15 mL) at room temperature and the
(
2CH ), 28.31 (3CH ), 63.80 (CH ), 75.89 (C), 84.55 (C), 110.89 (C),
3 3 2
mixture was stirred for 25 h. Evaporation of the solvent and purifi-
cation of the residue by flash chromatography on silica gel (petro-
leum ether/ethyl acetate 10:1) provided 28 (229 mg, 85%) as
a highly viscous, light-yellow oil. H NMR (600 MHz, [D ]acetone):
d=1.57 (s, 3H), 1.59 (s, 3H), 1.63 (s, 3H), 1.70 (s, 9H), 1.89–1.99 (m,
1
(
(
15.68 (CH), 118.91 (CH), 119.52 (C), 120.25 (C), 121.05 (CH), 121.76
CH), 123.50 (CH), 123.68 (2CH), 126.13 (C), 126.19 (CH), 127.06
CH), 130.92 (2CH), 136.07 (C), 136.23 (C), 140.20 (C), 150.63 and
1
6
1
3
1
1
8
2
51.30 and 151.81 (2C and C=O), 164.82 ppm (C=O); IR (ATR): n=
107, 3081, 3055, 2978, 2931, 1869, 1844, 1828, 1771, 1717, 1685,
651, 1639, 1609, 1559, 1522, 1453, 1421, 1367, 1341, 1302, 1260,
231, 1201, 1150, 1115, 1070, 1045, 1014, 975, 947, 918, 891, 866,
2
1
7
1
H), 2.20–2.28 (m, 2H), 5.14 (t, J=7.1 Hz, 1H), 5.95 (d, J=10.0 Hz,
H), 6.77 (d, J=10.0 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 7.48 (t, J=
.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.32 (s,
À1
49, 829, 813, 753, 711, 645 cm ; UV (MeOH): lmax =235, 256 (sh),
13
H), 10.54 ppm (s, 1H); C NMR and DEPT (150 MHz, [D ]acetone):
6
66 (sh), 275, 299, 310 (sh) nm; fluorescence (MeOH): l =275,
ex
d=17.68 (CH ), 23.46 (CH ), 25.35 (CH ), 25.80 (CH ), 28.21 (3CH ),
3
2
3
3
3
+
lem =350, 472 nm; MS (ESI; 10 V): m/z: 546 [M+NH ] ; elemental
analysis (%) calcd for C H N O : C 68.17, H 5.34, N 5.30; found: C
6
4
4
1
0.81 (CH ), 79.87 (C), 85.93 (C), 111.70 (C), 116.05 (CH), 119.03 (CH),
20.50 (CH), 121.54 (C), 122.12 (CH), 124.74 (C and CH), 124.85
2
3
0
28
2
7
8.50, H 5.66, N 5.33.
(
1
CH), 126.41 (C), 127.84 (CH), 128.03 (CH), 132.25 (C), 140.12 (C),
41.36 (C), 151.36 (C=O), 156.88 (C), 188.85 ppm (CHO); IR (ATR):
n=3055, 2974, 2928, 2856, 2056, 1918, 1869, 1844, 1829, 1792,
Murrafoline-E (5-[(1-methoxy-3-methylcarbazol-9-yl)methyl]-3,3-
dimethyl-3,11-dihydropyrano[3,2-a]carbazole) (6): A mixture of
the activated carbazole 25 (100 mg, 0.189 mmol), 8a (62.0 mg,
1
1
7
3
771, 1732, 1699, 1678, 1651, 1636, 1592, 1509, 1474, 1438, 1414,
370, 1321, 1294, 1221, 1145, 1072, 1044, 1023, 923, 895, 851, 820,
46, 680 cm ; UV (MeOH): lmax =230, 267, 277 (sh), 292, 311 (sh),
À1
0
.293 mmol), copper(I) bromide (7.8 mg, 54 mmol), freshly dried po-
27 (sh), 380 nm; fluorescence (MeOH): l =266, l =494 nm; MS
ex
em
tassium phosphate (255 mg, 1.20 mmol), and pyrrole-2-carboxylic
acid (14.5 mg, 131 mmol) in DMSO (2 mL) was heated at 110 8C for
2
+
(
(
EI): m/z (%): 345 (3, [MÀBoc] ), 282 (8) 262 (100), 260 (15), 207
+
19), 204 (10); MS (ESI; 10 V): m/z: 446 [M+H] .
4 h. A saturated aqueous solution of ammonium chloride was
N-Boc-5-(hydroxymethyl)-3-methyl-3-(4-methylpent-3-en-1-yl)-
pyrano[3,2-a]carbazole: Sodium borohydride (55.0 mg,
.45 mmol) was added to a solution of aldehyde 28 (182 mg,
.408 mmol) in THF (15 mL) at 08C. The mixture was stirred for 4 h
added and the mixture was extracted with ethyl acetate (4”). The
combined organic layers were washed with a saturated aqueous
solution of sodium chloride and dried over magnesium sulfate.
Evaporation of the solvent and purification of the residue by flash
chromatography on silica gel (isohexane/ethyl acetate 1:0!7:3)
1
0
at 08C and a further portion of sodium borohydride (40.0 mg,
.06 mmol) was added. The mixture was stirred for 90 min, the sol-
1
provided 6 (23.2 mg, 26%) as a light-red–brown solid. M.p. 110–
1
vent was evaporated, and diethyl ether was added. The resulting
mixture was washed with saturated aqueous ammonium chloride.
The aqueous layer was extracted with diethyl ether (3”) and the
combined organic layers were dried over magnesium sulfate. Evap-
oration of the solvent and purification of the residue by flash chro-
matography on silica gel (petroleum ether/ethyl acetate 4:1) pro-
1
15 8C (ref. [13]: colourless oil); H NMR (500 MHz, CDCl ): d=1.47
3
(
s, 6H), 2.55 (s, 3H), 3.86 (s, 3H), 5.73 (d, J=9.8 Hz, 1H), 5.96 (s,
2
0
7
1
1
H), 6.65 (d, J=9.8 Hz, 1H), 6.77 (s, 1H), 7.03 (ddd, J=7.9, 7.1,
.9 Hz, 1H), 7.16 (ddd, J=7.8, 6.7, 1.2 Hz, 1H), 7.21–7.26 (m, 2H),
.30–7.35 (m, 3H), 7.57 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.88 (brs,
1
H), 8.06 ppm (d, 7.8 Hz, 1H); H NMR (500 MHz, [D ]acetone): d=
6
vided the product (183 mg, 100%) as a highly viscous, colourless
.41 (s, 6H), 2.50 (s, 3H), 3.94 (s, 3H), 5.79 (d, J=9.9 Hz, 1H), 6.01
1
oil. H NMR (500 MHz, CDCl ): d=1.50 (s, 3H), 1.58 (s, 3H), 1.67 (s,
3
(
d, J=0.4 Hz, 2H), 6.89 (s, 1H), 6.92 (d, J=9.9 Hz, 1H), 6.98 (ddd,
J=8.0, 7.1, 0.9 Hz, 1H), 7.13 (ddd, J=7.9, 7.0, 0.8 Hz, 1H), 7.20
ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.30 (ddd, J=8.3, 7.1, 1.2 Hz, 1H),
1
2
1
2H), 1.84 (d, J=8.0 Hz, 1H), 1.86 (d, J=8.5 Hz, 1H), 2.10–2.23 (m,
H), 2.38 (brs, 1H), 4.78 (d, JAB =12.9 Hz, 1H), 4.81 (d, JAB =12.9 Hz,
H), 5.11 (tt, J=7.1, 1.3 Hz, 1H), 5.65 (d, J=10.0 Hz, 1H), 6.72 (d,
(
7
7
.34 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.57–
.60 (m, 2H), 8.07 (d, J=7.8 Hz, 1H), 10.34 ppm (brs, 1H); C NMR
13
J=10.0 Hz, 1H), 7.33 (td, J=7.4, 0.8 Hz, 1H), 7.37 (ddd, J=8.4, 7.1,
.3 Hz, 1H), 7.75 (s, 1H), 7.84 (dd, J=7.5, 0.6 Hz, 1H), 8.11 ppm (d,
1
and DEPT (125 MHz, CDCl ): d=21.86 (CH ), 27.60 (2CH ), 44.31
3
3
3
13
J=8.2 Hz, 1H); C NMR and DEPT (125 MHz, CDCl ): d=17.79
3
(
CH ), 55.94 (CH ), 76.35 (C), 104.49 (C), 109.32 (CH), 109.94 (CH),
2 3
(
(
CH ), 23.00 (CH ), 25.48 (CH ), 25.81 (CH ), 28.34 (3CH ), 40.67
3 2 3 3 3
110.38 (CH), 112.87 (CH), 117.16 (C), 117.26 (CH), 118.73 (CH), 118.78
CH ), 62.42 (CH ), 78.31 (C), 84.33 (C), 110.59 (C), 115.66 (CH),
2
2
(
CH), 119.58 (CH), 119.78 (CH), 119.98 (C), 120.15 (CH), 123.12 (C),
118.87 (CH), 119.34 (CH), 120.31 (C), 122.22 (CH), 123.40 (CH),
1
23.88 (C), 124.55 (CH), 125.02 (C), 125.49 (CH), 128.88 (C), 128.98
1
23.96 (CH), 125.02 (C), 125.90 (CH), 125.93 (CH), 126.41 (C), 132.18
(
1
2
C), 129.71 (CH), 135.37 (C), 139.52 (C), 141.47 (C), 146.95 (C),
1
3
(C), 135.48 (C), 140.13 (C), 151.14 and 151.39 ppm (C and C=O); IR
ATR): n=3417, 3048, 2973, 2926, 2863, 2056, 2030, 1918, 1869,
48.77 ppm (C); C NMR and DEPT (125 MHz, [D ]acetone): d=
6
(
1.72 (CH ), 27.67 (2CH ), 44.87 (CH ), 56.11 (CH ), 76.97 (C), 105.55
3
3
2
3
1
844, 1771, 1725, 1685, 1649, 1593, 1421, 1369, 1336, 1296, 1236,
(
1
1
(
C), 110.08 (CH), 110.90 (CH), 111.42 (CH), 113.45 (CH), 117.62 (C),
18.37 (CH), 119.31 (CH), 119.49 (CH), 119.75 (CH), 119.78 (CH),
20.00 (C), 120.74 (CH), 123.92 (C), 124.21 (C), 125.15 (CH), 125.69
C), 126.10 (CH), 129.51 (C), 129.72 (C), 130.25 (CH), 136.83 (C),
À1
1147, 1121, 1075, 1046, 983, 924, 880, 853, 819, 746, 656 cm ; UV
(
MeOH): lmax =236, 259 (sh), 269 (sh), 277, 301, 310 (sh) nm; fluo-
rescence (MeOH): l =277, l =351 nm; MS (ESI; 10 V): m/z: 430
ex
em
+
+
+
[
MÀOH] , 912 [2M+NH ] , 917 [2M+Na] .
4
1
3
1
9
2
3
41.05 (C), 142.13 (C), 147.83 (C), 149.62 ppm (C); IR (ATR): n=
412, 3055, 2969, 2926, 2860, 2057, 1696, 1643, 1606, 1581, 1493,
455, 1403, 1377, 1352, 1301, 1266, 1238, 1204, 1145, 1121, 1039,
N-Boc-3-methyl-3-(4-methylpent-3-en-1-yl)-5-{[(4-nitrobenzoy-
l)oxy]methyl}pyrano[3,2-a]carbazole (29): DMAP (47 mg,
0.38 mmol) and 4-nitrobenzoyl chloride (72 mg, 0.39 mmol) were
added to a solution of N-Boc-5-(hydroxymethyl)-3-methyl-3-(4-
methylpent-3-en-1-yl)pyrano[3,2-a]carbazole (116 mg, 0.259 mmol)
À1
46, 891, 826, 739 cm ; UV (MeOH): lmax =230 (sh), 237, 253 (sh),
62 (sh), 286, 340 nm; fluorescence (MeOH): l =286, l
75 nm; MS (EI): m/z (%): 472 (35, [M ]), 262 (100), 247 (24), 246
=
em
ex
+
Chem. Eur. J. 2016, 22, 2487 – 2500
www.chemeurj.org 2498
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
in dichloromethane (12 mL) and the mixture was stirred at room
temperature for 76 h. A saturated aqueous solution of sodium bi-
carbonate was added and the layers were separated. The aqueous
layer was extracted with dichloromethane (3”). The organic layers
were combined and dried over magnesium sulfate. Evaporation of
the solvent and purification of the residue by flash chromatogra-
(CH ), 44.29 (CH ), 55.90 (CH ), 78.78 (C), 104.19 (C), 109.28 (CH),
2
2
3
109.92 (CH), 110.36 (CH), 112.88 (CH), 117.02 (C), 117.65 (CH), 118.74
(2CH), 119.57 (CH), 119.77 (C and CH), 120.16 (CH), 123.13 (C),
123.90 (C), 124.31 (CH), 124.50 (CH), 125.03 (C), 125.50 (CH), 128.63
(CH), 128.88 (C), 128.98 (C), 131.93 (C), 135.40 (C), 139.51 (C),
13
141.46 (C), 146.95 (C), 148.88 ppm (C); C NMR and DEPT
phy on silica gel (petroleum ether/ethyl acetate 8:1) provided 29
(125 MHz, [D ]acetone): d=17.77 (CH ), 21.74 (CH ), 23.71 (CH ),
25.84 (CH ), 26.29 (CH ), 41.71 (CH ), 44.99 (CH ), 56.10 (CH ), 79.45
3 3 2 2 3
6
3
3
2
1
(
153 mg, 99%) as a yellow solid. M.p. 62–658C; H NMR (500 MHz,
CDCl ): d=1.46 (s, 3H), 1.51 (s, 3H), 1.63 (s, 3H), 1.68 (s, 9H), 1.77–
(C), 105.27 (C), 110.06 (CH), 110.87 (CH), 111.41 (CH), 113.47 (CH),
117.50 (C), 118.86 (CH), 119.41 (CH), 119.48 (CH), 119.73 (CH), 119.76
(CH), 120.75 (CH), 123.94 (C), 124.23 (C), 125.10 (CH), 125.27 (CH),
125.66 (C), 126.06 (CH), 129.10 (CH), 129.53 (C), 129.70 (C), 131.86
(C), 136.88 (C), 140.92 (C), 141.05 (C), 142.10 (C), 147.80 (C),
3
1
.83 (m, 2H), 2.12 (m, 2H), 5.03 (tt, J=7.1, 1.3 Hz, 1H), 5.54 (d,
JAB =11.9 Hz, 1H), 5.57 (d, JAB =11.9 Hz, 1H), 5.66 (d, J=10.0 Hz,
H), 6.71 (d, J=10.0 Hz, 1H), 7.32 (td, J=7.4, 0.8 Hz, 1H), 7.38
ddd, J=8.4, 7.1, 1.3 Hz, 1H), 7.85 (dd, J=7.6, 0.7 Hz, 1H), 7.87 (s,
1
(
13
+
1
H), 8.11 ppm (d, J=8.2 Hz, 1H), 8.22–8.27 ppm (m, 4H); C NMR
149.82 ppm (C); MS (EI): m/z (%): 540 (29, [M ]), 330 (100), 162 (17),
and DEPT (125 MHz, CDCl ): d=17.74 (CH ), 22.87 (CH ), 25.50
248 (14), 247 (15), 246 (15), 211 (42), 208 (12), 196 (30); IR (ATR):
n=3415, 2969, 2916, 2850, 1721, 1643, 1608, 1580, 1494, 1456,
1404, 1351, 1299, 1265, 1239, 1204, 1145, 1121, 1080, 1039, 1017,
3
3
2
(
CH ), 25.78 (CH ), 28.33 (3CH ), 40.76 (CH ), 63.85 (CH ), 78.20 (C),
3 3 3 2 2
8
1
1
4.54 (C), 110.70 (C), 115.67 (CH), 118.89 (CH), 119.32 (C), 120.20 (C),
21.28 (CH), 122.03 (C), 123.50 (CH), 123.64 (2CH), 123.97 (CH),
26.16 (C and CH), 126.32 (CH), 130.95 (2CH), 132.05 (C), 136.01
À1
947, 905, 826, 739, 676 cm ; UV (MeOH): lmax =230 (sh), 238, 253
(sh), 262 (sh), 287, 340, 351 nm; fluorescence (MeOH): l =287,
ex
À
(
C), 136.29 (C), 140.20 (C), 150.60 and 151.30 and 151.93 (2C and
lem =384 nm; MS (ESI; À10 V): m/z: 539 [MÀH] ; HRMS: m/z calcd
C=O), 164.83 ppm (C=O); IR (ATR): n=3111, 3051, 2973, 2927, 2853,
for C H N O : 540.2777; found: 540.2772.
37
36
2
2
1
1
1
918, 1869, 1844, 1828, 1792, 1771, 1723, 1684, 1650, 1603, 1575,
558, 1527, 1449, 1422, 1396, 1369, 1338, 1266, 1238, 1148, 1099,
075, 1047, 1013, 930, 871, 852, 818, 783, 755, 716 cm ; UV
À1
Acknowledgements
(
MeOH): lmax =236, 257 (sh), 267 (sh), 276, 300, 310 (sh) nm; fluo-
rescence (MeOH): l =276, l =317 nm; MS (ESI; 10 V): m/z: 614
We are grateful to Professor Chihiro Ito (Faculty of Pharmacy,
Meijo University, Nagoya, Japan) for providing us copies of the
original spectra of natural murrastifoline-C. We thank Dr. Phil-
ipp Linning for experimental support.
ex
em
+
[
M+NH ] ; elemental analysis (%) calcd for C H N O : C 70.45, H
4
35 36
2
7
6
.08, N 4.69; found: C 70.22, H 6.14, N 4.68.
Murrastifoline-C (5-[(1-methoxy-3-methylcarbazol-9-yl)methyl]-
-methyl-3-(4-methylpent-3-en-1-yl)pyrano[3,2-a]carbazole] (7):
3
Three batches of the reaction mixture were prepared as follows:
Carbazole 29 (40 mg, 0.067 mmol), 8a (21.5 mg, 0.102 mmol), cop-
per(I) bromide (2.0 mg, 14 mmol), freshly dried potassium phos-
phate (60.0 mg, 0.283 mmol), pyrrole-2-carboxylic acid (3.0 mg,
Keywords: alkaloids
cyclisation · natural products · palladium
·
CÀH bond activation
· copper ·
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7 mmol), and DMSO (1 mL) were put together in a flask. Each flask
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and these mixtures were extracted with ethyl acetate (3”). The
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(
22.2 mg, 20%) as a light-red–brown solid. M.p. 85–868C (ref. [12]:
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2
0
enantiomer, t =13.3 min, [a]D = +0.23 (c=0.1 in MeOH); second
R
2
0
enantiomer, t =19.2 min, [a]D =À0.22 (c=0.1 in MeOH); see the
R
1
General section for the experimental details; H NMR (500 MHz,
CDCl ): d=1.43 (s, 3H), 1.61 (s, 3H), 1.69 (s, 3H), 1.74–1.82 (m, 2H),
3
2
1
1
7
7
1
.16–2.22 (m, 2H), 2.55 (s, 3H), 3.85 (s, 3H), 5.14 (tt, J=7.0, 1.3 Hz,
H), 5.70 (d, J=9.9 Hz, 1H), 5.93 (d, JAB =16.8 Hz, 1H), 5.99 (d, JAB
6.8 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 6.76 (s, 1H), 7.03 (ddd, J=7.8,
.2, 0.8 Hz, 1H), 7.16 (ddd, J=7.8, 6.7, 1.1 Hz, 1H), 7.23 (m, 2H),
=
5256.
.29–7.35 (m, 3H), 7.57 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.87 (brs,
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H), 8.05 ppm (d, J=7.8 Hz, 1H); H NMR (500 MHz, [D ]acetone):
6
d=1.37 (s, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.69–1.72 (m, 2H), 2.11–
2
5
1
.18 (m, 2H), 2.51 (s, 3H), 3.93 (s, 3H), 5.13 (tt, J=7.1, 1.3 Hz, 1H),
.77 (d, J=9.9 Hz, 1H), 6.01 (d, JAB =16.7 Hz, 1H), 6.05 (d, JAB
6.7 Hz, 1H), 6.89 (s, 1H), 6.96 (d, J=9.9 Hz, 1H), 6.98 (m, 1H), 7.12
=
(
ddd, J=7.8, 7.1, 0.7 Hz, 1H), 7.20 (ddd, J=8.2, 7.1, 1.1 Hz, 1H),
7
1
1
1
.29 (ddd, J=8.3, 7.1, 1.1 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.36 (s,
H), 7.46 (d, J=8.3 Hz, 1H), 7.58–7.60 (m, 2H), 8.07 (d, J=7.8 Hz,
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1
3
H), 10.36 ppm (brs, 1H); C NMR and DEPT (125 MHz, CDCl ): d=
3
7.87 (CH ), 21.87 (CH ), 23.11 (CH ), 25.86 (CH ), 26.05 (CH ), 41.17
3
3
2
3
3
Chem. Eur. J. 2016, 22, 2487 – 2500
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2499
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: November 20, 2015
Published online on January 20, 2016
Chem. Eur. J. 2016, 22, 2487 – 2500
www.chemeurj.org
2500
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim