Enantioselectivity-switchable organocatalytic [4 + 2]-annulation to access the spirooxindole?norcamphor scaffold

Article abstract of DOI:10.1021/acs.orglett.0c04164

An organocatalyzed enantiodivergent synthesis of a multifunctionalized spirooxindole?norcamphor scaffold via a [4 + 2]-annulation between cyclicα, β-unsaturated ketone and methylene indolinones has been established. The presence of CaCl₂ in DMF could reverse the enantioselectivity to facilely deliver the enantiomers of the corresponding spirooxindoles. Both enantiomers of the corresponding spirooxindoles were obtained in excellent yield and diastereo-/enantioselectivity by employing one single prolinosulfonamide catalyst.

Full text of DOI:10.1021/acs.orglett.0c04164

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Letter
Enantioselectivity-Switchable Organocatalytic [4 + 2]-Annulation to
Access the Spirooxindole−Norcamphor Scaffold
Jing Wang, Xian-Zhou Zheng, Jun-An Xiao, Kai Chen,* Hao-Yue Xiang, Xiao-Qing Chen,*
and Hua Yang*
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ABSTRACT: An organocatalyzed enantiodivergent synthesis of a multifunctionalized spirooxindole−norcamphor scaffold via a [4 +
2]-annulation between cyclicα, β-unsaturated ketone and methylene indolinones has been established. The presence of CaCl2 in
DMF could reverse the enantioselectivity to facilely deliver the enantiomers of the corresponding spirooxindoles. Both enantiomers
of the corresponding spirooxindoles were obtained in excellent yield and diastereo-/enantioselectivity by employing one single
prolinosulfonamide catalyst.
nantioselective organocatalysis has been established as a
Epowerful synthetic tool in academic and industrial research,
which has found extensive applications in the construction of
diverse chiral molecules.1 As most enantiomers have marked
different biologic activities, accessing both enantiomers of
important bioactive scaffolds through asymmetric organo-
catalysis is still a vital task in pharmaceutical chemistry. In
general, the most straightforward pathway is still dependent on
the availability of both enantiomers for the chiral organocatalyst,
respectively. Given the scarcity of two enantiomers for certain
chiral sources, enantiodivergent synthesis by utilizing a single
chiral catalyst would be extremely critical.2 So far, there are some
encouraging examples,3 in which the enantioselectivity of the
organocatalytic processes can be readily switched by modifying
the reaction conditions, such as solvent,4 temperature,5
additives,6 and others.7 Given the serendipity of the discovery
and the mechanistic uncertainty, the pursuit of enantioselectiv-
ity-switchable organocatalytic protocols is highly desirable and
challenging.
+ 2] cycloaddition of methyleneindolinone and α,β-unsaturated
ketone to achieve spirocyclic oxindole with multiple stereo-
centers (Scheme 1a).9 Gong developed a highly enantioselective
cycloaddition between methyleneindolinone and Nazarov
reagents catalyzed by a Brønsted acid−Lewis base bifunctional
chiral organocatalyst.10 In 2016, Ramachary presented a primary
amine-catalyzed stereoselective asymmetric synthesis of six-
membered spirooxindoles through a Barbas [4 + 2] cyclo-
addition reaction.11 Very recently, Yan reported stereoselective
formal [4 + 2] cycloaddition reactions of isatylidenemalononi-
triles with activated diene or 3-benzofuranyl vinyl ketone by a
chiral naphthyl-C2-indole bifunctional phosphine organo-
catalyst.12 In sharp contrast to the well-established asymmetric
organocatalyzed [4 + 2] annulation of isatylidenes with open-
chain enones, cyclic enones were surprisingly underexplored,
which would be expected to offer facile accesses to interesting
multicyclic scaffolds. In 2018, Chen developed a double catalytic
system by combining chiral primary amine with 2-mercapto-
Spirooxindoles have attracted great attentions from synthetic
chemists due to their remarkable structural complexities and
interesting biological activities. Specifically, the spirocyclic
oxindole family bearing a chiral spiro[cyclohexone-1,3′-indo-
line] core is a promising subset with potential bioactivity. Thus,
considerable efforts have been devoted to this area.8 Melchiorre
disclosed a cinchona alkaloid hydroquinine-catalyzed formal [4
Received: December 16, 2020
Published: January 22, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04164
© 2021 American Chemical Society
Org. Lett. 2021, 23, 963−968
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3a in 70% yield with 79% ee and >20:1 dr (Table 1, entries 1−5).
Interestingly, upon addition of 10 equiv of water, the yield and
Scheme 1. State-of-the-Art of Formal [4 + 2]-Cycloaddition
for α,β-Unsaturated Ketones and Methylene Oxindoles
a
Table 1. Optimization of Reaction Conditions
b
c
entry
solvent
additive
yield (%)
ee (%)
1
2
3
4
5
6
7
8
DCM
CHCl3
CH3CN
DMF
MeOH
DCM
DCM
DCM
MeOH
DMF
70
57
45
58
22
91
50
15
82
92
96
88
94
76
79
77
54
76
6
93
32
0
69
−59
−55
−40
−98
50
H2O (10eq)
4 Å MS (40 mg)
CaCl2 (2eq)
CaCl2 (2eq)
CaCl2(2eq)
CaCl2(1eq)
CaCl2(5eq)
CaCl2 (2eq), K2CO3
CaCl2 (2eq), H2O
9
10
11
12
13
14
DMF
DMF
DMF
DMF
d
e
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of isatylidene (2a) using 4 equiv of 2-cyclopentenone (1), 20
mol % catalyst, and x equiv of additive in 1 mL of solvent at rt for 48
b
h. Solvents were used without further treatment. Isolated yield, dr >
c
d
e
20:1. Determined by HPLC. With 20 mol % K2CO3. With 0.1 mL
of H2O.
stereoselectivity of the reaction were significantly improved to
91% yield and 93% ee as well as >20:1 dr, respectively (Table 1,
entry 6). As expected, when 4 Å molecular sieves were added at
the beginning of the reaction to remove water, both yield and
enantioselectivity decreased (entry 7). To our surprise, in the
presence of the frequently used drying agent CaCl2, the
enantioselectivity dropped to nearly 0% ee (entry 8). This
suggested that CaCl2 might affect the stereocontrol to favor the
formation of the other enantiomer in this asymmetric trans-
formation. These preliminary results encouraged us to further
evaluate the effect of CaCl2 in other solvents (entries 9 and 10).
To our delight, the enantioselectivity of the transformation was
completely reversed in the presence of 2 equiv of CaCl2 in DMF
at room temperature (entry 10). Increasing or decreasing the
loading of CaCl2 will not improve the reaction yield or
enantioselectivity (entries 11 and 12). However, the addition
of inorganic base K2CO3 could further promote this asymmetric
transformation and afford product 3a in 94% yield with −98% ee
and >20:1 dr (entry 13). Other bases such as Na2CO3 and Et3N
were also evaluated but gave inferior results (see the SI for
details). Moreover, the effect of CaCl2 could be eliminated if 0.1
mL of H2O was added, possibly due to the coordination of water
molecules with calcium ion (entry 14). To be noted, the
diastereoselectivity is as high as >20:1 and not influenced by the
variation of reaction conditions.
benzoic acid to achieve asymmetric [4 + 2] annulations of 2-
cyclopentenone with isatylidenes (Scheme 1b).13 It is worth
noting that the resulting spirooxindole−norcamphor scaffold
might hold broad potentials for biological studies by merging
two bioactive moieties. As part of our continuous efforts on
seeking efficient asymmetric organocatalyzed functionalization
of isatylidenes,14 we herein disclose our efforts on the
exploration of [4 + 2]-annulation of isatyledene with 2-
cyclopentenone catalyzed by prolinosulfonamide catalyst
(Scheme 1c). Interestingly, the enantioselectivity of this
protocol can be effectively switched by simply manipulating
the additives.
We started our investigations by monitoring the reaction of 2-
cyclopentenone and isatyledene in the presence of proline-
derived organocatalyst at room temperature. It was rationalized
that the prolinosulfonamide bearing pyrrole and acidic
sulfonamide group was expected to activate both electrophilic
and nucleophilic centers of both reaction partners.15 Con-
sequently, various prolinosulfonamide bifunctional organo-
catalysts were screened, and 4-tert-butyldimethylsiloxy-L-
prolinosulfonamide (cat*) was found to give the best
enantioselectivity (see the Supporting Information for details).
The further evaluation of different solvents revealed that1,2-
dichloroethane was a suitable solvent, giving the desired product
Encouraged by these promising results, we further examined
the substrate scope of the established enantiodivergent formal [4
+ 2]-cyclization transformation (Scheme 2). Under the catalysis
of prolinosulfonamide (cat*) in DCM with the addition of 10
equiv of H2O (conditions A), a series of spirooxindole−
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Letter
a
Scheme 2. Substrate Scope
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of isatylidene (2) using 4 equiv of 2-cyclopentenone (1), 20 mol %
catalyst at room temperature for 48 h, under conditions A: 1 mL of DCM as solvent, with the addition of 10 equiv of H2O, or conditions B, 1 mL of
DMF as solvent, with the addition of 2 equiv of CaCl2 and 20 mol % K2CO3. Isolated yield was reported, with dr > 20:1.
norcamphor products 3 were always obtained in excellent
enantioselectivity, while the products 3′ with the opposite
configuration were achieved in DMF by adding CaCl2 and
K2CO3 (conditions B). The structure and configuration of the
cyclization product was unambiguously confirmed by X-ray
crystallographic analysis of 3e (CCDC: 2048262). Irrespective
of the variations of the substituents attached to the phenyl rings
of the oxindole backbones, high yields and excellent
enantioselectivities were mostly secured by employing this
catalytic system (3a−l, 3a′−l′). It is worth mentioning that the
reaction is amenable to various terminal substituents of the C
C double bond at isatylidene. Isatylidene with ester groups,
ketone group, or cyano group at the terminal position of the C
C double bond could be utilized as the suitable substrates, giving
the corresponding products 3m−o in high yields (80−95%) and
excellent ee (94−98%) under conditions A or products 3m′−o′
in yields 92−97% and ee 91−96% under conditions B.
Moreover, different substituent groups such as methyl and
benzyl on the nitrogen atom of isatylidene were found to be
compatible with the reaction conditions and give the
corresponding products 3p−q and 3p′−q′ in good yields and
high enantioselectivities. To further explore the generality of this
enantiodivergent protocol, cyclohexenone was also examined. A
similar switch of enantioselectivity was also observed upon
changing conditions A to conditions B, albeit with a low
diastereoselectivity (dr 1.5:1). However, no desired product was
detected in the reaction of isatylidene 2a with acyclic enones
such as benzylideneacetone (see the SI for details).
To gain insight into the reaction mechanism, control
experiments were conducted (Scheme 3). Considering the
interesting reversal of enantioselectivity with the addition of
CaCl2 in DMF, other polar solvents were also evaluated.
However, the reversal of enantioselectivity was only observed in
another dipolar aprotic solvent dimethylacetamide (DMAc)
(entry 1, see more details in the SI). It is interesting that alkaline-
earth metal chlorides such as MgCl2 or BaCl2 could also
effectively switch the enantioselectivity, albeit with lower
enantioselectivities (entries 2 and 3). However, the addition of
ZnCl2 completely muted the reactivity, and no cyclization
product was observed. To understand the roles of CaCl2 and
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Int-2 will stereoselectively attack the 3-C of the isatylidene
moiety, and then the resulting Michael adduct would further
undergo an iminium-catalyzed intramolecular Michael addition
to realize a formal [4 + 2] cyclization. Finally, the isomerization
and hydrolysis of Int-3 will release product 3a and regenerate
the organocatalyst. To be noted, the proposed species Int-1 and
Int-2 were observed in the HRMS studies on the reaction
solutions. Presumably, the first Michael addition is the
selectivity-determining step, where hydrogen-bonding inter-
action between the acidic amide group of catalyst and ketone
group of oxindole directs the possible attack pattern. In this
transition state, hydrogen bonding between sulfonamide N−H
and pyrrolidine N atom would facilitate the generation of
(1R,2S,3S,4R) product 3a. However, under conditions B, the
coordination of Ca2+ with a sulfonyl group and oxindole ketone
group will increase the stability of TS1′, thus leading to the
selective formation of the product 3a′.
Scheme 3. Further Exploration of the Switch of
Enantioselectivity
DMF, 2 equiv of CaCl2 and 200 μL of DMF were added in DCM
as solvent. To our delight, the corresponding product 3a was
obtained in 86% yield, and −60% ee (Scheme 3, entry 5), similar
to that with the addition of CaCl2 in DMF as solvent (Table 1,
entry 10). These results suggest synergistic effect of CaCl2 and
DMF is important to switch the enantioselectivity, which is also
supported by our NMR experiments (see details in SI).
Furthermore, structural modification of the catalyst shows that
the sulfonyl group is essential to achieve the switch of
enantioselectivity (see details in the SI).
On the basis of the above observations and the related
mechanistic research,16 a plausible catalytic cycle is proposed in
Scheme 4. Cyclopentenone is most likely activated by
pyrrolidine moiety to generate the corresponding iminium ion
Int-1, which proceeds the isomerization to afford the enamine
intermediate Int-2. The resulting chiral nucleophilic dienamine
In summary, we developed a novel enantiodivergent synthetic
protocol to access multifunctionalized spirooxindole-norcam-
phor scaffolds via a formal [4 + 2] cyclization between cyclic
cyclopentenone and methyleneindolinones. The addition of
CaCl2 in DMF could effectively switch the enantioselectivity. As
a result, both enantiomers of the corresponding spirooxindoles
were obtained in excellent yield and diastereo-/enantioselectiv-
ity by using one single prolinosulfonamide catalyst. Mechanistic
studies were well performed, which suggested the coordination
of Ca2+ with DMF molecules and the sulfonyl group of
organocatalyst is essential to achieve the reversal of
enantioselectivity. Moreover, this discovery would inspire the
design of new stereoswitchable asymmetric organocatalytic
processes.
ASSOCIATED CONTENT
■
sı
* Supporting Information
Scheme 4. Proposed Reaction Pathway
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04164.
Experimental procedures and characterization data,
HPLC data, and X-ray data for 3e (PDF)
Accession Codes
CCDC 2048262 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Kai Chen − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, China;
Email: kaichen@csu.edu.cn
Xiao-Qing Chen − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083,
China; orcid.org/0000-0002-8768-8965;
Email: xqchen@csu.edu.cn
Hua Yang − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, China;
orcid.org/0000-0002-5518-5255; Email: hyangchem@
csu.edu.cn
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Jing Wang − College of Chemistry and Chemical Engineering,
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Xian-Zhou Zheng − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083,
China
Jun-An Xiao − Guangxi Key Laboratory of Natural Polymer
Chemistry and Physics, Nanning Normal University, Nanning
530001, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
́
́
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (22078370,
22003077, 21776318, 72088101, 81703365), Natural Science
Foundation of Hunan Province (2017JJ3401), Central South
University.
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