Rational design of highly effective asymmetric Diels-Alder catalysts bearing 4,4-sulfonamidomethyl groups

Article abstract of DOI:10.1021/ja906098b

(Chemical Equation Presented) The rational design of bis(oxazoline)- copper(II) catalysts based on postulated intramolecular secondary n-cation interaction for the highly enantioselective Diels-Alder reaction is presented. A theoretical calculation sugges

Full text of DOI:10.1021/ja906098b

Published on Web 11/19/2009
Rational Design of Highly Effective Asymmetric Diels-Alder Catalysts
Bearing 4,4′-Sulfonamidomethyl Groups
Akira Sakakura,† Rei Kondo,‡ Yuki Matsumura,‡ Matsujiro Akakura,§ and Kazuaki Ishihara*,‡
EcoTopia Science Institute, Graduate School of Engineering and JST, CREST, Nagoya UniVersity, Furo-cho,
Chikusa, Nagoya, 464-8603, Japan, and Department of Chemistry, Aichi UniVersity of Education, Igaya-cho,
Kariya, 448-8542, Japan
Received July 21, 2009; E-mail: Ishihara@cc.nagoya-u.ac.jp
Scheme 1. Working Hypothesis: Chiral Catalysts Based on
Intramolecular Secondary n-Cation Interaction
Although numerous chiral Lewis acid catalysts have been
reported for the asymmetric Diels-Alder (DA) reaction,1,2 there
are still some drawbacks with regard to catalytic activity, enanti-
oselectivity, and the range of substrates. For example, M(SbF6)n is
often used with chiral chelating ligands to increase the catalytic
activity, counteranions of which are thought to be completely
liberated from the catalyst.2e However, labile cationic catalysts often
cause the decomposition of catalyst, product inhibition and an
undesired side reaction.3 To overcome these problems, the rational
design of a chiral cationic catalyst using weak secondary interactions
might be essential for the stabilization of cation species and the
construction of a rather flexible but highly efficient asymmetric
environment around the metal center.
We previously reported that Cu(II)•3-aryl-L-alanine amide
complexes were highly effective for the asymmetric DA reaction.4
An asymmetric environment for induction of the enantioselective
reaction was constructed around the metal center through intramo-
lecular π-cation attractive interaction between the aromatic ring of
the ligands and the Cu(II) center. In this context, intramolecular
n-cation interaction between heteroatoms (Y:) of a ligand and a
metal cation is one of the most promising candidates for obtaining
higher enantioselectivity and a broader range of substrates (Scheme
1). In general, coordination of a Lewis basic site to a metal cation
decreases its Lewis acidity. However, rationally designed additional
Lewis basic sites are expected to increase the Lewis acidity by
displacing counteranions.5 In this case there is an equilibrium
between complexes A and B. To overcome this equilibrium, we
envisioned that chiral bis(oxazoline)s bearing 4,4′-protic substituents
(HZ:) would predominantly stabilize n-cation complex C, since
released counteranions may interact with HZ through hydrogen
bonding.6 We report here the rational design of bis(oxazoline)-
copper(II) catalysts7-9 based on intramolecular secondary n-cation
interaction for the highly enantioselective DA reaction.
We first examined the catalytic activities of Cu(OTf)2 complexes
with 2 bearing Lewis basic sites at the 4,4′-substituents10 in the
reaction of cyclopentadiene (CP, 3 equiv) with 3a in CH2Cl2,
according to the conditions reported by Evans and co-workers2e
(Table 1). When the reaction was conducted with 2a (Y ) OMe)
or 2b (Y ) OAc), DA adduct 4a was obtained with poor
enantioselectivity (8 and 24% ee, entries 1 and 2). The use of 2c
(Y ) OMs) also gave excellent enantioselectivity although reactivity
was low11 (entry 3). The use of ligands 2d (ZH ) NHMs) and 2e
(ZH ) NHTf) successfully gave excellent enantioselectivities and
reactivities (93 and 80% ees, entries 4 and 8). These results suggest
that the sulfonamido groups of 2d and 2e may play a key role in
the construction of an efficient asymmetric environment. The use
a
Table 1. DA Reaction of CP with 3a Catalyzed by 2•CuX2
conditions
(°C, h)
conv
(%)b
ee (%)b
[config]
entry
ligand [Y or ZH]
endo/exo
1
2
3
2a [OMe]
2b [OAc]
2c [OMs]
-20, 12
-40, 23
-72, 21
-72, 16
-72, 9
63
99
18
97
99
95
90:10
98:2
98:2
99:1
99:1
99:1
99:1
98:2
98:2
98:2
99:1
99:1
97:3
98:2
8 [2R]
24 [2R]
84 [2R]
93 [2R]
91 [2R]
98 [2R]
98 [2R]
80 [2R]
96 [2R]
92 [2R]
96 [2R]
91 [2S]
86 [2S]
-
4
2d [NHMs]
2d [NHMs]
2d [NHMs]
2d [NHMs]
2e [NHTf]
2e [NHTf]
2e [NHTf]
2e [NHTf]
ent-1d [NHMs]
ent-1f [i-Pr]
none
5c
6c d
7e
8
-72, 1
,
-72, 9
97 [94f]
99
-72, 8.5
-72, 1.5
-72, 8.5
-72, 20
-72, 6
9c d
97
96
73
92
33
86
,
10g
11c g
,
12c d
,
13c d
-72, 6
-72, 1.5
,
14c d
,
a The reaction of CP (3 equiv) with 3a (0.2 mmol) was conducted in
the presence of Cu(OTf)2 (5 mol %) and a ligand (5.5 mol %) in
CH2Cl2 (1 mL). b Ee of endo-4a. c EtNO2 was used instead of CH2Cl2.
d Cu(NTf2)2 was used instead of Cu(OTf)2. e The reaction of CP (3
equiv) with 3a (1 mmol) was conducted in the presence of
2d•Cu(NTf2)2 (1 mol %) in EtNO2 (1 mL). f Isolated yield. g Cu(SbF6)2
was used instead of Cu(OTf)2.
of EtNO2 instead of CH2Cl2 significantly increased the reactivity
as reported by Jørgensen and co-workers,12 while the enantiose-
lectivity was not improved (entry 5). The use of EtNO2 and
Cu(NTf2)2 instead of CH2Cl2 and Cu(OTf)2 successfully improved
† EcoTopia Science Institute, Nagoya University.
‡ Graduate School of Engineering, Nagoya University.
§ Aichi University of Education.
9
17762 J. AM. CHEM. SOC. 2009, 131, 17762–17764
10.1021/ja906098b  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. 2d•Cu(NTf2)2-Catalyzed DA Reaction with 3aa
Table 3. Catalytic DA Reaction with ꢀ-Substituted Dienophiles 3a
ee (%)b
[config]c
conditions
(°C, h)
isolated
yield (%)
entry
3
diene
isomer ratio
1d e
3b
3c
3c
3c
3c
3d
CP
CP
CP
5a
5b
5a
-20, 7
-72, 19
-40, 21
rt, 60
0, 48
rt, 66
4b, 58f
4c, 99
4c, 99
11, 87
12, 68
13, 76
93:7g
95:5g
89:11g
94:6i
-
95 [2R]
94 [2S]
89 [2S]
90 [1R,6S]
81 [1R,6S]
95 [1S,6S]
,
ee (%)b
[config]c
2d e
,
conditions
(°C, h)
isolated
yield (%)
isomer
ratio
entry
diene
3h
4
1
CH
0, 30
-20, 25
-72, 72
-20, 24
0, 44
-20, 52
-20, 6
-40, 7.5
-20, 24
-20, 24
0, 72
7, 95
7, 57
99:1d
92 [2R]
86 [2R]
98 [2R]
99 [1R]
98 [1R]
95 [1R]
91 [1R]
86 [1R]
94 [1R]
98 [1R]
92 [1R,2S]
99 [1R,2S]k
2e f
CH
furang
5a
5a
5b
5c
5d
5e
5f
6a
6b
99:1d
,
5
3e f
8, 92h
9a, 93
9a, 91
9b, 83
9c, 91
9d, 68
9e, 67
9f, 76
76:24d
>99:1i
>99:1i
-
6j
>99:1i
,
4
5j
6
a The reaction of a diene (3 equiv) with 3 (0.2 mmol) was conducted
in the presence of 2d•Cu(NTf2)2 (5 mol %) in MeNO2 (1 mL). b Ee of
major isomer. c See SI. d EtNO2 was used instead of MeNO2. e 2e was
used instead of 2d. f Conversion yield determined by 1H NMR analysis.
g Diastereomer. h The reaction of CP (10 equiv) with 3c (1 mmol) was
conducted in the presence of 2d•Cu(NTf2)2 (1 mol %) in MeNO2 (1
mL). i Regioisomer. j The reaction of isoprene (10 equiv) was conducted
in the presence of 2d•Cu(NTf2)2 (20 mol %).
7
>99:1i
>99:1i
>99:1i
>99:1i
85:9:6d,i
52:48d
8e
9e f
,
10f
11
10a, 92
10b, 96
12e f
-20, 12
,
a The reaction of
a diene (3 equiv) with 3a (0.2 mmol) was
conducted in the presence of 2d•Cu(NTf2)2 (5 mol %) in MeNO2 (1
mL). b Ee of major isomer. c See Supporting Information (SI).
d Diastereomer. e EtNO2 was used instead of MeNO2. f 2e was used
instead of 2d. g 10 equiv of furan were used. h Conversion yield
determined by 1H NMR analysis. i Regioisomer. j The reaction of 5a (3
equiv) with 3a (1 mmol) was conducted in the presence of
2d•Cu(NTf2)2 (1 mol %) in MeNO2 (1 mL). k Minor diastereomer was
91% ee [1R,2R].
gave the corresponding 2-substituted adducts 10a and 10b with high
enantioselectivities (92 and 99% ee), albeit the reactivities and
diastereoselectivities were moderate (entries 11 and 12).
The present DA reaction was also effective for ꢀ-substituted
dienophiles (Table 3). The reaction of CP with 3b (R3 ) Me) and
3c (R3 ) CO2Et) proceeded smoothly to give the corresponding
adducts 4b and 4c with high enantioselectivities, even when the
reaction was conducted in the presence of 1 mol % of 2d•Cu(NTf2)2
(89-95% ees, entries 1-3). The DA reaction of acyclic dienes
with ꢀ-substituted dienophiles, which was one of the most chal-
lenging sets, gave the corresponding adducts 11-13 with high
enantioselectivities (81-95% ees) albeit the reactivities were
moderate (entries 4-6). The absolute configuration of 13 was
determined to be (1S,6S) after conversion to the corresponding
benzyl ester (BnOLi, THF, rt).15 Sorensen and co-workers synthe-
sized the benzyl ester as a key intermediate for the synthesis of the
decahydrofluorene core of hirsutellones via the diastereoselective
DA reaction using the chiral auxiliary.15
the reactivity and the enantioselectivity (entries 6 and 9). Only 1
mol % of 2d•Cu(NTf2)2 efficiently promoted the reaction to give
4a in 94% isolated yield with 98% ee (entry 7). When a labile
catalyst, 2e•Cu(SbF6)2, was used,2e the chemical yield of 4a was
less reproducible although the enantioselectivity was constantly high
(entries 10 and 11).3,13 The catalytic activity of ent-1f•Cu(NTf2)2
was much lower than that of Cu(NTf2)2 itself (entries 13 versus
14). In contrast, the use of 2d, 2e, and 1d bearing 4,4′-sulfonamide
groups significantly increased the catalytic activities and enanti-
oselectivities (entries 6, 9, and 12 versus 13). In particular, the
catalytic activities of 2d•Cu(NTf2)2 and 2e•Cu(NTf2)2 were higher
than that of Cu(NTf2)2 itself (entries 6 and 9 versus 14).
To explore the generality and scope of the present enantiose-
lective DA reaction, the reactions of various dienes were examined
under optimized conditions (Table 2). For the reaction at -20 °C
or higher, the use of MeNO2 instead of EtNO2 improved the
reactivity. The DA reaction of cyclic dienes such as cyclohexadiene
(CH) and furan also gave the corresponding endo adducts 7 and 8
with high enantioselectivities (entries 1-3).14 For the reaction of
CH, 2d gave higher enantioselectivity than 2e, while 2e gave higher
catalytic activity than 2d. Evans and co-workers reported that the
t-Bu-bis(oxazoline)•Cu(OTf)2-catalyzed DA reaction of isoprene
(5a) with 3a gave 9a with 59% ee.2e,5 In contrast, the present DA
reactions using 2d•Cu(NTf2)2 and 2e•Cu(NTf2)2 were highly
effective for a series of 2-substituted butadienes and gave the
corresponding 4-substituted adducts 9 with excellent regio- and
enantioselectivities (>99:1 dr, 86-99% ee, entries 4-10). The
reaction of 5a was also successfully promoted by 1 mol % of
2d•Cu(NTf2)2 (entry 5). 1-Substituted butadienes such as 6a and
6b were also suitable substrates for the present DA reaction and
The postulated intramolecular secondary n-cation interaction
of sulfonyl oxygens was considered based on theoretical
calculations5 for a 2d•Cu(NTf2)2-3a complex. As shown in
Figure 1, the sulfonyl oxygens coordinate with the Cu(II) cation
(n-cation interaction), where counteranions (Tf2N-) do not
coordinate to the Cu(II) cation but rather to protons of sulfona-
mido groups, as expected.12 It is conceivable that dienes
predominantly approach the si-face side of s-cis acrylimides,
since a sulfomanide group and a Tf2N- preferentially shielded
the re-face of the acrylimide moiety (Figure 1, right).
In conclusion, we have designed a new class of bis(oxazoline)
ligands bearing 4,4′-sulfonamidomethyl groups for the DA reaction
with 3. A theoretical calculation suggested that the sulfonamide
groups successfully interact with the Cu(II) cation and that the
counteranions with protons of sulfonamido groups. These weak
secondary interactions might contribute to the high catalytic activity,
the broad range of substrates, and the high level of induction of
the enantioselectivity. The present DA reaction gave the best results
among those previously reported.
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J. AM. CHEM. SOC. VOL. 131, NO. 49, 2009 17763

C O M M U N I C A T I O N S
Figure 1. B3LYP/6-31G(d) optimized geometry of 2d•Cu(NTf2)2-3a (left) and proposed transition-state assembly (right). Hydrogen atoms, except for
protons of sulfonamido groups, are omitted for clarity.
(6) See the Supporting Information for details.
Acknowledgment. Financial support for this project was
provided by MEXT.KAKENHI (20245022), the Toray Science
(7) For reviews of chiral bis(oxazoline) ligands, see: (a) Rasappan, R.;
Laventine, D.; Reiser, O. Coord. Chem. ReV. 2008, 252, 702. (b) Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. ReV. 2006, 106, 3561. (c) Johnson,
J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (d) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
(8) Bis(oxazoline)-based ligands bearing additional Lewis basic sites have been
reported. Bis(oxazolinyl)pyridines (pybox): (a) Desimoni, G.; Faita, G.;
Quadrelli, P. Chem. ReV. 2003, 103, 3119. Tris(oxazoline)s: (b) Zhou, J.;
Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (c) Foltz, Stecker, B.; Marconi,
G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Commun.
2005, 5115. Other tridentate ligands: (d) Rasappan, R.; Hager, M.; Gissibl,
A.; Reiser, O. Org. Lett. 2006, 8, 6099. The additional Lewis basic sites
for the interaction with an additional metal cation to form bimetallic
catalysts: (e) Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett.
2001, 3, 4259.
(9) Bis(oxazoline)-based ligands bearing additional Brønsted acid sites have
also been reported. The additional Brønsted acid sites interacted with a
substrate to control the selectivity: (a) Matsumoto, K.; Jitsukawa, K.;
Masuda, H. Tetrahedron Lett. 2005, 46, 5687. (b) Schinnerl, M.; Bo¨hm,
C; Seitz, M.; Reiser, O. Tetrahedron: Asymmetry 2003, 14, 765.
(10) Ligands 2 were prepared from L-threonine methyl ester using molybde-
num(VI) oxide catalyzed dehydrative cyclization as a key reaction. See
the Supporting Information for details. (a) Sakakura, A.; Kondo, R.;
Umemura, S.; Ishihara, K. Tetrahedron 2009, 65, 2102. (b) Sakakura, A.;
Umemura, S.; Ishihara, K. Chem. Commun. 2008, 3561. (c) Sakakura, A.;
Kondo, R.; Umemura, S.; Ishihara, K. AdV. Synth. Catal. 2007, 349, 1641.
(d) Sakakura, A.; Umemura, S.; Kondo, R.; Ishihara, K. AdV. Synth. Catal.
2007, 349, 551. (e) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005,
7, 1971.
Foundation, the Global COE Program of MEXT, DAIKO FOUN-
DATION, JSPS Research Fellowships for Young Scientists (R.K.),
and the joint research program of the EcoTopia Science Institute,
Nagoya University. Calculations were performed at the Research
Center for Computational Science (RCCS), Okazaki Research
Facilities, National Institutes of Natural Science (NINS).
Supporting Information Available: Experimental procedures and
full characterization of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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