Chiral Phosphoric Acid-Catalyzed Enantioselective Construction of 2,3-Disubstituted Indolines

Article abstract of DOI:10.1021/acs.orglett.0c03947

Highly enantio- and regioselective (3 + 2) formal cycloaddition of β-substituted ene- and thioenecarbamates as well as cyclic enamides with quinone diimides catalyzed by a BINOL- and SPINOL-derived phosphoric acid is reported. A wide variety of 2,3-disubstituted 2-aminoindolines, including polycyclic ones, were prepared in generally high yields (up to 98%) with moderate to complete diastereoselectivities and in most cases excellent enantioselectivities (up to 99% ee).

Full text of DOI:10.1021/acs.orglett.0c03947

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Letter
Chiral Phosphoric Acid-Catalyzed Enantioselective Construction of
2,3-Disubstituted Indolines
Wei-Yang Ma,§ Coralie Gelis,§ Damien Bouchet, Pascal Retailleau, Xavier Moreau, Luc Neuville,
́
and Geraldine Masson*
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ABSTRACT: Highly enantio- and regioselective (3 + 2) formal cycloaddition of β-substituted ene- and thioenecarbamates as well
as cyclic enamides with quinone diimides catalyzed by a BINOL- and SPINOL-derived phosphoric acid is reported. A wide variety of
2,3-disubstituted 2-aminoindolines, including polycyclic ones, were prepared in generally high yields (up to 98%) with moderate to
complete diastereoselectivities and in most cases excellent enantioselectivities (up to 99% ee).
hiral 2,3-disubstituted indolines are privileged hetero-
cyclic rings that are frequently encountered in various
(3 + 2) cycloaddition is one of the most convergent
methods for the synthesis of five-membered heterocycles fused
with aromatic rings.5 More specifically, (3 + 2) formal
cycloaddition of quinones (or quinone monoimines) with
electron-rich alkenes affords a convenient synthesis of
dihydrofurans, the oxygen analogues of indolines.4r,6,7 The
aza variant8 of this reaction using quinone diimides9 to
produce indolines has not been well-explored. Furthermore, in
these examples, there are few methods to synthesize 2,3-
disubstituted indolines.8d,e Indeed, while the chemistry of
quinone diimides is rich, their unfriendly preparation (often
relying on lead tetraacetate), their sensitivity toward hydrolysis
of the carbon−nitrogen double bond, and their redox
properties leading to self-rearomatization or oxidative
coupling10 hamper their wide use.11 In this context, it is not
surprising that catalytic enantioselective transformations
involving quinone diimides remain extremely rare.12 To the
best of our knowledge, only one example of an enantioselective
cycloaddition involving p-quinone diimides has been recently
reported.4x We describe here the development of chiral
C
natural bioactive alkaloids (e.g., (−)-physostigmine, (+)-aspi-
dospermidine, and pircrinine; Figure 1)1 and biologically active
Figure 1. Representative bioactive indolines and indoline derivatives.
drugs (e.g., pentopril and relcovaptan).2 In addition, they have
been successfully employed as chiral auxiliaries and organo-
catalysts in asymmetric synthesis.3 As a result, several
asymmetric catalytic approaches have been established for
the construction of indoline rings.4 Despite these elegant
achievements, the development of novel asymmetric synthetic
routes for 2,3-disubstituted indolines is still highly desirable.
Received: November 29, 2020
Published: January 6, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03947
© 2021 American Chemical Society
Org. Lett. 2021, 23, 442−448
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phosphoric acid (CPA)-catalyzed enantioselective formal (3 +
2) cycloaddition of quinone diimides and enecarbamates that
provides simple and practical access to 2,3-disubstituted
indolines (Scheme 1).
Table 1. Optimization of the Catalytic Enantioselective
Synthesis of Indolines
a
Scheme 1. Catalytic Enantioselective Formal (3 + 2)
Cycloaddition with Quinone Derivatives
b
c
de
,
entry
cat
2
solvent
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4d
4e
4d
4e
4e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
93
91
66
92
91
98
93
72
93
94
5:1
5:1
5:1
5:1
5:1
6:1
6:1
6:1
6:1
6:1
(+) 34
(+) 32
(+) 43
(+) 98
(−) 98
(+) 98
(+) 98
(+) 98
(−) 98
(−) 94
We previously reported a CPA-catalyzed enantioselective (3
+ 2) cycloaddition reaction of quinones with ene- and
thioenecarbamates.7a The reaction has a broad scope, offering
2,3-disubstituted 2-amino-2,3-dihydrobenzofurans with high
enantioselectivity. The diastereoselectivity is highly dependent
on the protecting group on the nitrogen atom of the
dipolarophile: the thiocarbamates gave high selectivity in
favor of the trans isomer, while the reactions with the
enecarbamates were poorly diastereoselective.
f
f
10
a
General conditions: 1a (0.10 mmol), 2a (0.12 mmol), and Cat (5
b
mol %) in solvent (0.1 M) at rt for 16 h. Yields of isolated pure
c
1
products after chromatography. Determined by H NMR analysis.
d
(+) refers to the (2S,3S) absolute configuration and (−) to the
On the basis of our previous work,7a,13 we initially
investigated the reaction between p-quinone di-p-toluenesulfo-
nimide (1a) and (E)-thioenecarbamate 2a in the presence of a
CPA catalyst (Table 1).14 Pleasingly, the desired 2,3-
disubstituted 2-aminoindoline 3a was obtained in high yield
albeit, with moderate selectivity, by the use of 5 mol % 4a as
the catalyst in toluene at room temperature for 16 h (entry 1).
To increase both the diastereo- and enantioselectivity of this
reaction, a series of CPA catalysts 4 were evaluated (entries 1−
5). Catalyst 4d bearing 2,4,6-triisopropylphenyl groups at the
3- and 3′-positions of BINOL as well as catalyst 4e derived
from SPINOL and having 1-naphthyl groups at the 6- and 6′-
positions provided the desired product with much better
enantioselectivity (98% ee; entries 4 and 5), but the
diastereomeric ratio was not significantly influenced by the
catalyst choice. A slight increase in the trans diastereoselectivity
was observed with CH2Cl2 as the solvent (entry 6 vs 4). On
one side, reducing the catalyst loading of 4d to 2.5 mol % led
to a reduction in yield (entry 8 vs 6). On the other side, no
activity loss was noted when 2.5 mol % 4e was used (entry 9 vs
7), thereby providing conditions that were selected for further
investigations. When we conducted the reaction with
enecarbamate 2b, the corresponding cycloadduct 3b was
formed with similar diastereo- and enantioselectivity as 2a,
thus indicating (contrary to our previous work)7a that the
protecting group of 2 did not have too much influence on the
stereoselectivity. Other solvents such as CHCl3, CH3CN,
THF, and toluene were evaluated to improve the diaster-
eoselectivity (see the Supporting Information). Although a
higher diastereomeric ratio was found only in THF (8:1), the
yield was reduced substantially.15 All attempts to separate the
diastereomers were unsuccessful.
(2R,3R) configuration as assigned by analogy to the X-ray crystal
structure analysis of 3c (see the Supporting Information).
e
f
Determined by HPLC analysis on a chiral stationary phase. With
2.5 mol % 4.
worked well for selected protecting groups bonded to the
nitrogen of 2, including benzyloxy, prop-2-yn-1-yl, and tert-
butoxy carbamates. A range of linear β-substituted ene- and
thioenecarbamates 2 reacted successfully, affording the
corresponding 2-aminoindolines 3c−k in high yields with
excellent enantioselectivities. An additional benzyl ether
functional group was well-tolerated on the enecarbamate,
providing cycloadduct 3f with good enantioselectivity. The
enecarbamate bearing an ethylbenzene side chain also
furnished a high level of enantioselectivity (3g, 99% ee). To
our satisfaction, the ene- and thioenecarbamate substituted
with an isopropyl group at the β-position furnished
compounds 3h and 3i with excellent diastereoselectivity
(10:1 to 14:1) possibly revealing a significant substrate control
effect. However, a slight decrease in enantioselectivity was
observed for the thioenecarbamate compared with the
enecarbamate. Surprisingly, performing the reaction with an
unsubstituted cyclopropyl side chain instead of an isopropyl
group led to a drastic reduction in diastereoselectivity, but the
enantioselectivity was kept high (3j; 2:1 dr, 98% ee). Only
trace of product was formed with the enecarbamate bearing a
phenyl group at the 2-position (data not shown). The presence
of an enantiopure predefined chiral center on the enecarba-
mate moiety did not interfere with catalyst induction. Hence,
compound 3k was prepared in 93% yield with 95% ee and a
satisfactory 4:1 diastereoselectivity relative to the two newly
formed chiral centers.
Having identified the optimum conditions (Table 1, entry
9), we explored the generality of the reaction by employing
different enecarbamates (Scheme 2). In general, the reactions
Alternative quinone diimines bearing various protecting
groups and substituents were also investigated. On the one
hand, dimethylsulfonimide uneventfully participated in the
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noteworthy because the corresponding methyl bis(tosyl)
imine was reluctant to form compound 3p.16 Boc-protected
quinone diimides having a stronger electron withdrawing
group such as NO2 were not stable enough to perform the
reaction (data not shown).16 We also demonstrated that the
reaction could be easily performed on a 1.0 mmol scale to
prepare cycloadduct 3c with 4d as the catalyst in similar yield
and selectivity as on the smaller scale, thus demonstrating the
practicality of this process (Scheme 2).
Scheme 2. Scope of the Enantioselective Formal (3 + 2)
Cycloaddition
a b c d
, , ,
The reaction could be further extended to the synthesis of
polycyclic structures using cyclic enecarbamates, and tetrahy-
dro-11aH-benzo[a]carbazol-11a-amide (6a) was obtained
from the corresponding benzyl (3,4-dihydronaphthalen-1-
yl)carbamate (5a) and Boc-protected quinone diimine 1f
(Scheme 3). Refinement of the reaction conditions, namely,
Scheme 3. Enantioselective (3 + 2) Formal Cycloaddition
a b c d
, , ,
with Cyclic Enes
a
General conditions: 1 (0.10 mmol), 2 (0.12 mmol), and 4e (2.5 mol
b
%) in CH2Cl2 (0.1 M) at rt for 16 h. Yields of isolated pure products
after chromatography are shown. The ee values were determined by
c
d
HPLC analysis on a chiral stationary phase. The dr values were
a
General conditions: 1 (0.10 mmol), 5 (0.20 mmol), and 4d (5 mol
e
f
determined by 1H NMR analysis. With 5 mol % 4d. With 1 mmol of
2.
b
%) in CH2Cl2 (0.1 M) at rt for 16 h. Yields of isolated pure products
after column chromatography are shown. The ee values were
determined by HPLC analysis on a chiral stationary phase. The dr
values were determined by H NMR analysis.
c
d
1
cycloaddition, giving 3l with 99% ee. On the other hand,
carboxybenzyl or acyl bisprotected diimines were not suitable
partners for the transformation (data not shown).16 However,
it was possible to move away from sulfonyl-type protection as a
Boc-protected quinone diimine delivered compound 3m in
excellent yield. With regard to enantioselectivity, SPINOL-
derived CPA 4e was far from ideal for such precursors. A brief
optimization revealed that 4d was suitable for high
enantioselective induction (see the Supporting Information).
These Boc-protected imines also tolerated substituents on the
quinone core. Methyl and chlorine were fully tolerated,
delivering compounds 3n and 3o as single regioisomers in
good yields and enantioselectivities. This is particularly
using 2.0 equiv of Boc-protected quinone diimide in an
otherwise identical setting, significantly improved the outcome
of the reaction, furnishing the desired product as a single
diastereoisomer in 85% yield with 80% ee. Cyclic acetamid-
es7e,17 derived from dihydronaphthalene, indene, and 2H-
chromene behaved particularly well in the transformation,
furnishing compounds 6b, 6d, and 6f in yields ranging from
82% to 96%, each time as a single diastereoisomer and with
nearly perfect enantioselectivity (≥99%). The presence of a
ring fusion in the acetamide seems to be an important factor to
achieve high enantioselectivity. Indeed, while N-(cyclohex-1-
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en-1-yl)acetamide allowed the synthesis of compound 6e in
excellent yield, only modest enantioselectivity was observed in
that case. The synthesis of highly enantioenriched adduct 6c
from methyl-substituted Boc-protected quinone diimine, albeit
in modest yield, is noteworthy since substitution of quinoid
monoimides is reported to hamper reactivity.7e In the initial
evaluation, the reaction of tosyl-protected quinone diimine 1a
with cyclic enamide was sluggish and long. A solubility issue
was identified as the main problem, and upon simple dilution
(×4), 6g could be isolated in a satisfying yield. Furthermore, a
less reactive cyclic enethiourea13b could also react with Boc-
protected quinone diimide to form the single diastereomer 6h
with excellent diastereoselectivity, albeit in modest yield and
enantioselectivity. Finally, the seven-membered cyclic enamide
5g was successfully employed in the present reaction, affording
the expected cycloadduct 6i in 94% yield with 3:1 dr and 76%
ee.
Scheme 5. Plausible Reaction Mechanism
As we could expect, dihydrofuran 3q was obtained as the
sole regioisomer when quinone monoimide 1e was reacted
with enecarbamate 2c (Scheme 4a).7b−d Complete selectivity
Scheme 4. Chemoselectivity of the Enantioselective (3 + 2)
Formal Cycloaddition
we became interested in pursuing control experiments to
propose a possible stereochemical model. No reaction
occurred when either an acyclic or cyclic tertiary enecarbamate
(2m or 2n, respectively) was employed as the dipolarophile
(Scheme 6). This suggests that the NH group of 2/6 plays a
Scheme 6. Control Experiments and Further
Transformations
was also observed when equal amounts of bis-Boc- and bis-
tosyl-protected imines (1f, 1a) were reacted with a limiting
amount of cyclic enamide 5a, furnishing exclusively compound
6b (Scheme 4b). Such selectivity was not a simple
consequence of solubility and could be further exploited for
the selective synthesis of heteroprotected compounds 3r and 6i
from the single heteroprotected quinone diimine 1j. While
higher azaphilicity of phosphoric acids compared with
oxaphilicity is well-known,7b,d,e,13e these results also establish
a relative affinity of such catalysts to differently N-protected
species. To the best of our knowledge, this represents the first
example in which CPAs were able to differentiate two common
nitrogen protecting groups in an enantioselective reaction.
On the basis of work by us7a and others,7b,d,e a possible
mechanism (Scheme 5) can be proposed that comprises the
following steps: Michael addition, isomerization, and intra-
molecular aminalization. This stepwise process is supported by
crucial role in the successful activation for the cycloaddition to
proceed smoothly. In addition, the reaction of 1a with β,β-
disubstituted enecarbamate 2o in the presence of 4e afforded
the corresponding cycloadduct 3s in nearly racemic form. This
result rules out the possibility that the catalyst maintained a
hydrogen bond with imine intermediate B to control the
asymmetric induction of the hemiaminal stereogenic center.
X-ray diffraction of 3c allowed us to determine the absolute
configuration of both diastereoisomers obtained with catalyst
(R)-4d. The configuration of the major trans isomer was
assigned as (2S,3S), while that of the minor cis isomer was
found to be (2R,3S). The absolute configurations of 6b and 6g
were also elucidated by X-ray analysis and found to be
1
the observation in the crude H NMR spectra of aldehyde
traces arising from hydrolyzed imine intermediate B/B′. Then
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(6aR,11aS), thereby highlighting that the protecting group did
not change the sense of selectivity. On the basis of these
results, two transition state models TS-A and TS-A′ in which
both substrates are activated at the same time by the catalyst,
with the formation of double hydrogen bonding, can be
proposed. According to Goodman’s proposal,18 electrophiles
and nucleophiles can be placed following type I or type II
arrangement. However, minimizing steric clashes with geo-
metrically defined enes and keeping in mind that reacting
centers of the nucleophile and the electrophile must be in close
proximity for reactivity allows building two favorable arrange-
ments of type I (also see the Supporting Information). Thus,
the acyclic enecarbamate would attack from the quinone
diimide Re face, while the cyclic derivative would attack from
the Si face using (R)-4d. Following a possible partial
decomplexation, tautomerization would lead to intermediate
B/B′ in which aniline would attack the acyl iminium, leading
to the final compound.
Interestingly, selective deprotection of the Cbz group could
be achieved. Indeed, hydrogenation of 3c with Pd−C at 70 °C
in a H2O/MeOH solvent mixture gave hemiaminal 7 in good
yield with complete retention of enantioselectivity (Scheme 6).
To conclude, we have successfully developed the first
enantioselective (3 + 2) cycloaddition of quinone diimides
with β-substituted ene- and thioenecarbamates and with cyclic
enamides using CPA catalysis. In addition, our work has
established the ability of phosphoric acid to differentiate
selected nitrogens on the basis of their individual protecting
groups, allowing various indolines to be obtained regio- and
chemoselectively, in each case in excellent yields and
enantioselectivities.
Coralie Gelis − Institut de Chimie des Substances Naturelles,
CNRS UPR 2301, Université Paris-Sud, Université Paris-
Saclay, Gif-sur-Yvette 91198 Cedex, France
Damien Bouchet − Institut de Chimie des Substances
Naturelles, CNRS UPR 2301, Université Paris-Sud,
Université Paris-Saclay, Gif-sur-Yvette 91198 Cedex, France
Pascal Retailleau − Institut de Chimie des Substances
Naturelles, CNRS UPR 2301, Université Paris-Sud,
Université Paris-Saclay, Gif-sur-Yvette 91198 Cedex, France
Xavier Moreau − Institut Lavoisier Versailles, UMR CNRS
8180, Université de Versailles-St-Quentin-en-Yvelines,
Université Paris-Saclay, Versailles, France; orcid.org/
0000-0002-6737-9671
Luc Neuville − Institut de Chimie des Substances Naturelles,
CNRS UPR 2301, Université Paris-Sud, Université Paris-
Saclay, Gif-sur-Yvette 91198 Cedex, France; orcid.org/
0000-0002-4648-2469
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03947
Author Contributions
§W.-Y.M. and C.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ICSN for financial support. W.-Y.M. thanks the
China Scholarship Council for the doctoral fellowship. C.G.
thanks Paris-Saclay University for the doctoral fellowship. D.B.
thanks CHARMMMAT LabEx for the Master’s fellowship.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03947.
■
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AUTHOR INFORMATION
Corresponding Author
■
́
Geraldine Masson − Institut de Chimie des Substances
Naturelles, CNRS UPR 2301, Université Paris-Sud,
Université Paris-Saclay, Gif-sur-Yvette 91198 Cedex, France;
orcid.org/0000-0003-2333-7047;
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Based Chiral Auxiliaries and Their Use in Diastereoselective
Email: geraldine.masson@cnrs.fr
Authors
Wei-Yang Ma − Institut de Chimie des Substances Naturelles,
CNRS UPR 2301, Université Paris-Sud, Université Paris-
Saclay, Gif-sur-Yvette 91198 Cedex, France
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