Central-to-Axial Chirality Conversion Approach Designed on Organocatalytic Enantioselective Povarov Cycloadditions: First Access to Configurationally Stable Indole–Quinoline Atropisomers

Article abstract of DOI:10.1002/chem.201904213

The first stereoselective synthesis of enantioenriched axially chiral indole–quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxi

Full text of DOI:10.1002/chem.201904213

A Journal of
Accepted Article
Title: Central-to-Axial Chirality Conversion Approach Designed on
Organocatalytic Enantioselective Povarov Cycloadditions: First
Access to Configurationally Stable Indole-Quinoline Atropisomers
Authors: Vasco Corti, Giulio Bertuzzi, Luca Bernardi, Mariafrancesca
Fochi, Andrea Mazzanti, Giorgio Bencivenni, Giogiana Denisa
Bisag, and Daniel Pecorari
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To be cited as: Chem. Eur. J. 10.1002/chem.201904213
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10.1002/chem.201904213
Chemistry - A European Journal
RESEARCH ARTICLE
Central-to-Axial Chirality Conversion Approach Designed on
Organocatalytic Enantioselective Povarov Cycloadditions: First
Access to Configurationally Stable Indole-Quinoline Atropisomers
Giorgiana Denisa Bisag,[a] Daniel Pecorari,[a] Andrea Mazzanti,[a] Luca Bernardi,[a] Mariafrancesca
Fochi,[a] Giorgio Bencivenni,[a] Giulio Bertuzzi[a]* and Vasco Corti[a]*
Abstract:
The
first
stereoselective
synthesis
of
architectures, displaying axial chirality, is a prominent goal of
current enantioselective catalysis.[13]
enantioenriched axially chiral indole-quinoline systems is
presented. The strategy takes advantage of an organocatalytic
enantioselective Povarov cycloaddition of 3-alkenylindoles and N-
arylimines, followed by an oxidative central-to-axial chirality
conversion process, allowing access to previously unreported
axially chiral indole-quinoline biaryls. The methodology is also
implemented for the design and the preparation of challenging
compounds exhibiting two stereogenic axes. DFT calculations
shed light on the stereoselectivity of the central-to-axial chirality
conversion, showing unconventional behaviour.
In this paper, we show that chiral Brønsted acid catalysed
Povarov reactions[14] of N-arylimines with specifically designed 3-
alkenylindoles 2[15] provide a convenient route to enantioenriched,
highly substituted, 1,2,3,4-tetrahydroquinolines 3, prone to be
oxidized into axially chiral 4-(indol-3-yl)quinolines 4 [Scheme 1,
b)] in a central-to-axial chirality conversion approach. Products 4
represent not only a rare and challenging example of axially chiral
5-membered heteroaryl - 6-membered heteroaryl compound, but
also, to the best of our knowledge, the first class of atropisomeric
indole-quinoline systems. These are indeed privileged structures,
that can be found, in tropo-isomeric forms, in several drug
candidates.[16] This methodology is also useful for the design of
structures exhibiting two stereogenic axes, at the C2 and at C4
positions of the quinoline.[17] The conversion of multiple
stereocenters into multiple atropisomeric elements is an important
extension of the chirality conversion approach. This was reported
for the first time very recently, restricted to the case of proximal
chirality axes.[18] In order to achieve this goal, challenges such as
the formation of a particularly demanding stereogenic axis, in
proximity of a pyridinic nitrogen, lacking any substituent, must be
faced.
Introduction
Enantioenriched axially chiral compounds are fascinating
privileged scaffolds in drug discovery,[1] catalyst design[2] and
material science.[3]
Many methodologies for the stereoselective preparation of
atropisomeric compounds have been developed,[4] such as
atroposelective cross-couplings,[5] cycloadditions,[6] (dynamic)
kinetic resolutions[7] and desymmetrizations[8] of stereochemically
not defined biaryls. More recently, central-to-axial chirality
conversion, hypothesized by Berson in 1955[9] and first
demonstrated by Meyers in 1984,[10] has been successfully
applied to a restricted number of substrates possessing central
chirality, prone to be turned into axially chiral molecules.[11] In this
context, a pioneering work by Bressy, Bugaut, Rodriguez and co-
workers for the preparation of enantioenriched atropisomeric 4-
arylpyridines[11i] [Scheme 1a)] has disclosed the potential of the
combination of enantioselective organocatalytic methodologies
with the oxidative central-to-axial chirality conversion approach.
The widest class of atropisomeric structures is represented by
hindered 6-membered homo-biaryls derivatives. On the other
hand, axially chiral systems featuring 5-membered rings are
intrinsically more challenging structures, requiring higher degrees
of demanding constraints to stabilize the stereogenic axis.[12] In
addition, the synthesis of optically active heterocyclic
Oxidative central to axial chirality conversion
a)
OMe
OMe
chirality
conversion
OMe
Py
O
O
O
organocatalysis
+
O
Py
X
X
X
N
Py
6-membered rings
homo-heteroaromatic
N
O
H
b) This work: unprecedented atropisomeric indole-quinoline systems
R1
R2
HN
HN
4
R3
N
R4
R1
R1
chirality
conversion
R2
R3
organocatalyst
R2
R3
R5
1
+
"Povarov"
"Oxidation"
2
N
R4
N
R4
H
4
3
5-membered ring
hetero-heteroaromatic system
possible second chiral axis
N
H
2
Scheme 1. Combining organocatalytic enantioselective Povarov cycloadditions
with the oxidative central-to-axial chirality conversion concept.
[a]
G. D. Bisag, D. Pecorari, Prof. Dr. A. Mazzanti, Prof. Dr. L.
Bernardi, Prof. Dr. M. Fochi, Prof. Dr. G. Bencivenni, Dr. G.
Bertuzzi, Dr. V. Corti
Department of Industrial Chemistry “Toso Montanari”
Alma Mater Studiorum – University of Bologna
Viale Risorgimento 4, 40136, Bologna Italy
giulio.bertuzzi2@unibo.it; vasco.corti2@unibo.it
With the aim of developing a proper central-to-axial chirality
conversion protocol, the initial centrally chiral compound (3, in this
case) must display free rotation of the sp3-sp2 σ-bond that has to
be the stereogenic axis of the corresponding atropisomer (4).[9]
Thus, in order to achieve a highly atropo-selective process, the
reaction must discriminate between two conformations (of 3),
leading to opposite enantiomers of the final product (4). This
Supporting information for this article is given via a link at the end
of the document.
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10.1002/chem.201904213
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RESEARCH ARTICLE
represents indeed the main challenge of such strategies. In most
of the oxidative methodologies a kinetical preference for the
transformation of the less stable conformer (usually the one
displaying the most accessible hydrogen to be removed), is
generally observed within a dynamic kinetic resolution process.
Carrying out the reaction in presence of 5 mol% of a chiral
phosphoric acid ((R)-TRIP) in toluene, 1,2,3,4-tetrahydroquinoline
3aa was smoothly obtained as a single all-trans diastereoisomer
in high yield and enantioselectivity (entry 1). Unfortunately, the
corresponding aromatized product 4aa did not yield stable
atropisomers, as confirmed by DFT calculations.
[10,11h]
On the contrary, the system we have studied shows a
complementary behavior, with the configuration of the axially
chiral product 4 deriving from the major conformer (of 3). DFT
calculations will investigate this aspect, elucidating a “kinetic
quench”[19] process, rather than the usual Curtin-Hammett
scenario, as a possible alternative mechanism operating in the
present case.
Compound 2b,[20] featuring a methyl group at position 2 of the
indole, was found to be poorly suitable for the Povarov reaction
with 1a, delivering the corresponding product 3ab in low yield and
enantioselectivity (entry 2). Oxidation of this compound afforded
configurationally stable quinoline 4ab, although with no retention
of the enantiomeric excess. In order to enhance the thermal
stability of the atropisomers of 4, while maintaining high efficiency
in the catalytic reaction, we turned our attention to the reaction
between N-2-naphthylimine 1b and 3-alkenylindole 2a, leading to
benzo[f]-1,2,3,4-tetrahydroquinoline 3ba and to benzo[f]-
quinoline 4ba after oxidation. As shown in entry 3, the Povarov
cycloaddition exhibited excellent results;[21] however, no satisfying
enhancement of the free rotational barrier of 4ba was observed.
Being imine 1b an excellent reagent for the first synthetic step, we
employed remotely substituted 4-bromo-3-alkenylindole 2c[22] to
raise the value of the rotational barrier of the indole-quinoline
system in 4bc (entry 4).
Results and Discussion
We set out the investigation of the substrate requirements in order
to obtain configurationally stable axially chiral quinolines 4 via a
Povarov reaction followed by DDQ oxidation (Table 1). Benzyl-
substituted 3-alkenylindole 2a[20] was selected as dienophile for
the Povarov cycloaddition with commonly employed imine 1a, as
at least three substituents around the stereogenic axis are
mandatory.
Table 1. Search of substrate requirements.[a]
Table 2. Optimization of the chirality conversion step.[a]
R'
HN
R'''
HN
HN
HN
Bn
R
R''
R'
(R)-TRIP
(5 mol%)
H
oxidant
(x equiv)
solvent,rt, 18h
R'''
Bn
Br
Bn
Br
Br
Bn
N
PhMe, rt, 18 h
R
R''
2a R'',R''' = H
Bn
+
N
+
H
Ph
N
H
Ph
N
Ph
N
Ph
N
Ph
1a
1b
R = OMe, R' = H
R,R' = -(CH)4-
H
2b
2c
R'' = Me, R''' = H
R'' = H, R''' = Br
3bc, 96%ee
4bc
5bc
3
DDQ (2 equiv)
CH2Cl2, rt, 18 h
Ar
Entry
oxidant
solvent
equiv
4bc/5bc ratio[b]
ee of 4bc[c]
O
O
O
[%]
P
HN
HN
OH
1[d]
2
MnO2
PCC
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
PhMe
20
>2:98
30:70
50:50
40:60
>98:2
>98:2
>98:2
>98:2
>98:2[h]
-
H
R''
R'
Br
Bn
Ar
(R)-TRIP
Ar = 2,4,6-(iPr) 3C6H2
R'''
Bn
4
CH2Cl2
CH2Cl2
PhMe
1+1[e]
1+1[e]
1+1[e]
1+1[e]
1+1[e]
2
63
R
3
67-90[f]
2
N
Ph
N
Ph
4bc
Optimal substrate
4
4
75
5
THF
50
Entry
3
ee [%]
3[c]
4
ee [%]
4[c]
ΔGǂ
rot
(yield%)[b]
(yield%)[b]
[kcal/mol][d]
6
CH3CN
CH3CN
CH3CN
CH3CN
65
1
2
3
4
3aa (60)
3ab (35)
3ba (85)
3bc (95)
87
4aa (30)
4ab (50)
4ba (55)
4bc (45)
-
23.4
7
40
30
92
96
rac
-
33.1
23.1
40.6
8
3
90
9[g]
3
94 (98% cp)
67-90[e]
[a] Reaction conditions: 3bc (96% ee, 0.03 mmol), oxidant (0.06 mmol), solvent
(900 μL), rt, 18 h. [b] Determined on the crude reaction mixture by 1 H NMR. [c]
Determined by CSP (chiral stationary phase) HPLC analysis after column
chromatography. [d] MnO2 (0.6 mmol), PhMe (1.6 mL) [e] One equivalent (0.03
mmol) was added at the reaction start, the other one (0.03 mmol) after 2 h of
stirring. [f] Range from multiple reactions sharing the same conditions, as a
result of scarce reproducibility (the other results in this table were confirmed by
repeating the experiments three times, giving the same values). [g] Reaction
run at 0 °C for 48 h. [h] Isolated yield of 4bc 97%.
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), PhMe (600 μL), (R)-TRIP
(0.005 mmol), rt, 18 h. Column chromatography to isolate 3, then: 3 (0.03 mmol),
DDQ (0.06 mmol), CH2Cl2 (300 μL), rt, 18 h. [b] Isolated yield after column
chromatography. [c] Determined by CSP (chiral stationary phase) HPLC
analysis after column chromatography. [d] At the B3LYP/6-311g(d,p) DFT level.
[e] Range from multiple reactions sharing the same conditions, as a result of
scarce reproducibility.
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Pleasingly, this modification did not affect the Povarov reaction
and simultaneously provided the configurationally stable product
4bc,[23] with partial retention of the chiral information derived from
the parent compound (3bc).
on the factors affecting this process. The addition of acids or
bases, the concentration of the reaction mixture and the presence
of either atmospheric oxygen, water or free radical species, lead
to inconclusive results (see SI). On the other hand, the retention
of the enantiomeric excess showed a strong dependence on the
solvent (entries 3-6) as well as the equivalents of DDQ added
(entries 6-8). In particular, polar solvents furnished product 4bc
with excellent reactivity but lower enantiomeric excess, when the
oxidant was added portion-wise (entries 5 and 6). Surprisingly,
the addition of an excess of DDQ in one portion resulted in
reproducible high enantiomeric retention for compound 4bc (entry
8). The optimized reaction conditions (entry 9) were eventually
found by running the reaction at 0 °C and consequently extending
the reaction time to ensure full conversion of 5bc.
The latter result demonstrated the feasibility of the overall
strategy and we thus moved to optimize the central-to-axial
chirality conversion step (Table 2). Preliminarily, oxidations of
compounds 3 were carried out using DDQ in CH2Cl2 at room
temperature,[11k] (see Table 1), albeit only moderate reactivity and
poorly reproducible results were obtained. Despite compounds 3
were readily consumed, partially oxidized imines 5 (Table 2) were
in fact generally observed in the reaction mixtures as major
products, or in equimolar ratio with the desired products. Indeed,
5bc was isolated and proved to be a stable reactive intermediate
in the step-wise conversion of 3bc to 4bc. (see SI).
We then moved to evaluate the reaction scope of the two-step
synthetic sequence [Scheme 2]. In each example, Povarov
adduct 3 was isolated and fully characterized prior to the oxidation
step in order to evaluate the corresponding cp factor[11h] of the
atropisomeric quinoline 4. Variations of the amine portion of N-
arylimines 1 showed that methyl and methoxy substituents were
very well tolerated in the Povarov reaction as well as in the
oxidation step, albeit with slight decrease in the isolated yields of
the final products (4cc-ec).
Any attempt to employ oxidants different from DDQ led to
unsatisfactory results. The use of MnO2 afforded selectively
intermediate 5bc (Table 2, entry 1), while PCC led to the
formation of small amounts of the desired product with low
retention of the enantioselectivity (entry 2, for other oxidants see
SI). On the other hand, the oxidation with DDQ in CH2Cl2 showed
better reactivity but lacked reproducibility of the enantiomeric
excess of final product 4bc, ranging from moderate to very good
values (entry 3). Many parameters were investigated to shed light
HN
R1
HN
R6
R5
R1
R6
R5
R2
R3
DDQ (3 equiv)
CH3CN, 0 °C, 48h[a]
R1
R6
R5
(R)-TRIP (5 mol%)
PhMe, rt, 18h[a]
+
R2
R3
R2
R3
N
N
R4
H
N
R4
: yield%[b], ee%[c]
N
R4
H
: yield%[b], ee%[c], cp%[d]
3
1
2
4
HN
R1
HN
HN
HN
R1
Br
Br
Bn
Br
R5
Br
R2
R3
R2
R3
Bn
R5
N
Ph
N
Ph
N
Ph
N
Ph
H
H
[e,f]
R1,R3 = Me; R2 = H 3cc: 83%, 99% ee
R5 = Me
: 96%, 98% ee
: 76%, 98% ee
: 75%, 89% ee, 91% cp
: 99%, 90% ee, 92% cp
4bf: 50%, 99% ee, 100% cp[e-g,j]
4cc
4dc
4ec
: 50%, 92% ee, 93% cp
: 44%, 92% ee, 98% cp
: 69%, 90% ee, 92% cp
3bd
3be
3bf
4bd
R1,R2,R3 = Me
: 79%, 94% ee
R
R
5 = n-Hept
3dc
4be
[e,f]h
R1,R2,R3 = OMe
R1,R3 = Cl; R2 = H
R1,R3 = H; R2 = OMe
3ec: 97%, 98% ee
5 = iPr
: 92%, 99% ee
[e-g]h
: 45%, 87% ee
R5 = iBu
: 94%, 98% ee
: 88%, 97% ee
: 80%, 97% ee, 99% cp
4bh: 83%, 96% ee, 99% cp+
g
4fc
3fc
: 70%, 86% ee, 99% cp
4ac: 87%, 90% ee, ~100% cp[g,h]h
3bg
4bg
3ac: 90%, 86% eeg
R
5 = allyl
1
3bh
HN
HN
HN
HN
Br
Br
R6
Bn
Br
Bn
R6
Bn
Br
Bn
N
R4
3gc: 77%, 97% ee
3hc
N
Ph
N
R4
: 53%, 97% ee, 100% cp
4hc: 61%, 81% ee, 83% cp[f]
N
Ph
H
H
[e,f]
4gc
R4 = p-MeOC6H4
R4 = p-NO2C6H4
R4 = 2-thienyl
R6 = Br
: 95%, 96% ee
4bc
: 97%, 94% ee, 98% cp
3bc
: 95%, 98% ee
3ic: 95%, 97% ee
R
R
6 = Cl
: 96%, 99% ee
[f,g]
4bi
4bj
3bi
3bj
: 97%, 91% ee, 92% cp
4ic
: 65%, 63% ee, 65% cp
: 64%, 60% ee, 91% cp
'
p
6 = Me
: 95%, 98% ee
[f]
y
[i]n
: 92%, 75% ee, 77% cp
4jc
R
4 = iPr
3jc
: 50%, 66% ee
Scheme 2. Scope of the Povarov cycloaddition-oxidative chirality conversion process. [a] Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), PhMe (2 mL), (R)-TRIP
(0.015 mmol), rt, 18 h. Column chromatography to isolate 3, then: 3 (0.1 mmol), DDQ (0.3 mmol), solvent (3 mL), 0 °C, 48 h. All compounds 3 were isolated as
single regio- and diastereoisomers. [b] Isolated yield after column chromatography. [c] Determined by CSP (chiral stationary phase) HPLC analysis after column
chromatography. [d] Ratio between ee of 4 and ee of 3. [e] 300 μL CH2Cl2 added. [f] Reaction time: 64 h. [g] Reaction run at room temperature. [h] Precipitation of
poorly soluble racemic 5ac intermediate from the reaction mixture may be the reason for the small enantioenrichment with respect to 3ac. [i] Product obtained
through a three-component Povarov reaction (see SI for details). [j] Isolated as a 0.64:1 5bf/4bf inseparable mixture in 82% overall yield.
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Electron-poor imine 1f showed sloppy reactivity in the
cycloaddition, but oxidation of corresponding 3fc proceeded with
full retention of the enantiomeric excess. Pleasingly, substituent
R1 on quinolines 4 was not strictly necessary to provide
configurational stability. Indeed, compound 4ac (R1 = H) was
obtained in good yield and enantioselectivity.[24] By modification
at the aldehyde portion on imines 1, we observed that an electron-
rich substituent (1g) afforded good results in both synthetic
steps,[25] while an electron-poor and a heteroaromatic one
delivered adducts 3hc and 3ic in high yields and selectivities but
caused less satisfactory retention of the chiral information in the
following oxidation step (see SI for details).[26] On the contrary,
product 3jc, derived by a three-component protocol , was
obtained with modest results but behaved efficiently in the
subsequent aromatization reaction. Variation of the terminal
substituent of the vinyl group on compounds 2 was smoothly
carried out achieving excellent results in both Povarov and
oxidation reactions (4bd, 4be, 4bg, 4bh); notably, only
encumbered product 3bf could not reach full conversion into the
desired quinoline 4bf. Modifications at the 4-position of the indole
moiety, crucial for the configurational stability of atropisomeric
products 4, were also possible, with no substantial detriment of
the final enantiomeric excess (4bi-bj).
This substituent allowed the stable formation of a particularly
demanding axis, in proximity of an unsubstituted nitrogen
(experimental ΔGǂ = 30.5 kcal/mol, see SI for further details).
rot
Easy isolation and characterization of the two diastereoisomers
was indeed possible.[28] In this case, the simultaneous formation
of the two axes was accomplished. We then undertook the
challenge to synthesize a compound having two stereogenic axes,
both featuring a five-membered ring. A 3-(2-methylindolyl) group
was found to be suitable to this purpose, being well tolerated in
the Povarov reaction and the subsequent oxidation step.
Unfortunately, HPLC analyses showed a slowly equilibrating
mixture of diastereoisomers. This indicates that in our case, a five
membered ring is not bulky enough to stabilize a stereogenic axis
around a non-substituted nitrogen. Thus, transformation of 4lc to
the corresponding N-oxide was performed to circumvent this
issue, generating a stable chirality axis in compound 6lc in good
yield, high diastereoselectivity and excellent retention of the
starting enantiomeric excess. In this case, the two stereogenic
axes were formed in separate synthetic steps in a stepwise
manner.
A one-pot protocol, leading from 1b and 2c to 4bc, without
purification of 3bc, was also developed without any significant
variation from the two-step procedure, affording very satisfactory
results [Scheme 4, a)]. Finally, the synthetic utility of products 4
was demonstrated by exploring the possibility to perform a
palladium catalysed cross-coupling on the 4-bromoindole moiety.
Suzuki reaction with phenylboronic acid towards compound 7bc
proceeded smoothly at 100 °C, with almost complete retention of
the enantiomeric excess, as a result of the excellent thermal
stability of the stereogenic axis [Scheme 4, b)].
Rational design of quinolines 4, possessing two stereogenic
axes was also possible upon introduction of specifically hindered
aromatic substituents at C2. This was accomplished following two
different strategies. First, product 4kc was prepared in high
enantiomeric excess, starting from imine 1k, bearing a 1-(2-
methoxynaphthyl) group, and indole 2c through a slightly modified
Povarov cycloaddition[27]-oxidation sequence.
HN
HN
a)
Br
Br
HN
Br
Bn
Br
Bn
1. (R)-TRIP (5 mol%)
PhMe, rt, 18h
2. solvent removal
3. DDQ (4 equiv)
CH3CN, 0 °C, 48 h
N
Ph
Br
Bn
1b
Br
2
2
+
N
N
H
H
Bn
NTs
MeO
3kc, 90% ee
N
Ph
3lc, 97% ee
4bc
N
76% overall yield
2. m-CPBA
CH2Cl2, rt, 2h
1. DDQ, CH3CN
0 °C, 64 h
DDQ, CH3CN
0 °C, 64 h
H
90% ee
2c
b)
HN
HN
HN
HN
OH
B
OH
Br
Br
Br
Bn
Br
Bn
Br
Bn
Ph
Bn
Pd(PPh3)4 (5 mol%)
K2CO3 (aq., 2.5 M)
PhMe/CPME 19:1
100 °C, 7h
2
2
N
N
N
Ph
N
Ph
MeO
NTs
O
4kc
4bc, 94% ee
7bc
anti-
,
15% yield, 96% ee (~100% cp)
+
80% yield, 91% ee
Scheme 4. a) One-pot protocol and b) Synthetic elaboration on 4bc.
HN
HN
Br
Br
The aS absolute configuration of 4gc and that of 3ic
(2S,3R,4S) were unambiguously determined by X-Ray
crystallography.[25,26] Analysis of the structure of 3ic suggested
that the aS atropisomer derives from the same conformation
observed in the solid state. The rotation of 4-bromoindole yields
two conformers with different energies (syn and anti periplanar,
sp and ap as in Scheme 5).
Br
Bn
Br
Bn
2
OMe
2
N
N
O
NTs
syn-4kc
6lc, 9.4:1 syn/anti
60% yield, 90% ee (93% cp, syn)
,
44% yield, 94% ee (~100% cp)
Scheme 3. Povarov cycloaddition-chirality conversion strategy towards doubly
axially chiral substrates (syn-4kc/anti-4kc = 3:1 in the crude mixture).
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sp-conformer
ap-conformer
a deep-coloured solution. Calculations on the DDQ complexes
revealed a large stabilization with respect to the isolated
compounds, with the sp conformer still more stable than the ap.
When the DDQ complex is formed, the imine can be converted to
enamine by proton relay from C3 to the nitrogen. Therefore, the
same complexes were then calculated for the enamines, and they
were found to be more stable than the corresponding imines (-7.7
kcal/mol for the sp and -5.5 kcal/mol for the ap conformer,
respectively). The removal of the H4 hydrogen by hydride transfer
to oxygen (HTO)[29] was calculated to be higher in energy for the
imines with respect to enamines, thus suggesting that the
oxidation mechanism should take place on the enamine. Due to
the less steric hindrance, the HTO TS was calculated to be easier
on the less stable ap-enamine with respect to the more stable sp-
enamine, in contrast to the experimental results (but in agreement
with literature examples).[10,11h] However, to achieve sp/ap
interconversion, the sp enamine must overcome a rotational
energy barrier of 19.2 kcal/mol (calculated at the M06-2x/6-
31G(d) level). The same energy barrier, calculated on the free
enamine is sensibly lower (15.1 kcal/mol, see SI). Indeed, the
presence of DDQ hampers the free rotation of the sp2-sp3
dihydroquinoline-indole bond in the complex, due to the restricted
rotational freedom of the benzyl group at C3, that is instead
required to make easier the rotation of the indole moiety.
H
N
Ph
Ph
NH
Ph
Ph
Br
H
H
Br
indole rotation
N
N
H
H
DDQ
DDQ
aR atropisomer
aS atropisomer
X
(minor)
(major)
indole rotation
Scheme 5. sp- and ap-conformers of 3bc and general pathway for the oxidation
process.
DFT calculations at the M06-2x/6-31G(d) level suggested that
the sp conformer (observed in the solid state) is much more stable
than the ap (9.5 kcal/mol), whose concentration in solution is
negligible. This implies that oxidation by DDQ takes place on the
more stable conformation.
A DFT computational study was carried out to rationalize the
stereoselectivity of the central-to-axial chirality conversion, that is
in sharp contrast with the reported literature examples[10,11h] (see
SI for full details). As from the experimental results, the first
oxidation of the Povarov adduct to the imine is not the rate-
determining step of the reaction. Thus, the proposed mechanism
was modelled starting from the imine intermediate (Figure 1).
When the imine is reacted with DDQ, the first stage of the reaction
is the formation of a DDQ-complex, as evident by the formation of
Figure 1. Proposed reaction pathway. Blue lines indicate rotations, red lines indicate tautomerism. The continuous line indicates the enantioselective pathway.
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10.1002/chem.201904213
Chemistry - A European Journal
RESEARCH ARTICLE
With this constraint, the classic Curtin-Hammett reaction scheme
is not applicable. We therefore propose that the reaction proceeds
by tautomerism from the imine-DDQ complex to enamine-DDQ,
followed by kinetic quench of the more stable sp enamine via the
HTO TS. Within this framework, the role of DDQ is not restricted
to a mere oxidant species, but seems to play a crucial role in the
stereoselection of the process. It is indeed responsible of the
increment of the rotational barrier between the two conformers, a
key feature for the retention of the selectivity in such a reactive
scenario. The formed DDQH- complex of the benzoquinolinium
ion undergoes deprotonation by DDQH- to yield the final
compound and DDQH2.It should be noted that the intermediates
determined by chiral stationary phase HPLC (Daicel Chiralpak AD-H or
Chiralcel OD-H columns), using an UV detector operating at 254 nm.
Products 3, 4, 5bc, 6lc and 7bc were found to be sensitive to traces of DCl
in CDCl3 darkening immediately upon contact and showing slow
decomposition upon prolonged standing. In order to conveniently record
the spectra in CDCl3 the solvent had to be filtered over basic alumina prior
to use. Products 3 were all obtained as single all-trans isomers.
General procedure for the synthesis of products 3. In a small vial
equipped with a magnetic stirring bar, 3-vinylindole 2 (1.5 equiv, 0.45 mmol,
E/Z mixture), N-arylimine 1 (1.0 equiv, 0.3 mmol), toluene (2 mL) and
catalyst (R)-TRIP (11 mg, 0.015 mmol, 5 mol%) were added in this order.
The resulting solution was stirred for 18 h at room temperature and then
directly purified by column chromatography on silica gel to afford the
desired compounds 3 as solids.
aS-4bcH+ꞏDDQH-
and
aR-4bcH+ꞏDDQH-
are
indeed
diastereoisomers because of the presence of the stereogenic axis
coupled with the position of DDQH- (leading to a transient element
of planar chirality), thus they have different energies (see Figure
1).
General procedure for the synthesis of products 4. In a test tube
equipped with a magnetic stirring bar, tetrahydroquinoline 3 (0.1 mmol) and
CH3CN (3 mL) were added. In the case of poorly soluble substrates, a small
amount of DCM (300 μL) could be added in order to ensure complete dissolution
(see Supporting Information). The resulting mixture was cooled to 0°C and DDQ
(68.4 mg, 0.03 mmol, 3 equiv.) was added in one portion. The resulting solution
was stirred for 48-64 h at 0°C and then poured into a solution of Na2SO3 (1 M,
10 mL) and extracted with DCM (3 x 30 mL). The combined organic phases
were dried over MgSO4, filtered and evaporated under reduced pressure. The
crude residue was then purified by column chromatography on silica gel.
Conclusion
In conclusion, we have developed the first stereoselective
synthesis of enantioenriched axially chiral indole-quinoline
systems, following a central-to-axial oxidative strategy. We have
thus proved that organocatalytic enantioselective Povarov
cycloadditions of 3-alkenylindoles and N-arylimines provide a
reliable tool for the preparation of highly hindered
tetrahydroquinolines in excellent yields and enantiomeric
excesses, tolerating exquisitely the high steric demand required
to provide stable atropisomeric quinolines after oxidation. The
oxidation reaction has been optimized to a high level of efficiency
and retention of the enantiomeric excess. This allowed a high-
Acknowledgements
We acknowledge financial support from the University of Bologna
(RFO program), MIUR (FFABR 2017), and F.I.S. (Fabbrica
Italiana Sintetici). We thank Luca Zuppiroli (University of Bologna)
for the HRMS analyses. We also thank Olaia Nkaity and
Emanuele Giuliani for preliminary investigations and preparation
of the starting materials.
yielding synthesis of
a broad range of optically active
atropisomeric 4-(indol-3-yl)quinolines. The methodology was
implemented for the design and the preparation of challenging
compounds exhibiting two chirality axes following two different
approaches. The process has been shown to be feasible in a one-
pot (Povarov cycloaddition – oxidation) protocol with optimal
results, and the axially chiral products have been subjected to
some synthetic elaborations. DFT calculations elucidated the
unconventional behaviour of the central-to-axial chirality
conversion. The observed absolute configuration of the axially
chiral compounds, reflecting the one possessed by the major
conformers of the tetrahydroquinolines, has been proposed to
arise from the kinetic quench of the more stable enamine
intermediate via HTO, occurring faster than the conformational
rearrangement between the two conformers due to the indole
rotation.
Keywords: chirality conversion, atropisomerism, Povarov
cycloaddition, asymmetric catalysis, indoles, quinolines.
[1]
a) J. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPlante, Angew. Chem.
Int. Ed. 2009, 48, 6398; b) S. L. LaPlante, L. D. Fader, K. R. Fandrick, D.
R. Fandrick, O. Hucke, R. Kemper, S. P. F. Miller, P. J. Edwards, J. Med.
Chem. 2011, 54, 7005; c) P. W. Glunz, Bioorg. Med. Chem. Lett. 2018,
28, 53.
[2]
a) R. Noyori, H. Takaia, Acc. Chem. Res. 1990, 23, 345; b) P. Kočovskŷ,
Š. Vyskočil, M. Smrčina, Chem. Rev, 2003, 103, 3213; c) S. Brandes, B.
Niess, M. Bella, A. Prieto, J. Overgaard, K. A. Jørgensen, Chem. – Eur.
J. 2006, 12, 6039; d) T. Kano, Y. Yamaguchi, K. Maruoka, , Chem. – Eur.
J. 2009, 15, 6678; e) S. Schenker, A. Zamufir, M. Freund, S. B. Tsogoeva,
Eur. J. Org. Chem. 2011, 2011, 2209; D. Parmar, E. Sugiono, S. Raja,
M. Rueping, Chem . Rev. 2014, 114, 9047.
Experimental Section
General Methods. 1H and 13C NMR spectra were recorded on a
Varian Inova 300, Mercury 400 or Inova 600 spectrometer. Chemical shifts
(δ) are reported in ppm relative to residual solvents signals[30] for 1H and
13C NMR. 13C NMR were acquired with 1 H broad-band decoupled mode.
Chromatographic purifications were performed using 70-230 mesh silica.
Mass spectra were recorded on a Waters Xevo Q-TOF spectrometer.
Optical rotations were measured on a Perkin Elmer 241 Polarimeter
ꢀ ꢂꢄꢅ°ꢆꢇ
(c =
[3]
[4]
a) Y. Wang, A. Urbas, Q. Li, J. Am. Chem. Soc. 2012, 134, .3342; b) S.
J. Wesemberg, F. Ferroni, S. Pieraccini, W. B. Schweizer, A. Ferrarini,
G. P. Spada, F. Diederich, RSC Adv. 2013, 3, 22845.
For reviews see: a) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M.
J. Gresser, J. Garner, M. Breuning, Angew. Chem. Int. Ed. 2005, 44,
5384; b) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem.
Rev. 2011, 111, 563; c) G. Bencivenni, Synlett, 2015, 26, 1915; d) J.
Wencel-Delord, A. Panossian, F. R. Lerouxb, F. Colobert, Chem. Soc.
provided with a sodium lamp and are reported as follows:
ꢁ
ꢃ
g/100 mL, solvent). The enantiomeric excess of the products (ee) were
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10.1002/chem.201904213
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RESEARCH ARTICLE
Rev., 2015, 44, 3418; e) Y.-B. Wang, B. Tan, Acc. Chem. Res. 2018, 51,
534. f) B. Zilate, A. Castrogiovanni, C. Sparr, ACS Catal. 2018, 8, 2981.
Song, B. Jiang, W. Du, Y.-C. Chen, ACS Catal. 2019, 9, 4374; g) S.-C.
Zheng, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2019, 58, 9215. f).
Oxidative methodologies: h) A. Straub, A. Goehrt, Angew. Chem. Int. Ed.
1996, 35, 2662; i) O. Quinonero, M. Jean, N. Vanthuyne, C. Roussel, D.
Bonne, T. Constantieux, C. Bressy, X. Bugaut, J. Rodriguez, Angew.
Chem., Int. Ed. 2016, 55, 1401; j) V. S. Raut, M. Jean, N. Vanthuyne, C.
Roussel, T. Constantieux, C. Bressy, X. Bugaut, D. Bonne, J. Rodriguez,
J. Am. Chem. Soc. 2017, 139, 2140; k) A. Link, C. Sparr, Angew. Chem.
Int. Ed. 2018, 57, 7136; l) Y.-L. Hu, Z. Wang, H. Yang, J. Chen, Z.-B. Wu,
Y. Lei, L. Zhou, Chem. Sci. 2019, 10, 6777; m) Y. Hayashi, A. Takikawa,
S. Koshino, K. Ishida, Chem. Eur. J. 2019, 25, 10319.
[5]
Metal catalyzed cross-couplings: a) T. Shimada, Y.-H. Cho, T. Hayashi,
J. Am. Chem. Soc. 2002, 124, 13396; b) J. Feng, B. Li, Y. He, Z. Gu
Angew. Chem. Int. Ed. 2016, 55, 2186; c) Y.-S. Jang, Ł. Woźniak, J.
Pedroni, N. Cramer, Angew. Chem. Int. Ed. 2018, 57, 12901.
Organocatalytic arene-arene bond forming reaction: d) G.-Q. Li, H. Gao,
C. Keene, M. Devonas, D. H. Ess, L. Kürti, J. Am. Chem. Soc. 2013, 135,
7414; e) C. K. De, F. Pesciaioli, B. List, Angew. Chem. Int. Ed. 2013, 52,
9293; f) Y.-H. Chen, D. Cheng, Z. Zhang, Y. Wang, X.-Y. Liu, B. Tan, J.
Am. Chem. Soc. 2015, 137, 15062; g) S. Narute, R. Parnes, F. D. Toste,
D. Pappo, J. Am. Chem. Soc. 2016, 138, 16553; h) H.-H. Zhang, C.-S.
Wang, C. Li, G.-J. Mei, Y. Li, F. Shi, Angew. Chem. Int. Ed. 2016, 56,
116; i) C. Ma, F. Jiang, F.-T. Sheng, Y. Jiao, G.-J. Mei, F. Shi, Angew.
Chem. Int. Ed. 2018, 58, 3014; h) L.-W. Qui, J.-H. Mao, J. Zhang, B. Tan,
Nat. Chem. 2018, 10, 58; j) L.-W. Qui, S. Li, S.-H. Xiang, J. (J.) Wang, B.
Tan, Nat. Catal. 2019, 2, 314; k) M. Moliterno, R. Cari, A. Puglisi, A.
Antenucci, C. Sperandio, E. Moretti, A. Di Sabato, R. Salvio, M. Bella,
Angew. Chem. Int. Ed. 2016, 55, 6525.
[12] a) D. Bonne, J. Rodriguez, Chem. Commun. 2017, 53, 12385; b) N. Di
Iorio, G. Filippini, A. Mazzanti, P. Righi, G. Bencivenni, Org. Lett. 2017,
19, 6692; c) D. Bonne, J. Rodriguez, Eur. J. Org. Chem. 2018, 2018,
2417.
[13] E. Kumarasamy, R. Raghunathan, M. P: Sibi, J. Sivaguru, Chem. Rev.
2015, 115, 11239.
[14] a) L. S. Povarov, B. M. Mikhailov, B. M., Izv. Akad. Nauk SSSR, Ser.
Khim. 1963, 953. Some references on Brønsted acid catalysed
enantioselective Povarov reactions: b) T. Akiyama, H. Morita, K. Fuchibe,
J. Am. Chem. Soc. 2006, 128, 13070; c) H. Liu, G. Dagousset, G.
Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598; d) G.
Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011, 133, 14804; e)
C. Min, C.-T. Lin, D. Seidel, Angew. Chem. Int. Ed. 2015, 54, 6608; for a
review, see: f) M. Fochi, L. Caruana, L. Bernardi, Synthesis 2014, 135.
[15] a) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi, A.
Ricci, Chem. Commun. 2010, 46, 327; for our additional contributions to
the Povarov reaction, see: b) L. Caruana, M. Fochi, S. Ranieri, A.
Mazzanti, L. Bernardi, Chem. Commun. 2013, 49, 880; c) L. Bernardi, G.
Bolzoni, M. Fochi, M. Mancinelli, A. Mazzanti, Eur. J. Org. Chem. 2016,
3208; d) D. Stevanović, G. Bertuzzi, A. Mazzanti, M. Fochi, L. Bernardi,
Adv. Synth. Catal. 2018, 360, 893;; for our additional work on the
chemistry of 3-alkenylindoles see: e) G. Bertuzzi, L. Lenti, G. D. Bisag,
M. Fochi, L. Bernardi. Adv. Synth. Catal. 2018, 360, 1296.
[6]
Proper cycloadditions: a) A. Gutnov, B. Heller, C. Fischer, H. J. Drexler,
A. Spannenberg, B. Sundermann, C. Sundermann, Angew. Chem. Int.
Ed. 2004, 43, 3795; b) T. Shibata, T. Fujimoto, K. Yokota, K. Takagi, J.
Am. Chem. Soc. 2004, 126, 8382; c) Y. Kwon, A. J. Chinn, B. Kim, J. S.
Miller, Angew. Chem. Int. Ed. 2018, 57, 6251; d) Y. Liu, X. Wu, S. Li, L.
Xue, C. Shan, Z. Zhao, H. Yan, Angew. Chem. Int. Ed. 2018, 57, 6491;
e) S.-C. Zheng, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2019, 58, 1494.
Other formations of aromatic rings: f) M. Terada, K. Dan, Chem.
Commun, 2012, 48, 5781; g) A. Link, C. Sparr, Angew. Chem. Int. Ed.
2014, 53, 5458; h) O. Quinonero, C. Bressy, X. Bugaut, Angew. Chem.
Int. Ed. 2014, 53, 10861; i) D. Lotter, M. Neuburger, M. Rickhaus, D.
Häussinger, C. Sparr, Angew. Chem. Int. Ed. 2016, 55, 2920; j) L. Zhang,
J. Zhang, J. Ma, D.-J. Keng, B. Tan J. Am. Chem. Soc. 2017, 139, 1714.
Chiral auxiliary: a) J. Clayden, S. P. Fletcher, J. J. W. McDouall, S. J. M.
Rowbottom, J. Am. Chem. Soc. 2009, 131, 5331; Bifunctional
organocatalysis: b) J. L. Gustafson, D. Lim, S. J. Miller, Science, 2010,
328, 1251; c) C. Yu, H. Huang, X. Li, Y. Zhang, W. Wang, J. Am. Chem.
Soc. 2016, 138, 6956; Phase-transfer organocatalysis d) S. Shirakawa,
X. Wu, K. Maruoka, Angew. Chem. Int. Ed. 2013, 52, 14200; e) J. D.
Jolliffe, R. J. Armstrong, M. D. Smith, Nat. Chem. 2017, 9, 558; Covalent
bonding organocatalysis: f) S. Lu, S. B. Poh, Y. Zhao, Angew. Chem. Int.
Ed. 2014, 53, 11041; g) G. Ma, J. Deng, M. P. Sibi, Angew. Chem. Int.
Ed. 2014, 53, 11818; Phosphoric acid organocatalysis: h) D.-J. Cheng,
L. Yan, S.-K. Tian, M.-Y. Wu, L.-X. Wang, Z.-L. Fan, S.-C. Zheng, X.-Y.
Liu, B. Tan, Angew. Chem. Int. Ed. 2014, 53, 3684; Metal catalysis: i) V.
Bhat, S. Wang, B. M. Stoltz, S. C. Virgil, J. Am. Chem. Soc. 2013, 135,
16829; j) P. Ramirez-Lopez, A. Ros, A. Romero-Arenas, J. Iglesias-
Sigüenza, R. Fernandez, J. M. Lassaletta, J. Am. Chem. Soc. 2016, 138,
12053.
[7]
[16] a) T. N. Birkinshaw, S. J. Teague C. Beech, R. V. Bonnert, S. Hill, A.
Patel, S. Reakes, H. Sanganee, I. G. Dougall, T. T. Phillips, S. Salter, J.
Schmidt, E. C. Arrowsmith, J. J. Carrillo, F. M. Bell, S. W. Paine, R.
Weaver, Bioorg. Med. Chem. Lett. 2006, 16, 4287; b) R. Pettipher, M.
Whittaker, J. Med. Chem. 2012, 55, 2915.
[17] a) K. Tanaka, A. Kamisawa, T. Suda, K. Noguchi, M. Hirano, J. Am.
Chem. Soc. 2007, 129, 12078; b) K. T. Barrett, A: J. Metrano, P. R.
Rablen, S. J. Miller, Nature 2014, 509, 71; c) D. Lotter, A. Castrogiovanni,
M. Neuburger, C. Sparr, ACS Cent. Sci. 2018, 4, 656; d) Q. Dherbassy,
J.-P. Djukic, J. Wencel-Delord, F. Colobert, Angew. Chem. Int. Ed. 2018,
57, 4668; e) Y. Tan, S. Jia, F. Hu, Y. Liu, L. Peng, D. Li, H. Yan, J. Am.
Chem. Soc. 2018, 140, 16893.
[18] This paper was published during the preparation of this manuscript, see
ref. 11k.
[8]
a) K. Mori, Y. Ichikawa, M. Kobayashi, Y. Shibata, M. Yamanaka, T,
Akiyama, J. Am. Chem. Soc. 2013, 135, 3964; b) R. J. Armstrong, M. D.
Smith, Angew. Chem. Int. Ed. 2014, 53, 12822; c) N. Di Iorio, P. Righi,
A. Mazzanti, M. Mancinelli, A. Ciogli, G. Bencivenni, J. Am. Chem. Soc.
2014, 136, 10250; d) J.-W. Zhang, J.-H. Xu, D.-J. Cheng, C. Shi, X.-Y.
Liu, B. Tan, Nat. Commun. 2016, 7, 10677; e) N. Di Iorio, F. Champavert,
A. Erice, P. Righi, A. Mazzanti, G. Bencivenni, Tetrahedron, 2016, 72,
5191; f) L. Zhang, S.-H Xiang, J. (J.) Wang, J. Xiao, J.-Q. Wang, B. Tan
Nat. Commun. 2019, 10, 566.
[19] a) H. Booth, J. H. Little, J. Chem. Soc. Perkin II. 1972, 1884; b) J.
McKenna Tetrahedron, 1974, 30, 1555; c) B. H. White, M. L. Snapper, J.
Am. Chem. Soc. 2003, 125, 14901.
[20] Synthesized according to: S. Sahu, A. Banerjee, M. S. Maji, Org. Lett.
2017, 19, 464 and obtained as a single trans-isomer.
[21] A single regioisomer was produced, according to the literature (ref. 15a).
[22] Synthesized following a modified literature procedure (C. Gioia, A.
Hauville, L. Bernardi, F. Fini, A. Ricci. Angew. Chem. Int. Ed. 2008, 47,
9236) through Wittig reaction and obtained in 65:35 cis/trans ratio.
Preliminary studies revealed that cis-2c did not take part in the Povarov
cycloaddition but underwent an acid-promoted equilibration to reactive
trans-2c (see SI and ref. 14c for more details).
[9]
J. A. Berson, E. Brown, J. Am. Chem. Soc. 1955, 77, 450.
[10] A. I. Meyers, D. G. Wettlaufer, J. Am. Chem. Soc. 1984, 106, 1135.
[11] a) T. T. Nguyen, Org. Biomol. Chem. 2019, Org. Biomol. Chem. 2019,
17, 6952.. Non oxidative methodologies: b) T. Hattori, M. Date, K.
Sakurai, N. Morohashi, H. Kosugi, S. Miyano, Tetrahedron Lett. 2001, 42,
8035; c) Y. Nishii, K. Wakasugi, K. Koga, Y. Tanabe, J. Am. Chem. Soc.
2004, 126, 5358; d) Y. Liu, K. Lu, M. Dai, K. Wang, W. Wu, J. Chen, J.
Quan, Z. Yang Org. Lett. 2007, 9, 805; e) F. Guo, L. C. Konkol, R. J.
Thomson, J. Am. Chem. Soc. 2011, 133, 18; f) X.-L. He, H.-R. Zhao, X.
[23] The thermal stability of the stereogenic axis was confirmed by refluxing
a toluene solution of 4bc for one week without significant decrease in the
ee. As suggested with the calculations, the ΔGǂ is too high to be
rot
evaluated experimentally.
[24] ΔGǂrot = 42.6 kcal/mol.
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[25] The absolute and relative configurations (along with the regiochemistry)
of compound 3ic was assigned by single-crystal X-ray diffraction analysis
and extended to all products 3 for analogy. CCDC-1940646.
[26] The absolute configuration of compound 4gc was assigned by single-
crystal X-ray diffraction analysis and extended to all products 4 for
analogy CCDC-1940645.
[27] The phosphoric acid derivative of (R)-6,6'-di(anthracen-9-yl)-1,1'-
spirobi[indane]-7,7'-diol was used as catalyst, delivering 4kc with
opposite configuration with respect of the product derived from (R)-TRIP
(for which 70% ee was observed). See supporting information for more
details.
[28] Precipitation of poorly soluble racemic intermediate 5kc from the reaction
mixture may be the reason for the small enantioenrichment with respect
to 3kc observed for both diastereoisomers.
[29] a) A. E. Wendlandt, S. S. Stahl, Angew. Chem. Int. Ed. 2015, 54, 14638;
b) B. Li, A. E. Wendlandt, A. A. Stahl, Org. Lett. 2019, 21,1176.
[30] H. E. Gottlieb, V. Kottlyar, A. Nudelman, J. Org. Chem. 1997, 62, 7512.
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Page No. – Page No.
Title
The Atropovarov reaction: The first stereoselective synthesis of enantioenriched
axially chiral indole-quinoline systems is presented. The strategy takes advantage
of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles
and N-arylimines, followed by an oxidative central-to-axial chirality conversion
process
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