C O M M U N I C A T I O N S
Table 2. DA Reaction of 2,3-Dimethylbutadiene with
R-Acyloxyacroleina
Table 3. DA Reaction of Dienes with
R-(p-Methoxybenzoyloxy)acroleina
time
yield
(%)
ee (%)b
[config]
time yield ee
entry
diene
solvent
(h)
exo:endo
entry
R6
HX
solvent
(h)
(%) (%)
1
CPc
THF
THF
THF
THF
EtNO2
EtNO2
EtNO2
EtNO2
11
48
24
28
48
24
12
48
97
99
72
81
84
92
95
90
86:14
87:13
81:19
88:12
7:93
80 [2S]
83 [2S]
74 [2S]
83 [2S]
91 [2R]
92 [-]
88 [-]
88 [-]
1
2
3
4
5
6
7
8
p-MeOC6H4 C6F5SO3H
EtNO2
EtNO2
no solvent
8
16
12
12
20
>99 90
97 87
95 85
85 85
81 82
67 80
60 78
56 83
2d
3
CPc
Ph
Ph
Ph
Ph
Ph
Ph
Me
C6F5SO3H
C6F5SO3H
2,4-(NO2)2C6H3SO3H EtNO2
2,4-(NO2)2C6H3SO3H H2O
BMCPc
BMCPc
CHc
4d
5
6
DMB
DMB
IPc
b
2,4-(NO2)2C6H3SO3H H2O-C4H8O2 20
7e
8
TsOH
EtNO2
15
24
99:1f
2,4-(NO2)2C6H3SO3H EtNO2
a Unless otherwise noted, the DA reaction of dienes (1.6 mmol) with
R-acyloxyacrolein (0.8 mmol) in THF (0.25 mL) or EtNO2 (0.125 mL)
was carried out. b Enantiomeric excess of major diastereomer. c See text.
d 1k•2.75C6F5SO3H (20 mol %) at -20 °C. e DA reaction of DMB (3.2
mmol) with R-acyloxyacrolein (1.6 mmol) in EtNO2 (0.125 mL) was carried
out in the presence of 1k•2.75C6F5SO3H (2.5 mol %) at room temperature.
f The molar ratio of 4-methyl and 3-methyl isomers is indicated.
a Unless otherwise noted, the DA reaction of 2,3-dimethylbutadiene (3.2
mmol) with R-acyloxyacrolein (0.8 mmol) in solvent (0.25 mL) was carried
out. b H2O (0.25 mL) and 1,4-dioxane (0.25 mL) were used.
developed by Kaiser and DeGrado9 was used in the solid-phase
dipeptide synthesis. The resin allows the preparation of dipeptides
using the BOC strategy and their subsequent cleavage from the
support by nucleophilic displacement with pyrrolidine at the
carboxyl terminus. Representative examples are shown in Figure
1. The enantiomeric excess was further increased to 79% by the
use of 1k derived from H-L-Phe-L-Leu-N(CH2CH2)2. The i-Bu
group of 1k probably helps to stabilize the conformation of R2.
R-Haloacrolein is known to be an outstanding dienophile in a
catalytic DA process because of its high reactivity and the
exceptional synthetic versatility of the resulting adducts.4,5 However,
R-haloacrolein is an irritant and is unstable at ambient temperature.
In contrast, R-acyloxyacrolein is relatively stable, and its reactivity
can be controlled by switching the acyloxy group.3 Ammonium
salt of 1k and HX was expected to be a catalyst for the
enantioselective DA reaction between 2,3-dimethylbutadiene and
R-acyloxyacrolein at room temperature (Table 2). The highest
enantiomeric excess (90%) and quantitative yield were attained in
the DA reaction with R-(p-methoxybenzoyloxy)acrolein in the
presence of 10 mol % of 1k and 27.5 mol % of C6F5SO3H in EtNO2
(entry 1); 25-30 mol % of HX per 10 mol % of 1k was suitable
for the enantioselective DA reaction. Interestingly, this reaction
proceeded with high enantioselectivity regardless of the concentra-
tion of the reactants (entries 2 and 3). Furthermore, this reaction
occurred even in water without a serious reduction in enantiose-
lectivity (entry 5 versus entries 4 and 6).
To explore the generality and scope of the DA reaction with
R-(p-methoxybenzoyloxy)acrolein catalyzed by 1k•2.75C6F5SO3H,
the DA reactions of representative dienes were examined at 0 or
-20 °C (Table 3). The DA reaction of cyclopentadiene (CP) and
5-(benzyloxymethyl)cyclopentadiene (BMCP) in THF gave the
(2S)-exo-adducts as major diastereomers with up to 83% ee (entries
1-4). With respect to the enantioselectivity, THF was more suitable
than EtNO2 as solvent for these two examples. The latter product
(entries 3 and 4) is an important intermediate for prostaglandin
synthesis.4a The DA reaction of cyclohexadiene (CH) gave the (2R)-
endo-adduct as a major diastereomer with 91% ee (entry 5).
Bicyclo[2.2.2]oct-5-en-2-one derived from this product (entry 5)
is useful as a common intermediate for the total syntheses of several
biologically active compounds.10 These results can be understood
through our predictive mechanistic model (cis-TS 2) shown in
Scheme 1. The DA reaction of not only cyclic but also acyclic
dienes, such as 2,3-dimethylbutadiene (DMB) and isoprene (IP),
gave the DA adducts with high enantioselectivities (entries 6-8).
It is noted that 2.5 mol % of the catalyst was active enough for the
DA reaction of DMB (entry 7).
In summary, we have realized the first enantioselective organo-
catalytic DA reactions with R-substituted acroleins, such as
R-acyloxyacroleins.11 Further studies are in progress to elucidate
the mechanism and the origin of the enantioselectivity.
Acknowledgment. Financial support for this project has been
provided by JSPS KAKENHI(15205021), the 21st Century COE
Program of MEXT, the Mitsubishi Chemical Corporation Founda-
tion, and the Nagase Science and Technology Foundation. We thank
Dr. Hideaki Ishibashi for his helpful discussion.
Supporting Information Available: Experimental procedures, full
characterization of new compounds. This material is available free of
References
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(8) For details, see the Supporting Information.
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