Quadruple domino organocatalysis: An asymmetric aza-Michael/Michael/ Michael/Aldol reaction sequence leading to tetracyclic indole structures with six stereocenters

Article abstract of DOI:10.1002/chem.201201493

Quadruple domino/Wittig-one pot: An organocatalytic, asymmetric, three-component quadruple cascade, which leads to tetracyclic double-annulated indole derivatives, is described. The domino products were further derivatized by aldehyde olefination under one-pot conditions to obtain complex isoindolo[2, 1-a]indole derivatives bearing six stereogenic centers in a highly stereoselective fashion. Copyright

Full text of DOI:10.1002/chem.201201493

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DOI: 10.1002/chem.201201493
Quadruple Domino Organocatalysis: An Asymmetric Aza-Michael/Michael/
Michael/Aldol Reaction Sequence Leading to Tetracyclic Indole Structures
with Six Stereocenters
Dieter Enders,*[a] Andreas Greb,[a] Kristina Deckers,[a] Philipp Selig,[a] and
Carina Merkens[b]
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
Organocatalyzed domino reactions by now are widely re-
garded as powerful tools in contemporary organic chemistry.
The progress in the development of new domino reactions
has been extremely rapid,[1] and today they are increasingly
applied in the synthesis of natural products and other bio-
logically active compounds, such as pharmaceuticals and
agrochemicals.[2] Secondary amines, like proline and deriva-
tives thereof, are especially useful organocatalysts, because
they are capable of promoting a variety of transformations
by their complementary iminium-ion and enamine activation
modes, thereby allowing for an efficient activation of both
donor- and acceptor-type molecules. In addition, secondary-
amine-catalyzed domino reactions are generally compatible
with numerous functional groups, avoid protecting groups,[3a]
are redox-,[3b] atom-, and step-economic,[3c,d] and can often
The introduction of an electron-withdrawing substituent at
the C-2 position, however, reduces the pKA value of the NH
position dramatically.[11] Based on this concept, we[10a]—and
independently the group of Wang and co-workers[10b]—de-
veloped the organocatalytic addition of indole-2-carbalde-
hydes to a,b-unsaturated aldehydes to give optically pure
3H-pyrroloACTHNUGRTNEUNG[1,2-a]indoles in high yields. Herein, we extend
the chemistry of related acidic 2-substituted indoles and
report a new quadruple domino reaction, which employs
a sequential iminium–enamine–iminium–enamine activation
approach to synthesize the tetracyclic structures shown in
Scheme 1.
imitate biosynthetic pathways.[3e,f] Accordingly,
a large
number of organocatalyzed domino reactions,[4] triple,[5] and
even quadruple cascades[6] were developed in the last few
years by the suitable combination of the different activation
modes.
The indole moiety is arguably the most abundant hetero-
cycle found in nature. Because of the great importance of
indole-based structures, a lot of effort has been devoted to
gain novel entries into this group of molecules. Indoles are
also suitable substrates for organocatalytic transforma-
tions,[7] of which most of the publications deal with the enan-
tioselective alkylation at the C-3[8] or C-2[9] position of the
pyrrolidine ring. In contrast, enantioselective N-alkylations
are rarely reported,[10] most likely owing to the insufficient
nucleophilicity of the indole NH group and the fact that
amino-based catalysts are unable to deprotonate unsubsti-
tuted indoles to obtain a sufficiently nucleophilic species.
Scheme 1. Asymmetric one-pot synthesis of polyfunctionalized tetracyclic
indole derivatives 6 by an organocatalytic three-component quadruple
cascade, followed by aldehyde olefination.
The organocatalytic quadruple cascade, leading to tetracy-
clic aldehydes 4, is initiated by the asymmetric aza-Michael-
type N-alkylation of indole-2-methylene malononitrile deriv-
atives 1 to different a,b-unsaturated aldehydes 2 under imi-
nium activation. The corresponding enamine derivative of
intermediate A then reacts in a Michael addition to the
methylene malononitrile to give tricyclic malononitrile de-
rivatives B, which can again act as nucleophiles to another
equivalent of the activated a,b-unsaturated aldehyde. Mi-
chael addition leads to intermediates C, suitable substrates
for an intramolecular aldol reaction to give tetracyclic alde-
hydes 4 (Scheme 2). This reaction sequence readily gives
[a] Prof. Dr. D. Enders, Dipl.-Chem. A. Greb, K. Deckers, Dr. P. Selig
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: enders@rwth-aachen.de
[b] C. Merkens
Institute of Inorganic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201493.
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Table 1. Optimization of the reaction conditions for the quadruple cas-
cade of indole derivative 1a and cinnamaldehyde (2a).
Scheme 2. Proposed mechanism for the organocatalytic asymmetric quad-
ruple domino reaction. Only the putative catalyst-free intermediates A–
C are shown for clarity. Im=iminium activation; En=enamine activa-
tion.
Entry[a]
Cat.
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3d
3d
3d
3d
3d
3d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
traces
traces
5
49
33
15
12
41
67
n.d.
n.d.
n.d.
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
n.d.
n.d.
n.d.
93
94
85
89
41
97
96
access to tetracyclic indole skeletons with N-fused 5-mem-
bered rings annulated to cyclohexanes, a structural motif
that is also found in some bisindole alkaloids, namely the
borreverines.[12]
We started our investigation of this sequence with the re-
action between cinnamaldehyde (2a) and 2-((1H-indol-2-yl)-
methylene) malononitrile (1a), which is easily obtained
from indole-2-carbaldehyde and malonitrile in a Knoevena-
gel reaction (Table 1).[13]
By using dichloromethane as solvent, the (S)-TMS-diphe-
nylprolinol catalyst (3d) gave a clean conversion of the
starting materials (Table 1, entry 4), while all other tested
catalysts 3a–c were ineffective in this reaction (Table 1, en-
tries 1–3). The isolation of the desired quadruple domino
product 4a by flash chromatography revealed that the prod-
uct aldehyde mainly exists in its corresponding enol form.
After due consideration, we decided to trap product 4a with
the stabilized Wittig reagent 5 and convert it into the well-
defined ester 6a. With the diastereo- and enantiomerically
pure product 6a in hand, we performed a short solvent
screening. The best results were obtained by using 2.5 equiv-
alents of cinnamaldehyde and 15 mol% of (S)-TMS-diphe-
nylprolinolether in chloroform (0.5m; Table 1, entry 9). With
lower catalyst loadings (5 mol% of 3d), the yield decreased
dramatically, while higher catalyst loadings (25 mol% of 3d)
gave no significant improvement of the yield and stereose-
lectivity of the reaction. In addition, the organocatalytic cas-
cade and subsequent aldehyde olefination could be conven-
iently performed in a one-pot fashion with no detrimental
impact on the reaction outcome (Table 1, entry 10).
THF
EtOH
MTBE
CHCl3
CHCl3
9
10[e]
70
[a] All reactions were performed on a 0.75 mmol scale with catalyst 3
(15 mol%) and solvent (1.5 mL) for 48 h. [b] Yield of isolated product
after flash chromatography. [c] Determined by 1H NMR spectroscopy of
the crude reaction mixture. [d] Determined by HPLC on a chiral station-
ary phase. [e] The organocatalytic quadruple cascade and aldehyde olefi-
nation were performed in a one-pot procedure. MTBE=methyl tert-
butyl ether; n.d.=not determined.
Table 2. Scope of the organocatalytic reaction sequence.
Entry
Product
R1
R2
Yield [%][a]
ee [%][b]
1
2[d]
3
4
5
6
7
8
9
6a
ent-6b
6c
H
H
H
H
H
H
H
H
Ph
70
70
60
63
25
43
45
33
54
63
60
97
96
99
92
92
99
94
78
98
98
91
p-OMe-C6H4
p-Cl-C6H4
p-F-C6H4
p-NMe2-C6H4
p-biphenyl
3,4-OCH2O-C6H3
2-furyl
6d
6e
6 f
6g
6h
6i
Me
OMe
Br
Ph
Ph
Ph
10
6j
ent-6k
Having established the optimum reaction conditions, we
started to screen the scope of the quadruple domino reac-
tion (Table 2). Different aromatic a,b-unsaturated aldehydes
(electron rich and electron poor) were tested, and the prod-
ucts 6a–k could be isolated in moderate to excellent yields
11[c]
[a] Yield of isolated, diastereomerically pure (d.r.>20:1) product after
flash chromatography. [b] Determined by HPLC on a chiral stationary
phase. [c] The reaction was performed with the opposite enantiomer of
the catalyst ent-3d.
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Quadruple Domino Organocatalysis
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(25–70%), good to excellent enantioselectivities (91–
99% ee), and as just a single diastereomer (>20:1 d.r.). Het-
eroaromatic groups, such as furyl, were also suitable sub-
stituents, but the yield and the enantioselectivity decreased.
Substitution at the 5 position of the indole had no big influ-
ence on either yield and/or selectivity. The 3-methyl-substi-
tuted analogue of 1 was unreactive and also aliphatic alde-
hydes did not give any clean conversion. A one-pot combi-
nation of the organocatalytic domino reaction and aldehyde
olefination was performed for entries 1–3 and 9–11 of
Table 2 and further increased the efficiency and simplicity of
the overall sequence. Since the quadruple cascade could not
be initiated by achiral amine catalysts, like pyrrolidine, all
reactions were performed equally successful with both enan-
tiomers of the catalyst to obtain racemic standards of the
products.
Further functionalization of the casade products, besides
the Wittig reaction, was achieved by reduction and acetali-
zation. While NaBH4 was ineffective in reducing the strong-
ly enolized aldehyde 4b, the reduction succeeded with the
Et3SiH/BF3 system. Transformation of the obtained 1,3-diol
7b by stirring in acetone with a catalytic amount of p-tolue-
nesulfonic acid (p-TSA) gave acetal 8b as a single diastereo-
mer (Scheme 3).
91% ee. Crystallization from benzene/n-hexane finally re-
sulted in a suitable, enantiomerically pure single crystal. The
observed stereochemical outcome of the N-alkylation is in
accordance with our results previously obtained in the Mi-
chael addition of indole-2-carbaldehyde.[10a,b] The addition of
the malonitrile group to the second equivalent of cinnamal-
dehyde showed the same sense of asymmetric induction as
described previously by Jørgensen,[14] which indicates a deci-
sive role of catalyst-controlled asymmetric induction by the
Jørgensen/Hayashi catalyst.
In conclusion, we have developed an organocatalytic
three-component quadruple cascade reaction between
indole-2-methylene malononitriles and a,b-unsaturated aro-
matic aldehydes, giving rise to tetracyclic double-annulated
indole derivatives. The highly enolized aldehydes obtained
were further derivatized in a one-pot fashion, thus produc-
ing six novel stereogenic centers, four newly formed C,C-
bonds, and one C,N-bond in both a diastereo- and enantio-
merically highly selective fashion. The very high degree of
molecular complexity, obtained from simple starting materi-
als and with minimal synthetic effort, and the excellent ste-
reoselectivity demonstrates again the enormous synthetic
utility of the young and rapidly growing field of organocata-
lytic domino reactions.
Experimental Section
Organocatalytic three-component quadruple cascade and aldehyde olefi-
nation (product 6a as an example): A solution of 2-((1H-indol-2-yl)me-
thylene)malononitrile (0.75 mmol), cinnamaldehyde (1.875 mmol,
2.5 equiv), and (S)-TMS-diphenylprolinol catalyst (15 mol%) in chloro-
form (1.5 mL) was stirred for 36 h at RT. Phosphorane Ph3P=CHCO2Et
(1.5 equiv) was then added and the reaction mixture was stirred for 5 h at
RT. The solvent was removed under reduced pressure and the crude
product was directly purified by flash column chromatography on silica
gel (eluent: pentane/diethyl ether 1:3) to give the product 6a (277 mg,
0.53 mmol, 70%) as a yellow solid.
Scheme 3. Derivatization of the cascade product 4b by reduction and
acetalization. Ar=p-MeO-C6H4.
The relative and absolute configuration of the products
was elucidated by NOESY experiments and X-ray crystal-
structure analysis of compound ent-6k (Figure 1). Surpris-
ingly, crystallization from 1,4-dioxane exclusively gave race-
mic crystals, despite an initial enantiomeric excess of
Acknowledgements
We thank the former Degussa AG and BASF SE for the donation of
chemicals and Prof. Dr. U. Englert, Institute of Inorganic Chemistry,
RWTH Aachen University, for the X-ray structure determination.
Keywords: asymmetric synthesis · domino reactions · one-
pot reactions · organocatalysis · quadruple cascade
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Received: March 29, 2012
Published online: && &&, 0000
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Quadruple Domino Organocatalysis
COMMUNICATION
Domino Organocatalysis
D. Enders,* A. Greb, K. Deckers,
P. Selig, C. Merkens ......... &&&& — &&&&
Quadruple Domino Organocatalysis:
An Asymmetric Aza-Michael/Michael/
Michael/Aldol Reaction Sequence
Leading to Tetracyclic Indole Struc-
tures with Six Stereocenters
Quadruple domino/Wittig–one pot: An
organocatalytic, asymmetric, three-
component quadruple cascade, which
leads to tetracyclic double-annulated
indole derivatives, is described. The
domino products were further derivat-
ized by aldehyde olefination under
one-pot conditions to obtain complex
isoindoloACTHUNTGRNEUNG[2,1-a]indole derivatives bear-
ing six stereogenic centers in a highly
stereoselective fashion.
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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These are not the final page numbers!