Powerful amino diol catalyst for effecting the direct asymmetric conjugate addition of aldehydes to acrylates

Article abstract of DOI:10.1021/ja307668b

Di-tert-butyl methylenemalonate (1) could be employed as a reactive equivalent of a three-carbon Michael acceptor such as acrylate in a direct asymmetric conjugate addition of aldehydes catalyzed by an axially chiral amino diol (S)-3a. Furthermore, acrylate, an unexplored and challenging substrate in enamine catalysis, has also been successfully employed in asymmetric conjugate addition reaction. Relatively inert acrylate is doubly activated by polyfluoroalkyl group of 2 and the hydroxyl group on the axially chiral amino diol catalyst (S)-3b, giving corresponding conjugate adducts in high yield with excellent enantiomeric excess. The obtained conjugate addition products were readily converted to synthetically useful and important chiral building blocks.

Full text of DOI:10.1021/ja307668b

Subscriber access provided by INDIANA UNIV PURDUE UNIV AT IN
Article
Powerful Amino Diol Catalyst for Effecting the Direct Asym-
metric Conjugate Addition of Aldehydes to Acrylates
Taichi Kano, Fumitaka Shirozu, Matsujiro Akakura, and Keiji Maruoka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja307668b • Publication Date (Web): 05 Sep 2012
Downloaded from http://pubs.acs.org on September 10, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Powerful Amino Diol Catalyst for Effecting the Direct Asym-
metric Conjugate Addition of Aldehydes to Acrylates
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Taichi Kano,† Fumitaka Shirozu,† Matsujiro Akakura‡ and Keiji Maruoka*,†
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡Department of Chemistry, Aichi University of Education, Igaya-cho, Kariya, Aichi 448-8542, Japan
Supporting Information Placeholder
ABSTRACT: A methylenemalonate 1 could be employed as a reactive equivalent of a three carbon Michael acceptor
such as acrylate in a direct asymmetric conjugate addition of aldehydes catalyzed by an axially chiral amino diol (S)-3a.
Furthermore, acrylate, unexplored and challenging substrate in enamine catalysis, has also been successfully employed
in asymmetric conjugate addition reaction. Relatively inert acrylate is doubly activated by polyfluoroalkyl group of 2 and
the hydroxyl group on the axially chiral amino diol catalyst (S)-3b, giving corresponding conjugate adducts in high yield
with excellent ee. The obtained conjugate addition products were readily converted to synthetically useful and important
chiral building blocks.
Introduction
The catalytic asymmetric conjugate addition of carbon
nucleophiles to electron-deficient olefins is one of the
most fundamental and reliable C-C bond forming reac-
Scheme 1. Challenging amine-catalyzed conju-
gate addition
tions in synthetic organic chemistry.1 In the area of or-
ganocatalysis, a large number of asymmetric conjugate
addition reactions have been developed to date.2,3 Conse-
quently, a wide variety of electron-deficient olefins are
now applicable as acceptor to the amine-catalyzed conju-
gate additions through an enamine intermediate.3,4 In
light of versatility of these reactions, it is surprising that
one of the simplest three-carbon Michael acceptors, alkyl
acrylate has not been utilized in enamine catalysis
(Scheme 1).5,6 This might be due to the combination of
relatively low nucleophilicity of the enamine intermedi-
Scheme 2. Consumption of pyrrolidine by highly
reactive acrylate derivatives
ate and low electrophilicity of acrylate.7,8 On the other
hand, highly reactive modified acrylates such as dialkyl
methylenemalonates9 and polyfluoroalkyl acrylates can
lead to the catalyst deactivation by the undesired conju-
gate addition and amidation (Scheme 2). To overcome
this intrinsic dilemma, we became interested in using the
amine catalyst with enzyme-like active site, which can
further activate the reactive dialkyl methylenemalonate
and polyfluoroalkyl acrylate at the appropriate position
by the acidic proton (Scheme 3). At the same time, the
catalyst amine moiety in the cavity is expected to allow
selective interaction with an aldehyde to generate the
enamine intermediate, while keeping a dialkyl meth-
ylenemalonate and polyfluoroalkyl acrylate out of the
catalyst cavity. Herein, we wish to report a highly enanti-
oselective conjugate addition reaction of aldehydes to the
dialkyl methylenemalonate and polyfluoroalkyl acrylate
catalyzed by an axially chiral amino diol of type (S)-3.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
1
2
3
4
5
6
Scheme 3. Catalyst design for conjugate addition
of aldehydes to highly reactive acrylate deriva-
tives
Table 1. Conjugate Addition of Aldehydes to 1a
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry catalyst
R
conditions yield
ee
(%)b
(%)c
(°C, h)
1d
2d
3d
4d
5d
6
7e
8e
9
pyrrolidine Bn
rt, 4
rt, 4
rt, 4
rt, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 4
0, 40
0, 40
0, 4
rt, 24
rt, 72
n.d.
48
69
93
74
94
83
38
80
79
83
83
70
69
94
65
82
87
80
89
-
–6
–89
76
L
-proline
Bn
(S)-4b
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-4b
(S)-3a
Bn
Bn
Bn
87
94
95
Bn
Bn
Bn
–97
96
96
94
94
86
93
95
Me
10e (S)-3a
Me
11f
12f
13f
14
15
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
Bu
Results and Discussion
Hex
We first investigated conjugate addition of 3-
phenylpropanal to di-t-butyl methylenemalonate 1 as a
reactive equivalent of acrylates in THF in the presence of
various secondary amine catalysts (10 mol%), and the
results are shown in Table 1.5g The use of pyrrolidine as a
catalyst did not afford the desired conjugate addition
product due to the undesired conjugate addition of pyr-
rolidine to 1 as shown in Scheme 2 (entry 1).10 On the
other hand, both sterically hindered amine catalysts (S)-
3a5g having hydroxydiphenylmethyl groups11 and (S)-
4b12 gave the conjugate adduct in good yield and enanti-
oselectivity, respectively (entries 3 and 4). By lowering
the temperature and using Et2O as solvent, further im-
provement of enantioselectivity in the reaction using (S)-
3a was achieved (entry 6). Under the optimized condi-
tions, a variety of aldehydes underwent addition to 1 with
high enantioselectivity (entries 9–20). The reactions with
a lower catalyst loading (3 mol%) also gave satisfactory
results (entries 7 and 10).
CH2Cy
CH2OBn
(CH2) 3OBn
CH2CO2Me
CH2NHZ
3-
16d,f (S)-3a
17d,f (S)-3a
18f (S)-3a
87
84
93
97
pyridylmethyl
19
(S)-3a
i-Pr
20f (S)-3a
Cy
94
a The reaction of an aldehyde (0.4 mmol) with 1 (0.13 mmol)
in a Et2O was carried out in the presence of a catalyst (0.013
mmol). b The conjugate addition product was isolated as the
corresponding alcohol to determine the enantioselectivity.
The ee of the product or its dibenzoate ester was determined
c
d
by HPLC analysis using a chiral column. Use of THF as
e
f
solvent. Use of 3 mol% of a catalyst. Use of 1.5 equiv. of
aldehyde.
While we have developed the asymmetric conjugate
addition using methylenemalonate as an acrylate surro-
gate, the conjugate addition of aldehydes to an acrylate
itself is still an attractive and challenging reaction in
enamine catalysis. Thus, we then investigated conjugate
addition of 3-phenylpropanal to various acrylates in Et2O
in the presence of biphenyl-based amino diol catalyst
(S)-3a (10 mol%), and the results are shown in Table 2.
The use of either methyl acrylate or phenyl acrylate did
not afford the corresponding conjugate addition product
as expected (entries 1 and 2). Several fluorinated acry-
lates were then employed as the activated and sterically
hindered
acrylate.
While
the
reaction
of
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7d
8
9
a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
THF
0
45
77
-
heptafluoroisopropyl acrylate resulted in the formation
of a trace amount of the conjugate adduct (entry 4),
1,1,1,3,3,3-hexafluoroisopropyl acrylate (2)13 was found
to be the optimal acrylate affording the desired conjugate
adduct in moderate yield with high enantioselectivity
(entry 3).
CH2Cl2
toluene
Et2O
0
n.d.
n.d.
73
0
-
15
15
15
15
15
90
97
97
-
(S)-3b Et2O
(S)-3b Et2O
73
86
(S)-4a
Et2O
n.d.
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Conjugate Addition of 3-Phenylpropanal
to Alkyl Acrylatea
(S)-4b Et2O
–71
The reaction of 3-phenylpropanal (0.10 mmol) with 2
(0.50 mmol) in a solvent was carried out in the presence of a
catalyst (0.010 mmol) for 24 h. The conjugate addition
product was isolated as the corresponding diol to determine
the enantioselectivity. The ee of the product was deter-
mined by HPLC analysis using chiral column. Use of 10
equiv of 2.
b
c
d
R
time (h)
24
yield (%)b ee (%)c
entry
Me
Ph
n.d.
n.d.
63
-
1
24
-
2
3
4
CH(CF3)2 (2) 24
92
-
In the presence of 10 mol% of (S)-3b, the direct
asymmetric conjugate addition of several other alde-
hydes to 2 was examined, and the results are shown in
Table 4. In general, these direct asymmetric conjugate
additions gave the corresponding adducts with excellent
enantioselectivity, while sterically hindered aldehydes
gave somewhat lower yield even with longer reaction
time (entries 7 and 8).
CF(CF3)2
72
72
<5
CMe(CF3)2
38
93
5
a
The reaction of 3-phenylpropanal (0.10 mmol) with an
alkyl acrylate (0.50 mmol) in Et2O was carried out in the
presence of (S)-3a (0.010 mmol) at 0 °C for 24 h. b The con-
jugate addition product was isolated as the corresponding
c
diol to determine the enantioselectivity. The ee of the
product was determined by HPLC analysis using chiral col-
umn.
Table 4. Conjugate Addition of Aldehydes to 2a
We then optimized the reaction conditions as shown in
Table 3. With 2, reactions were conducted in various
solvents, and we observed significant solvent effects on
the reactivity and selectivity (entries 1–4). Among the
solvents tested, Et2O was found to be the optimal solvent
in terms of both yield and enantioselectivity (entry 1).
The yield was slightly improved by increasing the reac-
tion temperature from 0 °C to 15 °C at the expense of
enantioselectivity (entry 5). Fine-tuning of amino diol
catalyst (S)-3a led to catalyst (S)-3b, which improved
the enantioselectivity (entry 6). We have also evaluated
two widely used chiral pyrrolidines, (S)-4a and (S)-4b12
for the ability to promote the present conjugate addition.
When a pyrrolidine-based amino alcohol (S)-4a was
used as catalyst, the formation of the conjugate adduct
was not detected (entry 8). (S)-Diphenylprolinol silyl
ether (S)-4b was also less effective in terms of both
reactivity and selectivity (entry 9).
entry
R
time (h)
72
yield (%)b ee (%)c
1
Me
80
70
86
70
60
76
46
57
96
96
97
92
88
94
94
95
2
3
4
5
6
7d
8
a
Bu
24
Bn
24
CH2Cy
CH2OBn
24
24
(CH2)3OBn 24
i-Pr
72
72
Cy
Unless otherwise specified, the reaction of an aldehyde
(0.050 mmol) with 2 (0.5 mmol) in Et2O was carried out in
the presence of (S)-3b (5.0 ꢀmol) at 15 °C for 24 h. The
b
conjugate addition product was isolated as the
corresponding diol to determine the enantioselectivity. c The
ee of the product was determined by HPLC analysis using
chiral column, after transformation to the corresponding
diol or its dibenzoate ester. d Use of (S)-3a instead of (S)-3b.
Table 3. Conjugate Addition of 3-Phenylpropanal
to 2a
The conjugate adduct 6 obtained from 1 was a versatile
intermediate in organic synthesis and readily converted to
important chiral building blocks (Scheme 4).5g When one-
pot conjugate addition-reduction product 5 was treated with
entry
1
catalyst solvent
(S)-3a Et2O
temp (°C)yield (%)b ee (%)c
63 92
0
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
1
2
3
4
5
6
7
8
9
TFA at 80 °C, δ-lactone 7 was obtained in quantitative yield
Scheme 5. Transformations of the conjugate ad-
duct
with complete retention of stereochemistry. Treatment of 5
with trifluoromethanesulfonyl chloride and DBU formed
cyclic ether 8 without loss of optical purity.14 The conjugate
addition product 6 could also be converted in situ to amine
9 by reductive amination. Amine 9 was transformed to δ-
lactam 10 in good yield using TFA. In the presence of (diac-
etoxyiodo)benzene and tetrabutylammonium iodide, amine
9 was directly cyclized to pyrrolidine 11.15 Moreover, cyclo-
hexene 12 was obtained in one-pot from the reaction of 6
with NaH and triphenyl(vinyl)phosphonium bromide.9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Transformations of the conjugate ad-
duct 6
Scheme 6. Synthesis of δ-lactone 7
1
Using H NMR, we monitored the rate of product for-
mation and discovered that the reaction catalyzed by (S)-
3a was much faster than that observed in the reaction
using more nucleophilic catalyst (S)-4b (Figure 1). In the
case of catalyst (S)-4b, the reaction proceeded gradually
over time. This result suggested the catalyst deactivation
by conjugate addition to 2 was suppressed somewhat by
the bulky substituent. Higher reactivity obtained by less
nucleophilic (S)-3a may at least in part be due to the
hydroxyl group of the catalyst, which can activate 2
through hydrogen bonding, in agreement with our initial
hypothesis.
The conjugate adduct obtained from 2 has a highly
reactive 1,1,1,3,3,3-hexafluoroisopropyl ester moiety, and
was also readily converted to important chiral building
blocks (Scheme 5). When one-pot conjugate addition-
protection product 13 was treated with benzylamine, the
corresponding amide 14 was obtained in quantitative
yield with complete retention of stereochemistry.
Treatment of 13 with alcohols such as methanol and
phenol in the presence of a base gave the corresponding
esters 15 and 16, respectively. Thioester 17 was also
obtained from the reaction between 13 and sodium
benzylthiolate without loss of optical purity. Moreover,
the conjugate addition product was readily converted to
δ-lactone 7 (Scheme 6).
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
3a
4b
(S)-
10
11
12
13
14
15
16
17
18
19
20
(S)-
Figure 1. Product formation over time. The reaction of 3-
phenylpropanal with 2 in THF-d8 was performed in the
presence of 10 mol% of (S)-3a or (S)-4b at room tempera-
ture. See the Supporting Information for details.
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The absolute configuration of the products obtained in
the present conjugate addition was determined by con-
verting to the known compounds and comparison of the
optical rotation with the value in the literature (see Sup-
porting Information).5g,16 Based on the observed
stereochemistry and the experimental findings that the
hydroxyl group of the catalyst promotes the conjugated
addition, a plausible transition state model can be
proposed as shown in Figure 2.5g The activated and ori-
ented 1 or 2 by hydroxyl group on the catalyst approach-
es the Re face of the enamine.
To elucidate the role of hydroxydiarylmethyl groups of
(S)-3a and (S)-3b, we prepared O-methyl-protected
catalyst (S)-3c, des-hydroxyl catalyst (S)-3d and catalyst
(S)-3e having mono-hydroxydiphenylmethyl group.
With (S)-3c or (S)-3d, both conjugate addition reactions
of 3-phenylpropanal to 1 and 2 resulted in only a trace
amount of the corresponding products or no product
(Scheme 7). The marked effect of hydroxyl groups on the
yield is apparent by comparison with (S)-3a, which affords
the products in good yield with high enantioselectivity, indi-
cating that hydroxyl group on the catalyst is necessary to
accelerate the conjugate addition. Moreover, (S)-3e was
found to promote neither the conjugate addition to 1 nor
2. These results suggested that sterically hindered hy-
droxydiphenylmethyl groups might create the cavity
around the amine moiety, which can discriminate
aldehydes from the bulky electrophiles, suppressing the
undesired side reaction between the catalyst and
electrophiles.
Scheme 7. Effects of diphenylhydroxymethyl
groups on (S)-3a
Figure 2. A plausible transition state model for the direct
asymmetric conjugate addition catalyzed by (S)-3a.
DFT calculations at the B3LYP/6-31G* level were also
done to address the observed stereoselectivities.17 The
most favorable transition state is in accord with the
above-mentioned transition state model for the conju-
gate addition reaction to 2 catalyzed by (S)-3a (Figure
3).18
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
2
8033. (c) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; p.
569. (d) Yamaguchi, M. In Comprehensive Asymmetric Cataly-
sis, Supplement 1; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Hidelberg, 2003; p. 151. (e) Alexakis, A.; Ben-
haim, C. Eur. J. Org. Chem. 2002, 3221. (f) Christoffers, J.;
Baro, A. Angew. Chem. Int. Ed. 2003, 42, 1688.
3
4
5
6
7
(2) For reviews, see: (a) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) Pellissi-
er, H. Tetrahedron 2007, 63, 9267.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) For recent reviews on organocatalytic asymmetric
conjugate additions, see: (a) Lelais, G.; MacMillan, D. W. C.
Aldrichim. Acta 2006, 39, 79. (b) Vicario, J. L.; Badía, D.;
Carrillo, L. Synthesis 2007, 2065. (c) Almasi, D.; Alonso, D. A.;
Najera, C. Tetrahedron: Asymmetry 2007, 18, 299. (d)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (e) Sulzer-
Mossé, S.; Alexakis, A. Chem. Commun. 2007, 3123.
(4) Pioneering work on the asymmetric conjugate addition of
chiral hydrazones to α,β-unsaturated esters, see: Enders, D.;
Rendenbach, B. E. M. Tetrahedron 1986, 42, 2235.
(5) Organocatalytic asymmetric conjugate additions to
activated acrylates having an electron withdrawing group at α-
position, see: (a) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli,
M.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem. Eur. J. 2008,
14, 4788. (b) Albrecht, Ł.; Richter, B.; Krawczyk, H.; Jørgensen, K.
A. J. Org. Chem. 2008, 73, 8337. (c) Zhao, G.-L.; Vesely, J.;
Sun, J.; Christensen, K. E.; Bonneau, C.; Córdova, A. Adv.
Synth. Catal. 2008, 350, 657. (d) Wen, L.; Shen, Q.; Lu, L. Org.
Lett. 2010, 12, 4655. (e) Chowdhury, R.; Ghosh, S. K. Tetrahe-
dron: Asymmetry 2010, 21, 2696. (f) Sun, X.; Ma, D. Chem.
Asian J. 2011, 6, 2158. (g) Kano, T.; Shirozu, F.; Tatsumi, K.;
Kubota, Y.; Maruoka, K. Chem. Sci. 2011, 2311.
(6) Organocatalytic asymmetric conjugate addition of alde-
hydes to α,β-unsaturated thiol esters, see: Zhu, S.; Wang, Y.; Ma,
D. Adv. Synth. Catal. 2009, 351, 2563.
(7) The reaction between an enamine and methyl acrylate
requires high temperature and long reaction time, see: Stork,
G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R.
J. Am. Chem. Soc. 1963, 85, 207.
(8) Simple enones can serve as Michael acceptors in the
enantioselective amine-catalyzed conjugate addition of
aldehydes, see: (a) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am.
Chem. Soc. 2005, 127, 11598. (b) Chi, Y.; Gellman, S. H. Org.
Lett. 2005, 7, 4253.
(9) M. E. Kuehne, P. J. Reider, J. Org. Chem. 1985, 50, 1464.
(10) The NMR analysis revealed that pyrrolidine in THF-d8
was completely consumed by equimolar 1 after 4 h of stirring at
room temperature. Under identical conditions, 88% of (S)-3a
and 81% of (S)-4b remained intact.
Figure 3. B3LYP/6-31G* optimized transition-state struc-
ture of the reaction.
Conclusions
In summary, we have developed a direct asymmetric
conjugate addition of aldehydes to highly reactive modi-
fied acrylates such as dialkyl methylenemalonate and
polyfluoroalkyl acrylate catalyzed by the novel axially
chiral amino diols (S)-3a and (S)-3b. The present study
represents the first example of conjugate addition to the
simple and useful alkyl acrylate, which is a particularly
challenging class of substrates in enamine catalysis. The
conjugate addition product obtained is a versatile inter-
mediate and could be readily converted to synthetically
useful and important chiral building blocks.
ASSOCIATED CONTENT
Supporting Information. Experimental procedure and
spectral data for all new compounds; computational details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am.
Chem. Soc. 2006, 128, 6046. (b) Kano, T.; Ueda, M.; Maruoka,
K. J. Am. Chem. Soc. 2008, 130, 3728.
(12) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A.; Angew. Chem., Int. Ed. 2005, 44, 794. (b)
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212.
(13) Highly reactive 1,1,1,3,3,3-hexafluoroisopropyl acrylate
(2) was employed in Morita-Baylis-Hillman reaction, Diels-
Alder reaction and [2+2] cycloaddition, see: (a) Iwabuchi, Y.;
Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219. (b) Inanaga, K.; Takasu, K.; Ihara, M. J. Am.
Chem. Soc. 2004, 126, 1352.
AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. F.S. thanks the Japan Society
for the Promotion of Science for Young Scientists for Re-
search Fellowships. We thank the Research Center for Com-
putational Science, Okazaki (Japan) for the use of their facil-
ity in our computational studies.
(14) Hakimelahi, G. H.; Just, G. Tetrahedron Lett. 1979, 20,
3645.
(15) (a) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156.
(b) Fan, R.; Wang, H.; Ye, Y.; Gan, J. Tetrahedron Lett. 2010,
51, 453.
REFERENCES
(1) For recent reviews on catalytic asymmetric conjugate ad-
dition, see: (a) Krause, N.; Hoffmann-Röder, A. Synthesis
2001, 171. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
(16) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45,
2419.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
(17) (a) Frisch, M. J. et al. Gaussian 03, revision E.01; Gauss-
ian Inc.: Wallingford, CT, 2004. (b) Gaussian 09, revision C.01;
Gaussian Inc.: Wallingford, CT, 2009.
(18) Some of the substrate functionalities have been omitted
to simplify the calculations. Other transition state structures
and calculation data bearing on the reaction are described in
the Supporting Information.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment