Contents
Contents
1
Papers included in this thesis
2
General introduction
3
Historical background
3
Structure and reactivity of indoles
5
2,2’-Biindolyls
9
Introduction
9
Reactions of 2,2’-biindolyl
13
Acid induced dimerization of 3-substituted indoles
17
Introduction
17
Results and discussion
18
Indolo[2,3-a]carbazoles
20
Structure and physiological activities
20
Protein kinase C
21
Biogenesis of indolocarbazoles
22
Synthesis
23
Results and discussion
26
Acid induced cyclization
31
Indolo[3,2-a]pyrrolo[3,4-c]carbazoles
34
Introduction
34
Reactions of indole with maleimides
34
Autoxidation of indolines
39
Additional acid induced cyclizations
42
Dimerization of indole-3-maleimides
42
Acknowledgements
44
References and notes
45
1
Papers included in this thesis
This thesis is based on the following papers, referred to in the text by roman numerals I-VI:
I.
2,2’-Biindolyl Revisited. Synthesis and Reactions.
Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron, 1995, 51, 5631
II.
Reactions of Indole-3-acetic Acid Derivatives in Trifluoroacetic Acid.
Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron Lett., 1995, 36, 3945
III.
2,2’-Biindolyl. Reactions with Aldehydes.
Bergman, J.; Desarbre, E.; Koch, E., Manuscript
IV.
Synthesis of Arcyriaflavin A.
Bergman, J.; Koch, E.; Pelcman, B., Manuscript
V.
Synthesis of Indolo[3,2-a]carbazole in one Step from Indole and
Maleimide.
Bergman, J; Desarbre, E. ; Koch, E. Tetrahedron, 1999, 55, 2363
VI.
Acid Induced Dimerization of 3-Indolylmaleimides. Formation of
Cyclopentindole Derivatives.
Bergman, J.; Janosik, T.; Koch, E., Manuscript
2
General introduction
Historical background
The chemistry1-3 of indole (1)
began in the midst of the 19th century with
extensive research on the natural dye indigo (2), a violet-blue dye, imported to
Europe mainly from India since the 16th century. It is more well known as the
colour of blue jeans. This research resulted in the early development of the German
organic chemical industry, culminating in the development of a viable industrial
process for indigo, as well as the first preparation of indole in 18664 by zinc dust
distillation of oxindole.
O
N
H
N
H
1
H
N
O
2
During the 1930’s it was discovered that a number of important natural products
contained indole moieties. The potent physiological properties of many of these
alkaloids have been utilized in traditional medicine, but now it added stimulus to
research, and many important indole syntheses were developed. During this
period, the essential amino acid tryptophan (3)5 was discovered, as well as the
plant growth hormone indole-3-acetic acid (4)6.
3
CO2H
H
NH2
CO2H
N
H
N
H
3
4
Tryptophan is a constituent of most proteins, and serves in man and animals as a
biosynthetic precursor for a wide variety of tryptamine and other indole containing
metabolites; several of them of paramount physiological importance. Thus, the
hormone serotonin (5)7 is an important neurotransmitter, and melatonin (6) is
thought to control the day and night rhythms.
HO
NH2
MeO
N
H
NHCOMe
N
H
5
6
Serotonin is widely distributed in nature, but occurs only in low concentrations,
therefore, the laboratory syntheses of serotonin made it possible to study and
classify the family of serotonin receptors. These findings resulted in the design and
syntheses of useful pharmaceuticals, e.g. the highly selective sumatriptan (7) for
treatment of migraine, but also more notorious compounds, such as lysergic acid
diethylamide (LSD) (8).
Et2NOC
NMe
H
NMe2
MeHNO2S
N
H
N
H
7
8
4
Structure and reactivity of indoles
Indole is a planar heteroaromatic molecule, with a benzene ring fused to the
b-face of the pyrrole ring. The numbering of the atoms of indole starts at the
nitrogen as shown in Figure 1.
4
3
5
¨1
N
6
2
H
7
Figure 1
Due to the delocalization of the nitrogen lone-pair into the
-system, indole is a
very weak base with a pKa value of -3.5. This means, for example, that you need a
strongly acidic solution (12 M H2SO4) to completely protonate indole.
Of the three possible cations, the 3-protonated 1b, is the thermodynamically
most stable, since it retains full benzene aromaticity (in contrast to the 2-protonated
cation 1c) with delocalisation over the nitrogen and the 2-carbon (in contrast to the
N-protonated cation 1a). Kinetically, however, the 1H-indolium cation is favoured.
H H
+
N
H
H
1H -Indolium cation
(formed fastest)
1a
+
+
N
H
N
H
3H -Indolium cation
(most stable)
1b
H
H
2H -Indolium cation
1c
Due to the electron rich character of the heterocyclic ring, the indole chemistry is
dominated by electrophilic substitution in the 3-position, for the same reasons as
5
discussed above.
However, all reactions of indoles do not lead simply to
substitution, which can be illustrated by considering the protonation of indoles.
3H-Indolium cations (1b) are electrophilic species and will react as such under
favourable conditions. In a reaction medium with partial protonation of the indole,
a 3H-indolium cation will be attacked by an unprotonated indole leading to
dimerization as well as trimerization, see scheme 1.
H
H
H
N
H
1b
N
H
¨
N
H
-H+
N
H
N
H
¨
N
H
Indole-dimer
H+
N
H H
¨
N
H
H
N
NH
¨
N
H
NH2
NH2
N
H
Indole-trimer
Scheme 1
The indole dimerization is an example of a Mannich reaction, where the
protonated indole (1b) is the Mannich reagent, an immonium ion, which is a fairly
reactive electrophile.
6
The Mannich reaction has long been utilized in biomimetic natural product
synthesis8, particularly as the key step in domino reaction sequences. A classical
example is the synthesis of tropinone (9) by Robinson9 in 1917 by a Mannich
reaction involving succinaldehyde (10), methylamine (11) and acetone (12) (see
Scheme 2).
Me
HN
H
O
H
+ MeNH2
+
Me
N
¨
H
H
O
O
10
O
OH
¨
O
11
12
9
Scheme 2
This thesis primarily deals with reactions where various indoles act as Mannich
reagents.
These studies have led to the synthesis of
some naturally occurring
indolocarbazoles (13), as well as some 3,3’-disubstituted 2,2’-biindolyls (14) (paper
III and II).
OR
H
N
O
O
O
H
N
N
H
N
H
N
H
O
RO
13
14
7
In paper V and VI, intermolecular and intramolecular Mannich reactions have
been applied in a tandem fashion in the syntheses of indolo[3,2-a]carbazoles (15)
and the cyclopentindole (16).
H
N
O
O
O
O
H
Ph
N
N
NH
Ph
N
H
15
O
O
NH N
H
16
The reactions involving 2,2’-biindolyl have led to several 3,3’-disubstituted
derivatives as well as more complicated compounds, e.g. 17 (paper I-II).
O
N
N
N
N
O
17
The aims which were defined when this work began were to finish a project
concerning formation of the naturally occurring indolocarbazoles (paper III-IV)
and to continue an ongoing investigation of the reactivity of 2,2’-biindolyls towards
different electrophiles (paper I-II).
8
2,2’-Biindolyls
Introduction
In our group we have developed a convenient synthesis of 2,2’-biindolyl (18) by
a modification of the original synthesis of Madelung10,11 (scheme 3).
O
N
H
H
N
O
H
N
C5H11ONa/ 360ÞC(26%)
or
t-BuOK/ 300ÞC(80%)
N
H
18
Scheme 3
2,2’-Biindolyl (18) as a structural element is present in some natural products like
the indolocarbazole arcyriaflavin A (13), isolated from the slime mold Arcyria
nutans, and the sponge pigment fascaplycin (19). The two nitrogens in 2,2’-biindolyl
have also been exploited in the construction of various ligand systems,12 e.g. 20.
H
N
O
-
O
OMe
MeO
Cl
N
N
H
N
H
13
N
H
N
N
Ni
MeO
N
O
19
OMe
N
20
Our primary interest in making 2,2’-biindolyl was based on a desire to
investigate its reactions with various dienophiles. On the basis of a simple
retrosynthetic analysis, arcyriaflavin A (13) should be directly accessible from
9
2,2’-biindolyl and maleimide, by way of a Diels-Alder reaction followed by a
dehydrogenation step.
H
N
O
O
H
N
O
O
+
N
H
N
H
N
H
N
H
13
Scheme 4
This strategy has however in our hand proved to be full of difficulties, and
several research workers13-15 have reported modest yields, harsh reaction
conditions and/or tedious work up procedures. The loss of resonance energy on
formation of the [4+2] transition state should considerably increase the activation
energy, and the indolocarbazoles obtained by this route are generally believed to
be the result of a stepwise, rather than concerted, process.
A successful total synthesis of K-252a (21) due to Wood16 et al., is based on an
initial coupling of the diazolactam (22) with 2,2’-biindolyl which is followed by a
cyclization to the aglycon staurosporinone (23) (scheme 5). Wood has suggested
that the reaction pathway includes a thermal electrocyclization of an intermediate
3-vinyl biindolyl (24).
10
R
N
O
H
N
O
22
O
N2
+
N
N
H
N
H
R
N
H3C
MeO2C
R
N
O
O
O N
21
OH
R
N
O
HO
O
N
H
N
H
N
H
N
H
N
H
24
25
N
H
23
Scheme 5
Later work by Pindur et al.17 has however, shown that high temperature
(o-dichloro benzene, 230 C) is necessary for this type of electrocyclization. In a
paper by Hudkins18, a lactam (27) regio-isomer is produced, as seen in scheme 6,
by condensation to the intermediate Michael adduct (26) using the same
temperature range which produced Wood’s staurosporinone (pinacolone, 120 C).
O
O
NH
O
N
H
N
H
H
N
TFA, 24h
120-125ÞC
NH
O
O
N
H
N
H
26
Scheme 6
11
N
H
N
H
27
In the original papers by Madelung11,19 several reactions of 2,2’-biindolyl (18)
with various electrophiles were investigated. However, as 18 is susceptible to
electrophilic substitution both at the nitrogen and at the 3-position, mixtures of
products were often encountered. Thus, treatment of 18 with acetic acid anhydride
gave mixtures of 1-acetyl- and 1,1’-diacetyl- 2,2’-biindolyl as well as 3-acetylated
products. Clean 3,3’-disubstitution could, in contrast, be achieved, when 18 was
reacted in hot benzoyl chloride giving 28. The magnesium-salt of indole are known
to give C-substitution in reactions with electrophiles, and this was found to be true
also for the magnesium-salt of 18. In this way 28 and 29 could be obtained from
benzoyl chloride and acetyl chloride, respectively, although the yield of the latter
was low.
O
N
H
O
H
N
H
N
N
H
O
28
O
29
Madelung11 also claimed, that the condensation products typical for indoles
could be obtained when 18 was reacted with formaldehyde, acetaldehyde as well
as benzaldehyde, but no details were given.
12
Reactions of 2,2’-biindolyl
When 2,2’-biindolyl was reacted with an excess (4 equivalents) of formaldehyde
in refluxing acetic acid a slightly yellow precipitate was collected after 15 minutes.
Mass spectral data featured a molecular ion (m/z=572 (70%)) and a fragmentation
pattern where two formaldehyde units are successively disconnected. The 1H-NMR
spectrum exhibited three different, unconnected, gem-coupling methylenes, no NH
signals and eight different signals from the indole rings. Based on these findings
we propose the following structure.
O
N
N
N
N
O
17
Due to the axis of symmetry the NMR-spectrum of 17 is simplified. The
formation of such a compound can be envisaged as a consequence of two
equilibrium reactions: substitution at the 3- and the 1-positions of the indole (see
Scheme 7).
13
HO
H
N
N
H
H
N
CH2O
+ H2O
N
H
CH2O
N
CH2O
30
N
H
31
O
N
N
O
O
Dimerization
N
N
N
N
H
N
CH2O
N
H
32
33
+ H2O
O
17
Scheme 7
The 3-position is
favoured and 2,2’-biindolyl will react readily with one
formaldehyde unit. In the acidic solution, the intermediate carbinol will easily lose
water which will create a stabilized carbocation 30. The free 3-position of 30 is,
however, deactivated due to the conjugation with the positive charge on the
nitrogen, so an attack by the indole nitrogen on a second unit of formaldehyde is
favoured leading to 31. An intramolecular Michael-addition will then create the
seven-membered ring 32. Substitution in the free 3-position will form the
intermediate 33 which can dimerize to 17. The driving force in these equilibrium
reactions is the insolubility of the product.
In a publication by Pindur,20 2,2’-biindolyl was reported to form a fivemembered ring (34) when reacted with dimethyl acetylenedicarboxylate under the
influence of a Lewis acid catalyst. The structure was confirmed by X-ray
crystallography. In the light of this work, we reacted 2,2’-biindolyl with the
relatively electron rich anisaldehyde. The intermediate should be less deactivated
in the 3-position due to the resonance structure 35a, and in contrast to the
14
resonance structure 35b a cyclization of 35a would be favoured according to the
Baldwin rules.21
+
OMe
OMe
CO2Me
MeO2C
N
H
+
N
H
N
H
34
N
H
N
H
35a
N
H
35b
In acetic acid, the reaction was sluggish and TLC-analysis of the reaction mixture
revealed a large number of products, but in acetonitrile with p-toluenesulfonic acid
in catalytic amount the reaction went smoothly and a white solid precipitated.
Mass spectral data featured a molecular ion (m/z=700), so the anticipated
product with a five membered ring could be ruled out .
The 1H-NMR-spectrum showed two different NH-signals and 13 signals in the
aromatic region as well as 12 aromatic CH and one aliphatic in 13C-NMR. Based on
these findings we propose the following structure (36).
H
N
H
N
H
Ar H
N
H
Ar =
Ar
OMe
N
H
36
There are two possible isomers of this compound, but 36 can adopt a tub-shaped
conformation of the ten-membered ring which will have a good overlap within the
15
bis-indolyl framework and the unsymmetry of the compound will give two sets of
indole signals in NMR. There is however, only one set of signals from the
p-methoxybenzene rings and the methines, but this can be explained by ring
inversion of the rather flexible ten-membered ring.
When p-nitrobenzaldehyde is reacted with 2,2’-biindolyl in acetic acid, an orange
precipitate can be collected in quantative yield. The product shows 8 signals from
the benzo ring of the indoles, a rather low singlet at 5.8 ppm, 1 singlet at 12.6 ppm
and a broad signal with an integral value of approximately 2, just below 12 ppm
and 4 different signals from the nitrobenzene ring with dd-couplings in 1H-NMR.
The
13C-NMR
showed 2 quarternary carbons at 169.3 and 68.7 ppm respectively,
and a CH at 47.4 ppm. We propose the following structure (37).
H
N
N
O
OH
N
N
HO
N
O
N
H
37
The low shift of the unsubstituted 3-position can be explained by a
delocalization of the charge on oxygen and the broad signal at ~12 ppm would
arise from the exchangable nitronic acid protons. The relatively high quarternary
carbons would then be a result of the electron withdrawing character of the nitronic
acid group.
In contrast to these findings, several 3,3’-disubstituted 2,2’-biindolyls could be
obtained, by methods that are known to introduce substituents in the 3-position of
16
an indole. Thus, the Vilsmeier reaction cleanly afforded 38 and the Mannich
reaction gave 39.
O
Me2N
H
EtO2C
H
N
N
H
N
H
N
H
O
H
38
H
N
H
N
NMe2
39
CO2Et
14c
To make 3,3’-diacetic acid derivatives of 2,2’-biindolyl we used a carbenoid
approach. Thus, 2,2’-biindolyl was reacted with 3 equivalents of ethyl diazoacetate
in refluxing xylene in the presence of copper, yielding the dimer (14c). In the light
of the work by Wood,16 it is noteworthy, that in our hands, rhodium catalysis gave
inferiour results.
Some of these 3,3’-substituted 2,2’-biindolyls can also be synthezised, by acid
induced dimerization of 3-substituted indoles, as will be discussed in the following
section.
Acid induced dimerization of 3-substituted indoles
Introduction
3-Substituted indoles will also dimerize readily when subjected to acidic
conditions, but the resulting dimer 40 is joined in the 2-positions. There is still a
controversy as to whether such substitutions proceed by direct electrophilic attack
at the 2-position, or by an indirect route involving an initial attack at the 3-position
followed by a rearrangement to the 2-position (see scheme 8).
17
H
R
R
R
R
-H+
+
¨
N
H
N
H
N
H
N
H
40
-H+
R
R
R
N
H
Rearrangement
+
+
N H
H
N
H
R
N
H
Scheme 8
A driving force for such migration clearly exists as the aromaticity of the
heterocyclic ring thereby is restored (the final step) and the high migratory
aptitude of the indoline (in practice an α-amino alkyl group) towards electron
deficient centers greatly facilitates the rearrangement.
Results and discussion
When indole-3-acetic acid 41a was dissolved in trifluoroacetic acid (TFA) for 3h
at room temperature, we obtained the expected dimer 42a in 90% yield. The
corresponding diester 42b in the same manner formed from 41b could be isolated
in 95% yield using careful work-up procedures. The diester was formed as a single
diastereomer and later work by other groups22,23 has shown that the trans-isomer is
formed. Dehydrogenation of 42a-c with DDQ gave the 2,2’-biindolyls 14a-c.
18
OR
O
OR
OR
O
N
H
O
H
N
TFA, rt
dioxane
N
H
OR
O
a, R = H
b, R = Me
c, R = Et
H
N
H
41a-c
H
N
DDQ
N
H
O
O
RO
RO
14a-c
42a-c
Scheme 9
The diacid 14a has been suggested to be the biologically active principle formed
from the plant hormone auxine, i.e. indole-3-acetic acid (41a).24 Of interest, in this
context, is the easy photo oxidation of 42b25 to the dimer 14b, which occurs at room
temperature under ambient light.
The amino diesters 42b-c showed a strong propensity to undergo lactamization
to 43b-c. Heating pure 14b above its melting point or gentle heating of 14b in
slightly acidified 2-propanol, completely converted 42b to 43b. This lactam shows
strong structural resemblance to the cytotoxic and anti-microbal fascaplycins,
especially homofascaplysin B (44).
OR
OMe
O
O
O
H
N
N
H
N
N
O
43b-c
44
19
Indolo[2,3-a]carbazoles
Structure and physiological activities
H
N
N
H
N
H
N
H
N
H
45
46
Indolo[2,3-a]carbazole 45 is a symmetrical ring system with an indole fused to
the a-face of a carbazole. Almost all of the known natural products of this class
possess an additional pyrrole ring annulated to the c-face of the carbazole ring
system and have the systematical name 1H-indolo[2,3-a]pyrrolo[3,4-c]carbazole 46,
but for simplicity, all of these ring systems will throughout this thesis be referred to
as indolo[2,3-a]carbazoles.
H
N
O
N
O
H
H
N
O
N
N
Cl
Me
HO
OCH3
NHCH3
47
O
N
H
OH
OH
OCH3
48
20
O
Cl
Staurosporinone 47, the first indolo[2,3-a]carbazole to be isolated from Nature,
was initially obtained from26 Streptomyces staurosporeus and was found to exhibit a
wide range of extraordinary and in some cases, unique biological activities.27 Most
noteworthy is the fact that it is up to date the most potent inhibitor of protein
kinase C (PKC) which has been discovered. The structurally related antibiotic
rebeccamycin (48), isolated from the microbe Saccharothrix aerocolonigeneses, has
shown antitumor properties in vitro, but this antiproliferative activity can be linked
to topoisomerase I inhibition.
Protein kinase C
The enzyme system PKC is widely distributed in the tissues and organs of
mammals and other organisms, where it is involved in the transmission of external
signals to the interior of the cells, and thereby in the regulation of many cellular
processes by phosphorylation of a range of cellular proteins, some of them critical
for cell growth and differentiation (e.g. topoisomerase I and II). It has therefore, not
surprisingly, been suggested that PKC should be targeted for anticancer drug
design. Further studies have, however, shown that PKC is involved in many basic
cell processes beyond cell proliferation. Up to date, 12 different isoenzymes have
been identified and it has been shown that in a wide range of tissue diseases,
specific isoforms of PKC are overexpressed or subexpressed. This means that PKC
modulators, like the indolo[2,3-a]carbazoles are potential drugs against a wide
range of diseases, but the lack of selectivity towards different families of kinases as
well as towards the isoforms could induce severe side effects and have led to
caution in their therapeutic use. Many derivatives and synthetic analogues have
been prepared in order to studie the structure-activity reationship, to determine the
different parameters necessary to make more specific PKC inhibitors.
21
Biogenesis of indolocarbazoles
Some work have been reported on the biogenesis of indolo[2,3-a]carbazole
natural products. Feeding experiments have indicated that staurosporine (47)28 is
produced from two intact tryptophan units. Labelling experiments29 have likewise
shown that two tryptophan units are involved in the biosynthesis of rebeccamycin
(48), but a feeding experiment with (15NH4)2SO4 indicates that the imide nitrogen in
rebeccamycin is not obtained from tryptophan. The authors suggest that
tryptophan may be converted to indole-3-pyruvic acid (49a), IPA, since precedents
exist for this biotransformation. IPA occurs predominantly in the corresponding
enol form 49b.
HO
O
O
OH
O H
O
N
H
N
H
49a
49b
The co-isolation of several bisindolyl maleimides, such as arcyriarubin A (50),
and indolo[2,3-a]carbazoles, such as arcyriaflavins A (13) from the brightly
coloured slime mold Arcyria nutans, has led Steglich30,31 to propose that they are
biogenetically related according to scheme 10.
22
H
N
O
H
N
O
O
O
NH
N
H
N
H
N
H
arcyriaflavins (13)
arcyriacyanins
[O]
H
N
O
O
[O]
H
N
O
O
[O]
N
H
N
H
N
H
[O]
dihydroarcyriarubins
O
H
N
N
H
arcyriarubins (50)
[O]
O
O
H
N
O
NH
N
H
N
H
O
arcyroxocins
O O
N
H
arcyriaverdins
Scheme 10
Several of these steps have been duplicated in the laboratory.
Synthesis
There are several excellent reviews27,32,33 covering the synthetic efforts towards
indolo[2,3-a]carbazoles. Therefore, I will only give a brief survey of some of these
syntheses.
23
The synthetic approach of Winterfeldt and Sarstedt34 is interesting as it
illustrates a biosynthetic model reaction. The amide 51, synthesized from
tryptamine and indol-3-yl acetyl chloride, was eventually transformed by an
intramolecular reductive coupling to the bisindole pyrrole 52. After deacetylation,
a final photocyclization yielded the staurosporine aglycon (53) (Scheme 11).
H
N
O
H
N
O
O
HO
O
DDQ
N
H
H
N
O
O
NaBH 4
N
H
N
H
N
H
N
H
N
H
51
Ac2O
DMAP
H
N
O
H
N
O
Ac
N
O
AcO
1. NaHCO 3
N
H
N
H
2. hυ
OAc
TiCl3
N
H
N
H
53
N
Ac
N
Ac
52
Scheme 11
Bergman and Pelcman35 have developed a synthesis where the indoles are
assembled by a double Fischer indolization of the Diels-Alder cycloadduct 54. The
cyclization requires PPSE as the cyclizing agent, since the conventional methods
failed. A mixture of dihydroarcyriaflavin A (55) and arcyriaflavin A (13) was
formed and dehydrogenation of this mixture with Pd/C afforded pure
24
arcyriaflavin A (13). In this fashion, about a dozen indolo[2,3-a]carbazoles have
been prepared.
O
O
TMSO
+
O
NH
tol ²
24h
TMSO
TMSO
MeOH HOAc
² 6h
TMSO
54
O
3 eq PhNHNH2
NH
O
H
N
O
90%
N N
H
N N
H
91%
PPSE
MeNO2
H
N
O
O
H
N
O
H
O
H
+
N
H
13
N
H
N
N
H 55 H
68%
Pd/C
diglyme ² 24h
Scheme 12
In a synthesis by Moody et al.,
36
the indolo[2,3-a]carbazole is constructed via an
intramolecular Diels-Alder reaction followed by a nitrene-mediated ring closure.
25
H
N
O
CO2Et
N
H
NO2
O
1. (COCl)2
N
H
2. ArCH=CHCH2NH2
CO2Et
76%
1. KOH, MeOH
2. Ac2O
H
N
O
O
NO2
O
H
N
O
N
H
H
N
O
80%
heat
(EtO)3P
N
H
N
H
N
H
O2N
42%
37%
Results and discussion
As already discussed, the indolo[2,3-a]carbazole skeleton is derived from
tryptophan moieties and it is reasonable to assume that the a or the b bond are the
first to be formed biosynthetically.
H
N
O
a
O
b
N
H
c N
H
In our biomimetic synthesis of arcyriaflavin A (13), the b bond is formed first by
oxidative coupling of the trianions of indole-3-acetic acid (41a) or the dianions of
the methyl ester (41b), as shown in scheme 13.
26
O
O
N
H
59
O
N
H
Ac2O
OH
O
O
OH HO
O
O
1. 0.5 eq. I2
1. 2 eq. n-BuLi
N
H
2. 1 eq. t-BuLi
41a
O
N
2. NaHSO3
N
H
56a
N
H
57
CH2N2
OMe
O
OMe
MeO
O
OMe
O
2 eq. LDA
1. 0.5 eq. I2
N
H
41b
O
N
2. NaHSO3
56b
N
H
58
N
H
Scheme 13
The trianion (56a) was formed by sequential addition of 2 eq. n-BuLi and 1 eq. tBuLi to indole-3-acetic acid (41a). Addition of 0.5 eq. iodine to a solution of this
trianion in THF at -70 C, followed by acidic work-up gave the bisindole succinic
acid (57). The reaction mixture was treated, without any attempts to purify the
diacid, with diazomethane or acetic anhydride to give the diester 58, as a mixture
of diastereomers, or the anhydride 59, as a single diastereomer. However, the
27
yields of 58 and 59 were not satisfactory (38% and 32% respectively). Fortunately,
the diester 58 could be obtained in a much higher yield (85%) by the iodine
promoted coupling of the dianion 56b, prepared from indole-3-acetic acid methyl
ester (41b) and lithium diisopropylamide (LDA).
Heating the diester 58 or the anhydride 59 with benzylamine gave the
succinimide 60 together with small amounts of the bisamide 61 (Scheme 14). The
imide was readily dehydrogenated with DDQ at room temperature to give the
bisindole maleimide 62. The indolo[2,3-a]pyrrolo[3,4-c]carbazole 63 was obtained
from 60, using two equivalents of DDQ and a catalytic amount of p-TsOH in
refluxing benzene.
Ph
Ph
N
O
Ph
HN NH
O
O
58 or 59
O
+
N
H
N
H
60
N
H
76-80%
N
H
61
DDQ/ cat TsOH
benzene/ rx
DDQ
benzene/ rt
Ph
N
O
N
H
Ph
O
N
H
N
O
N
H
94%
N
H
63
62
Scheme 14
28
O
90%
The dimer 58 was formed as a mixture of the dl-pair (58a) and the meso (58b)
form. On trituration with dioxane one of them crystallizes in pure form. When the
mixture was reacted with ammonium formate in refluxing triglyme, only one of
the two diastereomers cyclized to the succinimide. The other diastereomer,
identical with the one obtained from trituration with dioxane, could be regained
from the reaction mixture. For sterical reason we hypothesized that this would be
the less crowded imide (64a), formed from the dl-pair (58a) of the diester.
MeO OMe
O
H
MeO OMe
O
O
H
H
N
H
N
H
H
N
O
O
O
H
N
H
N
H
58a
N
H
N
H
58b
64a
This was confirmed by an independent synthesis of the succinimide 64b from
arcyriarubin A (50) (see scheme 15).
H
N
O
O
O
H2/Pd/C, r.t.
N
H
N
H
H
N
DMA
50
H
N
H
O
H
N
H
64b
Scheme 15
The succinimide 64b was not identical with our sample. The 1H-NMR spectrum
exhibited a singlet from the succinimide 3- and 4-position at 4.89 ppm (64a, 4.56) as
29
well as considerable differences in the aromatic region. In a publication by Davis et
al.37 the imide 64a was claimed to be formed by reaction of the indole Grignard
reagent (65) with 3-bromo maleimide (66) (scheme 16).
H
N
O
O
H
N
O
O
+
N
MgI
Br
65
N
H
N
H
66
64a
Scheme 16
The spectral data they reported for 64a did not match ours. However, no
13C-
NMR spectrum was given and the singlet for the 3- and 4-H of the succinimide was
surprisingly low (3.52 ppm). We propose that the compound
Davis obtained
actually is 67a. We have prepared the N-benzyl derivative of this compound (67b)
from 68 and the methylene of this succinimide displays a singlet at 3.63 in the 1HNMR spectrum.
O
R
N
OEt OEt
O
O
O
a, R = H
N
H
N
H
b, R = Bn
67a-b
N
H
N
H
68
Thereby we have conclusively ascertained the stereochemistry of the imide 64a
and from that deduced that the pure dimer obtained from dioxane crystallization
of 58 is the meso-form (58b).
30
Ph
MeO OMe
O
O
H
H
N
H
N
H
N
O
O
H
H
H
N
H
N
H
58b
O
O
O
H
N
H
N
H
60b
59
Heating the pure diastereomer 58b or the anhydride 59 with benzylamine gave
the same diastereomerically pure succinimide 60b, indicating that the anhydride
formed has meso-structure.
H
N
O
H
O
H
N
O
O
H
N
O
O
H
N
H
N
H
64a
N
H
N
H
50
N
H
N
H
13
The imide 64a could be dehydrogenated by DDQ to arcyriarubin A (50), but we
could not obtain arcyriaflavin A (13) with the same methodology which gave the
indolocarbazole 63.
Acid induced cyclization
As the dimer 58 has two unsubstituted 2-positions it should be able to undergo
intramolecular acid promoted ring closure. Indeed, treatment with TFA of the
diastereomerically pure 58b, yields the tetrahydro-indolocarbazole (69). Gentle
heating of the TFA-solution containing 69, furthermore gave the known38 diester
70, which might be attributed to the oxidizing ability of TFA.39
31
MeO OMe
MeO OMe
O
H
O
O
H
O
r.t.
O
O
²
TFA
N
H
N
H
MeO OMe
N
H
N
H
58b
TFA
69
N
H
N
H
70
The TFA-treatment gave at room temperature a single product and analysis of
the NMR-spectrum, including NOE, indicates the structure 69b. In particular the
large coupling constant between H2 and H3, and the absence of NOE enhancement
between these hydrogens, suggest a trans-configuration. The NOE enhancement
between H3 and H4 strongly implies that the cis-configuration is not lost during the
cyclization. So does the fact that the diastereomeric mixture of 58 gave three
different cyclized products when treated with TFA.
MeO OMe
H
11%
O
4% H4
H3
O
4%H
H2
N
H
H1
14% N
H
J12= 7.8 Hz
J23=11.5 Hz
J34= 5.3 Hz
69b
The imide 64b also gave a tetrahydro indolocarbazole (71b), as a single
diastereomer, when treated with TFA. Arcyriaflavin A (13) was obtained by
refluxing the TFA-solution of 71b for 8 hours (see scheme 17).
32
H
N
O
O
H
H
N
O
O
H
N
O
O
H
TFA, rt
²
N
H
N
H
N
H
N
H
64b
N
H
N
H
71b
13
Scheme 17
Van Vranken40 utilized the difference in reactivity of the indoline linked to the
indole in the syntheses of the unsymmetrical indolo[2,3-a]carbazole tjipanazole I
(72) (see scheme 18).
H
N
H
N
H
rt (97%)
N
H
NBS
DMF (73%)
N
H
N
H
N
H
Br 1. DDQ, dioxane
(73%)
3 eq. D-Xylose
MeOH, rx
(82%)
Br
H
TFA
N
H
2. CuCl, DMF
(83%)
N
O
Cl
N
H
N
O
OH
HO
OH
OH
HO
OH
72
Scheme 18
33
Indolo[3,2-a]pyrrolo[3,4-c]carbazoles
Introduction
For the arcyriaflavin A (13) several syntheses have been developed27 but
surprisingly little has been done to synthesize isomeric structures. Bergman and
Desarbre have prepared indolo[2,3-c]carbazoles (73) from 3,3’-biindolyl41 and the
alkaloid arcyriacyanin A (74) has been synthesized by Steglich et al.42
O
H
N
HN
O
O
H
N
O
H
N
O
O
NH
NH
N
H
73
NH
N
H
74
15a
We have prepared 15a and a few derivatives, in a one step reaction starting from
indole and various maleimides.
Reactions of indole with maleimides
Although a few scattered examples of acid induced additions of indoles to
maleimides yielding (indol-3-yl)-3-succinimide 75 had been published from 1962
and onwards, it was not until 1997, when Macor43 published a study of this
Michael type addition, that the generality of this reaction was recognized. The
conditions used were refluxing glacial acetic acid, with maleimide in excess, which
afforded Michael adducts such as 75 in high yields.
34
However, when we increased the ratio of indole to maleimide another product
with the composition C27H17N3O2, not observed by Macor, eventually became
predominant.
Thus when two equivalents of indole 1 and one equivalent of e.g. Nbenzylmaleimide 76c, were reacted in glacial acetic acid at 100 C, a yellow
precipitate was collected after 72 h. Its structure 15c was assigned based on the
following data. The mass spectrum featured the molecular ion (m/z=415) as the
base peak. The 1H-NMR spectrum exhibited two different indolic NH signals and
the 13C-NMR data featured two carbonyl signals at 168.4 and 169.2. The previously
described Michael adduct 75c was present in the mother liquor (Scheme 19).
R
N
O
O
R
N
O
+
1
NH
HOAc
N
H
76a-d
O
N
H
R
N
O
+
N
H
15a-d
O
a, R = H
b, R = Me
c, R = Bn
d, R = Et
75a-d
Scheme 19
The structure of the indolo[3,2-a]pyrrolo[3,4-c]carbazoles 15a-d were finally
confirmed by two independent syntheses, both starting with 2,3’-biindolyl as
outlined in scheme 20.
35
R
N
O
R
N
O
O
O
N
H
NH
N
H
DMAD
CO2Me
MeO2C
N
H
NH2R
NH
N
H
Scheme 20
Further studies showed that the ratio between the indolocarbazole 15 and the
Michael adduct 75 was dependent on the temperature and could also be regulated
by the ratio between indole and maleimide (see Table 1).
Indole
Maleimide
Temperatur
Indolocarbazole
Michael adduct
(mmol)
76b (mmol)
e
15b (ratio)
75b(ratio)
1
3
90 C
1
9
1
3
117 C
1
43
2
1
90 C
1
2
2
1
117 C
1
13
3
1
100 C
1
1.6
3
1
95 C
1
0.9
Table 1
The ratios were taken from the NMR spectra of the crude reaction mixtures. The
first 4 entries illustrate the effect of the temperature on the outcome of the
36
reactions. However at 90 C the reaction became inconveniently slow, and an
optimum, both in yield and ratio of indolocarbazole, was found at 95 C.
Scheme 21 is a rationalisation of the observed chemistry, in which the two
products are formed in competing reactions from a common intermediate, 78,
which can either deprotonate to the Michael adduct or react with a second
molecule of indole to form the crucial 2,3’-bond in 79, which eventually proceeds to
the hypothetical intermediate 80. The Michael adduct 75b failed to react with
indole under acidic conditions (HOAc, 100 C) indicating that the reaction is under
kinetic control, i.e. the Michael adduct does not equilibrate and it is not an
intermediate. The dehydrogenated maleimide 81b also failed to give the
indolocarbazole (15).
R
N
O
R
N
O
N
H
O
O
R
N
O
75b
N
H
O
81b
Indole
Indole
H
N
H
R
N
O
O
78
NH
Indole
R
N
O
N
H
O
O
1. dehydrogenation
NH
R
N
H
2. cyclization
N
H
79
O
H
H
N
H
15
dehydrogenation
NH
H
80
Scheme 21
37
Attempts to facilitate the dehydrogenation steps by adding Pd/C to the reaction
mixture were unsuccessful; no indolocarbazole was formed.
Here it might be added that it is known that maleimide can yield adducts (with
e.g. 1,5-dihydroflavin) that subsequently disintegrate to succinimide and
dehydrogenated products. (see Scheme 22)
CH3
N
N
N
H
O
N
O
O
N
R
O
O
N
N
H
X
H+
O
CH3
N
N
X
O
N
N
O
+
R
N
O
-
X
O
O
N
R
CH3
N
N
O
Scheme 22
It is, however, clear that the dehydrogenation of the presumed intermediates 79
and 80 is not effected by the maleimide as neither succinimide, nor any other
reasonable hydrogenated species thereof were found in the reaction mixture and
the mass balance did not show any lack of maleimide. We propose that the
oxidation is effected by air.
Attempts to isolate any of the postulated hydrogenated intermediates failed but
in the much faster reaction, of 2,3’-biindolyl with N-ethyl maleimide, the
tetrahydro-indolocarbazole, 80d, as well as the Michael adduct 82d, could easily be
obtained (see Scheme 20 and Scheme 23).
38
O
N
H
N
H
Et
N
HOAc
100ÞC
5 min
O
Et
N
Et
N
O
O
O
O
NH
+
N
H
N
H
N
H
82d
80d
Et
N
O
O
NH
N
H
15d
Scheme 23
The fact that both 80d and 82d yielded the indolocarbazole 15d (100 C, HOAc)
is in harmony with our presumed reaction mechanism in scheme 21 and in these
reactions there is no other oxidizing agent present, except air.
Autoxidation of indolines
In a paper by Van Vranken et al.25, the photo oxidation of 42b was investigated.
The photo oxidation is sluggish under ambient light, affording 50% conversion
after 11 days. However, irradiation with a 150 W lamp effects complete conversion
after 20 h. Solvent is an important parameter in the reaction and chlorinated
solvents are most effective. Peroxides are observed in increasing amounts as the
reaction progressed and in the absence of air, no reaction was observed.
39
MeO2C
MeO2C
H
N
N
H
H
N
ambient light
N
H
CHCl3
CO2Me
CO2Me
42b
14b
Scheme 24
We suggest that the apparent ease of oxidation can be explained by the
stability of an intermediate radical as indicated in figure 2.
MeO2C
MeO2C
MeO2C
H
N
N
H
H
N
N
H
H
N
N
H
CO2Me
CO2Me
CO2Me
Figure 2
The free radicals proceed by direct combination with oxygen, thereby producing
peroxides which by themselves will promote the reaction. Autoxidations are
known to be initiated by ultraviolet light due to the absorbation of enough energy
to effect the necessary homolysis and chlorinated solvents are also effective in
generating radicals.44 This is in harmony with our observation that 69 is easily
oxidized in TFA (scheme 25), which is also an excellent solvent for the generation
of radical cations45,46 and is itself an effective one-electron oxidant39.
40
MeO2C
MeO2C
CO2Me
CO2Me
40-50ÞC
N
H
TFA
N
H
N
H
N
H
69
70
Scheme 25
We suggest that the same mechanism is in action in the formation of the
intermediate 82d as well as in the final oxidation of 80d to form the
indolo[3,2-a]carbazole 15d.
O
Et
N
O
O
Et
N
Et
N
O
O
O
H+
[O]
NH
[O]
15d
N
H
N
H
79d
N
H
N
H
N
H
82d
80d
41
Additional acid induced cyclizations
Dimerization of indole-3-maleimides
A long time ago, Bergman47 prepared the bisindole 68 by simply refluxing
(HOAc) the commercially available sodium salt of diethyl oxaloacetate with 2
equivalents of indole. When the diester 68 was refluxed in benzylamine for 12 h the
succinimide 67b was produced.
Ph
EtO2C
O
N
CO2Et
O
HN
HN
N
H
N
H
68
67b
Our intention now was to provoke acid induced cleavage yielding indole and
81c, which might either dimerize or possibly add indole again forming a desired
60, which in turn might cyclize under the acidic conditions to a tetrahydro
indolocarbazole.
Ph
N
O
Ph
O
N
O
N
H
N
H
N
H
81c
60
42
O
However, the outcome of the treatment of 67b with the strong acid TFA, was an
unexpected product with the composition C38H28N4O4, which is composed of two
different indole units and two different benzyl groups, and featured 2 quarternary
signals in the aliphatic region of the 13C-NMR spectrum, as well as 3 CH2-groups.
We propose the structure 16 and the rationalization of the events leading to this
structure is outlined in scheme 26.
Ph
O
N
Ph
Ph
N
O
O
H
O
+
N
O
H+
O
+
HN
N
H
N
H
67b
N
H
H
81c
N
H
O
O
N
H
N
H
Ph
N
H
N
83
Ph
O
O
NH N
H
16
Scheme 26
In harmony with this presumed reaction pathway is the fact that the indole
maleimide 81c, when treated in TFA at 25 C, yielded within 2 minutes a
quantitative yield of 16. Interestingly enough, compound 16 can be considered as
an analogue of the bisindole alkaloid yuehchukene 83.48
43
Acknowledgements
First of all I would like to express my gratitude to my supervisor for introducing
me to this field of research. Your friendly guidance and deep knowledge of
chemistry has been truly appreciated.
I also wish to thank the former head of the department of organic chemistry at
KTH, professor Torbjörn Norin.
Daniel, Tomasz, Thomas, JB and my Father are gratefully acknowledged for proof
reading and comments on the contents of this thesis.
A special thank to my co-authors, Benjamin Pelcman, Eric Desarbre and Tomasz
Janosik.
Mamma, you are an inspiration! Thanks for all the late Fridays at the lab.
A lot of people have made these last months a lot easier by taking so good care of
Emil. Uwe, Auli, Pappa, Fredrik, Maria, Johanna, Mats, Ylva. Tack!
Daniel, for all the support (=huggings) and for taking care of everything at home.
Thank you! I owe you one.
All friends and collegues at the department and at Novum, for making all of this
fun! Especially: Peo, the best AK-assistent, ever! Hans V, for all the advices I never
followed. You were right! Ingvor and Lena, for taking care of me, Solveig for the
Black coffe, Daniel and Anette for being such good hood-mates, Dr(?!) Jocke,
Thomas, Göran and Ulf B, for all the non-chemistry talk, Pelle for the Baden-baden,
Tomasz for being Tomasz, Kerstin N and Magnus C for keeping me informed and
Nathalie for her big smile!
Financial support from the foundation Bengt Lundqvist minne is gratefully
acknowledged.
44
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