Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse-Electron-Demand Aza-Diels–Alder Reactions

Article abstract of DOI:10.1002/chem.201904902

A stable asymmetric intramolecular Povarov reaction has been established to provide an efficient method to access structurally diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-b]quinolines in high stereoselectivities of up to >99:1 diastereomeric

Full text of DOI:10.1002/chem.201904902

A Journal of
Accepted Article
Title: Enantioselective synthesis of complex fused heterocycles via
chiral phosphoric-acid catalyzed intramolecular inverse-electron
demand aza-Diels-Alder reaction
Authors: Vincent Gandon, Lucie JARRIGE JARRIGE, and Géraldine
Masson
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To be cited as: Chem. Eur. J. 10.1002/chem.201904902
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Enantioselective synthesis of complex fused heterocycles via
chiral phosphoric-acid catalyzed intramolecular inverse-electron
demand aza-Diels-Alder reaction
Lucie Jarrige,[a] Vincent Gandon,*[b] Géraldine Masson*[a]
reaction remain elusive (B, Scheme 1).[7] Meanwhile, in 2015,
Abstract: A stable asymmetric intramolecular Povarov reaction has
been established to provide an efficient method to access structurally
diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-
Seidel and co-workers pioneered the asymmetric intramolecular
Povarov reaction using a chiral catalyst with two Brønsted acid
sites, which achieved excellent diastereo- and enantioselectivity
when indolines were employed to generate in situ the reactive
2-azadienes (C, eq 1, Scheme 1).[8] Subsequently, the same
group reported chiral phosphoric acid catalyzed kinetic
asymmetric intramolecular Povarov reaction of racemic
2-substituted indolines (C, eq 2, Scheme 1).[9] Although the
cycloadducts were generally isolated with excellent diastereo-
and enantiomeric excesses, the necessity of using indolines as
reaction partners limited the structural diversity of THCQs that can
be accessed by these protocols. To address this limitation, the
first example of asymmetric intramolecular Povarov using primary
anilines as reaction partners was reported by our group in 2017
(D, Scheme 1).[10] Under mild conditions, a series of trisubstituted
tetrahydrochromeno[4,3-b]quinolin-6-ones and their nitrogen
b]quinolines in high stereoselectivities of up to >99:1 dr and 99% ee,
without any purification step. Additionally, in order to facilitate large-
scale application of this method, a low catalyst loading protocol was
employed, using 0.2 mol % of chiral phosphoric acid, providing the
cycloadducts without any loss in yield and enantioselectivity. The
theoretical studies revealed that the reaction occurred through a
sequential Mannich reaction and an intramolecular Friedel–Crafts
reaction, wherein the phosphoric acid acted as bifunctional catalyst to
activate para-phenolic dienophile and N-2-hydroxy-2-azadienes,
simultaneously.
Introduction
Chiral tetracyclic tetrahydroquinolines are privileged heterocyclic
scaffolds found in various bioactive natural products and
analogues
tetrahydrodibenzo[1,6]naphthyridin-6-ones
were
obtained in good to excellent yields with high diastereo- and
enantioselectivities by using a chiral phosphoric acid catalyst.
Remarkably, no purification was required to isolate each
cycloadduct in excellent purity. Our previous studies showed that
the presence of OH groups on both the aniline and dienophile
were crucial to reach excellent enantioselectivity. Moreover, para-
phenol on the dienophile was found to be critical for the success
of the intramolecular IEDADA reaction, since ortho- and meta-
analogs were completely unreactive in this cycloaddition.
pharmaceuticals.
For
instance,
tetrahydrochromeno[4,3-
b]quinolines (THCQs) exhibit significant biological activities such
as
progesterone
receptor
modulators,[1]
anticancer,[2]
anti-inflammatory.[4]
antibacterial,[3]
ulcerogenic,
and
Consequently, much effort has been made to develop effective
methods for the synthesis of enantioenriched
tetrahydrochromeno[4,3-b]quinolines. As such, intramolecular
inverse electron-demand aza-Diels-Alder reaction (IEDADA), also
called Povarov reaction, represents one of the most efficient,
straightforward, and atom-economic approaches allowing the
construction of two fused rings in a single transformation.[5] Up to
the present time, in contrast to intermolecular Povarov reaction (A,
Scheme 1),[5b,5g,6] for which there are several methods identified,
successful examples of enantioselective intramolecular Povarov
We would now like to report advances in the scope and limitations
of our methodology providing access to more diverse
enantioenriched
In particular, we extended this special protocol to the synthesis of
other fused tetraheterocycles such as
tetrahydrothiochromeno[4,3-b]quinolin-6-ones,
tetrahydrochromeno[4,3-b]quinolin-6-ones.
tetrahydrochromeno[4,3-b]quinolines,
and
hexahydrodibenzo[b,h][1,6]naphthyridines
and
excellent
[a]
[b]
Dr. L. Jarrige, Dr. G. Masson
Institut de Chimie des Substances Naturelles, CNRS,
UPR2301, Université Paris-Sud, Université Paris Saclay
1 Avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France
E-mail: geraldine.masson@cnrs.fr
diastereo- and enantioselectivities were achieved. Furthermore, a
computational study based on DFT calculations was performed to
elucidate the reaction mechanism, and rationalize the
stereochemical course of the reaction. Finally, the key role of the
para-phenol on the dienophile to the success of this
transformation was also explained by theoretical studies.
https://massongroup.wixsite.com/power/contact
Pr. V. Gandon
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS
UMR8182, Université Paris-Sud, Université Paris Saclay
Bâtiment 420, 91405 Orsay cedex (France),
and Laboratoire de Chimie Moléculaire (LCM), CNRS UMR9168
Ecole Polytechnique, Institut Polytechnique de Paris,
Route de Saclay, 91128 Palaiseau cedex, France
E-mail: vincent.gandon@u-psud.fr
Supporting information for this article is given via a link at the end of
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Scheme 1. Catalytic asymmetric IEDADA reactions: background and our strategy
(>99:1 dr).[10] Various substituents on the aromatic ring of phenolic
dienophile partners were also well-tolerated. At the same time,
few substituents on aromatic aldehydes were evaluated in our
previous studies and mainly limited to bromide, methyl and
methoxy groups. In this context, we turned our attention to
investigate further other substituted salicylaldehydes, possessing
synthetic handles for further synthetic elaboration. We began our
novel studies with the preparation of various formylaryl 3-(4-
Results and Discussion
We have previously demonstrated that bulky (S)–2,4,6-
triisopropylphenyl BINOL phosphoric acid 1 was able to efficiently
promote the enantioselective intramolecular Povarov reaction
between 2-formylphenyl 3-(4-hydroxyphenyl)acrylate derivatives
2 and 2-aminophenols 3. A wide range of 2-aminophenols
electron-donating and electron-withdrawing groups were
hydroxyphenyl)acrylates
2
containing
a
wide range of
electronically diverse salicylaldehydes (see the Supporting
Information) to examine the effect these would have on the
outcome and selectivity of the proposed reaction. Thus,
appropriate
tetrahydrochromeno[4,3-b]quinolin-6-ones
enantioselectivities (98->99% ee) and diastereoselectivities
substrates
affording
trans-trans
with both high
4
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substituents other than bromine on the
5
position of
achieving complete conversions were encountered. Pleasingly, a
slight increase of catalyst loading to 2 mol % furnished the
corresponding cycloadducts 8a and 8b in satisfying yields.
salicylaldehyde were examined under our standard conditions
(Table 1). Pleasingly, the 5-fluoro and 5-chloro derivatives 2b and
2c were successfully engaged in the process affording the
corresponding trans-trans tetrahydrochromeno[4,3-b]quinolin-6-
ones 4b and 4c, respectively as single diastereomers in high
yields and with excellent enantioselectivities.[11] Furthermore,
substrates having a bulky substituent, such as a tert-butyl group,
at the 5-position 2d did not affect the cycloaddition reaction, and
tetraheterocycle 4d was isolated in 95% yield with 97% ee.
Notably, substrate 2e with an ester group on the salicyladehyde
moiety was proven to be a suitable reaction partner, accessing
the corresponding product 4e as a sole diastereomer in 91% yield
and 94% ee. Moreover, methyl substituents at 4-position of the
arene ring of salicyladehyde 2f was also tolerated, albeit with
slightly lower enantioselectivity (89% ee). Surprisingly, the
doubly-substituted on the salicylaldehyde moiety showed different
reactivity towards the intramolecular Povarov reaction. For
instance, the 3-bromo-5-chlorosalicylaldehyde derivative 2g
reacted smoothly to give the corresponding cycloadduct 4g as a
single diastereomer, in good yield and with high enantioselectivity
(98% ee). However, the 4,6-dimethoxysalicylaldehyde which is
more congested gave no product 4h under the same conditions.
Presumably steric hindrance and electronic effects are
responsible for this effect, some further work is required to clarify
this point.
In our previous work, we observed that presence of the 2-hydroxy
group on the 2-azadiene played an important role for the
asymmetric induction.[10] In this context, we were then interested
in investigating the influence of using other hydrogen-bond
donors on the enantioselectivity. 2-Aminothiophenol (3b) and
Boc-monosubstituted-1,2-diaminobenzene (3c) were tested in the
intramolecular IEDADA with 2a and 5a. Surprisingly, the
2-aminothiophenol (3b) appeared unreactive whatever linear
partner used, no desired product was isolated (4i or 6a), even at
higher temperature (50 °C). However, while no reaction was seen
with the linear precursor bearing an ester linker 2a, the bulky
diaminobenzene 3c reacted efficiently with 5a having an amide
linker. Indeed, the hexahydrobenzo[1,6]naphthyridinone 6b was
produced in nearly quantitative yield (99% yield) as a single
diastereomer but in lower enantioselectivity (76% ee).
Unfortunately, no improvement in enantioselectivity was observed
at lower temperature (79% ee, at 0 °C). This result suggests that
the enantioselectivity is sensitive to both steric and pka properties
of H-bond donor of 2-azadiene.
Table 1. Scope of the enantioselective intramolecular Povarov reaction with
ester-, amide-, and thioester-based substrates 2, 5 and 7. General reaction
conditions: 2, 5 or 7 (0.10 mmol), 3a (0.10 mmol), 1 (0.001 mmol, 1 mol%), 1,2-
DCE (1.0 mL), RT, 18 h. Yields after isolation of the product by filtration. The dr
values were determined by 1H NMR spectroscopic analysis to be higher than
99:1. The ee values were determined by HPLC analysis using a chiral stationary
phase. [a] The reaction was carried out with 0.002 mmol of 1 (2 mol%). [b] The
reaction was carried out with 0.005 mmol of 1 (5 mol%). [c]The reaction was
carried out at 0 °C.
The chiral phosphoric acid-catalyzed intramolecular Povarov
reaction was then extended to thioester linear precursor 7 for the
synthesis of medicinally important thiochromanes (Table 1).
Indeed, they hold a special interest in medicinal chemistry due to
their presence in a number of bioactive compounds showing anti-
HIV and antibacterial activities.[12] However, to the best of our
knowledge, such intramolecular cycloaddition remained unknown
even in racemic form. The reactions between 2-aminophenol 3a
and thioester derivatives 7 were performed under the optimized
reaction conditions. Even though excellent diastereo- and
enantioselectivity were observed as well, some difficulties in
To further demonstrate the efficiency and scope of the present
method, we next applied linear precursors 9 and 11 bearing an
ether or amine group as a linker between the aromatic aldehyde
ring and the styrene group to the chiral phosphoric acid-catalyzed
intramolecular Povarov reaction (Table 2). Precursors with an
ether group as linker, were smoothly converted to the
corresponding tetrahydrochromeno[4,3-b]quinolines 10a-e in
excellent
yields,
enantioselectivities
and
trans,trans-
diastereoselectivities.[11] Both electron-withdrawing and electron-
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11 (0.10 mmol), 3 (0.10 mmol), 1 (0.001 mmol, 1 mol%), 1,2-DCE (1.0 mL), RT,
18 h. Yields after isolation of the product by filtration. The dr values were
determined by 1H NMR spectroscopic analysis to be higher than 99:1. The ee
values were determined by HPLC analysis using a chiral stationary phase. [a]
The reaction was carried out with 0.005 mmol of 1 (5 mol%). [b] The reaction
was carried out with 0.002 mmol of 1 (2 mol%).
donating substituents at the 5-position of the salicylaldehydes
were tolerated well under the standard catalytic conditions. In
addition, 2-amino-5-methylphenol (3d) participated in the reaction
to form the corresponding cycloadduct 10f in 98% ee. Then, we
explored the cycloaddition to linear precursors with an amine
linker
11
to
provide
access
to
hexahydrodibenzo[b,h][1,6]naphthyridines 12. With 2 mol %
catalyst loading, various cycloadducts 12a-g were synthetized in
excellent yields, enantio- and diastereoselectivities.[11] Diversely
substituted 2-aminophenols 3 were suitable partners to afford the
corresponding cycloadducts 12b and 12c in high yields and
excellent enantioselectivities (98% ee). Modification of the
protecting group on N afforded the desired products 12f and 12g
with similar yields, although with slightly lower enantioselectivity
(87 and 89% ee). It is also worth noting that all formed
cycloadducts precipitated in the reaction vessel and were isolated
by filtration under pure form, thus demonstrating the smart
procedure's simplicity.
In order to demonstrate the synthetic utility of our process, a
representative cycloaddition was carried out on gram-scale
(Scheme 2). Before this, we attempted to lower the catalyst
loading. It was found that the reaction could still proceed smoothly
at a 0.2 mol % catalyst loading with 0.1 mmol of 2a to give 4a in
93% yield and 94% ee. To our delight, the reaction on 10-fold
bigger scale of the linear precursor 2a (1.00 mmol) with
2-aminophenol 3a furnished cycloadduct 4a in the same yield and
enantioselectivity for this reaction.
Scheme 2. Scale-up reaction employing 0.2 mol% of catalyst 1.
We were then intrigued by the mechanism of this reaction for
which two different mechanisms remain possible: a concerted
Diels–Alder reaction or
a stepwise Mannich/Friedel-Crafts
alkylation process (Scheme 3). In order to validate which pathway
is the most likely, we carried out a control experiment. First, we
reacted 2a, 3a and 1 in presence of alcohol in order to trap
intermediate A’ generated after the Mannich reaction. Since there
was no trapped intermediate observed in the reaction, we could
not conclude at this stage. We therefore conducted
a
computational study based on Density-Functional Theory (DFT)
Table 2. Scope of the enantioselective intramolecular Povarov reaction from
ether- and amine-based substrates 9 and 11. General reaction conditions: 9 or
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Scheme 3. Plausible reaction mechanisms and calculated energy of the
enantioselective intramolecular Povarov reaction without catalyst (G298
,
kcal/mol).
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Scheme 4. Calculated energy profiles of the enantioselective intramolecular Povarov reaction in presence of a bulky chiral phosphoric acid catalyst (G298, kcal/mol).
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using the Gaussian 09 software package at the M06-2X/6-
311+G**//M06-2X/6-31G* level[13] to distinguish between the two
potential mechanisms mentioned above (see the Supporting
Information for details). The uncatalyzed version of this
cycloaddition was first modeled with imine A as model substrate,
resulting from the reaction between 2a and 3a (Scheme 3). While
the formation of cycloadduct 4a is appreciably exergonic by 24.3
kcal/mol, its formation requires a quite high free energy of
activation of 27.5 kcal/mol (TSAB). These calculations support a
concerted mechanism but the uncatalyzed version seems unlikely
(see the Supporting Information).
Then, we studied the same reaction in presence of a chiral
sterically demanding phosphoric acid catalyst (Scheme 4A, see
also the Supporting Information for the effect of the steric
hindrance, compounds C–L). When the imine coordinates in a
bidentate fashion to the chiral phosphoric acid via a nine-
membered cyclic transition state, the formation of the cycloadduct
can then be modeled in a stepwise fashion (see the Supporting
Information for more details). The activated imine reacted with the
double bond. These electrons are pushed by the para-phenol
moiety, leading to the triply H-bonded compound N in an
endergonic way (3.4 kcal/mol) with a free energy cost of
10.0 kcal/mol (Scheme 4). The newly formed amine N could react
with the double bond via an exo attack to provide the intermediate
O. This step requires 7.6 kcal/mol of free energy of activation and
is exergonic by 10.1 kcal/mol. It is important to note that the
binding of the two phenol moieties by the chiral anionic
phosphoric acid could be considered from the compound N. This
displacement promoted the deprotonation of the phenoxonium
group and led to the resulting complex P, more stable than N by
13.3 kcal/mol. The formation of the second C-C bond was then
determined as kinetically favored from P, TSPQ being
Scheme 5. Calculated free energy of the recycling of the catalyst for a new
turn-over (G298, kcal/mol).
Further, these calculations allowed us to explain the origin of the
stereoselectivity observed during this process. Indeed, geometry
constraints prevent the rotation of either the aminophenol or of the
methylene phenoxonium moieties in ion pairs N or P, due to the
presence of the phosphoric acid catalyst. The dissociation of this
later would be necessary to allow this rotation movement.
However, since the second cyclization barriers are low (7.6 and
9.2 kcal/ mol respectively), the reaction would remain much faster
than any dissociation/rotation/cyclization sequence. Therefore,
the high level of stereocontrol of this process was guaranteed,
despite the sequential nature of the mechanism. Of note, the
simplified phosphoric acid catalyst used in this computational
study predicts the right enantiomer. The formation of the minor
enantiomer is clearly less kinetically favored (see the Supporting
Information).
11.7 kcal/mol more stable than TSNO
. The newly-formed
cycloadduct Q (-10.5 kcal/mol) was also more stable than the
compound O (-6.7 kcal/mol). We finally computed the entire
reaction sequence with a double activation of phenol groups by
the catalyst. In this case, the first cyclization seemed possible
from the ion pair R, more stable than the compound M by
Then, we were interested to rationalize the absence of reactivity
of dienophiles having a free OH group in ortho or meta
11.8 kcal/mol, with an energetic cost of 8.1 kcal/mol. Therefore, it positions.[10] The above computations were partially
turns out that the favored mechanism in the reaction between the
substrate A and the model bulky catalyst is a sequential
mechanism involving the intermediates M, R, P and Q in the given
order. As a result, these calculations suggested that phosphoric
reinvestigated and the results are shown in Scheme 4B,
respectively in black and green color (see the Supplementary
Information for more details). Unlike para series, the chiral
phosphoric acid could interact with the ortho-substituted
substrates via the formation of three hydrogen bonds, leading to
the complex M’. The following displacement of the phosphate
provide the corresponding compound R’ which is more unstable
than the para-substituted analogue R (7.1 vs -11.8 kcal/mol), due
to the lack of second hydrogen bond. Next, the formation of the
first carbon-carbon occurred, leading to the resulting compound
P’ in an endergonic way (18.8 kcal/mol) with a free energy cost of
14.2 kcal/mol. Here, the presence of only one hydrogen-bond
explained the great difference of energy between P’ and its para-
substituted analogue P (18.8 kcal/mol vs -9.9 kcal/mol). Ion pair
Q’ finally resulted from the formation of the second bond, in an
exergonic way by 24.8 kcal/mol. In conclusion, the extra
stabilization of M’ as well as the lack of a second hydrogen bond
acids favored
a
stepwise reaction pathway, with ionic
intermediates, rather than a concerted one. Moreover, the
computed pathway involving the two phenol functions appeared
thermodynamically favored, even though various computed
pathways seemed viable with the model phosphoric acid used in
the computations. The renewable of the catalytic cycle was also
studied by calculating the energy barrier of the recycling reaction
of the chiral catalyst (Scheme 5). Calculations showed us that the
free energy of the reaction of Q with the substrate A to give M and
the final product 4a is exergonic by 13.6 kcal/mol. As a result, the
disassociation/association process of the catalyst is
thermodynamically favored.
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[1]
[2]
a) L. Zhi, C. M. Tegley, B. Pio, J. P. Edward, M. Motamedi, T. D. Jones,
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in species R’ and P’, involved very highly energetic transition
states of the cycloaddition TSR’P’ and TSP’Q’ compared to those
implied in the para series (21.3 and 20.7 kcal/mol vs -3.7
and -0.7 kcal/mol respectively). Such important energetic
differences could be the origin of the lack of the reactivity in the
ortho series. Despite the possible formation of two hydrogen
bonds between the catalyst and the phenol moieties of the
intermediates R’’ and P’’, the same issues are encountered in the
meta series. Indeed, even though the implied transition states
TSR’’P’’ and TSP’’Q’’ are more accessible than in the ortho series
(17.3 and 17.7 vs 21.3 and 20.7 kcal/mol), the entire reaction
sequence appeared endergonic in this case.
K. Nagaiah, A. Venkatesham, R. Srinivasa Rao, V. Saddanapu, J. S.
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Conclusion
In summary, we have disclosed
a highly efficient and
stereoselective enantioselective intramolecular Povarov reaction
using primary anilines as azadienes precursors. By using a bulky
chiral phosphoric acid as catalyst, a wide range of diverse
complex tetracyclic heterocycles were prepared with high yields
and excellent diastereo- and enantioselectivities without any
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required
purification
step.
Chiral
and
hexahydrodibenzo[b,h][1,6]naphthyridines
tetrahydrothiochromeno[4,3-b]quinolin-6-ones, which had never
been reported before, were readily synthesized in
a
stereoselective manner according to this process. Use of
low-catalyst loading, intramolecular Povarov reaction was
successfully accomplished, facilitating the synthesis of
tetrahydrochromeno[4,3-b]quinolones on increased scale in a
cost-effective manner. Finally, the theoretical studies revealed
that the reaction proceeded via a stepwise mechanism.
Experimental Section
2-Aminophenol 3a (0.1 mmol, 1 eq.) was added in one portion to a solution
of substrate 2, 5, 7, 9, or 11 (0.1 mmol, 1 eq.) and the appropriate amount
of TRIP catalyst 1 (0.001 or 0.002 mmol, 1 or 2 mol%) in 1,2-DCE (1 mL,
0.1 M). The reaction mixture was vigorously stirred overnight at room
temperature, heptane (2 mL) was then added, and the resulting mixture
was stirred for a further 10 min. The solution was filtered, and the resulting
solid was washed three times with pentane and then solubilized with
MeOH. The solvent was removed under reduced pressure to give the
desired product 4, 6, 8, 10, or 12 in pure form.
[7]
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Acknowledgements
We thank the CNRS and its ICSN unit for financial support. L.J.
gratefully acknowledges the Saclay University for a doctoral
fellowship. V. G. thanks U-Psud and Ecole Polytechnique for
financial support.
Keywords: chiral phosphoric acids • cycloaddition • tetracyclic
heterocycles • hydrogen bonds • intramolecular Povarov reaction
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10.1002/chem.201904902
Chemistry - A European Journal
RESEARCH ARTICLE
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which the absolute configuration was assumed by analogy with the
cycloadducts obtained in our previous works (see reference [10]).
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10.1002/chem.201904902
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RESEARCH ARTICLE
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A
highly efficient intramolecular
Lucie Jarrige, Vincent Gandon,*
Povarov reaction catalyzed by a chiral
phosphoric acid has been developed.
Various angular fused heterocycles
were obtained in high yields with
Géraldine Masson*
Page No. – Page No.
Enantioselective synthesis of
complex fused heterocycles via chiral
phosphoric-acid catalyzed
intramolecular inverse-electron
demand aza-Diels-Alder reaction
excellent
diastereo-
and
enantioselectivities. DFT calculations
was utilized to obtain better insight into
the mechanistic features of the chiral
Brønsted acid catalyzed aza-Diels-
Alder reaction.
Layout 2:
RESEARCH ARTICLE
Author(s), Corresponding Author(s)*
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Title
Text for Table of Contents
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