Efficient construction of pyrano [3, 2-a]carbazoles: Application to a biomimetic total synthesis of cyclized monoterpenoid pyrano [3, 2-a]carbazole Alkaloids

Article abstract of DOI:10.1002/chem.201301792

We have developed a highly efficient route to 2-hydroxy-3-methyl-carbazole (1) via a palladium-catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal (21) opened up an efficient route to girinimbine (3) and the corresponding reaction with citral (25) afforded mahanimbine (5). Oxidation of compounds 3 and 5 provided murraya-cine (4) and murrayacinine (6). Following the biogenetic proposal, mahanim-bine (5) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3, 2-a]carbazole alkaloids cyclomahanimbine (7), maha-nimbidine (8) and bicyclomahanimbine (9). The interconversions of 5, 7, 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X-ray crystal structure determinations. Moreover, cyclomahanimbine (7) was transformed into murrayazolinine (10) and exozoline (11).

Full text of DOI:10.1002/chem.201301792

DOI: 10.1002/chem.201301792
Efficient Construction of PyranoACTHNUTRGNE[UNG 3,2-a]carbazoles: Application to a
Biomimetic Total Synthesis of Cyclized Monoterpenoid
PyranoACTHNUGRTNEUNG[3,2-a]carbazole Alkaloids**
Ronny Hesse, Konstanze K. Gruner, Olga Kataeva, Arndt W. Schmidt, and
Hans-Joachim Knçlker*[a]
Abstract: We have developed a highly
efficient route to 2-hydroxy-3-methyl-
carbazole (1) via a palladium-catalyzed
construction of the carbazole skeleton.
Using 1 as relay compound, different
methods for annulations of pyran rings
by reaction with terpenoid building
blocks have been tested. The Lewis
forded mahanimbine (5). Oxidation of
compounds 3 and 5 provided murraya-
cine (4) and murrayacinine (6). Follow-
ing the biogenetic proposal, mahanim-
bine (5) has been exploited for efficient
biomimetic syntheses of the cyclized
monoterpenoid pyranoACTHNGUTERNNU[G 3,2-a]carbazole
alkaloids cyclomahanimbine (7), maha-
nimbidine (8) and bicyclomahanimbine
(9). The interconversions of 5, 7, 8 and
9 are described and mechanistic impli-
cations are discussed. Structural assign-
ments are unambiguously verified by
X-ray crystal structure determinations.
Moreover, cyclomahanimbine (7) was
transformed into murrayazolinine (10)
and exozoline (11).
À
Keywords: alkaloids · C H bond
acid promoted reaction of
1 with
activation · crystal-structure deter-
prenal (21) opened up an efficient
route to girinimbine (3) and the corre-
sponding reaction with citral (25) af-
mination
· cyclization · natural
products · palladium
Introduction
A broad structural variety of carbazole alkaloids has been
obtained from different natural sources, for example, terres-
trial plants, microorganisms, slime molds, and algae.[1,2] 3-
Methylcarbazole has been recognized as the parent com-
pound for the biogenesis of carbazole alkaloids in plants of
the genera Murraya, Clausena, Glycosmis, and Micromelum
(family Rutaceae) which represent the major natural sources
for carbazole alkaloids. Oxygenation at different positions
of the carbazole framework, oxidation of the methyl group,
prenylation or geranylation and subsequent annulation of
additional rings occur further downstream on the biogenetic
pathway and provide the structural variety of carbazoles
found in these plants.[2] On this biogenetic pathway, 2-hy-
droxy-3-methylcarbazole (1) is the first representative for 2-
oxygenated carbazole alkaloids (Scheme 1).
In 1986, Bhattacharyya et al. isolated 2-hydroxy-3-methyl-
carbazole (1) from the roots of the Indian medicinal plant
Murraya koenigii.[3] This plant is also known as curry-leaf
[a] R. Hesse, Dr. K. K. Gruner, Dr. O. Kataeva, Dr. A. W. Schmidt,
Prof. Dr. H.-J. Knçlker
Scheme 1. Potential biogenetic pathways from 2-hydroxy-3-methylcarba-
zole (1) to the pyrano[3,2-a]carbazole alkaloids 3–6 and the cyclized
monoterpenoid pyrano[3,2-a]carbazole alkaloids 7–9.
AHCTUNGTRENNUNG
Department of Chemistry, Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax : (+49)351-463-37030
AHCTUNGTRENNUNG
E-mail: hans-joachim.knoelker@tu-dresden.de
tree, or in Hindi karipatta, because the leaves of this tree
are used as flavor for curry.
[**] Transition Metal Complexes in Organic Synthesis, Part 109. For Part
108, see: reference [30t].
One year earlier, the same group had already reported
the isolation of 2-methoxy-3-methylcarbazole (2) from the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301792.
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FULL PAPER
seeds of the same plant.[4] Prenylation of 1 and subsequent
pyran annulation provides girinimbine (3), the first pyrano-
ACHTUNGTRENNUNG[3,2-a]carbazole alkaloid obtained from natural sources. Gir-
inimbine (3) was isolated by Chakraborty et al. from the
stem bark and by Joshi et al. from the leaves of Murraya
koenigii.[5,6] Moreover, 3 was found in the roots of Clausena
heptaphylla and in the root bark of Murraya euchrestifo-
lia.[7,8] More recently, it was reported that girinimbine (3)
has antitumor activity.[9] A formyl analogue of 3, murraya-
cine (4), was obtained by Chakraborty et al. from Murraya
koenigii and from Clausena heptaphylla.[5c,10,11] Geranylation
of 1 followed by pyran annulation to mahanimbine (5) is an
alternative pathway in the biogenesis of these alkaloids. The
first isolation of (+)-mahanimbine (5) was reported in 1966
by Chakraborty et al. who obtained this natural product
from the stem bark of Murraya koenigii.[12] Two years later,
Narasimhan et al. obtained compound 5 from the fruits of
the same plant and revised the original structural assignment
to the one shown.[13] The absolute configuration of (+)-ma-
hanimbine (5) is still unkown. Interestingly, the racemic al-
kaloid, (Æ)-mahanimbine (5), was subsequently isolated
from two further Murraya species, M. euchrestifolia and M.
siamensis.[8,14] Murrayacinine (6), the formyl analogue of 5,
was isolated by Chakraborty et al. from the stem bark of M.
koenigii.[15] An absolute configuration for 6 was not report-
ed. After introduction of the C10 moiety leading to maha-
nimbine (5), further cyclizations occur in vivo generating
Scheme 2. Murrayazolinine (10) and exozoline (11) derive from cyclo-
AHCTUNGTREGmNNUN ahanimbine (7).
for carbazole ring construction often involve transition
metal-mediated steps.[2,25,26] We described an efficient iron-
mediated approach which is especially useful for the synthe-
sis of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated car-
bazoles.[27,28] An alternative molybdenum-mediated route
has been successfully applied to the synthesis of 2-oxygenat-
ed carbazoles.[29] Our palladium-catalyzed synthesis is based
on a palladium(0)-catalyzed Buchwald–Hartwig amination
and a subsequent palladium(II)-catalyzed oxidative coupling
of the resulting N,N-diarylamine.[2,25] This approach can be
applied to the synthesis of a wide variety of carbazole alka-
loids with diverse substitution patterns.[30]
the cyclized monoterpenoid pyrano
N
We envisaged a versatile biomimetic synthesis of the cy-
7–9. In 1969, Kapil et al. isolated a pentacyclic pyrano
N
clized monoterpenoid pyranoACTHNGUTERNNU[G 3,2-a]carbazole alkaloids 7–11
a]carbazole alkaloid, called cyclomahanimbine (7), from the
leaves of M. koenigii.[16] In the same year, Dutta et al. isolat-
ed this alkaloid as curryanin (7) from the same plant.[17,18]
One year later, Chakraborty et al. described the isolation of
7 from the stem bark of M. koenigii and named it murraya-
zolidine.[18,19] In 1992, Reisch et al. obtained cyclomahanim-
bine (7) from the fruits of M. koenigii and confirmed the
stereochemistry.[20] Compound 8, resulting from further cyc-
lization of cyclomahanimbine (7), was isolated in 1969 inde-
pendently by the groups of Kapil and Dutta from the leaves
and the stem bark of M. koenigii and named mahanimbidine
and curryangin, respectively.[16,21] In a third isolation three
years later, Chakraborty et al. designated this natural prod-
uct as murrayazoline (8).[22] In an alternative biogenetic
pathway, an intramolecular [2+2] cycloaddition of mahanim-
bine (5) leads to bicyclomahanimbine (9) which was isolated
by Kapil et al. from the leaves of M. koenigii.[16]
Further biosynthetic transformations of cyclomahanim-
bine (7) are hydration of the double bond to murrayazoli-
nine (10) and reduction to exozoline (11) (Scheme 2). Mur-
rayazolinine (10) was obtained by Chakraborty et al. in 1973
from the stem bark of M. koenigii.[23] In 1978, Ganguly and
Sarkar reported the isolation of exozoline (11) from the
leaves of M. exotica.[24]
by using 2-hydroxy-3-methylcarbazole (1) as crucial inter-
mediate. Thus, the development of a very efficient route to
the key intermediate 1 was required first. Following the bio-
genetic route described above, elaboration of an annulation
procedure using 1 and an appropriate C5 moiety would pro-
vide the pyranoACHTUNTRGNEUNG[3,2-a]carbazoles 3 and 4. Pyran ring annula-
tion with a corresponding C10 building block followed by
further cyclization reactions should then lead to the cyclized
monoterpenoid pyranoACTHNUGRTENUNG[3,2-a]carbazole alkaloids 7–11.
Results and Discussion
The iron-mediated and molybdenum-mediated approaches
afforded 2-methoxy-3-methylcarbazole (2) in only moderate
yields (2 steps, 10 and 28% overall yield).[29a,31] Ether cleav-
age provided compound 1 in 78% yield.[29a] We have now
developed two alternative very efficient palladium-catalyzed
routes providing 2-hydroxy-3-methylcarbazole (1) in 78–
85% overall yield (Scheme 3).
The first route starts from the nitrophenol 12. O-Benzyla-
tion and subsequent reduction afforded the aniline 13 which
was then transformed to the diarylamine 14 by Buchwald–
Hartwig coupling with bromobenzene.[32] Palladium(II)-cata-
lyzed oxidative cyclization led to the carbazole 15 which on
hydrogenation afforded 2-hydroxy-3-methylcarbazole (1) (5
steps, 78% overall yield). Alternatively, commercially avail-
able 3-methoxy-4-methylaniline has been used as starting
The broad range of useful biological activities found for
carbazole alkaloids promises a high pharmacological poten-
tial and thus, diverse synthetic methods directed towards
their synthesis have been developed.[1,2] Modern methods
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H.-J. Knçlker et al.
Scheme 4. Synthesis of girinimbine (3) via propargylation and Claisen re-
arrangement. a) 17c (X=OCOOMe), Cs2CO3, 1.6 mol% CuI, MeCN,
RT, 29 h; b) toluene, 1118C, 29 h (55% 3 [2 steps], 19% 19 [2 steps]).
Table 1. Product distribution of the propargylation of 1 with subsequent
[3,3]-sigmatropic rearrangement and cyclization.
Scheme 3. Palladium-catalyzed synthesis of 2-hydroxy-3-methylcarbazole
(1). a) PhCH2Br, K2CO3, DMF, reflux, 5 h (99%); b) Fe, HOAc, 458C,
Yield [%]
17
X
18
3
19
20
4 h (100%); c) PhBr, 6 mol% Pd
uene, 1118C, 16 h (97%); d) 10 mol% Pd
HOPiv, air, 858C, 23 h (81%); e) 10% Pd/C, H2, MeOH/CH2Cl2 (4:1),
RT, 3 d (100%); f) PhI, 5 mol% Pd(OAc)2, 10 mol% SPhos, Cs2CO3, tol-
uene, 1008C, 26 h (96%); g) 5 mol% Pd(OAc)2, 5 mol% K2CO3, HOPiv,
ACHTUNGTRENNUNG
a[a]
Cl
32
26
52
3
–
–
AHCTUNGTRENNUNG
b[b]
OCOCF3
OCOOMe
OCOOMe
–
13
2
17
–
[d]
c[c] a)
46
AHCTUNGTRENNUNG
c[c] a,b)
–
55
19
–
[d]
AHCTUNGTRENNUNG
air, 1008C, 24 h (90%); h) BBr3, CH2Cl2, À788C to RT, 15.5 h (98%).
[a] 1, 17a, K2CO3, KI, 10 mol% CuBr, DMF, 908C, 20 h. [b] a) 1. 17d
(X=OH), DBU, (CF3CO)2O, 3 mol% CuCl2, MeCN, À408C to À108C,
30 min; 2. addition of 1, 5 h; b) toluene, 1118C, 22 h. [c] a) 1, slow addi-
tion of 17c, Cs2CO3, 1.6 mol% CuI, MeCN, RT, 29 h; b) toluene, 1118C,
29 h. [d] In this case, the intermediate propargyl ether 18 was not isolated
and submitted directly to the [3,3]-sigmatropic rearrangement.
material. Buchwald–Hartwig coupling with iodobenzene to
the diarylamine 16 followed by palladium(II)-catalyzed oxi-
dative cyclization directly provided 2-methoxy-3-methylcar-
bazole (2). The formation of an alternative regioisomer for
the cyclization product (compare ref. [30j,k]) could not be
observed under the present reaction conditions. Optimiza-
tion of the final ether cleavage of 2 by treatment with boron
tribromide at low temperature completed the best current
route to 2-hydroxy-3-methylcarbazole (1) (3 steps, 85%
overall yield). The spectroscopic data for 1 and 2 were in
full agreement with those reported for the corresponding
natural products.[3,4] The structure of compound 2 was addi-
tionally confirmed by an X-ray analysis (Figure 1).
ether 18 followed by [3,3]-sigmatropic rearrangement and
cyclization (Scheme 4, Table 1). Three reagents have been
tested for this process: the propargyl chloride 17a, the prop-
argyl trifluoroacetate 17b, and the methyl propargyl carbo-
nate 17c.[33]
The pyran annulation with 17b and 17c afforded the furo-
AHCTUNGTREG[NNNU 3,2-a]carbazole 19 as a by-product (13–19% yield). The
structure of compound 19 was unequivocally confirmed by
an X-ray crystal structure determination (Figure 2). The
highly reactive trifluoroacetate 17b afforded via a second
propargylation at the stage of intermediate 18 the 3,3-dime-
We have investigated different routes for the transforma-
tion of 1 into 3. The first route proceeds via propargylation
of the hydroxy group to afford the intermediate propargyl
thylallenyl-substituted pyranoACTHNUGRTNEUNG[3,2-a]carbazole 20 as an addi-
tional product (17% yield). Among these reagents, the
methyl carbonate 17c provided the best yield for 3 (55%).
Another established C5-building block is prenal (3,3-dime-
thylacrolein or 3-methylbut-2-enal) (21) which conveniently
can be applied for the annulation of pyran rings.[34] Under
optimized conditions (excess of titanium(IV) tetraisoprop-
oxide), the reaction with
1 led to 3 in 82% yield
(Scheme 5). Our three previous approaches to this natural
product, all using 5-amino-2,2,8-trimethylaminochromene as
building block, provided 3 either via a molybdenum-mediat-
ed synthesis (2 steps, 11% overall yield),[29b] a palladium-cat-
alyzed process (3 steps, 26% overall yield),[30l] or an iron-
mediated approach (2 steps, 58% overall yield).[35] The pres-
ent route via a palladium-catalyzed synthesis of 1 and subse-
quent annulation of the pyran ring affords 3 in 4 steps and
69% overall yield based on 3-methoxy-4-methylaniline and
Figure 1. Molecular structure of 1 in the crystal (ORTEP plot showing
thermal ellipsoids at the 50% probability level).
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Scheme 6. Synthesis of girinimbine (3) and the 1,1-di(carbazol-1-yl)prenyl
derivative 23. a) 0.5 equiv TiACHTNUGTRNEUNG(OiPr)4, prenal (21), toluene, 3 ꢂ molecular
sieves, RT, 30 h (53% 3 and 46% 23).
Figure 2. Molecular structure of the furoACTHNUGTRNEUNG[3,2-a]carbazole 19 in the crystal
(ORTEP plot showing thermal ellipsoids at the 50% probability level).
currently represents the best approach. Thus, 3 is available
in sufficient amounts and can be used as starting material
for further synthetic transformations. Oxidation with 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) using a mix-
ture of methanol, tetrahydrofuran, and water as solvent pro-
vided 4 in an improved yield (96%). In a previous study in
cooperation with the group of Professor Katsuki (Kyushu
University, Fukuoka, Japan), we have shown that 3 can be
transformed into natural (À)-trans-dihydroxygirinimbine
(22) via asymmetric epoxidation and subsequent hydrolysis
(98% ee).[35,36]
In an attempt to explore the feasibility of pyran annula-
tion using catalytic amounts of Lewis acid, the reaction of 1
with prenal (21) was carried out using 0.5 equiv of titanium
tetraisopropoxide (Scheme 6). However, these conditions
led to the formation of the 1,1-di(carbazol-1-yl)prenyl deriv-
ative 23 (46% yield) along with 3 (53% yield).
Scheme 7. Synthesis of 5 via Claisen rearrangement and conversion to 6.
a) 1. Cs2CO3, 1.4 mol% CuI, MeCN, RT, 16 h, 2. toluene, 1118C, 24 h
(49%); b) DDQ, MeOH/THF/H2O (5:1:1.5), RT, 1 h (70%).
The reaction of 2-hydroxy-3-methylcarbazole (1) with
citral (25) in the presence of titanium(IV) tetraisopropoxide
provided 5 in 82% yield which thus became readily availa-
ble on a multigram scale (Scheme 8). The present cyclization
procedure provides much better yields of 5 than previously
reported.[17,34a,38] Mahanimbine (5) was thought to represent
the starting material for our projected biomimetic synthetic
routes to the cyclized monoterpenoid pyranoACTHNUGRTENUNG[3,2-a]carbazole
alkaloids. Previous attempts of biomimetic cyclizations of 5
have provided mixtures of 7, 8, and additional unidentified
products.[17,19b,34a,38] We have been able to develop this ap-
proach into a selective process by very careful control of the
reaction conditions along with kinetic studies (vide infra). In
a first example, a solution of 5 in toluene was exposed to
direct sunlight for almost four weeks. These conditions in-
For the introduction of a C10-building block, we have in-
vestigated the same chemistry as described above. Reaction
of 2-hydroxy-3-methylcarbazole (1) with the propargyl car-
bonate 24[37] afforded 5 in 49% yield (Scheme 7). Subse-
quent oxidation of 5 with DDQ led to murrayacinine (6).
Scheme 5. Biomimetic synthesis of girinimbine (3) and conversion to
murrayacine (4). a) Ti
DDQ, MeOH/THF/H2O (10:3:1), RT, 90 min (96%).
N
Scheme 8. Biomimetic synthesis of 5 and 9. a) Ti
to RT, 15 h (82%); b) sunlight irradiation, toluene, 358C, 26.5 d (45%).
A
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H.-J. Knçlker et al.
duced a [2+2] cycloaddition to afford bicyclomahanimbine
(9) which could be isolated in 45% yield after chromatogra-
phy. Although the photolytically induced cycloaddition is
not very clean, the present route is superior to previous syn-
theses reported for 9.[16,38a] The structure and the stereo-
chemistry of
(Figure 3).
9 were confirmed by an X-ray analysis
Scheme 9. Synthesis of the tetrahydroindoloACTHNUTRGNE[UNG 3,2,1-de]acridine 26. a)
10 mol% camphor-10-sulfonic acid, toluene, RT, 13.5 h (42%).
Figure 3. Molecular structure of 9 in the crystal (ORTEP plot showing
thermal ellipsoids at the 50% probability level).
Scheme 10. Transformation of 5 into 7 and the tetrahydroindoloACHTUNGTRENNUNG[3,2,1-de]-
In an attempt to achieve a Brønsted acid-catalyzed annu-
lation of citral, a solution of 1 and citral (25) in toluene was
stirred in the presence of 10 mol% camphor-10-sulfonic acid
(CSA) or, alternatively, trifluoroacetic acid (Scheme 9).
However, these conditions led to the pentacyclic compound
phenanthridine 29. a) 0.8 equiv EtAlCl2, toluene, À788C to RT, 44 h
(15% of 7 and 33% of 29); b) 3.0 equiv EtAlCl2, toluene, À788C to RT,
6 h (52% of 29).
26 which represents a tetrahydroindolo
[3,2,1-de]acridine. An
On treatment with equimolar amounts of a Brønsted acid
(camphor-10-sulfonic acid or trifluoroacetic acid) in a solu-
tion of toluene or chloroform, 5 is converted into cycloma-
hanimbine (7) in 89% yield in less than two days
(Scheme 11, Table 2, entry 1).
initial nucleophilic attack of the carbazole nitrogen atom at
the protonated formyl group of 25 may lead to intermediate
27. The subsequent cyclization sequence via 28 would be ter-
minated by a Friedel–Crafts alkylation at C1 of the carba-
zole framework. Alternatively, the formation of 26 may be
explained by a preceding Prins-type cyclization of 25,[39] sub-
sequent nucleophilic attack at the resulting cation by C1 of
carbazole 1, and a final cyclization with loss of water. The
trans ring junction of the hydroquinoline portion of 26 has
been confirmed by a NOESY spectrum (see Supporting In-
formation).
The structural assignment for 7 is based on comparison of
its spectroscopic data with those reported for the natural
product[16] and has been additionally confirmed by an X-ray
crystal structure determination (Figure 4). Compound 7 ex-
hibits polymorphism and crystallizes either in a monoclinic
¯
(P21/c) or in a triclinic (P1) form (see Experimental Sec-
tion).
We then investigated the synthesis of cyclized monoterpe-
The study of the transformation of 5 into 7 using catalytic
amounts of Brønsted acid revealed that the course of this
noid pyranoACHTUNGTRENNUNG[3,2-a]carbazole alkaloids by annulation of addi-
tional rings starting from the readily available
5
(Scheme 10). Reaction of 5 with ethylaluminum dichloride
initially provided 7. However, a Lewis acid-promoted subse-
quent transformation led to the tetrahydroindoloACTHNUTRGENUG[N 3,2,1-de]-
phenanthridine 29. Using an excess of the Lewis acid, 7 is
smoothly converted to compound 29. Obviously, this reac-
tion is a sequence of elimination to form a cyclohexene fol-
lowed by attack of the carbazole nitrogen at the tertiary car-
benium ion generated from the isopropenyl group. The cis
ring junction of the hydroisoquinoline moiety of 29 is sup-
ported by a NOESY spectrum (see Supporting Informa-
tion).
Scheme 11. Biomimetic synthesis of 8 and 7. a) 1.0 equiv CSA, toluene,
RT, exclusion of light, 41.5 h (89% of 7); b) 20 mol% CSA, CDCl3, RT,
exclusion of light, 17 d (93% 7, 7% 8).
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Cyclized Monoterpenoid PyranoACTHNUGRTNEUNG[3,2-a]carbazole Alkaloids
FULL PAPER
Table 2. Brønsted acid-promoted conversion of 5 into 7 and 8.
Entry
CSA [equiv][a]
Reaction time [h][b]
Yield [%]
1
2
3
4
5
1.0
0.4
41.5
136
30
232
45
89, 7
87, 7
0.05[c]
0.05[c]
0.05[e]
94, 7, 8 (ratio, 1.8:1)[d]
90, 7
96, 7, 8 (ratio, 1:6.6)[d]
[a] CSA=camphor-10-sulfonic acid. [b] Reaction conditions: toluene, RT,
exclusion of light. [c] Solvent: CDCl3. [d] Determined by GC-MS. [e] Sol-
vent: hexane.
Figure 5. Kinetics for the transformation of 5 (c) into 8 (c) and 7
(c) followed by 1H NMR spectroscopy; reaction conditions: c0 =0.2m
5 in CDCl3, 5 mol% CSA, RT.
These observations can be rationalized by the mechanism
proposed for the biomimetic transformations of
5
(Scheme 12). Initial protonation of 5 generates the cation
30. Cycloaddition of 30 is a fast process and affords 31
which by proton loss leads to 8. The tertiary carbenium ion
32 may be formed either by cyclization of the secondary car-
benium ion 30 or by ring opening of 31. In any case, the ki-
netics for the formation of 7 (Figure 5) shows that this must
be a slow process on the time scale of the overall transfor-
mation leading to 7. Proton loss of 32 provides 7 which rep-
resents the most stable product under the present reaction
conditions (catalytic amounts of a Brønsted acid and room
temperature). However, we have been able to demonstrate
that in the presence of Lewis acid, 7 rearranges to 29 (vide
supra, Scheme 10) and in the presence of Brønsted acid at
elevated temperature an isomerization of the double bond
of 7 occurs which leads to isocyclomahanimbine (33) (vide
infra, Scheme 13).
Figure 4. Molecular structure of 7 in the crystal (monoclinic crystal form;
ORTEP plot showing thermal ellipsoids at the 50% probability level).
cyclization is more complicated than originally anticipated.
With 40 mol% of CSA, a reaction time of over 5.5 days was
required in order to achieve complete conversion into 7
(Table 2, entry 2) and with 5 mol% of CSA, over 9.5 days
were needed for complete conversion to 7 (Table 2, entry 4).
Interestingly, at shorter reaction times, mixtures of 7 and 8
were isolated. We decided to monitor the course of the
1
proton-catalyzed conversion of 5 into 7 using H NMR spec-
troscopy. Workup of a reaction of 5 in a solution of CDCl3
in the presence of 5 mol% CSA after 30 h provided a mix-
ture of 7 and 8 in a ratio of 1.8:1 (Table 2, entry 3) and thus
demonstrated that in this solvent the cyclization was basical-
ly following the same course. We then followed the proton-
catalyzed cyclization of 5 in a solution of CDCl3 in the pres-
ence of 5 mol% CSA by determining the concentration of
the starting material and the products, 7 and 8, at certain re-
action times till complete conversion was achieved after
about 9.5 days (Figure 5). The data demonstrate that proto-
nation results in a rapid conversion of 5 into 8. However,
obviously both, the direct conversion of 5 into 7 and the
transformation of 8 into 7, are comparatively slow processes.
In consequence, after addition of the Brønsted acid, 5 disap-
pears completely within three days, whereas the concentra-
tion of 8 is reaching a maximum after about one day and
then slowly but constantly decreases due to the slow trans-
formation into 7.
Scheme 12. Mechanism proposed for the proton-catalyzed biomimetic
transformations of 5 into 8 and 7 and of 8 into 7.
Chem. Eur. J. 2013, 19, 14098 – 14111
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14103

H.-J. Knçlker et al.
should be converted into 7 under the same reaction condi-
tions but only very slowly. In fact, using 5 mol% of CSA as
catalyst (CDCl3, RT) the turnover for the conversion of 8 to
7 is less than 10% even after a reaction time of 2 d. With
20 mol% of CSA, this transformation still needs 17 days in
order to provide 7 in 93% yield (Scheme 11). The kinetics
for the transformation of 8 into 7 was also followed by using
1H NMR spectroscopy (Figure 7). The detailed study of the
Scheme 13. Synthesis of 33, 10 and 11. a) 1.0 equiv CSA, toluene, 1008C,
68 h (62%); b) 1. Oxone, NaHCO3, acetone, EtOAc/H2O (1:2), RT, 2 h,
2. LiAlH4, Et2O, À15 to À58C, 2.25 h (72%); c) 10% Pd/C, H2 (1 atm),
MeOH/CH2Cl2 4:1, RT, 2d (100%).
We observed that in much less polar solvents, for example
hexane, the conversion of 8 into 7 is retarded due to precipi-
tation of compound 8. Thus, treatment of a solution of com-
pound 5 in hexane with 5 mol% CSA at room temperature
provided after almost two days in 96% yield a mixture of 8
and 7 in a ratio of 6.6:1 (Table 2, entry 5). Since both com-
pounds could be separated using preparative HPLC (see Ex-
perimental Section), pure 8 became available in 80% yield.
The structural assignment for 8 was based on comparison of
its full set of spectroscopic data with those previously re-
ported.[16] Additional confirmation was derived from an X-
ray crystal structure determination of single crystals of 8
(Figure 6).
Figure 7. Kinetics for the transformation of 8 (c) into 7 (c) followed
by 1H NMR spectroscopy; reaction conditions: c0 =0.02m 8 in CDCl3,
20 mol% CSA, RT.
course of this reaction confirmed that the concentration of 8
is continuously decreasing and to the same extent the con-
centration of 7 is increasing. After a reaction time of 15.5
days a turnover of about 90% has been reached. An inter-
mediate formation of 5 could not be observed under the ap-
plied reaction conditions (20 mol% CSA, CDCl3, RT). Thus,
these results support the mechanism we proposed for the
proton-catalyzed transformation of 7 (Scheme 12).
Treatment of 7 with equimolar amounts of CSA in tol-
uene at 1008C results in an isopropenyl-to-isopropylidene
isomerization of the double bond and leads to the thermo-
dynamically more stable isocyclomahanimbine (33) which
has not been identified in nature so far (Scheme 13).[34a] Ep-
oxidation of the isopropenyl double bond of compound 7
using Oxone (potassium peroxymonosulfate) in acetone[41]
followed by reduction with lithium aluminum hydride af-
forded murrayazolinine (10). The spectroscopic data of com-
pound 10 were in full agreement with those reported for the
natural product.[23] Moreover, the structural assignment has
been additionally confirmed by an X-ray analysis of single
crystals of 10 (Figure 8). Finally, hydrogenation of the iso-
propenyl group in 7 provided exozoline (11), which based
on its spectroscopic data was identical with the natural prod-
uct.[24]
Our biomimetic approach provides the hexacyclic alkaloid
8 in five steps and 56% overall yield based on 3-methoxy-4-
methylaniline. In comparison, the synthesis reported by
Chida et al. afforded 8 in 11 steps and 5% overall yield
based on 1,5-dithiaspiroACHTNUGRTNEUNG
[5,5]undecan-9-one.[40]
Following the mechanism we have proposed for the
proton-catalyzed transformation of 5 into 7 (Scheme 12), 8
Girinimbine (3), mahanimbine (5), and bicyclomahanim-
bine (9) were reported to show antitumor activity.[9,42] Other
carbazole derivatives were found to exhibit anti-TB activi-
ty.[30r,43] The present results are paving the way to study the
pharmacological potential of the cyclized pyranoACTHNUTRGENUG[N 3,2-a]car-
bazole alkaloids in more detail. These studies are ongoing
and the results will be reported in due course.
Figure 6. Molecular structure of 8 in the crystal (ORTEP plot showing
thermal ellipsoids at the 50% probability level).
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Chem. Eur. J. 2013, 19, 14098 – 14111

Cyclized Monoterpenoid PyranoACTHNUGRTNEUNG[3,2-a]carbazole Alkaloids
FULL PAPER
Experimental Section
General: All reactions were carried out using dry solvents in oven-dried
glassware under an argon atmosphere. Tetrahydrofuran, ethyl acetate, di-
chloromethane, and acetonitrile were dried using a solvent purification
system (MBraun-SPS). Toluene was purchased from Acros Organics
(water content less than 50 ppm). Dry methanol was purchased from
VWR Prolabo (water content less than 20 ppm). Palladium(II) acetate
was recrystallized from glacial acetic acid. All other chemicals were used
as received from commercial sources. Flash chromatography was per-
formed using silica gel from Merck (0.040–0.063 mm). Thin layer chroma-
tography was performed with TLC plates from Merck (60 F254) using
CeACTHNURGTNEG(UN SO4)2/phosphomolybdic acid/sulfuric acid staining reagent for visuali-
zation. Melting points were measured on an Electrothermal IA9100 melt-
ing point apparatus. Ultraviolet spectra were recorded on a Perkin Elmer
25 UV/VIS spectrometer. Infrared spectra were recorded on a Thermo
Nicolet Avatar 360 FT-IR spectrometer using the ATR method (Attenu-
ated Total Reflectance). NMR spectra were recorded on Bruker DRX
500 and Avance III 600 NMR spectrometers. Complete assignment of the
1H and 13C signals was achieved by HSQC experiments. Chemical shifts d
are reported in ppm with the deuterated solvent as internal standard.
The following abbreviations have been used: s: singlet, d: doublet, dd:
doublet of doublets, dt: doublet of triplets, t: triplet, q: quartet, sext:
sextet, sept: septet, m: multiplet, br: broad. Mass spectra were recorded
on a Finnigan MAT-95 spectrometer (electron impact, 70 eV) or by GC/
MS-coupling using an Agilent Technologies 6890N 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 analyser. X-
ray analyses: Bruker-Nonius Kappa CCD equipped with a 700 series
Cryostream low temperature device from Oxford Cryosystems. Software:
SHELXS-97 (G. M. Sheldrick, 1997), SADABS version 2.10 (G. M. Shel-
drick, Bruker AXS Inc., 2002), SHELXL-97 (G. M. Sheldrick, 1997),
ORTEP-3 for Windows.[44]
Figure 8. Molecular structure of 10 in the crystal (ORTEP plot showing
thermal ellipsoids at the 50% probability level).
Conclusion
2-Hydroxy-3-methylcarbazole (1) is a natural product which
represents a crucial intermediate in the biogenesis of
pyranoACHTUNGTRENNUNG[3,2-a]carbazole alkaloids. We have described two
simple palladium-catalyzed routes which provide compound
1 in 80–85% overall yield on a multigram scale. Our easy
access to key intermediate 1 was paving the way to develop
efficient constructions of pyrano
ACHTUNGTRENNUNG
mimetic access to cyclized monoterpenoid pyrano
AHCTUNGTRENNUNG
bazole alkaloids. The titanium tetraisopropoxide-mediated
annulation of prenal (21) opened up the best current route
to 3 (4 steps, 69% overall yield), a precursor for 4 and (À)-
trans-dihydroxygirinimbine (22). The reaction of 1 with 25
in the presence of titanium tetraisopropoxide led to 5,
whereas reaction of the same starting materials with catalyt-
Synthesis of 3-benzyloxy-4-methylaniline (13) and 3-methoxy-4-methyl-
AHCTUNGTRENNaGUN niline: See Supporting Information.
3-Benzyloxy-4-methyl-N-phenylaniline (14): 3-Benzyloxy-4-methylaniline
(13) (1.02 g, 4.79 mmol), cesium carbonate (1.97 g, 5.59 mmol), palladium
acetate (53.7 mg, 0.239 mmol), and XPhos (223 mg, 0.468 mmol) were
dissolved in toluene (13 mL) and the mixture was heated at reflux. A sol-
ution of bromobenzene (626 mg, 3.99 mmol) in toluene (7 mL) was
added within 1 h and the reaction mixture was heated at reflux for addi-
tional 15 h. Removal of the solvent in vacuum and flash chromatography
of the residue on silica gel (petroleum ether/ethyl acetate, 9:1) afforded
3-benzyloxy-4-methyl-N-phenylaniline (14) (1.12 g, 97%) as a yellow
solid. M.p. 85 8C; IR (ATR): n˜ = 3394, 3060, 3034, 2920, 2859, 1616,
1598, 1513, 1496, 1453, 1381, 1339, 1320, 1251, 1235, 1170, 1127, 1081,
ic amounts of
tetrahydroindolo[3,2,1-de]acridine 26. Treatment of 5 with a
Lewis acid (ethylaluminum dichloride) provided in a step-
wise reaction via 7 the tetrahydroindolo[3,2,1-de]phenanthri-
a
Brønsted acid afforded the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
dine 29. On the other hand, the proton-catalyzed conversion
of 5 to 7 proceeds via 8 and affords the product in 90%
yield after a reaction time of almost 10 days. In less polar
solvents such as hexane, the conversion of 8 into 7 is very
slow due to crystallization of 8 and thus allows the isolation
of 8 in 80% yield. The course of these transformations was
investigated in detail and based on kinetic studies a mecha-
nistic proposal has been presented. Using an optimized pro-
cedure, the titanium tetraisopropoxide-mediated annulation
of 1 and 25 to 5 followed by proton-catalyzed cycloisomeri-
zation provides the hexacyclic carbazole alkaloid 8 in 66%
yield over both steps. Cyclomahanimbine (7) was further
converted into isocyclomahanimbine (33), murrayazolinine
(10), and exozoline (11). Thus, the efficient total synthesis of
1
1016, 967, 911, 824, 735, 693 cmÀ1; H NMR (500 MHz, CDCl3): d = 2.23
(s, 3H), 5.03 (s, 2H), 6.62 (dd, J = 7.9, 1.7 Hz, 1H), 6.70 (d, J = 1.7 Hz,
1H), 6.90 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 7.04 (d, J =
8.0 Hz, 1H), 7.22 (m, 2H), 7.32 (m, 1H), 7.36–7.43 ppm (m, 4H); 13C
NMR and DEPT (125 MHz, CDCl3): d = 15.77 (CH3), 69.68 (CH2),
103.16 (CH), 110.88 (CH), 117.14 (CH), 120.33 (C), 120.59 (CH), 127.02
(2 CH), 127.69 (CH), 128.50 (2 CH), 129.32 (2 CH), 131.04 (2 CH),
137.28 (C), 141.44 (C), 143.47 (C), 157.26 ppm (C); MS (EI): m/z (%):
289 (63)
[M+], 91 (100); elemental analysis calcd (%) for C20H19NO: C 83.01, H
6.62, N 4.84; found: C 82.99, H 6.81, N 4.95.
2-Benzyloxy-3-methyl-9H-carbazole (15): 3-Benzyloxy-4-methyl-N-phe-
nylaniline (14) (1.04 g, 3.59 mmol), palladium acetate (80.9 mg,
0.361 mmol), potassium carbonate (49.9 mg, 0.361 mmol), and pivalic
acid (3.15 g) were heated under air at 858C for 23 h. After cooling, ethyl
acetate was added, the solution was washed several times with a saturat-
ed solution of potassium carbonate, and dried over magnesium sulfate.
The solvent was evaporated and the residue was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate, 5:1) to provide
2-benzyloxy-3-methyl-9H-carbazole (15) (838 mg, 81%) as a yellow solid.
a whole series of cyclized monoterpenoid pyranoACTHNUTRGNE[UNG 3,2-a]car-
bazole alkaloids could be completed via the biomimetic ap-
proach described above.
Chem. Eur. J. 2013, 19, 14098 – 14111
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14105

H.-J. Knçlker et al.
M.p. 168–171 8C; UV (MeOH): l = 236, 260 (sh), 302, 332 nm; IR
(ATR): n˜ = 3390, 3028, 2920, 2853, 1630, 1606, 1497, 1458, 1385, 1339,
1304, 1228, 1209, 1176, 1151, 1140, 1106, 1026, 883, 815, 748, 724,
[M+], 196 (71), 168 (23), 167 (27); HRMS: m/z: calcd for C14H13NO
[M+]: 211.0997; found: 211.1014; elemental analysis (%) calcd for
C14H13NO: C 79.59, H 6.20, N 6.63; found: C 79.62, H 6.34, N 6.58.
691 cmÀ1 1H NMR (500 MHz, CDCl3): d = 2.43 (s, 3H), 5.15 (s, 2H),
;
2-Hydroxy-3-methyl-9H-carbazole (1) (Method B): 2-Methoxy-3-methyl-
9H-carbazole (2) (1.04 g, 4.92 mmol) was dissolved in dichloromethane
(55 mL). After cooling to À788C, a solution of boron tribromide (1m in
dichloromethane, 7.9 mL, 7.9 mmol) was added over a period of 11 min
and the solution was allowed to warm to room temperature. The reaction
mixture was stirred for 15.5 h at room temperature. The mixture was sub-
sequently quenched with methanol (10 mL) under cooling, transferred to
a separation funnel with ethyl acetate, and washed several times with
water and brine. After extraction of the aqueous layer with ethyl acetate,
the combined organic layers were dried over sodium sulfate, the solvent
was evaporated, and the crude product was purified by chromatography
on silica gel (petroleum ether/ethyl acetate 6:1 to 4:1) to provide 1
(950 mg, 98%) as a slightly yellow solid. M.p. 2448C (lit. 2458C);[3]
1H NMR (500 MHz, [D6]acetone): d =2.35 (s, 3H), 6.97 (s, 1H), 7.08
(brt, J=7.4 Hz, 1H), 7.23 (brt, J=7.6 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H),
7.78 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 8.27 (s, 1H), 9.94 ppm (brs, 1H);
13C NMR and DEPT (125 MHz, [D6]acetone): d =16.68 (CH3), 96.83
(CH), 111.03 (CH), 116.84 (C), 117.53 (C), 119.26 (CH), 119.60 (CH),
122.12 (CH), 124.34 (C), 124.44 (CH), 140.64 (C), 140.74 (C), 155.47 ppm
(C); IR (ATR): n˜ =3513, 3390, 3054, 2939, 2906, 2850, 1630, 1604, 1574,
1452, 1395, 1352, 1310, 1287, 1246, 1215, 1181, 1129, 1102, 1017, 936, 889,
866, 828, 766, 748, 725, 671, 640 cmÀ1; UV (MeOH): l=236, 253, 258,
303, 332 nm; fluorescence (MeOH): lex =303, lem =341, 356 nm; MS
(EI): m/z (%): 197 (100) [M+], 196 (66), 180 (9), 168 (19), 167 (31);
HRMS: m/z: calcd for C13H11NO [M+]: 197.0841; found: 197.0826; ele-
mental analysis (%) calcd for C13H11NO: C 79.16, H 5.62, N 7.10; found:
C 78.95, H 5.78, N 7.03.
6.89 (s, 1H), 7.18 (m, 1H), 7.29–7.35 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H),
7.49 (d, J = 7.3 Hz, 2H), 7.82 (s, 1H), 7.85 (br s, 1H), 7.95 ppm (d, J =
7.8 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d = 16.90 (CH3),
70.08 (CH2), 93.90 (CH), 110.26 (CH), 116.44 (C), 119.29 (CH), 119.34
(CH), 119.65 (C), 121.58 (CH), 123.43 (C), 124.18 (CH), 127.06 (2 CH),
127.75 (CH), 128.54 (2 CH), 137.42 (C), 138.97 (C), 139.29 (C),
156.38 ppm (C); MS (EI): m/z (%): 287 (62) [M+], 196 (100), 167 (18),
91 (20); HRMS: m/z calcd for C20H17NO [M+]: 287.1310; found:
287.1292.
2-Hydroxy-3-methyl-9H-carbazole (1) (Method A): A mixture of 2-ben-
zyloxy-3-methyl-9H-carbazole (15) (324 mg, 1.12 mmol) and 10% Pd/C
(50 wt%, 162 mg) in methanol/dichloromethane (30 mL, 4:1) was stirred
at room temperature under a hydrogen atmosphere for 72 h. Subsequent
flash chromatography on silica gel (petroleum ether/ethyl acetate, 2:1) af-
forded 2-hydroxy-3-methyl-9H-carbazole (1) (220 mg, 100%) as a color-
less solid; spectroscopic data, see below.
3-Methoxy-4-methyl-N-phenylaniline (16): 3-Methoxy-4-methylaniline
(5.00 g, 36.4 mmol), palladium acetate (333 mg, 1.48 mmol), SPhos
(1.20 g, 2.92 mmol), and cesium carbonate (13.4 g, 41.2 mmol) were dis-
solved in toluene (45 mL). After heating the suspension to 1008C, a solu-
tion of iodobenzene (5.95 g, 29.2 mmol) in toluene (5 mL) was added
dropwise over a period of 16 h. The mixture was stirred at 1008C for ad-
ditional 10 h. After a total of 26 h, the reaction mixture was cooled to
room temperature, the solvent was removed under reduced pressure, and
the residue was purified by chromatography on silica gel (petroleum
ether/dichloromethane/ethyl acetate 60:5:1 to 45:5:1) to provide 16
(5.96 g, 96%) as
a
colorless solid. M.p. 828C; 1H NMR (500 MHz,
Crystallographic data for 1: C13H11NO, M=197.23 gmolÀ1, crystal size:
0.48ꢃ0.40ꢃ0.06 mm3, monoclinic, space group: P21/c, a=7.615(1), b=
[D6]acetone): d =2.10 (s, 3H), 3.77 (s, 3H), 6.64 (dd, J=8.0, 2.0 Hz, 1H),
6.70 (d, J=2.0 Hz, 1H), 6.81 (t, J=7.3 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H),
7.10 (m, 2H), 7.21 (m, 2H), 7.26 ppm (brs, 1H); 13C NMR and DEPT
(125 MHz, [D6]acetone): d =15.65 (CH3), 55.39 (CH3), 101.85 (CH),
110.20 (CH), 117.42 (2CH), 118.81 (C), 120.34 (CH), 129.92 (2CH),
131.42 (CH), 143.56 (C), 145.23 (C), 159.19 ppm (C); IR (ATR): n˜ =
3391, 3053, 3005, 2922, 2849, 1615, 1593, 1508, 1491, 1451, 1390, 1318,
1306, 1256, 1237, 1206, 1197, 1165, 1128, 1077, 1033, 995, 953, 888, 831,
813, 760, 740, 691, 650, 617 cmÀ1; UV (MeOH): l=285 nm; MS (EI): m/z
(%): 213 (100) [M+], 198 (5), 182 (8), 167 (7), 154 (5), 77 (5); HRMS:
m/z: calcd for C14H15NO [M+]: 213.1154; found: 213.1150; elemental
analysis (%) calcd for C14H15NO: C 78.84, H 7.09, N 6.57; found: C
78.67, H 7.22, N 6.35.
5.796(1), c=21.276(2) ꢂ, b=93.212(4)8, V=937.6(2) ꢂ3, Z=4, 1calcd
=
1.397 gcmÀ3, m=0.089 mmÀ1, l=0.71073 ꢂ, T=173(2) K, q range=1.92–
30.548, reflections collected: 18987, independent: 2849 (Rint =0.0477), 141
parameters. The structure was solved by direct methods and refined by
full-matrix least squares on F2; final R indices [I>2s(I)]: R1 =0.0493;
wR2 =0.1023; maximal residual electron density: 0.271 eꢂÀ3
Girinimbine (3), 3-methyl-2-(2-methylbut-3-yn-2-yloxy)-9H-carbazole
(18), and 1,1,4-trimethyl-2-methylene-2,10-dihydro-1H-furo[3,2-a]carba-
.
AHCTUNGTRENNUNG
zole (19): Compound 1 (3.77 g, 19.1 mmol), cuprous iodide (18.7 mg,
0.098 mmol), and cesium carbonate (12.4 g, 38.2 mmol) were dissolved in
acetonitrile (250 mL) and a solution of 17c (4.07 g, 28.6 mmol) in aceto-
nitrile (50 mL) was added dropwise over a period of 13 h. The mixture
was stirred at room temperature for 22 h, then transferred to a separation
funnel, and washed several times with a saturated solution of ammonium
chloride, diluted hydrochloric acid, and brine. After extraction with ethyl
acetate, the combined organic layers were dried over sodium sulfate, the
solvent was removed under reduced pressure and the residue was puri-
fied by chromatography on silica gel (pentane/dichloromethane/ethyl ace-
tate 100:5:1 to 60:5:1) to afford 19 (81.6 mg, 2%), 3 (156 mg, 3%), and
18 (2.31 g, 46%) as colorless solids.
2-Methoxy-3-methyl-9H-carbazole (2): 3-Methoxy-4-methyl-N-phenylani-
line (16) (2.05 g, 9.61 mmol), potassium carbonate (66.8 mg, 0.483 mmol),
and pivalic acid (8.64 g) were placed in a 25 mL test tube. The mixture
was heated to 1008C and then, palladium acetate (64.6 mg, 0.288 mmol)
was added. After stirring vigorously for 7.5 h at 1008C, additional palladi-
um acetate (43.3 mg, 0.193 mmol) was added. After 24 h, the mixture was
cooled to room temperature, poured into ethyl acetate, and washed sev-
eral times with a saturated solution of potassium carbonate and brine.
After extraction with ethyl acetate, the combined organic layers were
dried over sodium sulfate, the solvent was evaporated under reduced
pressure, and the residue was purified by chromatography on silica gel
(petroleum ether/dichloromethane/ethyl acetate 50:5:1 to 25:5:1) to pro-
vide 16 (101 mg) and 2 (1.82 g, 90%) as colorless solid. M.p. 2218C (lit.
2238C);[4] 1H NMR (500 MHz, [D6]acetone): d =2.32 (s, 3H), 3.89 (s,
3H), 7.02 (s, 1H), 7.12 (brt, J=7.4 Hz, 1H), 7.27 (brt, J=7.6 Hz, 1H),
7.43 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.97 (d, J=7.7 Hz, 1H), 10.05 ppm
3: see below.
18: M.p. 121–1248C; 1H NMR (600 MHz, [D6]acetone): d=1.70 (s, 6H),
2.33 (s, 3H), 3.17 (s, 1H), 7.11 (brt, J=7.4 Hz, 1H), 7.29 (ddd, J=8.2,
7.2, 1.1 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.86 (s, 1H), 7.99
(d, J=7.9 Hz, 1H), 10.13 ppm (brs, 1H); 13C NMR and DEPT
(150 MHz, [D6]acetone): d=17.54 (CH3), 30.02 (2CH3), 73.02 (C), 75.21
(C), 87.47 (CH), 102.31 (CH), 111.34 (CH), 118.82 (C), 119.43 (CH),
120.13 (CH), 121.90 (CH), 122.51 (C), 123.92 (C), 125.18 (CH), 139.99
(C), 141.21 (C), 154.10 ppm (C); IR (ATR): n˜ =3390, 3282, 2991, 2933,
2863, 1630, 1604, 1574, 1490, 1458, 1395, 1373, 1336, 1310, 1226, 1180,
1115, 1018, 941, 883, 865, 842, 752, 726, 682, 634, 600 cmÀ1; UV (MeOH):
l=212, 230 (sh), 236, 249 (sh), 258, 301, 323, 337 nm; fluorescence
(MeOH): lex =301, lem =347, 362 nm; MS (EI): m/z (%): 263 (23) [M+],
248 (100); elemental analysis (%) calcd for C18H17NO: C 82.10, H 6.51, N
5.32; found: C 82.13, H 6.35, N 5.29.
(brs, 1H); 13C NMR and DEPT (125 MHz, [D6]acetone):
d =16.87
(CH3), 55.68 (CH3), 93.36 (CH), 111.27 (CH), 116.73 (C), 118.95 (C),
119.43 (CH), 119.79 (CH), 121.94 (CH), 124.14 (C), 124.60 (CH), 140.61
(C), 140.73 (C), 158.20 ppm (C); IR (ATR): n˜ =3402, 3054, 2992, 2919,
2851, 1631, 1609, 1496, 1455, 1373, 1340, 1304, 1261, 1230, 1194, 1175,
1139, 1109, 1038, 1014, 1003, 965, 885, 868, 819, 766, 749, 725, 694,
675 cmÀ1; UV (MeOH): l=236, 251, 258, 264 (sh), 302, 331 nm; fluores-
cence (MeOH): lex =302, lem =356 nm; MS (EI): m/z (%): 211 (100)
14106
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Chem. Eur. J. 2013, 19, 14098 – 14111

Cyclized Monoterpenoid PyranoACTHNUGRTNEUNG[3,2-a]carbazole Alkaloids
FULL PAPER
19: M.p. 143–1458C; 1H NMR (500 MHz, [D6]acetone): d = 1.68 (s, 6H),
2.39 (d, J=0.7 Hz, 3H), 4.37 (d, J=2.6 Hz, 1H), 4.65 (d, J=2.6 Hz, 1H),
7.13 (brt, J=7.4 Hz, 1H), 7.28 (td, J=7.6, 1.0 Hz, 1H), 7.42 (d, J=
8.0 Hz, 1H), 7.77 (s, 1H), 7.99 (dd, J=7.9, 0.4 Hz, 1H), 10.26 ppm (brs,
1H); 13C NMR and DEPT (125 MHz, [D6]acetone): d =15.37 (CH3),
28.75 (2CH3), 45.05 (C), 82.13 (CH2), 111.54 (CH), 112.29 (C), 115.77
(C), 119.79 (CH), 119.91 (CH), 120.18 (C), 121.07 (CH), 124.25 (C),
125.29 (CH), 134.63 (C), 141.29 (C), 154.05 (C), 173.44 ppm (C); IR
(ATR): n˜ =3416, 3339, 3050, 2969, 2933, 1693, 1664, 1638, 1612, 1491,
1451, 1436, 1395, 1356, 1324, 1306, 1245, 1211, 1186, 1160, 1120, 1103,
1043, 964, 919, 879, 837, 771, 744, 671, 625 cmÀ1; UV (MeOH): l=214,
(CH), 129.33 (CH), 134.78 (C), 139.42 (C), 149.74 ppm (C); 1H NMR
(500 MHz, [D6]acetone): d =1.47 (s, 6H), 2.30 (d, J=0.7 Hz, 3H), 5.77
(d, J=9.8 Hz, 1H), 6.92 (d, J=9.8 Hz, 1H), 7.11 (brt, J=7.6 Hz, 1H),
7.27 (brt, J=7.6 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.73 (s, 1H), 7.95 (d,
J=7.8 Hz, 1H), 10.27 ppm (brs, 1H); 13C NMR and DEPT (125 MHz,
[D6]acetone): d =16.20 (CH3), 27.83 (2CH3), 76.46 (C), 105.39 (C),
111.33 (CH), 117.48 (C), 118.29 (C), 118.57 (CH), 119.64 (CH), 119.84
(CH), 121.71 (CH), 124.39 (C), 124.87 (CH), 129.78 (CH), 136.27 (C),
140.97 (C), 150.42 ppm (C); IR (ATR): n˜ =3311, 3065, 2972, 2922, 2852,
1709, 1641, 1608, 1578, 1493, 1458, 1439, 1402, 1381, 1359, 1344, 1319,
1241, 1206, 1175, 1157, 1143, 1118, 1055, 1022, 978, 956, 938, 923, 900,
879, 811, 784, 755, 739, 687, 667, 647, 607 cmÀ1; UV (MeOH): l=223,
237, 277 (sh), 287, 326, 342, 358 nm; fluorescence (MeOH): lex =237,
lem =360 nm; MS (EI): m/z (%): 263 (21) [M+], 248 (100), 204 (8), 124
(8); elemental analysis (%) calcd for C18H17NO: C 82.10, H 6.51, N 5.32;
found: C 82.00, H 6.68, N 5.15.
243, 256, 261, 305, 322, 333 nm; fluorescence (MeOH): lex =305, lem
=
339, 354 nm; MS (EI): m/z (%): 263 (33) [M+], 248 (100), 233 (7), 204
(12), 124 (9); elemental analysis (%) calcd for C18H17NO: C 82.10, H
6.51, N 5.32; found: C 81.78, H 6.83, N 5.26.
Crystallographic data for 19: C18H17NO, M=263.33 gmolÀ1, crystal size:
0.33ꢃ0.30ꢃ0.12 mm3, monoclinic, space group: Cc, a=13.830(3), b=
1,1-Bis(2-hydroxy-3-methyl-9H-carbazol-1-yl)-3-methylbut-2-ene
(23):
14.216(3), c=8.515(2) ꢂ, b=122.95(3)8, V=1404.8(5) ꢂ3, Z=4, 1calcd
=
1H NMR (500 MHz, [D6]acetone): d =1.66 (s, 3H), 1.78 (s, 3H), 2.47 (s,
6H), 6.33 (d, J=7.9 Hz, 1H), 6.54 (d, J=7.9 Hz, 1H), 7.07 (t, J=7.5 Hz,
2H), 7.25 (t, J=7.6 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.71 (s, 2H), 7.90
(d, J=7.8 Hz, 2H), 8.26 (s, 2H), 10.23 ppm (brs, 2H); 13C NMR and
DEPT (125 MHz, [D6]acetone): d =17.53 (2CH3), 18.23 (CH3), 25.80
(CH3), 35.51 (CH), 111.47 (2CH), 114.27 (2C), 118.22 (2C), 118.75 (2C),
119.53 (2CH), 119.89 (2CH), 120.31 (2CH), 124.39 (2C), 124.94 (2CH),
125.24 (CH), 134.01 (C), 139.58 (2C), 140.67 (2C), 150.51 ppm (2C); IR
(ATR): n˜ =3484, 3369, 3337, 3058, 2962, 2910, 2850, 1610, 1576, 1543,
1497, 1460, 1444, 1372, 1310, 1276, 1255, 1211, 1160, 1141, 1059, 1013,
964, 923, 866, 845, 792, 770, 739, 703, 665 cmÀ1; ESI-MS (+25 V): m/z:
264.0 [MÀC13H10NO]; ESI-MS (À25 V): m/z: 458.9 [MÀH]À, 919.1
[2MÀH]À.
1.245 gcmÀ3, m=0.077 mmÀ1, l=0.71073 ꢂ, T=198(2) K, q range=3.51–
27.008, reflections collected: 9823, independent: 2971 (Rint =0.0263), 188
parameters. The structure was solved by direct methods and refined by
full-matrix least squares on F2; final R indices [I>2s(I)]: R1 =0.0365;
wR2 =0.0792; maximal residual electron density: 0.153 eꢂÀ3
3,11-Dihydro-3,3,5-trimethyl-1-(3-methylbuta-1,2-dienyl)pyranoACHTNUGTRNEUN[G 3,2-a]car-
.
bazole (20): 1H NMR (500 MHz, [D6]acetone): d = 1.42 (s, 6H), 1.77 (d,
J=2.9 Hz, 6H), 2.32 (d, J=0.6 Hz, 3H), 5.72 (d, J=0.8 Hz, 1H), 6.23 (m,
1H), 7.11 (dt, J=0.9, 7.5 Hz, 1H), 7.26 (dt, J=1.1, 7.7 Hz, 1H), 7.48 (d,
J=8.0 Hz, 1H), 7.79 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 9.71 ppm (brs,
1H); 13C NMR and DEPT (125 MHz, [D6]acetone): d =16.54 (CH3),
20.32 (2CH3), 26.92 (2CH3), 76.06 (C), 90.32 (CH), 98.61 (C), 107.01 (C),
111.73 (CH), 118.40 (C), 119.00 (C), 119.64 (CH), 119.71 (CH), 122.08
(CH), 123.91 (C), 124.97 (CH), 128.07 (CH), 128.64 (C), 135.70 (C),
140.82 (C), 151.58 (C), 204.37 ppm (C); ESI-MS (+25 V): m/z: 330.2
[M+H]+, 659.3 [2M+H]+; ESI-MS (À50 V): m/z: 327.9 [MÀH]À, 657.0
[2MÀH]À.
Murrayacine (4): DDQ (115 mg, 0.507 mmol) was added in portions to a
solution of 3 (60.6 mg, 0.230 mmol) in a mixture of methanol (20 mL),
THF (6 mL), and water (2 mL). The reaction mixture was stirred for
1.5 h at room temperature, diluted with 10% NaOH and extracted sever-
al times with diethyl ether. The combined organic layers were washed
with brine and dried over magnesium sulfate. Removal of the solvent
and flash chromatography of the crude product on silica gel (petroleum
ether/ethyl acetate 4:1 to 1:1) provided 4 (61.5 mg, 96%) as colorless
crystals. M.p. 248–2508C (lit. 244–2458C);[5c,11] 1H NMR (500 MHz,
CDCl3): d=1.56 (s, 6H), 5.81 (d, J=9.9 Hz, 1H), 6.63 (d, J=9.9 Hz,
1H), 7.24–7.30 (m, 1H), 7.37–7.41 (m, 2H), 7.98 (d, J=7.8 Hz, 1H), 8.16
(brs, 1H), 8.43 (s, 1H), 10.50 ppm (s, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d=27.81 (2CH3), 77.73 (C), 104.28 (C), 110.87 (CH),
116.31 (CH), 118.33 (C), 118.82 (C), 119.98 (CH), 120.42 (CH), 121.09
(CH), 124.21 (C), 126.11 (CH), 130.28 (CH), 140.20 (C), 140.36 (C),
154.95 (C), 189.40 ppm (CHO); IR (ATR): n˜ =3217, 3156, 3088, 2955,
2921, 2853, 1717, 1663, 1635, 1602, 1575, 1508, 1489, 1474, 1453, 1408,
1374, 1352, 1331, 1271, 1233, 1198, 1186, 1160, 1118, 1047, 1012, 953, 942,
922, 893, 854, 833, 787, 756, 735, 690, 655 cmÀ1; UV (MeOH): l=225, 239
Girinimbine (3) and 1,1,4-trimethyl-2-methylene-2,10-dihydro-1H-furo-
ACHTUNGTRENNUNG[3,2-a]carbazole (19) (Method A): Compound 1 (51.0 mg, 0.259 mmol),
cuprous iodide (0.8 mg, 0.004 mmol), and cesium carbonate (110 mg,
0.337 mmol) were dissolved in acetonitrile (10 mL) and a solution of 17c
(51.4 mg, 0.362 mmol) in acetonitrile (2 mL) was added dropwise over a
period of 5 h. The mixture was stirred at room temperature for a total of
29 h, then transferred to a separation funnel, and washed several times
with water, diluted hydrochloric acid, and brine. After extraction with
ethyl acetate, the combined organic layers were dried over sodium sul-
fate, the solvent was removed under reduced pressure, and the residue
was dried in high vacuum. The crude mixture was dissolved in toluene
(10 mL) and heated at reflux for 29 h. Then, the reaction mixture was
cooled to room temperature, the solvent was evaporated, and the residue
was purified by chromatography on silica gel (pentane/dichloromethane/
ethyl acetate 80:5:1 to 60:5:1) to provide 19 (13.2 mg, 19%) and 3
(37.7 mg, 55%) as colorless solids.
(sh), 282, 302, 349 (sh), 361 nm; fluorescence (MeOH): lex =282, lem
=
395, 521 nm; MS (EI): m/z (%): 277 (13) [M+], 262 (100), 261 (5), 260
(25), 233 (5), 232 (5), 204 (19); elemental analysis (%) calcd for
C18H15NO2: C 77.96, H 5.45, N 5.05; found: C 77.93, H 5.34, N 4.91.
Girinbimbine (3) (Method B): Compound 1 (50.5 mg, 0.256 mmol) was
dissolved in toluene (5 mL), cooled to À788C, and 21 (44.5 mg,
0.529 mmol) was added. Then, titanium tetraisopropoxide (0.306 mL,
1.023 mmol) was added slowly. The reaction mixture was allowed to
warm up slowly to room temperature and stirred for 5 h, then transferred
to a separation funnel, and washed several times with water, diluted hy-
drochloric acid, and brine. After extraction with ethyl acetate, the com-
bined organic layers were dried over sodium sulfate, the solvent was re-
moved under reduced pressure, and the residue was purified by chroma-
tography on silica gel (pentane/dichloromethane/ethyl acetate 80:5:1 to
60:5:1) to provide 3 (55.1 mg, 82%) as slightly yellow solid. M.p. 1758C
(lit. 1768C);[5a] 1H NMR (500 MHz, CDCl3): d =1.51 (s, 6H), 2.37 (s,
3H), 5.69 (d, J=9.7 Hz, 1H), 6.60 (d, J=9.7 Hz, 1H), 7.21 (t, J=7.4 Hz,
1H), 7.34 (m, 2H), 7.70 (s, 1H), 7.88 (brs, 1H), 7.94 ppm (d, J=7.8 Hz,
1H); 13C NMR and DEPT (125 MHz, CDCl3): d =16.07 (CH3), 27.56
(2CH3), 75.83 (C), 104.42 (C), 110.40 (CH), 116.69 (C), 117.20 (CH),
118.54 (C), 119.28 (CH), 119.42 (CH), 121.11 (CH), 123.83 (C), 124.22
Mahanimbine (5) (Method A): Compound 1 (53.0 mg, 0.269 mmol), cu-
AHCTUNGTREGpNNUN rous iodide (0.7 mg, 0.004 mmol), and cesium carbonate (175 mg,
0.537 mmol) were dissolved in acetonitrile (10 mL) and a solution of the
carbonate 24 (90.4 mg, 0.430 mmol) in acetonitrile (2 mL) was added
dropwise over a period of 12 h. The mixture was stirred at room tempera-
ture for a total of 16 h, transferred to a separation funnel, and washed
several times with water, dilute hydrochloric acid, and brine. After ex-
traction with ethyl acetate, the combined organic layers were dried over
sodium sulfate, the solvent was removed under reduced pressure, and the
residue was dried at high vacuum. Then, the crude product was dissolved
in toluene (10 mL) and heated at reflux for 24 h. The reaction mixture
was cooled to room temperature, the solvent was removed, and the resi-
due was purified by chromatography on silica gel (pentane/dichlorome-
thane/ethyl acetate 100:5:1 to 80:5:1) to provide 5 (44.0 mg, 49%) as
slightly yellow solid. M.p. 918C (lit. 92–948C);[8] 1H NMR (500 MHz,
Chem. Eur. J. 2013, 19, 14098 – 14111
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14107

H.-J. Knçlker et al.
CDCl3): d =1.47 (s, 3H), 1.61 (s, 3H), 1.69 (s, 3H), 1.79 (t, J=8.3 Hz,
2H), 2.19 (m, 2H), 2.37 (s, 3H), 5.14 (t, J=7.1 Hz, 1H), 5.66 (d, J=
9.8 Hz, 1H), 6.63 (d, J=9.8 Hz, 1H), 7.19 (brt, J=7.3 Hz, 1H), 7.32 (brt,
J=7.5 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.68 (s, 1H), 7.87 (brs, 1H),
7.93 ppm (d, J=7.7 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d
=16.07 (CH3), 17.55 (CH3), 22.72 (CH2), 25.65 (CH3), 25.79 (CH3), 40.72
(CH2), 78.12 (C), 104.16 (C), 110.36 (CH), 116.56 (C), 117.49 (CH),
118.36 (C), 119.25 (CH), 119.41 (CH), 121.15 (CH), 123.86 (C), 124.16
(2CH), 128.44 (CH), 131.65 (C), 134.82 (C), 139.41 (C), 149.86 ppm (C);
IR (ATR): n˜ =3319, 3051, 2963, 2917, 2852, 1733, 1699, 1640, 1606, 1490,
1455, 1399, 1374, 1346, 1325, 1310, 1239, 1212, 1163, 1078, 1058, 1029,
978, 930, 901, 881, 830, 781, 743, 719, 680, 648, 623 cmÀ1; UV (MeOH):
l=222, 238, 277 (sh), 288, 314, 329, 343, 358 nm; fluorescence (MeOH):
lex =238, lem =361 nm; MS (EI): m/z (%): 331 (22) [M+], 316 (7), 288
(6), 248 (100), 210 (17); elemental analysis (%) calcd for C23H25NO: C
83.34, H 7.60, N 4.23; found: C 83.02, H 7.84, N 4.17.
115.74 (C), 119.26 (CH), 119.28 (CH), 119.31 (CH), 120.00 (C), 123.87
(CH), 124.16 (C), 137.75 (C), 139.21 (C), 150.35 ppm (C); IR (ATR): n˜ =
3465, 2934, 2859, 1611, 1486, 1456, 1436, 1372, 1339, 1305, 1213, 1142,
1112, 1064, 1028, 967, 923, 868, 769, 740, 686, 665, 602 cmÀ1
; UV
(MeOH): l=218, 242, 254, 261, 304, 333 nm; fluorescence (MeOH): lex
=
304, lem =346, 360 nm; MS (EI): m/z (%): 331 (20) [M+], 316 (4), 248
(100), 204 (6); elemental analysis (%) calcd for C23H25NO: C 83.34, H
7.60, N 4.23; found: C 82.76, H 7.93, N 4.13.
Crystallographic data for 9: C23H25NO, M=331.44 gmolÀ1, crystal size:
0.35ꢃ0.30ꢃ0.24 mm3, triclinic, space group: P1, a=9.776(2), b=
¯
19.573(4), c=19.607(4) ꢂ, a=94.07(3), b=92.89(3), g=103.70(3)8, V=
3627.0(13) ꢂ3, Z=8, 1calcd =1.214 gcmÀ3, m=0.073 mmÀ1, l=0.71073 ꢂ,
T=198(2) K, q range=3.04–27.008, reflections collected: 92183, inde-
pendent: 15805 (Rint =0.0778), 917 parameters. The structure was solved
by direct methods and refined by full-matrix least squares on F2; final R
indices [I> 2s(I)]: R1 =0.0666; wR2 =0.1375; maximal residual electron
density: 0.223 eꢂÀ3
6,8,8,11-Tetramethyl-8a,9,10,12a-tetrahydro-8H-indoloCATHNUGTRENUN[G 3,2,1-de]acridin-7-
.
Murrayacinine (6): DDQ (66.4 mg, 0.293 mmol) was added in portions to
a solution of 5 (44.1 mg, 0.133 mmol) in a mixture of methanol (10 mL),
THF (2 mL), and water (3 mL) under argon. The reaction mixture was
stirred for 1 h at room temperature, diluted with diethyl ether, and
washed twice with 2n NaOH and once with brine. The organic layer was
dried over sodium sulfate and the solvent was evaporated. Flash chroma-
tography of the crude product on silica gel (petroleum ether/ethyl acetate
3:1) provided 6 (32.1 mg, 70%) as a yellow solid. M.p. 102–1058C (lit.:
1058C);[15] 1H NMR (500 MHz, [D6]acetone): d=1.58 (s, 6H), 1.66 (d, J=
0.7 Hz, 3H), 1.89–1.92 (m, 2H), 2.22–2.29 (m, 2H), 5.17 (brt, J=7.2 Hz,
1H), 5.95 (d, J=10.0 Hz, 1H), 7.03 (d, J=10.0 Hz, 1H), 7.26 (brt, J=
7.5 Hz, 1H), 7.41 (brt, J=7.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 8.16 (d,
J=7.8 Hz, 1H), 8.41 (s, 1H), 10.54 (s, 1H), 10.85 ppm (brs, 1H);
13C NMR and DEPT (125 MHz, [D6]acetone): d=17.58 (CH3), 23.40
(CH2), 25.74 (CH3), 26.14 (CH3), 41.42 (CH2), 80.39 (C), 105.11 (C),
111.89 (CH), 117.92 (CH), 118.81 (C), 119.02 (C), 119.82 (CH), 120.82
(CH), 121.11 (CH), 124.62 (C), 124.86 (CH), 126.64 (CH), 129.90 (CH),
132.11 (C), 141.57 (C), 141.87 (C), 155.40 (C), 188.36 ppm (CHO); IR
(ATR): n˜ =3223, 3150, 3089, 3046, 2978, 2910, 2854, 1716, 1659, 1631,
1600, 1575, 1475, 1454, 1411, 1375, 1355, 1331, 1304, 1230, 1181, 1134,
1105, 1078, 1049, 1020, 916, 893, 857, 839, 787, 737, 690, 551 cmÀ1; UV
(EtOH): l=226, 241 (sh), 283, 300, 348 (sh), 362 nm; fluorescence
(EtOH): lex =362, lem =506 nm; MS (EI): m/z (%): 345 (19) [M+], 262
(100). HRMS: m/z: calcd for C23H23NO2 [M+]: 345.1729; found:
345.1722; elemental analysis (%) calcd for C23H23NO2: C 79.97, H 6.71, N
4.05; found: C 80.29, H 6.81, N 3.99.
ol (26): Compound 1 (101 mg, 0.513 mmol) and camphor-10-sulfonic acid
(12.6 mg, 0.054 mmol) were dissolved in toluene (10 mL), and 25
(0.13 mL, 0.758 mmol) was added. The reaction mixture was stirred for
13.5 h, then transferred to a separation funnel, and washed several times
with a saturated solution of potassium carbonate and with brine. After
extraction with ethyl acetate, the combined organic layers were dried
over sodium sulfate, the solvent was removed under reduced pressure,
and the residue was purified by chromatography on silica gel (pentane/di-
chloromethane/ethyl acetate 100:5:1 to 70:5:1) to provide 26 (71.4 mg,
42%) as a brownish solid. 1H NMR (500 MHz, CDCl3): d =1.25 (s, 3H),
1.56–1.66 (m, 1H), 1.77 (s, 3H), 1.85 (s, 3H), 2.06 (m, 1H), 2.16–2.24 (m,
3H), 2.41 (s, 3H), 4.69 (brd, J=9.9 Hz, 1H), 4.86 (s, 1H), 6.72 (s, 1H),
7.16 (t, J=7.4 Hz, 1H), 7.32 (brt, J=7.7 Hz, 1H), 7.65 (s, 1H), 7.71 (d,
J=8.3 Hz, 1H), 7.96 ppm (d, J=7.7 Hz, 1H); 13C NMR and DEPT
(125 MHz, CDCl3): d =16.53 (CH3), 21.94 (CH3), 22.23 (CH2), 23.44
(CH3), 24.72 (CH3), 31.69 (CH2), 34.53 (C), 48.80 (CH), 54.19 (CH),
111.42 (CH), 115.33 (C), 115.74 (C), 115.80 (C), 118.32 (CH), 118.78
(CH), 119.52 (CH), 120.58 (CH), 123.61 (CH), 124.07 (C), 137.66 (C),
138.44 (C), 139.86 (C), 150.04 ppm (C); MS (EI): m/z (%): 331 (77) [M+
], 316 (100), 300 (10), 288 (14), 248 (9).
2,9,9,12-Tetramethyl-9a,10,11,13a-tetrahydro-9H-indoloACTHNUTRGNEU[GN 3,2,1-de]-phenan-
thridin-1-ol (29) (Method A): Mahanimbine (5) (36.5 mg, 0.110 mmol)
was dissolved in toluene (4 mL), cooled to À788C, and a solution of eth-
ylaluminum dichloride (0.9m in heptane, 0.1 mL, 0.09 mmol) was added
slowly. The reaction mixture was allowed to warm to room temperature
and stirred for 13.5 h. After addition of methanol (1 mL) under cooling,
the solution was transferred to a separation funnel, washed several times
with a saturated solution of potassium carbonate and brine, and extracted
with ethyl acetate. The combined organic layers were dried over sodium
sulfate, the solvent was removed, and the residue was purified by chro-
matography on silica gel (pentane/dichloromethane/ethyl acetate 100:5:1
to 70:5:1) to provide 29 (17.1 mg, 47%) as a brownish solid. 1H NMR
(500 MHz, CDCl3): d =1.32–1.41 (m, 1H), 1.43 (s, 3H), 1.80 (s, 3H), 1.87
(ddd, J=12.3, 4.4, 2.5 Hz, 1H), 1.91–1.96 (m, 1H), 2.00–2.14 (m, 2H),
2.06 (s, 3H), 2.40 (s, 3H), 3.93 (brs, 1H), 5.42 (brs, 1H), 6.37 (dd, J=6.1,
1.3 Hz, 1H), 7.15 (brt, J=7.4 Hz, 1H), 7.28 (ddd, J=8.4, 7.2, 1.3 Hz,
1H), 7.64 (d, J=7.7 Hz, 1H), 7.65 (s, 1H), 7.95 ppm (d, J=7.5 Hz, 1H);
13C NMR and DEPT (125 MHz, CDCl3): d =16.65 (CH3), 20.35 (CH2),
23.55 (CH3), 27.47 (CH3), 27.54 (CH3), 31.08 (CH2), 32.59 (CH), 46.79
(CH), 57.10 (C), 108.16 (C), 111.07 (CH), 115.26 (C), 117.06 (C), 118.21
(CH), 118.97 (CH), 119.56 (CH), 120.83 (CH), 123.61 (CH), 124.26 (C),
137.13 (C), 138.42 (C), 139.59 (C), 151.14 ppm (C); MS (EI): m/z (%):
331 (99) [M+], 316 (100), 288 (18), 248 (36).
Mahanimbine (5) (Method B): Compound 1 (1.04 g, 5.27 mmol) was dis-
solved in toluene (120 mL), cooled to À788C, and 25 (1.54 g, 10.1 mmol)
was added. Then, titanium tetraisopropoxide (6.07 mL, 20.3 mmol) was
added slowly. The reaction mixture was allowed to warm to room tem-
perature slowly, stirred for total 15 h, then transferred to a separation
funnel, and washed several times with water, diluted hydrochloric acid, a
solution of hydroxylamine hydrochloride and sodium acetate, and brine.
After extraction with ethyl acetate, the combined organic layers were
dried over sodium sulfate, the solvent was removed, and the residue was
purified by chromatography on silica gel (pentane/dichloromethane/ethyl
acetate 100:5:1 to 80:5:1) to afford 5 (1.43 g, 82%) as a slightly yellow
solid; spectroscopic data, see above.
Bicyclomahanimbine (9): Mahanimbine (5) (53.9 mg, 0.163 mmol) was
dissolved in toluene (25 mL) and stirred for 26.5 days at room tempera-
ture under sunlight irradiation till all starting material was converted.
Then, the solvent was evaporated and the residue was purified by chro-
matography on silica gel (pentane/dichloromethane/ethyl acetate 200:5:1
to 100:5:1) to provide 9 (24.3 mg, 45%) as a slightly yellow solid. M.p.
145–1478C (lit. 1458C);[16] 1H NMR (500 MHz, CDCl3): d =0.75 (s, 3H),
1.45 (s, 3H), 1.57 (s, 3H), 1.64–1.76 (m, 3H), 2.06–2.09 (m, 1H), 2.36 (s,
3H), 2.51 (brt, J=6.6 Hz, 1H), 2.71 (dd, J=9.3, 7.9 Hz, 1H), 3.30 (d, J=
9.5 Hz, 1H), 7.18 (brt, J=7.4 Hz, 1H), 7.30 (brt, J=7.6 Hz, 1H), 7.38 (d,
J=8.0 Hz, 1H), 7.43 (brs, 1H), 7.69 (s, 1H), 7.94 ppm (d, J=7.7 Hz,
1H); 13C NMR and DEPT (125 MHz, CDCl3): d =16.70 (CH3), 18.58
(CH3), 25.60 (CH2), 27.41 (CH3), 35.07 (CH3), 37.34 (CH), 37.78 (CH),
38.31 (CH2), 39.27 (C), 46.40 (CH), 83.51 (C), 106.30 (C), 110.25 (CH),
2,9,9,12-Tetramethyl-9a,10,11,13a-tetrahydro-9H-indoloACTHNUTRGNEU[GN 3,2,1-de]-phenan-
thridin-1-ol (29) (Method B): Cyclomahanimbine (7) (33.8 mg,
0.102 mmol) was dissolved in toluene (10 mL), cooled to À788C, and a
solution of ethylaluminum dichloride (0.9m in heptane, 0.34 mL,
0.306 mmol) was added slowly. The reaction mixture was allowed to
warm to room temperature and stirred for 6 h. After addition of metha-
nol (1 mL) under cooling, the solution was transferred to a separation
14108
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 14098 – 14111

Cyclized Monoterpenoid PyranoACTHNUGRTNEUNG[3,2-a]carbazole Alkaloids
FULL PAPER
funnel, washed several times with a saturated solution of ammonium
chloride and brine, extracted with ethyl acetate, and the combined organ-
ic layers were dried over sodium sulfate. The solvent was evaporated and
the residue was purified by chromatography on silica gel (pentane/di-
chloromethane/ethyl acetate 100:5:1 to 70:5:1) to afford 29 (17.7 mg,
52%) as a brownish solid; spectroscopic data, see above.
(ddd, J=8.3, 7.1, 1.2 Hz, 1H), 7.46 (s, 1H), 7.48 (d, J=8.3 Hz, 1H),
7.89 ppm (d, J=7.3 Hz, 1H); 13C NMR and DEPT (150 MHz, CDCl3): d
=15.37 (CH3), 21.79 (CH2), 22.95 (CH3), 28.30 (CH), 29.26 (CH3), 30.13
(CH3), 36.10 (CH2), 36.80 (CH2), 48.66 (CH), 60.45 (C), 76.07 (C), 107.28
(C), 113.46 (CH), 113.90 (C), 118.42 (C), 119.12 (CH), 119.21 (CH),
119.78 (CH), 122.57 (CH), 127.34 (C), 140.60 (C), 142.37 (C), 155.01 ppm
(C); IR (ATR): n˜ =3058, 3012, 2974, 2938, 2906, 2056, 2030, 1735, 1717,
1699, 1639, 1597, 1447, 1381, 1343, 1325, 1295, 1250, 1217, 1206, 1180,
1149, 1118, 1076, 1059, 1010, 987, 958, 902, 884, 869, 848, 808, 772, 740,
700, 683, 635, 615 cmÀ1; UV (MeOH): l=245, 307, 342 nm; fluorescence
(MeOH): lex =245, lem =371 nm; MS (EI): m/z (%): 331 (100) [M+], 316
(88), 288 (13), 248 (58); elemental analysis (%) calcd for C23H25NO: C
83.34, H 7.60, N 4.23; found: C 83.38, H 7.74, N 4.19.
Cyclomahanimbine (curryanin, murrayazolidine) (7): Mahanimbine (5)
(103 mg, 0.310 mmol) and camphor-10-sulfonic acid (72.4 mg,
0.312 mmol) were stirred in toluene (10 mL) for 41.5 h. Then, the reac-
tion mixture was transferred to a separation funnel, washed several times
with a saturated solution of potassium carbonate and brine, extracted
with ethyl acetate, and the combined organic layers were dried over
sodium sulfate. The solvent was evaporated and the residue was purified
by chromatography on silica gel (pentane/dichloromethane/ethyl acetate
200:5:1 to 100:5:1) to provide 7 (91.6 mg, 89%) as a colorless solid. M.p.
1398C (lit. 1468C);[16] 1H NMR (500 MHz, CDCl3): d =1.44 (s, 3H),
1.48–1.50 (m, 1H), 1.51 (s, 3H), 1.59–1.68 (m, 2H), 1.90 (dt, J=12.8,
3.1 Hz, 1H), 2.03 (dd, J=12.8, 2.6 Hz, 1H), 2.10 (dt, J=9.1, 2.1 Hz, 1H),
2.34 (s, 3H), 2.59 (m, 1H), 3.42 (d, J=2.6 Hz, 1H), 4.75 (s, 1H), 4.82 (s,
1H), 7.15 (brt, J=7.4 Hz, 1H), 7.27 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.32
(d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.73 (brs, 1H), 7.90 ppm (d, J=7.7 Hz,
1H); 13C NMR and DEPT (125 MHz, CDCl3): d =16.76 (CH3), 21.59
(CH3), 23.08 (CH2), 28.98 (CH3), 36.22 (CH), 37.35 (CH2), 39.90 (CH2),
48.69 (CH), 73.91 (C), 105.19 (C), 110.15 (CH), 112.02 (CH2), 114.57 (C),
117.58 (C), 119.02 (CH), 119.08 (CH), 119.47 (CH), 123.47 (CH), 124.24
(C), 138.31 (C), 139.34 (C), 150.06 (C), 153.61 ppm (C); IR (ATR): n˜ =
3439, 3054, 3012, 2969, 2927, 2843, 1629, 1613, 1578, 1487, 1455, 1442,
1376, 1342, 1307, 1211, 1173, 1156, 1104, 1054, 1038, 1012, 959, 904, 875,
864, 774, 737, 689, 662, 644, 608 cmÀ1; UV (MeOH): l=213, 241, 255, 260
(sh), 306, 333 nm (sh); fluorescence (MeOH): lex =306, lem =358 nm; MS
(EI): m/z (%): 331 (67) [M+], 316 (8), 248 (100), 210 (12); elemental
analysis (%) calcd for C23H25NO: C 83.34, H 7.60, N 4.23; found: C
83.27, H 7.78, N 4.19.
Crystallographic data for 8: C23H25NO, M=331.44 gmolÀ1, crystal size:
0.27ꢃ0.25ꢃ0.14 mm3, monoclinic, space group: P21/n, a=11.1144(5), b=
10.9145(5), c=14.7178(6) ꢂ, b=107.560(2)8, V=1702.19(13) ꢂ3, Z=4,
1calcd =1.293 gcmÀ3
,
m=0.078 mmÀ1
,
l=0.71073 ꢂ, T=150(2) K,
q
range=2.03–29.238, reflections collected: 96537, independent: 4612
(Rint =0.0766), 230 parameters. The structure was solved by direct meth-
ods and refined by full-matrix least squares on F2; final R indices [I>
2s(I)]: R1 =0.0523; wR2 =0.1416; maximal residual electron density:
0.705 eꢂÀ3
.
Isocyclomahanimbine (33): Cyclomahanimbine (7) (208 mg, 0.627 mmol)
and camphor-10-sulfonic acid (146 mg, 0.630 mmol) were stirred in tol-
uene (12 mL) at 1008C for 2 days and 20 h. The reaction mixture was
transferred to a separation funnel, washed several times with a saturated
solution of potassium carbonate and brine, extracted with ethyl acetate,
and the combined organic layers were dried over sodium sulfate. The sol-
vent was removed under reduced pressure and the residue was purified
by chromatography on silica gel (pentane/dichloromethane/diethyl ether
200:5:1 to 100:5:1) to afford 33 (128 mg, 62%) as a colorless solid.
1H NMR (500 MHz, CDCl3): d =1.44 (s, 3H), 1.60 (td, J=13.6, 5.7 Hz,
1H), 1.67 (d, J=0.9 Hz, 3H), 1.88 (m, 1H), 1.93 (dd, J=12.6, 2.6 Hz,
1H), 2.01 (dt, J=12.6, 3.2 Hz, 1H), 2.05–2.09 (m, 1H), 2.14 (d, J=
2.0 Hz, 3H), 2.35 (d, J=0.6 Hz, 3H), 2.40 (dd, J=14.5, 5.6 Hz, 1H), 4.27
(brs, 1H), 7.17 (brt, J=7.4 Hz, 1H), 7.27 (ddd, J=8.0, 7.1, 1.0 Hz, 1H),
7.35 (d, J=8.0 Hz, 1H), 7.45 (brs, 1H), 7.63 (s, 1H), 7.89 ppm (d, J=
7.7 Hz, 1H); 13C NMR and DEPT (125 MHz, CDCl3): d =16.64 (CH3),
20.40 (CH3), 20.48 (CH3), 23.30 (CH2), 28.93 (CH3), 32.08 (CH), 36.82
(CH2), 40.77 (CH2), 74.13 (C), 107.06 (C), 110.32 (CH), 114.84 (C),
117.88 (C), 119.10 (CH), 119.15 (CH), 119.29 (CH), 120.78 (C), 123.59
(CH), 124.38 (C), 132.33 (C), 136.78 (C), 139.26 (C), 153.23 ppm (C); IR
(ATR): n˜ =3474, 3045, 2969, 2926, 2853, 1628, 1611, 1577, 1561, 1486,
1457, 1435, 1397, 1375, 1340, 1304, 1243, 1213, 1159, 1127, 1111, 1076,
1049, 959, 903, 876, 864, 776, 745, 674, 663, 641, 612 cmÀ1; UV (MeOH):
Crystallization of 7 from a mixture of pentane/dichloromethane/ethyl
acetate afforded two polymorphic forms of single crystals.
Crystallographic data for 7 [monoclinic crystal form]: C23H25NO, M=
331.44 gmolÀ1
,
crystal size: 0.38ꢃ0.11ꢃ0.02 mm3, monoclinic, space
group: P21/c, a=17.631(2), b=9.8110(10), c=27.282(3) ꢂ, b=
130.069(7)8, V=3611.4(7) ꢂ3, Z=8, 1calcd =1.219 gcmÀ3, m=0.074 mmÀ1
,
l=0.71073 ꢂ, T=150(2) K, q range=1.51–25.008, reflections collected:
48408, independent: 6217 (Rint =0.1501), 465 parameters. The structure
was solved by direct methods and refined by full-matrix least squares on
F2; final R indices [I> 2s(I)]: R1 =0.0446; wR2 =0.0857; maximal residual
electron density: 0.205 eꢂÀ3
Crystallographic data for
.
7
[triclinic crystal form]: C23H25NO, M=
331.44 gmolÀ1, crystal size: 0.21ꢃ0.16ꢃ0.13 mm3, triclinic, space group:
l=214, 240, 254, 305, 330 nm (sh); fluorescence (MeOH): lex =240, lem
=
355 nm; MS (EI): m/z (%): 331 (100) [M+], 316 (23), 288 (40), 274 (17),
263 (19), 248 (42), 197 (16); elemental analysis (%) calcd for C23H25NO:
C 83.34, H 7.60, N 4.23; found: C 83.55, H 7.90, N 4.13.
¯
P1, a=11.524(2), b=11.661(1), c=16.142(2) ꢂ, a=88.368(8), b=
72.488(8), g=62.443(7)8, V=1818.2(4) ꢂ3, Z=4, 1calcd =1.211 gcmÀ3, m=
0.073 mmÀ1, l=0.71073 ꢂ, T=150(2) K, q range=1.33–25.008, reflections
collected: 44366, independent: 6297 (Rint =0.1155), 465 parameters. The
structure was solved by direct methods and refined by full-matrix least
squares on F2; final R indices [I> 2s(I)]: R1 =0.0585; wR2 =0.1333; maxi-
Murrayazolinine (10): Cyclomahanimbine (7) (40.4 mg, 0.122 mmol) and
sodium hydrogen carbonate (52.4 mg, 0.624 mmol) were dissolved in a
mixture of ethyl acetate (1.2 mL) and water (1.2 mL). Then, acetone
(70.8 mg, 1.22 mmol) was added, the mixture was stirred at room temper-
ature and a solution of Oxone (90.9 mg, 0.145 mmol) in water (1 mL)
was added over a period of 1.75 h. After 2 h, the reaction mixture was
transferred to a separation funnel, washed several times with a saturated
solution of sodium hydrogen carbonate and brine, extracted with ethyl
acetate, and the combined organic layers were dried over sodium sulfate.
The solvent was removed under reduced pressure and the residue was
dried in high vacuum. The crude epoxide was dissolved in diethyl ether
(10 mL), cooled to À158C, and lithium aluminum hydride (13.9 mg,
0.366 mmol) was added. The suspension was allowed to warm to À58C
over a period of 2.25 h. Then, the mixture was transferred to a separation
funnel, washed several times with water, a saturated solution of ammoni-
um chloride, and brine. After extraction with ethyl acetate, the combined
organic layers were dried over sodium sulfate, the solvent was evaporat-
ed, and the residue was purified by chromatography on silica gel (pen-
tane/dichloromethane/ethyl acetate 25:5:1 to 18:5:1) to provide 10
mal residual electron density: 0.302 eꢂÀ3
.
Mahanimbidine (curryangin, murrayazoline) (8): A solution of mahanim-
bine (5) (50.0 mg, 0.151 mmol) and camphor-10-sulfonic acid (1.9 mg,
0.008 mmol) in hexane (1 mL) was stirred for 45 h. After addition of
sodium hydrogen carbonate, the mixture was purified by flash chroma-
tography (pentane/dichloromethane/ethyl acetate 200:5:1 to 100:5:1) to
provide a mixture of 8 and 7 (47.8 mg, 96%, 8/7 6.6:1) as a colorless
solid. Separation of the two isomers by preparative HPLC on a Grace
Vydac C8 column (208TP1050, 50ꢃ250 mm) by gradient elution with
55 mLminÀ1 (THF/H2O, 35–55% THF in 25 min) afforded 8 (40 mg,
80%) as colorless crystals. M.p. 266–2678C (lit. 2668C);[16] 1H NMR
(600 MHz, CDCl3): d =0.17 (ddt, J=13.7, 7.1, 11.7 Hz, 1H), 1.28 (s, 3H),
1.30 (m, 1H), 1.46 (s, 3H), 1.48–1.54 (m, 1H), 1.63 (ddd, J=15.3, 6.9,
3.1 Hz, 1H), 1.911 (dd, J=13.1, 0.8 Hz, 1H), 1.909 (s, 3H), 1.97 (ddd, J=
11.1, 5.5, 2.4 Hz, 1H), 2.33 (d, J=0.7 Hz, 3H), 2.39 (ddd, J=13.1, 5.3,
3.3 Hz, 1H), 3.30 (d, J=4.9 Hz, 1H), 7.15 (brt, J=7.4 Hz, 1H), 7.24
Chem. Eur. J. 2013, 19, 14098 – 14111
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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14109

H.-J. Knçlker et al.
(30.8 mg, 72%) as a slightly yellow solid. M.p. 183–1848C (lit. 1848C);[23]
1H NMR (600 MHz, CDCl3): d =0.55 (s, 3H), 1.28–1.31 (m, 1H), 1.32 (s,
3H), 1.41–1.45 (m, 1H), 1.43 (s, 3H), 1.60–1.65 (m, 1H), 1.85 (dt, J=
12.9, 3.0 Hz, 1H), 1.88 (dd, J=12.9, 2.8 Hz, 1H), 1.90–1.94 (m, 1H), 2.10
(m, 1H), 2.34 (s, 3H), 3.80 (brd, J=2.7 Hz, 1H), 7.13 (brt, J=7.4 Hz,
1H), 7.26 (brt, J=7.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.66 (d, J=
0.5 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 9.59 ppm (brs, 1H); 13C NMR and
DEPT (150 MHz, CDCl3): d =16.80 (CH3), 22.86 (CH2), 23.22 (CH3),
28.87 (CH3), 29.21 (CH), 33.36 (CH3), 38.28 (CH2), 40.41 (CH2), 52.76
(CH), 74.26 (C), 74.32 (C), 105.82 (C), 110.51 (CH), 114.71 (C), 117.40
(C), 118.65 (CH), 118.99 (CH), 119.41 (CH), 123.30 (CH), 124.35 (C),
138.91 (C), 139.69 (C), 153.64 ppm (C); IR (ATR): n˜ =3520, 3260, 2966,
2928, 2860, 1611, 1577, 1496, 1455, 1362, 1310, 1232, 1210, 1154, 1122,
1091, 1052, 1009, 952, 903, 868, 793, 736, 699, 610 cmÀ1; UV (MeOH): l=
213, 240, 253, 258 (sh), 305, 331 nm; fluorescence (MeOH): lex =305,
lem =356 nm; MS (EI): m/z (%): 349 (90) [M+], 331 (13), 316 (26), 288
(11), 248 (100), 210 (17), 197 (48); elemental analysis (%) calcd for
C23H27NO2: C 79.05, H 7.79, N 4.01; found: C 78.65, H 7.95, N 4.04.
G. W. Kirby, W. Steglich, C. Tamm), Springer, Wien, 1991, pp. 71–
152; b) D. P. Chakraborty, in The Alkaloids, Vol. 44 (Ed.: G. A. Cor-
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4303–4427; b) H.-J. Knçlker, Top. Curr. Chem. 2005, 244, 115–148;
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Cordell), Academic Press, London, 2008, pp. 1–430; d) K. K.
Gruner, H.-J. Knçlker, in Heterocycles in Natural Product Synthesis
(Eds.: K. C. Majumdar, S. K. Chattopadhyay), Wiley-VCH, Wein-
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Crystallographic data for 10: C23H27NO2, M=349.46 gmolÀ1, crystal size:
0.15ꢃ0.13ꢃ0.08 mm3, monoclinic, space group: P21/c, a=10.930(2), b=
10.889(2), c=17.484(3) ꢂ, b=111.57(3)8, V=1935.2(6) ꢂ3, Z=4, 1calcd
=
1.199 gcmÀ3, m=0.076 mmÀ1, l=0.71073 ꢂ, T=198(2) K, q range=3.13–
25.408, reflections collected: 33375, independent: 3560 (Rint =0.0844), 244
parameters. The structure was solved by direct methods and refined by
full-matrix least squares on F2; final R indices [I> 2s(I)]: R1 =0.0522;
[7] B. S. Joshi, V. N. Kamat, D. H. Gawad, T. R. Govindachari, Phyto-
chemistry 1972, 11, 2065–2071.
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4, 233–241.
wR2 =0.1038; maximal residual electron density: 0.179 eꢂÀ3
.
Exozoline (11):
A
mixture of cyclomahanimbine (7) (76.1 mg,
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Agarwal, S. Cꢀmmerer, S. Filali, W. Frçhner, J. Knçll, M. P. Krahl,
K. R. Reddy, H.-J. Knçlker, Curr. Org. Chem. 2005, 9, 1601–1614;
c) H.-J. Knçlker, in Modern Alkaloids—Structure, Isolation, Synthe-
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0.229 mmol) and 10% Pd/C (20 wt%, 15.0 mg) in methanol/dichlorome-
thane (10 mL, 4:1) was stirred at room temperature under a hydrogen at-
mosphere for 2 d. Subsequently, the reaction mixture was filtered over
Celite (diethyl ether). Evaporation of the solvent under reduced pressure
and purification of the crude product by flash chromatography on silica
gel (petroleum ether/ethyl acetate 2:1) afforded 11 (75.9 mg, 100%), col-
orless solid. M.p. 175–1788C (lit.: 180–1828C);[24] 1H NMR (500 MHz,
CDCl3): d=0.67 (d, J=6.1 Hz, 3H), 1.15 (m, 1H), 1.30 (d, J=6.1 Hz,
3H), 1.40–1.45 (m, 2H), 1.42 (s, 3H), 1.53–1.67 (m, 2H), 1.90 (m, 2H),
2.05 (m, 1H), 2.45 (s, 3H), 3.44 (s, 1H), 7.15–7.18 (m, 1H), 7.26–7.30 (m,
1H), 7.35 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.71 (brs, 1H), 7.91 ppm (d,
J=8.0 Hz, 1H). 13C NMR and DEPT (125 MHz, CDCl3): d=16.83
(CH3), 20.02 (CH3), 22.64 (CH2), 22.74 (CH3), 28.86 (CH), 29.54 (CH3),
32.05 (CH), 37.12 (CH2), 40.45 (CH2), 49.84 (CH), 73.93 (C), 105.43 (C),
110.08 (CH), 114.65 (C), 117.79 (C), 119.00 (CH), 119.18 (CH), 119.38
(CH), 123.53 (CH), 124.15 (C), 138.09 (C), 139.01 (C), 153.98 ppm (C);
IR (ATR): n˜ =3461, 3058, 2925, 2866, 1722, 1628, 1612, 1486, 1455, 1436,
1376, 1341, 1306, 1250, 1211, 1157, 1082, 1049, 956, 905, 867, 774, 738,
673, 644, 605 cmÀ1; UV (EtOH): l=213, 241, 259 (sh), 306, 333 nm (sh);
fluorescence (EtOH): lex =306, lem =357 nm; MS (EI): m/z (%): 333
(100) [M+], 248 (92), 234 (10), 210 (14); HRMS: m/z: calcd for
C23H27NO [M+]: 333.2093; found: 333.2087.
CCDC-881413 (10), CCDC-881414 (19), CCDC-881415 (7, triclinic),
CCDC-881416 (7, monoclinic), CCDC-881417 (9), CCDC-881418 (1),
and CCDC-881419 (8) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
Acknowledgements
We would like to thank the Deutsche Forschungsgemeinschaft for finan-
cial support (grants Kn 240/15-1 and Kn 240/16-1). We are grateful to
Regina Czerwonka, Arlett Großmann, Anne Jꢀger, and Sebastian Kutz
for their experimental support.
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: May 10, 2013
Published online: September 12, 2013
Chem. Eur. J. 2013, 19, 14098 – 14111
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www.chemeurj.org
14111