Remote Control of Axial Chirality: Synthesis of Spirooxindole-Urazoles via Desymmetrization of ATAD

Article abstract of DOI:10.1021/acs.orglett.8b02361

For the first time, a desymmetrization strategy empowered the assembly of a class of optically pure spirooxindole-urazoles possessing an N-Ar stereogenic axis via remote control of axial chirality in an asymmetric three-component reaction. This transformation was realized by a tandem bisthiourea-catalyzed asymmetric Diels-Alder reaction and substrate-controlled asymmetric ene reaction. The driving force derived from aromatization and the high reactivity of 4-aryl-1,2,4-triazole-3,5-dione enophiles mediated the occurrence of the successive ene reaction under mild conditions.

Full text of DOI:10.1021/acs.orglett.8b02361

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Remote Control of Axial Chirality: Synthesis of Spirooxindole−
Urazoles via Desymmetrization of ATAD
Lin-Lin Zhang,†,‡ Ji-Wei Zhang,‡ Shao-Hua Xiang,*,§ Zhen Guo,*,† and Bin Tan*,‡
†College of Material Science & Engineering, Taiyuan University of Technology, Shanxi 030024, China
‡Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, China
§Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: For the first time, a desymmetrization strategy empowered the assembly of a class of optically pure
spirooxindole−urazoles possessing an N-Ar stereogenic axis via remote control of axial chirality in an asymmetric three-
component reaction. This transformation was realized by a tandem bisthiourea-catalyzed asymmetric Diels−Alder reaction and
substrate-controlled asymmetric ene reaction. The driving force derived from aromatization and the high reactivity of 4-aryl-
1,2,4-triazole-3,5-dione enophiles mediated the occurrence of the successive ene reaction under mild conditions.
he past two decades has witnessed surging interest in
axially chiral frameworks by virtue of their significant
T
applications in many fields.1 Utmost dedication has been given
to biaryl atropisomers, fostering the accomplishment of
numerous elegant synthetic strategies.1,2 The development of
atropisomeric N-Ar skeletons, by contrast, lags behind in view
of their ubiquity in natural products3 and bioactive molecules4
and as ligands5 and catalysts6 for chirality induction. The wide
utilization of low-yielding optical resolution using costly chiral
resolution agents or chromatography calls for novel and
efficient approaches to induce axial chirality with high
enantioselectivity. Of the few successful cases reported,7 the
desymmetrization strategy pioneered by Curran8 offers an
effective solution to access optically active N-Ar axially chiral
compounds, which has engendered a suite of synthetically
useful chiral C−C bond formation protocols applying
maleimides as the prochiral precursors.9 Capitalizing on their
electrophilic nature, Hayashi documented the asymmetric 1,4-
addition of arylboronic acids with a chiral rhodium catalyst,9b
whereas Bencivenni devised the aminocatalytic stereoselective
vinylogous Michael addition9c and subsequently a Diels−Alder
(D−A) desymmetrization reaction with enones (Figure 1a).9d
With our recent discovery of a new class of axially chiral
urazoles containing a chiral N-Ar axis that are synthesized via
an organocatalytic tyrosine click reaction employing 4-aryl-
1,2,4-triazole-3,5-dione (ATAD) as the electrophile (Figure
1b),10 we were inspired to cover more chemical space of N-Ar
axially chiral compounds of synthetic origin through a
desymmetrization strategy to access analogues with broader
structural diversity (Figure 1c).
Figure 1. Desymmetrization strategy for atroposelective formation of
N-Ar axes.
Beyond their conspicuous role as electrophiles, the enhanced
electrophilicity and lower NN π-bond dissociation energy of
ATADs render them equally competent as enophiles in ene
reactions.11 While the ene reaction forges C−C and C−X
bonds with high atom-economy, to the best of our knowledge
it has yet to be leveraged for the enantioselective synthesis of
axially chiral N-Ar compounds. Additionally, we surmised that
Received: July 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02361
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
adopting a preceding D−A reaction for in situ generation of
the ene partner would further impart flexibility and diversity.
To this end, the spirooxindole generated from a D−A reaction
between 3-vinylindole12 and methyleneindolinone13 could be a
prime candidate given its facile conversion to indole following
an aromaticity-driven [1,3]-H shift, thus releasing a ready ene
partner for the ensuing ene reaction.14 To actualize this
proposition, the following challenges had to be tackled: (1) the
complexity of a three-component reaction system, especially
with the presence of the highly reactive ATAD reactant, and
(2) exquisite stereocontrol of the ene reaction undeterred by
the scarcity of reported success. Herein we report a rationally
designed multicomponent reaction (MCR)15 for the asym-
metric construction of an N-Ar axis via desymmetrization with
remote stereocontrol, furnishing complex spirooxindole−
urazoles possessing multiple central or axial chiralities with
good stereoselectivities.
Initial investigation of this reaction commenced with 3-
vinylindole (1a), methyleneindolinone 2a, and 4-(2-tert-
butylphenyl)-3H-1,2,4-triazole-3,5-dione (3a) as model sub-
strates, CH2Cl2 as the solvent, and bisthiourea C1 as the
catalyst. Not surprisingly, byproducts were predominantly
formed from the competitive reactions at room temperature in
only 5 min because of the high reactivity of ATAD, and only a
trace amount of desired product 4a was detected (Table 1,
entry 1). To inhibit the formation of the byproducts,
meticulous control of individual reaction rates became
imperative. Commonly reported factors such as the solvent,
catalyst, and temperature were then considered. Remarkably,
the reaction solvent dramatically changed the reaction course
(Table 1, entries 1−6), and it was evident that the nonpolar
solvent hexane was the most conducive for this reaction among
all of the tested ones, affording 4a in 52% yield (Table 1, entry
6). Despite the much longer reaction time (48 h) for complete
conversion, the product formation was accomplished with high
stereocontrol (8:1 dr and 95% ee). To our delight, conducting
the reaction at a lower temperature (0 °C) but with longer
duration fruitfully improved the chemical yield to 80% and the
ee value to 99% (Table 1, entry 7). Attempts to further
improve the reaction outcome upon evaluation of various
chiral catalysts met with failure (Table 1, entries 8−14). The
addition of CH2Cl2 (10%) could shorten the reaction duration,
but both the yield and enantioselectivity dropped obviously
(Table 1, entry 15). Thus, the optimal reaction conditions
were concluded to be the following: bisthiourea C1 as the
catalyst and hexane as the solvent at a reaction temperature of
0 °C. Under this set of reaction conditions, the desired product
4a was isolated in 78% yield with 8:1 dr and >99% ee.
Table 1. Optimization of the Reaction Conditions
temp
yield
b
ee
c
d
entry catalyst
solvent
CH2Cl2
Et2O
toluene
pentane
cyclohexane
hexane
hexane
hexane
hexane
hexane
(°C)
(%)
dr
(%)
1
2
C1
C1
C1
C1
C1
C1
C1
C2
C3
C4
C5
C6
C7
C8
C1
rt
rt
rt
rt
rt
rt
0
0
0
0
0
−
−
−
41
34
52
80 (78)
28
53
69
35
38
46
46
67
−
−
−
−
−
−
98
95
95
>99
20
93
−77
69
3
4
5
6
8:1
8:1
8:1
8:1
6:1
8:1
8:1
7:1
8:1
5:1
6:1
8:1
7
8
9
10
11
12
13
14
15
hexane
hexane
hexane
hexane
0
0
0
0
1
−20
−48
90
e
hexane/CH2Cl2
a
Reactions were carried out with 1a (0.15 mmol, 1.5 equiv), 2a (0.10
mmol, 1.0 equiv), 3a (0.15 mmol, 1.5 equiv), and 15 mol % catalyst in
b
1
4 mL of solvent. Determined by H NMR analysis using CH2Br2 as
the internal standard. An isolated yield is given in parentheses.
c
Determined by 1H NMR analysis of the crude products.
d
e
Determined by chiral HPLC analysis. hexane/CH2Cl2 = 10/1.
both the dr and ee values dropped when an electron-
withdrawing cyano group was employed instead (4f).
Introduction of an electron-donating methoxy substituent on
the aromatic ring led to a low yield of 49% (4g), while methyl
substitution had a negligible impact (4h). Next, methylenein-
dolinones bearing halide substituents with varied substitution
positions were examined, all of which afforded respective
products with satisfactory results (4i−l). When the methyl-
eneindolinone with a bromide substituent at C-4 was tested,
very poor yield and stereoselectivity were observed. The
absolute configuration of compound 4k was confirmed by
crystallographic analysis after recrystallization, and those of
other products in this scheme were assigned by analogy.
Subsequently, we moved to extend the substrate scope of 3-
vinylindoles 1, and the results are summarized in Scheme 2.
Substrates carrying an electron-donating methyl group
furnished products 4m and 4n in very good chemical yields
with excellent enantioselectivities but dissimilar diastereose-
lectivities arising from the distinct substitution positions.
Indole-derived substrates possessing a halogen atom were also
compatible, delivering the respective products with moderate
results (4o−q).
With the optimized conditions in hand, we next turned our
attention to exploring the substrate scope of methyleneindo-
linones 2 for this three-component reaction (Scheme 1).
Notwithstanding the long duration required for complete
reaction (2−6 days), all of the tested substrates were well-
suited for this chemistry to give axially chiral spirooxindole−
urazoles 4 in moderate chemical yields with good diaster-
eoselectivities and, gratifyingly, excellent enantiopurities. First,
replacement of the methyl moiety on the ester by an ethyl
group provided the desired product 4b in 69% yield with 8:1
dr and 98% ee. Similar reaction outcomes were observed with
substrates containing benzyl (4c) and tert-butyl (4d) esters.
Apart from the ester group, ketone functionality was equally
well tolerated to give the corresponding product 4e with good
stereocontrol (98% ee) in moderate yield (59%). However,
Finally, we examined the scope of ATAD enophiles.
Although inferior diastereoselectivities were observed, the
B
DOI: 10.1021/acs.orglett.8b02361
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Letter
a
Scheme 1. Substrate Scope of Methyleneindolinones
Scheme 2. Substrate Scopes of 3-Vinylindoles and ATAD
Enophiles
a
a
Reaction conditions: 2a (0.20 mmol) and C1 (15 mol %) in hexane
(8 mL) were stirred for 15 min at 0 °C and then 1 (0.30 mmol) and 3
(0.30 mmol) were added, unless otherwise specified. Isolated yields of
the pure major diastereomers are provided.
a
Reaction conditions: 2 (0.10 mmol) and C1 (15 mol %) in hexane
(4 mL) were stirred for 15 min at 0 °C and then 1a (0.15 mmol) and
3a (0.15 mmol) were added, unless otherwise specified. Isolated
b
yields of the pure major diastereomers are provided. The reaction
scale was doubled.
chemical yields were modest, and the enantiopurities remained
satisfactory (4r−t). An attempt to replace the tert-butyl group
with a phenyl group for better control of the axial chirality
hampered the diastereoselectivity of product 4u significantly to
3:1 while maintaining a moderate yield of 60% with 98% ee.
To validate the utility of this catalytic enantioselective
reaction, a preparative-scale synthesis of product 4a was carried
out under the optimal reaction conditions. As outlined in
Figure 2a, axially chiral compound 4a was obtained in 67%
yield with excellent enantioselectivity, albeit with a moderate
dr value. Compared to the small-scale synthesis, no obvious
deterioration of the yield or stereochemical integrity was
observed for the preparative-scale one. To verify the role of the
catalyst in the ene reaction, intermediate 5 was then
synthesized from 1a and 2a by a D−A reaction.14 With 3a
as the enophile, no apparent differences in the stereo-
selectivities were detected for all of the tested conditions,
including in the absence of catalyst, with racemic catalyst C1,
and with enantiopure catalyst C1 (Figure 2b). These results
imply that the spatial configuration of intermediate 5a is more
decisive than catalyst C1 for stereoselective formation of the
C−N bond. On the basis of previous results and our
investigations, a bisthiourea-catalyzed D−A reaction between
1 and 2 to afford spirooxindole derivative 5 is proposed as the
Figure 2. Gram-scale reaction, control experiments, and plausible
mechanism.
first step. Subsequently, the ene reaction of the generated
alkene with an allylic hydrogen and ATAD 3 affords the
desired product 4. Notably, the ATAD can approach the
double bond only from the face opposite the bulky ester group
and the bicyclic structure adjacent to the double bond,
resulting in the excellent selectivity of the central chirality.
Thus, the dr value is given in regard to the atroposelectivity.
However, the remote control over the stereoselectivity of the
C
DOI: 10.1021/acs.orglett.8b02361
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Letter
axial chirality is still unclear at this stage since the tert-butyl
group is far away from the bulky groups (Figure 2c).
of Biomedicine, Internet, New Energy, and New Material
Industries (JCYJ20150430160022510). B.T. thanks the
Thousand Young Talents Program for financial support.
In conclusion, we have developed the first asymmetric three-
component reaction to construct a class of novel axially chiral
spirooxindole−urazoles employing a desymmetrization strat-
egy. An organocatalyst-controlled asymmetric D−A reaction
and a substrate-controlled asymmetric ene reaction were
arrayed lucidly to enable the in situ generation of complex
olefinic D−A product as the ene partner for the subsequent
ene reaction, thereby endowing substrate flexibility and
product diversity. A gamut of 3-vinylindoles, methyleneindo-
linones, and ATADs were examined for modular construction
of these axially chiral structures in good yields with satisfactory
stereoselectivities. Several noteworthy attributes of the current
methodology are recounted: (1) product diversity and chiral
information is relayed between two tandem stereochemical
events; (2) prudent choices of the chiral bisthiourea catalyst
and the solvent inhibited the formation of byproducts from
competing reactions; (3) the stereogenic axis was facilely
introduced in the spirooxindole−urazole scaffold via remote
control of the axial chirality; and (4) the driving force derived
from the formation of an aromatic indole facilitated the
occurrence of the ene reaction under mild conditions. This
concise and highly efficient methodology is anticipated to offer
an alternative approach to build complex axially chiral
spirooxindole−urazole skeletons with multiple stereogenic
elements.
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*E-mail: tanb@sustc.edu.cn.
*E-mail: guozhen@tyut.edu.cn.
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ORCID
Shao-Hua Xiang: 0000-0003-4262-5626
Zhen Guo: 0000-0001-9528-1383
Bin Tan: 0000-0001-8219-9970
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (21572095 and
21772081) and Shenzhen Special Funds for the Development
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