Stereocontrolled creation of all-carbon quaternary stereocenters by organocatalytic conjugate addition of oxindoles to vinyl sulfone

Article abstract of DOI:10.1002/anie.201003837

Multifunctional catalysts in operation: A novel class of trifunctional thiourea catalysts containing natural amino acid residues have been prepared (see scheme), and found to be very effective towards the asymmetric addition of 3-alkyl-oxindoles to 1,1-bi

Full text of DOI:10.1002/anie.201003837

Angewandte
Chemie
DOI: 10.1002/anie.201003837
Asymmetric Catalysis
Stereocontrolled Creation of All-Carbon Quaternary Stereocenters by
Organocatalytic Conjugate Addition of Oxindoles to Vinyl Sulfone**
Qiang Zhu and Yixin Lu*
Oxindole motifs are widely present in natural products
and bioactive molecules.[1] In particular, oxindole com-
pounds bearing a quaternary stereogenic center[2] at the
3-position are extremely useful. In this context, various
synthetic strategies have been devised in recent years for
the asymmetric synthesis of 3,3-disubstituted oxindole
derivatives. Most approaches, including fluorination,[3]
hydroxylation,[4] amination,[5] aldol and Mannich reac-
Scheme 1. Construction of 3,3-dialkyl-substituted or 3-alkyl-3-aryl-disubstituted
oxindoles and indolines. R=aryl or alkyl, R’=alkyl.
tions,[6] allylic alkylation,[7] and conjugate addition,[8]
employ 3-substituted oxindoles as nucleophiles. The
research groups of Vedejs and Fu have achieved the
synthesis of 3-acylated oxindoles[9] bearing a quaternary
stereocenter through a rearrangement mediated by a chiral
nucleophilic catalyst. In spite of the aforementioned synthetic
advances, organocatalytic approaches to access chiral 3,3-
dialkyl-substituted or 3-alkyl-3-aryl-disubstituted oxindole
derivatives are very limited.[10] It is thus highly desirable to
develop asymmetric synthetic methods for the preparation of
such medicinally useful and synthetically challenging mole-
cules.
Vinyl sulfones are valuable and unique acceptors in
conjugate addition.[11] Recently, our research group and
others[12] have reported a wide range of asymmetric organo-
catalytic conjugate additions, which employed vinyl sulfones
as acceptors. We envisioned that an organocatalytic conjugate
addition of 3-aryl- or 3-alkyl-substituted oxindole to 1,1-
bis(benzenesulfonyl)ethylene, and subsequent desulfonation,
might provide a viable approach for the construction of
optically enriched 3,3-alkyl/aryl-disubstituted oxindoles.
Moreover, facile reduction of the carbonyl moiety of oxin-
doles allows easy access to 3,3-disubstituted indolines, which
are known to be extremely important structural elements in
many biologically active compounds and natural products
(Scheme 1).[13] Herein, we document the first highly stereo-
selective conjugate addition of 3-aryl- or 3-alkyl-substituted
oxindoles to 1,1-bis(benzenesulfonyl)ethylene, thus leading to
an enantioselective preparation of 3-alkyl-3-aryl-disubsti-
tuted or 3,3-dialkyl-substituted oxindoles and indolines bear-
ing an all-carbon quaternary stereogenic center.
To effect a stereoselective conjugate addition of oxindoles
to vinyl sulfone, a bifunctional tertiary amine catalyst with a
properly installed Brønsted acid moiety is an obvious choice.
We began our investigation by examining a number of
bifunctional tertiary amine catalysts in the conjugate addition
of oxindole 1a to vinyl sulfone 2 (Table 1). Quinidine 4 gave
disappointing results (Table 1, entry 1), 6’-demethylated qui-
nidine[14] 5 and quinidine-derived sulfonamide[15] 6 were found
to be poor catalysts (Table 1, entries 2 and 3). Quinidine-
derived tertiary amine thiourea catalyst 7[16] turned out to be
an excellent catalyst (Table 1, entry 4). Other thioureas, such
as tryptophan-derived 8[16i] and Takemotoꢀs catalyst 9[16a] were
ineffective (Table 1, entries 5 and 6). By lowering the reaction
temperature to À788C, we were able to obtain the desired
adduct in 97% yield and with 94% ee (Table 1, entry 7). The
absolute configurations of the adducts were assigned based on
X-ray crystallographic analysis of a single crystal of 3b.[17] It
should be noted that the Boc protecting group on the nitrogen
atom is crucial for the observed enantioselectivity, as the same
reaction catalyzed by 7 employing oxindole 1b gave racemic
product, thus suggesting the important role of the N-Boc
group in asymmetric induction.
The generality of the conjugate addition was subsequently
investigated. A wide range of 2-aryl-substituted oxindoles
were employed as acceptors, and very high yields and
excellent enantioselectivities were attainable in all the
examples examined (Table 2, entries 1–10). However, when
3-benzyloxindole was used, the corresponding adduct 3m was
obtained in 76% yield, but only with 28% ee (Table 2,
entry 11).[18]
[*] Q. Zhu, Prof. Dr. Y. Lu
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: (+65)6779-1691
E-mail: chmlyx@nus.edu.sg
Prof. Dr. Y. Lu
It is not surprising that conjugate addition catalyzed by 7
was not applicable to 3-alkyl-substituted substrates. In fact, all
the examples reported in the literature only worked well
either for 3-aryl- or 3-alkyl-substituted oxindoles.[3–8] To
achieve high enantioselectivity in the projected conjugate
addition, it is essential for the catalyst to interact with
oxindole and vinyl sulfone simultaneously in a cooperative
Medicinal Chemistry Program, Life Sciences Institute
National University of Singapore (Singapore)
[**] We thank the National University of Singapore and the Ministry of
Education (MOE) of Singapore (R-143-000-362-112) for generous
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003837.
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Communications
Table 1: Screening of catalysts in the conjugate addition of 3-phenyl-
substituted oxindole 1a to vinyl sulfone 2.[a]
Table 2: Conjugate additions of various 3-aryl-substituted oxindoles 1 to
vinyl sulfone 2 catalyzed by 7.[a]
Entry
Product 3: R/R’
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
3c: p-MeC6H4/H
3d: m-MeC6H4/H
3e: o-MeC6H4/H
3 f: p-OMeC6H4/H
3g: o-OMeC6H4/H
3h: p-FC6H4/H
3i: p-PhC6H4/H
3j: 2-naphthyl/H
3k: Ph/CH3
92
97
93
95
94
97
98
95
95
94
76
90
90
91
91
99
94
96
93
90
93
28
10
11
3l: Ph/F
3m: Bn/H
[a] Reactions were performed with oxindole (0.5 mmol), 2 (0.05 mmol),
and 7 (0.01 mmol) in anhydrous toluene (0.4 mL) at À788C for 12 h.
[b] Yield of the isolated product. [c] Determined by HPLC analysis on a
chiral stationary phase. Bn=benzyl.
Entry
Catalyst
T [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
4
5
6
7
8
9
7
À20
À20
À20
À20
À20
À20
À78
91
90
88
95
92
88
97
20
2
12
81
28
38
94
[a] Reactions were performed with 1a (0.06 mmol), 2 (0.05 mmol), and
the catalyst (0.01 mmol) in toluene (0.4 mL) at the specified temper-
ature. See the Supporting Information for solvent screening. [b] Yield of
the isolated product. [c] Determined by HPLC analysis with a chiral
stationary phase. Boc=tert-butoxycarbonyl.
manner; hence, we reasoned that multifunctional catalysts
may be the key. Utilizing the existing bifunctional catalyst
scaffolds, simple insertion of a chiral building block can result
in novel trifunctional catalysts (Scheme 2). Recently, primary
amino acid based synthetic methods have found wide
applications in asymmetric synthesis.[19] To further expand
the uses of primary amino acids in asymmetric catalysis, we
decided to derive novel trifunctional catalysts by incorporat-
ing primary amino acid moieties into the bifunctional
cinchona alkaloids, and thus a number of cinchonidine-
derived trifunctional catalysts 10 were prepared.
The catalytic effects of the trifunctional catalysts 10 on the
conjugate addition of 3-benzyl-substituted oxindole 1n to
vinyl sulfone 2 were examined (Table 3). Catalysts with small
substituents were not very effective (Table 3, entries 1 and 2),
however, high enantioselectivity was achieved with the
phenylalanine-containing catalyst 10c (Table 3, entry 3).
Tryptophan-containing catalyst 10e was better than the
catalyst with a phenylalanine moiety (Table 3, entry 5). We
were pleased to find that 10d, with a valine moiety
incorporated, afforded the desired adduct in 81% yield and
90% ee (Table 3, entry 4). Further tuning of the steric
Scheme 2. Novel trifunctional catalysts containing an amino acid unit.
FG=functional group, TBS=tert-butyldimethylsilyl.
hindrance at the amino acid side chain did not result in
better catalysts (Table 3, entries 6–8). These results suggested
that the steric hindrance at the R site in 10 may be important
to enable the thiourea moiety to adopt a relatively con-
strained conformation; however, a group that is too sterically
hindered could be detrimental as the chiral pocket in 10 is
rather crowded. Conjugate addition to vinyl sulfone 2
mediated by the trifunctional catalyst 10d is applicable to
different 3-alkyl-substituted oxindoles, and high yields and
good to excellent enantioselectivities were generally attain-
able (Table 3, entries 9–14).
3-Alkyl-3-aryl-disubstituted oxindoles and indolines are
useful synthetic intermediates and they are also important in
biological sciences and medicinal chemistry.[13c,20] The method
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Table 3: Conjugate addition of various 3-alkyl-substituted oxindoles to
vinyl sulfone 2 mediated by novel trifunctional catalysts.[a]
structural elaboration. For example, allylation of 14, and
subsequent desulfonation led to the formation of indoline 16
with an all-carbon quaternary center at the 3-position, which
represents an important class of compounds in the develop-
ment of therapeutic agents for central nervous system
diseases.[21]
Although the mechanisms of reactions reported here
remain to be clarified, plausible transition-state models are
proposed (Scheme 4). For 3-aryl-substituted oxindoles, ter-
tiary amine thiourea 7 catalyzes the reaction in a bifunctional
mode, and it appears that aromatic interactions may be
involved when the vinyl sulfone reagent approaches the
oxindole substrate. In the conjugate addition of 3-alkyl
oxindoles, we hypothesize that the amide group facilitates
the orientation of vinyl sulfone 2, most likely through multiple
hydrogen-bonding interactions.[22]
In conclusion, we have disclosed highly enantioselective
organocatalytic conjugate additions of both 3-aryl- and 3-
alkyl-disubstituted oxindoles to 1,1-bis(benzenesulfonyl)-
ethylene. In particular, we introduced for the first time a
class of trifunctional thiourea catalysts containing natural
amino acid residues, which offered excellent stereocontrol in
the reactions of 3-alkyl oxindole substrates. Thus, by using the
synthetic method developed as a key step, enantioselective
synthesis of medicinally important 3-alkyl-3-aryl-disubsti-
tuted oxindoles and indolines with an all-carbon quaternary
Entry
Cat.
Product 3: R
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10a
10b
10c
10d
10e
10 f
10g
10h
10d
10d
10d
10d
10d
10d
3n: PhCH2
3n: PhCH2
3n: PhCH2
3n: PhCH2
3n: PhCH2
3n: PhCH2
3n: PhCH2
3n: PhCH2
3o: 4-FC6H4CH2
3p: 4-OMeC6H4CH2
3q: n-C3H7
48
48
48
48
48
48
48
48
60
48
60
60
72
96
76
72
77
81
67
54
67
64
85
88
84
76
80
72
41
37
70
90
81
37
87
75
91
90
77
80
77
80
3r: n-C4H9
3s: n-C6H13
3t: n-C11H23
[a] Reactions were performed with oxindole (0.06 mmol), 2 (0.05 mmol),
and the catalyst (0.01 mmol) in toluene (0.4 mL) at À788C. [b] Yield of
the isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase.
described here represents an efficient
approach to synthesize such scaffolds
(Scheme 3). Treatment of adduct 3a with
magnesium/methanol gave the desired desul-
fonated product 12 in low yield, together with
retro-Michael side products. To provide a
practical solution,
a
two-step synthetic
sequence was then devised. Selective removal
of one aryl sulfone group was achieved by
treating the reaction mixture with samarium
diiodide, and the subsequent desulfonation
with magnesium/methanol yielded 3-alkyl-3- Scheme 4. Plausible reaction mechanisms.
aryl-disubstituted oxindole 12.[10b] Reduction
of oxindole 11 afforded the corresponding indoline 13.
Compound 14 is an excellent intermediate for further
stereogenic center were realized. Investigations aimed at fully
understanding the reaction mechanisms and applications of
novel trifunctional catalysts of type 10 in
other asymmetric organic reactions are cur-
rently ongoing.
Received: June 23, 2010
Published online: September 6, 2010
Keywords: amino acids · asymmetric synthesis ·
.
conjugate addition · multifunctional catalysts ·
oxindoles
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