Asymmetric synthesis of spiro-epoxyoxindoles by the catalytic darzens reaction of isatins with phenacyl bromides

Article abstract of DOI:10.1021/ol501941n

The asymmetric Darzens reaction between phenacyl bromides and N-protected isatins was developed to synthesize potentially bioactive spiro-epoxyoxindoles. The optically active products were obtained in moderate to good yields and enantioselectivities catalyzed by chiral N,N′-dioxide-Co(acac)₂ complexes. A retro-aldol process accompanying the ring-closure step was observed in the process. A chiral control step was determined to be the initial aldol addition.

Full text of DOI:10.1021/ol501941n

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Spiro-epoxyoxindoles by the Catalytic
Darzens Reaction of Isatins with Phenacyl Bromides
Yulong Kuang, Yan Lu, Yu Tang, Xiaohua Liu, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: The asymmetric Darzens reaction between phenacyl
bromides and N-protected isatins was developed to synthesize
potentially bioactive spiro-epoxyoxindoles. The optically active
products were obtained in moderate to good yields and enantio-
selectivities catalyzed by chiral N,N′-dioxide-Co(acac)2 complexes. A
retro-aldol process accompanying the ring-closure step was observed
in the process. A chiral control step was determined to be the initial
aldol addition.
piro-epoxyoxindoles and their closest derivatives have been
formations. It may be due to the conflict demand of electronic
properties of nucleophilic species between enolization and the
ring-closure step under basic conditions, for which the electron-
withdrawing group can facilitate the enolization and the
electron-donor group is in favor of the cyclization step.6 On
the other hand, ketones were less used as electrophiles in the
asymmetric Darzens reaction because the steric hindrance of
the substrates might hamper both the nucleophilic addition and
the ring-closure step.7 Additionally, competitive reactions,
retro-aldol processes, as well as epimerization of the halohydrin
intermediate under strong basic conditions have prevented the
development of the highly efficient and enantioselective
Darzens reaction.8 We envisioned that chiral Lewis acids
could mediate the first addition process wherein the initial
stereochemistry of the reaction is established. The subsequent
intramolecular SN2 reaction step proceeds to give enantiomeri-
cally enriched epoxides. Herein, we report the Co(acac)2-N,N′-
dioxide-catalyzed9 asymmetric Darzens reaction of phenacyl
bromides with N-methyl-protected isatins. The method allows
diastereo- and enantioselective construction of trans-spiro-
epoxyoxindoles in moderate to good yields and stereo-
selectivities.
Initially, N-methyl-protected isatin 1a was employed to react
with phenacyl bromide to prevent the generation of N-alkylated
byproduct.1d Racemic trans-spiro[indoline-3,2′-oxiran]-2-one
3aa could be exclusively obtained in the K2CO3/EtOH system
with 99% yield.10 We commenced the catalytic asymmetric
reaction with various metal salts as the catalyst in combination
with chiral N,N′-dioxide ligand L1 (see Supporting Information
for details). It was found that the less expensive metal salt of
Co(acac)2 was better in terms of yield, diastereoselectivity, and
enantioselectivity than Mg(OTf)2, In(OTf)3, and Ni-
(Tfacac)2.10 However, the enantioselective induction was
S
identified as a kind of privileged skeleton with important
biological activities.1 Benzoyl-substituted oxiranes are partic-
ularly noticeable as antifungal and antitubercular agents (Figure
1). For instance, trans-3a is against Rhizoctonia solani; cis-3b
Figure 1. Representative biologically active benzoyl-substituted spiro-
epoxyoxindoles.
and trans-3d have anti-Fusarium oxysporum activity, and trans-
3a and cis-3d even have higher antitubercular activity than the
standard drug rifampicin.2 Compound 3c (NSC 621179) is also
found to be significant against both melanoma and leukemia at
p < 0.05.3 As a consequence, synthesis of optically active spiro-
epoxyoxindoles is interesting and valuable. However, there are
sparse reports related to accessing to chiral spiro-epoxy-
oxindoles via catalytic asymmetric reactions.1b,k,p,4 In 2007,
̀
Briere and co-workers first attempted a stereoselective Darzens
reaction using stoichiometric enantiopure sulfides, although
only 30% ee was achieved.1p The Gasperi group succeeded in
asymmetric organocatalytic epoxidation of α-ylideneoxindoles
with a terminal ester substituent to obtain spiro-oxirane.1k Very
recently, the Xiao group reported an asymmetric synthesis of
epoxyoxindoles by employing chiral sulfur ylides generated in
situ from camphor-derived sulfonium salts.1b Nevertheless,
highly enantioselective synthesis of a series of benzoyl-
substituted targets remains elusive.1d The catalytic asymmetric
Darzens reaction5 between phenacyl bromide and isatins gives a
straightforward route to benzoyl-substituted spiro-oxirane-
oxindoles.
The catalytic asymmetric Darzens reaction continues to be a
challenge among tremendously developed asymmetric trans-
Received: July 4, 2014
Published: August 4, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
poor (28% ee; Table 1, entry 1). To improve the enantio-
selectivity, we modified the amide and amino acid backbone of
K3PO4 was subjected in batch and the reaction time was
prolonged, the spiro-epoxyoxindole 3aa was obtained in 60%
yield and 95% ee (Table 1, entry 13). Thus, the optimized
condition is Co(acac)2/L2 (1.1/1, 10 mol %), 5 Å MS (30 mg),
and batch addition of K3PO4/K2HPO4 (10/1, 1.0 equiv) in
THF/acetone (3/1) at −30 °C.
With the optimized reaction conditions, we next examined
the scope of substituted phenacyl bromides and analogues. As
summarized in Table 2, various bromopropanone derivatives
a
Table 1. Optimization of the Reaction Conditions
Table 2. Catalytic Asymmetric Darzens Reaction of N-Me
a
Isatin (1a) with Substituted α-Bromoketones
b
c
entry
L
base
yield [%]
ee [%]
1
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
L2
L2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Ag2CO3
iPr2NEt
89
95
99
82
81
16
49
13
18
41
20
43
60
28
37
29
33
40
85
60
84
77
89
96
94
95
2
3
4
d
5
de
,
6
de
,
7
de
,
8
de
,
9
de
,
10
11
12
13
[K3PO4]
d f
−
[K3PO4]/[K2HPO4]
[K3PO4]/[K2HPO4]
[K3PO4]/[K2HPO4]
d g
−
degh
, , ,
a
Unless otherwise noted, reactions were performed with 1a (0.1
mmol), 2a (0.11 mmol), and base (0.1 mmol) in THF (0.2 mL) at 30
b
c
°C for 24 h. Isolated yield. Determined by HPLC on a chiral
d
e
stationary phase (chiralcel IB). 5 Å MS (30 mg) was added. At −30
f
g
°C for 48 h. [K2HPO4] (0.01 mmol) was added. The mixed solvent
h
THF/acetone (3/1, 0.2 mL) was used. [K3PO4] (0.06 mmol)/
a
Unless otherwise noted, reactions were performed with 1a (0.1
[K2HPO4] (0.01 mmol) was added. After 2 days, [K3PO4] (0.04
mmol) was added and the mixture stirred continuously for 4 h.
[K3PO4] = K3PO4·7H2O; [K2HPO4] = K2HPO4·3H2O.
mmol), 2 (0.11 mmol), Co(acac)2/L2 (1.1/1, 10 mol %), 5 Å MS (30
mg), and [K3PO4]/[K2HPO4] (10/1, 0.10 mmol; 6/1, 0.06 mmol) in
b
THF/acetone (3/1, 0.2 mL) at −30 °C for 48−72 h. Isolated yield.
c
d
Determined by HPLC on a chiral stationary phase. Data in
e
parentheses were obtained from ligand L5 instead of L2. Data in
parentheses were obtained after recrystallization. Absolute config-
f
the N,N′-dioxide ligand. It showed that the backbone of N,N′-
dioxide greatly affected the enantioselectivity of the reaction
(Table 1, entries 1−4). In the presence of Co(acac)2 and ligand
L2 derived from L-proline and 2,4,6-iPr3aniline, the desired
product could be given in 37% ee with 95% yield (Table 1,
entry 2). The addition of 5 Å molecular sieves (MS) enhanced
the enantiomeric excess to 40% (Table 1, entry 5). To
minimize base-mediated background reaction, the reaction
temperature and various bases were screened (Table 1, entries
6−10). When K3PO4 was used instead of K2CO3 and the
reaction temperature was decreased to −30 °C, Darzens
reaction proceeded with maintaining exclusive diastereo-
selectivity and higher enantioselectivity (89% ee) but delivered
the desired product in 41% isolated yield (Table 1, entry 10).
When K2HPO4 was added to adjust the basicity of the system,
the enantioselectivity increased to 96% ee but with decreasing
yield (Table 1, entry 11). However, the yield of the reaction
increased from 20 to 43% in the presence of a mixed solvent of
THF/acetone without obviously compromising the enantiose-
lectivity (Table 1, entry 12 vs entry 11). When basic additive
uration of 3ak was determined to be (2′R,3′R) by X-ray crystallo-
graphic analysis.
smoothly reacted with N-methyl isatin 1a to afford the
corresponding trans-spiro-epoxyoxindoles in moderated to
good results (47−85% ee). The substituent on phenacyl
group had a great effect on both the reactivity and the
enantioselectivity. The para-substituted one was a better
candidate than the meta- and ortho-substituted ones (Table 2,
entries 8−10). Electron-donating groups were prior to electron-
withdrawing groups (Table 2, entries 2−5 vs 6−12). Besides, 2-
thiophenyl- and 2-naphthyl-substituted bromopropanones
produced the epoxylated targets in moderate enantioselectiv-
ities, albeit in lower yields (Table 2, entries 13 and 14). It
should be noted that the strategy could also be extended to
aliphatic-substituted α-bromoketones, which afforded the
corresponding products with good yields and moderate ee
values (Table 2, entries 15−17). Additionally, an improved
result (95% ee and 80% yield) was observed when the reaction
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Organic Letters
Letter
of isatin 1a and phenacyl bromide 2a was performed with the
cobalt complex of N,N′-dioxide L5 (Table 2, entry 1, data in
parentheses), but it is not good for the other substrates
compared with L2. Moreover, the absolute configuration of the
product 3ak was determined to be (2′R,3′R) by X-ray
crystallographic analysis11 (Scheme 2). The others exhibited a
similar Cotton effect in their CD spectras.10 The reaction can
be carried out on a gram scale with higher yield and slightly
decreased enantioselectivity, and optically active 3af could be
achieved by recrystallization (99% ee).10
Table 4. Catalytic Asymmetric Darzens Reaction of
Substituted N-Me Isatin 1
a
Next, we evaluated the effect of altering the N-protecting
group of isatins and the substituent on phenacyl bromide
(Table 3, entries 1−6). The enantioselectivity of the reaction
a
Table 3. Scope of N-Protecting Groups of Isatins
b
c
a
entry
Pg
2
3
yield [%]
ee [%]
The reactions were performed with 1 (0.1 mmol), 2b (0.11 mmol), 5
Å MS (30 mg), Co(acac)2/L2 (1.1/1, 10 mol %), and [K3PO4]/
[K2HPO4] (10/1, 1.0 equiv) in THF/acetone (3/1, 0.2 mL) at −30
1
2
3
4
5
6
Et (1b)
Et (1b)
iPr (1c)
iPr (1c)
Mom (1d)
Bn (1e)
2b
2a
2b
2a
2b
2b
3bb
3ba
3cb
3ca
3db
3eb
64
18
60
24
54
69
89
81
89
78
81
73
b
c
°C for 72 h. Isolated yield. Determined by HPLC on a chiral
stationary phase.
analysis,11 which could be converted to the desired trans-spiro-
epoxyoxindole through the SN2 reaction (Scheme 2).
Subsequently, we carried out the cyclization reaction from
isolated bromohydrin intermediates of an asymmetric catalytic
reaction (Scheme 1). Upon addition of TBAF, spiro-epoxide
a
Unless otherwise noted, reactions were performed with 1 (0.1
mmol), 2a or 2b (0.11 mmol), 5 Å MS (30 mg), Co(acac)2/L2 (1.1/1,
10 mol %), and [K3PO4]/[K2HPO4] (10/1, 1.0 equiv) in THF/
acetone (3/1, 0.2 mL) at −30 °C for 72 h. Isolated yield.
Determined by HPLC on a chiral stationary phase. Mom = methoxy
b
c
Scheme 1. Control Experiments from Bromohydrin
methyl.
was obviously affected by the N-substituent of isatin, and the
sterically hindered group diminished the ee value (Table 3,
entries 2 and 4). However, N-Mom- and N-Bn-substituted
isatins, which could easily be removed, also obtained moderate
yields and ee values (Table 3, entries 5 and 6). When we
compared the data in entries 1−4, it showed that the electron-
donating 3,4-dioxylmethene-substituted group at the phenacyl
bromide displayed better results in terms of both yield and ee.
The chiral N,N′-dioxide cobalt(II)-catalyzed Darzens reac-
tion was further applied to a range of substituted isatins. 5-
Substituted isatins could be readily transformed into the desired
spiro-epoxyoxindoles in obviously high yields (92−99%), but
the enantioselectivities decreased significantly (Table 4, entries
2−4). The corresponding products of 6- or 7-substituted isatins
could be obtained in relatively higher ee values under optimal
conditions (Table 4, entries 5−9 vs 2−4). Benzoindole-2,3-
dione 1p and its analogue 1o could be converted to the desired
spiro-epoxides in moderate enantioselectivities (67% ee; Table
4, entries 11 and 12).
To elucidate the varied yield and enantioselectivity of the
reactions, an intermediate of the aldol reaction, 4a, was isolated
from the standard procedure for preparation of 3aa (Table 1,
entry 13). Unfortunately, enantioselectivity of bromohydrin 4a
could not be determined as a result of the instability under
HPLC analysis conditions. The diastereomeric ratio of
intermediate 4a was determined to be 5:1 by 1H NMR
spectroscopy. The relative configuration of the major
diastereomer was defined as (S′,S′) by X-ray crystallographic
3aa was obtained in complete conversion and 57% ee. When
bromohydrin 4a was resubjected into the asymmetric catalytic
system, product 3aa was obtained in 91% ee and only 54%
yield, accompanying the detection of 1a. It was in keeping with
the facts that bromohydrin 4 and isatin 1 existed in the most
catalytic reaction (Tables 2−4). The comparison implied that
epimerization happened in the presence of TBAF, and a retro-
aldol process accompanied the ring-closure process, which
might account for the moderate yield achieved in most
asymmetric catalytic cases. Furthermore, if racemic bromohy-
drin generated from the non-asymmetric catalyzed reaction was
employed under the optimal condition, the epoxide was
obtained in 78% yield and only 8% ee. It turned out that the
enantiocontrol step of this Darzens reaction was the initial
nucleophilic addition.
Based on the above observations, a plausible induction model
is proposed (Scheme 2). First, the chiral N,N′-dioxide ligand
was chelated with the cobalt(II) precursor to form the chiral
catalytic species.9 Isatin 1a coordinated with the metal in a
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Organic Letters
Letter
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In summary, we have addressed a catalytic asymmetric
synthesis of benzoyl-substituted spiro-epoxyoxindoles based on
the Darzens reaction between phenacyl bromides and N-
protected isatins. A diverse range of spiro-epoxyoxindoles were
prepared with moderate to good results. Benzoyl-substituted
spiro-epoxyoxindoles 3aa and 3af, which can be used as
potential antifungal and antitubercular agents, were obtained in
high optical purity. Studies of the mechanism illustrated that
the chiral control step was the aldol addition step. The
occurrence of a retro-aldol process stunted the efficient
generation of epoxide products to some extent. Further
improvement of the efficiency of the related reaction is
ongoing.
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44, 574. (b) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem. Front. 2014,
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(10) For more details, see the Supporting Information.
(11) CCDC 1006835 (3ak) and CCDC 1006842 (4a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_requst/cif.
́
ez-Rego,
́
̈
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of products, and
copies of 1H and 13C NMR spectra are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xmfeng@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21321061, 21290182, and 21172151), the Ministry of
Education (20110181130014), and the Basic Research Program
of China (973 Program: 2010CB833300) for financial support.
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