One-pot synthesis of chiral α-substituted β,γ-epoxy aldehyde derivatives through an asymmetric aldol reaction of chloroacetaldehyde

Article abstract of DOI:10.1002/anie.201005577

Water is welcome! Chiral α-substituted β,γ-epoxides have been prepared in good yields and with excellent enantioselectivities in a one-pot synthetic procedure. The key reaction of this process, which involves a series of uninterrupted sequential reactions, is an asymmetric aldol reaction of aqueous chloroacetaldehyde mediated by a diarylprolinol derivative (see scheme). Copyright

Full text of DOI:10.1002/anie.201005577

Communications
DOI: 10.1002/anie.201005577
Asymmetric Synthesis
One-Pot Synthesis of Chiral a-Substituted b,g-Epoxy Aldehyde
Derivatives through an Asymmetric Aldol Reaction of
Chloroacetaldehyde
Yujiro Hayashi,* Yusuke Yasui, Tsuyoshi Kawamura, Masahiro Kojima, and Hayato Ishikawa
Epoxides are among the most important functional groups in
organic synthesis,[1] and there are many reliable synthetic
methods for the preparation of chiral epoxides. The asym-
metric catalytic epoxidation of the corresponding alkene is
one of the well-established methods, which include the
Katsuki–Sharpless epoxidation,[2] the chiral salen-mediated
epoxidation developed independently by Jacobsen[3] and
Katsuki,[4] Shi’s epoxidation using a sugar-derived ligand,[5]
and Yamamoto’s chiral epoxidation of homoallylic alcohols
mediated by a vanadium reagent.[6] Asymmetric epoxidation
of a,b-unsaturated carbonyl compounds is also a well-inves-
Scheme 1. Organocatalysts investigated in the present study.
TMS=trimethylsilyl.
tigated reaction.[7] In addition to enantioselective epoxidation
through oxidation of the corresponding alkene, there is also a
method for the formation of an epoxide that involves the
generation of a new carbon–carbon bond.[8]
mediated aldol reaction, in which there is one example using
chloroacetaldehyde.[15]
Since the discovery of the proline-mediated intermolec-
ular aldol reaction reported by List et al.,[9] the field of
organocatalysis[10] has been developing very rapidly. The
asymmetric cross-aldol reaction of two different aldehydes
was first reported by MacMillan and co-workers.[11] When an
a-halo aldehyde acts as an electrophilic aldehyde and reacts
with an enamine, which is generated from another aldehyde, a
b-hydroxy-g-halo aldehyde is formed, which can be treated
with a base and transformed into a b,g-epoxy aldehyde. To our
knowledge, the synthesis of a chiral b,g-epoxy aldehyde
through a one-pot process has not been described yet. As
chloroacetaldehyde is commercially available as a hydrated
form in an aqueous solution (40%), it would be a synthetic
advantage to employ the aqueous solution directly from a
commercial source without removal of water, in the presence
of which the aldol reaction is necessarily performed.[12]
Because we have already described an organocatalyst-medi-
ated aldol reaction in the presence of water or in water,[13,14]
we expected that the aldol reaction would proceed using an
aqueous solution of chloroacetaldehyde directly. With these
scenarios in mind, we investigated the aldol reaction of
aqueous chloroacetaldehyde. During the preparation of this
manuscript, Mahrwald and co-workers reported a histidine-
First, the reaction of chloroacetaldehyde and 3-phenyl-
propanal was investigated with several organocatalysts
(Scheme 1). The reaction proceeded, and the product was
isolated and characterized after conversion into the corre-
sponding dimethyl acetal by treatment of the reaction mixture
Table 1: The effect of the catalyst and solvent in the aldol reaction of
aqueous chloroacetaldehyde and 3-phenylpropanal.[a]
Entry Catalyst Solvent t [h] Yield [%][b] anti/syn[c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
proline
THF
THF
100
82
48
60
48
<5
72
<5
75
52
60
70
53
57
41
–
–
99
–
95
94
94
À77
92
4
1
1
1
1
1
2
3
4
5
4.9:1
–
CH2Cl2
DMF
MeOH
CH3CN
THF
THF
THF
THF
2.8:1
3.0:1
4.0:1
2.9:1
1.1:1
1.0:1
1.7:1
60
100
100
100
72
À7
[a] Unless otherwise shown, the reaction was performed by employing
chloroacetaldehyde (0.75 mmol, 123 mL, 40% aqueous solution), 3-
phenylpropanal (0.50 mmol), and organocatalyst (0.05 mmol) in the
indicated solvent (0.5 mL) at room temperature for the indicated time.
After that, CH(OMe)3 (6.0 mmol) and TsOH·H2O (0.1 mmol) were
added, and the reaction mixture was stirred for 1 h at room temperature
(see the Supporting Information for details). [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopy. [d] Determined by
HPLC on a chiral stationary phase. DMF=N,N-dimethylformamide, Ts=
4-toluenesulfonyl.
[*] Prof. Dr. Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, Dr. H. Ishikawa
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005577.
2804
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Angew. Chem. Int. Ed. 2011, 50, 2804 –2807

Table 2: One-pot aldol/acetalization or aldol/Wittig reaction.[a]
with CH(OMe)3 and a catalytic amount of TsOH·H2O. The
catalyst and solvent were screened (Table 1). The diaryl-
prolinol derivative with a trifluoromethyl substituent is an
effective catalyst,[16] which leads to the aldol product in good
yield with good diastereoselectivity and excellent enantiose-
lectivity when tetrahydrofuran (THF) is used as a solvent
(Table 1, entry 2). Despite the excellent result obtained with
diarylprolinol, its corresponding silyl ether[17] gave a lower
stereoselectivity (Table 1, entry 7). A nearly racemic aldol
product was obtained when diphenylprolinol 3, its silyl ether
4, or siloxyproline 5 were employed as catalysts (Table 1,
entries 9 and 10).
Entry Product
x
y
t
Yield anti/ ee
[equiv][b] [equiv][c] [h] [%][d] syn[e] [%][f]
Next, the generality of the reaction was investigated using
several aldehydes. The aldol product was isolated after
conversion not only into the corresponding dimethyl acetal,
but also into the a,b-unsaturated ester through a reaction with
a Wittig reagent (Table 2). Both dimethyl acetal and a,b-
unsaturated ester were obtained with excellent enantioselec-
tivities. Not only propanal, but also butanal, pentanal, and
isovaleraldehyde turned out to be suitable aldehydes that led
to the aldol products in good yield and with excellent
enantioselectivity. In these reactions, two equivalents of the
aldehydes have been employed (Table 2, entries 1–4, 8–11).
When the nucleophilic aldehyde is expensive or precious, it
should be used in a lower amount than the inexpensive
chloroacetaldehyde. The reaction also proceeds efficiently
even though chloroacetaldehyde and nucleophilic aldehydes
such as 3-phenylpropanal, (Z)-5-octenal, and 5-trimethylsilyl-
4-pentynal were used at 1.5 and 1.0 equivalents, respectively,
to afford the aldol products with excellent enantioselectivity
(Table 2, entries 5–7, 12, 13). Double bonds and triple bonds
do not interfere with the reaction and the Z/E isomerization
of double bond is not observed.
1
1
2
2
2
2
1
33 90
38 81
36 82
90 68
82 72
5.9:1 95
9.0:1 97
5.9:1 98
9.1:1 97
4.9:1 99
2
1
3
1
4[g]
1
5
1.5
6[g]
1.5
1.5
1
1
46 76
86 66
5.9:1 98
3.0:1 90
7[g]
Because the aldol product possesses a b-chloro hydroxy
moiety, the synthetically useful epoxide would be prepared
through treatment with a base. When ethyl 6-chloro-5-
hydroxy-2-hexenoate, the isolated product derived from the
sequential aldol and Wittig reactions, was treated with several
bases, the corresponding epoxide was found to be obtained in
good yield (78%) by treatment with K2CO3 at 658C [Eq. (1)].
8
1
2
2
2
2
1
33 75
38 74
36 66
90 44
82 70
4.2:1 95
5.6:1 94
5.9:1 99
8.7:1 98
6.9:1 98
9
1
10
11[g]
12
1
1
1.5
The synthesis of the epoxides was carried out from
chloroacetaldehyde in a one-pot reaction as follows. After the
aldol reaction, a Wittig reagent was added and the reaction
mixture was stirred for one hour at room temperature. After
addition of EtOH and K2CO3 in the same flask, the epoxide
was generated in good yield by stirring the reaction mixture at
658C for three hours [Eq. (2)]. The enantioselectivity
13[g]
1.5
1
46 74
5.9:1 96
[a] Unless otherwise shown, the catalyst 1 was employed in 10 mol%
(see the Supporting Information for experimental details). [b] Amount of
chloroacetaldehyde. [c] Amount of nucleophilic aldehyde. [d] Yield of
isolated product. [e] Determined by 1H NMR spectroscopy. [f] See the
Supporting Information. [g] Catalyst 1 (15 mol%) was employed.
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Communications
(98% ee) was found to be the same as that of the aldol
product.
After establishing the one-pot synthesis of chiral epoxides,
Because the epoxide is a reactive intermediate, its further
transformation in a one-pot three-component reaction was
investigated. After the aldol and acetalization reaction, a b-
chloro hydroxy derivative has been generated, which has
reacted with a nucleophile and a base in the same flask, thus
affording a highly functionalized chiral alcohol. The success-
ful results are summarized in Table 4. When NaH and MeOH
or allyl alcohol were added into the reaction mixture after
formation of the acetal, a methoxy or allyloxy alcohol were
obtained in good yield with excellent enantioselectivity
(Table 4, entries 1 and 2). While azido alcohol was obtained
with excellent enantioselectivity by the addition of NaN3 and
K2CO3 (Table 4, entry 3), cyanation also proceeded to afford
cyano alcohol with excellent enantioselectivity by the reac-
tion of NaCN and K2CO3 (Table 4, entry 4). When LiAlH4
was used as a nucleophile, the chiral alcohol was obtained
with excellent enantioselectivity (Table 4, entry 5). This
reaction is the synthetic equivalent of an asymmetric cross-
aldol reaction between acetaldehyde as an electrophile and
propanal as a nucleophile—such a reaction is very challeng-
ing.
the generality of the process was investigated (Table 3). A
chiral epoxide with a dimethyl acetal moiety is obtained in
good yield with good diastereoselectivity and excellent
enantioselectivity through aldol/acetalization/epoxidation
reactions. One-pot aldol/Wittig reaction/epoxidation reac-
tions also proceed to provide epoxides with an a,b-unsatu-
rated ester moiety in good yield with good diastereoselectivity
and excellent enantioselectivity.
Table 3: One-pot synthesis of epoxide through aldol/acetalization/epoxidation
or aldol/Wittig/epoxidation.[a]
The absolute configuration of the products[18] is reason-
ably explained by the transition state shown in Scheme 2,
which is similar to that proposed for the aldol reaction of ethyl
glyoxylate catalyzed by the same diarylprolinol (1) cata-
lyst.[16c] Chloroacetaldehyde is activated by the coordination
to the proton of the hydroxy group of the catalyst through
hydrogen bonding.
Entry Product
x
y
t1
t2
Yield anti/ ee
[equiv][b] [equiv][c] [h][d] [h][e] [%][f] syn[g] [%][h]
1
1
2
2
2
1
33
38
5
8
82
80
78
4.8:1 95
6.7:1 97
8.3:1 97
8.3:1 99
2
1
3[i]
4
1
90 10
1.5
82
46
1.5 63
Scheme 2. The transition state of intermediate enamine and chloro-
acetaldehyde. Ar=3,5-bis(trifluoromethyl)phenyl.
5[i]
1.5
1
5
82
5.3:1 98
In conclusion, we have developed a one-pot synthesis of
a-substituted b,g-epoxy aldehyde derivatives through unin-
terrupted sequential reactions that include either an asym-
metric, direct aldol reaction of chloroacetaldehyde catalyzed
by diarylprolinol 1, acetalization, and epoxide formation, or
an asymmetric aldol reaction, Wittig reaction, and epoxide
formation. There are several noteworthy features in this
process. 1) Synthetically useful chiral epoxides with an acetal
moiety or with an a,b-unsaturated ester moiety have been
prepared in a single flask with good anti selectivity and
excellent enantioselectivity. 2) Commercially available aque-
ous chloroacetaldehyde has been used directly without
removal of water prior to use. 3) a,a-Unsubstituted chiral
epoxide, a useful synthetic intermediate, has been prepared
with excellent enantioselectivity through the formation of a
carbon–carbon bond. 4) A three-component coupling reac-
tion led to the formation of a multifunctional alcohol with
excellent enantioselectivity (Table 4). 5) This is one of the
rare reactions in which a diarylprolinol is successfully used as
an efficient catalyst,[16,19] while its silyl ether is widely used as
6
1
2
2
2
2
1
33
33
38
6
7
75
79
4.8:1 95
5.0:1 94
4.6:1 99
6.3:1 98
9.1:1 98
7
1
8
1
8.5 72
9[i]
10
1
90 12
61
70
1.5
82
46
3
6
11[i]
1.5
1
78
4.8:1 96
[a] Unless otherwise shown, the catalyst 1 was employed in 10 mol% (see the
Supporting Information for experimental details). [b] Amount of chloroacetal-
dehyde. [c] Amount of nucleophilic aldehyde. [d] Reaction time for the aldol
reaction. [e] Reaction time for the treatment with K2CO3. [f] Yield of isolated
product. [g] Determined by 1H NMR spectroscopy. [h] See the Supporting
Information. [i] Catalyst 1 (15 mol%) was employed. Bn=benzyl.
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Table 4: One-pot, three-component coupling reaction through aldol/
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Entry Reagents
Product
t
Yield anti/
ee
[h][b] [%][c] syn[d]
[%][e]
1
2
3
4
5
MeOH, NaH
6
3
66
76
4.0:1
3.9:1
3.5:1
4.6:1
4.3:1
96
95
95
95
95
allylalcohol,
NaH
NaN3, K2CO3
20 65
16 63
NaCN,
K2CO3
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LiAlH4
4
68
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in the presence of water, see: S. Kobayashi, I. Hachiya, J. Org.
Chem. 1994, 59, 3590.
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Received: September 6, 2010
Published online: February 17, 2011
Keywords: aldol reaction · asymmetric synthesis ·
.
diarylprolinol derivatives · epoxidation · organocatalysis
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