An enantioselective inverse-electron-demand imino diels-alder reaction

Article abstract of DOI:10.1002/anie.201309022

The imino Diels-Alder reaction is an efficient method for the synthesis of aza-heterocycles. While different stereo- and enantioselective inverse-electron-demand imino Diels-Alder (IEDIDA) reactions have been reported before, IEDIDA reactions including electron-deficient dienes are unprecedented. The first enantioselective IEDIDA reaction between electron-poor chromone dienes and cyclic imines, catalyzed by zinc/binol complexes is described. The novel reaction provides a facile entry to a natural product inspired collection of ring-fused quinolizines including a potent modulator of mitosis. Copyright

Full text of DOI:10.1002/anie.201309022

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Angewandte
Communications
DOI: 10.1002/anie.201309022
Asymmetric Synthesis
An Enantioselective Inverse-Electron-Demand Imino Diels–Alder
Reaction**
Vincent Eschenbrenner-Lux, Philipp Kꢀchler, Slava Ziegler, Kamal Kumar,* and
Herbert Waldmann*
Abstract: The imino Diels–Alder reaction is an efficient
method for the synthesis of aza-heterocycles. While different
stereo- and enantioselective inverse-electron-demand imino
Diels–Alder (IEDIDA) reactions have been reported before,
IEDIDA reactions including electron-deficient dienes are
unprecedented. The first enantioselective IEDIDA reaction
between electron-poor chromone dienes and cyclic imines,
catalyzed by zinc/binol complexes is described. The novel
reaction provides a facile entry to a natural product inspired
collection of ring-fused quinolizines including a potent mod-
ulator of mitosis.
T
he imino Diels–Alder reaction is among the most powerful
Scheme 1. Strategy for heterocycle synthesis by means of imino Diels–
Alder reactions. a and b) Combination of electron-rich and electron-
poor dienes and dienophiles in IEDIDA reactions. c) Structure of
centrocountin-1. d) IEDIDA reaction between various imines and
electron-deficient chromone dienes. EDG=electron-donating group,
EWG=electron-withdrawing group.
methods for the synthesis of chiral nitrogen heterocycles.[1] In
this cycloaddition, typically electron-poor or electron-neutral
imines[2] and electron-rich dienes are employed in the
presence of Lewis acid catalysts (Scheme 1a).[3] However,
cycloaddition reactions between electron-rich imines and
electron-deficient dienes, that is the inverse-electron-demand
imino Diels–Alder (IEDIDA) reactions (Scheme 1b) have
not been reported.[4] Herein we describe the first example of
an IEDIDA reaction, that is, the cycloaddition between the
imines 1 and 6–9 (Tables 1–4) and the dienes 2. The reaction
proceeds with high enantioselectivity in the presence of
a chiral zinc Lewis acid catalyst. The centrocountins (Sche-
me 1c) are novel mitosis modulators, accessible by means of
a one-pot, 12-step cascade reaction sequence.[5] To extensively
explore their bioactivity, we envisaged an alternative efficient
and enantioselective synthesis by a Lewis acid catalyzed
IEDIDA reaction between electron-rich imines (1; Scheme 1,
Table 1: IEDIDA reaction between imine 1a and diene 2a.
Entry
Lewis Acid
Solvent
T [8C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
none
AlCl3
DMSO
CH2Cl2
THF
80
RT
60
80
RT
80
80
RT
48
12
12
12
12
12
1
61
–
–
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
DMF
–
CH2Cl2
toluene
DMSO
DMSO
69
83
94
85
[*] M. Sc. V. Eschenbrenner-Lux, Dipl.-Biol. P. Kꢀchler, Dr. S. Ziegler,
Dr. K. Kumar, Prof. H. Waldmann
12
Max-Planck- Institut fꢀr molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: kamal.kumar@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
[a] Yields of isolated products. DMF=N,N-dimethylformamide,
DMSO=dimethylsulfoxide, THF=tetrahydrofuran.
M. Sc. V. Eschenbrenner-Lux, Dipl.-Biol. P. Kꢀchler, Dr. K. Kumar,
Prof. H. Waldmann
Technische Universitꢁt Dortmund, Fachbereich Chemie und
Chemische Biologie, 44221 Dortmund (Germany)
Tables 1–3) and chromone-derived dienes (2) through the
intermediary formation of the cycloadducts 3 (Scheme 1d).
Indeed, treatment of the imine 1a with the diene 2a in
DMSO at 808C for 48 hours induced the desired IEDIDA
reaction and led to the formation of the desired indoloqui-
nolizine 4a in 61% yield (Table 1, entry 1). Variation of
solvent and temperature, and exploration of different Lewis
acids revealed that the cycloaddition proceeds best in the
presence of ZnCl2 in toluene or DMSO at 808C (Table 1,
entries 6–8).
[**] This work was funded by the German Federal Ministry for Education
and Research through the German National Genome Research
Network-Plus (NGFNPlus) (grant no. BMBF 01GS08104). We
acknowledge funding from the European Research Council under
the European Union’s Seventh Framework Programme (FP7/2007-
2013) (ERC Grant no. 268309).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309022.
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Table 2: Enantioselective IEDIDA reaction of 1a and 2a.
The absolute configuration of the cycloadduct 4a was
determined by comparison of its CD spectrum with the
spectrum recorded for the structurally closely related cen-
trocountin-1 (Scheme 1) reported earlier (see the Supporting
Information).[5a]
For exploration of the bioactivity of the centrocountins
and to explore the scope of the IEDIDA reaction, we
investigated different electron-poor dienes (2) and electron-
rich cyclic heterodienophiles (1) for the synthesis of a com-
pound collection. Introduction of substituents onto the
chromone ring of the diene consistently yields cycloadducts
with high ee values (Table 3) and does not markedly influence
the reactivity. Thus, both chromenyl acrylates (2, R5 =
CO2Me) and chromenyl acrylonitriles (2, R5 = CN) reacted
smoothly with imines (1) to provide the indoloquinolizines 4
in excellent yields (Table 3). Indole-derived imines incorpo-
rating a methoxy group yielded the cycloadducts in high yields
and with high to very high ee values. Imines with a substituent
(R4) at the imine carbon atom yielded the desired indoloqui-
nolizines in very high yields and predominantly with high
enantioselectivity (Table 3, entries 1–12). In contrast, in the
absence of a substituent at the imine carbon atom (R4 = H)
the enantioselectivity was low (Table 3, entries 13–14; for
additional examples, see the Supporting information).
Different hetero- and carbocyclic imines (6–9) yielded the
corresponding cycloadducts 10–13 in good to excellent yields
(Table 4). Only for the imine 9 (n = 2), which is prone to
trimerization,[8] were moderate yields of the cycloadducts 14
recorded. Additionally, selected electron-poor cyclic dienes
(see Reference [9]) did not react with the indole derived
imines 1 under the developed reaction conditions.[9]
Entry
Ligand
Solvent
T[8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
toluene
toluene
toluene
toluene
CH2Cl2
methanol
THF
toluene
toluene
toluene
toluene
toluene
RT
0
24
24
24
24
24
24
24
24
24
24
24
24
83
72
69
66
71
83
94
67
0
24
39
61
88
47
14
68
90
–
À15
À78
À78
À78
À78
À78
À78
À78
À78
À78
9
10
11
12
70
13
51
83
89
93
[a] Yields of isolated products. [b] Determined by HPLC analysis using
a chiral stationary phase.
To develop an enantioselective IEDIDA reaction we
employed binol ligands[6] and envisioned that tetracoordina-
tion of a zinc Lewis acid by the binol ligand, the imine
nitrogen atom, and the vinylogous
Both (R)-5a and (R)-5e yielded the cycloadducts with
high ee values, and electron-donating and electron-accepting
substituents on the chromone ring of the dienes as well as
ester incorporated into the chro-
mone-derived diene, would allow
for efficient steric discrimination.[7]
Treatment of 1a and 2a with cata-
lysts formed from 20 mol% of
ZnEt2 and 40 mol% of a chiral
binol ligand (5) in different solvents
and at different temperatures
revealed that 1) lowering the tem-
perature to À788C prevented the
uncatalyzed non-enantioselective
reaction and led to an increase of
the eevalue to 88% (Table 2,
entries 1–4), 2) toluene is best
among the explored solvents
(Table 2, entries 4–7), 3) introduc-
tion of sterically demanding sub-
stituents into the 3- and 3’-positions
of the binol ligand leads to an
increase in enantioselectivity. The
use of dibromo (R)-5b led to
decomposition of the starting mate-
rial.
Table 3: Enantioselective synthesis of tetrahydro-indoloquinolizines 4 by means of the IEDIDA reaction.
Entry
4
Ligand R1
R2
R3
R4
R5
R6 R7
Yield
Yield
ee
[%][a,b] [%][a,c] [%][d]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4i
(R)-5e
(R)-5e
(R)-5e
(R)-5e
(R)-5a
(R)-5a
(R)-5a
(R)-5e
(R)-5e
(R)-5a
(R)-5a
(R)-5a
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me CO2Me
Me CN
Me CO2Me
Me CN
Me CO2Me
Me CO2Me
Me CO2Me Cl Cl
H
H
H
H
H
H
H
H
H
H
91
85
94
89
51
82
81
79
94
80
95
91
90
96
79
93
82
84
93
92
95
91
90
91
71
94
89
91
88
89
19
23
OMe
OMe
OMe
OMe
OMe
Me 94
Cl
97
94
97
97
OMe Me Me CO2Me
OMe Me Me CN
OMe Me Me CO2Me
OMe Me Me CN
OMe Me Me CO2Me
H
H
H
H
H
H
H
H
H
9
10
11
12
13
14
4j
4k
4l
H
H
H
Me 93
Me 96
Cl
H
H
89
71
97
4m (R)-5a
4n (R)-5a
H
H
H
H
H
H
H
H
CO2Me
CN
[a] Yields of isolated products. [b] Racemic synthesis (Method 1). [c] Enantioselective synthesis (Method
2). [d] Determined by HPLC analysis using a chiral stationary phase.
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Table 4: IEDIDA reaction of various cyclic imines 6–9 with chromone dienes 2.
Rapid reorganization of the hexacyclic inter-
mediate (3; Scheme 1) into quinolizines (4, 10–14)
led us to employ the chromone diene 17 to identifiy
the primary cycloadduct 18. We assumed that in the
absence of an a-acidic proton in 18, chromone ring-
opening might be prevented. Indeed, the reaction
between 1b and 17 (Scheme 2b) provided the
hexacyclic indoloquinolizine 18 in 64% yield. How-
ever, 18 is sensitive to Brønsted acids which facili-
tates retro-IEDIDA reaction.
Entry Prod. Ligand R1
R2
R3 R4
R5 R6 Yield Yield ee
For a phenotypic cell based investigation[10] into
whether the new compounds share the ability of the
centrocountins to impair centrosome integrity,[5a]
which leads to defects in chromosome congression
and to arrest of cells in metaphase of mitosis, human
cervical carcinoma HeLa cells were treated with the
compounds for 24 hours. Cells were then stained for
DNA and the mitotic marker phospho-histone H3 to
determine the proportion of cells arrested in mitosis.
High-content analysis was employed to calculate the
percentage of mitotic cells. Several compounds led to
accumulation of mitotic cells and the compound 10p
was identified as most potent (Figure 1).
Only the S-configured cycloadduct arrested the
cells in mitosis whereas the R enantiomer was
inactive (see Figure 1a). Treatment of HeLa cells
for 48 hours with the racemate of 10p and the
enantiomers, and determination of cell viability by
means of the WST-1 reagent revealed that (Æ)10p
reduced the viability of HeLa cells with a half-
maximal inhibitory concentration (IC50) of (9.7 Æ
1.1) mm, whereas (S)-10p more potently inhibited
cell proliferation with an IC50 of (4.7 Æ 0.5) mm
(Figure 1b). The R enantiomer again proved to be
inactive. Notably, (Æ)10p and (S)-10p were more
potent than the guiding centrocountin-1 [IC50 (17.2 Æ
2.4) mm]. Accumulation of mitotic cells upon treat-
ment with 10p followed by cell death was independ-
[%][a,b] [%][a,c] [%][d]
1
2
3
4
5
6
7
8
10a (R)-5e
10b (R)-5e
H
H
H
H
H
H
H
H
H
H
Me CO2Me
Me CN
Et CO2Me
iPr CO2Me
Cy CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
89
91
84
80
79
83
75
79
54
51
47
41
71
84
67
90
86
71
80
86
90
81
84
–
93
91
83
69
91
84
87
80
82
88
86
83
83
87
83
27
24
10c
(R)-5e
10d (R)-5e
10e (R)-5e
10 f
(R)-5a OMe OMe Cy CN
10g (R)-5e OMe OMe Me CO2Me
10h (R)-5a OMe OMe Me CN
Me 92
Me 94
Me 81
9
10i
10j
(R)-5a OMe OMe Et CO2Me
(R)-5a OMe OMe Me CO2Me Cl Cl 91
Cl Cl 97
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
10k (R)-5a OMe OMe Me CN
10l (R)-5a OEt OEt Me CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
76
77
10m (R)-5a OEt OEt Me CN
10n (R)-5a OMe OMe Me CO2Me
10o (R)-5a OMe OMe Me CN
10p (R)-5a
10q (R)-5a
Cl 92
Cl 96
H
H
–
–
–
–
–
–
–
–
–
–
H
H
–
–
–
–
–
–
–
–
–
–
H
H
H
H
H
H
H
H
CO2Me
CN
CO2Me
CN
CO2Me
CN
CO2Me
CN
H
H
H
H
H
H
93
96
87
91
95
97
11a
11b
12a
12b
12c
12d
–
–
–
–
–
–
–
–
–
–
Cl 77
Cl 83
H
H
H
H
–
13a (R)-5a
13b (R)-5a
Me CO2Me
Me CN
66
68
51
54
62
62
–
44
29
14a
14b
–
–
H
H
CO2Me
CN
–
[a] Yields of isolated products. [b] Racemic synthesis (Method 1), [c] Enantioselec-
tive synthesis (Method 2). [d] Determined by HPLC analysis using a chiral stationary
phase.
different a-substituents on the imines 6–9 were tolerated
(Table 4, entries 1–15). In general, unsubstituted dienophiles
yielded the corresponding cycloadducts in good to high yields,
however, in these cases stereoselectivity was low (Table 4,
entries 16–23, 26, and 27). Most of these heterodienophiles
were not stable, however, for imine 9 (n = 1) the cycloadducts
were formed with moderate ee values (Table 4, entries 24 and
25).
To rationalize the stereochemical course of the IEDIDA
reaction we assume that a preformed zinc/binol complex
coordinates the imine nitrogen atom and the vinylogous ester
oxygen atom of the diene (Scheme 2a). In the ensuing
complex 15, one naphthalene ring would be oriented orthog-
onal to the plane of the heterodienophile and thus shields the
Si face of the imine. Thereby the attack of the diene is
directed to the Re face of the imines. a-Alkyl groups on the
imines will avoid the steric bias of the naphthalene ring, thus
leading to high stereoselectivity. Consequently, for nonsub-
stituted imines enantioselectivity is lower.
Scheme 2. a) Rationale for stereoselection in the asymmetric imino
Diels–Alder reaction. b) Synthesis of the hexacyclic cycloadduct 18.
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IEDIDA reaction as the key transformation in the synthesis
of quinolizines yielded centrocountin analogue with
a
increased potency compared to that of centrocountin-1.
Received: October 16, 2013
Revised: November 21, 2013
Published online: January 27, 2014
Keywords: asymmetric catalysis · cycloadditions · heterocycles ·
.
natural products · zinc
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Figure 1. The compound 10p induces chromosome congression
defects and mitotic arrest in HeLa cells. a) HeLa cells were treated
with compounds for 24 hours prior to staining with an anti-phospho-
histone H3 antibody and 4’,6-diamidino-2-phenylindole (DAPI) to
detect the mitotic marker phospho-histone H3 and DNA, respectively.
High-content analysis was performed to determine the percentage of
mitotic cells in the cell populations. Data are shown as mean values
with standard deviations. b) Influence of (Æ)-10p , (S)- and (R)-10p
on the viability of HeLa cells. Cells were treated with the compounds
for 48 h prior to determination of cell viability using the WST-1
proliferation reagent. Data were normalized to DMSO and represent
mean values with standard deviations. c) (Æ)-10p and (S)-10p cause
chromosome congression defects. HeLa cells were treated with
compounds at a concentration of 10 mm for 24 h prior to staining with
anti-a-tubulin antibody coupled to FITC (green) and DAPI (blue) to
visualize tubulin and DNA respectively. Arrows indicate misaligned
chromosomes during metaphase. Scale bar: 10 mm.
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[9] Electron-poor cyclic dienes (19–21) were investigated in the
IEDIDA reaction with various indole-derived imines (1) but did
not give the desired products.
ently confirmed by means of live-cell imaging (see the
Supporting movies 1 and 2). Mitotic HeLa cells accumulated
after 6 hours of treatment with 7.5 mm (Æ)10p. Cell death was
observed as early as 24 hours post compound addition.
Immunostaining of DNA and tubulin revealed misaligned
chromosomes during metaphase induced by (Æ)10p and (S)-
10p (Figure 1c). In contrast, cells that were treated with (R)-
10p underwent proper mitosis.
In conclusion, we have developed a catalytic and asym-
metric inverse-electron-demand imino Diels–Alder reaction
between various cyclic imines and chromone-derived dienes.
To the best of our knowledge, this is the first report of an
asymmetric IEDIDA reaction involving electron-deficient
dienes and electron-rich imines. Use of the asymmetric
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