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Enantioselective Redox-Divergent Chiral Phosphoric
Acid Catalyzed Quinone Diels–Alder Reactions
Thomas Varlet, Coralie Gelis, Pascal Retailleau, Guillaume Bernadat, Luc
Neuville, Geraldine Masson
To cite this version:
Thomas Varlet, Coralie Gelis, Pascal Retailleau, Guillaume Bernadat, Luc Neuville, et al..
Enantioselective Redox-Divergent Chiral Phosphoric Acid Catalyzed Quinone Diels–Alder Reac-
tions. Angewandte Chemie International Edition, Wiley-VCH Verlag, 2020, 59 (22), pp.8491-8496.
�10.1002/anie.202000838�. �hal-03009619�
HAL Id: hal-03009619
https://hal.archives-ouvertes.fr/hal-03009619
Submitted on 20 Nov 2020
HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entic research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diusion de documents
scientiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.
Enantioselective Redox-Divergent Chiral Phosphoric
Acid Catalyzed Quinone Diels–Alder Reactions
Thomas Varlet, Coralie Gelis, Pascal Retailleau, Guillaume Bernadat, Luc
Neuville, Geraldine Masson
To cite this version:
Thomas Varlet, Coralie Gelis, Pascal Retailleau, Guillaume Bernadat, Luc Neuville, et al..
Enantioselective Redox-Divergent Chiral Phosphoric Acid Catalyzed Quinone Diels–Alder Reac-
tions. Angewandte Chemie International Edition, Wiley-VCH Verlag, 2020, 59 (22), pp.8491-8496.
�10.1002/anie.202000838�. �hal-03009619�
COMMUNICATION
Enantioselective Redox-Divergent Chiral Phosphoric Acid-Catalyzed
Quinone Diels–Alder Reactions
Thomas Varlet,
[a]‡
Coralie Gelis,
[a]‡
Pascal Retailleau,
[a]
Guillaume Bernadat,
[b]
Luc Neuville
[a]
and
Géraldine Masson
[a]
*
Abstract: An efficient enantioselective construction of
tetrahydronaphthalene-1,4-diones as well as dihydronaphthalene-
1,4-diols via a chiral phosphoric acid catalyzed quinone Diels–Alder
reaction with dienecarbamate was reported. The nature of the
protected group on diene was key to the success showing a
remarkable influence for achieving high enantioselectivity. The
divergent “redox” selectivity is controlled by adequate amount of
quinones used. Reversible redox switching without erosion of
enantioselectivity was possible from individual redox isomers.
Quinones have been recognized as important units because of
their rich and important reactivity.
[1]
Indeed, the reversible redox
properties
[2]
of the couple benzoquinone/hydroquinone play a
central role in a number of biological systems.
[3,4a]
Among these,
the two redox isomers
dihydronaphthalene-1,4-diol 1 and
tetrahydronaphthalene-1,4-dione 2 (Scheme 1, A), are valuable
structural units found in various natural products.
[4]
In 1928, Diels and Alder uncovered an easy transformation
allowing to build hydronaphthoquinonoids,
[4b,5]
and since then the
[4+2] cycloaddition involving quinones has continuously been an
active research area.
[4b,6]
Early on, it has been recognized as a
valuable tool for the synthesis of natural products, as first
demonstrated by Woodward during the total synthesis of
steroids.
[7]
However, in spite of a long history, catalytic quinone
centered enantioselective [4+2] cycloaddition remains
underdeveloped.
[8]
Moreover, as far as we are aware, there is still
no example of enantioselective process targeting selectively at
will both, the reduced or oxidized form of the naphthoquinone
through Diels-Alder (DA) reaction.
Efficient asymmetric quinone DA reactions are known (Scheme 1,
B),
[1a,b,9]
but essentially rely on the use of biased or suitably
designed quinones (masked ones,
[10]
bearing an additional
activation site
[11]
or substituted with sterically and electronically
demanding groups).
[12]
Indeed, reaction with unbiased
benzoquinones, remains a significant challenge, as the presence
of two potential carbonyl binding sites for the catalyst and two
reacting C=C bonds in the quinone render the enantiocontrol
rather difficult. Only very few efficient enantioselective DA
reactions with simple quinones have been developed so far. The
first example was reported in 2001 by White et al. using a (S)-Bi-
2,2-naphthotitanium dichloride complex as catalyst for the
enantioselective synthesis of (-)-ibogamine.
[13]
In 2005, Jacobsen
et al. described a highly enantioselective quinone DA reaction
catalyzed by a monomeric tridentate [(Schiff base)Cr
III
]
complex.
[14]
However it should be noticed that a single example
using benzoquinone was documented and a moderate
enantiomeric excess value was obtained. More recently, Coeffard,
Greck et al. reported an elegant enantioselective organocatalytic
sequential oxidative quinone DA reaction / Michael reaction
sequence.
[15]
Despite these notable achievements, general and
broadly applicable catalytic enantioselective DA reaction,
moreover leading selectively to the quinone or hydroquinone form,
is still unprecedented. Therefore, the development of a not only
highly stereocontrolled, but also a divergent process to reach both
redox isomers, would be significantly rewarding.
Scheme 1. Quinone DA reaction.
Our interest in catalytic, enantioselective cycloaddition extends
back over several years.
[16]
We originally reported an
enantioselective (3+2) cycloaddition of benzoquinones and
enecarbamates using chiral phosphoric acids as catalysts.
[16e]
Inspired by this work and our recent success in the development
of a variety of cycloadditions with dienecarbamates,
[12d,g,j,16]
we
envisaged an enantioselective switchable process
[18]
to access
hydronaphthoquinonoids.
[19]
Redox-selective phosphoric acid-
catalyzed asymmetric DA reaction of dienecarbamates and
[a] T. Varlet,
‡
Dr. C. Gelis,
‡
P. Retailleau, Dr. L. Neuville, Dr. G.
Masson
Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-
Saclay, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex,
France
Fax: +33 1 69077247
E-mail: geraldine.masson@cnrs.fr
[b] G. Bernadat
Laboratoire Chimie Thérapeutique, Faculté de Pharmacie – Biocis
8076, LabEx LERMIT,5, rue J.B Clément, 92296 Châtenay Malabry
[
‡
] These authors contributed equally to this work;
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
COMMUNICATION
unbiased quinones should lead to both enantioenriched
dihydronaphthalene-1,4-diols 4 and tetrahydronaphthalene-1,4-
diones 5 according to a judicious choice of the experimental
conditions. In addition, considering access to both redox isomers,
allows to envisage the reversible redox interconversion between
4 and 5. We report herein the first enantioselective redox-
divergent quinone DA reaction leading to tetrahydronaphthalene-
1,4-diones and/or dihydronaphthalene-1,4-diols in high yields with
excellent regio-, diastereo-, and enantioselectivities (Scheme 1,
C). In addition, conditions allowing fully reversible switching
between both isolated redox isomers were established. Finally,
versatile post transformations increased the accessible molecular
diversity from individual isomers.
Table 1. Survey of Reaction Conditions for Enantioselective [4+2]
Cycloaddition
[a]
Entry
Ratio 6:7
(Y:Z)
4 Yield
[%]
[b]
4 ee
[%]
[c]
5 Yield
[%]
[b]
5 ee
[%]
[c]
1
1:1
59 [4a]
46 [4a]
17 [5a]
49 [5a]
2
1:0.8
93 [4a]
49 [4a]
-
-
3
[d]
1:3
ND
ND
96 [5a]
60 [5a]
4
1:1
92 [4b]
92 [4b]
< 5 [5b]
92 [5b]
5
1:0.8
99 [4b]
93 [4b]
-
-
6
1:3
-
-
90 [5b]
90 [5b]
7
[d]
1:3
-
-
87 [5b]
94 [5b]
8
[e]
1:0.8
98 [4a]
-
-
-
9
[e]
1:0.8
34 [4b]
-
34 [5b]
-
10
[f]
1:0.8
94 [4b]
93 (4b)
-
-
11
[d,f]
1:3
-
-
93 [5b]
92 [5b]
[a] Reaction conditions: 7a (Y time 0.05 mmol), 6 (Z time 0.05 mmol) and 8
(0.00125 mmol) in 1.0 mL of toluene for 24 h. [b] Yields refer to
chromatographically pure all cis-isomer 4 determined to be higher than 98/2 by
1
H NMR. [c] ee values were determined by HPLC with a chiral stationary phase.
[d] at 0°C. [e] Without catalyst. [f]
With 1 mmol of 6b.
As a model reaction, we investigated the reactivity of benzyl
(penta-1,3-dien-1-yl) carbamate 6a with p-benzoquinone 7a in the
presence of 2.5 mol % of (S)-6,6'-bis(1-naphthyl)-SPINOL
phosphoric acid 8. While hexahydronaphthalene-1,4-dione 3a
was not isolated after purification, we identified the cis-
tetrahydronaphthalene-1,4-dione 4a (49% yield) along with cis-
dihydronaphthalene-1,4-diol 5a (17% yield). However, the
enantioselectivity for both 4a and 5a did not exceed 50% ee. This
preliminary result encouraged us to investigate different
conditions in an attempt to improve enantioselectivity and redox-
selectivity. Unfortunately, no better result was achieved in further
screening of catalysts and solvents (Cf Tables S1 and S2 in
Supporting Information). However, changing the N-protecting
group of 6 from carbamate to (S)-thiocarbamate gave rise to a
dramatic increase in enantioselectivity (4b: 92% ee and 5b: 92%
ee, entry 4). Additionally, the redox-selectivity was enhanced but
not satisfactory yet. To address this issue, we reasoned that since
the tetrahydronaphthalene-1,4-dione 5 probably resulted from the
oxidation of 4 by the unreacted quinone 7a, it should be possible
to control its formation according to the amount of quinone
used.
[20]
Indeed, with 0.8 equiv. of 6a, the dihydronaphthalene-
1,4-diol product 4b was obtained almost exclusively and isolated
in excellent yield (99%, entry 5). It should be noted that such
hydroquinone form is sensitive to autooxidation and often requires
further functionalization to be isolable,
[21]
which was not required
in our case. In contrast, as already noted by others,
[12j]
when an
excess amount of quinone (3 equiv.) was used in the reaction
mixture, the targeted tetrahydronaphthalene-1,4-dione 5b was
exclusively produced at RT (entry 6) with highest enantiocontrol
at 0 °C (entry 7).
Scheme 2. Scope of the enantioselective synthesis of dihydronaphthalene-1,4-
diols 4.
[a,b,c,d]
[a] General reaction conditions: 6 (0.06 mmol), 7 (0.05 mmol) and
8 (0.00125 mmol) in toluene at RT for 24 h [b]
Yield of isolated pure product
after column chromatography. [c]
Determined by HPLC analysis on a chiral
stationary phase. [e]
The relative configuration was assigned based on NOESY
spectroscopy (Cf. Supporting Information)
Having established the optimized conditions, the scope of
enantioselective synthesis of dihydronaphthalene-1,4-diol 4 using
a slight deficit of benzoquinones was explored (Scheme 2). In
general, good yields and excellent regio-, diastereo-, and
enantioselectivities (up to 98% ee) were obtained in this
asymmetric [4+2] cycloaddition/aromatization sequence
COMMUNICATION
regardless of the substituents at the γ position of 6. For instance,
diene-thiocarbamates bearing different linear alkyl groups were
converted to the corresponding cycloadducts 4b-4e with excellent
yields and enantioselectivities. Additional functional groups (such
as silyl ether, 4f) could also be introduced into 4 without any
influence on the results. Noteworthy is that the diene (S)-
thiocarbamate derived from (S)-citronellol gave 4g as a single
diastereomer in an excellent yield and enantioselectivity. In a
similar manner, the diene γ-substituted by phenyl led to product
4h in 98% yield with 88% ee. Pleasingly, other benzoquinones
reacted smoothly to give the corresponding dihydronaphthalene-
1,4-diols 4i-4m with excellent regio- and enantioselectivities. The
electronic property of the quinone ring did not affect much the
enantioselectivity, but did impact the yield. For instance, quinones
bearing weak electron-donating substituents produced the
corresponding products in good yields (4j and 4l), although
electron poor (4i and 4m) and strongly electron-rich (MeO group,
4k) substituents showed lower yields. Sterically demanding
substituted quinones (t-Bu substituted one, 4l) were also well
tolerated. Challenging symmetrical disubstituted p-
benzoquinones such as 2,5-dimethylquinone provided the
corresponding hexahydronaphthalene-1,4-dione 3c and 3d with a
complete control of configuration at all four stereocenters (96%
ee).
Scheme 3. Scope of the enantioselective synthesis of tetrahydronaphthalene-
1,4-diones 5.
[a,b,c,d,e]
[a] General reaction conditions: 6 (0.06 mmol), 7 (0.15
mmol) and 8 (0.00125 mmol) in toluene at 0 °C for 24 h [b]
Yield of isolated pure
product after column chromatography. [c]
Determined by HPLC analysis on a
chiral stationary phase. [e] The absolute configuration (1S,4R) was assigned by
X-ray single crystal structure analysis of enantioenriched 5c (see Supporting
Information.
We next turned our attention to the scope of enantioselective DA
reaction/oxidation sequence (Scheme 3). A variety of selected
thioenecarbamates 6 reacted with similar diastereo- and
enantioselectivities in comparison to the model reaction. As
previously, the reaction conditions tolerate various substituent
patterns on the p-benzoquinones 7 such as methyl and chloride
providing the tetrahydronaphthalene-1,4-diones 5h and 5i in 86%
and 87% yields, respectively, with total regio- and
diastereoselectivity and excellent enantiomeric excesses (up to
96% ee). Interestingly, use of allyl thiocarbamate diene instead of
benzyl analogue also yielded to cycloadduct 5j in good yield and
enantioselectivity. It can be noted that cis-tetrahydronaphthalene-
1,4-diones 5 were generally obtained with slightly higher
enantiomeric excess when compared to analogous
dihydronaphthalene-1,4-diols 4; difference in reaction
temperature (0° C vs rt) can account for this increase.
Relatively few mechanistic studies on quinones centered [4+2]
cycloaddition have been conducted but a concerted
mechanism
[22]
rather than a stepwise
[23]
mechanism has been
often suggested. However, based on a recent theoretical study, a
stepwise ionic mechanism has been proposed.
[12m]
In this context,
to determine whether the cycloaddition proceeds through a
stepwise or concerted mechanism, we evaluated the effect of
substituents on the quinone ring. Correlations between the
Hammett parameters (σ) of quinone substituents and the
corresponding conversions obtained after 5 min (Cf Supporting
Information) have shown a drop in yields in the presence of
substituents with σ values inferior or superior to 0. The concave
downward deviation indicates a maintained mechanism, but a
change in rate determining step;
[24]
in other world, they are at least
two steps, which excludes a concerted mechanism.
[25]
In addition,
when the reaction was carried out with 1,4-benzoquinone and
trifluoromethylated-one and diene 6b in toluene-d
8
as solvent
under standard conditions, an imine intermediate 10 was
observed by
1
H-NMR (Cf Supporting Information). Further
characterization of the imine 10 could not be achieved, as 10
gradually evolves to cycloadduct 3 (Cf Supporting Information).
[26]
These findings fully support that the reaction operates in a
stepwise fashion which involves 1,4-Michael addition and
intramolecular Mannich reaction (Scheme 4, 9 to 3).
Scheme 4. Activation models and possible reaction mechanism.
Subsequently, additional experiments were undertaken to gain
more insight into the redox-switch. Firstly, the cycloadditions
between 6b and 7a were carried out under both conditions (0.8
and 3 equiv. of 7a) and monitored by
1
H NMR spectroscopy. In