Asymmetric synthesis of druglike six-membered spirooxindoles through an amino enyne catalysis

Article abstract of DOI:10.1021/ol401227q

An effective reflexive-Michael (r-M) reaction has been disclosed to access drug-like six-membered spirooxindoles in good yields and excellent enantioselectivities by using an aminoenyne-catalysis.

Full text of DOI:10.1021/ol401227q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of Druglike
Six-Membered Spirooxindoles through
an Amino Enyne Catalysis
D. B. Ramachary,* Chintalapudi Venkaiah, and R. Madhavachary
Catalysis Laboratory, School of Chemistry, University of Hyderabad, Central
University (PO), Hyderabad 500 046, India
ramsc@uohyd.ernet.in; ramchary.db@gmail.com
Received May 2, 2013
ABSTRACT
An effective reflexive-Michael (r-M) reaction has been disclosed to access drug-like six-membered spirooxindoles in good yields and excellent
enantioselectivities by using an aminoenyne-catalysis.
A spirooxindole core structure is the centerpiece of a
wide variety of natural and unnatural compounds that
exhibit diverse biological activities.1 Although great prog-
ress has been made toward the asymmetric synthesis of
spirooxindoles, new approaches that can accomplish the
simultaneous creation of spiro quaternary centers with
multiple chiral centers are still in high demand.2 In particular,
the stereocontrolled high-yielding synthesis of functionalized
six-membered spirooxindoles from the more environmen-
tally friendly substrates and catalysts in a catalytic asym-
metric manner are still limited.3,4 Thus, an enantioselective
catalytic approach for the direct construction of six-
membered spirooxindole skeletons is a significant challenge.
Recently, we have developed an organo-click strategy
for the construction of oxindoles with a quaternary C-3
center.5 Later, it was recognized that the functionalized six-
membered spirooxindole core structure is featured in a
number of natural products as well as medicinally relevant
compounds (Figure 1),1 but its stereocontrolled asymmetric
(1) (a) Robertson, G. L. Nat. Rev. Endocrinol. 2011, 7, 151. (b)
Collins, M. A.; Hudak, V.; Bender, R.; Fensome, A.; Zhang, P.; Miller,
L.; Winneker, R. C.; Zhang, Z.; Zhu, Y.; Cohen, J.; Unwalla, R. J.;
Wrobel, J. Bioorg. Med. Chem. Lett. 2004, 14, 2185. (c) Fensome, A.;
Bender, R.; Cohen, J.; Collins, M. A.; Mackner, V. A.; Miller, L. L.;
Ullrich, J. W.; Winneker, R.; Wrobel, J.; Zhang, P.; Zhang, Z.; Zhu, Y.
Bioorg. Med. Chem. Lett. 2002, 12, 3487. (d) Sheikh, Z.; Steel, R.;
Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 763.
(2) For reviews on spirooxindole synthesis, see: (a) Honga, L.; Wang,
R. Adv. Synth. Catal. 2013, 355, 1023. (b) Dalpozzo, R.; Bartolib, G.;
Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247. (c) Singh, G. S.; Desta,
Z. Y. Chem. Rev. 2012, 112, 6104. For the original papers, see: (d)
Albertshofer, K.; Tan, B.; Barbas, C. F., III. Org. Lett. 2012, 14, 1834. (e)
Tessier, J. D.; O’Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 4963. (f) Bergonzini, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 971. (g) Tan, B.; Zeng,
X.; Leong, W. W. Y.; Shi, Z.; Barbas, C. F., III; Zhong, G. Chem.;Eur.
J. 2012, 18, 63. (h) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang, F.; Wang,
R. Angew. Chem., Int. Ed. 2011, 50, 9124. (i) Tan, B.; Candeias, N. R.;
Barbas, C. F., III Nat. Chem. 2011, 3, 473. (j) Tan, B.; Candeias, N. R.;
Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 4672. (k) Jiang, X.; Cao,
Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132,
15328.
(3) (a) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem.;Eur. J.
2012, 18, 6737. (b) Tan, B.; Torres, G. H.; Barbas, C. F., III. J. Am.
Chem. Soc. 2011, 133, 12354. (c) Jia, Z.-J.; Jiang, H.; Li, J.-L.;
Gschwend, B.; Li, Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jorgensen,
K. A. J. Am. Chem. Soc. 2011, 133, 5053. (d) Jiang, K.; Jia, Z.-J.; Yin, X.;
Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 2766. (e) Wei, Q.; Gong, L.-Z.
Org. Lett. 2010, 12, 1008.
(4) (a) Sun, J.; Sun, Y.; Gong, H.; Xie, Y.-J.; Yan, C.-G. Org. Lett.
2012, 14, 5172. (b) Jiang, X.; Sun, Y.; Yao, J.; Cao, Y.; Kai, M.; He, N.;
Zhang, X.; Wang, Y.; Wang, R. Adv. Synth. Catal. 2012, 354, 917. (c)
Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.;Eur. J. 2010,
ꢀ
16, 2852. (d) Companyo, X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.;
Moyano, A.; Rios, R. Chem. Commun. 2010, 46, 6953. (e) Bencivenni,
G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (f)
Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008,
130, 15786.
(5) Ramachary, D. B.; Reddy, G. B.; Mondal, R. Tetrahedron Lett.
2007, 48, 7618.
r
10.1021/ol401227q
XXXX American Chemical Society

synthesis with spiro-quaternary stereocenter poses a great
synthetic challenge. Only a few asymmetric transforma-
tions have proven suitable for achieving this challenging
goal.3,4
Table 1. Reaction Preliminary Optimizationa
catalyst 3/4
solvent
(0.2 M)
time
(h)
yieldb
eec
entry (20/30 mol %)
(%) of 5aa (%) of 5aa
Figure 1. Medicinally important spirooxindoles.
1
3a
C5H5CH3
C6H5CH3
C6H5CH3
C6H5CH3
C5H5CH3
DCM
72
72
72
36
12
72
60
60
72
36
72
72
27
50
70
70
60
60
68
70
60
55
27
85
92
85
87
88
93
90
86
84
2
3a/4a
3a/4b
3a/4b
3b/4b
3a/4b
3a/4b
3a/4b
3b/4b
3a/4b
3a/4c
3a/4b
3
To address this synthetic challenge, we sought to design
an organocatalytic reflexive-Michael (r-M) reaction that
would involve a reaction between two simple and readily
available starting materials. Given the recent discovery of
2-aminobuta-1,3-enynes (amino enynes) as mild nucleo-
philes in the organocatalytic r-M and aldol reactions,6 we
envisioned that r-M reactions between unmodified ynones
1 and 2-(2-oxoindolin-3-ylidene)malononitriles 2 would
yield the desired spirooxindole skeletons in a highly stereo-
selective manner (Scheme 1). From the pioneering studies
of Deng and other co-workers on cinchona alkaloid
catalysis7 and also from our own findings on these class
of catalysts,8 we focused our attention to use this class of
organocatalysts (Scheme 1). Herein, we present novel
organocatalytic asymmetric r-M reactions between unmo-
dified ynones 1 and 2-(2-oxoindolin-3-ylidene)malono-
nitriles 2 that would provide the highly functionalized
six-membered spirooxindoles 5 in good yields with high
enantioselectivities.
4d
5d
6
7
DCE
8e
9
DCE
DCE
10d
11
12
DCE
C6H5CH3
CH3CN
a Reactions were carried out in solvent (0.2 M) with 2 equiv of 1a
relative to the 2a (0.2 mmol) in the presence of 20/30 mol % of catalyst
3/4. b Yield refers to the column-purified product. c Ee determined by
CSP HPLC analysis. d Reaction performed at 60 °C. e Co-catalyst 4b was
taken as 40 mol %.
We initiated our studies by evaluating the r-M reac-
tion between ynone 1a and 2-(2-oxoindolin-3-ylidene)-
malononitrile 2a using epi-quinine-NH2 3a as the catalyst
in toluene at 25 °C (Table 1, entry 1). We found that the
reaction proceeded in very poor manner and afforded the
desired product 5aa in low yield with poor selectivity.
Surprisingly, the same reaction with benzoic acid 4a as
the cocatalyst at 25 °C for 72 h furnished the chiral
spirooxindole (ꢀ)-5aa in 50% yield with 85% ee
(Table 1, entry 2). After thorough investigation of epi-
quinine-NH2 3a-catalyzed asymmetric r-M reaction, we
found that the solvent, cocatalyst, and temperature have
significant effect on the ee’s and yields. Subsequent opti-
mization studies, we obtained the high enantioselectivities
(up to 93% ee) with the combination of epi-quinine-NH2
3a and o-FC6H4CO2H 4b as cocatalyst in DCE or toluene
(Table 1). In the final optimization, asymmetric r-M
reaction of 1a and 2a through 3a/4b-catalysis in toluene
at 25 °C for 72 h furnished the chiral spirooxindole (ꢀ)-5aa
in 70% yield with 92% ee (Table 1, entry 3). The same r-M
reaction in DCE furnished the (ꢀ)-5aa in 68% yield with
93% ee (Table 1, entry 7).
Scheme 1. Design for Spirooxindole Synthesis through an
Amino Enyne Catalysis
(6) For the previous work on amino enyne catalysis, see: (a)
Ramachary, D. B.; Venkaiah, Ch.; Krishna, P. M. Chem. Commun.
2012, 48, 2252. (b) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett.
2006, 8, 5417.
(7) For the excellent reviews, see: (a) Melchiorre, P. Angew. Chem.,
Int. Ed. 2012, 51, 9748. (b) Yeboah, E. M. O.; Yeboah, S. O.; Singh, G. S.
Tetrahedron 2011, 67, 1725. (c) Marcelli, T.; Hiemstra, H. Synthesis
2010, 1229. For the original papers, see: (d) McDaid, P.; Chen, Y.; Deng,
L. Angew. Chem., Int. Ed. 2002, 41, 338. (e) Christensen, C.; Juhl, K.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875.
(8) Ramachary, D. B.; Sakthidevi, R.; Shruthi, K. S. Chem.;Eur. J.
2012, 18, 8008and references cited therein.
We were interested in testing the electronic factor of
N-substitution and alsothe solvent factorbetween toluene/
DCE of the designed r-M reaction (Table 2). Reaction of
1a with 2-(1-methyl-2-oxoindolin-3-ylidene)malononitrile
2b under the catalysis of 3a/4b in toluene at 25 °C for 72 h
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. N-Substitution Effect on the r-M Reaction
Table 3. Scope of the Asymmetric Amino Enyne Catalysis
solvent
(0.2 M)
time yielda (%) of
eeb (%)
entry
R
(h)
5abꢀad
5abꢀad
ynone
olefin
time
(h)
yielda ee for 5b
1
2
3
4
5
2b: Me
2b: Me
C6H5CH3
DCE
72
48
36
12
72
5ab (50)
5ab (58)
5ac (50)
5ac (50)
5ad (<10)
93
86
88
82
entry
1
2
products
(%)
(%)
1
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2c
2c
2e
2e
2f
60
60
48
60
60
60
72
72
60
72
72
72
120
72
5ba
5ca
5da
5ea
5fa
5gc
5hc
5be
5ce
5af
5ag
5ah
5bi
5bj
60
60
50
60
55
50
40
50
50
55
50
50
40
40
90
93
91
89
85
88
81
92
96
88
87
90
85
91
2c: CH2OMe C6H5CH3
2c: CH2OMe DCE
2
3
2d: COCH3
DCE
4
a Yield refers to the column-purified product. b Ee determined by
CSP HPLC analysis.
5
6
1g
1h
1b
1c
1a
1a
1a
1b
1b
7c
8
furnished the (ꢀ)-5ab in 50% yield with 93% ee (Table 2,
entry 1). Interestingly, the same reaction in DCE at 25 °C
for 48 h furnished the (ꢀ)-5ab in 58% yield with reduced
(86%) ee (Table 2, entry 2). In a similar manner, r-M
reaction of 1a with 2-(1-(methoxymethyl)-2-oxoindolin-3-
ylidene)malononitrile 2c under 3a/4b-catalysis in toluene
at 25 °C for 36 h furnished the (ꢀ)-5ac in 50% yield with
88% ee and the same reaction in DCE gave the (ꢀ)-5ac in
50% yield with reduced (82%) ee (Table 2, entries 3ꢀ4).
Surprisingly, rate of the r-M reaction between 1a and 2-
(1-acetyl-2-oxoindolin-3-ylidene)malononitrile 2d under
the 3a/4b-catalysis is very slow (Table 2, entry 5). In a
furtherunderstanding of the reaction, wetreated 1awith2c
in DCE at 25 °C for 72 h under the 9-epi-aminoquinine
thiourea 3c-catalysis to furnish the only Michael adduct
6ac in <10% yield (eq S1, Supporting Information). This
result clearly explaining that the nucleophilic nature of 3,
acidic/counteranion nature of 4 and also nature of olefin 2
is crucial for the success of designed r-M reaction.
After realizing the electronic factors of N-substitution
and also toluene as the best solvent, we further explored
scope of the epi-quinine-NH2/o-FC6H4CO2H-catalyzed
r-M reaction by developing diversity-oriented synthesis
of optically pure spirooxindoles 5 through the reaction of
ynones 1aꢀh with olefins 2aꢀj (Table 3). The chiral
spirooxindoles 5 were obtainedin good yieldsand excellent
ee’s with variety of olefins containing neutral, electron-
donating, electron-withdrawing, and halogenated 2aꢀj
and ynones containing neutral, electron-donating, haloge-
nated and heteroatom substituted 1aꢀh from the asym-
metric r-M reaction (Table 3). Herein, variety of un-
modified ynones 1aꢀh are used as source for the in situ
generation of 2-aminobuta-1,3-enynes as novel mild nu-
cleophiles in a r-M reaction to furnish the functionalized
drug-like spirooxindoles 5baꢀbj with up to >96% ee in
good yields (Table 3). Surprisingly, the r-M reaction of
aliphatic ynone 4-(trimethylsilyl)but-3-yn-2-one 1h with 2c
under the catalysis of 3a/4b furnished the directly desilylation
product (þ)-5hc (R = H) in 40% yield with 81% ee
9
10
11
12
13
14
2g
2h
2i
2j
a Yield refers to the column-purified product. b Ee determined by
CSP HPLC analysis. c Product 5hc obtained as desilylation product (R = H).
(Table 3, entry 7). Interestingly, the r-M reaction of ynone
containing R0-branched aliphatic group 1i with 2c under
the 3a/4b catalysis furnished the unexpected cyclopenta-
nulation product 7ic in 40% yield with >99% de and
<5% ee (Table 4, entry 1). In a similar manner, reaction of
ynone 1j with 2c also furnished the cyclopentanulation
product 7jc in 40% yield with >99% de and <5% ee
(Table 4, entry 2). But the reaction of benzyloxy ynone 1k
with 2c under the 3a/4b catalysis gave the Michael product
6kc in 40% yield with >99% de and 95% ee (Table 4, entry 3).
These results clearly indicating that the ynones 1iꢀk
containing R0-branched substitution is controlling enough
to generate the reactive intermediate species like 2-amino-
buta-1,3-enynes versus 4-aminobuta-3-en-2-ones with cat-
alyst epi-quinine-NH2 through 1,2- or 1,4-addition and
which are the responsible for six-membered versus five-
membered ring formation, respectively. The structure and
absolute stereochemistry of the products 5-7 were con-
firmed by NMR analysis and also finally confirmed by
X-ray structure analysis on (ꢀ)-5af and 7ic as shown in
Figures S1 and S2 (Supporting Information).9
With the synthetic applications in mind, we explored the
utilization of spiranes 5 in the high-yielding synthesis of
functionalized chiral spiranes 8 and 9 via simple reduction
and chlorination reactions (Scheme 2). High-yielding re-
duction of chiral spirooxindoles (ꢀ)-5ag and (ꢀ)-5ac with
(9) CCDC-927184 for (ꢀ)-5af and CCDC-927185 for 7ic contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. XX, No. XX, XXXX
C

the crystal structure studies, we can rationalize the ob-
served high stereoselectivity through an allowed transition
state where the si-face of olefin 2 approaches the si-face of
2-aminobuta-1,3-enynes (amino enynes) due to the strong
hydrogen-bonding/electrostatic attraction/CH-π and ha-
logen (F)ꢀπ interactions10 and less steric hindrance/elec-
trostatic repulsion as shown in the TS-1. Formation of the
minor enantiomer may be explained by model TS-2, in
which there is strong electrostatic repulsions between the
amine/methoxy portion of the catalyst and the carbonyl/
amine group of olefins 2 (eq 1). Formation of the un-
expected cyclopentanulation products 7 may be explained
through stepwise reaction between in situ generated 4-ami-
nobuta-3-en-2-ones with olefins 2 as similar to the Tomita
phosphine-catalyzed zipper cyclization (see full details in
the Scheme S1, Supporting Information).11b
Table 4. Designed r-M Reaction with Other Ynones
yield (%)
de
ee
entry
R
product 5 product 6 product 7 6/7 (%) 6/7 (%)
1
2
3
CH3 (1i)
CH2CH3 (1j)
OBn (1k)
7ic (40)
7jc (40)
>99
>99
>99
<5
<5
95
6kc (40)
1.2 equiv of NaBH4 in dry CH3OH at 0ꢀ25 °C for 1.5 h
furnished the allylic alcohols (ꢀ)-8ag and (ꢀ)-8ac in
80ꢀ85% yield with 87ꢀ88% ee and 1:1 dr, respectively
(Scheme 2). Interestingly, diastereomerically pure allylic
alcohols (ꢀ)-8ag and (ꢀ)-8ac were separated through
column chromatography. Surprisingly, treatment of the
chiral allylic alcohol (ꢀ)-8ac with 1.2 equiv of MeSO2Cl
and Et3N in dry DCE at 70 °C for 12 h furnished the
chlorination product (þ)-9ac in 35% yield with 88% ee
and 1:2 dr instead of simple mesylation or elimination
products. In a similar manner, treatment of (ꢀ)-8ac with
1.0 equiv of Ph3PO and 8.0 equiv of (COCl)2 in dry CHCl3
at 25 °C for 2 h furnished the chlorination product (þ)-9ac
in55%yield with 88%eeand 1:1.25dr. Diastereomerically
pure allyl chlorides (þ)-9ac were separated through col-
umn chromatography. Compounds (ꢀ)-8ac, (ꢀ)-8ag, and
(þ)-9ac would be precursors for the synthesis of druglike
molecules as shown in the Figure 1.
In summary, building on a powerful but largely un-
exploited mode of catalytic amino enyne reactivity discov-
ered by Gouverneur and our group,6 we have developed a
versatile new method for the room-temperature synthesis
of functionalized chiral spirooxindoles 5 from acyclic
precursors. The products of the r-M reaction 5 were
derivatized with good to moderate diastereoselection into
an array of highly functionalized druglike molecules 8
and 9. Future investigations within the group will continue
to explore the scope of novel modes of catalytic amino
enynes reactivity furnished by chiral amines with unmodi-
fied ynones.
Scheme 2. Synthetic Applications of Chiral Spirooxindoles
Acknowledgment. This work was made possible by a
grant from the DST, New Delhi. C.V. and R.M. thank
CSIR, New Delhi, fortheirresearchfellowships. Thiswork
is dedicated to Professor Goverdhan Mehta (University of
Hyderabad, India) on the occasion of his 70th birthday.
Supporting Information Available. Experimental pro-
cedures, compound characterization, X-ray crystal struc-
tures, and analytical data (1H NMR, 13C NMR, HRMS,
and HPLC) for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Although supplementary studies are needed to securely
elucidate the mechanism of r-M reactions through
3a/4b-catalysis, the reaction proceeds by stepwise manner
between in situ generated 2-aminobuta-1,3-enynes or
4-aminobuta-3-en-2-ones with olefins 2 (eq 1). Based on
(11) (a) Wilson, J. E.; Sun, J.; Fu, G. C. Angew. Chem., Int. Ed. 2010,
49, 161. (b) Kuroda, H.; Tomita, I.; Endo, T. Org. Lett. 2003, 5, 129.
(10) (a) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Chem. Sci. 2011,
2, 1793. (b) Nishio, M. Tetrahedron 2005, 61, 6923. (c) Venu, V. R.;
Nangia, A.; Lynch, V. M. Chem. Commun. 2002, 1304. (d) Yamakawa,
M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX