Asymmetric organocatalyzed epoxidation of 2-oxoindoline-3-ylidene acetaldehydes

Article abstract of DOI:10.1002/cctc.201402811

The asymmetric epoxidation of 2-oxoindoline-3-ylidene acetaldehydes, catalyzed by diarylprolinol silyl ether, has been developed. The reaction provides oxindole derivatives possessing chiral epoxides in good yield with good diastereoselectivity and excell

Full text of DOI:10.1002/cctc.201402811

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DOI: 10.1002/cctc.201402811
Asymmetric Organocatalyzed Epoxidation of 2-
Oxoindoline-3-ylidene Acetaldehydes
Takasuke Mukaiyama, Kento Ogata, Tsuyoshi Ono, and Yujiro Hayashi*[a]
The asymmetric epoxidation of 2-oxoindoline-3-ylidene acetal-
dehydes, catalyzed by diarylprolinol silyl ether, has been devel-
oped. The reaction provides oxindole derivatives possessing
chiral epoxides in good yield with good diastereoselectivity
and excellent enantioselectivity.
Introduction
Chiral epoxides are often used as intermediates of pharma-
ceutical products and natural products because they can react
with a plethora of nucleophiles to generate a variety of chiral
compounds. Owing to this importance, many research groups
have developed methods to achieve asymmetric epoxidation.
Since the discovery of Sharpless asymmetric epoxidation of
allyl alcohols,[1] chiral metal catalysts have largely contributed
to the development of asymmetric epoxidation methods, in-
cluding manganese-salen complex mediated epoxidations as
developed independently by Jacobsen[2] and Katsuki.[3] Shibasa-
ki also developed lanthanoid-BINOL complexes for asymmetric
epoxidation reactions.[4]
disubstituted-a,b-unsaturated aldehydes have been limited to
iminium-ion mediated nucleophilic epoxidation methods.[2,12,20]
Pertinent to our current investigation is the asymmetric syn-
thesis of oxindole derivatives via epoxides. These have attract-
ed attention because they show a variety of bioactivities, for
example, as lead compounds for cancer treatment.[21] Hirama’s
group synthesized the oxindole derivative TMC-95A, a potent
proteasome inhibitor, via a chiral epoxide intermediate.[22] Gas-
peri’s group reported the asymmetric epoxidation of oxindole
derivatives possessing b,b-disubstituted-a,b-unsaturated esters
when catalyzed by diarylprolinol.[23]
In 2010, we reported the asymmetric epoxidation of a-sub-
stituted-a,b-unsaturated aldehydes by using diphenylprolinol
silyl ether as the chiral catalyst.[24] This organocatalyst was de-
veloped independently by our group[25] and Jørgensen’s
group[26] [Scheme 1a]. Recently, we have also reported the
asymmetric Michael addition of nitromethane to 2-oxoindo-
line-3-ylidene acetaldehydes as catalyzed by diarylprolinol silyl
ether to construct all-carbon quaternary stereogenic centers
with excellent enantioselectivity [Scheme 1b].[27] As 2-oxoindo-
Organocatalysts have also been applied to effect asymmetric
epoxidations, and the field of organocatalysis is still expanding
today.[5] For instance, Shi developed a sugar derived organoca-
talyst for asymmetric epoxidations.[6] A pyrrolidine-based cata-
lyst,[7] chiral iminium salt,[8] and chiral tripeptide[9] have also
been found to be effective. For electron deficient olefins such
as a,b-unsaturated carbonyl compounds, a number of asym-
metric epoxidations have been developed using organocata-
lysts.[10] Examples include the epoxidation of a,b-unsaturated
aldehydes as catalyzed by diarylprolinol silyl ethers,[11] chiral
phosphoric amine salts,[12] diphenylfluoromethylpyrrolidines,[13]
and imidazolidinones,[14] whereas a-substituted-a,b-unsaturat-
ed aldehydes have been catalyzed by cinchona-based amines
and chiral phosphoric acids.[15] The diphenylprolinol,[16] amino
alcohol,[17] guanidine-based,[18] and cinchona-based[19] amine
catalysts have all been used for the asymmetric epoxidation of
a,b-unsaturated ketones. Although a,b-unsaturated aldehydes
have been frequently used as starting materials, reports of b,b-
[a] T. Mukaiyama, K. Ogata, T. Ono, Prof. Y. Hayashi
Department of Chemistry, Graduate School of Science
Tohoku University
6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6566
Tel : (+81)22-795-3554
E-mail: yhayashi@m.tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402811.
Scheme 1.
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line-3-ylidene acetaldehydes have been successfully employed
in the Michael reaction of indoles and malonates,[28] we expect-
ed that hydrogen peroxide would function as a nucleophile to
form chiral epoxides of the oxindole [Scheme 1c].
Herein, we report the organocatalyzed asymmetric epoxida-
tion of 2-oxoindoline-3-ylidene acetaldehydes, possessing b,b-
disubstituted-a,b-unsaturated aldehydes, with hydrogen perox-
ide to afford chiral epoxides in excellent yield and enantio-
selectivity.
Figure 1. Organocatalysts used in the asymmetric epoxidation.
dehyde 9a to the epoxy alcohol 10a. Since the O-silyl prolinol
4 is known to be effective for the asymmetric epoxidation of
a-substituted-a,b-unsaturated alkenes,[24] the organocatalyst 4
was tried first. The epoxy aldehyde 9a was generated as a mix-
ture of diastereomers in a ratio of 1:1.8; subsequent aldehyde
reduction provided the epoxy alcohol 10a in 56% yield with
moderate enantioselectivity (entry 1). A change of the silyl sub-
stituents to a trimethylsilyl (TMS) group increased the diaste-
reoselectivity, but decreased the yield and enantioselectivity
(entry 2). When the Michael addition of nitromethane
to 3a was performed, the trfluoromethylated diary-
lprolinol silyl ether 6 was found to be optimal. There-
fore, diarylprolinol catalysts like 6 were explored
more. Eventually, the yield, diastereo and enantiose-
lectivity were all improved (entry 3). In case of cata-
lyst 7, the enantioselectivity and yield increased
slightly, although the diastereoselectivity decreased
Results and Discussions
We have very recently reported the preparation of the 2-oxoin-
doline-3-ylidene acetaldehyde 3a from the isatin derivative 1a
with acetaldehyde during a three “one-pot” sequential synthe-
sis of (À)-horsfiline and (À)-coerulescine.[27] Herein, we ex-
plored this procedure to prepare other 2-oxoindoline-3-ylidene
acetaldehydes, including 3b, 3c, and 3d (Table 1). The isatin
derivatives 1 were thus mixed with acetaldehyde in the pres-
Table 1. Synthesis of 2-oxoindoline-3-ylidene acetaldehydes.[a]
Entry
R
E:Z[b]
Yield of 3 [%][c]
(entry 4). The bulky triisopropyl silyl (TIPS) group
gave the best enantioselectivity, but the reaction was
very slow (entry 5). We thus selected 7 as the best or-
ganocatalyst by considering the balance of yield and
stereoselectivity. It should be noted that the diaste-
reomeric ratio of epoxy alcohol 10a was 1:3.8 with
excellent enantioselectivity (90%ee for major isomer)
even though the E/Z ratio of 3a was 1:2. Stereoselec-
tivity issues will be discussed later.
1
2
3
4
H (1a)
1:2
Z only
1:2
89 (3a)
99 (3b)
89 (3c)
90 (3d)
4-Br (1b)
5-Me (1c)
6-Br (1d)
1:2
[a] Unless noted otherwise, the reaction was performed by employing isatin derivative
1 (4.2 mmol), acetaldehyde (21 mmol), and DBU (0.42 mmol) in THF (8 mL) at À258C
for 15 h. After evaporation, H2O (1 mL), AcOH (3 mL), and H2SO4 (0.21 mL) were added
and the mixture was refluxed until completion of reaction. [b] E/Z ratio was deter-
1
mined by H NMR. [c] Yield after isolation of the product.
Solvent screening was performed using the cata-
ence of a catalytic amount of DBU to give b-hydroxyaldehyde
2, followed by dehydration under acidic conditions, to afford
the 2-oxoindoline-3-ylidene ace-
lyst 7 (Table 3). As the epoxy aldehyde 9a was found to be
stable enough for isolation, the yield, diastereo- and enantiose-
taldehydes 3 in excellent yield.
Table 2. Organocatalyzed asymmetric epoxidation of 2-oxoindoline-3-ylidene acetaldehyde 3a[a]
Although 3a, 3c, and 3d were
obtained as a mixture of E/Z iso-
mers (entry 1, 3, 4), only the Z-
isomer 3b was generated in
case of the 4-Br substrate 1b
(entry 2).
The organocatalyzed asym-
metric epoxidation was investi-
gated next (Table 2). The 2-ox-
Entry
Catalyst
Temp. [8C]
Time [h]
Yield of 10a [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
4
5
6
7
8
0
0
RT
RT
RT
1.5
1.5
2.5
6
56
49
63
68
26
1:1.8
1:3.7
1:6
1:3.8
1:6
46/79
38/67
68/86
64/90
80/98
oindoline-3-ylidene
acetalde-
hyde, 3a, was treated with hy-
drogen peroxide in the presence
of various catalysts (Figure 1).
The yield, diastereo- and enan-
tioselectivities were determined
after reduction of the epoxy al-
7
[a] Unless otherwise noted, the reaction was performed by employing 3a (0.1 mmol), hydrogen peroxide
(0.3 mmol), and catalyst (0.01 mmol) in CH2Cl2 (1 mL) at indicated temperature and time. [b] Yield after isolation
of the product. [c] The diastereomeric ratio was determined by H NMR. [d] The enantiomeric excess was deter-
mined by HPLC analysis on a chiral phase.
1
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Table 3. Effect of solvent in the epoxidation of 3a[a]
Table 4. Substrate scope.[a]
Entry
R
E:Z of 3 Time [h] Yield [%][b] dr[c]
ee [%][d]
Entry
Solvent
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
H (3a)
1:2
Z only
1:2
7
28
9
24
6
80 (9a)
61 (9b)
81 (9c)
68 (9d)
55 (1e)[e]
1:5.0
1:>20 –/94
1:4.4
1:3.6
–
70/90
1
2
3
4
5
CH2Cl2
CHCl3
MeCN
iPrOH
toluene
6
7
60
120
7
83
74
46
31
80
1:4.8
1:4.2
1:3.1
1:1.9
1:5.0
62/85
72/78
20/80
64/81
70/90
4-Br (3b)
5-Me (3c)
6-Br (3d)
73/91
69/98
–
1:2
6-OMe (3e) 1:1.3
[a] Unless otherwise noted, the reaction was performed by employing 3a
(0.1 mmol), hydrogen peroxide (0.3 mmol), and catalyst 7 (0.01 mmol) in
toluene (1 mL) at room temperature for the indicated time. [b] Yield after
isolation of the product. [c] The diastereomeric ratio was determined by
1H NMR. [d] The enantiomeric excess was determined by HPLC analysis
on a chiral phase. [e] Isolated yield of 1e, epoxy aldehyde 9e was not
isolated.
[a] Unless noted otherwise, the reaction was performed by employing 3a
(0.1 mmol), hydrogen peroxide (0.3 mmol), and catalyst (0.01 mmol) in
solvent (1 mL) at room temperature for the indicated time. [b] Yield after
isolation of the product. [c] The diastereomeric ratio was determined by
1H NMR. [d] The enantiomeric excess was determined by HPLC analysis
on a chiral phase.
lectivities were determined at the stage of 9a. When halogen-
ated solvents such as CH2Cl2 or CHCl3 were used, good yield,
diastereo- and enantioselectivities were observed (entry 1, 2).
In case of MeCN or iPrOH, the enantioselectivity was good, but
the reaction progressed very slowly (entry 3, 4). Toluene was
found to be the best in terms of diastereo- and enantioselec-
tivity (entry 5).
formation provided 12 and 13. The relative and absolute con-
figuration of 12 and 13 were determined by comparison of
the NMR spectra and optical rotation to reported data.[23]
A postulated reaction mechanism is shown in Scheme 4.
Both E/Z iminium ions would be formed from by combination
of the amino-catalyst with the E/Z-mixture of 2-oxoindoline-3-
ylidene acetaldehydes. As reported already,[27] isomerization of
E/Z-iminium ions would exist via an addition/elimination pro-
cess to the iminium ion by a hydroxyl ion or hydroperoxide
anion. Owing to the steric repulsion between the bulky sub-
stituents on the pyrrolidine and the aromatic hydrogen atom,
the Z-iminium ion would likely predominate. Hydroperoxide
anion attack onto the Z-iminium ion, facially-opposite to the
bulky substituents on the pyrrolidine, would then form a chiral
enamine. Intramolecular carbon-attack of the enamine to the
oxygen atom, expelling hydroxide, forms the epoxide. Subse-
quent hydrolysis then generates the major epoxy aldehyde ste-
reoisomer. Here, good diastereo- and enantioselectivities were
observed from a mixture of E/Z isomers of the 2-oxoindoline-3-
ylidene acetaldehyde. We propose the electron withdrawing Br
atom on the 6-position lowers the LUMO of the iminium ion,
thus accelerating the addition step of the hydroperoxide anion
(step A). However, the reaction time increased when the 5- or
6-position of aromatic ring was substituted by a Br atom, as
compared to hydrogen (Table 4, entry 2, 4 vs 1). Here, the reac-
tivity of enamine 13 is anticipated to decrease with Br substi-
As the optimum condition was identified, substrate scope
was investigated next (Table 4). An E/Z mixture of 2-oxoindo-
line-3-ylidene acetaldehyde 3 was thus treated with hydrogen
peroxide in the presence of catalyst 7 in toluene. With no aro-
matic substituents, the epoxy aldehyde 9a was obtained in
80% yield as a diastereomeric mixture (dr=1:5) with excellent
enantioselectivity (90%ee, major isomer) (entry 1). When the Z-
isomer of 4-Br substrate 3b was used, excellent diastereo- and
enantioselectivities were observed (entry 2). Excellent enantio-
selectivity was also realized with both an electron donating 5-
Me substrate 3c and an electron withdrawing 6-Br substrate
3d (entry 3, 4). In case of the 6-OMe substrate 3e, isatin 1e
was obtained in 55% yield. The isatin 1e is likely generated via
its epoxide by CÀC bond cleavage by virtue of the electron do-
nating OMe group [Scheme 2]. It is noteworthy that better dia-
stereoselectivity (1:3.6 to 5.0) was obtained even though a mix-
ture of E/Z isomer 3 (1:2) was used as starting material
(entry 1, 3, 4). In addition, the reaction time increased when
the electron withdrawing Br group is appended to the aromat-
ic ring (entry 2, 4).
The relative and absolute con-
figuration of epoxy aldehyde 9a
was determined as follows
(Scheme 3). After the asymmetric
epoxidation of 3a with hydro-
gen peroxide and catalyst 6, the
aldehyde 9a was oxidized to car-
boxylic acid 11 and ethyl ester Scheme 2.
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2-oxoindoline-3-ylidene acetalde-
hydes pre-existed as a mixture
of E/Z-isomers.
Acknowledgements
This work was supported by Mit-
subishi Foundation and a Grant-
in-Aid for Scientific Research on
Innovative Areas “Advanced Mo-
lecular Transformations by Orga-
nocatalysts” from The Ministry of
Education, Culture, Sports, Science
and Technology, Japan.
Scheme 3. Determination of absolute configuration.
Keywords: asymmetric
reaction
·
epoxide
·
organocatalysis · oxindole
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Received: October 11, 2014
Published online on && &&, 0000
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FULL PAPERS
T. Mukaiyama, K. Ogata, T. Ono,
Y. Hayashi*
Giving metal catalysis the slip: The
asymmetric epoxidation of 2-oxoindo-
line-3-ylidene acetaldehydes with hydro-
gen peroxide, catalyzed by diarylprolinol
silyl ether, has been developed. Good to
excellent diastereo- and enantioselectiv-
ities were realized even though the
starting material 2-oxoindoline-3-ylidene
acetaldehydes pre-existed as a mixture
of E/Z-isomers.
&& – &&
Asymmetric Organocatalyzed
Epoxidation of 2-Oxoindoline-3-
ylidene Acetaldehydes
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