Asymmetric One-Pot Mukaiyama Michael/Michael Reaction Catalyzed by Diphenylprolinol Silyl Ether

Article abstract of DOI:10.1002/ejoc.202000925

The asymmetric catalytic Mukaiyama Michael reaction between α,β-unsaturated aldehydes and silyl enol ether derived from a cyclic ketone was catalyzed by diphenylprolinol silyl ether to afford Michael products with excellent diastereo- and enantioselectivities. Bicyclo[2.2.2]octanone derivatives can be synthesized as a single isomer in a nearly optically pure form via a two-step, one-pot reaction, comprising the sequential Mukaiyama Michael reaction and intramolecular Michael reaction starting from dienol silyl ether and α,β-unsaturated aldehydes, catalyzed by diphenylprolinol silyl ether. In the second Michael reaction, positive kinetic resolution occurred to increase the enantioselectivity.

Full text of DOI:10.1002/ejoc.202000925

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Asymmetric domino Mukaiyama Michael/Michael reaction
catalyzed by diphenylprolinol silyl ether
Authors: Nariyoshi Umekubo and Yujiro Hayashi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000925
Link to VoR: https://doi.org/10.1002/ejoc.202000925
01/2020

10.1002/ejoc.202000925
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric domino Mukaiyama Michael/Michael reaction
catalyzed by diphenylprolinol silyl ether
Nariyoshi Umekubo,[a] and Yujiro Hayashi*[a]
[a]
N. Umekubo, Prof. Dr. Y. Hayashi
Department of Chemistry, Graduate School of Science
Tohoku University
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: yujiro.hayashi.b7@tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
Previous work
Abstract: The asymmetric catalytic Mukaiyama Michael reaction
between a,b-unsaturated aldehydes and silyl enol ether derived from
a cyclic ketone was catalyzed by diphenylprolinol silyl ether to afford
Michael products with excellent diastereo- and enantioselectivities.
Bicyclo[2.2.2]octanone derivatives can be synthesized as a single
isomer in a nearly optically pure form via a two-step, one-pot reaction,
comprising the sequential Mukaiyama Michael reaction and
intramolecular Michael reaction starting from dienol silyl ether and
a,b-unsaturated aldehydes, catalyzed by diphenylprolinol silyl ether.
In the second Michael reaction, positive kinetic resolution occurred to
increase the enantioselectivity.
N
H
O
S
N
O2N
NO2
+
R
(1a)
O
R
S
O
O
Quinine
N
H
OH
CO2H
(1b)
R
+
H
O
R
OMe
N
2 TFA
NH2
O
1)
O
O
O
N
S
(1c)
The bicyclo[2.2.2]octane structure has been found in several
natural products,[1] and its efficient synthesis is one of the
important topics in synthetic organic chemistry. Recently,
organocatalysts[2] have been successfully employed for the
synthesis of a chiral bicyclo[2.2.2]octane moiety.[3] The [4+2]
cycloaddition reaction is one of the most straightforward methods
for the synthesis of bicyclo[2.2.2]octane derivatives, and there are
a couple of examples using cyclohexenone as a four-carbon
component. The asymmetric Diels–Alder reaction of cyclohex-2-
enone and nitroalkene was catalyzed by a chiral diamine, in which
an amino diene is an intermediate (Scheme 1, 1a).[4] Domino
Michael/intramolecular aldol reaction of aldehyde and cyclohex-
2-enone was catalyzed by the combined use of quinine and
secondary amine to afford bicyclo[2.2.2]octanone with good
S
O
R
H
R
+
N
2) Na2CO3
Present work
O
OTMS
OHC
Ph
+
H
O
Ph
Scheme 1. The synthesis of chiral bicyclo[2.2.2]octanone derivatives from
cyclohex-2-enone or its silyl enol ether derivative
amine (Eq. 1),[8] and asymmetric domino Michael/Michael
reaction of a,b-unsaturated aldehyde and ethyl 4-oxopent-2-
enoate to afford trisubstituted cyclopentanone derivatives (Eq.
2).[9] As an extension of this reaction, we expected a following
domino Michael/Michael reaction. When we employ cyclohex-2-
enone 2a instead of cyclohexanone, the Michael reaction of a,b-
unsaturated aldehyde as a Michael acceptor would proceed to
afford an enamine, from which the second intramolecular Michael
reaction would proceed to provide a bicyclo[2.2.2]octanone
derivative 4aa (Scheme 2). When we treated cinnamaldehyde 1a
and cyclohex-2-enone 2a in the presence of diphenylprolinol silyl
ether 3a, 4-hydroxyproline, p-nitrophenol, and water, which is the
best condition for the Michael reaction of cyclohexanone and a,b-
unsaturated aldehyde, the reaction proceeded to provide the
bicyclo[2.2.2]octanone derivative 4aa in low yield (25%) with low
diastereoselectivity (2.9:1) with moderate enantioselectivity (75%
ee). To improve the yield and selectivity, the reaction conditions
including the two amine catalysts, acid additive, and solvent were
enantioselectivity (1b).[5]
Domino Michael/aldol/Smiles
rearrangement was catalyzed by an organocatalyst derived from
cinchona alkaloid (1c).[6] Although there are several excellent
methods,[3] there is no asymmetric catalytic reaction using silyl
dienol ether of a cyclohex-2-enone and a,b-unsaturated aldehyde
for the formation of bicyclo[2.2.2]octanone derivative, which is a
formal Diels–Alder reaction, even including the metal catalyst and
Lewis acid catalyst. In this paper, we describe the first
asymmetric one-pot Michael/Michael reaction for the formation of
chiral bicyclo[2.2.2]octanone derivatives from silyl dienol ether of
cyclohex-2-enone and a,b-unsaturated aldehyde with excellent
diastereo- and enantioselectivities.
Recently, we reported the asymmetric Michael reaction of
cyclohexanone and a,b-unsaturated aldehyde catalyzed by the
combined use of diphenylprolinol silyl ether[7] and secondary
1
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10.1002/ejoc.202000925
European Journal of Organic Chemistry
COMMUNICATION
investigated in detail, but we could not obtain satisfactory results
(see SI).
furyl also afforded products with excellent results. The reaction
also proceeded in the presence of 5 mol% of the catalyst 3a in
good yield with excellent enantioselectivity, although the reaction
was slow. When we employ crotonaldehyde, a complex mixture
was obtained. For the silyl enol ether (Table 2), not only silyl enol
ether of cyclohexanone but also those of cyclopentanone and
cycloheptanone can be employed successfully to afford the
Michael products with excellent enantioselectivity although
diastereoselectivity is moderate.
15 mol%
Ph
7.5 mol%
HO
Ph
CO2H
N
N
OSiMePh2
H
3a
H
O
Ph
O
O
H2O (3.0 equiv.)
p-nitrophenol (30 mol%)
O
(1)
+
H
Ph
H
EtOH/toluene (4/1), rt
74%, syn:anti = 15:1, 97% ee
Ph
10 mol%
Ph
N
OTMS
H
3b
p-nitrophenol (100 mol%)
H2O (3.0 equiv.
O
O
O
)
Table 1. The generality of the Michael reaction of a,b-unsaturated aldehyde in
the asymmetric Michael reaction of silyl enol ether 6a[a]
CO2Et
O
+
(2)
Ph
H
CO2Et
i-PrOH, rt, 1 h
Ph
98%, single isomer, >99% ee
10 mol%
Ph
10 mol%
HO
10 mol%
Ph
Ph
N
O
Ph
OSiMePh2
H
N
OTMS
N
H
OSiMePh2
OH
H
3a
H2O (3.0 equiv.)
Ar
O
3a
Ph OSiMePh
O
p-nitrophenol (30 mol%)
H2O (3.0 equiv.)
2Ph
O
O
OHC
Ph
EtO2C
O
+
Ph
N
+
Ar
1.0 equiv.
H
MeCN, rt, time
; Ph3P=CHCO2Et
toluene
O
Ph
H
i-PrOH, rt
6a
2.0 equiv.
4aa
25%, dr = 2.9:1, 75% ee
2a
1a
Entry
1
Ar
t [h]
syn/anti[b]
6:1
Yield [%][c]
Ee [%][d]
99
Scheme 2. Domino Michael/Michael reaction for the synthesis of
bicyclo[2.2.2]octanone derivative 4aa
phenyl
phenyl
6
97
89
99
96
97
95
87
89
90
91
95
92
2[e]
3
24
5
5:1
96
Next, we decided to examine the Mukaiyama
Michael[10]/Michael reaction using silyl dienol ether 5a (Figure 1)
instead of using cyclohex-2-enone 2a. Before the investigation of
silyl dienol ether 5a, we checked the Mukaiyama Michael reaction
of silyl enol ether 6a catalyzed by organocatalyst. Although it is
known that the Mukaiyama Michael reaction of silyl enol ether with
a,b-unsaturated aldehyde is catalyzed by organocatalysts, the
reported reactions are limited to the silyl enol ether of aryl methyl
ketone[11] and S-alkyl and 1-pyrrolyl silyl ketene acetals,[12] while
siloxyfuran[13] and 2-siloxypyrrole derivative,[14] and dienol silyl
ether[15] were employed in the vinylogous Mukaiyama Michael
reaction. There is no report of the organocatalyst-mediated
Mukaiyama Michael reaction of silyl enol ether 6a of nonactivated
carbonyl compounds such as cyclohexanone, as far as we were
aware. Before the investigation of the reaction of silyl dienol ether
5a, the Mukaiyama Michael reaction of silyl enol ether 6a using
organocatalyst was investigated.
2-naphthyl
p-MeC6H4
p-MeOC6H4
3,4-(MeO)2C6H3
o-FC6H4
5:1
96
4
6
5:1
98
5
8
4:1
98
6
7
5:1
98
7
6
4:1
98
8
o-ClC6H4
8
2:1
99
9
o-BrC6H4
p-ClC6H4
10
4
3:1
97
10
11
12
4:1
98
p-BrC6H4
2-furyl
4
5:1
97
10
3:1
98
[a] Unless otherwise shown, the reaction was performed by employing a,b-enal
(0.50 mmol), silyl enol ether 6a (1.0 mmol), organocatalyst 3a (0.050 mmol),
water (1.5 mmol), in MeCN (0.50 mL) at room temperature. After the reaction,
solvent was removed. Then, Wittig reagent (0.75 mmol) and toluene (0.50 mL)
were added. See supporting information for details. [b] Determined by 1H-NMR.
[c] Yield of diastereomer mixtures. [d] Determined by HPLC analysis on a chiral
column material. [e] Catalyst 3a (0.025 mmol) was employed.
OTMS
OTMS
5a
6a
Figure 1. Silyl dienol ether 5a and silyl enol ether 6a used in this study
Once the reaction conditions of the asymmetric Michael
reaction of silyl enol ether of cyclohexanone 6a were determined,
the Michael reaction of silyl dienol ether 5a was examined.
Because silyl dienol ether 5a is labile compared with silyl enol
ether 6a, 5a was decomposed under the best reaction condition
of cyclohexanone 6a at room temperature. Thus, the reaction
was carried out at 0 °C, but the reaction was slow, affording the
desired Michael product in low yield (Table 3, entry 1). After the
screening of the reaction conditions (Table 3), good results were
obtained, when 3 equiv of silyl dienol ether 5a was employed in
the presence of 20 mol% of the catalyst and 5 equiv of water
(entry 4). It should be noted that the successive Michael reaction,
After the optimization of reaction conditions (Table S1), we
could obtain good results using diphenylmethylsilyl ether 3a[16] in
MeCN in the presence of 3 equiv. of water. The generality of the
reaction was investigated.
For the b-substituent of a,b-
unsaturated aldehyde (Table 1), not only electron-rich
substituents such as p-tolyl, p-methoxyphenyl, and 3,4-
dimethoxyphenyl substituents but also electron-deficient
substituents such as o-fluorophenyl, o-chlorophenyl, o-
bromophenyl, p-chloro, and p-bromophenyl substituents are
suitable to afford products with excellent yield and diastereo-[17]
and enantioselectivities. Heteroaromatic substituents such as
2
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10.1002/ejoc.202000925
European Journal of Organic Chemistry
COMMUNICATION
namely domino Michael/Michael reaction, does not proceed at all
without the formation of a bicyclo[2.2.2]octanone derivative.
diastereo- and enantioselectivities without the treatment with
Wittig reagent (Eq. 3).
20 mol%
Ph
Ph
N
3a
Table 2. The generality of the Michael reaction of silyl enol ether in the
asymmetric Michael reaction of cinnamaldehyde[a]
OSiMePh2
OTMS
O
Ph
O
H
O
+
(3)
H2O (5.0 equiv.)
MeCN, rt, 12 h
H
10 mol%
Ph
Ph
H
Ph
N
1a
1.0 equiv.
5a
7aa
OSiMePh2
3a
H2O (3.0 equiv.)
H
3.0 equiv.
Ph
O
85%, syn:anti = 7:1, 94% ee
OTMS
O
EtO2C
+
Because the first Michael reaction of 1a and silyl dienol
ether 5a proceeded to afford the Michael product 7aa in good
yield with excellent enantioselectivity, we then investigated the
second Michael reaction. Although the second intramolecular
Michael reaction did not proceed at all under the first Michael
reaction conditions at 0 °C, we found that the second Michael
reaction proceeded in the presence of the same catalyst 3a at a
higher temperature in a different solvent (i-PrOH). That is, when
7aa was treated with diphenylprolinol silyl ether 3a at reflux in i-
PrOH, the bicyclo[2.2.2]octanone derivative 4aa was obtained in
good yield (88%) with excellent enantioselectivity (98% ee) with
the recovery of anti-isomer 7aa (Eq. 4). It should be noted that
the enantioselectivity of the bicyclo[2.2.2]octanone derivative 4aa
is found to be higher (98% ee) than that of the first Michael product
7aa (94% ee) vide infra.
R’
R’
Ph
H
MeCN, rt, time
; Ph3P=CHCO2Et
toluene
R
R
1a
1.0 equiv.
2.0 equiv.
Entry
1
Silyl enol ether
t [h]
6
syn/anti[b]
Yield [%][c]
97
Ee [%][d]
99
OTMS
6:1
OTMS
2
3
6
3:1
3:1
90
85
97
91
OTMS
10
[a] Unless otherwise shown, the reaction was performed by employing
cinnamaldehyde 1a (0.50 mmol), silyl enol ether (1.0 mmol), organocatalyst 3a
(0.050 mmol), water (1.5 mmol), in MeCN (0.50 mL) at room temperature. After
the reaction, solvent was removed. Then, Wittig reagent (0.75 mmol) and
toluene (0.50 mL) were added. See supporting information for details. [b]
Determined by 1H-NMR. [c] Yield of diastereomer mixture. [d] Determined by
HPLC analysis on a chiral column material.
20 mol%
Ph
Ph
N
O
Ph
O
EtO2C
OSiMePh2
Ph3P=CHCO2Et
toluene , rt
H
3a
(4)
H
O
i-PrOH, reflux, 8 h
syn:anti=7:1, 94% ee
Ph
7aa
4aa
88%, 98% ee
anti-7aa was recoverd.
Table 3. The effect of amount of silyl enol ether, catalyst and water in the
asymmetric Michael reaction of cinnamaldehyde and silyl dienol ether 5a[a]
The bicyclo[2.2.2]octanone derivative 4aa was synthesized
using two pots, in which the same catalyst 3a was employed.
One-pot operations are an effective method for both carrying out
several transformations and forming several bonds in a single pot,
while at the same time cutting out several purifications, minimizing
chemical waste generation, and saving time.[9, 18] Next, we tried
to make the two single-pot operations into one single-pot reaction.
Although the best solvents in the first and second reactions are
MeCN and i-PrOH, respectively, we found that the second
reaction also proceeded efficiently in a mixed solvent of MeCN
and i-PrOH. Thus, these two separate reactions can be combined
in the same pot without a solvent switch. That is, after the first
Michael reaction, the addition of i-PrOH and heating the reaction
mixture under reflux conditions gave the bicyclo[2.2.2]octanone
derivative 4aa in good yield with excellent enantioselectivity after
the treatment with Ph3P=CHCO2Et (Table 4, entry 1). Compared
with the two-pot reaction (0.85 Í 0.88 = 0.75), the yield of the
one-pot synthesis is little better (78%).
Y mol%
Ph
Ph
OSiMePh2
N
H
OTMS
3a
Ph
O
O
H2O (Z equiv.)
EtO2C
+
Ph
H
MeCN, 0 ºC, time
; Ph3P=CHCO2Et
toluene
1a
1.0 equiv.
5a
X
equiv.
Entry
X
Y
Z
t
[h]
syn/
anti[e]
Yield
[%][f]
Ee
[%][g]
[equiv] [b]
[mol%] [c]
[equiv] [d]
1
2
3
4
2
3
3
3
10
10
20
20
3
3
3
5
48
36
36
12
7:1
7:1
7:1
6:1
40
n.d.[h]
n.d.[h]
n.d.[h]
94
45
53
86
Once the reaction condition of the two-step, one-pot
synthesis of chiral bicyclo[2.2.2]octanone derivatives 4 was
established, the generality of the reaction was investigated (Table
4). For the b-substituent of a,b-unsaturated aldehyde, not only
electron-rich aryls such as p-tolyl and p-methoxyphenyl groups
but also electron-deficient aryls such as p-fluorophenyl, p-
chlorophenyl, p-bromophenyl, and m-bromophenyl substituents
are suitable to afford the products with excellent yield as a single
[a] Unless otherwise shown, the reaction was performed by employing
cinnamaldehyde 1a (0.5 mmol), silyl dienol ether 5a (X equiv.), organocatalyst
3a (Y mol%), and water (Z equiv.) in MeCN (0.50 mL) at 0 °C. After the reaction,
solvent was removed. Then, Wittig reagent (0.75 mmol) and toluene (0.50 mL)
were added. See supporting information for details. [b] Amount of silyl enol
ether. [c] Amount of organocatalyst 3a. [d] Amount of water. [e] Determined by
1H-NMR. [f] Yield of diastereomer mixtures. [g] Determined by HPLC analysis
on a chiral column material. [h] n.d. = not determined.
Under the best reaction conditions, the Michael adduct 7aa
isomer in
a
nearly optically pure form.
Heteroaromatic
was isolated as its aldehyde form in 85% yield with excellent
substituents such as furyl also afforded a bicyclo[2.2.2]octanone
3
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10.1002/ejoc.202000925
European Journal of Organic Chemistry
COMMUNICATION
derivative with excellent enantioselectivity. It should be noted that
only a single isomer was obtained in a nearly optically pure form
in all the cases examined. In all cases, anti-isomer of the first
Michael product is unreactive in the second Michael reaction. A
complex mixture was obtained in the reaction of crotonaldehyde.
NaClO2
20 mol%
Ph
(1.0 equiv.)
NaHPO4•2H2O
(1.5 equiv.)
2-metyl-2-butene
(2.0 equiv.)
Ph
N
OSiMePh2
O
Ph
O
H
3a
OTMS
O
Ph
O
O
H2O (5.0 equiv.)
MeCN, 0 ºC, 12 h
H
+
HO
Ph
H
t-BuOH/H2O (3:1)
rt, 5 min
7aa
1a
5a
Table 4. The generality of the one-pot Michael/Michael reaction of silyl dienol
ether 5a and a,b-unsaturated aldehyde[a]
O
Ph
O
Ph
O
TMSCHN2 (1.2 equiv.)
H2, Pd/C (10 wt%)
MeOH, rt, 2 h
MeO2C
MeO
Et2O/MeOH (4:1)
rt, 10 min
8
20 mol%
Ph
[α]27D - 21.2
Four reaction steps in one-pot sequence, total yield 61%
Ph
N
OSiMePh2
H
3a
OTMS
Scheme 3. The determination of the absolute configuration of 7aa determined.
EtO2C
H2O (5.0 equiv.)
O
Ph3PCH=CO2Et
toluene, rt
+
MeCN, 0 ºC, time;
i-PrOH, reflux, 8 h
Ar
H
O
Because we are interested in the increase of the
enantioselectivity from the first Michael reaction product 7aa to
the second Michael product 4aa, we investigated the second
Michael reaction in detail. We examined the second Michael
reaction using the racemic material 7aa with chiral
diphenylprolinol silyl ether catalyst 3a (Eq. 5). When we stopped
the reaction after 3.5 h, which is shorter than Eq. 4, the product
4aa was obtained in 41% yield with 36% ee, while the starting
material was recovered in 35% yield with 32% ee, in which the
opposite enantiomer was predominantly recovered. anti-Isomer
of 7aa was also recovered. From these results, diphenylprolinol
silyl ether 3a, a chiral amine, affects the enantioselectivity in the
second intramolecular Michael reaction. Thus, it is clear that
kinetic resolution occurs in the second Michael reaction, and the
minor enantiomer does not react readily (S value is 3.1, see SI).
Although the S value in the kinetic resolution of the second step
is not so large, it is enough to increase the enantioselectivity of
4aa from 94% ee to 99% ee. Moreover, the anti-isomer in the first
Michael reaction did not react in the second Michael reaction.
Thus, in the two successive Michael reactions, the same chiral
catalyst 3a acts positively, increasing both diastereo- and
enantioselectivities to afford the bicyclo[2.2.2]octanone
derivatives 4 as a single isomer in nearly optically pure form.
Ar
1
5a
4
1.0 equiv.
3.0 equiv.
Entry
Ar
t [h]
12
Yield [%][b]
Ee [%][c]
98
1
2
3
4
5
6
7
8
9
phenyl
78
74
76
74
75
72
73
73
51
2-naphthyl
p-MeC6H4
p-MeOC6H4
p-FC6H4
15
18
10
10
10
12
10
20
99
99
99
99
p-ClC6H4
p-BrC6H4
m-BrC6H4
2-furyl
99
99
99
99
[a] Unless otherwise shown, the reaction was performed by employing a,b-enal
(0.50 mmol), silyl dienol ether 5a (1.0 mmol), organocatalyst 3a (0.10 mmol),
and water (2.5 mmol) in MeCN (0.50 mL) at 0 °C for indicated time. After the
addition of i-PrOH (2.0 mL), a reaction mixture was stirred for 8 h at reflux
temperature. After the reaction, solvent was removed. Then, Wittig reagent
(0.75 mmol) and toluene (0.50 mL) were added. See supporting information for
details. [b] Isolated yield. [c] Determined by HPLC analysis on a chiral column
material.
20 mol%
EtO2C
Ph
Ph
N
The absolute configuration of the Michael adduct of
cinnamaldehyde 1a and silyl enol ether 6a was determined by
comparison of the optical rotation with the reported value.[8] The
absolute configuration of the first Michael product 7aa of
cinnamaldehyde 1a and silyl dienol ether 5a was determined as
follows (Scheme 3). After the Michael reaction, the Michael
adduct 7aa was converted into a carboxylic acid by Kraus–Pinnick
oxidation[19] in the same reaction vessel. Then, methyl ester
formation with TMSCHN2, followed by hydrogenation afforded 8.
Because 8 is a known compound,[20] the absolute configuration
was determined by comparison of the optical rotation. It should
be noted that 8 was synthesized from the Michael reaction of 1a
and 5a in a single reaction vessel with a good yield based on the
pot economy, although there are four reaction steps. The
absolute configuration of 4aa was assigned in analogy to that of
7aa.
O
OSiMePh2
4aa
H
Ph
O
Ph
O
3a
Ph3P=CHCO2Et
toluene, rt
41%, 36% ee
H2O (5 equiv.)
H
+
(5)
i-PrOH, reflux, 3.5 h
Ph
O
(±)-7aa
EtO2C
syn:anti = 7:1, racemic
enantiomer of 7aa
35%, 32% ee
In summary, asymmetric catalytic Mukaiyama Michael
reaction of the silyl enol ether of a cyclic ketone and a,b-
unsaturated aldehyde proceeds efficiently, catalyzed by
diphenylprolinol silyl ether to afford the Michael products with
excellent diastereo- and enantioselectivities. Dienol silyl ether
also can be employed as a Michael donor in the Mukaiyama
Michael reaction to afford the Michael product with excellent
enantioselectivity. The second intramolecular Michael reaction is
also catalyzed by the same diphenylprolinol silyl ether to afford
the bicyclo[2.2.2]octanone derivatives in nearly optically pure
form, higher than the first Michael reaction, in which kinetic
resolution occurred. These two reactions can be combined into a
one-pot operation.
Thus, a two-step, one-pot sequential
Mukaiyama Michael reaction and intramolecular Michael reaction
of dienol silyl ether and a,b-unsaturated aldehyde proceeds,
4
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10.1002/ejoc.202000925
European Journal of Organic Chemistry
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5
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10.1002/ejoc.202000925
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Intramolecular Michael reaction
+ Kinetic resolution
Ph
Ph
O
Ar
O
OTMS
N
EtO2C
OSiMePh2
H
O
H
+
reflux then
Ph3P=CHCO2Et
O
Ar
H
Ar
single isomer
mostly 99% ee
Synthetically useful chiral bicyclo[2.2.2]octanone derivatives can be synthesized with excellent diastereo- and enantioselectivity via a
two-step, one-pot reaction using diphenylprolinol silyl ether as an effective organocatalyst, where positive kinetic resolution occurred
to generate the desired compounds in a nearly optically pure form.
Key Topic: Organocatalytic domino reaction
6
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