A facile approach for the asymmetric synthesis of oxindoles with a 3-sulfenyl-substituted quaternary stereocenter

Article abstract of DOI:10.1021/ol402579x

With the employment of a threonine-incorporating multifunctional catalyst 9, Michael addition of 3-sulfenyloxindoles to nitroolefins proceeded stereoselectively, leading to the formation of oxindoles with a 3-sulfenyl-substituted quaternary center in excellent yields, and with high diastereoselectivities and excellent enantioselectivities.

Full text of DOI:10.1021/ol402579x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Facile Approach for the Asymmetric
Synthesis of Oxindoles with a 3‑Sulfenyl-
Substituted Quaternary Stereocenter
Xiaowei Dou, Bo Zhou, Weijun Yao, Fangrui Zhong, Chunhui Jiang, and Yixin Lu*
Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543
chmlyx@nus.edu.sg
Received July 3, 2013
ABSTRACT
With the employment of a threonine-incorporating multifunctional catalyst 9, Michael addition of 3-sulfenyloxindoles to nitroolefins proceeded
stereoselectively, leading to the formation of oxindoles with a 3-sulfenyl-substituted quaternary center in excellent yields, and with high
diastereoselectivities and excellent enantioselectivities.
3,3-Disubstituted oxindoles are widelypresent innatural
products and bioactivemolecules.1 Inparticular, oxindoles
bearing a 3-heteroatom-substituted quaternary stereo-
genic center are extremely important in medicinal chem-
istry, and thus their asymmetric synthesis has been
intensively investigated in recent years.2 A wide range of
synthetic methods have been developed for catalytic
asymmetric synthesis of 3-substituted-3-heteroatom oxi-
ndoles, such as 3-aminooxindoles,3 3-hydroxyoxindoles,4
3-fluorooxindoles,5 among others.6 For sulfur-containing
molecular frameworks, direct asymmetric sulfenylation7
and C-alkylation of sulfenyl derivatives are commonly
used. Surprisingly, 3-sulfenyloxindoles, an important class
of biologically important molecules, were less explored.8
Only a handful of examples appeared in the literature
(1) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (b) Dounay, A. B.; Overman, L. E. Chem.
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327. (e) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem.
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r
10.1021/ol402579x
XXXX American Chemical Society

recently. Feng et al. employed the N,N0-dioxide-Sc(OTf)3
complex to catalyze an enantioselective sulfenylation
of 3-substituted oxindoles.9 Asymmetric sulfenylations
catalyzed by organiccatalysts wereindependently reported
by the groups of Enders,10a Cheng,10b and Jiang.10c Very
recently, Zhou et al. disclosed an efficient synthesis of
3-sulfenyl-3-amino-oxindoles via asymmetric aminations
of 3-thio/alkoxyoxindoles.11 Our group has been actively
investigating the synthesis of chiral oxindole derivatives
bearing a quaternary stereogenic center.12 Given the bio-
logical significance of oxindoles containing a 3-sulfenyl-
substituted quaternary carbon, we intended to develop
an efficient asymmetric synthetic method to access these
molecules.
materials, which can be readily prepared from inexpensive
nitroolefins.13 Subsequent reactions with thio nucleophiles
are expected to install sulfenyl groups at the 3-position
of oxindoles. In the presence of suitable catalysts, reac-
tions between 3-sulfenyloxindoles14 and electrophiles can
yield the desired chiral 3-sulfenyl-3-substituted oxindole
products (Scheme 1).
Scheme 1. Preparation of 3-Sulfenyl-3-substituted Oxindoles
In the reported direct asymmetric sulfenylation meth-
ods, expensive isatins were commonly used as starting
materials to prepare 3-substituted oxindoles. Moreover,
the chiral 3-sulfenyloxindole products prepared contained
only aryl or alkyl groups at the 3-position, which certainly
posed restrictions to their synthetic manipulations. In
our proposal, 3-chlorooxindoles are employed as starting
We started our investigations by examining the catalytic
effects of various organic catalysts on the asymmetric
Michael addition of 3-sulfenyloxindole 1a to nitroolefin
2a (Table 1). Bifunctional tertiary amine catalysts15 con-
taining a Brønsted acid moiety are expected to effectively
promote the projected reaction through cooperative inter-
actions with both substrates. Cinchonidine-derived 4
showed high catalytic activity; however, the stereoselectiv-
ity of the reaction was poor (entry 1). L-Threonine-derived
516 led to the formation of the desired product in relatively
low yield, and with moderate diastereo- and enantioselec-
tivity (entry 2). To further improve the results, we chose to
employ our recently developed amino acid incorporating
multifunctional catalysts.17 To our delight, all the multi-
functional catalysts were much more effective, affording
the desired products in high yields and with high enantio-
and diastereoselectivities. All the catalysts containing
silylated L-threonine worked very well (entries 3ꢀ6),
and quinine-derived 9 with a TBDPS-L-threonine moiety
proved to be the best catalyst (entry 6). The silyl protection
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Evaluation of Different Catalysts for the Michael
Addition of 3-Sulfenyloxindole 1a to Nitroolefin 2aa
Table 2. Optimizing Reaction Conditionsa
cat. loading
t
yield
dr
ee
entry
(x mol %)
solvent additive (h) (%)b
(%)c (%)d
1
2
3
4
5
6
7
8
9
5
CH2Cl2 none
4
93
>20:1 97
5
THF
none
12
<10
ꢀ
ꢀ
5
xylene
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
none
1.5 96
>20:1 96
19:1 97
˚ꢀ
5
3 A MS 1.5 98
˚ꢀ
5
4 A MS 1.5 98
>20:1 97
>20:1 96
>20:1 97
>20:1 97
˚ꢀ
5
5 A MS 1.5 98
˚ꢀ
2.5
1.0
0.5
4 A MS
3
8
98
98
96
˚ꢀ
4 A MS
˚ꢀ
4 A MS 15
19:1
95
a Reactions were performed with 1a (0.1 mmol), 2a (0.12 mmol), and
the 9 (x mol %) in the solvent (1.0 mL) specified at rt. b Isolated yield.
c Determined by 1H NMR. d Determined by HPLC analysis on a chiral
stationary phase; ee value of the major isomer.
entry
catalyst
t (h)
yield (%)b
dr (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
4
2
96
83
95
98
96
98
97
95
97
1.6:1
4:1
51, 53
78
5
24
3
6
16:1
12:1
16:1
19:1
13:1
10:1
19:1
96
substitution patterns (entries 1ꢀ6). Aryls other than phe-
nyls could also be employed in the nitroolefin structures
(entries 7 and 8). The reaction was also applicable to
3-sulfenyloxindoles containing different aromatic moieties
(entries 9 and 10). Moreover, alkyl nitroolefins could
also be employed, and the desired products were obtained
with excellent diastereo- and enantioselectivities, although
the yields were slightly lower (entries 11 and 12). In all
the examples examined, very high diastereoselectivities
(14:1 to >20:1 dr) and enantioselectivities (up to 99% ee)
were attainable. Oxindoles containing different 3-thioether
moieties were also examined. Various alkyl thioether sub-
strates all worked well (entries 13ꢀ15). However, a phenyl
thioether substrate displayed lower reactivity, and the
stereoselectivities of the reaction also dropped (entry 16).
If the oxindole NH was protected as a carbamate, the
reaction became faster but less stereoselective (entry 17).
To demonstrate the practicality of our method, a gram scale
synthesis of 3a was performed (entry 2).
7
6
92
8
2
97
9
1.5
2
97
90
10
11
86
2
83
ꢀ86e
2
a Reactions were performed with 1a (0.1 mmol), 2a (0.12 mmol), and
the catalyst (0.05 mmol) in toluene (1.0 mL) at rt. b Isolated yield.
c Determined by 1H NMR. d Determined by HPLC analysis on a chiral
stationary phase; ee value of the major isomer. e The opposite enantio-
mer was obtained.
was essential for the observed stereoselectivities; both
diastereo- and enantioselectivities decreased when the non-
silylated catalyst 90 was used (entry 7). Moreover, tert-
leucine-derived 10 was also shown to be less effective
(entry 8). Interestingly, the opposite enantiomer could be
obtained with the employment of a quinidine-derived 11
containing a TBDPS-D-threonine (entry 9).
Having identified 9 as the best catalyst, we then carried
out further studies to optimize the reaction conditions
(Table 2). Solvent screening confirmed that toluene is
a solvent of choice for our reaction (entries 1ꢀ3). Additive
3-Substituted-3-sulfenyloxindoles with a neighboring
nitro group are highly versatile synthetic intermediates.
The reduction of the nitro group in oxindole adducts and
subsequent manipulations of the resulting amino group
were well documented in the literature.18 We opted to
illustrate the synthetic value of our products via oxidation
of the nitro group (Scheme 2). Adduct 3a was smoothly
oxidized to the corresponding acid 12a.19 Subsequent
esterification, followed by reduction, then afforded hy-
droxy group containing oxindole 14. To realize an intra-
molecular cyclization, a Boc group was first installed to 13,
ꢀ
˚
studies proved that addition of 4 A molecular sieves
was beneficial (entries 4ꢀ6). The catalyst loading could
be reduced to as low as 1 mol % without sacrificing the
diastereo- and enantioselectivity of the reaction (entries 7ꢀ8).
A further decrease of the catalyst loading to 0.5 mol % was
feasible; both dr and ee values were practically maintained
(entry 9).
With the optimal reaction conditions in hand, we con-
tinued to examine the substrate scope of the reaction
(Table 3). Different aryl nitroolefins could be employed,
including aromatic rings with different halogen substitutions,
substituents of different electronic natures, and different
(18) (a) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009,
131, 8758. (b) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc.
2009, 131, 16620.
(19) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62,
234.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Reaction Scope of Asymmetric Conjugate Addition of
3-Sulfenyloxindoles 1 to Nitroolefins 2a
Scheme 2. Synthetic Manipulations of the 3-Sulfenyloxindole 3
t
yield
(%)b
ee
(%)d
entry
3, R1/R2/ R3/R4
(h)
drc
1
3a, H/Bn/H/C6H5
8
98
97
95
98
98
97
99
96
97
95
81
84
99
95
97
95
99
>20:1
>20:1
14:1
97
97
99
97
97
97
98
96
98
96
98
98
95
91
87
79
83
2e
3
3a, H/Bn/H/C6H5
12
10
12
12
16
10
12
12
10
12
12
6
3b, H/Bn/H/2-Br-C6H4
3c, H/Bn/H/3-Br-C6H4
3d, H/Bn/H/4-Cl-C6H4
3e, H/Bn/H/4-Me-C6H4
3f, H/Bn/H/2-naphthyl
3g, H/Bn/H/2-furyl
3h, 5-Me/Bn/H/C6H5
3i, 6-Cl/Bn/H/C6H5
3j, H/Bn/H/n-butyl
3k, H/Bn/H/phenethyl
3l, H/4-OMe-Bn/H/C6H5
3m, H/n-Bu/H/C6H5
3n, H/Me/H/C6H5
4
>20:1
>20:1
>20:1
>20:1
19:1
5
6
7
8
resulted in the formation of oxindole 17 containing a free
thiol group at the 3-position in high yield.
9
>20:1
19:1
10
11f
12f
13
14
15
16
17
In conclusion, we have prepared various 3-sulfenylox-
indoles from 3-chlorooxindoles, which were readily de-
rived from inexpensive nitroolefins. By utilizing our amino
acid incorporating organic catalysts, we showed that
Michael addition of 3-sulfenyloxindoles to nitroolefins
proceeded in a highly stereoselective manner, affording
oxindoles containing a 3-sulfenyl-substituted quaternary
stereogenic center in excellent yields, high diastereoselec-
tivities, and excellent enantioselectivities. The oxindole
adducts are versatile synthetic intermediates and could be
readily transformed into molecular structures of biological
significance.
19:1
16:1
19:1
12
20
40
0.5
>20:1
>20:1
5:1
3o, H/Ph/H/C6H5
3p, H/Bn/CO2Et/C6H5
13:1
a Reactions were performed with 1 (0.1 mmol), 2 (0.12 mmol), 9
(0.001 mmol), and 4 A MS (10 mg) in toluene (1 mL) at rt. b Isolated
ꢀ
˚
yield. c Determined by 1H NMR. d Determined by HPLC analysis on a
chiral stationary phase; ee value of the major isomer. e Reaction was
performed on 2.5 mmol scale; 0.98 g of 3a was obtained. f The catalyst
loading was 5 mol %.
Acknowledgment. We gratefully acknowledge the gen-
erous financial support from the National University of
Singapore (R-143-000-469-112), GSK-EDB (R-143-000-
491-592), and the Ministry of Education (MOE) of Singa-
pore (R-143-000-494-112).
and reduction of the ester group in 15 then resulted in a
smooth cyclization20 to yield furoindoline 16, which re-
presents a core structure of antitumor agents.7c The abso-
lute configurations of products were determined on the
basis of the X-ray crystal structure of a 12bꢀTHF complex
(see the Supporting Information). Furthermore, treatment
ofadduct3lwitha catalytic amount ofHg(OAc)2 inTFA21
Supporting Information Available. Representative
experimental procedures, HPLC chromatogram, and NMR
spectra of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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