Cascade syntheses routes to the centrocountins

Article abstract of DOI:10.1002/chem.201203714

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one-pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3-formylchromones as starting materials provided evidence that this one-pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis. Rolling transformations! Various cascade synthesis routes that employ easily accessible substrates and provide efficient access to diverse tetrahydroquinolizines are disclosed (see figure). Mechanistic insights into the long cascade process that gives centrocountins are also presented. Copyright

Full text of DOI:10.1002/chem.201203714

FULL PAPER
DOI: 10.1002/chem.201203714
Cascade Syntheses Routes to the Centrocountins
Vincent Eschenbrenner-Lux,[a, b] Heiko Dꢀckert,[a, b] Vivek Khedkar,[a] Hanna Bruss,[a, b]
Herbert Waldmann,*[a, b] and Kamal Kumar*[a, b]
Abstract: Cascade and domino reac-
tions that proceed through multiple
steps in one pot and include multiple
bond formations are promising meth-
ods for the rapid and efficient genera-
tion of complex molecular architec-
tures, including the scaffolds of classes
of complex natural product. We de-
scribe the development of various one-
pot cascade reaction sequences to yield
centrocountins, which are tetracyclic
indole derivatives with the basic scaf-
fold of numerous polycyclic alkaloids.
The mechanistic investigation of a se-
quence employing readily available
alkynes and 3-formylchromones as
starting materials provided evidence
that this one-pot synthesis proceeds
through at least twelve consecutive
transformations and includes at least
nine different chemical reactions,
making it the longest cascade reaction
sequence known to date. We describe
the scope and limitations of the cas-
cade synthesis approaches and the de-
velopment of an enantioselectively cat-
alyzed centrocountin synthesis.
Keywords: domino reactions · in-
doloquinolizines · Lewis bases · nat-
ural products · organocatalysis
Introduction
The development of new synthesis pathways, strategies and
methods is at the heart of organic synthesis and a key ena-
bling technology for chemical biology and medicinal chemis-
try research.[1] In these disciplines (neighbours to organic
chemistry), natural products, their derivatives, and analogues
have played prominent roles as tools for the elucidation of
biological processes and the development of new drugs.[2]
For example, complex indole alkaloids that are potent mod-
ulators of the tubulin cytoskeletons (Figure 1) were invalua-
ble in the study of mitosis and are important anticancer
drugs.[3] Furthermore, natural product inspired compounds
based on polycyclic indole alkaloids often display interesting
biological activities.[2d,4] Therefore, new synthesis methods
that give rapid and efficient access to these natural products
and compounds inspired by them are highly desired in or-
ganic synthesis as well as in chemical biology and medicinal
chemistry research.[5]
Figure 1. Structures of representative polycyclic indole alkaloids related
to mitosis and cancer.
Cascade and domino reactions that proceed through mul-
tiple steps in one pot and include multiple bond formations
are promising methods for the rapid and efficient generation
of complex molecular architectures.[6] If these cascades also
employ starting materials that embody natural product de-
rived structures, they may efficiently yield the scaffolds of
complex natural product classes. We have recently described
a one-pot cascade reaction sequence of unprecedented
length that combines readily available alkynes and formyl-
chromones as starting materials to yield tetracyclic indole
derivatives with the basic scaffold of numerous polycyclic al-
kaloids (Scheme 1).[2c] These compounds can induce delayed
mitosis, chromosomal congressional defects, formation of
multipolar spindles, and target the centrosome associated
proteins nucleophosmin (NPM) and Crm1. Because they
impair the mechanism that ensures the correct duplication
of one centrosome per cell into two daughter centrosomes
in the course of mitosis, they were termed centrocountins.
The unique biological activity of this compound class may
serve to inspire medicinal chemistry programs aimed at the
development of new anticancer drugs[3f,7] and the exception-
al length and efficiency of the cascade sequence culminating
[a] V. Eschenbrenner-Lux, Dr. H. Dꢀckert, Dr. V. Khedkar,
Dipl.-Chem. H. Bruss, Prof. Dr. H. Waldmann, Dr. K. Kumar
Max-Planck-Institut fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Str. 11
44227 Dortmund (Germany)
[b] V. Eschenbrenner-Lux, Dr. H. Dꢀckert, Dipl.-Chem. H. Bruss,
Prof. Dr. H. Waldmann, Dr. K. Kumar
Technische Universitꢁt Dortmund
Fakultꢁt Chemische Biologie
Otto-Hahn-Str. 6
44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
kamal.kumar@mpi-dortmund.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203714.
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Scheme 1. Proposed mechanism of the one-pot cascade sequence leading to the formation of centrocountins (1!8!11!17) and an alternative mecha-
nistic pathway (1!8!9!10!11!17).
in the formation of the centrocountins calls for a more de-
tailed investigation of the mechanism and intermediates of
the cascade sequence, which we report herein. We also ex-
plored the scope and limitations of the cascade synthesis,
the development of an enantioselectively catalyzed centro-
countin synthesis, and alternative methods to access this
unique natural product inspired compound class.
Results and Discussion
Mechanistic insights into the cascade synthesis of
tetrahydroindoloACTHNUTRGNE[NUG 2,3-a]quinolizines (centrocountins): The
one-pot cascade synthesis of the centrocountins reported
earlier commenced with the reaction of formylchromones 1
with alkynes 2 in the presence of triphenylphosphine as cat-
alyst.[8] It was envisioned that the phosphine would add to
the triple bond, thereby generating enolates 3 that would
undergo conjugate nucleophilic addition to the formylchro-
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Cascade Syntheses Routes to the Centrocountins
FULL PAPER
1
mones 1 to yield intermediates 4. These would then cyclize
by means of an addition–elimination mechanism to yield tri-
cyclic benzopyrones 5 with regeneration of the catalyst
(Scheme 1). Benzopyrones 5 embody multiple electrophilic
sites, inviting the attack of nucleophiles, such as tryptamine
derivatives 6, which would undergo conjugate addition to
ring C of the tricyclic benzopyrones, accompanied by ring
opening in which a phenol moiety serves as a leaving group.
The phenol 7 could add again to the generated a,b-unsatu-
rated carbonyl compounds, thereby initiating a pyran ring
opening to generate intermediates 8 with an enamine and
an a-keto ester in close proximity. Catalytic amounts of acid
would promote the condensation of the secondary amine
with the ketone, resulting in the formation of dihydropyri-
dines 11. Acid-promoted opening of the chromone ring,
with a phenol serving again as a good leaving group, and re-
addition of the phenolate to the intermediately-formed pyri-
dinium salts 12 would give rise to tricyclic dienes 13 and
would set the stage for a sigmatropic aza-Claisen rearrange-
ment that would yield iminoesters 14. The neighbouring
indole ring would then undergo
had similar H and 13C NMR spectra, which supported the
assignment of the structures (see below). Although the iso-
lation and characterization of these intermediates support
the proposed cascade reaction sequence, the unusual length
and efficiency of the sequence invites the possibility that al-
ternative pathways might also be possible. Therefore, a step-
wise investigation of the whole sequence was attempted.
The phosphine catalyzed [4+2] annulation of 3-formyl-
chromones 1 with acetylenecarboxylates 2 to yield benzopyr-
ones 5 was regarded as the starting sequence in the forma-
tion of indoloquinolizines 17. However, because benzopyr-
ones 5 embody electrophilic olefins, the addition of trypta-
mine may occur at either the tri- or the tetra-substituted
olefin. Because the addition of nucleophiles to tetra-substi-
tuted olefins is more difficult, we assume that tryptamine
undergoes an SN2’ addition as indicated by the arrow in
Scheme 2a, thereby leading to a chromone ring opening to
yield aminal 7. Aminal 7 may then form either the enamine
8 as shown in Scheme 1 or alternatively open up to form
aza-triene 9, which may undergo 6p-electrocyclization to
Pictet–Spengler cyclization with
the activated imine to generate
secondary amines 15. The final
steps of the sequence would
consist of conjugate aza-Mi-
chael addition of the secondary
amines to the doubly vinylo-
gous esters to yield addition
products 16 then a final acid-
mediated pyran ring opening
with phenol serving again as a
leaving group to culminate in
the formation of indoloquinoli-
zines 17.
Support for the proposed cas-
cade reaction sequence was ob-
tained by isolation and charac-
terization of the key intermedi-
ates. Thus, the intermediate tri-
cyclic benzopyrones
5
are
stable and can be stored under
nonacidic conditions.[9] The tri-
cyclic aminal 13a can be isolat-
ed and characterized by NMR
spectroscopy (see below). How-
ever, it is also sensitive to acidic
conditions and we could ob-
serve the formation of indolo-
quinolizine 17a during the re-
cording of NMR spectra of 13a
in CDCl3. On the contrary, 13b
(Scheme 1) is stable under both
acidic and basic conditions and
its structure was unambiguously
corroborated by X-ray analysis.
Scheme 2. Stepwise analysis and isolation of intermediates in the cascade reaction sequence. a) Isolation of di-
hydropyridine 10a as precursor to tricyclic aminal 13a; b) synthesis of the N-methyl analogue 13c; c) and
d) tricyclic intermediates 13b and 13d generated from 5b by the addition of tryptamine and methyl amine, re-
Compounds 13a and 13b also spectively.
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H. Waldmann, K. Kumar et al.
form the 2-hydroxy-dihydropyridine intermediate 10
(Schemes 1 and 2). Indeed, compound 10a could be isolated
in quantitative yield from a reaction of 5a with tryptamine
in dichloromethane by directly removing the solvent under
reduced pressure (see the Supporting Information for de-
tails). However, during purification over silica gel, aminal
10a was quantitatively converted into the tricyclic aminal
13a (Scheme 2a). By analogy, N-methyl analogue 13c was
obtained from 10c when methylamine was employed in the
cascade sequence (Scheme 2b).
Notably, the tricyclic benzopyrone 5b that was generated
from the reaction of 3-formylchromone and methyl propio-
late yielded the tricyclic aminal 13b directly on treatment
with tryptamine. All attempts to isolate intermediate 10b
failed. Intermediate 10b might be formed by the addition of
tryptamine to any of the two electrophilic olefinic sites (in-
dicated by arrows). Probably, in the absence of an ester
moiety the aminal is not stable enough and quickly dehy-
drates to form an azatriene that yields 13b (Scheme 2c). By
analogy, the treatment of 5b with methylamine instead of
tryptamine resulted in the formation of the N-methyl ana-
logue 13d in excellent yield (Scheme 2d).
As described above, tricyclic aminals 13 are formed only
under mild acidic conditions, for example, in the presence of
silica gel. If aminals 10 are
hydes 19 (Scheme 3b).[9] This rearrangement, by analogy,
proceeds through pyrylium cations 20, similar to the trans-
formation of 11 into 12. In addition, we observed that the
N-tosyl analogue 22 did not rearrange because the push–
pull effect is lacking in this acid-stable dihydropyridine
(Scheme 3c).[8a]
Unlike 13b, compound 13a did not give crystals of suffi-
cient quality for crystallographic analysis. However, the
1H NMR spectra of both 13a and 13b in CDCl3 at room
temperature showed similar broadened peaks. Moreover,
13a displayed slow conversion to indoloquinolizine 17a. For
better refinement of the NMR spectra, standard NMR sol-
vents and temperature were varied. The best results were
obtained in [D6]DMSO at 608C. However, even under these
conditions some broadened peaks and fewer signals than ex-
1
pected were detected in the H NMR spectrum (determined
by HRMS; in 13C NMR: expected: 26 signals, detected: 21
signals). Thus, a conclusive structural assignment to 13a was
not possible by means of NMR spectroscopy. However,
comparison of the NMR spectra of 13a and 13b clearly
proved their structural resemblance as depicted in Figure 2.
As shown in Scheme 1, the formation of centrocountins
involves tricyclic aminals 13. An alternative and direct path-
way could proceed by addition of the indole ring to the imi-
indeed intermediates to 13, two
different pathways are possible
(Scheme 3a). On the one hand,
tricyclic aminals 13 are directly
formed by addition of the
phenol to the a,b-unsaturated
vinylogous amide (dotted arrow
in Scheme 3a). However, isola-
tion of indoloquinolizine 18 as
a side product suggested the
formation of pyridinium salts
12 as intermediates. These in-
ternal salts must be formed
from the dihydropyridine 11
that was formed by an addi-
tion–elimination sequence from
10 (Scheme 3a).
Formation of 18 supports the
proposal that 10 and 11 are in-
termediates in the cascade
process. However, a direct one-
step conversion of 10 into 13
cannot be ruled out completely.
Intermediates 11 embody
a
push–pull system that favors
the formation of aromatic pyri-
dinium salts 12. The tricyclic
benzopyrones 5 are structurally
related to compound 11 and we
Scheme 3. Insights into the formation of key intermediates and side products in the cascade reaction sequence.
a) Proposed reaction sequence from aminal 10 to tricyclic aminal 13 via pyridinium salt 12 and isolation of a
indoloquinolizine side product; b) ring opening of tricyclic benzopyrones 5; c) attempted ring opening of
have previously reported
a
facile rearrangement of 5 into
the ring-open ketoesters/alde- N-tosyl analogues of 5 under acidic conditions.
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Cascade Syntheses Routes to the Centrocountins
FULL PAPER
lead to the fast formation of 17a from 13a involved a direct
nucleophilic addition of indole moiety on to dihydropyridine
ring in 13a, the same should have happened in 13b (R1 =
H). However, 13b is stable under acidic and basic condi-
tions. These observations clearly stand against the possible
direct conversion of either pyridinium salts 12 or tricyclic
aminals 13 to the indoloquinoizines 17.
To further validate this notion, we synthesized pyridinium
salt 26 by treating trisubstituted pyridine 24 with 3-(2-bro-
moethyl)indole (25) in the presence of triethylamine. Under
basic reaction conditions, centrocountin 17a was not
formed. Unexpectedly, the treatment of 26 with trifluoroace-
tic acid (TFA) or camphor sulphonic acid (CSA) led to de-
composition and the formation of centrocountin 17a was
not observed by means of LC-MS analysis of the crude reac-
tion mixture (Scheme 4b). By analogy, pyridinium salt 28
decomposed under acidic conditions. These results thus
strongly argue against the direct formation of centrocountins
from pyridinium salts 12.
In the proposed cascade sequence, imino esters 14 are
formed from tricyclic aminals embodying two ester groups
(Scheme 1). We assume that the aza-Claisen rearrangement
is facilitated by an energetically low-lying LUMO of 13a. In
13b, the LUMO will be higher in energy, resulting in a less
facile rearrangement. The imino esters are potent electro-
philes and substrates for the Pictet–Spengler reaction[11] and
yield the secondary amine 15 in a fast cyclization reaction.
This intermediate contains a reactive secondary amine in
proximity to a highly conjugated chromone moiety; thus, a
conjugated addition leads to hexacyclic intermediates 16
that undergo a retro-Michael-reaction and concomitant
chromone ring opening, thereby yielding centrocountins 17
(Scheme 1).
The proposed transformations from 13 to 17 proceed in
quick succession and all attempts to trap intermediates 14,
15, or 16 failed. Thus, the attempted reduction of intermedi-
ate 13a with sodium cyanoborohydride led to dihydropyri-
dines 29 (Scheme 4c). This formation can be explained by
either a direct 1,4-addition of hydride or the reduction of
iminoester 14a to a secondary amine that adds to the chro-
mone ring, which opens up and is followed by isomerization.
In light of the observations described above, we propose
that the cascade reaction sequence leading to
1
Figure 2. Comparison of the H NMR spectra of tricyclic aminals 13a and
13b. Aromatic region of the gHSQC spectra of a) compound 13b,
b) overlay, and c) compound 13a. The depicted sections of the spectra
show all detected gHSQC signals except the CH2 signals and the ethyl
ester or methyl ester signal, respectively.
tetrahydroindoloACTHNUTRGNE[NUG 2,3-a]quinolzines (Scheme 1) is initiated by
the phosphine-catalyzed reaction of 3-formylchromones 1
and alkynes 2 to yield tricyclic benzopyrones 5. For instance,
the complete formation of 5a can be achieved at 808C with
DMAD (dimethyl acetylenedicarboxylate, 1.3 equiv) and tri-
phenylphosphine (0.6 equiv) in times as short as 5 min. The
subsequent addition of tryptamine and then CSA to the re-
action mixture led to the formation of 17a in 58% yield.
The addition of tryptamine to 5a yields intermediate 10a.
Only at this stage does the cascade sequence need acidic
conditions for the next steps towards 17a. With these obser-
vations in mind, the cascade synthesis was optimized. The
best results were obtained if a solution of acetylenedicarbox-
ylate (1.3 equiv) and triphenylphosphine (0.6 equiv) in trypt-
noester moiety embedded in the pyridinium salts 12 (Sche-
me 4a). However, inspection of the literature suggests that
indole rings add to pyridinium cations only under basic reac-
tion conditions and not in the presence of acid, as is the
case in the cascade synthesis.[10] However, stirring an equi-
molar solution of 13a (R=Me, R1 =CO2Me) and triethyla-
mine in toluene resulted in no reaction, thus ruling out an-
other possible addition of the indole moiety to the dihydro-
pyridine ring in the intermediate 13 leading to indoloquino-
lizine 17. Furthermore, had the mild acidic conditions that
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H. Waldmann, K. Kumar et al.
aryl–alkylamines were em-
ployed. Tricyclic benzopyrone
5a reacted with electron-rich
dopamine 30a to provide the
expected product, which was
O-methylated to yield stable
tetrahydroisoquinoline 31a in
35% overall yield (Scheme 5).
A cascade reaction with 2-(3,4-
dimethoxyphenyl)ethylamine
30b led to the desired product
31b in 61% yield. The less elec-
tron-rich
2-phenylethylamine
did not yield the expected prod-
uct. However, electron-rich his-
tamine and histidine derivatives
32 yielded the desired annula-
tion products 33, albeit in low
yields. The N-methylated hista-
mine and histidine derivatives
also reacted with the tricyclic
benzopyrone to get the expect-
ed products in higher yields
than their NH counterparts
(Scheme 5). These results dem-
onstrate that the cascade se-
quence has good scope and is
amenable to the assembly of a
collection of compounds.
Scheme 4. Mechanistic insights into the cascade reaction sequence. a) Proposed reaction sequence from pyridi-
nium salts 12 to inodoloquinolizines 17; b) synthesis of pyridinium salts and their attempted conversion to cen-
trocountins; c) partial reduction of intermediate 13a.
Alternative cascade routes to
indoloquinolizines: As descri-
bed above, the tricyclic benzo-
amine at 808C were added slowly (2–5 min) to a heated
mixture of 3-formylchromone, followed by the addition of
CSA. The resulting mixture was stirred at 808C for 5–
30 min to yield indoloquinolizines 17. Differently substituted
3-formylchromones, acetylene dicarboxylates, and trypta-
mines were employed to obtain
pyrones 5 rearrange under mildly acidic conditions to yield
the ketoesters/aldehydes 19 in high yields (Scheme 3b). In-
terestingly, we observed that the addition of tryptamine to
ketoester 19a led to the same tricyclic aminal intermediate
13a (Scheme 6a). This set the stage for a different cascade
a small collection of indoloqui-
nolizines (Table 1, Method I).
Unexpectedly, halogen substi-
tuted 3-formylchromones pro-
vided the corresponding indolo-
quinolizines in low yields
(Table 1, 17o, p, z). Closer in-
spection of these cases revealed
that the low yield was due to
inefficient [4+2] annulation
leading to benzopyrones 5,
whereas the subsequent steps of
the sequence proceeded almost
quantitatively.
To further extend the scope
of the cascade reaction se-
quence to various ring-fused
Scheme 5. Cascade synthesis of diverse ring-fused quinolizines. Reaction conditions: a) For 33a and 31: DMF,
tetrahydroquinolizines, different Et3N, then TFA; for 33b–e: toluene, 808C, 2 h, TFA; b) K2CO3, Me2S, MW, 1208C, 2 h.
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Cascade Syntheses Routes to the Centrocountins
Table 1. Cascade synthesis of indoloquinolizines (Method I).
FULL PAPER
Table 2. Cascade synthesis of indoloquinolizines (Method II).
Product R1
R2 R3
R4 R5 R6
R7
R8 Yield[a] [%]
Product
R1
R2
R4
R5
R7
Yield[a] [%]
17a
17b
17c
17d
17e
17 f
17g
17h
17i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Br
Me
H
OMe
OH
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
58
56
66
88
65
39
76
17a
17b
17c
17d
17e
17 f
17g
17h
17i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
Me
Me
Me
Et
H
H
H
H
H
H
OMe
Br
Me
H
85
71
72
68
75
56
65
30
63
58
62
64
Me
iPr
H
Me
Cl
H
H
H
H
H
Me
iPr
H
Me
Cl
H
H
H
H
H
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
73
74[b]
59
17j
OBn Me Me
17j
17k
17L
17k
17L
17m
17n
17o
17p
17q
17r
H
H
H
H
H
H
H
H
H
H
Et
76
OMe
OH
H
Me
Me
Me
67[b]
62
H
Me
Br
Br
Cl
Br
[a] Yields of isolated products.
39
20
20
60
Cl Me
Br Me
Cl Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me CO2Me
tBu
Me
Me
Et
Et
Et
Et
Et
yields with respect to the use of 3-formylchromones 1
(Method I) and was superior to Method I only in selected
cases (see Table 2).
H
H
H
H
Br
Cl Cl
Me
iPr
Cl Me
H
H
H
H
H
69[b,c]
42
17s
17t
H
H
H
H
H
H
H
H
H
H
H
H
26
17u
17v
17w
17x
17y
17z
17aa
17ab
17ac
17ad
H
H
H
OMe
OMe
H
Me 78[b]
For the establishment of a further centrocountin synthesis,
we envisioned that dihydropyridine intermediate 11 could
be formed by an aza-Diels–Alder cycloaddition between
choromonylimines 36 and DMAD (Scheme 7a). In addition
to DMAD, dimethyl 2-hydroxyfumarate 37 might be em-
ployed. We expected this cascade sequence (Method III) to
provide higher yields of indoloquinolizines synthesized from
halogen substituted 3-formylchromones. Notably, in these
cases the limited yields obtained with Method I originated
from the low-yielding [4+2] annulation between 3-formyl-
chromones and acetylenedicarboxylates (Scheme 1). In this
alternative cascade, the phosphine-catalyzed annulation step
might be avoided. To explore this possibility, imine 36 was
generated from 3-formylchromone 1a and tryptamine in tol-
uene and subjected to reaction with the DMAD-equivalent
37 in the presence of CSA. The desired indoloquinolizine
was indeed formed in an overall yield of 10% [Scheme 7b,
Eq. (1)].
Given this low yield, we explored the aza-Diels–Alder re-
action of azadiene 36 and DMAD. In toluene at room tem-
perature, the reaction proceeded only slowly and yielded
only 21% of 17a. Different conditions for the aza-Diels–
Alder reaction were screened by increasing the reaction
time and temperature and by testing different solvents and
Lewis acids. The best results were observed by using
1.2 equivalents of ZnCl2 in DMSO at 808C for 24 h to pro-
duce 17a in 79% yield. Gratifyingly, differently substituted
3-formylchromones, in particular those with halogen sub-
stituents, reacted smoothly with acetylenedicarboxylates and
provided the indoloquinolizines in higher yields than by
means of the cascade reaction using either Method I or II
(Table 3).
H
H
H
H
H
H
H
H
H
52
20
45
65
40
65
63
54
52
H
H
Cl
Cl
Br
H
H
H
Et
Et
Et
Me
H
OMe
OMe
H
-Benzo-
[a] Yields of isolated products; [b] a hydrochloride salt of tryptamine was
used, reaction started from 5; [c] the product was obtained as a mixture
of isomers.
synthesis of centrocountins employing ketoesters 19 (Sche-
me 6b). Thus, treatment of ketoesters 19 with differently
substituted tryptamines under anhydrous conditions, fol-
lowed by the addition of TFA (10%) cleanly provided the
desired indoloquinolizines 17. Overall, the cascade synthesis
was highly efficient and high yielding (Table 2, Method II)
and in many cases the indoloquinolizines 17 could be direct-
ly precipitated from the crude reaction mixture by the addi-
tion of methanol. Otherwise, flash column chromatography
provided clean products.
We assume that the cascade reaction sequence in this case
begins by 1,2-addition of the amine to ketoester 19 to form
aminal 34. This equilibrates to zwitterion 35, finally forming
tricyclic aminals 13, which follow the cascade sequence
under acidic conditions leading to indoloquinolizines 17. Al-
though ketoester 19a provided the centrocountins 17a, on
reaction with tryptamine, aldehyde 19b formed the stable
tricyclic aminal 13b and did not yield any indoloquinolizine.
This cascade synthesis (Method II) proceeded in varying
Chem. Eur. J. 2013, 00, 0 – 0
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H. Waldmann, K. Kumar et al.
catalysts to direct the stereo-
chemical course of the Pictet–
Spengler reaction.[12] Among
the various chiral phosphoric
acids tested, 38a [3,3’-bis(2,4,6-
triisopropylphenyl)-1,1’-binaph-
AHCTUNGTRENGNtUN hyl-2,2’-diylhydrogenphosphate
(TRIP)][13] was found to be the
best catalyst for the Pictet–
Spengler
reaction
between
tryptamine derivatives and al-
dehydes, providing the cyclized
products with up to 96% enan-
tiomeric excess (ee). Because
the key step in the cascade syn-
thesis of the indoloquinolizines
that forms the stereocenter is
also a Pictet–Spengler reaction,
we investigated the use of these
catalysts for the asymmetric
synthesis of centrocountin 17a
(Scheme 8).
In order to avoid the use of
phosphines, we attempted the
asymmetric cascade synthesis of
17a using tricyclic benzopyrone
5a. However, none of the three
catalysts 38a–c catalyzed the
Scheme 6. Alternative cascade synthesis of centrocountins by employing ketoesters 19. a) Treatment of tricy-
clic benzopyrones 5 or the rearranged products 19 with tryptamine yields the same cascade intermediates 13;
b) cascade synthesis of indoloquinolizines from ketoesters 19 (Method II) and the proposed mechanism.
Enantioselectively catalyzed synthesis of centrocountin 17a:
Biological evaluation of the enantiomers of centrocountin
17a revealed that the R enantiomer is significantly more
active than the S enantiomer.[2c] Therefore, we explored an
enantioselective cascade synthesis of centrocountin 17a. List
et al. recently employed chiral phosphoric acids as Brønsted
transformation of 5a into 17a. As an alternative, an asym-
metric version of Method II using 19a was investigated.
However, catalysts 38 yielded 17a only at higher tempera-
tures in very low yields. Unexpectedly, TRIP was not ef-
fective in this case and catalyst 38c induced 46% ee and
approximately 10% yield in the formation of 17a
Scheme 7. Alternative cascade synthesis of centrocountins by means of an imino Diels–Alder reaction (Method III). a) Retrosynthetic analysis; b) Aza-
Diels–Alder reaction of 36.
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Cascade Syntheses Routes to the Centrocountins
FULL PAPER
Table 3. Aza-Diels–Alder synthesis of indoloquinolizines (Method III).
complete the reaction. In the presence of TRIP (38a),
only 26% of 17a was isolated with 48% ee. With the use
of 38b, both the yield and ee of 17a were higher (Sche-
me 8b) with (R)-17a obtained as major enantiomer. The
best results were obtained with catalyst 38c, yielding 17a
quantitatively in 63% ee and providing (S)-17a as the
major enantiomer. In light of the observation, made by
List et al., that lowering the reaction temperature (RT to
ꢀ308C) is the key to achieving high enantiomeric excess
in such reactions, the ee obtained in the reaction per-
formed at a higher temperature (408C, 48 h) is remarka-
ble.
Product
R1
R2
R4
R5
R7
Yield[a] [%]
17a
17 f
17g
17m
17n
17o
17p
17t
17v
17w
17aa
17ab
17ac
17ae
17af
17ag
17ah
17ai
17aj
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
Cl
Br
H
H
Cl
H
H
H
Br
H
D
Br
D
Br
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
H
H
OMe
OMe
H
H
H
H
H
79
91
64
62
77
53
83
29
64
40
93
87
69
82
74
91
51
31
42
Br
Br
Cl
Br
H
Br
Cl
Cl
Cl
Br
Br
Cl
Cl
Br
Cl
Br
Conclusions
We have developed an efficient cascade synthesis of
highly substituted tetrahydroindoloACTHNUTRGNEU[GN 2,3-a]quinolizines. The
H
H
sequence exclusively employs readily accessible substrates,
exploits two different modes of catalysis, and involves at
least twelve distinct reaction steps, including nine distinct
reaction types, to build up a collection of natural product
inspired indoloquinolizines. The cascade synthesis also
provides new tetrahydroquinolizines fused to, for example,
an imidazole ring. The proposed mechanism of this reac-
tion sequence is supported by isolation and characteriza-
tion of the key intermediates and different control experi-
ments. We also report two other cascade synthesis routes
to centrocountins and a short
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
Et
Me
Me
Me
Et
Et
[a] Yields of isolated products.
enantioselective cascade syn-
thesis of centrocountin 17a by
employing chiral phosphoric
acids as Brønsted acid catalysts.
Our results highlight that cas-
cade and domino reactions
allow us to efficiently synthe-
size complex natural product
inspired molecular architectures
that approach the structural
complexity of the guiding natu-
ral products.
Experimental Section
General: Unless otherwise noted,
chemicals were obtained from Aldrich,
Acros, TCI, or Alfa and were used
without further purification. Reactions
Scheme 8. Enantioselective synthesis of centrocountin 17a catalyzed by different chiral phosphoric acids.
a) Synthesis of centrocountin 17a from 5a and 19a; b) synthesis of centrocountin 17a from 13a.
were carried out in standard glassware
or a Radleys Carousel 12 parallel reac-
(Scheme 8a). In the course of these experiments we found
tor using anhydrous solvents. 1H and
13C NMR spectroscopic data were recorded on a Varian Mercury VX 400
or Varian 500–Inova 500 spectrometer at RT unless stated otherwise.
NMR spectra were calibrated to the solvent signals of CDCl3 or DMSO.
Enantiomeric resolution was performed using a Dionex UltiMate 2000
HPLC with a 10 mm Daicel IC column. HRMS-(FAB)-MS measure-
ments were taken on a Finnigan MAT MS 70. HRMS-ESI measurements
were taken on an Accela HPLC-System (HPLC column 50/1 Hypersil
that tryptamine negatively modulated the catalysis by phos-
phoric acid 38. Therefore, a modified cascade synthesis was
explored in which tricyclic aminal 13a was employed as the
key intermediate. Of the different solvents tested (see the
Supporting Information), toluene was found to be most ad-
vantageous, although two days at 408C were required to
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H. Waldmann, K. Kumar et al.
GOLD 1.9 mm) with an LTQ Orbitrap mass spectrometer from Thermo
Scientific. (ESI)-MS data were measured by using an Agilent 1100 series
binary pump together with a reversed-phase HPLC column (Macherey–
Nagel). Optical rotation was measured using a Schmidt & Hꢁnsch Polar-
tronic polarimeter in cuvettes with a path length of 10 cm. CD-spectra
were recorded on a J-815 CD-Spectrometer from Jasco. TLC was per-
formed on Merck silica gel 60 F254 aluminum sheets. For flash chroma-
tography, silica gel from Baker (40–70 mm) was used. MPLC was per-
formed using an Isco sq16 with prepacked cartridges (30 mm, spherical
silica gel) from Interchim. Melting points were recorded on a Bꢀchi
Melting point B-540 apparatus and are uncorrected.
1.6 Hz, 1H), 7.42–7.37 (m, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.16 (ddd, J=
8.2, 7.1, 1.1 Hz, 1H), 7.05 (dd, J=11.0, 3.9 Hz, 1H), 6.97 (dd, J=8.3,
1.0 Hz, 1H), 6.89–6.81 (m, 1H), 3.84 (s, 3H), 3.82 (s, 4H), 3.73 (dd, J=
13.2, 5.0 Hz, 2H), 3.09 (ddd, J=15.6, 12.0, 5.7 Hz, 1H), 2.98 ppm (dd, J=
15.5, 3.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) d=192.0, 170.0, 168.7,
161.3, 153.5, 136.3, 136.1, 134.5, 131.8, 130.4, 126.1, 123.0, 119.9, 119.9,
118.6, 118.4, 118.3, 113.4, 112.0, 108.2, 106.0, 68.0, 53.9, 52.6, 52.5,
23.2 ppm; HRMS (ESI): m/z calcd for C26H23O6N2: 459.15506 [M+H]+;
found: 459.15454.
17b: Compound 17b was synthesized according to Method Ia. Yellow
solid; m.p.: 1978C; TLC (cyclohexane/ethyl acetate, 3:2 v/v): RF =0.36;
1H NMR (400 MHz, CDCl3) d=10.99 (s, 1H), 9.03 (s, 1H), 7.93 (d, J=
1.4 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.35 (d, J=
8.1 Hz, 1H), 7.23–7.17 (m, 3H), 7.10 (dd, J=11.0, 3.9 Hz, 1H), 6.94–6.85
(m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.79–3.68 (m, 2H), 3.15 (ddd, J=15.7,
11.9, 9.9 Hz, 1H), 2.93 (dd, J=15.5, 3.6 Hz, 1H), 2.28 ppm (s, 3H);
13C NMR (101 MHz, CDCl3) d=192.1, 170.2, 168.9, 159.1, 153.5, 136.5,
136.2, 135.5, 132.0, 130.4, 127.8, 126.1, 123.1, 120.0, 119.7, 118.4, 118.2,
113.4, 112.0, 108.2, 106.1, 68.1, 54.0, 52.7, 52.5, 23.4, 20.8 ppm; HRMS
(ESI): m/z calcd for C27H25O6N2: 473.17071 [M+H]+; found: 473.17010.
General procedure for the cascade synthesis of indoloquinolizines (17)
using arylethylamines (Method Ia): A 3-formylchromone-derivative
1
(1.0 equiv) was dissolved in toluene (10 mLmmolꢀ1) by heating to 808C.
Acetylenedicarboxylate (1.3 equiv) was added, followed by triphenyl-
phosphine (0.6 equiv). Monitoring by TLC (dichloromethane/methanol
100:1) showed completion typically after 5–10 min. The tryptamine deriv-
ative (1.1 equiv) was added. After the tryptamine had dissolved, cam-
phorsulfonic acid (1.5 equiv) was added. Monitoring by TLC (cyclohex-
ane/ethyl acetate 60:40) showed that the reaction was complete after 5–
30 min. The reaction mixture was directly subjected to column chroma-
tography (30 g silica gel, cyclohexane/ethyl acetate 80:20). Removal of
the solvent yielded the product as a yellow solid. In case the purity was
not sufficient, the product was precipitated from methanol.
17c: Compound 17c was synthesized according to Method Ia. Yellow
solid; TLC (cyclohexane/ethyl acetate, 3:2 v/v): RF =0.41; 1H NMR
(400 MHz, CDCl3) d=10.99 (s, 1H), 9.04 (s, 1H), 7.94 (d, J=1.3 Hz,
1H), 7.66 (d, J=1.2 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz,
1H), 7.27–7.21 (m, 2H), 7.20–7.15 (m, 1H), 7.09 (dd, J=11.1, 3.8 Hz,
1H), 6.90 (d, J=9.1 Hz, 1H), 3.82 (s, 3H), 3.85–3.76 (m, 1H), 3.79 (s,
3H), 3.70 (dd, J=13.1, 5.3 Hz, 1H), 3.15 (ddd, J=17.5, 12.0, 5.6 Hz, 1H),
2.93 (dd, J=15.5, 3.8 Hz, 1H), 2.89–2.77 (m, 1H), 1.20 ppm (d, J=
6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) d=192.1, 170.1, 168.8, 159.2,
153.7, 138.9, 136.9, 136.1, 133.1, 132.0, 127.9, 126.1, 123.1, 120.0, 119.6,
118.4, 118.1, 112.9, 112.0, 108.2, 105.9, 68.1, 54.0, 52.6, 33.4, 27.1, 24.3,
24.3, 23.4 ppm; HRMS (ESI): m/z calcd for C29H29O6N2: 501.20201 [M+
H]+; found: 501.20134.
General procedure for the cascade synthesis of indoloquinolizines (17)
using arylethylamine hydrochlorides (Method Ib): To a solution of tricy-
clic benzopyrone 5 (1.0 equiv) and substituted tryptamine hydrochloride
(1.05 equiv) in DMF (5 mLmmolꢀ1
) was added triethylamine 6
(1.1 equiv). After 30 min, TLC (cyclohexane/ethyl acetate 3:2) showed
that the starting material had been consumed. TFA (4 equiv) was added
and after 30 min the formed intermediate could no longer be detected in
TLC (cyclohexane/ethyl acetate 3:2). The solution was then diluted with
ethyl acetate (30 mLmmolꢀ1) and washed with water (100 mLmmolꢀ1),
NaHCO3 (satd. 50 mLmmolꢀ1), and brine (50 mLmmolꢀ1), dried over
MgSO4, and the solvent was removed under reduced pressure. The crude
product was co-evaporated with methylene chloride and dissolved in
methanol (5 mLmmolꢀ1). After complete precipitation of the product,
the solvent was decanted and the product was washed with a small
amount of methanol and dried in vacuo.
17d: Compound 17d was synthesized according to Method Ia. Yellow
solid; m.p.: 2098C; TLC (cyclohexane/ethyl acetate, 3:2 v/v): RF =0.44;
1H NMR (400 MHz, CDCl3) d=11.26 (s, 1H), 9.11 (s, 1H), 7.93 (d, J=
1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.50–7.37 (m, 3H), 7.33 (dt, J=8.2,
0.9 Hz, 1H), 7.18 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 7.09 (ddd, J=8.0, 7.1,
1.0 Hz, 1H), 7.00 (dd, J=8.3, 0.9 Hz, 1H), 6.85 (ddd, J=7.8, 7.3, 1.2 Hz,
1H), 4.38–4.19 (m, 4H), 3.93–3.78 (m, 1H), 3.71 (dd, J=13.2, 4.9 Hz,
1H), 3.15 (ddd, J=15.5, 12.0, 5.6 Hz, 1H), 2.93 (dd, J=15.5, 3.5 Hz, 1H),
1.34 (t, J=7.1 Hz, 3H), 1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) d=192.07, 169.28, 168.39, 161.36, 153.62, 136.14,
135.83, 134.56, 131.98, 130.42, 126.11, 122.97, 120.03, 119.87, 118.61,
118.43, 118.33, 114.19, 111.99, 108.19, 106.12, 68.22, 63.24, 61.77, 52.41,
23.33, 14.48, 14.28 ppm; HRMS (ESI): m/z calcd for C28H27O6N2:
487.18636 [M+H]+; found: 487.18574.
Method II: Tryptamine (1 equiv) was added to a solution of chromone-
ketoester (1 equiv) in a mixture of dichloromethane, 19, and trimethyl or-
thoformate (5 mL; 2:1). The reaction mixture was stirred at room tem-
perature for 2–3 h under argon. The reaction was monitored by TLC (cy-
clohexane/ethyl acetate 7:3). After evaporation of the solvent, the crude
product was dried in vacuo and was dissolved in a mixture of methylene
chloride and trifluoroacetic acid (100:1). The reaction mixture was stirred
at room temperature for 4–8 h under argon. The reaction was monitored
by TLC (cyclohexane/ethyl acetate 7:3). After evaporation of the solvent,
the crude product was purified by column chromatography (silica gel, cy-
clohexane/ethyl acetate).
17e: Compound 17e was synthesized according to Method Ia. Yellow
solid; m.p.: 2088C; TLC (cyclohexane/ethyl acetate, 3:2 v/v): RF =0.45;
1H NMR (400 MHz, CDCl3) d=11.02 (s, 1H), 9.11 (s, 1H), 7.93 (d, J=
1.5 Hz, 1H), 7.61 (d, J=1.5 Hz 1H), 7.47 (dd, J=7.9, 0.5 Hz, 1H), 7.38–
7.29 (m, 1H), 7.22 (s, 1H), 7.21–7.15 (m, 2H), 7.09 (ddd, J=7.9, 7.1,
1.0 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.38–4.21 (m, 4H), 3.92–3.81 (m,
1H), 3.72 (dd, J=13.2, 5.3 Hz, 1H), 3.15 (ddd, J=15.5, 12.0, 5.6 Hz, 1H),
2.93 (dd, J=15.5, 3.7 Hz, 1H), 2.28 (s, 3H), 1.34 (t, J=7.1 Hz, 3H),
1.25 ppm (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d=192.1,
169.3, 168.4, 159.1, 153.6, 136.1, 136.0, 135.4, 132.1, 130.4, 127.7, 126.1,
123.0, 119.9, 119.7, 118.3, 118.2, 113.9, 112.0, 108.1, 106.1, 68.2, 63.2, 61.7,
52.4, 23.4, 20.8, 14.5, 14.3 ppm; HRMS (ESI): m/z calcd for C29H29O6N2:
501.20201 [M+H]+; found: 501.20133.
Method III: General procedure for the aza-Diels–Alder synthesis: Trypt-
amine (0.10 mmol; 1.0 equiv) was dissolved in 5 mL dry DMSO under an
argon atmoshphere, and 3-formylchromone (0.10 mmol; 1.0 equiv) and
molecular sieves (4 ꢃ) were added. The mixture was left at 808C for 2 h
and monitored by TLC (cyclohexane/EtOAc 2:1). The acetylenedicar-
boxylate (1.2 equiv; 0.12 mmol) and dry ZnCl2 (1.0 equiv; 0.10 mmol)
were added and the mixture was allowed to react for 12–24 h at 808C in
a sealed tube under Ar. Disappearance of DMAD as indicated by TLC
indicated the complete reaction (cyclohexane/ethyl acetate 2:1). The re-
action mixture was then diluted in brine (10 mL) and extracted with di-
chloromethane (3ꢄ10 mL). The organic phase was dried over Na2SO4
and evaporated to give a residue that was purified by flash chromatogra-
phy, as described in Method Ia, to yield a yellow solid, that can be recrys-
tallized in methanol.
17 f: Compound 17 f was synthesized according to Method III. Yellow
solid; m.p.: 2328C (decomposition); TLC (cyclohexane/ethyl acetate, 3:2
v/v): RF =0.38; 1H NMR (400 MHz, CDCl3) d=11.09 (s, 1H), 9.02 (s,
1H), 7.90 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.47 (d, J=7.9 Hz,
1H), 7.39 (d, J=2.5 Hz, 1H), 7.37–7.30 (m, 2H), 7.21–7.17 (m, 1H),
7.17–7.05 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H),
3.81–3.73 (m, 2H), 3.16 (ddd, J=15.6, 11.9, 5.8 Hz, 1H), 2.95 ppm (dd,
J=15.6, 3.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) d=190.6, 170.0, 168.7,
17a: Compound 17a was synthesized according to Method Ia. Yellow
solid; m.p.: 2378C (decomposition); TLC (cyclohexane/ethyl acetate, 3:2
v/v): RF =0.43; 1H NMR (400 MHz, CDCl3) d=11.25 (s, 1H), 9.05 (s,
1H), 7.92 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.45 (dd, J=7.9,
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Cascade Syntheses Routes to the Centrocountins
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159.8, 153.6, 136.2, 135.8, 134.3, 131.7, 129.5, 126.0, 123.4, 123.2, 120.8,
120.0, 120.0, 118.4, 114.0, 112.0, 108.2, 105.8, 68.2, 54.1, 52.8, 52.7,
23.4 ppm; HRMS (ESI): m/z calcd for C26H22O6N2Cl: 493.11609 [M+H]+;
found: 493.11565.
mann, Angew. Chem. 2002, 114, 3002–3015; Angew. Chem. Int. Ed.
2002, 41, 2879–2890; f) R. Balamurugan, F. J. Dekker, H. Wald-
mann, Mol. Biosyst. 2005, 1, 36–45; g) M. Kaiser, S. Wetzel, K.
Kumar, H. Waldmann, Cell. Mol. Life Sci. 2008, 65, 1186–1201;
h) O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U. Mayer, O.
Muller, H. Waldmann, Eur. J. Org. Chem. 2005, 4773–4788.
[3] a) J. R. Peterson, T. J. Mitchison, Chem. Biol. 2002, 9, 1275–1285;
b) D. T. Hung, J. Chen, S. L. Schreiber, Chem. Biol. 1996, 3, 287–
293; c) D. G. I. Kingston, J. Nat. Prod. 2009, 72, 507–515; d) S. J.
Haggarty, T. U. Mayer, D. T. Miyamoto, R. Fathi, R. W. King, T. J.
Mitchison, S. L. Schreiber, Chem. Biol. 2001, 8, 1265; e) Z. Maliga,
T. M. Kapoor, T. J. Mitchison, Chem. Biol. 2002, 9, 989–996; f) T. U.
Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber,
T. J. Mitchison, Science 1999, 286, 971–974.
[4] a) C. Rosenbaum, S. Rohrs, O. Muller, H. Waldmann, J. Med. Chem.
2005, 48, 1179–1187; b) C. Rosenbaum, P. Baumhof, R. Mazitschek,
O. Muller, A. Giannis, H. Waldmann, Angew. Chem. 2004, 116, 226–
230; Angew. Chem. Int. Ed. 2004, 43, 224–228; c) A. Nçren-Mꢀller,
I. Reis-CorrÞa, Jr., H. Prinz, C. Rosenbaum, K. Saxena, H. J.
Schwalbe, D. Vestweber, G. Cagna, S. Schunk, O. Schwarz, H.
Schiewe, H. Waldmann, Proc. Natl. Acad. Sci. USA 2006, 103,
10606–10611; d) A. P. Antonchick, H. Schuster, H. Bruss, M. Schur-
mann, H. Preut, D. Rauh, H. Waldmann, Tetrahedron 2011, 67,
10195–10202.
17g: Compound 17g was synthesized according to Method III. Yellow
solid; m.p.: 1638C (decomposition); TLC (cyclohexane/ethyl acetate, 3:2
v/v): RF =0.26; 1H NMR (400 MHz, CDCl3) d=11.25 (s, 1H), 8.92 (s,
1H), 7.93–7.92 (m, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.46–7.36 (m, 2H), 7.22
(s, 1H), 7.03–6.98 (m, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.88–6.81 (m, 2H),
3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80–3.67 (m, 2H), 3.12 (ddd, J=
15.6, 12.0, 5.7 Hz, 1H), 2.88 ppm (dd, J=15.4, 4.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3) d=192.1, 170.1, 168.8, 161.5, 154.5, 153.5, 136.3, 134.6,
132.5, 131.4, 130.4, 126.5, 120.0, 118.6, 118.5, 113.6, 113.3, 112.8, 107.9,
106.1, 100.4, 68.1, 56.2, 54.0, 52.7, 52.6, 23.3 ppm; HRMS (ESI): m/z calcd
for C27H25O7N2: 489.16563 [M+H]+; found: 489.16500.
31b: Compound 31b was synthesized according to Method Ia. TLC (di-
chloromethane/methanol, 95:5 v/v): RF =0.58; 1H NMR (400 MHz,
CDCl3) d=7.94 (s, 1H), 7.43–7.32 (m, 2H), 7.21 (d, J=7.3 Hz, 1H), 6.97
(t, J=7.3 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.57 (s, 1H),
3.80 (s, 6H), 3.78 (s, 3H), 3.75 (s, 3H), 3.69–3.58 (m, 2H), 3.16–3.03 (m,
1H), 2.86 ppm (dd, J=16.5, 3.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d=192.5, 173.4, 167.0, 163.5, 151.1, 148.2, 147.4, 135.2, 134.5, 131.1, 131.1,
129.0, 126.4, 122.7, 122.0, 118.4, 115.7, 114.9, 112.0, 81.7, 56.4, 56.4, 52.2,
52.1, 49.5, 29.7 ppm; HRMS (ESI): m/z calcd for C26H26O8N: 479.15802
[M+H]+; found: 479.15762.
[5] a) K. Kumar, H. Waldmann, Angew. Chem. 2009, 121, 3272–3290;
Angew. Chem. Int. Ed. 2009, 48, 3224–3242; b) S. Wetzel, R. S. Bon,
K. Kumar, H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 10800–
10826.
33c: Compound 33c was synthesized according to Method Ia. Amor-
phous yellow solid; TLC (ethyl acetate): RF =0.55; 1H NMR (400 MHz,
CDCl3) d=11.19 (s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.43 (dd,
J=8.2, 2.0 Hz, 1H), 7.39–7.35 (m, 1H), 7.16 (dd, J=8.2, 7.1 Hz, 1H),
7.02 (dd, J=11.5, 4.9 Hz, 1H), 6.86–6.79 (m, 1H), 3.92 (s, 3H), 3.90–3.86
(m, 4H), 3.48 (dd, J=13.2, 5.0, 2H), 3.13 (ddd, J=15.4, 12.2, 6.0 Hz,
1H), 2.98 ppm (dd, J=15.4, 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d=192.7, 171.2, 168.9, 161.5, 153.3, 135.9, 134.7, 134.3, 131.9, 130.3, 119.6,
119.6, 118.8, 118.3, 107.9, 106.2, 68.2, 54.0, 52.8, 52.8, 23.0 ppm; HRMS
(ESI): m/z calcd for C21H20N3O6: 410.13466 [M+H]+; found: 410.13501.
[6] a) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993–3009;
b) N. Elders, D. van der Born, L. J. D. Hendrickx, B. J. J. Timmer, A.
Krause, E. Janssen, F. J. J. de Kanter, E. Ruijter, R. V. A. Orru,
Angew. Chem. 2009, 121, 5970–5973; Angew. Chem. Int. Ed. 2009,
48, 5856–5859; c) L. F. Tietze, N. Rackelmann, Pure Appl. Chem.
2004, 76, 1967–1983; d) L. F. Tietze, Chem. Rev. 1996, 96, 115–136.
[7] a) T. U. Mayer, T. M. Kapoor, S. Haggarty, S. L. Schreiber, T. J.
Mitchison, Science 1999, 286, 971–974; b) F. Orosz, I. Horvꢆth, J.
Ovꢆdi, Mini Rev. Med. Chem. 2006, 6, 1145–1157; c) G. M. Cragg,
P. G. Grothaus, D. J. Newman, Chem. Rev. 2009, 109, 3012–3043;
d) J. E. Wulff, R. Siegrist, A. G. Myers, J. Am. Chem. Soc. 2007, 129,
14444–14451.
[8] a) H. Dꢀckert, V. Khedkar, H. Waldmann, K. Kumar, Chem. Eur. J.
2011, 17, 5130–5137; b) H. Waldmann, V. Khedkar, H. Dꢀckert, M.
Schꢀrmann, I. M. Oppel, K. Kumar, Angew. Chem. 2008, 120, 6975–
6978; Angew. Chem. Int. Ed. 2008, 47, 6869–6872.
[9] a) V. Khedkar, W. Liu, H. Dꢀckert, K. Kumar, Synlett 2010, 403–
406; b) V. Khedkar, W. Liu, H. Duckert, K. Kumar, Synlett 2010,
1576.
Acknowledgements
This work was supported in part by funding from the German Federal
Ministry for Education and Research through the German National
Genome Research Network-Plus (NGFNPlus) (Grant No. BMBF
01GS08104) and the Max-Planck-Gesellschaft.
[10] a) R. Lavilla, T. Gotsens, S. Rodriguez, J. Bosch, Tetrahedron 1992,
48, 6445–6454; b) E. Wenkert, C. J. Chang, H. P. S. Chawla, D. W.
Cochran, E. W. Hagaman, J. C. King, K. Orito, J. Am. Chem. Soc.
1976, 98, 3645–3655.
[11] J. Stçckigt, A. P. Antonchick, F. R. Wu, H. Waldmann, Angew.
Chem. 2011, 123, 8692–8719; Angew. Chem. Int. Ed. 2011, 50, 8538–
8564.
[12] J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128, 1086–
1087.
[13] a) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336–11337;
b) G. Adair, S. Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31–
39.
[1] a) P. J. Hajduk, W. R. J. D. Galloway, D. R. Spring, Nature 2011, 470,
42–43; b) J. P. Nandy, M. Prakesch, S. Khadem, P. T. Reddy, U.
Sharma, P. Arya, Chem. Rev. 2009, 109, 1999–2060; c) M. D. Burke,
S. L. Schreiber, Angew. Chem. 2004, 116, 48–60; Angew. Chem. Int.
Ed. 2004, 43, 46–58.
[2] a) A. Tavassoli, A. D. Hamilton, D. R. Spring, Chem. Soc. Rev. 2011,
40, 4269–4270; b) C. J. OꢅConnor, L. Laraia, D. R. Spring, Chem.
Soc. Rev. 2011, 40, 4332–4345; c) H. Dꢀckert, V. Pries, V. Khedkar,
S. Menninger, H. Bruss, A. W. Bird, Z. Maliga, A. Brockmeyer, P.
Janning, A. Hyman, S. Grimme, M. Schꢀrmann, H. Preut, K. Hꢀbel,
S. Ziegler, K. Kumar, H. Waldmann, Nat. Chem. Biol. 2012, 8, 179–
184; d) A. P. Antonchick, C. Gerding-Reimers, M. Catarinella, M.
Schurmann, H. Preut, S. Ziegler, D. Rauh, H. Waldmann, Nat.
Chem. 2010, 2, 735–740; e) R. Breinbauer, I. R. Vetter, H. Wald-
Received: October 17, 2012
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

H. Waldmann, K. Kumar et al.
Domino Reactions
V. Eschenbrenner-Lux, H. Dꢀckert,
V. Khedkar, H. Bruss, H. Waldmann,*
K. Kumar* ....................... &&& — &&&
Cascade Syntheses Routes to the
Centrocountins
Rolling transformations! Various cas-
cade synthesis routes that employ
easily accessible substrates and provide
efficient access to diverse tetrahydro-
quinolizines are disclosed (see figure).
Mechanistic insights into the long cas-
cade process to centrocountins are also
presented.
The longest cascade reaction…
…sequence known to date
provides natural product inspired
and biologically active centrocoun-
tins, or tetrahydroindoloquinoli-
zines, and related molecules. K.
Kumar, H. Waldmann et al.
unravel mechanistic insights into
this long cascade reaction
sequence in their Full Paper on
page && ff. by isolating and char-
acterizing various intermediates
and with control experiments. The
cover picture shows a natural setup
as symbolic source of inspiration.
As the reaction substrates in the
pool of water flow in different
streams, representing different
cascade reaction sequences, they are progressively transformed into different intermedi-
ates before settling as a collection of products, the tetrahydro
cules.
ACHTUNGTNER(NUNG indolo)quinolizine mole-
&
12
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!