Chiral Supramolecular U-Shaped Catalysts Induce the Multiselective Diels-Alder Reaction of Propargyl Aldehyde

Article abstract of DOI:10.1021/jacs.8b09974

The Diels-Alder reaction, which is a traditional [4 + 2] cycloaddition with two carbon-carbon bond formations, is one of the most powerful tools to synthesize versatile and unique six-membered rings. We show that chiral supramolecular U-shaped boron Lewis acid catalysts promote the unprecedented multiselective Diels-Alder reaction of propargyl aldehyde with cyclic dienes. Independent from the substrate control, enantio-, endo/exo-, π-facial-, regio-, site-, and substrate-selectivities could be controlled by the present U-shaped catalysts. The obtained reaction products could access the concise synthesis of chiral diene ligands and a key intermediate of (+)-sarkomycin. The results presented here might partially contribute to the development of artificial enzyme-like supramolecular catalysts for multiselective reactions, which will be able to target organic compounds that have thus far eluded synthesis.

Full text of DOI:10.1021/jacs.8b09974

Subscriber access provided by University of Sunderland
Article
Chiral Supramolecular U-Shaped Catalysts Induce the
Multiselective Diels–Alder Reaction of Propargyl Aldehyde
Manabu Hatano, Tatsuhiro Sakamoto, Tomokazu Mizuno, Yuta Goto, and Kazuaki Ishihara
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09974 • Publication Date (Web): 07 Nov 2018
Downloaded from http://pubs.acs.org on November 7, 2018
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 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 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.
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 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Chiral Supramolecular U-Shaped Catalysts Induce the Multiselective
Diels–Alder Reaction of Propargyl Aldehyde
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
Manabu Hatano, Tatsuhiro Sakamoto, Tomokazu Mizuno, Yuta Goto, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
ABSTRACT: Diels–Alder reaction, which is a traditional [4 + 2] cycloaddition with two carbon–carbon bond formations, is one of
the most powerful tools to synthesize versatile and unique 6-membered rings. We show that chiral supramolecular U-shaped boron
Lewis acid catalysts promote the unprecedented multiselective Diels–Alder reaction of propargyl aldehyde with cyclic dienes. Inde-
pendent from the substrate-control, enantio-, endo/exo-, p-facial-, regio-, site-, and substrate-selectivities could be controlled by the
present U-shaped catalysts. The obtained reaction products could access to the concise synthesis of chiral diene ligands and a key
intermediate of (+)-sarkomycin. The results presented here might partially contribute the development of artificial enzyme-like
supramolecular catalysts for multiselective reactions, which will be able to target organic compounds that have thus far eluded syn-
thesis.
Substrate-control
Chiral cavity-control
INTRODUCTION
(a)
(R)-5·2B(C6F5)3
(10 mol%)
The control of multiple selectivities is one of the most challeng-
ing subjects in modern organic chemistry. In this regard, the
CHO
Me
Me
+
(for 2a)
CHO
unusual endo-3a
83%, 99% ee
normal exo-4a
(By steric factor)
Diels–Alder (DA) reaction is a significant tool for the total syn-
+
1–8
thesis of complex organic molecules.
Nevertheless, the DA
R
CHO
(R)-6·2B(C6F5)3
(10 mol%)
reaction shows relatively strong substrate-dependence based
2a (R = Me)
2b (R = H)
1
CHO
+
9–11
H
on the HOMO/LUMO-frontier orbital theory,
and uni-
H
(for 2b)
CHO
versal control of multiselectivity is very difficult. When actual-
ly used in the DA reaction, conventional chiral catalysts can
discriminate the prochiral enantioface (i.e., re/si-face) of a
dienophile regardless of the diene (two-dimensional discrimi-
nation). However, most of them cannot control the diastereo-
(i.e., endo/exo-), p-facial-, regio-, site-, nor substrate-selectivity,
since this would require the three-dimensional discrimination
of isomeric transition-state structures. In general, enzymes in
vivo can realize such multiselectivity among a myriad of other
possibilities by using a chiral cavity, which provides a three-
unusual exo-4b
80%, 94% ee
normal endo-3b
(By orbital factor)
(b)
Deep & narrow
cavity
C6F5
C6F5
2nd. orbital
advantage
H
H
O
B
C6F5
CF3
O
O
P
O
O
Steric
hinderance
H
B
O
Me
O
CF3
C6F5
O
P
B
B
O
12
dimensional space that includes an active site. The cavities
C6F5
C6F5
Enantio-
of enzymes are conformationally flexible to catch substrates
and release products (induced fit function). To overcome the
limited selectivity due to the small cavity and conformational
Endo/exo-
(R)-5·2B(C6F5)3
selectivities
Ar
(c)
rigidity of conventional chiral Lewis acid catalysts, supramo-
Ar
Shallow & wide
cavity
13–16
lecular catalysts,
which are prepared in situ from small
C6F5
C6F5
N
H
H
components by coordinating bonds, have been considered.
Indeed, there are a few examples of the use of supramolecular
O
B
C6F5
Br
O
O
No 2nd. orbital
advantage
H
O-shaped catalysts that induce unusual reactivity and/or selec-
B
17–23
tivity in DA reactions.
However, their inherent catalytic
H
O
Br
C6F5
B
O
activities are sometimes reduced due to their conformationally
rigid structures. In contrast, we envisioned that chiral supra-
molecular U-shaped catalysts, which are more conformationally
flexible than O-shaped catalysts, can induce high catalytic activi-
ty with unusual multiselectivity. Here we show, for the first
B
N
C6F5
C6F5
Enantio-
Ar
(R)-6·2B(C6F5)3
Endo/exo-
Ar
selectivities
(Ar = 3,5-Me2-4-Oi-Pr-C6H2)
24
time, that an asymmetric DA reaction of propargyl aldehyde
Figure 1. Outline of our previous chiral cavity-controlled Diels–
Alder (DA) reaction of acroleins 2 with cyclopentadiene 1. (a)
Previous results for the catalyst-controlled endo/exo-selective DA
reaction using chiral U-shaped catalysts. (b) Endo-induced chiral U-
shaped catalyst (R)-5•2B(C6F5)3. (c) Exo-induced chiral U-shaped
catalyst (R)-6•2B(C6F5)3.
with cyclic dienes, triene, and tetraene can be controlled so as
to provide multiselectivity by using chiral supramolecular U-
25
shaped catalysts, which should hold great potential for the
non-enzymatic construction of fundamental and unusual mol-
ecules.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
(a)
BF3·Et2O
(10 mol%)
1
2
3
4
O
CHO
CHO
1
CHO
+
+
+
H
faster
CH2Cl2, MS 4Å
–78 °C, 5 h
slower
CHO
1
7
8
9, 32%
10, 14%
11, 43%
5
6
7
8
9
Favored
exo-
approach
of 1
(b)
8
Substrate-
selectivity
Disfavored
endo-
approach
of 1
1
7
1
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
H
H
H
Enantio-
O
O
B
O
B
Endo/exo-
B
selectivities
-Chiral cavity can control exo-induced 1st. Diels–Alder reaction.
-Chiral cavity can prevent 2nd. Diels–Alder reaction (Substrate-selectivity).
Figure 2. General strategy for the present multiselective DA reaction of propargyl aldehyde 7 with cyclopentadiene 1. (a) A control exper-
iment using BF3•Et2O in the reaction between 1 and 7. (b) Multiselective induction in the DA reaction of 7 with 1 with the use of chiral
supramolecular U-shaped catalysts.
In general, endo/exo-selectivity in the DA reaction strongly
depends on the substrates used (Figure 1a).
we have previously succeeded in the enantio- and endo/exo-
selective DA reactions of acroleins 2 with cyclopentadiene 1
induced by chiral supramolecular U-shaped catalysts, (R)-
visioned that our exo-induced chiral supramolecular U-shaped
catalysts would control such the enantio-, endo/exo-, and sub-
strate-selectivities through a conformationally flexible chiral
cavity with reasonable turnover, as if an artificial enzyme-like
cavity with three-dimensional stereocontrols under non-
aqueous conditions (Figure 2b).
26,27
In this regard,
25
5•2B(C6F5)3 and (R)-6•2B(C6F5)3 (Figures 1b and 1c). These
catalysts are prepared in situ from 3,3’-Lewis base-
functionalized chiral BINOL, arylboronic acid, and
tris(pentafluorophenyl)borane, and the size of the U-shaped
cavity can be tuned for each substrate: (R)-5•2B(C6F5)3, which
has a deep and narrow chiral cavity, gives catalyst-controlled
unusual endo-product 3a with 99% ee from methacrolein 2a
overriding of intrinsic exo-product 4a, whereas (R)-6•2B(C6F5)3
which has a shallow and wide chiral cavity, gives catalyst-
controlled unusual exo-product 4b with 94% ee from acrolein
RESULTS AND DISCUSSION
At the beginning of the study, we examined the previous en-
25
do-induced catalyst (R)-5•2B(C6F5)3 and exo-induced catalyst
(R)-6•2B(C6F5)3 in the reaction of 7 with 1 in dichloro-
methane with molecular sieves (MS) 4Å at –78 °C for 3 h (Ta-
ble 1, entries 1 and 2). As a result, (R)-5•2B(C6F5)3 showed a
poor result (entry 1). In contrast, the desired 1 DA-adduct 8
was actually obtained in 60% yield with 54% ee with the use
of (R)-6•2B(C6F5)3, but the undesired 2 DA-adducts 9–11
25
st
25
2b overriding of intrinsic endo-product 3b. Notably, the cen-
tered Lewis acidity of these catalysts was enhanced based on
the concept of a Lewis acid-assisted Lewis acid (LLA).
nd
and further reacted byproducts were also obtained (entry 2).
The size of the possible chiral cavity of the U-shaped catalysts
can be tuned by modification of the amide moieties and aryl-
boronic acid, since the distance between the two coordinated
B(C6F5)3 in a syn-relationship can be controlled by the steric
hindrance between two amide moieties and arylboronic acid
moieties. After the thorough optimization (see the SI, pages
S8–9 and S14–S15), 8 was obtained in 95% yield with 90% ee,
particularly when (R)-12a•2B(C6F5)3, which involves flat isoin-
doline-derived amides, was used (entry 3). Remarkably, >1
gram scale synthesis could be achieved with the reduced cata-
lytic amount (5 mol%) (entry 4). Ultimately, the more reduced
catalytic amount (2.5 mol%) was still effective, and 8 was ob-
tained in 90% yield with 90% ee (entry 5). The fine-tuning of
the aryl boronic acid part should also be important, and (R)-
12b•2B(C6F5)3 was much less effective than (R)-12a•2B(C6F5)3
in terms of the yield (49%), although the ee value was essential-
ly the same (89% ee) (entry 6).
28
In this context, we are currently interested in whether or
not these chiral supramolecular U-shaped catalysts can control
multiselectivities in DA reactions. Thus, we focused on a reac-
tion of propargyl aldehyde 7 with cyclopentadiene 1. To the
best of our knowledge, there has been only one prior study
with a chiral boron Lewis acid catalyst reported by Yamamoto
24
et al., although there are some examples of the use of alkynes
29,30
24
other than 7.
According to Yamamoto’s report, the de-
sired DA adduct 8 was obtained with 95% ee but in only 28%
yield due to the overreaction of 8 with 1. Indeed, our prelimi-
nary investigation of the DA reaction of 7 with 1 in the pres-
ence of BF3•Et2O (10 mol%) shows that the 2 DA reaction
was much faster than the 1 DA reaction and the 2 DA ad-
nd
st
nd
31
ducts (i.e., sesquinorbornadienes ) 9–11 were exclusively ob-
tained (Figure 2a, also see the Supporting Information (SI),
pages S10–S11). To avoid undesired overreactions, a catalyst
must control the substrate-selectivities of 7 and 8. Moreover,
24
Unfortunately, conformationally flexible (R)-12a•2B(C6F5)3
was not suitable for crystallization for X-ray analysis to give
crucial structural evidence, although NMR and ESI-MS anal-
yses could provide some information (see the SI, pages
as indicated by Yamamoto’s report, although the endo/exo-
selectivity is reflected convergently in the enantioselectivity, the
exo-transition state might be favored because of the secondary
repulsive HOMO–LUMO orbital interaction in the endo-
32
transition state (see the SI, pages S11–S13). Overall, we en-
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
(a)
(b)
Table 1. Initial Catalyst Screening and Mechanistic Consid-
eration in the DA Reaction of Propargyl Aldehyde 7 with Cy-
1
2
3
4
5
6
7
clopentadiene 1 by Using Chiral Supramolecular U-Shaped
Catalysts
F
a
E
catalyst
(10 or 5 mol%)
O
+
H
CH2Cl2, MS 4Å
E
E
–78 °C, 3 h
1
7
8
9
CHO
+
CHO
CHO
+
+
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
CHO
11
8
9
10
Figure 3. Theoretical study by a molecular mechanics method
for model compound (R)-15•H2O. Two hydrogen atoms of H2O
are omitted for clarity. (a) Top view. (b) Side view.
C6F5
C6F5
C6F5
C6F5
N
N
B
C6F5
B
C6F5
O
O
O
O
O
O
B
B
Possible chiral cavity
Possible chiral cavity
O
O
ArF
B
ArF
B
ArF
ArF
O
O
O
O
ArF
ArF
ArF
B
B
ArF
C6F5
C6F5
ArF
ArF
ArF
ArF
N
N
C6F5
C6F5
B
C6F5
C6F5
H
O
B
H
O
O
N
O
O
N
O
O
N
O
(R)-12a·2B(C6F5)3
(R)-12b·2B(C6F5)3
B
B
H
H
O
O
O
N
O
Active point
Active point
H
H
O
O
C6F5
C6F5
C6F5
C6F5
TS-13 (ArF = C6F5)
TS-16 (ArF = C6F5)
N
N
B
C6F5
B
C6F5
Enantio-
Endo/exo-
Enantio-
Endo/exo-
O
O
O
O
Substrate-
Substrate-
selectivities
selectivities
O
O
B
B
Figure 4. Possible transition states of the chiral supramolecular
U-shaped catalysts (R)-12a•2B(C6F5)3 without the macrocyclic
structure (TS-13) and (R)-15•2B(C6F5)3 with the macrocyclic
structure (TS-16).
O
O
O
O
O
O
B
B
C6F5
C6F5
N
N
C6F5
C6F5
C6F5
C6F5
(R)-15·2B(C6F5)3
(R)-14·2B(C6F5)3
S22–S27). To confirm the possible syn-B(C6F5)3/B(C6F5)3-
conformation of (R)-12a•2B(C6F5)3, we designed alkyl-chain-
linked catalyst (R)-15•2B(C6F5)3, which cannot geometrically
give an anti-B(C6F5)3/B(C6F5)3-conformation. The possible syn-
B(C6F5)3/B(C6F5)3-conformation of catalysts (or their transition
states) can be strongly assumed based on a preliminary theo-
retical study by a molecular mechanics method for the boron
BINOLate aqua complex (R)-15•H2O as a model unit (Figure
3, also see the SI, pages S35–S39). Although (R)-15•H2O does
not have two coordinated B(C6F5)3 molecules, (R)-15•H2O
alone clearly showed the syn-C=O/C=O-conformation. As
expected, the reaction proceeded smoothly even with the use
of (R)-15•2B(C6F5)3, and 8 was obtained in 72% yield with
80% ee (Table 1, entry 8). This result was comparable to the
result with the use of non-alkyl-chain-linked (R)-14•2B(C6F5)3
in a control experiment (80% yield and 81% ee of 8) (entry 7).
Therefore, the postulated TS-16, and thus TS-13, should be
acceptable based on the possible syn-B(C6F5)3/B(C6F5)3-
conformation (Figure 4).
Yield and
ee of 8
Yield of
9–11
32%
12%
3%
4%
3%
21%
9%
8%
Entry
Catalyst (mol%)
1
2
3
4c
5d
6
(R)-5•2B(C6F5)3 (10)
(R)-6•2B(C6F5)3 (10)
(R)-12a•2B(C6F5)3 (10)
(R)-12a•2B(C6F5)3 (5)
(R)-12a•2B(C6F5)3 (2.5)
(R)-12b•2B(C6F5)3 (10)
(R)-14•2B(C6F5)3 (10)
(R)-15•2B(C6F5)3 (10)
24%, –6% eeb
60%, 54% ee
95%, 90% ee
95%, 90% ee
90%, 90% ee
49%, 89% ee
80%, 81% ee
72%, 80% ee
7
8
a
The reaction was carried out with 1 (2.5 mmol), 7 (0.5 mmol),
and catalyst (10 mol%) in dichloromethane with MS 4Å at –78 °C
for 3 h unless otherwise noted. b ent-8 was obtained with 6% ee.
c
12 mmol of 7 was used. 1.37 g of 8 was obtained. d Reaction time
was 5 h.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
(a)
Next, we transformed 8 into synthetically useful optically
R
1
2
3
4
5
6
7
8
active compounds (Figure 5). Pinnick oxidation of 8 and sub-
sequent methylation gave a,b-unsaturated ester 17 in 92%
yield in two steps (Figure 5a). Ester 17 was much more stable
than aldehyde 8 and would be suitable for 1,2- and 1,4-
addition reactions with some nucleophiles. Indeed, 1,2-
O
(R)-12a·2B(C6F5)3
(10 mol%)
R
H
+
+
CH2Cl2, MS 4Å
–78 ºC, 5–16 h
21 22
40:60 ~ 50:50
7
33
Inseparable
R
CHO
R
CHO
CHO
CHO
+
addition of methyllithium provided compound 18 in 69%
+
+
34
yield, which is Corey’s chiral diene ligand for asymmetric
R
R
23
Product 26, total yield (ratio of 23:24:25:26 in 1H NMR), and enantioselectivity of 26:
CHO CHO CHO
24
25
26
transition-metal catalysis (Figure 5b). On the other hand, the
addition of benzyl alcohol under conventional basic conditions
gave 1,4-adduct 19a in 93% yield with high diastereoselectivi-
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
35
ty (dr = 98:2). Further transformation of 19a with LiAlH4
Me
n-Pr
i-Pr
26a
92% (0:0:1:99),
95% ee (5 h)
26b
26c
92% (0:0:3:97),
97% ee (7 h)
was conducted to afford 20 in 94% yield, which is a key in-
>99% (0:0:17:83),
89% ee (7 h)
36
termediate of (+)-sarkomycin. Other C-, N-, O-, P-, and S-
nucleophiles could also be used, and the corresponding novel
1,4-adducts 19b–g were selectively obtained via exo-facial ad-
dition (Figure 5c). The transformations to optically active
functionalized norbornenes 19a–g are valuable, since they
have not been synthesized directly in DA reactions using less
CHO
CHO
CHO
Bn
MeO2C
26d
26e
26f
80% (0:0:6:94),
97% ee (16 h)
>99% (0:0:2:98),
98% ee (7 h)
>99% (0:0:19:81),
96% ee (7 h)
37
reactive electron-rich b-substituted acroleins or acrylates.
CHO
CHO
CHO
O
Br
EtO
O
(a)
NaClO2, NaH2PO4•2H2O
2-methyl-2-butene
hydroquinone
26g
26i
93% (0:0:8:92),
97% ee (7 h)
26h
>99% (0:11:6:83),
94% ee (7 h)
84% (0:0:24:76),
96% ee (7 h)
MeI, K2CO3
CO2Me
17 (90% ee)
CHO
THF/H2O, 0 ºC, 2.5 h
DMF, 0 ºC, 4 h
8 (90% ee)
Unstable
92% (2 steps)
(b)
exo-
approach
of 22
Stable
exo-
approach
of 21
R
R
Me Me
(b)
MeLi
OH
THF, –78 ºC
10 min
1,2-addition
18 (90% ee), 69%
Corey's diene ligand
H
17
(90% ee)
O
B
H
BnOH
KH
15-Crown-5
O
O
ref. 36
LiAlH4
OBn
OBn
1,4-addition
Et2O
CO2Me
CH2OH
B
COOH
(+)-Sarkomycin
TS-28, favored
19a (90% ee)
93%, dr = 98:2
20, 94%
TS-27, disfavored
Endo/exo-
Enantio-
Regio-
Substrate-
(c)
1,4-Addition products by other nucleophiles:
selectivities
23
26
O
OMe
NHMe
P(OEt)2
CO2Me
CO2Me
19c (90% ee)
92%, dr = 90:10
CO2Me
(c)
OAc
Ph
19b (90% ee)
97%, dr = 95:5
19d (90% ee)
CHO
PhMgCl
89%, dr = 86:14
THF, –78 ºC to rt, 4 h
then AcCl
Bn
Bn
26d (97% ee)
29, 90%
CH2NO2
CH(CO2Et)2
SBn
CO2Me
CO2Me
CO2Me
Bn
Pd(PPh3)4
HCOOH, NEt3
19e (90% ee)
19f (90% ee)
19g (90% ee)
Bn
>99%, dr = 93:7
83%, dr = 97:3
>99%, dr = 93:7
(R,R)-Bn-nbd*
30 (97% ee), 75%
DMF, rt, 2 h
Figure 5. Transformation of DA adduct 8. (a) Oxidative trans-
formation of unstable 8 to stable ester 17. (b) Transformation to
Corey’s diene ligand 18 and key intermediate 20 for (+)-
sarkomycin. (c) Diastereoselective 1,4-addition to 17 with various
C-, N-, O-, P-, and S-nucleophiles.
Figure 6. Substrate- and regioselective DA reaction with 1-/2-
alkyl-substituted cyclopentadienes 21/22. (a) The DA reaction of
7 with 21/22 by using (R)-12a•2B(C6F5)3. (b) Possible exo-
approaches of 21 (disfavored TS-27) and 22 (favored TS-28) to
the activated 7. A regioselection rule is indicated by the purple
circles due to the theoretical orbital coefficients (see Supplemen-
tary Information). (c) Concise synthesis of Hayashi’s chiral diene
ligand 30 ((R,R)-Bn-nbd*).
Next, we considered the substrate- and regioselective DA
reaction of 7 with 2-alkyl-substituted cyclopentadienes 22
(Figure 6a). Although 22 cannot be isolated from a ca. 1:1
mixture of 1-/2-alkyl-substituted cyclopentadienes 21/22 due
nd
38
26 and numerous (theoretically, up to 64) corresponding 2
DA adducts. (±)-23 and (±)-26 were obtained almost equally
under thermal conditions without catalysts consistent with the
to isomerization, we envisioned that chiral U-shaped catalysts
might be effective to discriminate 22 from 21. In principle,
st
this reaction might give eight-isomeric 1 DA adducts (±)-23–
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
9–11
orbital symmetry/coefficient theory, whereas control exper-
iments with BF3•Et2O, B(C6F5)3, and EtAlCl2 as typical Lewis
acid catalysts provided a complex mixture and (±)-23–26
could not be detected due to the undesired cationic polymeri-
zation of dienes (see the SI, pages S52–S58). In sharp contrast,
(R)-12a•2B(C6F5)3 gave the desired DA adducts 26 in high
yield with high substrate-, enantio-, endo/exo-, and regioselec-
tivities (Figure 6a). Both primary and secondary alkyl-
substituted 21a–d/22a–d, as well as 21e–i/22e–i with a
functionalized group, such as ester, allyl, haloallyl, alkoxy, and
acetal moieties, could be used. These successful results can be
understood in terms of either selective stabilization of the
(1R,4R)-exo-transition state TS-28 or destabilization of other
transition states such as TS-27 in the chiral U-shaped cavity of
(R)-12a•2B(C6F5)3 (Figure 6b). Since C2-symmetric norborna-
dienes are very important chiral ligands for asymmetric Rh(I)-
corrosive and explosive trichlorosilane, which is part of the
1
2
3
4
5
6
7
8
original and improved synthesis of 30 in 4–9 steps from nor-
bornadiene (see the SI, pages S67–S69).
40,41
42
Moreover, the p-facial selective DA reaction of 5-alkyl-
substituted cyclopentadiene 31 was also examined (Figure 7a,
also see the SI, pages S71–S72). Unlike previous 21/22, 31
could be available without isomerization at low temperature
(less than 0 °C), and we could carefully use pure 31. From
sterically less-hindered 7, unlike acrolein 2b, the other p-
facial-adduct (±)-33 was obtained along with the expected (±)-
32 under EtAlCl2 or thermal reaction conditions. At that time,
compound (±)-34 was also obtained due to isomerization to
thermodynamically stable 31’ (Figure 7b). In contrast, 32 was
exclusively obtained in 94% yield with 94% ee with the use of
(R)-12a•2B(C6F5)3. The remarkable p-facial selectivity as well
as enantio-, endo/exo-, and substrate-selectivities might be rea-
sonably considered by the possible transition state model with
the chiral U-shaped catalyst as shown in Figure 7c.
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
39
and Ir(I)-catalysis, a concise synthesis of Hayashi’s repre-
40
sentative diene ligand 30 was demonstrated (Figure 6c).
Optically active DA product 26d (including 6% of 25d) react-
ed with PhMgCl and then acetyl chloride to give 29 in 90%
yield. Although compound 29 still involved 25d-derived by
products, subsequent deacetoxylation by Pd(0)-catalyzed re-
duction with formic acid and the purification could gave 30 in
75% yield with 97% ee. Overall, our method also could readi-
ly provide 30 from 7 and 21d/22d without the use of
We next tried to apply the catalysis to 1- or 2-alkyl-
substituted cyclohexadienes 36 and 37 (Figure 8, also see the
SI, pages S82–S87). Unlike 1-/2-alkyl-substituted cyclopenta-
dienes 21/22, 36 and 37 can be separated from each other.
As control experiments using 7 and 2-alkyl-substituted cyclo-
hexadienes 36, (±)-38 with adequate orbital coefficients rather
than (±)-39 with inadequate orbital coefficients were exclusive-
ly obtained under thermal conditions without any catalysts
(Figure 8a). In contrast, the use of achiral Lewis acid catalysts,
such as BF3•Et2O, B(C6F5)3, and EtAlCl2, could promote the
reaction of 7 with 36 but gave a complex mixture. In such a
situation, (R)-12a•2B(C6F5)3 was still effective, and 38 were
obtained with high enantio-, endo/exo-, regio-, and substrate-
selectivities. Next, 1-alkyl-substituted cyclohexadienes 37 were
also examined. As control experiments, (±)-40 with adequate
orbital coefficients were exclusively obtained under thermal
conditions without any catalysts (Figure 8b). As other control
(a)
(R)-12a·2B(C6F5)3
(10 mol%)
OBn
O
+
H
CH2Cl2, MS 4Å
–78 °C, 5 h
31
7
BnO
OBn
H
CHO
H
BnO
CHO
+
+
+
CHO
CHO
OBn
32
94%, 94% ee
33
34
35
0%
0%
0%
st
experiments, the use of EtAlCl2 gave both 1 DA-adducts (±)-
40 (major) and (±)-41 (minor), whereas the use of BF3•Et2O or
B(C6F5)3 gave a complex mixture. In sharp contrast, 41 with
inadequate orbital coefficients was selectively obtained with
enantio-, endo/exo-, regio-, and substrate-selectivities, particu-
larly with the use of another finely optimized U-shaped catalyst
(R)-12b•2B(C6F5)3. In both reactions of 36 and 37, steric con-
straints of these substrates in the chiral U-shaped cavity might
be reasonably considered for the possible transition states as
shown in Figures 8c and 8d.
0%
2%
6%
12%
9%
0%
0%
cf. Conditions A:
cf. Conditions B:
83%
Conditions A: EtAlCl2 (10 mol%), –78 °C, 5 h. [Overreaction occured.]
Conditions B: Without catalysts, reflux, 12 h.
(b)
OBn
OBn
31’
Thermodynamically
stable
7
34
31
Furthermore, we examined the site- and regioselective DA
reaction of triene 42, which has two DA reaction sites due to
the additional 3-vinyl moiety (Figure 9a, also see the SI, pages
S97–S101). As control experiments, the reaction of 7 with 42
with the use of promising EtAlCl2 gave a complex mixture,
whereas (±)-43 and (±)-45 with both adequate orbital coeffi-
cients were obtained in respective yields of 50% under thermal
conditions without catalysts. In sharp contrast, with the use of
(R)-12b•2B(C6F5)3, novel tetrahydronaphthalene 45 was mul-
tiselectively obtained in 94% yield with 97% ee without the
generation of 43, 44, 46, nor other byproducts. Moreover, we
examined tetraene 47 with 2,3-divinyl moieties (Figure 9b,
also see the SI, pages S107–S111), which showed similar re-
sults under the control reaction conditions. Remarkably, in
the presence of (R)-12b•2B(C6F5)3, 49 was obtained in 97%
(c)
exo-
approach
of 31
BnO
32
H
Enantio-
Endo/exo-
π-Facial-
H
O
B
Substrate-
selectivities
Figure 7. p-Facial selective DA reaction of with 5-alkyl-
substituted cyclopentadiene 31. (a) The DA reaction of 7 with 31
by using (R)-12a•2B(C6F5)3. (b) Isomerization of 31 to 31’ under
the thermal conditions. (c) Possible p-facial selective exo-approach
of 31.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
(a)
(R)-12a·2B(C6F5)3
1
2
3
O
R
(10 mol%)
R
CHO
CHO
+
+
H
CH2Cl2, MS 4Å
–78 ºC, 4 h
R
36
7
38
39
4
Product 38, total yield (ratio of 38:39 in 1H NMR), and enantioselectivity of 38:
5
6
CHO CHO
CHO
CHO
7
8
9
Me
Et
Bn
38a
38b
38c
38d
90% (99:1),
86% ee
98% (96:4),
87% ee
>99% (94:6),
90% ee
>99% (97:3),
86% ee
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
cf. Conditions A:
cf. Conditions B:
0%
0%
0%
0%
96% (92:8)
68% (92:8)
69% (88:12)
78% (89:11)
Conditions A: EtAlCl2 (20 mol%), –78 °C, 2 h. [Overreaction occured.]
Conditions B: Without catalysts, reflux, 16 h.
(b)
R
(R)-12b·2B(C6F5)3
O
R
(10 mol%)
CHO
CHO
+
+
H
CH2Cl2, MS 4Å
–78 ºC, 31 h
R
37
7
40
41
Product 41, total yield (ratio of 40:41 in 1H NMR), and enantioselectivity of 41:
CHO CHO
CHO
CHO
Et
Bn
Me
41a
41b
41c
41d
98% (3:97),
90% ee
96% (6:94),
94% ee
99% (3:97),
99% (2:98),
97% ee
94% ee
cf. Conditions A:
cf. Conditions B:
47% (74:26)
65% (100:0)
16% (81:19)
82% (100:0)
37% (81:19)
60% (100:0)
31% (94:6)
40% (100:0)
Conditions A: EtAlCl2 (20 mol%), –78 °C, 1 h. [Overreaction occured.]
Conditions B: Without catalysts, reflux, 15 h.
(c)
(d)
exo-
exo-
approach
of 37
approach
R
R
of 36
38
41
Enantio-
Endo/exo-
Regio-
Enantio-
Endo/exo-
Regio-
H
H
Substrate-
selectivities
Substrate-
O
B
O
B
selectivities
Figure 8. Regioselective DA reaction with 2- or 1-alkyl-substituted cyclohexadienes 36 and 37. (a) The DA reaction of 7 with 2-alkyl-
substituted cyclohexadienes 36 by using (R)-12a•2B(C6F5)3. (b) The DA reaction of 7 with 1-alkyl-substituted cyclohexadienes 37 by using
(R)-12b•2B(C6F5)3. (c) Possible exo-approach of 36. (d) Possible exo-approach of 37 regardless the less-favored orbital coefficients (see the
Supporting Information).
yield with 95% ee. Since the observed preference for 45 or 49
over other compounds cannot be explained by the substrate-
dependant orbital theory alone, the possible chiral cavity of the
U-shaped catalyst might preferentially induce these remarkable
enantio-, endo/exo-, regio-, site-, and substrate-selectivities (Fig-
ure 9c).
12a•2B(C6F5)3•7 was much more stable than anti-(R)-
12a•2B(C6F5)3•7 by using a semi-empirical method AM1 (see
the SI, page S117). In these intermediates, the formyl moiety
of 7 was doubly coordinated with the B-O(Naph) moiety at the
C(=O)H and C(=O)H parts. Based on these results, we further
optimized the intermediates before and after the transition
states, such as syn-(R)-12a•2B(C6F5)3•7 and syn-(R)-
12a•2B(C6F5)3•8, with the DFT method (B3LYP/6-31G*), and
the results are summarized in Figure 10 (also see the SI, page
S117–S119). The average of the five shortest distances be-
tween F atoms of the two different B(C6F5)3 moieties is 6.498 Å
Finally, we considered preliminary theoretical calculations
involving the possible geometry of the supramolecular catalyst
(R)-12a•2B(C6F5)3 as a working model. A chiral U-shaped cavi-
ty is assumed due to the six bulky and dynamic C6F5 moieties,
and the two C=O•••B(C6F5)3 moieties could have a syn-
conformation. As expected above, the geometry of syn-(R)-
in syn-(R)-12a•2B(C6F5)3•7 and 7.117
12a•2B(C6F5)3•8. Accordingly, the virtual bore size of the
Å
in syn-(R)-
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
CHO Me
(a)
(R)-12b·2B(C6F5)3
Me
Me
H
1
2
3
4
O
(10 mol%)
CHO
CHO
CHO
+
+
+
+
H
H
CH2Cl2, MS 4Å
–78 ºC, 21 h
Me
44
Me
46
45
43
42
7
0%
0%
0%
94%, 97% ee
0%
0%
0%
0%
5
6
7
0%
0%
cf. Conditions A:
cf. Conditions B:
50%
50%
Conditions A: EtAlCl2 (10 mol%), –78 °C, 2 h. [Overreaction occured.]
Conditions B: Without catalysts, reflux, 12 h.
8
9
CHO
(b)
(R)-12b·2B(C6F5)3
H
O
CHO
CHO
(10 mol%)
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
+
+
+
H
H
CH2Cl2, MS 4Å
–78 ºC, 3 h
49
50
48
7
47
0%
97%, 95% ee
0%
0%
0%
0%
0%
cf. Conditions A:
cf. Conditions B:
70%
30%
Conditions A: EtAlCl2 (10 mol%), –78 °C, 2 h. [Overreaction occured.]
Conditions B: Without catalysts, reflux, 12 h.
(c)
R1
R2
exo-
approach
of 42 or 47
45 or 49
Enantio-
Endo/exo-
Regio-
Site-
H
O
B
Substrate-
selectivities
Figure 9. Site- and regioselective DA reaction with cyclohexadiene-derived triene and tetraene. (a) The DA reaction of 7 with triene 42
by using (R)-12b•2B(C6F5)3. (b) The DA reaction of 7 with tetraene 47 by using (R)-12b•2B(C6F5)3. (c) Possible exo-approach of 42 or 47
due to the cavity’s steric controls.
(a)
(b)
5.5–6.0 Å
158.9°
5.0–5.5 Å
157.9°
Figure 10. DFT calculations of possible key intermediates. (a) syn-(R)-12a•2B(C6F5)3•7. (b) syn-(R)-12a•2B(C6F5)3•8. Hydrogen atoms of
the catalyst are omitted for clarity.
mediates might possibly include expansion and contraction of
the cavity, which might be featured by our conformationally
flexible supramolecular U-shaped catalysts. As a result, the
desired compounds can properly hold in the chiral cavity with
the ‘induced-fit function’. Actually, as shown above, our con-
cavity of syn-(R)-12a•2B(C6F5)3•8 (ca. 5.5–6.0 Å) is larger than
that of syn-(R)-12a•2B(C6F5)3•7 (ca. 5.0–5.5 Å). Moreover, the
angle of B–B–B (158.9°) in syn-(R)-12a•2B(C6F5)3•8 is slightly
larger than the angle (157.9°) in syn-(R)-12a•2B(C6F5)3•7. The
observed differences of the bore size in these calculated inter-
43
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
oselectivity of 8 was determined by HPLC analysis (90% ee,
formationally flexible chiral U-shaped cavity could avoid the
1
2
3
4
5
6
7
8
undesired overreactions in the DA reactions of propargyl al-
dehyde 7. In this regard, for example, the diameters of cylin-
der including each compound, such as 7 (2.0 Å), 8 (5.1 Å), 9
(6.9 Å), 10 (6.8 Å), and 11 (6.9 Å), might include a correlation
to the cavity size of the catalyst (See the SI, page S121). In
Daicel CHIRALPAK AS-H, n-hexane:i-PrOH = 9:1, 1.0
mL/min, tR = 8.3 min ((1R,4S)-8, major), 12.3 min ((1S,4R)-8,
minor). Compounds 9, 10, and 11 were also obtained as a
mixture by the same silica gel column chromatography. The
1
ratio of 9:10:11 was determined by H NMR analysis [9: 9.72
nd
particular, since the 2 DA-adducts 9–11 would be too large
ppm, 10: 10.02 ppm, 11: 9.42 ppm].
and mismatched to the present cavity, the related transition
states toward these compounds would be disfavored. Although
these preliminary theoretical study may somewhat help con-
sidering the reaction mechanism for extraordinary multiselec-
1 g scale DA reaction of 7 with 1 (Table 1, entry 4): A
pale brown solution of the chiral (R)-Ar2-BINOL ligand (405
mg, 0.60 mmol) and (3,5-bis(cyclopentyloxy)phenyl)boronic
acid (174 mg, 0.60 mmol) in dichloromethane (12 mL), THF
(1.8 mL), and water (108 µL, 6 mmol) was stirred at room
temperature for 12 h in a Pyrex Schlenk tube under a nitrogen
atmosphere. The volatiles were removed under reduced pres-
sure, and powdered MS 4Å (2.50 g, used as received commer-
cially) was added. The resulting pale yellow solid was heated
to 100 °C (bath temperature) under <5 Torr for 2 h. After the
sample was cooled to room temperature under a nitrogen at-
mosphere, tris(pentafluorophenyl)borane (614 mg, 1.2 mmol)
and freshly-distilled dichloromethane (48 mL) were added
under an argon atmosphere in a glove box. The pale brown
mixture was stirred at room temperature for 1 h. The mixture
was then cooled to –78 °C, and propargyl aldehyde 7 (d =
0.915, 85% purity) (835 µL, 12.0 mmol) was added. Subse-
quently, freshly-distilled cyclopentadiene 1 (5.04 mL, 60
mmol) was added at –78 °C over 30 min. The resultant mix-
ture was stirred at –78 °C for 3 h. Triethylamine (2.0 mL) was
poured into the reaction mixture at –78 °C to quench the re-
action. Solvent (dichloromethane) was removed under 150
Torr at 25 °C by a rotary evaporator. The product mixture
was purified by silica gel column chromatography (Kanto
Chemical Co., Inc. 37560; eluent: pentane:Et2O = 100:1 to
8:1). Solvents were removed under 200 Torr at 15 °C by a
rotary evaporator to give 8 (1.37 g, 95% yield). The enanti-
oselectivity of 8 was determined by HPLC analysis (90% ee) in
the same procedure described above.
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
44
tivity using the present supramolecular U-shaped catalysts,
further investigations must be necessary to full understanding
particularly the possible transition states. A continuous study
for the comprehensive mechanistic investigations is underway.
CONCLUSION
Despite remarkable developments in the field of asymmetric
catalysis, there are still many difficulties that are beyond the
reach of current synthetic technology in organic chemis-
try. We have developed here a new synthetic method based
on the supramolecular technology with conformationally flexi-
ble chiral supramolecular U-shaped catalysts particularly for the
enantio-, endo/exo-, p-facial, regio-, site-, and substrate-selective
Diels–Alder reactions of propargyl aldehyde with various cy-
clic dienes, triene, and tetraene. We hope that the results pre-
sented here might partially contribute the development of arti-
ficial enzyme-like supramolecular catalysts for multiselective
reactions, which will be able to target organic compounds that
have thus far eluded synthesis.
EXPERIMENTAL SECTION
Representative procedure of the DA reaction (0.50
mmol scale of 7): A pale brown solution of the chiral (R)-
Ar2-BINOL ligand (33.8 mg, 0.050 mmol) and 3,5-
bis(cyclopentyl)phenylboronic acid (14.5 mg, 0.050 mmol) in
dichloromethane (1 mL), THF (0.15 mL), and water (9 µL,
0.50 mmol) was stirred at room temperature for 12 h in a Py-
rex Schlenk tube under a nitrogen atmosphere. The volatiles
were removed under reduced pressure, and powdered MS 4Å
(250 mg, used as received commercially) was added. The dry-
ing agent MS 4Å was required to complete dehydrative prepa-
ration of (R)-12a and to prevent the release of B(C6F5)3•H2O
due to competitive coordination with water. The resulting
pale yellow solid was heated to 100 °C (bath temperature)
under <5 Torr for 2 h. After the sample was cooled to room
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.xxxxxxxxx.
Experimental procedure, characterization data, additional control
experiments, copies of 1H NMR and 13C NMR spectra of all new
compounds, and copies of HPLC/GC analysis to determine the
enantio-purity (PDF).
temperature
under
a
nitrogen
atmosphere,
tris(pentafluorophenyl)borane (51.2 mg, 0.10 mmol) and fresh-
ly-distilled dichloromethane (2 mL) were added under an ar-
gon atmosphere in a glove box. The pale brown mixture was
stirred at room temperature for 1 h. The mixture was then
cooled to –78 °C, and 7 (d = 0.915, 89% purity, 33.2 µL, 0.50
mmol) was added. Subsequently, freshly-distilled cyclopenta-
diene 1 (203 µL, 2.5 mmol) was added at –78 °C over 15 min.
The resultant mixture was then stirred at –78 °C for 3 h. Tri-
ethylamine (0.5 mL) was poured into the reaction mixture at –
78 °C to quench the reaction. The product mixture was puri-
fied by silica gel column chromatography (Kanto Chemical
Co., Inc. 37560; eluent: pentane:Et2O = 100:1 to 8:1). Sol-
vents were carefully removed under 200 Torr at 15 °C by a
rotary evaporator to give 8 (57.0 mg, 95% yield). The enanti-
AUTHOR INFORMATION
Corresponding Author
Kazuaki Ishihara
*E-mail: ishihara@cc.nagoya-u.ac.jp
ORCID
Manabu Hatano: 0000-0002-5595-9206
Kazuaki Ishihara: 0000-0003-4191-3845
Notes
The authors declare no competing financial interest.
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
M.; Ishihara, K., Boron tribromide-assisted chiral phosphoric acid
ACKNOWLEDGMENTS
catalyst for a highly enantioselective Diels–Alder reaction of 1,2-
dihydropyridines. J. Am. Chem. Soc. 2015, 137, 13472–13475. (b)
Hatano, M.; Ishihara, H.; Goto, Y.; Ishihara, K., Remote
tris(pentafluorophenyl)borane-assisted chiral phosphoric acid catalysts
for the enantioselective Diels–Alder reaction. Synlett 2016, 27, 564–
570. (c) Hatano, M.; Hayashi, K., Sakamoto, T.; Makino, Y.; Ishihara,
K. Enantioselective Diels–Alder reaction induced by chiral supramo-
lecular Lewis acid catalysts based on CN···B and PO···B coordina-
tion bonds. Synlett 2016, 27, 1061–1067.
1
2
3
4
5
6
7
Financial support was partially provided by JSPS KAKENHI
Grant Numbers JP17H03054, JP15H05755, JP15H05810 in Pre-
cisely Designed Catalysts with Customized Scaffolding, and
CREST, JST (Development of high-performance nanostructures
for process integration). T.S., T.M. and Y.G. are grateful for the
program in Nagoya University for Leading Graduate Schools
“IGER program in Green Natural Sciences”, MEXT, Japan.
8
9
(9) Woodward, R. B.; Hoffmann R., The conservation of orbital
symmetry. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853.
(10) Houk, K. N., Generalized frontier orbitals of alkenes and
dienes. Regioselectivity in Diels–Alder reactions. J. Am. Chem. Soc.
1973, 95, 4092–4094.
(11) Fukui, K., Role of frontier orbitals in chemical reactions. Science
1982, 218, 747–754.
(12) (a) Ose, T.; Watanabe, K.; Mie, T.; Honma, M.; Watanabe,
H.; Yao, M.; Oikawa, H.; Tanaka, I., Insight into a natural Diels–
Alder reaction from the structure of macrophomate synthase. Nature
2003, 422, 185–189. (b) Siegel, J. B.; Zanghellini, A.; Lovick, H. M.;
Kiss, G.; Lambert, A. R.; St.Clair, J. L.; Gallaher, J. L.; Hilvert, D.;
Gelb, M. H.; Stoddard, B. L.; Houk, K. N.; Michael, F. E.; Baker, D.,
Computational design of an enzyme catalyst for a stereoselective bi-
molecular Diels–Alder reaction. Science 2010, 329, 309–313.
(13) Lehn, J.-M., Supramolecular chemistry: receptors, catalysts,
and carriers. Science 1985, 227, 849–856.
(14) Raynal, M.; Ballester, P.; Vidal-Ferran, A; van Leeuwen, P. W.
N. M., Supramolecular catalysis. Part 1: non-covalent interactions as
a tool for building and modifying homogeneous catalysts. Chem. Soc.
Rev. 2014, 43, 1660–1733.
(15) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W.
N. M., Supramolecular catalysis. Part 2: artificial enzyme mimics.
Chem. Soc. Rev. 2014, 43, 1734–1787.
(16) (a) Brown, C. J.; Toste, F. D.; Bergman, R. G.; Raymond, K.
N., Supramolecular catalysis in metal–ligand cluster hosts. Chem. Rev.
2015, 115, 3012–3035. (b) Kaphan, D. M.; Levin, M. D.; Bergman,
R. G.; Raymond, K. N.; Toste, F. D., A supramolecular microenvi-
ronment strategy for transition metal catalysis. Science 2015, 350,
1235–1238. (c) Levin, M. D.; Kaphan, D. M.; Hong, C. M.; Bergman,
R. G.; Raymond, K. N.; Toste, F. D., Scope and mechanism of coop-
erativity at the intersection of organometallic and supramolecular
catalysis. J. Am. Chem. Soc. 2016, 138, 9682–9693. (d) Hong, C. M.;
Kaphan, D. M.; Bergman, R. G.; Raymond, K. N.; Toste, F. D.,
Conformational selection as the mechanism of guest binding in a
flexible supramolecular host. J. Am. Chem. Soc. 2017, 139, 8013–8021.
(e) Hong, C. M.; Bergman, R. G.; Raymond, K. N.; Toste, F. D.,
Self-assembled tetrahedral hosts as supramolecular catalysts, Acc. Chem.
Res. (ASAP) DOI: 10.1021/acs.accounts.8b00328.
(17) Kang, J.; Rebek, J. Jr., Acceleration of a Diels–Alder reaction
by a self-assembled molecular capsule. Nature 1997, 385, 50–52.
(18) Kang, J.; Hilmersson, G.; Santamaría, J.; Rebek, J. Jr., Diels–
Alder reactions through reversible encapsulation. J. Am. Chem. Soc.
1998, 120, 3650–3656.
(19) Yoshizawa, M.; Tamura, M.; Fujita, M., Diels–Alder in aque-
ous molecular hosts: unusual regioselectivity and efficient catalysis.
Science 2006, 312, 251–254.
(20) Nishioka, Y.; Yamaguchi, T.; Yoshizawa, M.; Fujita, M., Unu-
sual [2+4] and [2+2] cycloadditions of arenes in the confined cavity
of self-assembled cages. J. Am. Chem. Soc. 2007, 129, 7000–7001.
(21) Murase, T.; Horiuchi, S.; Fujita, M., Naphthalene Diels−Alder
in a self-assembled molecular flask. J. Am. Chem. Soc. 2010, 132, 2866–
2867.
(22) Ikemoto, K.; Inokuma, Y.; Fujita, M., Diels–Alder via molecu-
lar recognition in a crystalline molecular flask. J. Am. Chem. Soc. 2011,
133, 16806–16808.
(23) Zheng, L.; Sonzini, S.; Ambarwati, M.; Rosta, E.; Scherman,
O. A.; Herrmann, A., Turning cucurbit[8]uril into a supramolecular
nanoreactor for asymmetric catalysis. Angew. Chem. Int. Ed. 2015, 54,
13007–13011.
REFERENCES
(1) Kagan, H. B.; Riant, O., Catalytic asymmetric Diels–Alder re-
actions. Chem. Rev. 1992, 92, 1007–1019.
(2) Corey, E. J., Catalytic enantioselective Diels–Alder reactions:
methods, mechanistic fundamentals, pathways, and applications.
Angew. Chem. Int. Ed. 2002, 41, 1650–1667.
(3) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogi-
annakis, G., The Diels–Alder reaction in total synthesis. Angew. Chem.
Int. Ed. 2002, 41, 1668–1698.
(4) Funel, J.-A.; Abele, S., Industrial applications of the Diels–Alder
reaction. Angew. Chem. Int. Ed. 2013, 52, 3822–3863.
(5) Jiang, X.; Wang, R., Recent developments in catalytic asym-
metric inverse-electron-demand Diels–Alder reaction. Chem. Rev. 2013,
113, 5515–5546.
(6) Mackay, E. G.; Sherburn, M. S., The Diels–Alder reaction in
steroid synthesis. Synthesis 2015, 47, 1–21.
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
(7) For
a review. (a) Ishihara, K.; Sakakura, A., [4+2]-
Cycloaddition reactions. In Science of Synthesis, Stereoselective Synthesis, Eds.
Johannes, D. V.; Molander, G.; Evans, P. A., Thieme, Stuttgart, 2011,
vol 3, pp. 67–123. Also see the following references after the publica-
tion of this review. (b) Li, X.; Danishefsky, S. J., Cyclobutenone as a
highly reactive dienophile: expanding upon Diels–Alder paradigms. J.
Am. Chem. Soc. 2010, 132, 11004–11005. (c) Seiple, I. B.; Su, S.;
Young, I. S.; Nakamura, A.; Yamaguchi, J.; Jørgensen, L.; Rodriguez,
R. A.; O’Malley, D. P.; Gaich, T.; Köck, M.; Baran, P. S., Enantiose-
lective total syntheses of (–)-palau’amine, (–)-axinellamines, and (–)-
massadines. J. Am. Chem. Soc. 2011, 133, 14710–14726. (d) Mendoza,
A.; Ishihara, Y.; Baran; P. S., Scalable enantioselective total synthesis
of taxanes. Nat. Chem. 2012, 4, 21–25. (e) Li, G.; Liang, T.; Wojtas, L.;
Antilla, J. C., An asymmetric Diels–Alder reaction catalyzed by chiral
phosphate magnesium complexes: highly enantioselective synthesis of
chiral spirooxindoles. Angew. Chem. Int. Ed. 2013, 52, 4628–4632. (f)
Türkmen, Y. E.; Rawal V. H., Exploring the potential of diarylacety-
lenediols as hydrogen bonding catalysts. J. Org. Chem. 2013, 78, 8340–
8353. (g) Tian, X.; Hofmann, N.; Melchiorre, P., Asymmetric vinylo-
gous Diels–Alder reactions catalyzed by a chiral phosphoric acid.
Angew. Chem. Int. Ed. 2014, 53, 2997–3000. (h) Hashimoto, T.; Na-
katsu, H.; Maruoka, K., Catalytic asymmetric Diels–Alder reaction of
quinone imine ketals: a site-divergent approach. Angew. Chem. Int. Ed.
2015, 54, 4617–4621. (i) Gatzenmeier, T.; van Gemmeren, M.; Xie,
Y.; Höfler, D.; Leutzsch, M.; List, B., Asymmetric Lewis acid organo-
catalysis of the Diels–Alder reaction by a silylated C–H acid. Science
2016, 351, 949–952. (j) Reddy, K. M.; Bhimireddy, E.; Thirupathi,
B.; Breitler, S.; Yu, S.; Corey, E. J., Cationic chiral fluorinated oxa-
zaborolidines. More potent, second-generation catalysts for highly
enantioselective cycloaddition reactions. J. Am. Chem. Soc. 2016, 138,
2443–2453. (k) Liu, L.; Kim, H.; Xie, Y.; Farès, C.; Kaib, P. S. J.;
Goddard, R.; List, B., Catalytic asymmetric [4+2]-cycloaddition of
dienes with aldehydes. J. Am. Chem. Soc. 2017, 139, 13656–13659. (l)
Chen, T.-G.; Barton, L. M.; Lin, Y.; Tsien, J.; Kossler, D.; Bastida, I.;
Asai, S.; Bi, C.; Chen, J. S.; Shan, M.; Fang, H.; Fang, F. G.; Choi,
H.-w.; Hawkins, L.; Qin, T.; Baran; P. S., Building C(sp3)-rich com-
plexity by combining cycloaddition and C–C cross-coupling reactions.
Nature 2018, 560, 350–354. (m) Gatzenmeier, T.; Turberg, M.; Yepes,
D.; Xie, Y.; Neese, F.; Bistoni, G.; List, B., Scalable and highly dia-
stereo- and enantioselective catalytic Diels–Alder reaction of a,b-
unsaturated methyl esters. J. Am. Chem. Soc. 2018, 140, 12671–12676.
(8) Our recent contributions in DA reactions through the supra-
molecular catalysis: (a) Hatano, M.; Goto, Y.; Izumiseki, A.; Akakura,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
(24) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H.; Ohashi,
H., Cationic-oxazaborolidine-catalyzed enantioselective Diels–Alder
S.; Inagaki, S., First enantioselective catalytic Diels–Alder reaction of
dienes and acetylenic aldehydes: experimental and theoretical evi-
dence for the predominance of exo-transition structure. J. Org. Chem.
1997, 62, 3026–3027.
(25) (a) Hatano, M.; Mizuno, T.; Izumiseki, A.; Usami, R.; Asai, T.;
Akakura, M.; Ishihara, K., Enantioselective Diels–Alder reactions
with anomalous endo/exo selectivities using conformationally flexible
chiral supramolecular catalysts. Angew. Chem. Int. Ed. 2011, 50,
12189–12192. (b) Hatano, M.; Ishihara, K., Conformationally flexible
chiral supramolecular catalysts for enantioselective Diels–Alder reac-
tions with anomalous endo/exo selectivities. Chem. Commun. 2012, 48,
4273–4283.
1
2
3
4
5
6
7
8
reaction of a,b-unsaturated acetylenic ketones. Angew. Chem. Int. Ed.
2009, 48, 8060–8062. (e) Sibi, M. P.; Cruz, W. Jr.; Stanley, L. M.,
Enantioselective Diels–Alder cycloadditions with b-substituted pyra-
zolidinone propiolimides. Synlett 2010, 2010, 889–892. (f) Payette, J.
N.; Akakura, M.; Yamamoto, H., Selectivities in chiral Lewis acid
catalyzed Diels–Alder reactions of acetylenic ketones: explanation for
differences of selectivities between acylic and cyclic dienes. Chem. Asian
J. 2011, 6, 380–384. (g) Kang, T.; Wang, Z.; Lin, L.; Liao, Y.; Zhou,
Y.;
Liu,
Y.;
Feng,
X.,
N,N’-Dioxide/zinc
bis(trifluoromethylsulfonyl)imide complex catalyzed enantioselective
Diels–Alder reaction of cyclopentadiene with alkynones. Adv. Synth.
Catal. 2012, 357, 2045–2049.
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
(26) (a) Hoffmann, R.; Woodward, R. B., Orbital symmetries and
endo-exo relationships in concerted cycloaddition reactions. J. Am. Chem.
Soc. 1965, 87, 4388–4389. (b) Sauer, J., Diels–Alder reactions II: the
reaction mechanism. Angew. Chem. Int. Ed. Engl. 1967, 6, 16–33. (c)
Gouverneur, V. E.; Houk, K. N.; de Pascual-Teresa, B.; Beno, B.;
Janda, K. D.; Lerner, R. A., Control of the exo and endo pathways of
the Diels–Alder reaction by antibody catalysis. Science 1993, 262, 204–
208. (d) García, J. I.; Mayoral, J. A.; Salvatella, L., Do secondary
orbital interactions really exist? Acc. Chem. Res. 2000, 33, 658–664. (e)
Barba, C.; Carmona, D.; García, J. I.; Lamata, M. P.; Mayoral, J. A.;
Salvatella L.; Viguri, F., Conformational preferences of methacrolein
in Diels–Alder and 1,3-dipolar cycloaddition reactions. J. Org. Chem.
2006, 71, 9831–9840. (f) Wannere, C. S.; Paul, A.; Herges, R.; Houk,
K. N.; Schaefer, H. F. III; Schleyer, P. v. R., The existence of second-
ary orbital interactions. J. Comput. Chem. 2007, 28, 344–361. (g) Wang,
Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L., Asym-
metric Diels–Alder reactions of 2-pyrones with a bifunctional organic
catalyst. J. Am. Chem. Soc. 2007, 129, 6364–6365. (h) Sakata, K.; Fu-
jimoto, H., Origin of the endo selectivity in the Diels–Alder reaction
between cyclopentadiene and maleic anhydride. Eur. J. Org. Chem.
2016, 4275–4278. (i) Thamapipol, S.; Ludwig, B.; Besnard, C.; Sau-
dan, C.; Kündig, E. P., Ruthenium Lewis acid-catalyzed asymmetric
Diels–Alder reactions: reverse-face selectivity for a,b-unsaturated
aldehydes and ketones. Helv. Chim. Acta 2016, 99, 774–789.
(27) Catalyst-controlled exo-selective Diels–Alder reactions. (a)
Maruoka, K.; Imoto, H.; Yamamoto, H., Exo-selective Diels–Alder
reaction based on a molecular recognition approach. J. Am. Chem. Soc.
1994, 116, 12115–12116. (b) Kündig, E. P.; Saudan, C. M.; Alezra,
V.; Viton, F.; Bernardinelli, G., [(Indenyl)Ru(biphop-F)]+: A Lewis
acid catalyst that controls both the diene and the dienophile facial
selectivity in Diels–Alder reactions. Angew. Chem. Int. Ed., 2001, 40,
4481–4485. (c) Kano, T.; Tanaka, Y.; Maruoka, K., Exo-selective
asymmetric Diels−Alder reaction catalyzed by diamine salts as or-
ganocatalysts. Org. Lett. 2006, 8, 2687–2689. (d) Sibi, M. P.; Nie, X.;
Shackleford, J. P.; Stanley L. M.; Bouret, F., Exo- and enantioselective
Diels–Alder reactions: pyrazolidinone auxiliaries as a means to en-
hanced exo selectivity. Synlett 2008, 2008, 2655–2658. (e) Hayashi, Y.;
Samanta, S.; Gotoh, H.; Ishikawa, H., Asymmetric Diels–Alder reac-
tions of a,b-unsaturated aldehydes catalyzed by a diarylprolinol silyl
ether salt in the presence of water. Angew. Chem. Int. Ed. 2008, 47,
6634–6637. (f) Zhou, J.-H.; Jiang, B.; Meng, F.-F.; Xu, Y.-H.; Loh,
T.-P., B(C6F5)3: a new class of strong and bulky Lewis acid for exo-
selective intermolecular Diels–Alder reactions of unreactive acyclic
dienes with a,b-enals. Org. Lett. 2015, 17, 4432–4435. For catalyst-
controlled endo-selective Diels–Alder reactions, see ref. 25.
(30) Pioneering stoichiometric enantioselective catalysis: (a) Evans,
D. A.; Chapman, K. T.; Bisaha, J., Asymmetric Diels–Alder cycload-
dition reactions with chiral a,b-unsaturated N-acyloxazolidinones. J.
Am. Chem. Soc. 1988, 110, 1238–1256. (b) Evans, D. A.; Miller, S. J.;
Lectka, T.; von Matt, P., Chiral bis(oxazoline)copper(II) complexes as
Lewis acid catalysts for the enantioselective Diels–Alder reaction. J.
Am. Chem. Soc. 1999, 121, 7559–7573. (c) Buckle, R. N.; Burnell, D. J.,
A chiral probe for the asynchronous transition state of Diels–Alder
reactions with acetylenedicarboxylate. Tetrahedron 1999, 55, 14829–
14838. (d) Rahm, A.; Rheingold, A. L.; Wulff, W. D., Asymmetric
Diels–Alder reactions with chiral acetylenic carbene complexes as
dienophiles. Tetrahedron 2000, 56, 4951–4965.
(31) Butler, D. N.; Margetic, D.; O’Neill, P. J. C.; Warrener, R. N.,
Parity reversal: a new Diels–Alder strategy for the synthesis of
sesquinorbornadienes, including those with heterobridges and those of
unusual stereochemistry. Synlett 2000, 2000, 98–100.
(32) Exo-approach of dienes to the activated 7 should be required in
the multiselective synthesis of 26, 32, 38, 41, 45, and 49 as well as 8,
although how repulsive the disfavored HOMO-LUMO interactions
has not yet been quantitative in the present study. The ultimate ee
values through the enantioselective DA reaction of 7 should be affect-
ed by both enantio-facial selectivity of 7 and endo/exo-discrimination of
dienes, and these involvements cannot be individually considered
from the resulting ee value.
(33) Compound 8 is unstable particularly under acidic and/or
moisture conditions. Other DA-adducts in the present report, such as
26, 32, 38, 41, 45, and 49, are also not so stable, but more stable
than 8 at least.
(34) Brown, M. K.; Corey, E. J., Catalytic enantioselective for-
mation of chiral-bridged dienes which are themselves ligands for en-
antioselective catalysis. Org. Lett. 2010, 12, 172–175.
(35) Baldwin, S. W.; Tomesch, J. C., Stereoselective synthesis of 3-
exo-substituted 2-endo-acyl-5-norborene derivatives. J. Org. Chem. 1974,
39, 2382–2385.
(36) Linz, G.; Weetman, J.; Hady, A. F. A.; Helmchen, G., Asym-
metric Diels–Alder reactions: EPC-synthesis of a stable sarkomycin
precursor (cyclosarkomycin). Tetrahedron Lett. 1989, 30, 5599–5602.
(37) (a) Mamedov, E. G.; Klabunovskii, E. I., Asymmetric Diels–
Alder reactions of cyclopentadiene in the synthesis of chiral nor-
bornene derivatives. Russian J. Org. Chem. 2008, 44, 1097–1120. (b) Li,
C.; Liu, L.; Fu, X.; Huang, J., Norbornene in organic synthesis. Syn-
thesis 2018, 50, 2799–2823.
(38) (a) Payette, J. N.; Yamamoto, H., Regioselective and asymmet-
ric Diels–Alder reaction of 1- and 2-substituted cyclopentadienes
catalyzed by a Brønsted acid activated chiral oxazaborolidine. J. Am.
Chem. Soc. 2007, 129, 9536–9537. (b) Mironov, V. A.; Sobolev, E. V.;
Elizarova, A. N., Some general characteristic properties of substituted
cyclopentadienes. Tetrahedron 1963, 19, 1939–1958.
(39) (a) Shintani, R.; Hayashi, T., Chiral diene ligands for asym-
metric catalysis. Aldrichimica Acta 2009, 42, 31–38. (b) Feng, C.-G.; Xu,
M.-H.; Lin, G.-Q., Development of bicyclo[3.3.0]octadiene- or dicy-
clopentadiene-based chiral diene ligands for transition-metal-
catalyzed reactions. Synlett 2011, 2011, 1345–1356.
(40) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K., A
chiral chelating diene as a new type of chiral ligand for transition
metal catalysts: its preparation and use for the rhodium-catalyzed
asymmetric 1,4-addition. J. Am. Chem. Soc. 2003, 125, 11508–11509.
(b) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T., Chiral nor-
(28) Yamamoto, H.; Futatsugi, K., “Designer acids”: combined ac-
id catalysis for asymmetric synthesis. Angew. Chem. Int. Ed. 2005, 44,
1924–1942.
(29) (a) Maruoka, K.; Concepcion, A. B.; Yamamoto, H., Asym-
metric Diels–Alder reaction of cyclopentadiene and methyl acrylate
catalyzed by chiral organoaluminum reagents. Bull. Chem. Soc. Jpn.
1992, 65, 3501–3503. (b) Corey, E. J.; Lee, T. W., Enantioselective
Diels–Alder reactions between cyclopentadiene and a,b-acetylenic
aldehydes catalyzed by a chiral super Lewis acid. Tetrahedron Lett. 1997,
38, 5755–5758. (c) Ishihara, K.; Fushimi, M., Catalytic enantioselec-
tive [2 + 4] and [2 + 2] cycloaddition reactions with propiolamides. J.
Am. Chem. Soc. 2008, 130, 7532–7533. (d) Payette, J. N.; Yamamoto,
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
bornadienes as efficient ligands for the rhodium-catalyzed asymmetric
(42) (a) Cieplak, A. S., Inductive and resonance effects of substitu-
ents on p-face selection. Chem. Rev. 1999, 99, 1265–1336. (b) Ishida,
M.; Inagaki, S., p-Facial selectivity of Diels–Alder reactions. Top. Curr.
Chem. 2009, 289, 183–218.
(43) Conformational flexibility of our catalyst should be considera-
bly attributed to not only a rotation of 3,3’-substituents on the binaph-
thyl moiety (i.e., consecutive conformation favored syn- to disfavored
anti-(R)-12a•2B(C6F5)3) but also a rotation of the B(C6F5)3 units on the
O=C moieties. To evaluate the cavity expansion/contraction by
these factors, further mechanistic approach by Monte Carlo simula-
tions and/or calculation of related transition states, should be neces-
sary.
(44) The observed multiselectivity in the present DA reactions to
provide 8, 26, 32, 38, 41, 45, and 49 might be partially addressed by
the preliminary consideration of the result of the DFT-calculated
intermediate syn-(R)-12a•2B(C6F5)3•7. See the SI on detail (page
S120).
1,4-addition of arylboronic acids to fumaric and maleic compounds.
Org. Lett. 2004, 6, 3425–3427. (c) Tokunaga, N.; Otomaru, Y.; Oka-
moto, K.; Ueyama, K.; Shintani, R.; Hayashi, T., C2-Symmetric bicy-
clo[2.2.2]octadienes as chiral ligands: their high performance in rho-
dium-catalyzed asymmetric arylation of N-tosylarylimines. J. Am. Chem.
Soc. 2004, 126, 13584–13585. (d) Shintani, R.; Okamoto, K.;
Otomaru, Y.; Ueyama, K.; Hayashi, T., Catalytic asymmetric aryla-
tive cyclization of alkynals: phosphine-free rhodium/diene complexes
as efficient catalysts. J. Am. Chem. Soc. 2005, 127, 54–55. (e) Berthon-
Gelloz, G.; Hayashi, T., Expanding the C2-symmetric bicy-
clo[2.2.1]hepta-2,5-diene ligand family: concise synthesis and catalytic
activity in rhodium-catalyzed asymmetric addition. J. Org. Chem. 2006,
71, 8957–8960.
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
(41) Noël, T.; Vandyck, K.; Van der Eycken, J., Some new C2-
symmetric bicyclo[2.2.1]heptadiene ligands: synthesis and catalytic
activity in rhodium(I)-catalyzed asymmetric 1,4- and 1,2-additions.
Tetrahedron 2007, 63, 12961–12967.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title,
should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem,
etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.
1
2
3
4
5
6
7
8
9
O
n
R2
+
H
R3
(n = 1, 2)
H
C6F5
C6F5
N
O
B
C6F5
O
R1
Multiselective induction
O
O
Enantio-, endo/exo-,
π-facial-, regio-, site-,
& substrate-selectivities
B
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
R1
O
O
B
C6F5
n
N
C6F5
CHO
C6F5
R3
R2
Chiral supramolecular
U-shaped catalysts
No overreaction!
(6.82 cm wide × 4.75 cm long)
12
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
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
For Graphical Abstract (TOC)
112x78mm (300 x 300 DPI)
ACS Paragon Plus Environment