C2-symmetric bissulfoximines as ligands in copper-catalyzed enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ol027273e

(Matrix presented) Bissulfoximines have been used as chiral ligands in copper-catalyzed enantioselective Diels-Alder reactions between acryloyl-2-oxazolidinones and cyclopentadiene. After optimizing the ligand structure, the metal source, the counterions,

Full text of DOI:10.1021/ol027273e

ORGANIC
LETTERS
2003
Vol. 5, No. 4
427-429
C -Symmetric Bissulfoximines as
Ligands in Copper-Catalyzed
2
Enantioselective Diels−Alder Reactions
Carsten Bolm,* Marc Martin, Oliver Simic, and Marinella Verrucci
Institute of Organic Chemistry, RWTH Aachen Professor-Pirlet-Strasse 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received November 13, 2002
ABSTRACT
Bissulfoximines have been used as chiral ligands in copper-catalyzed enantioselective Diels−Alder reactions between acryloyl-2-oxazolidinones
and cyclopentadiene. After optimizing the ligand structure, the metal source, the counterions, and the solvent, products with up to 93% ee
have been obtained.
Over the past decades, asymmetric metal catalysis has
become a major area in organic chemistry.1 In this context,
it is particularly important to search for new compounds,
which can serve as chiral ligands, and to explore their
applicability in the synthesis of optically active compounds.
For several years, we2 and others3 have been involved in
the investigation of sulfoximines4 with the intention to use
their metal-binding properties5 in the development of new
chiral catalysts. Along these lines, C2-symmetric bissulfox-
imines have recently been introduced,3,6 which led to products
with very high enantiomeric excesses in allylic alkylations7
and hetero-Diels-Alder reactions,8 catalyzed by palladium
and copper complexes, respectively. To extend the compari-
son of catalysts bearing these new bissulfoximines with those
having well-established ligands9 such as bisoxazolines10 and
semicorrines,11 we investigated the [4+2]-cycloaddition
between cyclopentadiene (1) and acryloyl-2-oxazolidinones
2 (Scheme 1).12 Various bissulfoximines 4 and 5 with
(5) (a) Zehnder, M.; Bolm, C.; Schaffner, S.; Kaufmann, D.; Mu¨ller, J.
Liebigs Ann. 1995, 125. (b) Bolm, C.; Mu¨ller, J.; Zehnder, M.; Neuburger,
M. A. Chem. Eur. J. 1995, 1, 312.
(6) (a) For an early study on this topic, see: Bolm, C.; Bienewald, F.;
Harms, K. Synlett 1996, 775. (b) Bolm, C.; Hackenberger, C. P. R.; Simic,
O.; Verrucci, M.; Mu¨ller, D.; Bienewald, F. Synthesis 2002, 879.
(7) Bolm, C.; Simic, O.; Martin, M. Synlett 2001, 1878.
(8) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830.
(9) For excellent reviews on N,N′-donor ligands, see: (a) Togni, A.;
Venanzi, L. M. Angew. Chem. 1994, 106, 517; Angew. Chem., Int. Ed.
Engl. 1994, 33, 497. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire,
M. Chem. ReV. 2000, 100, 2159.
(10) (a) Bolm, C. Angew. Chem. 1991, 103, 556; Angew. Chem., Int.
Ed. Engl. 1991, 30, 542. (b) Gosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1. (c) Evans, D. A.; Rovis, T.; Johnson,
J. S. Pure Appl. Chem. 1999, 71, 1407. (d) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325.
(1) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Ojima, I., Ed. Catalytic Asymmetric Synthesis,
2nd ed.; VCH: Weinheim, Germany, 2000. (c) Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds. ComprehensiVe Asymmetric Catalysis; Springer:
Berlin, Germany, 1999. (d) Beller, M.; Bolm, C., Eds. Transition Metals
for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1998.
(2) (a) Bolm, C.; Felder, M.; Mu¨ller, J. Synlett 1992, 439. (b) Bolm, C.;
Felder, M. Tetrahedron Lett. 1993, 34, 6041. (c) Bolm, C.; Mu¨ller, J.;
Schlingloff, G.; Zehnder, M.; Neuburger, M. J. Chem. Soc., Chem. Commun.
1993, 182. (d) Bolm, C.; Seger, A.; Felder, M. Tetrahedron Lett. 1993, 34,
8079. (e) Bolm, C.; Felder, M. Synlett 1994, 655. (f) Bolm, C.; Mu¨ller, J.
Tetrahedron Lett. 1995, 36, 1625. (g) Bolm, C.; Mu¨ller, J. Acta Chem.
Scand. 1996, 50, 305. (h) Bolm, C.; Kaufmann, D.; Zehnder, M.; Neuburger,
M. Tetrahedron Lett. 1996, 37, 3985.
(3) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321.
(4) For reviews on sulfoximines see: (a) Johnson, C. R. Aldrichim. Acta
1985, 18, 3. (b) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341. (c) Johnson,
C. R. In ComprehensiVe Organic Chemistry; Barton, D., Ollis, W. D., Eds.;
Pergamon Press: Oxford, UK, 1979; Vol. 3, p 223. (d) Pyne, S. G. Sulfur
Rep. 1992, 12, 57. (e) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(11) (a) Pfaltz, A. Chimia 1990, 44, 202. (b) Pfaltz, A. Acc. Chem. Res.
1993, 26, 339. (c) Pfaltz, A. Synlett 1999, 835.
(12) (a) Narasaka, K.; Inoue, M.; Okada, N. Chem. Lett. 1986, 1109.
(b) Narasaka, K.; Iwasama, N.; Inoue, M.; Yamada, T.; Nakashima, M.;
Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340.
10.1021/ol027273e CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003

by changing the methyl to an isopropyl or a cyclopentyl
group reduced the enantioselectivity in the product formation
(49 and 15% ee, respectively) without affecting the endo/
exo ratio (entries 2 and 3). Modifying the aryl substituent
R2 had only a minor effect, except when a 2-methoxy group
was introduced (entries 6-9). In these cases the ee increased
and reached a maximum of 83% (entry 7). Generally,
lowering the reaction temperature had a beneficial effect on
the enantioselectivity (entries 7 and 9 versus 6 and 8).
The importance of the 2-methoxy substituent was also
observed when aryl-bridged bissulfoximines 5 were used as
ligands. Here, the ee of 3a was slightly higher in the catalysis
with 5b than with 5a (entries 10 and 11). To determine the
influence of electronic properties of the ligand, bissulfox-
imines 5c-e were synthesized, and their catalytic properties
were compared to those of 5a and 5b. Obviously, electron-
withdrawing substituents such as nitro or fluoro groups in
the 4 (R3) and 5 (R4) positions of the bissulfoximine arene
backbone reduced the enantioselectivity in the formation of
3a (entries 12 and 13). Electron-donating methyl groups,
however, had a positive effect (entry 14) on the ee of 3a.
Uniformly, S,S-bissulfoximines 4 and 5 afforded the
bicyclic product 3a with 2R configuration, whereas (R,R)-4
and (R,R)-5 gave (2S)-3a. A test reaction with 2b as substrate
and a Cu(OTf)2 catalyst bearing 4f as ligand afforded the
corresponding endo-product with 84% ee.13
Scheme 1
ethylene and arenes as bridging units, respectively, were
screened and evaluated on their ability to give enantiose-
lective copper catalysts. At this early stage, all reactions were
performed in dichloromethane as the solvent, using 2a as
dienophile and Cu(OTf)2 as the copper source.
First, the use of the ethylene-bridged bissulfoximines 4
was investigated. With 10 mol % of a catalyst prepared from
a 1:1 mixture of bissulfoximine 4a and Cu(OTf)2, 3a was
obtained in excellent yield (98%) having an enantiomeric
excess (ee) of 66% (Table 1, entry 1). The endo-isomer
dominated with a selectivity of 93:7. Increasing the steric
demand of the aliphatic substituent R1 of the bissulfoximine
Next, we turned our attention to the applicability of other
metal salts14 and found that the enantioselectivity was sig-
nificantly affected by the nature of the counterion (Table
2).15 Whereas copper dichloride and copper bistrifluoroace-
Table 2. Effect of the Counteriona
entry
copper salt
yield (%)
ee (%)c
endo/exo
1
2
3
4
5
6
7
Cu(OTf)2
CuCl2
Cu(OOCCF3)2
98
98
98
98
98
98
98
75
0
2
61
73
79
86
93:7
93:7
90:10
88:12
93:7
91:9
92:8
b
Table 1. Influence of the Ligand Structure on the Diels-Alder
b
Cu(BF4)2
Reactiona
b
Cu(SbF6)2
b
Cu(PF6)2
yield of
ee of
3a (%)b
b
entry
bissulfoximine
3a (%)
endo/exoc
Cu(ClO4)2
a Reaction conditions: 1 (4 equiv), 2a (1 equiv), copper(II) salt (10 mol
%), bissulfoximine 5a (10 mol %), CH2Cl2, -78 °C f rt. b Prepared in
situ from CuCl2 (10 mol %) and AgX (20 mol %). c Determined by HPLC,
using a chiral column (Chiralcel OD).
1
2
3
4
5
6
7d
8
9d
10
11
12
13
14
4a
4b
4c
4d
4e
4f
98
98
98
94
98
98
98
98
98
98
98
98
98
98
66
49
15
64
59
76
83
76
80
75
79
59
72
81
93:7
93:7
93:7
88:12
87:13
93:7
94:6
91:9
88:12
93:7
91:9
90:10
93:7
93:7
tate were unselective catalysts (Table 2, entries 2 and 3),
less coordinating counterions proved to be more suitable,
and among all those tested, copper(II) perchlorate led to the
best results with respect to product ee. Thus, with bissul-
foximine 5a16 as ligand the ee of 3a could be raised from
4f
4g
4g
5a
5b
5c
5d
5e
(13) With the same catalyst [4f, Cu(OTf)2; 10 mol % each] the reaction
between 2a and 1,3-cyclohexadiene gave the corresponding product with
63% ee in 98% yield.
(14) Other metal species such as Ti(OiPr)4, Sc(OTf)3, Fe(ClO4)2,
Fe(ClO4)3, Zn(OTf)2, Mg(OTf)2, Cu(OTf), Ag(ClO4), or Ni(SbF6)2 were
also tested and gave products with less than 35% ee
a Reaction conditions: 1 (4 equiv), 2a (1 equiv), Cu(OTf)2 (10 mol %),
bissulfoximine (10 mol %), CH2Cl2, -78 °C f rt. b Determined by HPLC,
using a chiral column (Chiralcel OD). c Determined by 1H NMR spectros-
copy. d Performed at -50 °C, 48 h.
(15) Significant counterion effects have also been observed in reactions
with Cu(II)-BOX catalysts (for examples, see refs 10c,d).
428
Org. Lett., Vol. 5, No. 4, 2003

75 to 86% ee when changing from Cu(OTf)2 to Cu(ClO4)2
as the metal source. The endo/exo ratio remained essentially
unaffected (entries 1 and 7).
bissulfoximine copper catalyst for this Diels-Alder reaction
so far, leading to 3a with 93% ee in 98% yield (endo/exo
ratio: 89:11) after 48 h at -70 °C.
Furthermore, the solvent had a major effect on the
enantioselectivity of the product formation (Table 3), even
Under these optimized conditions, the Diels-Alder reac-
tion was then performed with substrates 2b-d as well (Table
4).18 In the case of 2b no reaction occurred at -70 °C. At
Table 3. Effect of the Solventa
Table 4. Substrate Scopea
entry
solvent
temp (°C) ee (%)b endo/exo
entry
product
yield (%)
ee (%)b
endo/exo
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
-70
-60
-30
-25
-25
-25
-25
-70
0
75
92
58
67
80
64
40
15
73
93:7
85:15
92:8
89:11
89:11
90:10
91:9
1
2
3
4
3a
3b
3c
3d
98
97
94
0
84
84
82
92:8
87:13
76:24
1,1,1-trichlorethane
1,2-dichloroethane
1,1,2-trichloroethane
benzotrifluoride
CH3NO2
a Reaction conditions: 1 (4 equiv), 2a-d (1 equiv), CuCl2 (10 mol %),
AgClO4 (20 mol %), bissulfoximine 5f (10 mol %), CHCl3, room
temperature. b Determined by HPLC using a chiral column (Chiralcel OD).
THF
(CF3)2CHOH
92:8
89:11
a Reaction conditions: 1 (4 equiv), 2a (1 equiv), Cu(OTf)2 (10 mol %),
bissulfoximine 5a (10 mol %); yields 98%. b Determined by HPLC, using
a chiral column (Chiralcel OD).
room temperature almost full conversion was achieved after
24 h, leading to 3b with an ee of 84% (endo/exo ratio: 87:
13). Acryloyl-2-oxazolidinones 2a and 2c afforded 3a and
3c with 84% and 82% ee, respectively, at this temperature.19
The diastereomeric ratios were 92:8 for 3a and 76:24 for
3c. A low catalytic activity was observed with 2c and 2d as
substrates. With the latter, even at 40 °C no reaction took
place.
In summary, we demonstrated that various C2-symmetric
bissulfoximines can serve as ligands in copper-catalyzed
enantioselective Diels-Alder reactions, and we designed a
new system with superior properties. Since the substrate
range is still rather limited, further studies are focused on
extending the scope of this process, and by ongoing
investigations we hope to illustrate the applicability of those
new ligands in other asymmetric catalyses.
when it was only changed within a relatively narrow range
of chlorinated types. Thus, by simply switching from
CH2Cl2 to CHCl3, the ee of 3a increased from 75 to 92% in
a catalysis by using 10 mol % of Cu(OTf)2 and 5a as ligand
(entries 1 and 2). Unfortunately, the endo/exo ratio was now
reduced to 85:15, and the reaction was much slower. Other
chlorinated solvents (at slightly higher temperatures) gave
3a with 58 to 64% ee (entries 3-6). Nitromethane and THF
proved unsuitable and provided 3a with only 40 and 15%
ee, respectively (entries 7 and 9). To our surprise, even at 0
°C the catalysis in hexafluoro-2-propanol gave almost the
same result as the one performed in CH2Cl2 at -70 °C
affording 3a with 73% ee.
From the entire screening process we deduced that an
optimal catalytic system for the Diels-Alder reaction
between cyclopentadiene (1) and acryloyl-2-oxazolidinones
2 catalyzed by copper(II)/bissulfoximine complexes required
first, Cu(ClO4)2 as copper(II) source, second, chloroform as
solvent, and third, a novel ligand having an electron-rich
bridging arene and methoxy substituents at the ortho-
positions of the sulfoximine aryl units. For that purpose,
dimethyl-substituted 5f was synthesized17 and evaluated in
the test reaction.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (SFB 380) and the Fonds der
Chemischen Industrie for financial support. M.M. and M.V.
thank DFG (Graduiertenkolleg 440) for predoctoral fellow-
ships. We also acknowledge the Degussa AG and OMG AG
& Co KG-dmc2 division for the donation of chemicals.
Supporting Information Available: Experimental pro-
cedures and spectral data for 5a-f. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL027273E
(16) We chose to use 5a in this optimization process, because it is readily
available in a one-step process from commercially available starting
materials. For details see ref 8.
(17) Bissulfoximines of this type with stronger electron-donating sub-
stituents at C4 and C5 have remained inaccessible to date.
(18) For details see the Supporting Information.
(19) In comparison, [Cu((S,S)-t-Bu-box)](SbF6)2 affords cycloadducts of
type 3 with enantiomeric excesses >94% at ambient temperatures. For
details, see: Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von
Matt, P.; Miller, S.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.;
Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.
Pleasingly, we found that our hypothesis was fully
confirmed, and that 5f indeed gave the most enantioselective
Org. Lett., Vol. 5, No. 4, 2003
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