Enantioselective organocatalytic addition of nitroalkanes to oxindolylideneindolenines for the construction of chiral 3,3-disubstituted oxindoles

Article abstract of DOI:10.1002/adsc.201300373

An enantioselective organocatalytic addition of nitroalkanes to oxindolylideneindolenines in the presence of bifunctional organocatalysts has been established to provide an efficient entry to 3,3-disubstituted oxindole derivatives in high yields and with excellent enantioselectivities. The transformation has been applied to the preparation of the key intermediate for a formal total synthesis of (+)-gliocladin C. Copyright

Full text of DOI:10.1002/adsc.201300373

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DOI: 10.1002/adsc.201300373
Enantioselective Organocatalytic Addition of Nitroalkanes to
Oxindolylideneindolenines for the Construction of Chiral
3,3-Disubstituted Oxindoles
Jian-Zhou Huang,a Xiang Wu,a and Liu-Zhu Gonga,*
a
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, Peopleꢀs Republic of China
Fax : (+86)-551-360-6266; e-mail: gonglz@ustc.edu.cn
Received: April 30, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300373.
Abstract: An enantioselective organocatalytic addi-
tion of nitroalkanes to oxindolylideneindolenines in
the presence of bifunctional organocatalysts has
been established to provide an efficient entry to
3,3-disubstituted oxindole derivatives in high yields
and with excellent enantioselectivities. The transfor-
mation has been applied to the preparation of the
key intermediate for a formal total synthesis of
(+)-gliocladin C.
in a wide array of biologically and pharmacologically
relevant natural products (Figure 1).[1] Of particular
interest are 3-functionalized 3-indolyloxindole skele-
tons I, which are commonly existing in alkaloids.[1f–h]
Furthermore, these building blocks have been exten-
sively used as key intermediates in the total synthesis
of natural products.[1f,2] Due to the importance of the
structural motif and the challenge in the construction
of all-carbon quaternary stereogenic centers,[3] various
methodologies leading to the preparation of 3,3-dis-
ubstituted oxindoles in an asymmetric fashion have
been developed in recent decades.[4,5]
In terms of synthetic efficiency in the production of
3-functionalized 3-indolyloxindoles IV, structurally
similar to I, the enantioselective substitution with II
via a 3-(3H-indol-3-ylidene)indolin-2-one intermedi-
ate of type III represents the most straightforward ap-
Keywords: arylsulfonyloxindoles; asymmetric syn-
thesis; 3,3-disubstituted oxindoles; nitroalkanes; or-
ganocatalysis; quaternary stereogenic centers
The 3,3-disubstituted oxindole skeleton, containing proach (Figure 2a). Very recently, we found that the
all-carbon quaternary stereogenic centers, is prevalent 3-hydroxy-3-indolyloxindole V was able to undergo
Figure 1. Natural products containing the 3,3-disubstituted oxindole scaffold.
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derivatives.[8] Johnston established an enantioselective
Brønsted base-catalyzed alkylation of nitroalkanes
with arylsulfonylindoles, which proceeded via the con-
jugate addition to the eneindolenine, in high yields
and with fairly good enantiomeric excesses.[9] Petrini,
Bernardi and co-workers found that the Cinchona al-
kaloids-derived bifunctional catalysts showed excel-
lent catalytic activity and provided high levels of
enantioselectivity for the similar reaction under sol-
vent-free conditions.[10] Very recently, Arai established
an enantioselective addition of indoles to isatin-de-
rived nitroalkenes for the synthesis of 3-nitromethyl
3-indolyloxindoles.[4l] Inspired by these fundamental
achievements, we proposed that in the presence of
a bifunctional catalyst, 3-(1H-indol-3-yl)-3-tosylindo-
lin-2-ones of type 1 would be converted into oxindoly-
lideneindolenine intermediate III, which might partic-
ipate in an enantioselective conjugate addition with
nitroalkanes, to furnish 3-alkyl-3-indolyloxindole 3
(Figure 2c). Herein, we report our efforts directed
toward this reaction and its application to a catalytic
enantioselective formal total synthesis of (+)-gliocla-
din C.
A variety of structurally different chiral organocata-
lysts 4 were first investigated in the reaction between
nitromethane 2a and the 3-(1H-indol-3-yl)-3-tosylin-
dolin-2-one 1a in the presence of K3PO4 as an inor-
ganic base in dichloromethane (Table 1, entries 1–5).
Chiral ammonium salt 4a[11] and bifunctional thiourea
4b[12a] were able to catalyze the alkylation reaction
but in lower yield and with moderate ee (entries 1 and
2). In comparison with the thiourea, bifunctional
urea-based organocatalysts 4c–4e[12,13] proved to be
much more enantioselective (entries 3–5). In particu-
lar, the organocatalyst 4c afforded the product with
the highest level of enantioselectivity (entries 1–5).
Subsequently, different solvents were also surveyed
for the reaction catalyzed by 4c and it was found that
Figure 2. Alkylideneindolenine intermediates and their pre-
cursors.
asymmetric substitution via sequential dehydration toluene was the most suitable medium (entries 3, 6–
and enantioselective conjugate addition in the pres- 8). The variation of bases exerted a considerable
ence of chiral Brønsted acids (Figure 2b).[5] Independ- impact on the reaction (entries 9–13). In addition, the
ently, Guo and Peng established an enantioselective N-substituents in the oxindole moieties had salutary
alkylation of ketones with 3-hydroxyoxindole via the effects on both the yield and enantioselectivity (en-
intermediate VI catalyzed by chiral phosphoric acids tries 14–17). Notably, the introduction of a benzyl
(Figure 2b).[6] However, these two Brønsted acid-cata- group gave a much higher yield (90%) and excellent
lyzed asymmetric protocols only worked well with enantioselectivity (95%) (entry 15). However, no re-
enolizable ketones or enamides. This inherent limita- action occurred when the nitrogen of the indole ring
tion to some degree inhibits their synthetic applica- was methylated, as shown for 1f (entry 18), suggesting
tion. Thus, alternative enantioselective reactions that reaction proceeds via the proposed pathway
based on the intermediate III are undoubtedly a valua- rather than the indol-2-one (Figure 2). Notably,
ble desire.[5,6]
a scale-up procedure also afforded the product in
Petrini and co-workers found that the reactive in- good yield with retained enantiomeric excess
dolenine intermediates could be readily generated by (entry 19).
the elimination of the leaving group from 3-(1-arylsul-
The optimized reaction conditions were then uti-
fonylalkyl)indoles under basic conditions,[7] allowing lized to the substitution reaction of nitroalkanes with
the realization of a large variety of nucleophilic sub- a variety of substituted 3-(arylsulfonylalkyl)oxindoles
stitution reactions to produce functionalized indole (Table 2). Either the indole or oxindole moiety substi-
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Enantioselective Organocatalytic Addition of Nitroalkanes to Oxindolylideneindolenines
Table 1. Catalysts screening and optimization of the reaction conditions.[a]
Entry
4
1
Base
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1e
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Et3N
KHCO3
K2HPO4
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
15
16
22
25
5
19
23
24
–
55
36
56
52
52
58
66
82
–
DCE
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
19
–
–
–
–
78
63
77
90
95
79
–
32
30
94
95
92
95[d]
–
64
95[e]
[a]
Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol), base(0.101 mmol), 10 mol% catalyst 4, with 1 mL solvent.
Isolated yield.
The ee value was determined by HPLC analysis using a chiral stationary phase.
The reaction was carried out under argon in the presence of 50 mg Na2SO4.
0.5 g of 1 was used.
[b]
[c]
[d]
[e]
tuted with either electron-donating or electron-with- ing products 3w and 3x in good yields (83% and 78%,
drawing substituents was well tolerated and afforded respectively) and high levels of enantioselectivity (en-
products in good to excellent yields (79–98%) and tries 17 and 18).
with excellent enantioselectivities (89–98% ee) (en-
More significantly, the reaction conditions were
tries 1–16). Notably, the a-branched nitroalkanes 2b also amenable to asymmetric substitution reactions
and 2c were also able to participate in the substitution with acidic methylene nucleophiles. For example, the
reaction and, respectively, furnished the correspond- dibenzyl malonate 2d smoothly underwent a highly
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Table 2. The scope of 3-(1-arylsulfonylalkyl)oxindoles.[a]
Entry
1 (R1, R2)
2
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1g (5-Cl, H)
1h (5-Br, H)
1i (5-Me, H)
1j (5-OMe, H)
1k (6-F, H)
1l (6-Cl, H)
1m (7-Me, H)
1n (2-Me, H)
1o (H, 5-F)
1p (H, 5-Cl)
1q (H, 5-Br)
1r (H, 5-Me)
1s (H, 5-OMe)
1t (H, 6-Br)
1u (H, 7-Br)
1v (H, 7-CF3)
1p (H, 5-Cl)
1c (H, H)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
80
98
97
85
90
77
95
97
76
97
92
96
84
95
79
88
83
78
89
90
97
92
93
92
94
90
93
99
93
98
90
95
96
93
92[d]
78
9
10
11
12
13
14
15
16
17
18
[a]
Reaction conditions: 1 (0.1 mmol), 2 (0.5 mmol), K3PO4 (0.101 mmol), 10 mol% catalyst 4c, with 1 mL toluene.
Isolated yield.
The ee value was determined by HPLC analysis using a chiral stationary phase.
The values refer to the main diastereoisomerꢀs ee; the other diastereoisomerꢀs ee=90%; dr=1.2/1, determined by
1H NMR spectroscopy.
[b]
[c]
[d]
enantioselective substitution reaction with 1c, to pro- against the murine P388 lymphocytic leukemia
duce 3y in 60% yield and with 87% ee under the opti- cells.[1g] Thus, great efforts have been directed toward
mized conditions [Eq. (1)].
the development of synthetic approaches for the total
synthesis of natural products of this family and indeed
led to several elegant total synthesis.[2a–d,5,14] However,
new synthetic routes to access this molecule are still
of great importance.
Thus, we finally investigated the feasibility to apply
the asymmetric reaction to the catalytic enantioselec-
tive formal total synthesis of (+)-gliocladin
C
(Scheme 1). The reduction of the compound 3e[15] af-
forded the corresponding hemiaminal 5 in 95% yield
with a single diastereomer. Then, the TMS group and
Boc group were respectively introduced to protect the
hydroxy and nitrogen atom of hemiaminal 5 in the
indole ring. Afterwards, the TMS group was removed
with TBAF, providing the hemiaminal 6 in a 90%
yield over 3 steps. The obtained hemiaminal 6 was ex-
(+)-Gliocladin C is a typical member of the alka- posed to a solution of trimethyl orthoformate and
loid family containing the 3-alkyl-3-indolyloxindole BF3·Et2O at room temperature, to generate 7 as a 2/
skeleton, exhibiting significant cytotoxic activity 1 (7a/7b) diastereomeric mixture in 70% overall yield.
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Enantioselective Organocatalytic Addition of Nitroalkanes to Oxindolylideneindolenines
Scheme 1. Application in the synthesis of the intermediate towards (+)-gliocladin C. Reaction conditions: (a) NaBH4,
MeOH/THF, room temperature (95% ee, >99% ee after a single recrystallization); (b) TMSCl, imidazole, CH2Cl2, room
temperature; (c) (Boc)2O, DMAP, CH2Cl2, room temperature; (d) TBAF, THF, room temperature; (e) BF3·Et2O,
CHACHTUNGTRENNUNG(CH3O)3, Et2O, room temperature; (f) NaNO2, AcOH, DMSO, 358C; (g) ClCOOMe, Et3N, THF, room temperature; (h)
NaBH4, MeOH, room temperature.
Basically, the completion of the synthesis required the generation of a quaternary all-carbon stereogenic
conversion of the primary nitro group of 7a to an al- center at C-3. More importantly, this method could be
dehyde via the Nef reaction.[16] However, the alde- applied to the enantioselective formal total synthesis
hyde could not be generated although a variety of hy- of (+)-gliocladin C.
drolytic or oxidative conditions were examined. For-
tunately, an acid 8 could be generated from com-
pound 7a by a protocol developed by Mioskowski.[17]
By sequential protection and reduction, the acid 8
Experimental Section
was transformed into an alcohol 9, which was in
agreement with the data reported by Overman. Final-
ly, with the key intermediate 9 in hand, (+)-gliocladin
General Procedure for the Addition of Nitroalkanes
to Oxindolylideneindolenines
To a solution of 3-(1-arylsulfonylalkyl)oxindole 1 (0.1 mmol)
in toluene (1 mL) were added catalyst 4c (10 mol%, 5.8 mg)
and K3PO4 (0.101 mmol, 21.4 mg). The reaction mixture was
stirred at room temperature for 15 min. Nitroalkane 2
C could undoubtedly be accessed by following the
synthetic route developed by Overman.[2c]
In conclusion, we have developed a highly enantio-
selective organocatalytic addition of nitroalkanes to
(0.5 mmol) was then added to the mixture. The resulting
oxindolylideneindolenines catalyzed by a Cinchona-
suspension was stirred at room temperature for 3 days, then
was diluted with EtOAc (15 mL), followed by washing with
H2O (10 mL). The organic phase was dried over anhydrous
derived urea catalyst under basic reaction conditions.
The protocol represents a new approach to access
polyfunctionalized 3,3-disubstituted oxindoles with Na2SO4 and concentrated under vacuum. The residue was fi-
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nally purified by flash chromatography (petroleum ether:-
ethyl acetate=2: 1) on silica gel to give product 3.
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Acknowledgements
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We are grateful for financial support from NSFC (20732006),
MOST (973 program 2009CB825300), the Ministry of Edu-
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8 Enantioselective Organocatalytic Addition of Nitroalkanes
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Adv. Synth. Catal. 2013, 355, 1 – 8
Jian-Zhou Huang, Xiang Wu, Liu-Zhu Gong*
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