Asymmetric diels-alder reactions of α,β-unsaturated aldehydes catalyzed by a diarylprolinol silyl ether salt in the presence of water

Article abstract of DOI:10.1002/anie.200801408

(Chemical Equation Presented) Water, water, everywhere: The title reaction predominantly affords the exo isomer with excellent enantioselectivity (see scheme; TMS=trimethylsilyl). The synthesis can be carried out without organic solvents and provides the products by distillation. Water increases the rate and enantioselectivity of the reaction.

Full text of DOI:10.1002/anie.200801408

Communications
DOI: 10.1002/anie.200801408
Synthetic Methods
Asymmetric Diels–Alder Reactions of a,b-Unsaturated Aldehydes
Catalyzed by a Diarylprolinol Silyl Ether Salt in the Presence of
Water**
Yujiro Hayashi,* Sampak Samanta, Hiroaki Gotoh, and Hayato Ishikawa
The Diels–Alder reaction is a powerful synthetic method for
the construction of regio- and stereochemically defined
cyclohexane frameworks. There are several catalytic enantio-
selective methods,[1] and MacMillan and co-workers devel-
oped the first Diels–Alder reaction involving an organo-
catalyst, which proceeds by a LUMO-lowering activation
mechanism.[2] Since then several asymmetric Diels–Alder
reactions involving organocatalysts have been reported.[3,4]
Our group[5] and that of Jørgensen[6] developed a diary-
lprolinol silyl ether as an effective organocatalyst in 2005, and
this type of catalyst has since been employed widely in several
asymmetric reactions.[7] Recently, we found that diarylproli-
nol silyl ether 1 combined with CF3CO2H is an effective
Diels–Alder catalyst in toluene.[8]
and enantioselectivity of the reaction, which is different from
that of the “on water” reaction and will be described herein.
First, we chose the model reaction between cinnamalde-
hyde and cyclopentadiene, which we had found to be
promoted by a combination of 1 (Figure 1) and CF3CO2H in
In contrast, water has attracted a lot of interest as a
reaction medium in current organic chemistry because of its
unique properties.[9] In the Diels–Alder reaction, for instance,
the reaction is accelerated “in water” (homogeneous dilute
conditions)[10] and “on water” (biphasic conditions).[11] We
reported the positive effect of water on diastereo- and
enantioselectivities for the asymmetric aldol reaction in the
presence of water.[12] Palomo et al.[13] and Ma and co-work-
ers[14] reported the enantioselective Michael reaction cata-
lyzed by dialkyl- and diphenylprolinol silyl ethers, respec-
tively in the presence of water. Some organocatalyzed
reactions are known to be affected by dissolved water,[15]
and on the basis of our interest in reactions in the presence of
water,[16] we have examined the enantioselective Diels–Alder
reaction by using diarylprolinol silyl ether as an organo-
catalyst. Although Northrup and MacMillan[2b] and Ogilvie
and co-workers[3c,g,h] reported the asymmetric Diels–Alder
reaction in the presence of water, we developed a green and
practical procedure that does not require an organic solvent,
even for the purification step. We also observed an interesting
phenomenon, namely the positive effect of water on the rate
Figure 1. The organocatalysts examined in this study.
toluene within 20 hours (Table 1, entry 1).[8] When we used
water as a solvent, a biphasic system formed and the reaction
proceeded slowly, affording the product in lower yield with
moderate enantioselectivity (Table 1, entry 2). Acid was
found to have an important effect on the yield of the reaction
(Table 1). The reaction was slower in the presence of a weaker
acid such as CCl3CO2H (Table 1, entry 3), whereas the
enantioselectivity increased in the presence of fluorinated
Table 1: The effect of additives on the Diels–Alder reaction.[a]
Entry Amount of Acid
[equiv]
Solvent
t
Yield
exo/
ee [%][d]
endo[c]
[b]
[h][%]
exo endo
1
2
3
4
5
6
7
CF3CO2H (20)
CF3CO2H (20)
CCl3CO2H (20)
CF3(CF2)3SO3H(10) H2O
CF3(CF2)7SO3H(10) H2O
toluene 20 86
84:16
76:24
76:24
79:21
41:59
82:18
80:20
95
58
56
86
83
41
33
58
H2O
H2O
20 54
20 39
20 66
20 16
20 63
[*]Prof. Dr. Y. Hayashi, Dr. S. Samanta, H. Gotoh, Dr. H. Ishikawa
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
n.d. n.d.
TsOH (10)
HClO4 (10)
H2O
H2O
92
95
76
90
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
4
100
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[a]Unless otherwise shown, the reaction was conducted by using
catalyst 1 (0.07 mmol), acid (0.14 or 0.07 mmol), cinnamaldehyde
(0.7 mmol), and cyclopentadiene (2.1 mmol) at room temperature in
toluene (1.4 mL) or in water (1.4 mL). [b]Yields of isolated products as a
mixture of exo and endo isomers. [c]Determined by 1H NMR (400 MHz)
spectroscopy. [d]The ee value was determined by HPLC on a chiral
stationary phase or GC analysis. n.d.=not determined, Ts=para-
toluenesulfonyl.
[**]This work was partially supported by the Toray Science Foundation,
and a Grant-in-Aid for Scientific Research from MEXT. S.S. is
grateful to the Japan Society for the Promotion of Science (JSPS) for
a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801408.
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Angewandte
Chemie
sulfonic acid (Table 1, entry 4). Fluorinated sulfonic acid with
long alkyl chains formed an emulsion and increased the
interface area between the organic and aqueous phases, but
the yield remained low (Table 1, entry 5). When we employed
HClO4, the reaction was complete within 4 hours and
afforded the Diels–Alder product quantitatively with excel-
lent enantioselectivity (Table 1, entry 7). Notably, the reac-
tion with 1 and HClO4 run in the presence of water was much
faster (4 h) than the reaction run with 1 and CF3CO2H in
toluene (20 h).
selectivities in both the exo and endo isomers (Table 2,
entry 8).
Various dienes were investigated and the results are
shown in Table 3. Isoprene and 2,3-dimethylbutadiene both
worked well for the reaction (Table 3, entries 1, 2, and 4).
Table 3: Enantioselective Diels–Alder reaction between acrolein or its
derivatives and dienes, catalyzed by diarylprolinol silyl ether salt 2.[a]
As 1 and HClO4 were found to be a suitable combination
for the reaction in the presence of water, the isolation of this
key salt was examined. Salt 2 was precipitated as a white
powder, when aqueous HClO4 was slowly added to an ether
solution of 1 at 08C. By using 5 mol% of this salt as a catalyst
the reaction proceeds with the same efficiency.
The scope of the reaction was investigated and the results
are shown in Table 2. Phenyl-substituted, as well as p-
bromophenyl- and p-nitrophenyl-substituted acrolein deriva-
Entry
R
Diene Product
X
t [h]Yield
[%][b]
ee [%][c]
[mol%]
1
2
EtO2C
EtO2C
5
5
11
11
93
94
85
89
3[d]
4[d]
H
H
10
10
48
36
41
72
87 (R)[f]
90 (R)[f]
Table 2: Enantioselective Diels–Alder reaction between cyclopentadiene
and an a,b-unsaturated aldehyde catalyzed by the HClO4 salt of a
diarylprolinol silyl ether (2).[a]
5[e]
H
10
28
71
88
[a]Unless otherwise shown, the reaction was conducted by using a,b-
enal (0.5 mmol), diene (1.5 mmol), water (252 mL), and catalyst 2 at 48C.
[b]Yields of isolated product. [c]The ee values were determined by chiral
HPLC or GC analysis. [d]Water (126 mL) was employed. [e]Acrolein
[b]
Entry
R
t [h]Yield [%]
exo/endo[c]
ee [%][d]
endo
(1.0 mmol), diene (0.25 mmol), water (126 mL) and catalyst
2
exo
97 (2S)[e] 92 (2S)[e]
96
95
(0.025 mmol) at 48C. [f]Absolute configuration; see the Supporting
Information.
1
Ph
7
7
93
89
94
76
73
95
91
85
80:20
84:16
84:16
76:24
72:28
80:20
85:15
62:38
2[f]
3[f]
4[f,g]
5
p-BrPh
p-NO2Ph
2-furyl
Me
nBu
Cy
86
86
5
40
4
92 (2S)[e] 84 (2S)[e]
Although butadiene is a useful diene component in the Diels–
Alder reaction, its reaction is rather limited as a result of its
low reactivity.[18] The first successful Diels–Alder reaction of
butadiene and acrolein proceeded to provide the adduct with
high enantioselectivity (Table 3, entry 3).
99
98
98
98
99
92
98
97
6
2
7
24
7
8[h]
H
[a]Unless otherwise shown, the reaction was conducted by using
catalyst 2 (0.025 mmol), cinnamaldehyde (0.5 mmol), and cyclopenta-
diene (1.5 mmol) at room temperature and in the presence of water
(252 mL). [b]Yields of isolated products as a mixture of exo and
endo isomers. [c]Determined by 1H NMR (400 MHz) methods. [d]The
ee value was determined by chiral HPLC or GC analysis. [e]Absolute
configuration, see reference [2a]. [f] Cyclopentadiene (2 mmol) was
employed. [g]Catalyst (10 mol%) was used. [h]The reaction was
conducted by using trifluoroacetic acid salt 3 (0.05 mmol), acrolein
(1.0 mmol), and cyclopentadiene (3.0 mmol) at À608C in the presence
of water (54 mL). Cy=cyclohexyl.
The large-scale preparation of the Diels–Alder adduct of
cinnamaldehyde and cyclopentadiene under our conditions
was investigated. After stirring a reaction mixture containing
cinnamaldehyde
(20 mmol,
2.64 g),
cyclopentadiene
(4.7 mL), and water (10 mL) in the presence of catalyst 2
(1.0 mmol, 700 mg) at room temperature for 8 hours, the
water phase was removed by decantation. A 1H NMR
analysis of the crude mixture indicated that there was
quantitative conversion of the dienophile. Direct distillation
of the crude mixture gave the Diels–Alder product in 81%
yield with excellent optical purity (exo/endo = 82:18, exo
97% ee, endo 92% ee). Notably, no organic solvent is needed
for any step, including the purification.
The effect of water on the reaction was examined for the
reaction of cinnamaldehyde and cyclopentadiene (Table 4).
Contrary to the excellent results in the presence of water,
immediate polymerization of cyclopentadiene occurred when
run neat, in toluene, or in CH2Cl2 (Table 4, entries 1–3). The
reaction is slow in MeOH and provides the Diels–Alder
adduct with moderate enantioselectivity in low yield along
recovered starting material (Table 4, entry 4). Thus, water has
tives gave good yields with excellent enantioselectivities.
Aromatic and heteroaromatic groups, such as furyl groups,
are suitable substituents for the reaction (Table 2, entry 4),
and reactions of alkyl-substituted acrolein derivatives
resulted in nearly perfect enantioselectivity (Table 2,
entries 5–7). Although catalyst 2 did not afford good results
in the reaction of reactive acrolein with cyclopentadiene,
trifluoroacetic acid salt 3 was found to be a suitable catalyst in
this particular reaction[17] and provided the Diels–Alder
adduct at low temperature (À608C) with excellent enantio-
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Table 4: The effect of solvent on the Diels–Alder reaction.[a]
water was developed and provides the Diels–Alder adducts
with high exo selectivities and excellent enantioselectivities.
There are several noteworthy features in the present reaction:
1) completely organic solvent-free procedures, including the
purification step, have been established and provide an ideal
method for the preparation of chiral Diels–Alder products,
2) the exo isomer is predominantly obtained, in contrast with
the existing chiral Lewis acid mediated method, 3) some of
the combinations of diene and dienophile are the first
successful examples of those enantioselective Diels–Alder
reactions, 4) water accelerates the reaction and increases the
enantioselectivity, and 5) the role of water in the present
reaction is different from that of Breslowꢀs well-known
homogeneous reaction “in water” and that of Sharplessꢀ “on
water” reaction.
Entry Solvent (mL)
Cat.
[mol%][%]
t [h]Yield
exo/endo[c]
ee [%][d]
exo endo
[b]
1
2
3
4
5
6
7
8
9
neat (0)
10 0.1
0
0
0
toluene (250) 10
CH2Cl2 (250) 10
MeOH (252) 10
H2O (252)
H2O (36)
0.1
0.1
5
37
91
59
70
92
93
100
90
44
67:38
80:20
77:23
80:20
80:20
80:20
80:20
81:19
84:16
86
97
92
95
97
97
97
97
94
58
95
80
88
92
92
92
92
82
10
5
3
7
H2O (90)
5
7
H2O (126)
H2O (252)
H2O (252)
H2O (900)
brine (126)
5
7
5
7
10[e]
11
12
5
7
5
7
5
7
Experimental Section
Typical experimental procedure (Table 2, entry 1): Cyclopentadiene
(1.5 mmol, 117 mL) was added to a stirred heterogeneous mixture
[a]Unless otherwise shown, the reaction was conducted by using
catalyst 2 (0.025 mmol), cinnamaldehyde (0.5 mmol), and cyclopenta-
diene (1.5 mmol) at room temperature in the indicated solvent.
[b]Yields of the isolated product as a mixture of exo and endo isomers.
[c]Determined by 1H NMR (400 MHz) methods. [d]The ee values were
determined by chiral HPLC analysis. [e]The reaction was stirred for only
the first minute.
containing catalyst
2 (17.5 mg, 5 mol%), trans-cinnamaldehyde
(66 mg, 63 mL, 0.5 mmol), and water (14 mmol, 252 mL) at room
temperature. After completion of the reaction (monitored by TLC),
the reaction was quenched with a saturated NaHCO3 solution, the
organic materials were extracted by using ethyl acetate and then the
organic solution was dried over Na2SO4. After filtration, low boiling
compounds were removed under reduced pressure to leave the crude
product, which was purified by column chromatography on silica gel
to furnish the pure product (92 mg, 93% yield). The endo/exo ratio
a positive effect on the rate and enantioselectivity of the
reaction. The amount of water was also found to be
important. In the presence of a small amount of water
(Table 4, entries 6 and 7), the reaction was slow and the
enantioselectivity decreased, whereas in the presence of more
than 126 mL of water led to excellent results that were
consistently obtained. The reaction even proceeds efficiently
in the presence of a large amount of water (Table 4, entry 11)
for the reaction of hydrophobic cinnamaldehyde, in which
two phases were formed. In contrast, too much water
decreased the reactivity for the reaction of acrolein, which
dissolves in water (Table 2, entry 8). This evidence suggests
that the reaction proceeds in organic phase. Moreover,
stirring is not essential; for a reaction in which there was
initial stirring for one minute, the reaction efficiency was
unchanged without additional stirring (Table 4, entry 10).
When brine was used instead of water, the reaction was slow
and the enantioselectivity decreased, indicating a salting out
effect that reduces the reactivity. These results indicate that
1) the reaction proceeds in the organic phase and does not
proceed at the interface between the water and organic
phases and 2) a small amount of water dissolved in the organic
phase accelerates the reaction and affects the transition state,
resulting in increased enantioselectivity. This water effect is
completely different from that observed by Rideout and
Breslow, in which all the reagents dissolved homogeneously
“in water”,[10] and it is also different from the effect of the “on
water reaction” reported by Sharpless and co-workers, in
which vigorous stirring was essential for the reaction to
proceed at the interface of two phases.[11a]
1
was determined from the H NMR spectrum of the crude material.
The product was converted into the corresponding alcohol by using
NaBH4 and the enantioselectivity was determined by HPLC methods
by using a Chiralcel OJ-H column.
Received: March 24, 2008
Revised: May 28, 2008
Published online: July 21, 2008
Keywords: asymmetric synthesis · cycloaddition ·
.
enantioselectivity · organocatalysis · water chemistry
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