Phosphine-catalyzed enantioselective γ-addition of 3-substituted oxindoles to 2,3-butadienoates and 2-butynoates: Use of prochiral nucleophiles

Article abstract of DOI:10.1002/anie.201307757

The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed. Both 3-alkyl- and 3-aryl-substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all-carbon quaternary center at the 3-position in high yields and excellent enantioselectivity. The synthetic value of these γ-addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.

Full text of DOI:10.1002/anie.201307757

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DOI: 10.1002/anie.201307757
Phosphine Catalysis
Phosphine-Catalyzed Enantioselective g-Addition of 3-Substituted
Oxindoles to 2,3-Butadienoates and 2-Butynoates: Use of Prochiral
Nucleophiles**
Tianli Wang, Weijun Yao, Fangrui Zhong, Guo Hao Pang, and Yixin Lu*
Abstract: The first phosphine-catalyzed enantioselective
g-addition with prochiral nucleophiles and 2,3-butadienoates
as the reaction partners has been developed. Both 3-alkyl- and
3-aryl-substituted oxindoles could be employed in this process,
which is catalyzed by a chiral phosphine that is derived from an
amino acid, thus affording oxindoles that bear an all-carbon
quaternary center at the 3-position in high yields and excellent
enantioselectivity. The synthetic value of these g-addition
products was demonstrated by the formal total synthesis of
two natural products and by the preparation of biologically
relevant molecules and structural scaffolds.
nitrogen[8e] pronucleophiles to g-substituted allenoates and/or
alkynoates by utilizing C2-symmetric chiral phosphine cata-
lysts. To date, g-substituted allenes have been employed
in a vast majority of the reported phosphine-mediated
g-additions, and only the enantioselective formation of
stereocenters at the g-position was successfully demonstrated.
In sharp contrast, there is virtually no progress on the use of
prochiral nucleophiles for phosphine-triggered g-addition
reactions (Scheme 1), despite the fact that this type of
N
ucleophilic catalysis with chiral phosphines has captured
considerable attention in recent years.[1] In the most common
mode of activation, a phosphine activates an alkene, allene, or
alkyne by forming a phosphonium enolate intermediate,
which reacts with a suitable electrophile. Reactions in this
category include phosphine-catalyzed (aza)-Morita–Baylis–
Hillman (MBH) reactions[2] and various cycloadditions.[3] The
high nucleophilicity of the phosphorus atom is also well
utilized for chiral phosphine promoted kinetic resolution,[4]
and a number of catalytic processes that employ MBH-type
adducts.[5] On the other hand, the phosphonium enolate
intermediate that is generated upon phosphine addition is
basic in nature and could thus be utilized for the activation of
pronucleophiles. In this context, we recently developed the
first chiral phosphine catalyzed asymmetric Michael addition
reaction.[6] Phosphine-mediated g-addition reactions are
mechanistically similar, and a few examples of their applica-
tions in organic synthesis have been reported. Pioneering
studies on phosphine-mediated g-addition reactions of pro-
nucleophiles to allenoates or alkynoates were first disclosed
by the groups of Trost[7a–c] and Lu[7d] in the 1990s. However,
asymmetric variants of the g-addition reaction were not
reported until more than a decade later.
Scheme 1. Phosphine-catalyzed g-addition of oxindoles.
addition reaction can be synthetically highly valuable. To
the best of our knowledge, there has been only one report by
Zhang and co-workers that describes the g-addition of b-
ketoesters to allenoates.[9] However, the enantioselectivity
and the scope of that reaction were disappointing. The
difficulty in achieving an adequate level of stereochemical
control in g-addition reactions with prochiral nucleophiles
may be attributed to the fact that the newly formed
stereogenic center is rather distant from the allene/alkyne
reaction partner. It thus became our goal to demonstrate that
excellent stereochemical control can be realized in a phos-
phine-catalyzed g-addition of pronucleophiles to an allene.
Optically active 3,3’-disubstituted oxindole frameworks
are a prominent substructure in bioactive molecules. In
particular, oxindoles that bear an allyl-substituted quaternary
stereogenic center at the 3-position[10] have attracted consid-
erable attention owing to their biological significance and
great synthetic value. In their pioneering studies, Trost and co-
workers developed palladium-[11a,b] and molybdenum-cataly-
zed[11c–f] asymmetric allylic alkylation (AAA) reactions of 3-
substituted oxindoles to synthesize chiral 3-allyl-3’-substi-
tuted oxindoles. Kozlowski and Taylor utilized Pd-catalyzed
processes for the synthesis of allyl-substituted oxindoles.[12]
Krische et al. developed the iridium-catalyzed enantioselec-
tive allylation, crotylation, and reverse prenylation of sub-
Recently, Fu and co-workers described enantioselective
g-addition reactions of oxygen,[8a] carbon,[8b,c] sulfur,[8d] and
[*] T. Wang, W. Yao, F. Zhong, G. H. Pang, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute
National University of Singapore 3
Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmlyx@nus.edu.sg
[**] We thank the National University of Singapore, the Ministry of
Education (MOE) of Singapore (R-143-000-362-112), and GSK-EDB
(R-143-000-491-592) for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307757.
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stituted isatins.[13] The only reported organocatalytic variant
entails the utilization of MBH carbonates in an AAA reaction
of 3-substituted oxindoles, which was described by Chen and
co-workers.[14] There clearly exists a need for an effective non-
metal-based approach to access enantioenriched 3-allyl-3’-
substituted oxindoles. Herein, we describe a highly enantio-
selective allyl-type functionalization of 3-substituted prochi-
ral oxindoles by a chiral phosphine mediated g-addition
reaction that employs simple 2,3-butadienoates (Scheme 1).
To begin our investigations, we first wanted to establish
that phosphine catalysts may effectively promote the
g-addition of 3-pentyloxindole to an allenoate. A range of
amino acid based chiral phosphines[15] were used in this study
(Scheme 2). It was very encouraging to see that all of the
Table 1: Screening and optimization for the asymmetric g-addition of
3-alkyl-substituted oxindoles to allenoates.[a]
Entry
Catalyst
t [h]
R
8
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
2a
2b
2c
2d
2e
2 f
2g
3
15
15
15
18
15
15
24
24
15
15
15
24
24
15
15
15
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
Et
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-4
8a-1
8a-2
8a-3
67
78
62
82
93
90
79
79
90
85
83
90
86
96
95
94
20
27
21
53
86
79
60
60
80
79
78
5
9
10
11
12
13
14
15
16
4a
2a
2a
2a
11
90
94
75
tBu
Bn
[a] Reactions were performed with 6a (0.1 mmol), 7 (0.15 mmol), and
catalyst (0.01 mmol) in toluene (1.0 mL) at room temperature. [b] Yield
of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldime-
thylsilyl, TIPS=triisopropylsilyl, TMS=trimethylsilyl, Ts=4-toluenesul-
fonyl.
(94% ee; entry 15). A solvent screen and varying the reaction
temperature did not lead to further improvements.[16]
With the optimized reaction conditions in hand, the scope
of this reaction was evaluated. Different 3-alkyl-substituted
oxindoles were smoothly transformed into the corresponding
products; the reaction was insensitive to the length of the
alkyl chain, and both linear and branched alkyl groups were
tolerated (Table 2, entries 1–10). Furthermore, substituents
on the oxindole core had only small effects on both the
reactivity and the enantioselectivity (entries 11 and 12). 2-
Butynoate (7’) could also be employed instead of the
allenoate. Although the reactions proceeded more slowly,
the enantioselectivity remained the same [Eq. (1) and
Eq. (2)]. The absolute configuration of the g-addition prod-
ucts was determined by comparing the optical rotation of
derivative 14 (Scheme 3) with a previously reported value.[11c]
Scheme 2. Phosphine catalysts employed in this study.
bifunctional phosphines that were tested effectively catalyzed
the reaction. l-Valine-derived phosphines led to the forma-
tion of the desired g-addition product in good yields, but the
stereoselectivity was poor (Table 1, entries 1–4). However, by
changing the substituent on the nitrogen atom, efficient
phosphine catalysts were obtained, which furnished the
desired products with good enantioselectivities (entries 5–
11). Alanine-derived phosphine 2a turned out to be the most
suitable catalyst, affording the g-addition product in 93%
yield and with 86% ee. Dipeptide phosphines only led to poor
stereoselectivity (entries 12–13). Subsequently, we further
optimized the reaction conditions by varying the ester moiety
of the allenoate (entries 14–16). Among all of the allenoates
examined, the tert-butyl ester was found to provide the
corresponding product with the highest enantioselectivity
Our next goal was to extend the scope of this trans-
formation to 3-aryl-substituted oxindoles. This seems to be
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Table 2: Substrate scope for the asymmetric g-addition of 3-alkyl-
substituted oxindoles to allenoate 7b.[a]
Table 3: Asymmetric g-addition of 3-aryl-substituted oxindoles 9 to
allenoate 7d.[a]
Entry Ar
R
Cat. 10
Yield[b] [%] ee[c] [%]
Entry
R1
R2
8
Yield[b] [%]
ee[c] [%]
1
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
5a
5b
5c
5d
5d
5d
5d
5d
5d
5d
5d
5d
10a
89
87
94
90
89
95
94
96
93
91
92
96
86
96
95
96
90
80
66
83
89
88
91
86
90
88
90
90
88
89
90
92
90
86
82
2
C6H5
10a
10a
10a
10a
10a
10b
10c
10d
10e
10 f
10g
10h
10i
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
5-MeO
5-Br
H
nC5H11
Me
Et
nPr
iPr
nC4H9
nC6H13
CH(CH2)4
CH(CH2)5
CH(CH2)6
Me
8a
8b
8c
8d
8e
8 f
8g
8h
8i
95
96
96
95
98
95
98
92
97
91
98
98
97
94
88
92
89
94
93
90
90
93
92
89
85
81
3
C6H5
4
C6H5
5
C6H5
6
C6H5
7
8
9
3-Me-C6H4
4-Me-C6H4
4-tBu-C6H4
4-Ph-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
3,5-Me-C6H3
C6H5
10
11
12
13
14
15
16
17
18
9
10
11
12
13
8j
8k
8l
iPr
CH2Ph
8m
5-MeO 5d
5-Me
5-F
10j
[a] Reactions were performed with 6 (0.10 mmol), 7b (0.15 mmol), and
2a (0.01 mmol) in toluene (1.0 mL) at room temperature for 15 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase.
C6H5
C6H5
C6H5
5d
5d
10k
10l
5,7-Me 5d
10m 94
[a] Reactions were performed with 9 (0.1 mmol), 7d (0.12 mmol), and
the catalyst (0.01 mmol) in toluene (1.0 mL) at room temperature for
12 h. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase.
challenging as a catalytic system rarely works for both alkyl-
and aryl-substituted substrates, but we speculated that we
might be able to tackle this task with our highly tunable
dipeptide-based catalytic systems. To our delight, g-addition
of 3-phenyloxindole to allenoate 7d proceeded smoothly in
the presence of dipeptide-based phosphines (Table 3).[16]
Phosphines that are derived from l-Thr–l-Thr were found
to be effective catalysts of this transformation and afforded
the desired product in high yields and with excellent
enantioselectivity (entries 1–6). When the most suitable
catalyst of the series, namely 5d, was employed, the reaction
worked very well for various 3-aryl-substituted oxindoles
(entries 7–14) and oxindole cores with different substituents
(entries 15–18). The absolute configuration of the g-addition
products was assigned by comparing the optical rotation of
derivative 12 (Scheme 3) with a previously reported value.[17]
The products of the g-addition process
formed into the known aldehyde 14 in high yield; this
compound can be converted into (À)-esermethole and (À)-
physostigmine according to literature precedents.[11c,18] The g-
addition adducts bear a crotonic acid subunit at the quater-
nary carbon center, which offers great opportunities for
further structural elaborations. Compound 8e was trans-
formed into acid 16 in high yield through a few trivial steps; 16
was further converted into key intermediate 17 (Scheme 4).
Treatment of amide 17 with LiAlH4 led to a smooth intra-
molecular cyclization and furnished 18, a structural analogue
of the core motif of many bioactive natural alkaloids with
a seven-membered ring.[19] Furthermore, g-addition adduct
8d was transformed into the known acid 20 in high yield,
possess an all-carbon quaternary stereogenic
center at the 3-position with a latent allyl group;
these structures are not only interesting from
a biological point of view, but also synthetically
valuable. Adduct 10a could be readily con-
verted into 3-allyl-substituted oxindole 12 in
high yield through a few simple transformations
(Scheme 3). Aside from the metal-mediated
allylation processes that were reported by
Trost and co-workers[11], this process is the
only alternative asymmetric method to access
these types of compounds. Moreover, the utility
of the oxindole products that were obtained by
g-addition was demonstrated by a formal total
synthesis of (À)-esermethole and (À)-physos-
tigmine. Oxindole 8k, which was obtained by
Scheme 3. Preparation of 3-allyl-substituted oxindoles and formal total synthesis of
a g-addition process catalyzed by 2a, was trans- (À)-esermethole and (À)-physostigmine.
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=
subsequent attack to the C C bond. We
presumed that both the Brønsted acid
moiety of the chiral phosphine and Boc
protection of the oxindole nitrogen atom
are essential for the observed asymmetric
induction. To provide experimental sup-
port, we prepared methylated catalyst 2a’
and substrate 6g’ which does not contain
a Boc group. The presence of the free NH
group in 2a and the utilization of the N-
Boc-protected substrate 6g were crucial
for both reactivity and enantioselectivity
of the reaction. When methylated 2a’ was
used as the catalyst or oxindole 6g’ was
employed as the substrate, the reaction
proceeded much more slowly, and the
enantioselectivities decreased substan-
tially (Table 4).
In conclusion, we have developed the
Scheme 4. Synthetic manipulations of g-addition adducts.
first phosphine-catalyzed asymmetric g-
addition reaction that involves 2,3-buta-
which can be converted into neurokinin receptor antagonists
using procedures that are described in the literature.[20a]
The mechanism of the g-addition described herein was not
rigorously studied at this stage, and we believe that the
reaction follows the general mechanism that is described in
the literature.[8b] When the reaction was performed in the
presence of D2O,[21] deuterium incorporation into the product
was observed, which suggests the beneficial role of water in
the catalytic cycle; this result is in good agreement with
previous mechanistic findings that were reported by Yu and
co-workers.[22] In our proposed transition state model, the
dienoates as the reaction partner for the enantioselective
allyl-type functionalization of 3-substituted oxindoles. This
process enabled the formation of oxindole derivatives with an
all-carbon quaternary stereogenic center at the 3-position in
high yields and excellent enantioselectivities. Its synthetic
utility was amply demonstrated by the formal total synthesis
of two natural products and the preparation of molecules and
structural motifs of biological significance. We are currently
extending the concept described herein to other organic
reactions.
Received: September 3, 2013
Revised: December 16, 2013
Published online: February 12, 2014
À
amide N H bond forms hydrogen bonds with the oxindole
enolate and the carbamate functionality and directs the
Keywords: allylation · bifunctional phosphines · g-addition ·
oxindoles · quaternary carbon centers
Table 4: Asymmetric g-addition promoted by different phosphines and
.
proposed transition state model.[a]
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Entry
6
Catalyst
t [h]
8
Yield[b] [%]
ee[c] [%]
1
2
3
6g
6g
6g’
2a
2a’
2a
15
36
36
8g
8g
8g’
98
77
81
90
44
53
[a] Reaction conditions: 6 (0.10 mmol), 7b (0.15 mmol), and catalyst
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