Single-Handed Helical Poly(quinoxaline-2,3-diyl)s Bearing Achiral 4-Aminopyrid-3-yl Pendants as Highly Enantioselective, Reusable Chiral Nucleophilic Organocatalysts in the Steglich Reaction

Article abstract of DOI:10.1021/jacs.6b12349

Helically chiral poly(quinoxaline-2,3-diyl)s bearing 4-aminopyrid-3-yl pendants were synthesized as new helical-polymer-based chiral nucleophilic organocatalysts. The obtained chiral nucleophilic polymer catalysts exhibited high catalytic activity, enantioselectivity, and reusability in asymmetric Steglich rearrangement of oxazolyl carbonate to C-carboxyazlactone. The polyquinoxaline-based, helically chiral DMAP catalyst mediated intramolecular acyl transfer selectively, by contrast with known small-molecule-based chiral organocatalysts, which also mediate intermolecular acyl transfers.

Full text of DOI:10.1021/jacs.6b12349

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Communication
Single-Handed Helical Poly(quinoxaline-2,3-diyl)s Bearing Achiral
4-Aminopyrid-3-yl Pendants as Highly Enantioselective, Reusable
Chiral Nucleophilic Organocatalysts in the Steglich Reaction
Takeshi Yamamoto, Ryo Murakami, and Michinori Suginome
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12349 • Publication Date (Web): 05 Feb 2017
Downloaded from http://pubs.acs.org on February 5, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Single-Handed Helical Poly(quinoxaline-2,3-diyl)s Bearing Achiral 4-
Aminopyrid-3-yl Pendants as Highly Enantioselective, Reusable Chi-
ral Nucleophilic Organocatalysts in the Steglich Reaction
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
Takeshi Yamamoto, Ryo Murakami, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
Supporting Information Placeholder
enantioselectivity.9 Moreover, we have shown that the induction
ABSTRACT: Helically chiral poly(quinoxaline-2,3-diyl)s
bearing 4-aminopyrid-3-yl pendants were synthesized as new
of helical chirality largely depends upon the nature of solvents10:
the helicity can be inverted between two solvents such as
chloroform/1,1,2-trichloroethane,10a,b cyclopentyl methyl ether/t-
butyl methyl ether,10c and even n-octane/cyclooctane.10d Our
current interest is to verify the extensibility of PQX as a general
chiral platform onto which various achiral pendants are attached
to gain high enantioselectivities in various asymmetric reactions.
helical-polymer-based chiral nucleophilic organocatalysts. The
obtained chiral nucleophilic polymer catalysts exhibited high
catalytic activity, enantioselectivity, and reusability in asymmetric
Steglich rearrangement of oxazolyl carbonate to C-
carboxyazlactone. The polyquinoxaline-based, helically chiral
DMAP catalyst mediated intramolecular acyl transfer selectively,
by contrast with known small-molecule-based chiral
organocatalysts, which also mediate intermolecular acyl transfers.
Incorporation of pyridyl pendants is highly attractive, because
they serve not only as a ligand in transition-metal catalysts,11 but
also as chiral bases or nucleophilic organocatalysts.12,13 In this
paper, we report the synthesis of a series of PQXs bearing 4-
aminopyrid-3-yl pendants and their use in asymmetric Steglich
rearrangement.13,14,15 We found high catalytic activity of one of
the derivatives, which allows us to attain high enantioselectivity
with remarkably low catalyst loading and to reuse the catalyst at
least 11 times without any drop of selectivity or catalytic activity.
Polymer-based immobilized chiral catalysts, in which
conventional small-molecule-based chiral catalysts are embedded
in common polymers, attract much interest from the viewpoint of
practical asymmetric synthesis because they are easily separable
from the reaction mixtures and reusable by virtue of the insoluble
nature of the polymer backbones.1 By contrast, increasing
attention is being focused on utilization of the helical
macromolecular scaffold2 as a source of chirality in catalytic
asymmetric reactions.3 In addition to the separability/reusability
issues, the macromolecular chiral scaffold is highly expected to
serve as huge chiral steric shielding, which could be superior to
small-molecule-based chiral structures. However, there has been
only limited success in the use of helical macromolecules as the
scaffolds of chiral catalysts. There are some successes in the use
of helically chiral poly(arylacetylene)s bearing chiral
organocatalytic pendants such as cinchona alkaloids,4 proline-
based groups,5 and oligopeptides.6 In these cases, the
enantioselectivities mainly arise from the chiral pendants with
relatively minor contribution of macromolecular chirality. There
is another class of polymer-based chiral catalysts whose enantio-
discrimination relies solely on the main-chain chirality of helical
macromolecules with attachment of achiral ligand/organocatalytic
pendants.7 This approach is extremely attractive because it only
requires the introduction of simple, achiral ligand/organocatalytic
pendants, although there has been no highly enantioselective
macromolecular catalyst within this class.
Our molecular design is shown in Scheme 1. 4-Amino-
substituted pyrid-3-yl groups are introduced at the 5-position of
the quinoxaline rings in the helical backbone of PQX, of which
right-handed (P-) helicity is induced by the (R)-chiral side chains.
The axial chirality between the pyridyl and the quinoxaline rings
is not fixed and induced thermodynamically by the P-helical
structure of PQX. Their synthesis was performed by
postpolymerization functionalization of PQXboh bearing
a
boronyl pendant at the 5-position of the quinoxaline ring (Scheme
2). Synthesis of the corresponding ortho-diisocyanobenzene
monomer 1 bearing a B(pin) pendant is shown in the SI. In the
presence of an organonickel initiator, living random
copolymerization of 1 and chiral monomer 2, which has (R)-2-
butoxymethyl side chains, gave (P)-(R)-PQXbpin bearing 10
boronyl units along with 190 chiral units on average. Hydrolysis
of the B(pin) group on the quinoxaline ring proceeded smoothly
in a mixture of THF/H2O, giving (P)-(R)-PQXboh. (P)-(R)-
PQXdmap (C1) bearing the DMAP pendant was obtained in high
yield through Suzuki–Miyaura cross-coupling of (P)-(R)-
PQXboh with 3-bromo-4-dimethylaminopyridine, which is
readily available by bromination of the corresponding 4-
(dimethylamino)pyridine. Conversion of the boronyl group on
PQXboh was confirmed by 1H NMR spectroscopy. PQX
derivatives bearing a 4-dialkyl amino group (C2 and C3), cyclic
amino group (C4, PQXppy (C5), and C6), and fused cyclic
amino group (PQXmdpp (C7) and C8)) were also prepared under
similar reactiotn conditions.
In 2009, we established poly(quinoixaline-2,3-diyl)s (hereafter
PQX) as the first chiral macromolecular scaffolds that achieve
high enantioselectivities (up to 98% ee) without the assistance of
additional chiralities in the pendants.8 In this system, attachment
of achiral o-(diarylphosphino)phenyl pendants allows high
enantioselectivity in palladium-catalyzed hydrosilylation of
styrenes. Subsequently, we could successfully apply the catalysts
Scheme 1. (P)-PQX-based Nucleophilic Organocatalyst
to
several
palladium-catalyzed
reactions
with
high
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
while C6 bearing piperidino group exhibited low catalytic activity
1
2
3
4
5
6
7
8
and enantioselectivity (entry 6). PQXs bearing a fused cyclic
amino group also served as efficient catalysts (entries 7 and 8). In
these
series,
PQXmdpp
(C7)
bearing
N-
methyldihydropyrrolopyridine (MDPP) pendants afforded the
highest catalytic activity and enantioselectivity. These results
clearly suggest that higher coplanarity of the dialkylamino moiety
and the pyridine ring enhances both the catalytic activity and
enantioselectivity. The effect of the substituents in 2-
methyloxazolyl carbonates
4
on the reactivity and
9
enantioselectivity was also evaluated using (P)-(R)-C7. The
presence of an electron-withdrawing group on the benzene ring
significantly enhanced the reactivity of the substrate (entries 9 and
10). The ee of the product at 0 °C was improved to 75% ee by
using 4Ca bearing a 4-trifluoromethyl group.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Asymmetric Steglich Rearrangement Using (P)-
(R)-PQXdmap Derivativesa
Scheme 2. Synthesis of Polyquinoxaline-based Helically
Chiral Nucleophilic Catalysts
entry cat.
Ar
time (h)
% yieldb % eec
92 (5Aa) 62
84 (5Aa) 60
90 (5Aa) 52
89 (5Aa) 62
96 (5Aa) 60
77d (5Aa) 42
99 (5Aa) 69
83 (5Aa) 50
91 (5Ba) 72
88 (5Ca) 75
78 (5Ca) –45
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
C7
4-MeOC6H4 (4Aa)
35
96
120
12
12
300
3
11
1
1
4Aa
4Aa
4Aa
4Aa
4Aa
4Aa
4Aa
4-ClC6H4 (4Ba)
4-CF3C6H4 (4Ca)
4-CF3C6H4 (4Ca)
10 C7
11e C7
1
a4Aa (0.3 mmol), and (P)-(R)-PQXdmap derivatives (0.5 mol%
pyridyl pendants) were stirred in solvent (6.0 mL) at 0 °C. bI-
d
solated yield. cDetermined by chiral SFC analysis. 88% conver-
sion. NMR yield. e The reaction was carried out using (M)-(R)-C7
in a 1:1 mixture of toluene and 1,1,2-trichloroethane.
According to our previous works,9,10 we also conducted
solvent-dependent helix inversion of C7 to reverse the
enantioselectivity.13i We found that the helical chirality of (P)-
(R)-C7 could be completely changed to (M)-helix in a 1:1 mixture
of toluene and 1,1,2-trichloroethane (see SI). Thus obtained (M)-
(R)-C7 afforded enantiomeric product 5Ca in 78% yield but with
lower enantiomeric excess (45% ee), probably because of
negative solvent effect of 1,1,2-trichloroethane used as a co-
solvent in the reaction (entry 11).
The obtained (P)-(R)-PQX derivatives were used in asymmetric
The catalytic activities of PQXdmap (C1) and PQXmdpp
(C7) were compared by NMR experiments at 24 °C in benzene-d6
(See SI). In terms of the half-life of 4Aa (t1/2), C7 showed 9-fold
higher catalyst activity (t1/2 = 27 min) than C1 (t1/2 = 247 min). It
should be noted that t1/2 of C7 was identical to that of MDPP in
spite of the presence of the highly sterically demanding helical
polymer backbone.
Steglich rearrangement,13,15 in which oxazolyl carbonates
isomerize to C-carboxyazlactones forming
a
quaternary
stereocenter (Table 1). In the presence of (P)-(R)-PQXdmap (C1)
(0.5 mol% pyridyl pendants), rearrangement of oxazolyl
carbonate 4Aa proceeded at 0 °C. In the screening of reaction
solvent, toluene showed the higher enantioselectivity than
chloroform and THF, giving 5Aa in 92% yield with 62% ee (entry
1, see Supporting Information (SI)). Replacement of the methyl
group(s) on the amino group of catalyst C1 with ethyl group(s)
(C2 and C3) decreased both catalytic activity and
enantioselectivity (entries 2 and 3). PQXs bearing azetidino (C4)
or pyrrolidino group PQXppy (C5) showed high catalytic
activities with moderate enantioselectivities (entries 4 and 5),
Based on these results, further optimization of catalyst structure
was performed at –60 °C, keeping the polymerization degree of
the catalysts (m + n = 200, Scheme 3). With (P)-(R)-C7, ee of the
product was improved to 88% by lowering the reaction
temperature to –60 °C. Under the same reaction conditions, (P)-
(R)-C9 (n = 10) bearing (R)-2-octyloxymethyl side chains, which
induces the right-handed structure more efficiently,10b showed
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
higher enantioselectivity, giving 5Ca with 90% ee. Increase of the
12
13e
14f
11Ca
11Ca
12Ca
Bn
Bn
Bn
allyl
allyl
Ph
82 (18Ca) 93
88 (18Ca) 92
79 (19Ca) 18
1
2
3
4
5
6
ratio of the pyridyl units ((P)-(R)-C10, n = 20) resulted in a little
decrease in enantioselectivity (88% ee). We finally obtained 91%
ee by using (P)-(R)-C11, in which less pyridyl units (n = 5) are
contained.
aOxazolyl carbonate (0.1 mmol), and PQXmdpp (0.5 mol%
pyridyl pendants) were stirred in solvent (2.0 mL) at –60 °C.
Scheme 3. Optimization of the Polymer Structure
bIsolated yield. Determined by chiral SFC analysis. NMR yield.
c
d
e11Ca (3.0 mmol), and PQXmdpp (0.1 mol% pyridyl pendants)
f
7
8
were stirred in solvent (3.0 mL) at –60 °C. Reaction at 0 °C for
48 h.
9
Taking advantage of using a polymer scaffold, we demonstrated
reuse of PQXmdpp C11 (Scheme 4). After the initial reaction of
11Ca with 1.0 mol% (P)-(R)-C11, acetonitrile was added to the
reaction mixture to precipitate (P)-(R)-C11. Centrifugation of the
resulting suspension under air allowed recovery of (P)-(R)-C11
along with separation of the product in the solution. After drying
under vacuum, the recovered (P)-(R)-C11 could be reused 11
times without any fall in the catalytic activity and enantioselec-
tivity. On average, 95% (P)-(R)-C11 was recovered in each cycle.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Reuse of the Polymer Catalyst
Under the optimized conditions using (P)-(R)-C11, substrate
structure was varied at –60 °C by using oxazolyl carbonates
bearing a 4-trifluoromethylphenyl group (Table 2). As for the
effect of the acyl groups, benzyl, p-substituted benzyl, and 1-
naphthyl groups afforded high enantioselectivities (entries 1–4).
While methylcarbonate 4Ce showed lower ee (entry 5), 2-
methoxyethyl carbonate 4Cf gave high ee (entry 6). Substituents
on the oxazole core were varied using benzyl carbonates.
Oxazolyl carbonates bearing alkyl groups such as ethyl, propyl,
and isobutyl groups afforded the corresponding products with
94%, 92%, and 86% ee, respectively (entries 7–9). Benzyl,
methylthioethyl, and allyl substituted carbonates also afforded the
run
initial
% yield
99
% ee
91
run
6
% yield
99
% ee
92
1
2
3
4
5
99
99
99
98
92
92
92
92
7
8
9
10
11
99
99
97
96
93
92
93
93
corresponding products in high
yields
with
high
enantioselectivities (entries 10–12). It is noteworthy that gram-
scale synthesis of allyl substituted 18Ca needed catalyst loading
of 0.1 mol% of (P)-(R)-C11, giving 1.07 g of 18Ca in 88% yield
with 92% ee (entry 13). To our knowledge, there has been no
single example of the use of less than 0.5 mol% of chiral
nucleophilic catalyst in the asymmetric Steglich rearrangement.13h
Phenyl substituted 12Ca, which resulted in low conversion at –
60 °C, was converted to 19Ca in 79% yield at 0 °C with low
enantioselectivity (entry 14).
97
93
99
93
To elucidate the reaction mechanism of the Steglich rearrange-
ment in the presence of PQXmdpp, crossover experiments were
conducted using an equimolar amount of 4Aa and 10Ae in the
presence of several nucleophilic catalysts at 0 °C (Table 3).13a The
use of DMAP or MDPP resulted in the formation of crossover
products (CO) along with noncrossover products (NCO) in ratios
of 2.4:1 and 1:1, respectively (entries 1 and 2). Similar formation
of crossover products was generally observed in asymmetric
Steglich reactions in which crossover experiments were conduct-
ed.13a,13h,15a,,f,g This scrambling has been well explained by the
involvement of intermolecular acyl transfer from acylpyridinium
intermediate to the enolate generated from the substrate. A
DMAP-type catalyst 20 bearing a quinoxalinyl group at 3-position
also afforded a significant amount of the crossover products (entry
3). Moreover, PS-DMAP, i.e., DMAP immobilized on polysty-
rene, afforded crossover products with the same ratio as DMAP
(entry 4). By contrast, no crossover products were observed when
PQXdmap C1 and PQXmdpp C7 and C9 were employed as
catalysts (entries 5–7). These results strongly suggest that the
highly sterically demanding polymer scaffold of PQX protects the
acylpyridinium intermediate from attack by the enolates generated
on the other PQXmdpp molecules or promotes the intramolecular
acyl transfer significantly.
Table 2. Scope of the Substratea
entry substrate
R1
R2
Me
Me
Me
Me
Me
Me
Et
% yieldb % eec
91 (5Ca) 92
88 (5Cb)d 90
72 (5Cc) 92
98 (5Cd) 94
57 (5Ce)d 71
71 (5Cf) 90
96 (13Ca) 94
86 (14Ca) 92
79 (15Ca) 86
93 (16Ca) 91
1
2
3
4
5
4Ca
4Cb
4Cc
4Cd
4Ce
4Cf
Bn
4-MeC6H4CH2
4-CF3C6H4CH2
1-naphthylmethyl
Me
6
MeOCH2CH2
7
8
9
10
11
6Ca
7Ca
8Ca
9Ca
10Ca
Bn
Bn
Bn
Bn
Bn
Table 3. Crossover Experimenta
Pr
iPrCH2
Bn
MeSCH2CH2 85 (17Ca) 87
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
Chiral Polymer Synthesis. John Wiley and Sons: 2011. (d) Itsuno, S.;
Hassan, M. M. RSC Adv. 2014, 4, 52023.
1
2
3
4
5
6
7
8
(2) (a) Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013. (b)
Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.; Nagai, K. Chem. Rev.
2009, 109, 6102. (c) Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.;
Ikai, T.; Maeda, K. Chem. Rev. 2016, 116, 13752.
(3) Megens, R. P.; Roelfes, G. Chem. Eur. J. 2011, 17, 8514.
(4) Tang, Z.; Iida, H.; Hu, H.-Y.; Yashima, E. Acs Macro Lett. 2012, 1,
261.
(5) Ikeda, A.; Terada, K.; Shiotsuki, M.; Sanda, F. J. Polym. Sci. A: Polym.
Chem. 2011, 49, 3783.
(6) Maeda, K.; Tanaka, K.; Morino, K.; Yashima, E. Macromolecules
2007, 40, 6783.
9
entry
catalyst
NCO : COb
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) (a) Reggelin, M.; Schultz, M.; Holbach, M. Angew. Chem. Int. Ed.
2002, 41, 1614. (b) Reggelin, M.; Doerr, S.; Klussmann, M.; Schultz, M.;
Holbach, M. Proc. Natl. Acad. Sci.U.S.A. 2004, 101, 5461. (c) Roelfes, G.;
Feringa, B. L. Angew. Chem. Int. Ed. 2005, 44, 3230. (d) Coquière, D.;
Feringa, B. L.; Roelfes, G. Angew. Chem. Int. Ed. 2007, 46, 9308. (e)
Boersma, A. J.; Feringa, B. L.; Roelfes, G. Angew. Chem. Int. Ed. 2009,
48, 3346. (f) Boersma A. J.; Coquière, D.; Geerdink, D.; Rosati, F.;
Feringa, B. L.; Roelfes, G. Nature Chem. 2010, 2, 991. (g) Boersma, A. J.;
Megens, R. P.; Feringa, B. L.; Roelfes, G. Chem. Soc. Rev. 2010, 39, 2083.
(h) Takata, L. M. S.; Iida, H.; Shimomura, K.; Hayashi, K.; dos Santos, A.
A.; Yashima, E. Macromol. Rapid Commun. 2015, 36, 2047.
(8) (a) Yamamoto, T.; Suginome, M. Angew. Chem. Int. Ed. 2009, 48, 539.
(b) Yamamoto, T.; Yamada, T.; Nagata, Y.; Suginome, M. J. Am. Chem.
Soc. 2010, 132, 7899.
(9) (a) Yamamoto, T.; Akai, Y.; Nagata, Y.; Suginome, M. Angew. Chem.
Int. Ed. 2011, 50, 8844. (b) Akai, Y.; Yamamoto, T.; Nagata, Y.; Ohmura,
T.; Suginome, M. J. Am. Chem. Soc. 2012, 134, 11092. (c) Suginome, M.;
Yamamoto, T.; Nagata, Y.; Yamada, T.; Akai, Y. Pure Appl. Chem. 2012,
84, 1759. (d) Akai, Y.; Konnert, L.; Yamamoto, T.; Suginome, M. Chem.
Commun. 2015, 51, 7211. (e) Yamamoto, T.; Akai, Y.; Suginome, M.
Angew. Chem. Int. Ed. 2014, 53, 12785.
1
2
3
4c
5
DMAP
MDPP
20
PS-DMAP
(P)-(R)-C1
(P)-(R)-C7
(P)-(R)-C9
2.4:1
1:1
1.7:1
2.4:1
>50:1
>50:1
>50:1
6
7
a10Ae (0.15 mmol), 4Aa (0.15 mmol), and catalyst (1.0 mol%
b
pyridyl pendants) were stirred in toluene (6.0 mL) at 0 °C. De-
termined by 1H NMR analysis. c8.8 mol% pyridyl pendants
(10) (a) Yamada, T.; Nagata, Y.; Suginome, M. Chem. Commun. 2010,
46, 4914. (b) Nagata, Y.; Yamada, T.; Adachi, T.; Akai, Y.; Yamamoto,
T.; Suginome, M. J. Am. Chem. Soc. 2013, 135, 10104. (c) Nagata, Y.;
Kuroda, T.; Takagi, K.; Suginome, M. Chem. Sci. 2014, 5, 4953. (d)
Nagata, Y.; Nishikawa, T.; Suginome, M. J. Am. Chem. Soc. 2014, 136,
15901.
In conclusion, we established the synthesis of helically chiral
polyquinoxaline-based DMAP-type nucleophilic catalysts via
postpolymerization functionalization of polyquinoxalines bearing
boronyl pendants. The obtained (P)-(R)-PQXmdpp showed high
catalyst activity and enantioselectivity in an asymmetric Steglich
rearrangement, giving C-carboxyazlactones in high yields up to
94% ee. The observed macromolecular effect on the selective
intramolecular reaction pathway opens up a new synthetic
strategy using the polymer catalyst. Application of the helical-
polymer-based chiral nucleophilic catalysts in other catalytic
asymmetric reactions is now being undertaken in our laboratory.
(11) Kwong, H.-L.; Yeung, H.-L.; Yeung, C.-T.; Lee, W.-S.; Lee, C.-S.;
Wong, W.-L. Coord. Chem. Rev. 2007, 251, 2188.
(12) (a) Vedejs, E.; Chen, X. H. J. Am. Chem. Soc. 1996, 118, 1809. (b)
Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230. (c) Kawabata, T.;
Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (d)
Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (e) Spivey, A. C.; Fekner, T.;
Spey, S. E. J. Org. Chem. 2000, 65, 3154. (f) Pelotier, B.; Priem, G.;
Campbell, I. B.; Macdonald, S. J. F.; Anson, M. S. Synlett 2003, 679. (g)
Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (h) Wurz, R. P. Chem. Rev.
2007, 107, 5570. (i) Crittall, M. R.; Rzepa, H. S.; Carbery, D. R. Org. Lett.
2011, 13, 1250. (j) Larionov, E.; Mahesh, M.; Spivey, A. C.; Wei, Y.;
Zipse, H. J. Am. Chem. Soc. 2012, 134, 9390. (k) Ma, G. Y.; Deng, J.; Sibi,
M. P. Angew. Chem. Int. Ed. 2014, 53, 11818. (l) Fujii, K.; Mitsudo, K.;
Mandai, H.; Suga, S. Bull. Chem. Soc. Jpn. 2016, 89, 1081.
(13) (a) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. (b)
Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 3921. (c) Shaw, S.
A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (d) Shaw,
S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am.
Chem. Soc. 2006, 128, 925. (e) Nguyen, H. V.; Butler, D. C. D.; Richards,
C. J. Org. Lett. 2006, 8, 769. (f) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J.
Am. Chem. Soc. 2009, 131, 14. (g) Mandai, H.; Fujiwara, T.; Noda, K.;
Fujii, K.; Mitsudo, K.; Korenaga, T.; Suga, S. Org. Lett. 2015, 17, 4436.
(h) Mandai, H.; Fujii, K.; Yasuhara, H.; Abe, K.; Mitsudo, K.; Korenaga,
T.; Suga, S. Nat. Commun. 2016, 7, 11297. (i) Chen, C.-T.; Tsai, C.-C.;
Tsou, P.-K.; Huang, G.-T.; Yu, C.-H. Chem. Sci. 2017, 8, 524.
(14) Steglich, W.; Höfle, G. Tetrahedron Lett. 1970, 11, 4727.
(15) (a) Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8, 3785.
(b) Joannesse, C.; Johnston, C. P.; Concellón, C.; Simal, C.; Philp, D.;
Smith, A. D. Angew. Chem. Int. Ed. 2009, 48, 8914. (c) Uraguchi, D.;
Koshimoto, K.; Miyake, S.; Ooi, T. Angew. Chem. Int. Ed. 2010, 49, 5567.
(d) Zhang, Z.; Xie, F.; Jia, J.; Zhang, W. J. Am. Chem. Soc. 2010, 132,
15939. (e) De, C. K.; Mittal, N.; Seidel, D. J. Am. Chem. Soc. 2011, 133,
16802. (f) Campbell, C. D.; Concellón, C.; Smith, A. D. Tetrahedron:
Asymmetry 2011, 22, 797. (g) Joannesse, C.; Johnston, C. P.; Morrill, L.
ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
suginome@sbchem.kyoto-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number
JP15H05811 in Precisely Designed Catalysts with Customized
Scaffolding.
REFERENCES
(1) (a) Ding, K.; Uozumi, Y. Handbook of Asymmetric Heterogeneous
Catalysis; Wiley-VHC: Weinheim, 2008. (b) Lu, J.; Toy, P. H. Chem.
Rev. 2009, 109, 815. (c) Itsuno, S. Polymeric Chiral Catalyst Design and
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
C.; Woods, P. A.; Kieffer, M.; Nigst, T. A.; Mayr, H.; Lebl, T.; Philp, D.;
Bragg, R. A.; Smith, A. D. Chem. Eur. J. 2012, 18, 2398.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
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
145x73mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 7 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
Scheme 1. (P)-PQX-based Nucleophilic Organocatalyst
145x101mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
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
Scheme 2. Synthesis of Polyquinoxaline-based Helically Chiral Nucleophilic Catalysts
138x200mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 9 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
Scheme 3. Optimization of the Polymer Structure
102x91mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
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
Scheme 4. Reuse of the Polymer Catalyst
103x35mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 11 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
Table 1
92x32mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
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
Table 2
94x32mm (300 x 300 DPI)
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
Table 3
134x126mm (300 x 300 DPI)
ACS Paragon Plus Environment