Molecular Design of a Chiral Br?nsted Acid with Two Different Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-Diels-Alder Reaction of Azopyridinecarboxylate with Amidodienes Catalyzed by Chiral Carboxylic Acid-Monophosphoric Acid

Article abstract of DOI:10.1021/jacs.6b07150

A chiral Br?nsted acid containing two different acidic sites, chiral carboxylic acid-monophosphoric acid 1a, was designed to be a new and effective concept in catalytic asymmetric hetero-Diels-Alder reactions of azopyridinecarboxylate with amidodienes. The multipoint hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarboxylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excellent stereocontrol in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels-Alder reactions by chiral Br?nsted acid catalysis.

Full text of DOI:10.1021/jacs.6b07150

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Article
Molecular Design of a Chiral Brønsted Acid with Two Different
Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-
Diels–Alder Reaction of Azopyridinecarboxylate with Amidodienes
Catalyzed by Chiral Carboxylic Acid–Monophosphoric Acid
Norie Momiyama, Hideaki Tabuse, Hirofumi Noda, Masahiro Yamanaka,
Takeshi Fujinami, Katsunori Yamanishi, Atsuto Izumiseki, Kosuke Funayama,
Fuyuki EGAWA, Shino OKADA, Hiroaki Adachi, and Masahiro Terada
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07150 • Publication Date (Web): 16 Aug 2016
Downloaded from http://pubs.acs.org on August 16, 2016
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Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
Molecular Design of a Chiral Brønsted Acid with Two Different
Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-Diels–
Alder Reaction of Azopyridinecarboxylate with Amidodienes Cata-
lyzed by Chiral Carboxylic Acid–Monophosphoric Acid
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
,
†,‡
§
||
||
†
Norie Momiyama,* Hideaki Tabuse, Hirofumi Noda, Masahiro Yamanaka, Takeshi Fujinami,
†
†,‡
§,#
§
¶
Katsunori Yamanishi, Atsuto Izumiseki, Kosuke Funayama, Fuyuki Egawa, Shino Okada, Hi-
¶
,§,
⊥
roaki Adachi, Masahiro Terada*
†
Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
‡
§
SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Department of Chemistry, Faculty of Science, Rikkyo University, Toshima-ku, Tokyo, 171-8501, Japan
|
|
#
Graduate Research on Cooperative Education Program of IMS with Tohoku University, Okazaki, Aichi 444-8787, Japan
¶
SOSHO, Inc., 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
⊥Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
ABSTRACT: A chiral Brønsted acid containing two different acidic sites, chiral carboxylic acid–monophosphoric acid 1a, was
designed to be a new and effective concept in catalytic asymmetric hetero-Diels–Alder reactions of azopyridinecarboxylate with
amidodienes. The multi-point hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarbox-
ylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excel-
lent stereo control in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels–
Alder reactions by chiral Brønsted acid catalysis.
INTRODUCTION
G
Chiral Brønsted acid catalysis has recently been recognized
1
as one of the fundamental tools in asymmetric synthesis. A
number of useful chiral Brønsted acids have been developed
with appropriate acidic functional groups. Many such catalysts
incorporate two of the same type of acidic functional groups,
while others have one acidic site in a seven-membered ring
structure, such as those in binaphthyl systems. Furthermore,
combinations of these have effectively produced powerful
CO H
2
O
O
P
OH
O
G'
Figure 1. (R)-1,1′-Bi-naphthol-derived chiral carboxylic acid–
monophosphoric acid.
2
chiral Brønsted acid catalysts. In this context, we have been
fascinated for some time with the development of hetero-
elaborate the chiral environment using properly oriented mul-
tiple hydrogen bonds during catalysis. Describing primary
interactions, an intramolecular hydrogen bond between car-
boxylic acid and monophosphoric acid would allow the cata-
3
combined Brønsted acid catalyst systems, with a particular
4
focus on combinations of monophosphoric acids with other
5
Brønsted acids. Despite having the potential for unprecedent-
ed catalytic activity because of a distinctive hydrogen-bond
interaction using each acidic functional group, such a design
concept remains poorly studied in the development of chiral
Brønsted acid catalysts.
lyst to establish a favorable diastereomeric structure for high
3c,3d,6
stereoselectivities
(Figure 2). This intramolecular hydro-
gen bond design would not only regulate the diastereomeric
catalyst structure, but the acidity of the catalyst would be in-
creased, enabling catalytic activity that would be entirely
unique when compared to chiral Brønsted acids with one acid-
ic functional group. Intermolecular hydrogen bonds among the
catalyst, the substrate, and the reactant are responsible for
facilitating the bond-forming reaction. In addition, we envi-
sioned that a secondary, weaker interaction would exist as an
intermolecular hydrogen bond between the acidic functional
6
Encouraged by recent reports from our group, we became
7
interested in hydrogen bond-mediated multi-point control
with two different acidic functional groups in catalytic asym-
metric reactions. We report herein a chiral Brønsted acid cata-
lyst with two different acidic sites, carboxylic acid–
monophosphoric acid (Figure 1), designed specifically to
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
groups and Lewis basic sites of the substrates, and this would comparison, the reaction in the absence of catalyst yielded not
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
contribute to the stereo- and regioselectivity of the reaction.
only 5a but also a considerable amount of 6a (entry 6). Finally,
when the reaction was conducted in the presence of chiral
monophosphoric acid 2, the yield and stereoselectivity de-
creased significantly (entry 7). These observations clearly
indicate the significant effects of carboxylic acid–cyclic
monophosphoric acid 1a in this transformation.
Multi-point Control via
Intra- and Intermolecular Hydrogen Bond
1
7
δ−
*
B
H
A
H
ZH
Table 1. Catalytic Enantioselective Hetero-Diels–Alder
Reaction of 2-Azocarboxylate with Amidodienes
Y
δ+
a
X
Substrate
Reactant
NHCbz
NHCbz
NHCbz
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
catalyst
(10 mol %)
R
:
Primary Interaction
*
R
Cbz
·
··
N
N
*
+
N
N
+
N
N
Intramolecular Hydrogen Bond
ClCH CH Cl
2
2
Cbz
·
establish the favorable diastereomeric catalyst structure
Cbz
R
–
20 °C, 48 h
· enhance the acidity of activation site
4
a
3
5
6
Intermolecular Hydrogen Bond
· facilitate the bond-forming reaction
Ph
SiPh3
3a : R = Cbz
·
····: Secondary Interaction
CO2H
O
O
O
O
O
R
Intermolecular Hydrogen Bond
P
P
6
·
elaborate chiral environment for high stereoselectivities
OH
OH
O
N
Py :
2
SiPh3
SiPh3
Figure 2. Design concept of a chiral Brønsted acid with two dif-
ferent acidic sites: Multi-point control by intra- and intermolecu-
1
a
2
3b: R = Py (R = H)
3
c : R = Py (R = Me)
lar hydrogen bond. AH/BH indicates either CO
2 3
H/PO H or
3d: R = Py (R = CF3)
PO H/CO H. X/Y/Z indicates Lewis basic sites such as O, N, etc.
3
2
d
ee (%)
b
c
entry
catalyst
3
yield (%)
5:6
RESULTS AND DISCUSSION
. Enantioselective Hetero-Diels–Alder Reaction of Azo-
5
6
1
1
2
3
4
1a
1a
3a
3b
3c
3d
3d
3d
3d
<1
41
61
52
89
49
25
—
2.4:1
>9:1
>99:1
>99:1
1:2
—
carboxylates with N-H-Amidodienes. Enantioselective het-
79
88
97
99
—
32
74
—
—
—
—
29
8
ero-Diels–Alder reactions of azocarboxylates with N-H-
1a
amidodienes were selected as an initial probe to test the hy-
pothesis that multiple hydrogen bonds will provide enhanced
1a
9,10
reactivity and selectivity in catalysis.
Initial experiments
e
5
1a
used two types of azocarboxylates, 3a and 3b, as the hydrogen
bond acceptors with the carboxylic acid–monophosphoric acid
f
6
none
2
g
1
a (Table 1, entries 1 and 2). The reaction of dibenzyl azodi-
7
1.9:1
carboxylate (3a) gave no Diels–Alder product at –20 °C in
a
1
1
Reactions were conducted with 1.0 equiv 3 and 1.0 equiv 4a in
the presence of 10 mol % catalyst in 1,2-dichloroethane at –20 °C
1,2-dichloroethane (entry 1). On the other hand, the reaction
1
2
of 2-azopyridinecarboxylate (3b), which contained a rela-
tively basic pyridine nitrogen when compared with the car-
bonyl oxygen of the Cbz group, gave rise to products 5 and 6
b
c
1
d
for 48 h. Isolated yield. Determined by H NMR. Determined
by chiral HPLC. Reaction was conducted with 1.0 equiv 3 and
2
chloromethane at –60 °C for 24 h. Reaction was conducted at
room temperature for 12 h. Reaction was conducted with 1.0
2 2
equiv 3 and 2.0 equiv 4a in CH Cl at –40 °C.
e
.0 equiv 4a in the presence of MS 4Å and 5 mol % 1a in di-
1
3,14
(
entry 2).
Although the reaction of 3b was not fruitful with
f
g
regard to yield and regioselectivity, the observed ee of both
1
5
regioisomers were quite high. To confirm the role of the
1
2b,16
pyridine nitrogen,
the reaction of 2-azophenylcarboxylate
To gain further insight into the importance of the phosphoric
acid and carboxylic acid groups of the catalyst, as well as the
N–H proton of the amidodiene, we conducted experiments
varying these functional groups (Table 2). Methylcarboxylate–
phosphoric acid 1b and carboxylic acid–phosphoric acid
methylester 1c were synthesized, and the reactions of 3d with
was attempted, and no product was observed under the same
conditions. These experiments reveal that hydrogen bond ac-
ceptor such as pyridine nitrogen is the requirement in 1a-
catalyzed azo-hetero-Diels–Alder reaction.
To improve the stereoselectivity in the system of 2-
azopyridinecarboxylate, substitution at the 6-position of the 2-
azopyridine was explored; a substituent at the vicinal position
of pyridine nitrogen was expected to favorably influence the
chiral environment of the transition state (entries 3 and 4).
Fascinatingly, improvements in both the regio- and enantiose-
lectivities were indeed realized with the reaction of 3c and 3d.
The best result was obtained with the reaction of 6-
trifluoromethyl-2-azopyridinecarboxylate (3d), providing
product 5a with 97% ee as a single regioisomer (entry 4). Fi-
nally, high yields and complete regio- and enantioselectivities
were achieved under the optimized reaction conditions, i.e., 2
equiv of 4a and 1 equiv of 3d were stirred in the presence of
molecular sieves 4Å and 5 mol % 1a at –60 °C (entry 5). For
4
a were examined in the presence of these catalysts (entries 1
and 2). We confirmed that the carboxylic acid moiety signifi-
cantly affected the reactivity and selectivity of the present azo-
hetero-Diels–Alder reaction; replacement of the carboxylic
acid with a methylcarboxylate considerably decreased not only
the yield but also the regio- and enantioselectivities (entry 1 vs.
2
, compare also with entry 7 of Table 1). Moreover, methyl
phosphate 1c was unable to catalyze the reaction under the
same conditions (entry 3). We also found that the reaction
with N-Me-amidodiene 4a′ gave excellent regioselectivities,
albeit with extremely poor catalytic and chiral efficiency (en-
18
try 4). These results strongly imply that the phosphoric acid–
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a,b,c
carboxylic acid moieties, the 6-trifluoromethylpyridine sub-
stituent, and the N–H of the amidodienes are required to facili-
Chart 1. Reaction Scope
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NHG2
tate both the selectivity and reactivity of the reaction. We pre-
sume the intra- and intermolecular hydrogen-bonding interac-
tions among these contribute to creating the chiral environ-
ment to produce the excellent regio-, diastereo-, and enantiose-
lectivity of this reaction.
NHG2
1
a
CF3
6
Py
N
N
(5 mol %)
Py
+
R2
N
N
N
Py :
R1
MS 4Å
CH2Cl2
R2
2
R1
–
60 °C
4
3
5
a
NHCbz
NHG2
Table 2. Control Experiments
Py
Py
N
N
N
N
1
NG Cbz
1
1
NG Cbz
NG Cbz
1
Py
R1
Cbz
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
(5 mol %)
*
Py
*
Cbz
+
N
N
N
G2 = CO CH Ar
+
2 2
5
e: 91%, 99% ee
5a: R = Cbz 89%, 99% ee
1
(Ar: 4-BrC H )
6 4
MS 4Å
CH Cl
Cbz
N
5b: R = Boc 77%, 99% eed
5c: R1 = Fmoc 76%, 98% eed
1
5f: G2 = Boc
41%, 98% eef
Cbz
Py
2
2
a : G1 = H
a': G1 = Me
–60 °C, 24 h
5a : G1 = H
5a': G1 = Me
6a : G1 = H
6a': G1 = Me
5g: G2 = CO Me
62%, 98% eef
4
4
3d
2
5d: R1 = Troc 47%, 98% eee
5h: G2 = Troc
97%, 98% eef
NHCbz
NHCbz
Py
Ph
CO R
Ph
Py
N
N
N
CO H
2
2
N
Cbz
R2 >99:1 dr
O
O
O
R2
O
O
Cbz
P
P
OH
OMe
5i: R2 = Me 82%, 89% ee
j: R2 = Bn 80%, 93% ee
5k: R2 = Me 84%, 98% eeg
O
5l: R2 = n-Pr 82%, 97% eeh
5
SiPh3
SiPh3
5m: R2 = Ph 65%, 99% eei
1
1
a (R = H)
b (R = Me)
1c
NHCbz
NHCO CH Ar
2
2
NHCbz
Py
d
Py
N
ee (%)
N
N
Me
Me
Py
1
yield
c
N
N
entry
1
G
b
5:6
N
Cbz
(
%)
5
6
Cbz
Cbz
Me
1
2
3
4
1a
1b
1c
1a
H
H
89
29
<1
10
>99:1
2.2:1
—
99
6
—
11
—
—
5
n
5o
5p
(
Ar: 4-BrC H )
96%, 77% eej
58%, 94% eek
6
4
78%, 98% eeg
>99:1 dr
>99:1 dr
H
—
36
a
Me
>99:1
Reactions were conducted with 1.0 equiv 3 and 2.0 equiv 4 in the
presence of 5 mol % catalyst and MS 4Å in CH Cl at –60 °C for
4 h. Isolated yield. Determined by chiral HPLC. 45 h. 55 h.
a
2
2
Reactions were conducted with 1.0 equiv 3d and 2.0 equiv 4a in
the presence of 5 mol % catalyst and MS 4Å in CH Cl at –60 °C
for 24 h. Isolated yield. Determined by chiral HPLC.
b
c
d
e
2
f
g
h
i
2
2
4
–
0 h. –40 °C, 48 h. –40 °C, 72 h. 10 mol %, –20 °C, 72 h. ꢀ ꢀ
b
c
j
k
60 °C, 72 h. 10 mol %, –40 °C, 48 h.
The scope of the azo-hetero-Diels–Alder reaction was inves-
tigated (Chart 1). High enantiomeric excess was observed with
a—5h regardless of the acyloxy group on both 2-
TS models in which 3d and 4a are activated by the phosphoric
acid moiety of 1a. Based on the previously reported theoretical
5
6b
study of the bis-phosphoric acid catalysis, various coordina-
azopyridines 3 and amidodienes 4. Moreover, a variety of 3-
and 4-substituted amidodienes were applicable to give 5i—5n
in good yields, with high enantioselectivities. In the cases of 4-
substituted compounds, the products 5k—5n were obtained as
single diastereomers. When 2,3-disubstituted amidodiene was
used, the enantiomeric excess of 5o dropped significantly. In
contrast, 3,4-disubstituted amidodiene gave 5p in high enanti-
omeric excess, but the yield was moderate.
tion models were explored (Figure 3(a)). There are two possi-
bilities of the carboxylic acid-bridged 1a structures: 1a-model
A and 1a-model B. In spite of the thermodynamic stability of
a-model B, the most energetically favored TS structures in-
clude 1a-model A (see Supporting Information). This is due to
1
6,21
the enhancement of the acidity while keeping the basicity in
the phosphoric acid and phosphoryl oxygen residues, both
which induce the strong interaction with 3d and 4a. Regarding
diastereomeric TSs derived from 1a-model A corresponding to
the enantiofacial selection of 4a (leading to (R) and (S) enanti-
omers of 5a, TSr, and TSs), the relative orientation of 3d
(TS_endo, TS_exo), and three coordination modes (TS1:
2. Computational Study by Density Functional Theory
(DFT) Calculations. To explore the hydrogen-bonding net-
work in the present catalysis, theoretical investigations of the
detailed transition state (TS) models were conducted on the
1
0
2
0
3
0
1
a-catalyzed reaction of 3d with 4a using density functional
N ,H ; TS2: O , H ; TS3: N , H ) were compared (Figure 3(b),
see Supporting Information). TSr3_endo leads to the major
1
9
22
theory (DFT) calculations. Regarding the axial chirality of
the phenyl–naphthyl axis in 1a, both DFT calculations and X-
ray diffraction analysis showed the (S)-configuration is more
stable than the (R)-configuration due to the intervention of
hydrogen bond between carboxylic acid and monophosphoric
(R)-enantiomer and is energetically most favored of all of the
diastereomeric TSs. For TSs leading to the minor (S)-
enantiomer, TSs2_endo and TSs3_exo are located at a similar
energy level, albeit 4.9 kcal/mol and 3.9 kcal/mol less stable,
respectively, than the most stable TSr3_endo. These computa-
tional results are qualitatively consistent with the experimental
results. In the energetically disfavored TS1_endo, pyridinium
phosphate is formed through the proton transfer from the
20
acid. The control experiments shown in Table 2 suggest that
the phosphoric acid moiety is needed to promote the present
azo-hetero-Diels–Alder reaction and the carboxylic acid moie-
ty plays an important role for achieving the high chemical
yields and selectivities. Under this hypothesis, we focused on
2
3
phosphoric acid moiety.
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(a) TS models (Combination of catalyst and substrates)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
:
acidic site
: basic site
O
O
O
O
O
H0
N3 N1 CF3
O
O
SiPh3
O
H
O
SiPh3
N
OBn
H
P
P
BnO
N
Ph
Ph
O
O
O
O
O2
H
H
1a-model A
1a-model B
3d
4a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
b) Energetically favored diastereomeric TSs (based on 1a-model A)
*
*
*
*
*
O
O
O
O
O
O
O
O
O
O
O
O
O
O
P
O
P
O
P
O
O
O
O
O
O
O
O
O
H
O
H
O
O
H
H
H
P
P
O
H
O
H
H
N
H H
N
H
H
Cbz
N
N
Cbz
N
F3C
H
Cbz
H
N
H
F3C
Cbz
O
N Cbz
CF3
N
N
O
N
N
N
N
O
O
N
N
N
O
N
N
N
N
BnO
CF3
OBn
OBn
BnO
OBn F3C
TSr1_endo
11.9 (+11.4)
TSr2_endo
+2.9 (+1.2)
TSr3_endo
0.0 (0.0)
major
enantiomer
TSr2_exo
+9.9 (+9.1)
TSr3_exo
+16.7 (+14.6)
+
TSs1_endo
12.7 (+13.1)
TSs2_endo
+4.9 (+4.7)
TSs3_endo
+13.1 (+11.3)
minor
enantiomer
TSs2_exo
+7.8 (+5.1)
TSs3_exo
+3.9 (+4.3)
+
Figure 3. (a) Coordination models of diastereomeric TSs and (b) the relative energy differences of energetically favored diastereomeric
1
0
2
0
3
0
TSs. Coordination modes: TS1 (N , H ), TS2 (O , H ), TS3 (N , H ).
To reveal the origin of the high enantioselectivity, the no-
table structural features of the relatively stable TSr3_endo,
TSs2_endo, and TSs3_exo were investigated in detail (Fig-
ure 4). Both 3d and 4a fit well in the chiral space of 1a con-
structed by the intramolecular hydrogen bond between two
acidic functional groups in TSr3_endo. As predicted in our
catalyst design discussed with Figure 2, there exist multiple
secondary interactions—weak intermolecular hydrogen
bonds—between 3d and 1a in TSr3_endo. Furthermore, the
non-classical CH/O hydrogen bonds are formed between the
benzene ring (Cbz) of 3d and the carboxylic moiety of 1a.
The lack of significant steric stress and the formation of the
effective hydrogen-bonding network stabilize TSr3_endo
between the N-Cbz group and the diene moiety, exerts a
significant influence in the stability of TSs3_exo. This is
attributed to destabilization of TSs3_exo. These structural
and distortion/interaction analyses indicate the elaborated
chiral space and the effective hydrogen-bonding network
derived from the two acidic functionalities in 1a synergisti-
cally control the stereoselectivity of 5.
Table 3. Distortion/interaction analysis of TSr3_endo,
TSs2_endo, and TSs3_exo (kcal/mol)
DEFcat
O
O
O
(
Figure 4(a)). In contrast, TSs2_endo, leading to the minor
enantiomer, has unfavorable steric interactions between two
aryl groups (Cbz and 6-trifluoromethylpyridine) of 3d and
O
H
O
SiPh3
P
Ph
O
O
INT
H
H
the sterically demanding SiPh
3
group of 1a. Such steric re-
H
H
O
N
pulsions result in the lack of the hydrogen-bonding network
between 3d and 1a, destabilizing TSs2_endo (Figure 4(b)).
In a manner similar to TSr3_endo, both 3d and 4a are well
oriented in the chiral space of 1a in TSs3_exo without any
unfavorable steric interactions with 1a. As for 4a, however,
the C–N bond rotation leading to the facial selectivity inver-
sion of 4a (i.e., leading to minor enantiomer) induces the
strong steric repulsion between the N-Cbz group and the
diene moiety. This is responsible for destabilization of
TSs3_exo (Figure 4(c)).
Cbz
N
N
DEFsub
N
CF3
a
a
b
entry
1
TS
ΔDEFcat
0
ΔDEFsub
ΔINT
TSr3_endo
TSs2_endo
TSs3_exo
0
0
2
3
a
–6.4
+0.1
+4.8
b
+11.2
+1.5
–2.4
ΔDEF = DEF(TS) – DEF(TSr3_endo). ΔINT = INT(TS) –
INT(TSr3_endo).
To identify the main factor in determining the relative en-
ergy difference among TSr3_endo, TSs2_endo, and
2
4
TSs3_exo, a distortion/interaction analysis was carried out
Table 3). The interaction energy difference between 1a and
d/4a (ΔINT = +11.2 kcal/mol) has a larger impact on desta-
bilization of TSs2_endo than other factors. On the other
hand, the distortion energy difference of 3d/4a (ΔDEFsub
4.8 kcal/mol), mainly derived from the steric interaction
(
3
=
+
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2
3
4
5
6
7
8
9
(a)
(b)
(c)
a : 1.872
b : 2.955
c : 2.049
a : 1.928
b : 2.762
c : 1.918
a : 1.844
b : 2.804
c : 2.071
d : 1.776
e : 2.497
f : 1.567
g : 2.439
h : 2.319
i : 2.696
j : 2.953
O
O
O
O
O
O
g
O
O
SiPh3 d : 1.888
e : 2.507
O
O
SiPh3 d : 1.957
e : 1.637
g
O
H
O
SiPh3
H
H
a
P
a
P
a
P
Ph
Ph
Ph
O
O d
O
O
f : 2.922
g : 2.434
O
O d
f : 1.621
g
H
h
H
h
H
j
j
H
H
d
f
H
H
H
e
H
g : 2.479
h : 2.351
i : 2.752
j : 2.800
e
H
e
H
f
f
N
i
N Cbz
O
i
N
O
O
Cbz
N
N
N O
N
N
O
N
N
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
Cbz
N
N
CF3
CF3
CF3
a
g
g
g
a
e
f
a
e
f
h
h
e
d
j
j
d
f
d
i
i
b
b
b
c
c
c
front view
front view
front view
g
g
h
h
g
j
c
c
c
b
b
b
side view
side view
side view
TSr3_endo (0.0, 0.0)
TSs2_endo (+4.9, +4.7)
TSs3_exo (+3.9, +4.3)
Figure 4. Length of hydrogen bonds, front and side views of 3D structures, the relative energies (in plain, kcal/mol), and the relative Gibbs
free energies (in italics, kcal/mol) of (a) TSr3_endo, (b) TSs2_endo, and (c) TSs3_exo.
interactions among the carboxylic acid, monophosphoric
acid, 2-azopyridinecarboxylate, and N-H-amidodiene moie-
CONCLUSIONS
We have developed a chiral Brønsted acid with two differ-
ent acidic sites, carboxylic acid–monophosphoric acid 1a,
and this novel catalyst structure has proven to be a highly
effective catalyst for asymmetric hetero-Diels–Alder reac-
tions between 6-trifluoromethyl-2-azopyridinecarboxylates
and N-H-amidodienes. The reactions proceed in good yields
and excellent regio-, diastereo-, and enantioselectivities with
a wide range of substituent patterns. A mechanistic study by
DFT calculations revealed the multi-point hydrogen-bonding
ties are key in this catalysis. The two Brønsted acidic sites,
the carboxylic acid and monophosphoric acid groups, coop-
eratively function to result in high catalytic and chiral effi-
ciencies. The present work represents the first successful
design of a combined carboxylic acid–phosphoric acid in
chiral Brønsted acid catalysis, and further studies on chiral
Brønsted acids with different acidic sites are underway in
our laboratories and will be reported in due course.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
Supporting Information
The Supporting Information is available.
*
momiyama@ims.ac.jp, *mterada@m.tohoku.ac.jp
Experimental details, characterization data, HPLC enanti-
omer analysis, NMR spectra for new compounds, X-ray
diffraction analysis, and Cartesian coordinates (PDF)
Crystallographic data of 1a and regioisomers 5e/6 (CIF)
This material is available via the Internet at http://pub.acs.org.
Notes
The authors declare no competing financial interest.
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(
10) For reviews of enantioselective aza-Diels–Alder reaction, see:
(a) Yamamoto, H.; Kawasaki, M.; Bull. Chem. Soc. Jpn. 2007, 80,
95–607. (b) Ukaji, Y. In Comprehensive Chirality, Carreira, E. M.,
Yamamoto, H. Eds.; Elsevier: Oxford, 2012, Vol. 5, pp 470–501.
11) Amidodiene 4a decomposed during the reaction.
12) (a) Srinivasan, V; Jebaratnam, D. J.; Budil, D. E. J. Org. Chem.
ACKNOWLEDGMENTS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Support was partially provided by IMS, JSPS via Grant-in-Aid
for Scientific Research C (No. 23550114) for N.M., and Grant-
in-Aid for Scientific Research on Innovative Area “Advanced
Molecular Transformations by Organocatalysts” from MEXT,
Japan (No. 23105002 for M.T., No. 23105005 for M.Y.)”. We
sincerely thank Dr. Koji Yamamoto, Research Center of Inte-
grative Molecular System, Institute for Molecular Science for
the X-ray crystallographic analysis of 5e, and Fuji Silysia
5
(
(
1999, 64, 5644–5649. (b) Kawasaki, M.; Yamamoto, H. J. Am.
Chem. Soc. 2006, 128, 16482–16483.
(13) (a) Nakamura, S.; Nakashima, H.; Yamanura, A.; Shibata, N.;
Toru, T. Adv. Synth. Catal. 2008, 350, 1209–1212. (b) Nakamura,
S.; Sakurai, Y.; Nakashima, H.; Shibata, N.; Toru, T. Synlett 2009,
1639–1642. (c) Nakamura, S.; Maeno, Y.; Ohara, M.; Yamamura,
A.; Funahashi, Y.; Shibata, N. Org. Lett. 2012, 14, 2960–2963.
(14) For X-ray crystallographic analyses of Brønsted acid–pyridine
complexes, see: (a) Panneerselvam, K.; Hansongnern, K.; Rattana-
wit, N.; Liao, F-L.; Lu, T-H. Anal. Sci. 2000, 16, 1107–1108. (b)
Hashimoto, T.; Kimura, H.; Nakatsu, H.; Maruoka, K. J. Org. Chem.
®
Chemical LTD. for the gift of CHROMATOREX -DIOL. N.M.,
T.F., and K.Y. gratefully acknowledge JST-ACCEL for finan-
cial support. H.T. acknowledges JSPS for a Research Fellow-
ship for Young Scientists. K.F. thanks the Yoshida Scholarship
Foundation.
0
1
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3
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5
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7
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2
3
4
5
6
7
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0
1
2
3
4
5
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7
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9
0
1
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2
(
011, 76, 6030–6037.
15) Absolute configuration of each regioisomer was determined by
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16) (a) Yin, L.; Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Am.
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(
17) The reactions were also attempted in the presence of 10 mol %
(
2) For references of each chiral Brønsted acid catalysts, see the
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with 2,4,6-triisopropylphenyl group: 58% yield, 5a:6a = 19:1, 99%
ee of 5a. In the presence of monophosphoric acid with 3,5-bis-
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(
1
K.; Yamamoto, H. Org. Lett. 2006, 8, 3175–3178. (c) Jones, C. R.;
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18) The reaction of 3d with 1-methoxybuta-1,3-diene was also
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~
40% ee for major regioisomer).
(
4) For representative reviews of chiral phosphoric acid, see: (a)
(19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
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Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant,
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Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jara-
millo, 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. Gaussian 09, Revision D.01.; Gaussian,
Inc.:Wallingford, CT, 2013. Details of DFT calculations are shown
in Supporting Information.
Terada, M. Synthesis 2010, 2, 1929–1982. (b) Akiyama, T. In
Asymmetric Synthesis II, Christmann, M., Brase, S. Eds.; Wiley-
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1, 16976–16979.
(
6) (a) Momiyama, N.; Konno, T.; Furiya, Y.; Iwamoto, T.; Terada,
M. J. Am. Chem. Soc. 2011, 133, 19294–19297. (b) Momiyama, N.;
Funayama, K.; Noda, H.; Yamanaka, M.; Akasaka, N.; Ishida, S.;
Iwamoto, T.; Terada, M. ACS Catal. 2016, 6, 949–956.
(7) For representative reviews of multi-point control by chiral metal
catalyst, see: (a) Matsunaga, S.; Shibasaki, M. Synthesis 2013, 45,
4
5
21–437. (b) Matsunaga, S.; Shibasaki, M. Chem. Commun. 2014,
0, 1044–1057.
(
8) For representative reviews of asymmetric hetero-Diels–Alder
reaction, see: (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39,
3558–3588. (b) Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093–
2
102. (c) Lin, L.; Liu, X.; Feng, X. Synlett 2007, 2147–2157. (d)
(20) Details for X-ray diffraction analysis of 1a, see: Supporting
Information.
Pellissier, H. Tetrahedron 2009, 65, 2839–2877. (e) Masson, G.;
Lalli, C.; Benohoud, M.; Dagousset, G. Chem. Soc. Rev. 2013, 42,
(
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J.; Ren, L.; Gong, L. Z. J. Am. Chem. Soc. 2011, 133, 13504-13518.
22) Both TSr1_exo and TSs1_exo were unable to be optimized by
9
02–923. (f) Du, H.; Ding, K. In Comprehensive Enantioselective
Organocatalysis: Catalysts, Reactions, and Applications, Kalko, P.
I. Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2013,
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hensive Organic Synthesis 2nd ed., Knochel, P., Molander, G. A.
Eds.; Elsevier: Oxford, 2014, Vol. 5, pp 409–465.
(
structural and geometric restrictions.
(23) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem.
Soc. 2007, 129, 6756-6764.
(
24) The energies of TS were dissected into the distortion (DEF)
(
9) For representative examples of enantioselective azo-hetero-
and interaction energies (INT) for the two distorted fragments (1a
and 3d/4a) constructing TS. The differences for each energies
Diels–Alder reactions, see: (a) Aburel, P. S.; Zhuang, W.; Hazell, R.
G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2344–2349. (b)
Liu, B.; Li, K-N.; Luo, S-W.; Huang, J-Z.; Huan, P.; Gong, L-Z. J.
Am. Chem. Soc. 2013, 135, 3323–3326. (c) Liu, B.; Liu, T-Y.; Luo,
S-W.; Gong, L-Z. Org. Lett. 2014, 16, 6164–6167.
(
DDEF and DINT) among diastereomeric TSs were calculated by
the counterpoise method. The original distortion/interaction analysis,
see: (a) Morokuma, K.; Kitaura, K. in Chemical Applications of
Atomic and Molecular Electrostatic Potentials, Politzer, P., Truhlar,
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Houk, K. N. Angew. Chem., Int. Ed. 2011, 50, 10366-10368. (f)
1
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Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646–10647; (c) Ess, D.
H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187–10198. (d)
Lam, Y.-H.; Cheong, P. H.-Y.; Blasco Mata, J. M.; Stanway, S. J.;
Gouverneur, V.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 1947–
Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc.
2014, 136, 4575–4583.
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957. (e) Paton, R. S.; Kim, S.; Ross, A. G.; Danishefsky, S. J.;
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CF3
Ph
NHG
G
G
N
NH
NH
CO H
2
R1
+
O
O
Py
+
*
N
N
O
N
N
P
R2
N
OH
N
R1
R2
R1
R2
Py
SiPh3
Mul$%point+Control+via+Hydrogen+Bond+
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single+regioisomer+
up+to+99ꢀ+ee,+>9:1+dr+
8
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