Hydrogen Bonds-Enabled Design of a C1-Symmetric Chiral Br?nsted Acid Catalyst

Article abstract of DOI:10.1021/acscatal.5b02079

We have developed new C₁-symmetric, chiral bis-phosphoric acids with an electron-withdrawing group as one of the two substituents. This C₁-symmetric, chiral bis-phosphoric acid with a pentafluorophenyl group performs exceptionally we

Full text of DOI:10.1021/acscatal.5b02079

Subscriber access provided by NORTHERN KENTUCKY UNIV STEELY
Article
1
Hydrogen Bonds-Enabled Design of a C-
Symmetric Chiral Brønsted Acid Catalyst
Norie Momiyama, Kosuke Funayama, Hirofumi Noda, Masahiro Yamanaka,
Naohiko Akasaka, Shintaro Ishida, Takeaki Iwamoto, and Masahiro Terada
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02079 • Publication Date (Web): 21 Dec 2015
Downloaded from http://pubs.acs.org on December 22, 2015
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.
ACS Catalysis 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 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
Hydrogen Bonds-Enabled Design of a C1-Symmetric Chiral Brønsted Acid
Catalyst
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
Norie Momiyama,*,† Kosuke Funayama,‡,§ Hirofumi Noda,¶ Masahiro Yamanaka,¶
Naohiko Akasaka,‡ Shintaro Ishida,‡ Takeaki Iwamoto,‡ and Masahiro Terada*,‡,
⊥
†Institute for Molecular Science, and SOKENDAI (The Graduate School for Advanced Studies),
Okazaki, Aichi 444-8787, Japan
‡Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai
980-8578, Japan
§Graduate Research on Cooperative Education Program of IMS with Tohoku University
¶Department of Chemistry, Faculty of Science, Rikkyo University, Toshima-ku, Tokyo,
171-8501, Japan
⊥Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University,
Aoba-ku, Sendai 980-8578, Japan
ABSTRACT: We have developed new C1-symmetric, chiral bis-phosphoric acids with an
electron-withdrawing group as one of the two substituents. This C1-symmetric, chiral
bis-phosphoric acid with a pentafluorophenyl group performs exceptionally well in the
asymmetric Diels–Alder reaction of acrolein, methacrolein, and α-haloacroleins with
substituted amidodienes. Control over the atropisomeric catalyst structure, enhancement of the
catalytic activity, and differentiation of the asymmetric reaction space is possible by the remote
control of the pentafluorophenyl group. Furthermore, we have conducted theoretical studies to
clarify the roles of both intra- and intermolecular hydrogen bonds in the C1-symmetric chiral
environment of chiral bis-phosphoric acid catalysts. The developed strategy, C1-symmetric
catalyst design through hydrogen bonding, is potentially applicable to the development of other
chiral Brønsted acid catalysts.
Ar
Ar
OH
O
O
O
O
Cbz
R1
NHCbz
P
P
NH
3
O
O
H
X
X
CHO
O
H
CHO
+
O
P
O
R3
R1
O
O
O
O
R3
3'
P
R2
R2
O
HO
up$to$98%$ee$$
17$examples'
Ar
EWG
Ar
EWG
Design'of'a'C1,Symmetric'Chiral'Brønsted'Acid'Catalyst'
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 21
1
2
3
4
5
6
KEYWORDS: asymmetric catalysis, chiral Brønsted acid, cycloaddition, enantioselectivity,
7
8
organocatalysis
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
n
INTRODUCTION
Asymmetric catalysis has been an active field of research since the early 1980s,1 and
the design of chiral ligands and chiral molecules has been recognized as one of the most
valuable strategies. Therefore, a great deal of effort has been dedicated to this task.2 On
the other hand, design strategies for chiral catalysts have not changed much over the
past two decades. Typically, conformationally rigid and C2- or pseudo C2-symmetry are
elements used in catalyst design; for example, the axially chiral binaphthyl frameworks,
which is a representative source of chirality.3 Modification of this class of framework
has proved fruitful and has greatly expanded the variety of catalytic asymmetric
reactions that can be performed with a wide range of substrates and in a highly
enantioselective fashion.
We
previously
developed
C2-symmetric
the
(R)-3,3'-di(2-hydroxy-3-arylphenyl)binaphthol-derived
chiral
bis-phosphoric acid (C2-BISPA) catalyst, 1a (Ar: 2,4,6-triisopropylphenyl (TRIP)),
which efficiently catalyzes the enantioselective Diels–Alder reaction of α-H or
α-alkylated acroleins with amidodienes (Eq 1, Figure 1).4,5 An inherently atropisomeric,
conformationally flexible naphthyl—phenyl framework has been successfully used as a
new chiral component in the design of a chiral Brønsted acid catalyst.6–9 X-ray
diffraction analysis of C2-BISPA 1b, which possesses a phenyl group, indicates the
existence of an intramolecular hydrogen bond between the two phosphoric acid moieties
responsible for the creation of a C1-symmetric, chiral environment (Figure 1(b) and
1(c)),4a in which high chiral efficiency and reasonable catalytic activity have been
attained. Therefore, to establish strategies for the molecular design of chiral Brønsted
acid catalysts with conformationally flexible frameworks, an understanding of how the
hydrogen bond creates the C1-symmetric chiral environment and how this controls the
asymmetric reactions is especially important.10 However, no detailed studies on either
the intra- or intermolecular hydrogen bonding in these catalysts have been made. Herein,
we describe our development of a new C1-symmetric, chiral bis-phosphoric acid
(C1-BISPA), 2, that possesses an electron-withdrawing group at the CNaph(3')—CAr(3)
position to clarify the role of both intra- and intermolecular hydrogen bonding in
2
ACS Paragon Plus Environment

Page 3 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
catalysis (Figure 2).11 Moreover, the present study also establishes a new strategy to
elaborate the asymmetric reaction space through hydrogen bonding directed by the
remote control of the electron-withdrawing substituent.
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
Cbz
C2-BISPA 1a
(Ar : 2,4,6-i-Pr3C6H2)
(2.5 mol%)
NHCbz
+
NH
R2
CHO
R2 CHO
(1)
toluene
MS4Å
R1
R1
R2 = H, Alkyl
up to ~ 99% ee
(a)!
(b) ꢀ
(c) ꢀ
Ar
Ar
(S)ꢀ
O
OH
O
OH
O
P
O
O
O
O
OH
O(1)ꢀ
O(2)ꢀ
(S)#
P
H
P
Ar
O
O
O
O
P
O
O
(S)ꢀ
O(1)—O(2)'''
2.490'Åꢀ
Ar
(R)#
(S)#
C2-BISPA!
1ꢀ
1b !
(Ar: Ph)ꢀ
$$$#Hydrogen#bond#
Figure 1. From a previous study on the C2-symmetric bis-phosphoric acid (C2-BISPA)
1. (a) General chemical structure of C2-BISPA 1. (b) X-ray diffraction analysis of
C2-BISPA 1b (Ar: Ph). Pink dashed line indicates the hydrogen bond. O(1)—O(2) =
2.490 Å. (c) Schematic structure of C2-BISPA 1 indicating the hydrogen bond with red
dashed line.
Ar
3
O
OH
O
P
C1-Symmetric Design!
ꢀ Activation unit!
ꢁ H-bond donor site for O=P!
ꢂ Tuning site!
O
O
ꢀ!
ꢁ!
OH
O
P
O
ꢂ!
Ar
3'
3
EWG
C1-BISPA!
2ꢀ
Figure 2. From this study: C1-symmetric design of the chiral Brønsted acid, C1-BISPA
2, catalyst.
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 21
1
2
3
4
5
6
7
n
RESULTS AND DISCUSSION
Structural Requirements for Design of C1-Symmetric Bis-Phosphoric Acid
(C1-BISPA) 2. The hydrogen-bonding interaction was considered to play two roles in
enantioselective Diels–Alder reaction of acroleins with amidodienes:4a controlling the
atropo diastereomeric behavior derived from the naphthyl—phenyl axis, and activating
an acrolein and a diene to facilitate enantioselective product formation. To apply the
hydrogen-bonding interaction for C1-symmetric catalyst design, we initially attempted
to clarify the requirements of each catalyst component in detail.
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
We assembled C1-BISPA 2a and C1-symmetric mono-phosphoric acids 3a and 3b to
evaluate the importance of two phosphoric acid moieties in the catalytic
enantioselective Diels–Alder reactions of α-haloacroleins12 with N-Cbz amidodiene,13
considering the synthetic versatility of the resulting adducts and, in addition, the
advancement of this methodology (Table 1).14–16 Treatment of α-bromoacrolein (5a)
(1.5 equiv) with N-Cbz amidodiene 4a (1.0 equiv) in toluene in the presence of 2.5
mol% of 2a at –78 °C for 24 h resulted in the formation of 6aa in 29% yield with 71%
ee (1S,6S) (entry 1). In sharp contrast, the enantioselectivities in the presence of 5 mol%
of 3a or 3b dropped significantly (8% ee) under the same conditions (entries 2 and 3).
To gain supportive evidence of the importance of the hydrogen bond to improve the
chemical and optical yields, we prepared C1-BISPA 2b. This catalyst possesses a
bis-trifluoromethylphenyl substituent as an electron-withdrawing group at the
CNaph(3')—CAr(3) position. We found, as hoped, that the chemical yield and the
enantioselectivity improved to 65% yield and 85% ee (1S,6S), respectively, in the
reaction catalyzed by 2b (entry 4).
Table 1. Enantioselective Diels–Alder Reaction of α-Bromoacrolein (5a) with N-Cbz
Amidodiene 4a.a
4
ACS Paragon Plus Environment

Page 5 of 21
ACS Catalysis
1
2
3
4
5
6
7
i-Pr
Ar :
Cbz
NHCbz
NH
i-Pr
i-Pr
Br
CHO
*
*
8
9
Br
CHO
catalyst
+
toluene
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
4a
endo : exo = >20 : 1
6aa
5a
Ar
Ar
OH
Ar
OH
O
OH
O
O
O
OH
O
OMe
P
O
P
P
O
O
O
O
P
OMe
O
P
O
O
O
O
3'
H
R
3
2a : R = H
2b : R = 3,5-(CF3)2C6H3
3a
3b
entry
catalyst (mol%)
2a (2.5)
yield (%)b
ee (%)c
1
2
3
4
29
51
50
65
71 (1S,6S)
8 (1R,6R)
8 (1S,6S)
85 (1S,6S)
3a (5.0)
3b (5.0)
2b (2.5)
a Reactions were conducted with 1.0 equiv of 4a and 1.5 equiv of 5a in the presence of 2.5 mol% 2 or 5.0
mol% 3 in toluene at –78 °C. b Isolated yield. c Determined by chiral HPLC.
To give further insight into the structural differences and the enantioselectivities, we
attempted to obtain crystal structures to verify their 3D structures. X-ray diffraction
analysis revealed a diastereomeric mixture of 3b. No obvious intra- or intermolecular
hydrogen bonds were found, based on the distance between the oxygen atoms in the
phosphoryl and methoxy groups.17 In contrast, a single atropo diastereomer (S,R,S) of
C1-BISPA 2b was obtained among the four possible atropo diastereomers: (S,R,S),
(S,R,R), (R,R,R), and (R,R,S) (Figure 3).18 Notably, although the atropo diastereomer
(S,R,S) of 2b is the same as those of C2-BISPA catalysts 1a and 1b, two kinds of
intramolecular hydrogen bonds were inferred based on the distance of the two oxygen
atoms: -O(3)H—O(2)=P: 2.467 Å and -O(2')H—O(3')=P: 2.464 Å, indicating that both
phosphoric acids, O(2)=P-O(1)H and O(3')=P-O(4')H, may function as activation units
for the acroleins and amidodienes in C1-BISPA 2.
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 21
1
2
3
4
5
6
7
8
O(2))—)O(3)):)2.467)Å)
O(2’)—O(3’)):)2.464)Åꢀ
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
O(2)ꢀ
O(1)ꢀ
(S)ꢀ
(S)ꢀ
O(3’)ꢀ
O(2’)ꢀ
O(3)ꢀ
O(1’)ꢀ
O(4)ꢀ
O(4’)ꢀ
(S)ꢀ
(S)ꢀ
O(4)—O(4’)):)2.494)Å)
Figure 3. X-ray diffraction analysis of 2b. Intramolecular distance between the two
oxygen atoms (O(2)—O(3) = 2.467 Å, O(2')—O(3') = 2.464 Å, intramolecular
hydrogen bonds are indicated by dashed pink line.) and intermolecular distance of two
oxygen atoms (O(4)—O(4') = 2.494 Å, intermolecualar hydrogen bond is indicated by
dashed light blue line.).
Combining the results of initial experiments and X-ray diffraction analyses, we
inferred that the two phosphoric acid moieties and the presence of hydrogen bonding are
primarily responsible for asymmetric induction, i.e., controlling the atropisomerism of
the naphthyl—phenyl framework and transferring the axial chirality of binaphthyl to
produce the enantiomerically enriched product. On the other hand, to be highly
enantioselective, the reaction should proceed at the side of the sterically bulky TRIP
substituent in C1-BISPA 2 (Figure 4).
Ar
Ar
δ+
Ar
O
O
O
O
O H
O
OH
O
OH
O
P
δ−
P
O
O
O
O
P
O H
O
O
δ−
P
P
O
O H
δ+
P
O H
O
O
O
O
Ar
Ar
Ar
EWG
EWG
EWG
C1-BISPA
2
Unfavorable form
Favorable form
Figure 4. Two possible intramolecular hydrogen bondings and reaction spaces in
C1-BISPA 2.
The C1-symmetric catalyst design discussed above provides a powerful strategy if
the following criteria can be satisfied; i.e., (i) the stereodynamic behavior of two
6
ACS Paragon Plus Environment

Page 7 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
atropisomeric naphthyl—phenyl axes can be controlled by intramolecular hydrogen
bond between the two phosphoric acids, (ii) they have the requisite catalytic activity by
using the influence of the electron-withdrawing group, while keeping the sterically
demanding TRIP group fixed as one of two substituents, and, (iii) of the two
asymmetric reaction spaces, the asymmetric reaction take place on the side of the
sterically demanding TRIP substituent at the CNaph(3)—CAr(3) position by the
electron-withdrawing group. To further develop this strategy, we studied the details of
the molecular design of C1-BISPA modified with an electron-withdrawing group.
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
Development of C1-BISPA 2-catalyzed Enantioselective Diels–Alder Reaction of
Substituted Acroleins 5 with N-Cbz Amidodienes 4. The ability of C1-BISPA 2b was
initially evaluated for a variety of α-haloacroleins 5 in the catalytic enantioselective
Diels–Alder reaction with N-Cbz amidodiene 4a. The preliminary experiments showed
that C1-BISPA 2b can be used for the Diels–Alder reactions of α-chloroacrolein
(5b) and α-iodoacrolein (5c).19 For instance, in the case of α-chloroacrolein (5b),
while the yield was not sufficient, the enantioselectivity of the Diels–Alder adduct 6ab
was high (38% yield, 90% ee after 24 h and 45% yield, 90% ee after 48 h). Therefore,
we next focused on exploring the use of an electron-withdrawing group at the
CNaph(3')—CAr(3) position to improve the product yield (Table 2). The reaction of 5b
with 4a catalyzed by C1-BISPA 2c, which has a 3,4,5-trifluorophenyl group, produced a
higher yield than that of C1-BISPA 2b (entries 1 and 2). We also confirmed that the
pentafluorophenyl substitution of C1-BISPA catalysts 2d and 2e improved not only the
product yields but also the enantioselectivities (entries 3 and 4). For this reaction, the
optimal quantities were found to be 1 equiv of 5b with 2 equiv of 4a, yielding the endo
adduct 6ab in the highest yield with higher enantioselectivity (entry 5).
We postulated that the acidity of one phosphoric acid proton near the TRIP
substituent at the CNaph(3)—CAr(3) position is enhanced, and, at the same time, the
asymmetric reaction space is controlled by the electron-withdrawing substituent at the
CNaph(3')—CAr(3) and CNaph(3')—CAr(5) positions through intramolecular hydrogen
bonding between the phosphoric acid proton and phosphoryl oxygen
(-OHEWG···O=PTRIP).20 Consequently, the improved catalytic activity and the strongly
directed hydrogen bond would improve the chemical and optical yields.
Finally, the corresponding reactions catalyzed by C2-BISPA catalysts 1a, 1c, and 1d
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 21
1
2
3
4
5
6
7
8
9
were conducted to assess the roles of both the steric- and electronic substituents (entries
6–8). C2-BISPA 1a produced a comparable yield and enantioselectivity to C1-BISPA 2d
(entry 3 vs. 6). In sharp contrast, C2-BISPA catalysts 1c and 1d were inferior to that of
C1-BISPA 2d (entry 3 vs. 7 and 8), demonstrating the importance of the C1-symmetric
design and the steric- and electronic substituents. Moreover, these results suggested
that the highly enantioselective reaction catalyzed by C1-BISPA 2d occurred around the
asymmetric reaction space near the TRIP group, not near the electron-withdrawing
group.
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. Effect of the Electron-withdrawing Group of C1-BISPA 2, and a Comparison
of 2 with C2-BISPA 1 in the Enantioselective Diels–Alder Reaction of α-Chloroacrolein
(5b) with N-Cbz Amidodiene 4a.a
Cbz
NHCbz
NH
Cl
CHO
1 or 2
(2.5 mol%)
Cl
CHO
+
toluene
4a
endo : exo = >20 : 1
6ab
5b
i-Pr
i-Pr
Ar
Ar
3
i-Pr
O
O
OH
O
OH
O
OH
O
P
P
O
O
O
O
OH
O
P
P
O
O
3'
Ar
3
EWG
R
C1-BISPA
C2-BISPA
1
2
2b : ArEWG = 3,5-(CF3)2C6H3, R = H 1a : Ar = 2,4,6-i-Pr3C6H2
2c : ArEWG = 3,4,5-F3C6H2, R = H 1c : Ar = 3,5-(CF3)2C6H3
ArEWG = C6F5, R = H Ar = C F
2d :
2e : ArEWG = C6F5, R = CF3
1d :
6
5
entry
catalyst
2b
yield (%)b
ee (%)c
1
2
3
4
38
47
67
74
90 (1S,6S)
92 (1S,6S)
98 (1S,6S)
97 (1S,6S)
2c
2d
2e
8
ACS Paragon Plus Environment

Page 9 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
5d
6
2d
1a
1c
1d
98
61
30
25
97 (1S,6S)
93 (1S,6S)
5 (1S,6S)
14 (1R,6R)
9
7
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
8
a Reactions were conducted with 1.0 equiv of 4a and 1.5 equiv of 5b in the presence of 2.5 mol% catalyst
b
c
in toluene at –60 °C. Isolated yield. Determined by chiral HPLC. Reactions were conducted with 2.0
d
equiv of 4a and 1.0 equiv of 5b.
With the rationally designed C1-BISPA 2d in hand, we turned our attention to
testing its performance for substrate generality in the catalytic enantioselective Diels–
Alder reaction of acroleins 5 with substituted amidodienes 4. As can be seen in Table 3,
the reactions were highly enantioselective for a range of acroleins and substituted
amidodienes. The reactions to produce the corresponding cyclohexyl β-amino
aldehydes (6) with high enantiofacial control proceeded smoothly for α-bromoacrolein
(5a), α-chloroacrolein (5b), α-iodoacrolein (5c), acrolein (5d), and methacrolein (5e)
(entries 2–5). Use of 3- or 3,4-disubstituted amidodienes 4 allows facile
enantioselective access to substituted cyclohexyl β-amino aldehydes 6 (entries 6–16). In
particular, 3,4-disubstituted amidodienes 4e–4i substrates can be used (entries 11–16).
Moreover, the first example of the catalytic enantioselective elaboration of
6-formyl-cyclo-2-hexcene-5-methyl (6af), which is a key intermediate in the synthesis
of pumiliotoxin C reported by Overman,21 can be carried out using the present method;
however, the yield was low (entry 17).
Table 3. Enantioselective Diels–Alder Reaction of Acroleins 5 with Substituted
Amidodienes 4a
Cbz
NH
NHCbz
+
X
X
CHO
2d (2.5 mol%)
CHO
R3
toluene
R1
R1
R3
endo : exo = >15 : 1
R2
R2
4
5
6
9
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 21
1
2
3
4
5
6
7
8
entry
1
6
yield (%)b
ee (%)c
97
X = Br (6aa)
95
98
90
67
99
98
85
98
98
77
9
Cbz
2
X = Cl (6ab)
97
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
NH
X
3d
4e
X = I (6ac)
96
CHO
X = H (6ad)
98
5
X = Me (6ae)
96
6d
7d
8d
9d
10d
R1 = Me, X = Br (6ba)
R1 = Me, X = Cl (6bb)
R1 = Me, X = I (6bc)
R1 = Et, X = Br (6ca)
R1 = Bn, X = Br (6da)
96
95
Cbz
NH
X
97
CHO
96
R1
88
Cbz
NH
Br
CHO
11d
(6ea)
83
93
Me
Me
12f,g
13f
14
n = 1, X = Br (6fa)
n = 2, X = Br (6ga)
n = 2, X = Cl (6gb)
n = 3, X = Br (6ha)
91
98
76
85
80
91
90
79
Cbz
NH
X
CHO
H
15d,g
n
Cbz
NH
Br
CHO
16f
(6ia)
76
87
H
Cbz
17h,i
18h
X = H (6af)
X = Br (6ag)
34
<1
88
—
NH
X
CHO
Me
aReactions were conducted with 2.0 equiv of 4 and 1.0 equiv of 5 in the presence of 2.5 mol% 2d in
toluene at –60 °C. bIsolated yield, see Supporting Information. Determined by chiral HPLC, see
c
Supporting Information. dReactions were conducted with 3.0 equiv of 4 and 1.0 equiv of 5 in the presence
e
of 2.5 mol% 2d in toluene. Reaction was conducted with 1.0 equiv of 4 and 1.5 equiv of 5e in the
presence of 2.5 mol% 2d and MS4Å in toluene at –80 °C. fReactions were conducted at –50 °C.
gendo : exo = ~5 : 1. hReactions were conducted with 1.0 equiv of 4a and 12 equiv of 5 in the presence of
5.0 mol% 2d in toluene. iendo:exo = ~7:1.
10
ACS Paragon Plus Environment

Page 11 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
Computational Study by Density Functional Theory (DFT) Calculations for the
C2-BISPA 1a-catalyzed Enantioselective Diels–Alder Reaction of Acrolein with
N-Cbz Amidodiene. The intriguing behavior of C2- and C1-BISPA catalysts motivated
us to study the reaction mechanism in detail. Computational studies were carried out in
the following order: (i) the structure of C2-BISPA 1a was optimized; (ii) the
conformations of the amidodienes were optimized, and diastereofacial selection and a
simplified transition state (TS) model without any catalyst were investigated; and (iii) a
realistic TS model for the C2-BISPA 1a-catalyzed enantioselective Diels–Alder reaction
based on studies (i) and (ii) was explored.22 All calculations were performed with the
Gaussian 09 package.23 Geometries were fully optimized at the B3LYP/6-31G* level
and with ONIOM (B3LYP/6-31G*:HF/3-21G) calculations24 and characterized by
frequency calculations. To evaluate the dispersion interactions such as π-π and CH-π
interactions of the Ar groups, single-point energy calculations of the realistic TS models
were conducted at the B3LYP-D3/6-31+G** level.25
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
DFT calculations of 1a showed that the atropo diastereomer (S,R,S) is
conformationally more stable than either the (R,R,S) or (R,R,R) diastereomers by 4.2
and 6.7 kcal/mol, respectively. This stability is due to the hydrogen bond between two
phosphoric acids (Figure 5). In particular, the hydrogen bond to the phosphoryl oxygen
(-O(2)H···O(1)=P) is more stabilizing toward the atropo diastereomeric structure than
that toward the ester oxygen (-O(2)H···O(3)-P). This atropo diastereomer (S,R,S) of 1a
is consistent with the X-ray diffraction analysis of C2-BISPA 1b, which possesses a
phenyl group.
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 21
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
(S)ꢀ
O(1)ꢀ
O(2)ꢀ
O(1)ꢀ
(R)ꢀ
O(3)ꢀ
(R)ꢀ
O(1)ꢀ
(R)ꢀ
O(3)ꢀ
(R)ꢀ
O(3)ꢀ O(2)ꢀ
(R)ꢀ
(S)ꢀ
(R)ꢀ
(S)ꢀ
O(2)ꢀ
O(1)—O(2)(:(2.655(Å(
O(2)—O(3)(:(4.219(Åꢀ
0.0!
O(1)—O(2)(:(4.090(Å(
O(2)—O(3)(:(2.772(Åꢀ
+4.7!
+6.7!
(R,R,R)ꢀ
(S,R,S)ꢀ
(R,R,S)ꢀ
Figure 5. Conformational stability of three atropo diastereomers in C2-BISPA 1a.
Hydrogen bonds are indicated by dashed lines. Relative energies (kcal/mol) were
calculated based on single-point energy calculation at the B3LYP/6-31G* level.
Based on the optimized catalyst structure of 1a and the simplified TS model without
catalyst, the identified TS models are summarized in Figure 6.26 To reveal the factors
contributing to asymmetric induction, the structural differences between the
energetically lowest TS11s6r and TS11r6s structures were investigated. In contrast to the
well-established C2-symmetric chiral environment by the mono-phosphoric acid,27,28
C2-BISPA 1a provides a distinctive chiral environment due to the presence of a
hydrogen-bonding network. In TS1, one of the phosphoric acid group acts as a
bifunctional catalyst, where the OH group (proton) activates the acrolein and the P=O
group accepts the amidodiene with the intervention of hydrogen bonds. A distorted
chiral space is formed by one of the phosphoric acid groups activating both the acrolein
and the amidodiene. The binaphthyl skeleton of 1a acts as a linker to position the
TRIP group in distorted C2-symmetric fashion. The inter- and intramolecular
hydrogen-bonding networks are similar in both TS11s6r and TS11r6s. The origin of the
energy difference is due to differences in steric repulsion. The benzyl group of the
amidodiene is located far from the TRIP group of 1a, and, thus, there is no unfavorable
steric interaction in TS11s6r. In contrast, the serious repulsive steric interaction (pink
curve in Figure 6) between the benzyl group of amidodiene and the TRIP group of 1a is
29
responsible for the destabilization of TS11r6s
.
12
ACS Paragon Plus Environment

Page 13 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
e
H
H
O
b
O
O
b
O
d
c
Ar
H
O
H
Ph
P
O
Ph
Ar
O
H
N
O
d
N
H
O
O
P
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
O
O
O
O
a
O
c
a
e
H
O
O
H
O
O
P
Ar
O
P
a : 1.613!
b : 1.085!
c : 1.814!
d : 3.102!
e : 2.438ꢀ
a : 1.619!
b : 1.112!
c : 1.879!
d : 3.168!
e : 2.401ꢀ
Ar
O
O
TS11s6r (0.0)ꢀ
TS11r6s (+1.1)ꢀ
Figure 6. 3D structures, schematic representation models, and relative energies
(kcal/mol) of TS11s6r and TS11r6s. Bond lengths are shown in Å.
DFT Calculations of C1-BISPA 2d-catalyzed Enantioselective Diels–Alder Reaction
of Acrolein 5d with N-Cbz Amidodiene 4a. To reveal the influence of the
electron-withdrawing groups in the C1-symmetric design in more detail, theoretical
investigations of the TS models were conducted for the C1-BISPA 2d-catalyzed reaction
of acrolein 5d with amidodiene 4a (Table 3, entry 4: 98% ee) based on the DFT
calculations for C2-BISPA 1a. There are two possible coordination sites on the
phosphoric acid units, one close to the TRIP group (TS2a) and the other close to the
C6F5 group (TS2b). The different chiral spaces are modified both sterically and
electronically, allowing fine tuning of chiral spaces in C1-BISPA 2d. The chiral spaces
lead to major and minor enantiomers via transition states TS21s6r and TS21r6s
.
Therefore, four diastereomeric TS2 models were compared to establish the optimal
C1-symmetric catalyst design (Figure 7).30
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 21
1
2
3
4
5
6
*
*
7
8
9
*
*
*
*
O
O
O
O
O
O
O
H
O
H
P
O
P
O
O
P
O
P
H
H
Ar
ArF5
ArF5
Ar
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
O
O
O
O
O
O
H
H
N
O
Ph
N
O
Ph
O
O
H
H
TS2a1s6r
(0.0)
TS2b1s6r
(+3.8)
TS2a1r6s
(+2.8)
TS2b1r6s
(+0.8)
Figure 7. Two possible coordination sites, and the relative energies (kcal/mol) of four
diastereomeric TS2 models.
Each favorable TS model that we identified for both major and minor enantiomers is
summarized in Figure 8. The chiral space in TS2a1s6r is smaller than that in TS2b1r6s
,
and the intramolecular hydrogen bond between the two phosphoric acid units becomes
shorter in TS2a1s6r (1.587 Å) than in TS2b1r6s (1.632 Å) due to the increased acidity of
the bridged phosphoric acid close to the C6F5 group. A comparison of the favorable TS
models for major and minor enantiomers shows that TS2a1s6r is more stable than
TS2b1r6s by 0.8 kcal/mol. We believe that the energy differences arise from the inherent
conformational stability of the catalyst structure and from the steric repulsion between
the benzyl group of amidodiene 5a and the C6F5 group of 2d. In fact, as we reported
previously, 99% ee was obtained in the reaction catalyzed by the C2-BISPA catalyst 1a
that has a TRIP substituent. In contrast, the enantioselectivity dropped in the reaction
catalyzed by C2-BISPA 1d, which has C6F5 substituents (60% ee), corroborating our
hypothesis that the highly enantioselective reaction by C1-BISPA 2d (98% ee)
preferentially occurs on the side of the catalyst nearest the TRIP substituent and
between the two asymmetric reaction spaces in C1-BISPA 2d. This differentiation of the
asymmetric reaction space created by the electronic effects is an important feature of
our catalyst design.
14
ACS Paragon Plus Environment

Page 15 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
e
H
H
O
b
O
O
b
d
O
c
Ar
H
Ph
H
O
O
ArF5
P
Ph
O
N
H
H
N
O
d
P
O
O
O
O
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
O
O
a
O
c
a
e
H
O
O
H
O
O
P
ArF5
a : 1.587!
b : 1.082!
c : 1.840!
d : 3.115!
e : 2.486ꢀ
a : 1.632!
b : 1.079!
c : 1.846!
d : 3.173!
e : 2.424ꢀ
O
P
Ar
O
O
TS2a1s6r (0.0)ꢀ
TS2b1r6s (+0.8)ꢀ
Figure 8. 3D structures, schematic representations, and relative energies (kcal/mol) in
TS2. Bond lengths are shown in Å.
n
CONCLUSION
In summary, we have successfully developed the C1-BISPA 2d catalyst that
possesses both TRIP and C6F5 groups, which efficiently catalyzed the highly diastereo-
and enantioselective Diels–Alder reactions of acrolein, methacrolein, and
α-haloacroleins with amidodienes. Furthermore, we have conducted DFT calculations
for TS models of the C2-BISPA 1a and C1-BISPA 2d-catalyzed enantioselective Diels–
Alder reaction of acrolein with amidodiene. We have confirmed that intramolecular
hydrogen bonding between the phosphoric acid proton and phosphoryl oxygen
(-OHC6F5···O=PTRIP) plays an important role in creating the C1-symmetric chiral
environment, in which high enantioselectivities and yields were realized. The
asymmetric reaction space could be elaborated by the electronic and steric effects of the
naphthyl—ortho-biphenyl framework at the side of the CNaph(1')—CNaph(3')-CAr(3)
position. The catalytic activity was adequately provided by the electron-withdrawing
C6F5 group to improve the chemical yields of the Diels–Alder products. This design
concept based on a C1-symmetric framework has great potential and is broadly
applicable to the development of other chiral Brønsted acid catalysts. Further studies on
this are underway in our laboratories and will be reported in due course.
15
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 21
1
2
3
4
5
6
7
8
n
ASSOCIATED CONTENT
The Supporting Information Available:
9
Experimental details, characterization data, HPLC enantiomer analysis, NMR spectra for
new compounds, X-ray diffraction analysis, and description of mechanistic features,
structural details of the transition states, and Cartesian coordinates (PDF).
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
15 KF C1-BISPA ACS Catalysis 150918 SI cif C1BISPA(CF3)2C6H3 2b (CIF)
15 KF C1-BISPA ACS Catalysis 150918 SI cif OMe protected CMPA 3b (CIF)
This material is available free of charge via the Internet at http://pub.acs.org.
n
AUTHOR INFORMATION
Corresponding Authors
*E-mail: momiyama@ims.ac.jp
*E-mail: mterada@m.tohoku.ac.jp
Notes
The authors declare no competing financial interest.
n
ACKNOWLEDGMENTS
Support was partially provided by JSPS via Grant-in-Aid for Scientific Research C (No.
23550114), and Grant-in-Aid for Scientific Research on Innovative Areas “Advanced
Molecular Transformations by Organocatalysts” from MEXT, Japan (No. 23105002, No.
23105005). We thank Prof. Yasuhiro Uozumi (Institute for Molecular Science) and Associate
Prof. Souji Shimizu (Graduate School of Engineering, Kyushu University) for helpful
discussion. We also thank the Yoshida Scholarship Foundation (K. F.).
n
REFERENCES
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999. (c) Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2010.
(2) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693. (b) Privileged
Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, 2011.
16
ACS Paragon Plus Environment

Page 17 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
(3) For selected reviews, see: (a) Brunel, J. M. Chem. Rev. 2005, 105, 857-897. (b)
Akiyama, T. Chem. Rev. 2007, 107, 5744-5758. (c) Shibasaki, M.; Kanai, M.;
Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117-1127. (d) Hatano, M.;
Ishihara, K. Synthesis 2010, 3785-3801. (e) Pereira, M. M.; Abreu, A. R.; Calvete, M. J.
F.; Carrilho, R. M. B. Adv. Chem. Res. 2013, 19, 111-153.
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
(4) (a) Momiyama, N.; Konno, T.; Furiya, Y.; Iwamoto, T.; Terada, M. J. Am. Chem.
Soc. 2011, 133, 19294-19297. (b) Hong, L.; Kai, M.; Wu, C.; Sun, W.; Zhu, G.; Li, G.;
Yao, X.; Wang, R. Chem. Commun. 2013, 49, 6713-6715.
(5) For linked BINOL-derived chiral bis-phosphoric acid catalyst, see: (a) Chen, X. H.;
Zhang, W. Q.; Gong, L. Z. J. Am. Chem. Soc. 2008, 130, 5652-5653. (b) Yu, J.; He, L.;
Chen, X. H.; Song, J.; Chen, W. J.; Gong, L. Z. Org. Lett. 2009, 11, 4946-4949. (c) Yu,
J.; Chen, W. J.; Gong, L. Z. Org. Lett. 2010, 12, 4050-4053. (d) He, L.; Chen, X. H.;
Wang, D.; Luo, S. W.; Zhang, W. Q.; Yu, J.; Ren, L.; Gong, L. Z. J. Am. Chem. Soc.
2011, 133, 13504-13518. (e) Guo, C.; Song, J.; Gong, L. Org. Lett. 2013, 15,
2676-2679.
(6) For related studies, see: (a) Inanaga, J. Organomet. News 2008, 20-24. (b) Inanaga, J.
Fain Chemical 2008, 37, 33-40.
(7) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; RSC Publishing:
Cambridge, 2008.
(8) For selected reviews on the use of conformationally flexible achiral and meso biaryl
ligands in transition metal catalyzed asymmetric synthesis, see: (a) Walsh, P. J.; Lurain,
A. E.; Balsells, J. Chem. Rev. 2003, 103, 3297-3344. (b) Mikami, K.; Yamanaka, M.
Chem. Rev. 2003, 103, 3369-3400. (c) Reetz, M. T. Angew. Chem., Int. Ed. 2008, 47,
2556-2588. (d) Aikawa, K., Mikami, K. Chem. Commun. 2012, 48, 11050-11069.
(9) For impressive reports on the use of an achiral, conformationally flexible biphenyl
subunit for the molecular design of chiral organocatalyst, see: (a) Ooi, T.; Uematsu, Y.;
Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551-1554. (b) Matsui, K.;
17
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 21
1
2
3
4
5
6
7
Takizawa, S.; Sasai, S. Synlett 2006, 761-765.
8
9
(10) For reviews of hydrogen bonding, see: (a) Seebach, D.; Beck, A.; Heckel, K.
Angew. Chem., Int. Ed. 2001, 40, 92-138. (b) Steiner, T. Angew. Chem., Int. Ed. 2002,
41, 48-76.
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
(11) For optically active BINOL-derived C1-symmetric catalyst, see: (a) Amano, M.;
Watanabe, M.; Baba, N.; Oda, J.; Inouye, Y. Bull. Chem. Soc. Jpn. 1983, 56, 3672-3678.
(b) Uraguchi, D.; Koshimoto, K.; Ooi, T. Chem. Commun. 2010, 46, 300-302. (c)
Uraguchi, D.; Koshimoto, K.; Sanada, C.; Ooi, T. Tetrahedron: Asymmetry 2010, 21,
1189-1190.
(12) For selected examples of catalytic enantioselective Diels–Alder reaction of
α-haloacrolein, see: (a) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113,
8966-8967. (b) Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979-3982. (c)
Hatano, M.; Mizuno, T.; Izumiseki, A.; Usami, R.; Asai, T.; Akakura, M.; Ishihara, K.
Angew. Chem., Int. Ed. 2011, 50, 12189-12192.
(13) For selected examples of enantioselective reaction using amino dienes, see: (b)
Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 7843-7844. (c)
Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 5950-5951. (d)
Huang, Y.; Iwama, T.; Rawal, V. H. Org. Lett. 2002, 4, 1163-1166. (e) Tian, X.;
Hofman, N.; Melchiorre, P. Angew. Chem., Int. Ed. 2014, 53, 2997-3000. (f) Kong, L.;
Han, X.; Jiao, P. Chem. Commun. 2014, 50, 14113-14116. (g) Pous, J.; Courant, T.;
Bernadat, G.; Iorga, B. I.; Blanchard, F.; Masson, G. J. Am. Chem. Soc. 2015, 137,
11950-11953.
(14) (a) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43,
2164-2167. (b) Overman, L. E.; Jessup, P. J. J. Am. Chem. Soc. 1978, 100, 5179-5185.
(15) (a) Wipf, P.; Wang, X. Tetrahedron Lett. 2000, 41, 8747-8751. (b) Huang, J.;
Bergmeier, S. C. Tetrahedron 2008, 64, 6434-6439.
18
ACS Paragon Plus Environment

Page 19 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
(16) Selected examples of chiral Brønsted acid catalyzed enantioselective Diels–Alder
reaction of α,β-unsaturated carbonyl compounds with dienes, see: (a) Nakashima, D.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627. (b) Borovia, A.; Nagorny, P.
Tetrahedron 2013, 69, 5719-5725. (c) Tian, X.; Hofmann, N.; Melchiorre, P. Angew.
Chem., Int. Ed. 2014, 53, 2997-3000.
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
(17) X-ray diffraction analysis of 3b was shown in Supporting Information.
(18) Details for X-ray diffraction analysis of 2b were shown in Supporting Information.
(19) Details for the reactions of α-haloacroleins were provided in Supporting
Information.
(20) For selected examples, see: (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V.
H. Nature 2003, 424, 146. (c) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5846-5850. (d) Unni, A. K.; Takenaka, N.;
Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336-1337. (e) Momiyama,
N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 1080-1081. (f) Hasegawa, A.;
Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 3175-3178.
(g) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054-10055. (h)
Hashimoto, T.; Kimura, H.; Nakatsu, H.; Maruoka, K. J. Org. Chem. 2011, 76,
6030-6037. (i) Ratjen, L.; Gemmeren, M.; Pesciaioli, F.; List, B. Angew. Chem., Int. Ed.
2014, 53, 8765-8769.
(21) (a) Overman, L. E.; Jessup, P. J. Tetrahedron Lett. 1977, 18, 1253-1256. (b)
Overman, L. E.; Jessup, P. J. J. Am. Chem. Soc. 1978, 100, 5180-5185. (c) Masamune,
S.; Reed, L. A.; Davis, J. T.; Choy, W. J. Org. Chem. 1983, 48, 4441-4444.
(22) Details were provided in Supporting Information.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R. Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
19
ACS Paragon Plus Environment

ACS Catalysis
Page 20 of 21
1
2
3
4
5
6
7
8
9
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene,
M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J.
V.; Cioslowski, J.; Fox, D. J. Gaussian09, Revision D.01; Gaussian, Inc.: Wallingford,
CT, 2013.
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
(24) For selected examples, see: (a) Dapprich, S.; Komaromi, I.; Byun, K. S.;
Morokuma, K.; Frisch, M. J. J. Mol. Struct. (THEOCHEM) 1999, 461-462, 1-21. (b)
Svensson, M.; Humbel, S.; Morokuma, K. J. Chem. Phys. 1996, 105, 3654-3661. (c)
Vreven, T; Morokuma, K. J. Comput. Chem. 2000, 21, 1419-1432.
(25) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104.
(26) Details were provided in Supporting Information.
(27) Seminal study, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566-1568. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356-5357. (c) Terada, M.; Kanomata, K. Synlett 2011, 1255-1258.
(28) For recent reviews, see: (a) Akiyama, T. In Science of Synthesis, Asymmetric
Organocatalysis 2, Brønsted Base and Acid Catalysts, and Additional Topics, Maruoka,
K. Ed.; Georg Thieme Verlag KG: New York, 2012; Vol. 2, pp 169-217. (b) Terada,
M.; Momiyama, N.; In Science of Synthesis, Asymmetric Organocatalysis 2, Brønsted
Base and Acid Catalysts, and Additional Topics, Maruoka, K. Ed.; Georg Thieme
Verlag KG: New York, 2012; Vol. 2, pp 219-296. (c) Parmar, D.; Sugiono, E.; Raja, S.;
Rueping, M.; Chem. Rev. 2014, 114, 9047-9153.
20
ACS Paragon Plus Environment

Page 21 of 21
ACS Catalysis
1
2
3
4
5
6
7
8
9
(29) Although the benzyl group is freely rotating, there is still significant steric
repulsion caused by two TRIP groups. The other TS model obtained by rotation of the
benzyl group toward the opposite side of the TRIP group is 2.7 kcal/mol less stable than
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
TS11r6s
.
(30) Details were shown in Supporting Information.
21
ACS Paragon Plus Environment