Quinine-Based Trifunctional Organocatalyst for Tandem Aza-Henry Reaction-Cyclization: Asymmetric Synthesis of Spiroxindole-Pyrrolidine/Piperidines

Article abstract of DOI:10.1021/acs.orglett.7b02150

A quinine-derived trifunctional sulphonamide catalyst has been developed for the effective asymmetric organocatalytic tandem aza-Henry reaction-cyclization of isatin-derived ketimines and nitroalkane-mesylates for the synthesis of spiro-pyrrolidine/piperidine-oxindoles. Demethylation of traditional bifunctional catalyst to incorporate an additional hydrogen bonding C6′-OH group plays the key role toward remarkable enantioselectivity.

Full text of DOI:10.1021/acs.orglett.7b02150

Letter
pubs.acs.org/OrgLett
Quinine-Based Trifunctional Organocatalyst for Tandem Aza-Henry
Reaction-Cyclization: Asymmetric Synthesis of Spiroxindole-
Pyrrolidine/Piperidines
Saumen Hajra*,† and Bibekananda Jana†,§
†Centre of Biomedical Research (CBMR), Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Raebareli Road,
Lucknow 226014, UP, India
§Department of Chemistry, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur 721302, WB, India
S
* Supporting Information
ABSTRACT: A quinine-derived trifunctional sulphonamide catalyst has been developed for the effective asymmetric
organocatalytic tandem aza-Henry reaction-cyclization of isatin-derived ketimines and nitroalkane-mesylates for the synthesis of
spiro-pyrrolidine/piperidine-oxindoles. Demethylation of traditional bifunctional catalyst to incorporate an additional hydrogen
bonding C6′−OH group plays the key role toward remarkable enantioselectivity.
n the past decade, organocatalysis has emerged as one of the
cornerstones for asymmetric synthesis.1 Environmentally
Scheme 1. Literature-Reported Bifunctional Catalysts and
Our Hypothesis of Trifunctional Catalysis
I
benign and structurally unique organic frameworks have been
designed for stereodefined activation of nucleophiles and
electrophiles to render unparalleled stereoselectivity. Cinchona
alkaloid-derived catalysts are one of the important subclasses of
the organocatalyst library.2 The mode of activation and catalytic
activity have been studied using computational methods.3
Particularly, in the thiourea I catalyzed addition of nitro-
methane4 and squaramide II catalyzed reaction of nitroolefins,5
catalysts exhibit double-point hydrogen binding with two N-Hs
(Scheme 1). Later, the Song and List group reported a newly
designed quinine-based sulphonamide catalyst III for desym-
metrization of meso anhydrides6a and decarboxylative aldol
reaction.6b Very recently, a comprehensive computational and
NMR study on the mechanism of sulphonamide catalysis has
been disclosed3b where the quinuclidine moiety, after
subsequent protonation, acts as an alternative hydrogen bond
donor to facilitate effective enantioactivation (Scheme 1).
We hypothesized that further modification of the sulphona-
mide catalysts III can be done by demethylation of C6′-O-
methyl group on the quinoline ring to incorporate an additional
hydrogen bonding group dedicated for the activation of an
electrophile (Scheme 1). Such tailored trifunctionality of the
catalyst IV would be one step further to the traditional
bifunctional organocatalysts, encompassing both the activation
of electrophile and nucleophile, resulting in a more rigid
transition state of the reaction. We envisioned that this class of
trifunctional catalysts would be particularly effective for the
Received: July 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Catalyst Screening of Tandem Aza-Henry Reaction-Cyclization
a
General reaction conditions: 1a (0.1 mmol), 2a (0.5 mmol) in 0.5 mL CH2Cl2, catalyst (0.01 mmol), NaHCO3 (0.5 mmol) at 25 °C. Isolated yield
after flash column chromatography; ee determined by HPLC analysis on a chiral stationary phase.
reactions where bifunctional catalysts are inadequate and
thereby providing an alternate aid to the toolbox of
organocatalysts.
To prove our hypothesis, we selected isatin-derived ketimine
1a as a model substrate7 for the enantioselective aza-Henry
reaction with nitro alkane 2a (Scheme 2).8 The nitro alkane 2a
was equipped with a distant leaving group purposely designed
for tandem cyclization9 to afford spiroxindole 3,2′-heterocycle
3a under mild conditions. 3,2′-Pyrrolidines10 are of recent
interest for their potential therapeutic activities.11
Cinchona alkaloids were first loaded in a model reaction of
N-Boc ketimine 1a with 3-nitropropylmethanesulfonate 2a in
dichloromethane in the presence of NaHCO3 at 25 °C
(Scheme 2). Quinine (C1) furnished excellent yield and an
encouraging 55% ee. It is to be noted that the nitro group so
formed exists exclusively in enol form as confirmed by the
NMR experiment (see the Supporting Information). Change of
H-bond donor group from secondary −OH to a C6′−OH in
C2 led to reversal of selectivity (−50% ee) with reduced yield.
Bifunctional thiourea catalyst C3 and squaramide catalyst C4
were unable to render any enantioinduction (0% ee).
Interestingly, corresponding sulphonamide catalyst C5 gave
31% ee with 56% yield. The presence of an additional −OH
group in C6 straightaway increased the enantioselectivity to
−62%. This result encouraged us to verify our initial hypothesis
of the effect of added hydroxyl moiety in the catalyst.
Trifunctional catalyst C7 possessing the C6′−OH group12
straightaway increased the ee from 0% (C3) to 68%. When
demethylated catalyst C8 was employed, selectivity was
elevated to 74% from 0% (C4). Reaction with trifunctional
sulphonamide catalyst C9 increased the enantioinduction to
90% from 31% (C5). Selectivity sharply reduced when aromatic
amide catalyst C10 was employed (87% yield, 49% ee). Because
the stereoelectronic environment of the aromatic moiety largely
affects the extent and ease of the H-bonding, we then evaluated
these effects in the enantioinduction (Scheme 2). Electron-rich
as well as electron-withdrawing substituents at the aromatic ring
were extensively studied (C11−C15) but failed to induce any
better selectivity.
Effect of solvent was then studied ranging from nonpolar to
polar aprotic solvents, but dichloromethane was best in terms
of isolated yield and enantioselectivity (see the Supporting
Information). Gratifyingly, lowering the reaction temperature
to 0 °C afforded the desired product in an increased
enantioselectivity (95% yield and 93% ee) (Table 1, entry 2).
Finally, the use of MS 4 Å to trap H2O (MsOH so formed in
the reaction was quenched by NaHCO3 to form CO2 and
H2O) resulted in remarkable stereoselection of the product
(95% yield and 96% ee) (entry 3). Further lowering of
temperature or reduced catalyst loading resulted in a reduced
yield with no improvement in the enantioselectivity (entries 4
and 5). Pivotal effect of isatin N-protection as well as imine
functionalization was observed in the reaction (entries 6 and 7).
Upon identifying our optimal catalyst C9, we expanded the
scope of the aza-Henry reaction-cyclization with a variety of
aromatic substituted N-benzyl isatin-derived N-Boc ketimines
B
DOI: 10.1021/acs.orglett.7b02150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Synthesis of Spiroxindole 3,2′-Piperidines and
a
Nitroalkane Addition
b
c
entry
R
R′
t (°C)
time (h)
yield (%)
ee (%)
1
2
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Bn
Bn
Bn
Bn
Bn
Me
Bn
25
0
36
72
72
96
96
72
72
95
95
95
95
62
92
95
90
93
96
96
96
89
90
d
3
0
d
4
−10
−20
0
d
5
d
6
d
7
0
a
Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol) in 0.5 mL
CH2Cl2, catalyst (0.01 mmol), NaHCO3 (0.5 mmol) at specific
b
c
temperature. Isolated yields after flash column chromatography. ee
d
determined by HPLC analysis on a chiral stationary phase. In the
presence of MS 4 Å.
a
General reaction conditions: 1a (0.1 mmol), 2b (0.5 mmol) in 0.5
(1a−i) (Table 2). Gratifyingly, regardless of the differences in
mL CH2Cl2, C9 (0.01 mmol), NaHCO3 (0.5 mmol) at 0 °C, 96 h.
Reaction of nitroalkanes: 1a (0.1 mmol), nitroalkane (0.25 mL), 0.25
mL toluene, C9 (0.01 mmol) at −20 °C. Isolated yields after flash
column chromatography; ee determined by HPLC analysis on a chiral
stationary phase. For 1c, 1d, 1e, and 1f, time: 120 h.
the stereoelectronic nature, all the ketimines were smoothly
Table 2. Substrate Scope of the Tandem Aza-Henry
a
Reaction-Cyclization
of the nitromethane addition product 6a was assigned as R
isomer by comparing the HPLC data with the reported
literature,8i and from this analogy, the stereochemistry of
spiroxindoles 4a−i and 5a−h were tentatively assigned.
As an appended application, spiroxindole 3,2′-pyrrolidine 4a
was further methylated to form compound 7a in excellent yield
(93%) and stereoselectivity (dr: >20:1; 95% ee) (Scheme 4).
The configuration of the newly formed stereocenter was
assigned as 3′S by NOESY analysis.
b
c
entry
imine
R1
R2
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
H
H
Me
H
H
H
H
F
4a
4b
4c
4d
4e
4f
95
87
94
91
95
95
95
95
94
93
96
96
96
95
92
94
94
93
96
95
Me
Me
Br
I
Scheme 4. Methylation of 4a
Cl
F
1g
1h
1i
4g
4h
4i
H
OMe
H
H
H
d
10
1a
4a
a
Reaction conditions: 1a (0.1 mmol), 2a (0.5 mmol) in 0.5 mL
CH2Cl2, C9 (0.01 mmol), NaHCO3 (0.5 mmol), MS 4 Å, 72 h at 0
b
c
°C. Isolated yields after flash column chromatography. ee
d
determined by HPLC analysis on a chiral stationary phase. Reaction
To obtain a clear insight into the reaction mechanism and
the mode of catalytic activation, we performed ESI-MS analysis
of the crude reaction mixture (Scheme 5). To our great delight,
we were able to detect the catalyst-imine adduct B. However,
no mass of catalyst-nitroalkane complex was detected. This
indicated the ligation of imine to the catalyst prior to the
chelation of nitroalkane 2a. In light of these observations, we
proposed a plausible transition state of the reaction where the
addition of nitroalkane can be facilitated only from the Re face
of the imine, which led to excellent stereoinduction.
In summary, we disclose the reactivity of a new class of
trifunctional catalysts in the enantioselective aza-Henry
reaction-cyclization of isatin-derived ketimines. The unprece-
dented increase in yield and enantioselectivity was achieved
with the installation of C6′−OH group in the catalyst. Further
was performed with 1a (2.0 mmol), 2a (10.0 mmol) in 10 mL CH2Cl2,
C9 (0.2 mmol), NaHCO3 (10 mmol), MS 4 Å, 72 h at 0 °C.
reacted to afford spiroxindole 3,2′-pyrrolidines (4a−i) with
excellent yields and enantioselectivities (Table 2, entries 1−9).
We are pleased to report that the reaction in 2.0 mmol scale
also proceeded without any significant reduction in yield and
enantioselectivity (93% yield, 95% ee; entry10).
To further demonstrate the effectiveness of the trifunctional
catalysis, nitrobutanol-mesylate 2b was reacted with ketimines
(1a−h) to afford spiroxindole 3,2′-piperidines (5a−h) in
moderate to high isolated yields with high enantioselectivity
(Scheme 3). The catalyst was also effective for the direct
addition reaction of nitroalkanes (6a−b). The stereochemistry
C
DOI: 10.1021/acs.orglett.7b02150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Song, C. E. In Cinchona Alkaloids in Synthesis
and Catalysis Ligands, Immobilization and Organocatalysis; Wiley-VCH:
Weinheim, 2009.
Scheme 5. Proposed Catalytic Cycle and Crude Reaction
ESI-MS Analysis
(3) (a) Hamza, A.; Schubert, G.; Soos, T.; Papai, I. J. Am. Chem. Soc.
2006, 128, 13151. (b) Blise, K.; Cvitkovic, M. W.; Gibbs, N. J.;
Roberts, S. F.; Whitaker, R. M.; Hofmeister, G. E.; Kohen, D. J. Org.
Chem. 2017, 82, 1347. (c) Grayson, M. N. J. Org. Chem. 2017, 82,
4396.
(4) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7,
1967.
(5) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008,
130, 14416.
(6) (a) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin,
J.; Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872. (b) Bae, H. Y.;
Sim, J. H.; Lee, J. W.; List, B.; Song, C. E. Angew. Chem., Int. Ed. 2013,
52, 12143.
(7) (a) Liu, Y.-L.; Zhou, F.; Cao, J.-J.; Ji, C.-B.; Ding, M.; Zhou, J.
Org. Biomol. Chem. 2010, 8, 3847. (b) Yan, W.; Wang, D.; Feng, J.; Li,
P.; Zhao, D.; Wang, R. Org. Lett. 2012, 14, 2512. (c) Hara, N.;
Nakamura, S.; Sano, M.; Tamura, R.; Funahashi, Y.; Shibata, N. Chem.
- Eur. J. 2012, 18, 9276. (d) Wang, D.; Liang, J.; Feng, J.; Wang, K.;
Sun, Q.; Zhao, L.; Li, D.; Yan, W.; Wang, R. Adv. Synth. Catal. 2013,
355, 548. (e) Liu, Y.-L.; Zhou, J. Chem. Commun. 2013, 49, 4421.
(f) Li, T.-Z.; Wang, X.-B.; Sha, F.; Wu, X.-Y. J. Org. Chem. 2014, 79,
4332. (g) Wang, X.-B.; Li, T.-Z.; Sha, F.; Wu, X.-Y. Eur. J. Org. Chem.
2014, 2014, 739. (h) Yu, J.-S.; Zhou, J. Org. Biomol. Chem. 2015, 13,
10968. (i) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J.; Song, Y.
Org. Lett. 2015, 17, 5168. (j) Montesinos-Magraner, M. M.; Vila, C.;
development and application of these trifunctional catalysts for
new efficient asymmetric transformations are currently in
progress in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Canton, R.; Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R. Angew.
́
́
̃
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Chem., Int. Ed. 2015, 54, 6320. (k) Arai, T.; Tsuchiya, K.; Matsumura,
E. Org. Lett. 2015, 17, 2416. (l) Nakamura, S.; Takahashi, S. Org. Lett.
2015, 17, 2590. (m) Liu, T.; Liu, W.; Li, X.; Peng, F.; Shao, Z. J. Org.
Chem. 2015, 80, 4950. (n) Montesinos-Magraner, M.; Vila, C.;
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02150.
Rendon-Patino, A.; Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R.
́
́
̃
̃
ACS Catal. 2016, 6, 2689. (o) He, Q.; Wu, L.; Kou, X.; Butt, N.; Yang,
G.; Zhang, W. Org. Lett. 2016, 18, 288. (p) Chen, J.; Wen, X.; Wang,
Y.; Du, F.; Cai, L.; Peng, Y. Org. Lett. 2016, 18, 4336.
All the experimental and spectroscopic data of
compounds (PDF)
(8) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113,
AUTHOR INFORMATION
Corresponding Author
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2887. (c) Nunez, M. G.; Farley, A. J. M.; Dixon, D. J. J. Am. Chem. Soc.
́
̃
2013, 135, 16348. (d) Arai, T.; Matsumura, E.; Masu, H. Org. Lett.
*E-mail: saumen.hajra@cbmr.res.in. Fax: (+91)-522-2668995.
Tel: (+91)-522-2668861.
ORCID
2014, 16, 2768. (e) Holmquist, M.; Blay, G.; Pedro, J. R. Chem.
Commun. 2014, 50, 9309. (f) Holmquist, M.; Blay, G.; Munoz, M. C.;
̃
Pedro, J. R. Adv. Synth. Catal. 2015, 357, 3857. (g) Kumar, A.; Kaur, J.;
Chimni, S. S.; Jassal, A. K. RSC Adv. 2014, 4, 24816. (h) Zhao, K.; Shu,
T.; Jia, J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2015, 21, 3933.
(i) Fang, B.; Liu, X.; Zhao, J.; Tang, Y.; Lin, L.; Feng, X. J. Org. Chem.
2015, 80, 3332.
Saumen Hajra: 0000-0003-0303-4647
Notes
The authors declare no competing financial interest.
(9) Baricordi, N.; Benetti, S.; Biondini, G.; De Risi, C.; Pollini, G. P.
Tetrahedron Lett. 2004, 45, 1373.
ACKNOWLEDGMENTS
■
(10) (a) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi, Y. R. Org. Lett.
2012, 14, 5412. (b) Cui, B. D.; Zuo, J.; Zhao, J. Q.; Zhou, M. Q.; Wu,
Z. J.; Zhang, X. M.; Yuan, W. C. J. Org. Chem. 2014, 79, 5305.
(c) Chen, L.; Wu, Z. J.; Zhang, M. L.; Yue, D. F.; Zhang, X. M.; Xu, X.
Y.; Yuan, W. C. J. Org. Chem. 2015, 80, 12668. (d) Jiang, D.; Dong, S.;
Tang, W.; Lu, T.; Du, D. J. Org. Chem. 2015, 80, 11593. (e) Chen, K.
Q.; Li, Y.; Zhang, C. L.; Sun, D. Q.; Ye, S. Org. Biomol. Chem. 2016, 14,
2007. (f) Yang, P.; Wang, X.; Chen, F.; Zhang, Z. B.; Chen, C.; Peng,
L.; Wang, L. X. J. Org. Chem. 2017, 82, 3908.
(11) (a) Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 91. (b) Murugan,
R.; Anbazhagan, S.; Narayanan, S. S. Eur. J. Med. Chem. 2009, 44, 3272.
(c) Gollner, A.; et al. J. Med. Chem. 2016, 59, 10147.
(12) Zhang, T.; Cheng, L.; Hameed, S.; Liu, L.; Wang, D.; Chen, Y. J.
Chem. Commun. 2011, 47, 6644.
This research was supported by SERB, New Delhi (SR/S1/
OC-97/2012 and EMR/2016/001161). B.J. thanks UGC, New
Delhi for research fellowship. We thank Director, CBMR for
research facilities.
DEDICATION
■
Dedicated to Professor Chunni Lal Khetrapal (CBMR,
Lucknow) on his 80th birthday.
REFERENCES
■
(1) (a) Berkessel, A.; Groger, H. In Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005. (b) List, B.; Yang, J. W. Science 2006, 313,
1584. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (d) MacMillan, D. W. C. Nature 2008, 455, 304.
(e) Lee, J. W.; Gall, T. M.; Opwis, K.; Song, C. E.; Gutmann, J. S.; List,
B. Science 2013, 341, 1225.
D
DOI: 10.1021/acs.orglett.7b02150
Org. Lett. XXXX, XXX, XXX−XXX