Enantioselective Diels-Alder reaction of simple α,β-unsaturated ketones with a cinchona alkaloid catalyst

Article abstract of DOI:10.1021/ja078251w

The simple α,β-unsaturated ketones and 2-pyrones are readily available and synthetically important dienophiles and dienes, respectively, for Diels-Alder reactions. However, both prove to be challenging substrates for catalytic asymmetric Diels-Alder reactions. By exploring a new catalysis strategy featuring cooperative catalysis with readily available cinchona catalysts, an unprecedented asymmetric Diels-Alder reaction of simple α,β-unsaturated ketones with 2-pyrones has been successfully developed. With broad scopes for both reactants, the reaction provides a direct and versatile asymmetric access to a wide range of structurally novel bicyclic chiral building blocks amenable for further synthetic elaborations. Copyright

Full text of DOI:10.1021/ja078251w

Published on Web 02/06/2008
Enantioselective Diels-Alder Reaction of Simple r,â-Unsaturated Ketones
with a Cinchona Alkaloid Catalyst
Ravi P. Singh, Keith Bartelson, Yi Wang, Heng Su, Xiaojie Lu, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received October 29, 2007; E-mail: deng@brandeis.edu
Table 1. D-A Reaction with Cinchona Alkaloidsa
The extremely broad scope of both the dienes and dienophiles
renders the Diels-Alder (D-A) reaction one of the most versatile
reactions in organic synthesis. This in combination with the ability
of asymmetric Diels-Alder reactions to directly transform achiral
starting materials to stereochemically complex cyclic structures in
a diastereoselective and enantioselective manner underscores the
importance and necessity to continue the development of efficient
catalytic enantioselective variants of the Diels-Alder reactions,
especially those being promoted by practical catalysts and involving
readily accessible yet synthetically valuable dienes and dienophiles.1
Herein, we wish to describe the development of a highly general
and efficient asymmetric Diels-Alder reaction of R,â-unsaturated
ketones 6 and 2-pyrones 5 with a readily accessible cinchona
alkaloid catalyst (4) that had not been previously explored for
asymmetric Diels-Alder reactions.
Although R,â-unsaturated ketones 6 and 2-pyrones 5 have been
extensively used as dienophiles and dienes, respectively, in Diels-
Alder reactions, both prove to be challenging classes of substrates
to be incorporated into asymmetric Diels-Alder reactions.2-4 In
fact, the first efficient asymmetric Diels-Alder reaction of a general
scope with respect to R,â-unsaturated ketones 6 was reported only
recently by MacMillan using chiral imminium catalysis.2a,b Our
group recently disclosed the first highly enantioselective Diels-
Alder reaction with 2-pyrones, which was realized with cinchona
alkaloid-derived bifunctional catalysts such as 1 and 2.5 Although
1 and 2 afforded high diastereoselectivity and enantioselectivity
for D-A reactions of 2-pyrones 5 and active dienophiles with the
double bond substituted with two strongly electron-withdrawing
functionalities, they were found to be ineffective for reactions of 5
and simple R,â-unsaturated ketones 6 (entries 1 and 2, Table 1).
Additional cinchona alkaloids containing hydrogen bond donors
and acceptors, such as quinine and 3, were examined and were
found to provide similarly low diastereoselectivity and enantio-
selectivity (entries 3 and 4, Table 1).
acid
(0.2 equiv)
temp (
time (h)
°
C), conv.
drb
ee (%)c DA:MAb
8:9)
entry catalyst
(%) (7A:8A) of 7A (7 +
1d Q-1
2d Q-2
-
-
rt, 24
rt, 24
rt, 24
rt, 24
rt, 24
rt, 24
rt, 24
rt, 24
92 1.1:1
98 1.4:1
95
59 2.3:1
96 1.2:1
5
29
63
74 1.4:1
73
91 3.6:1
95 4.8:1
99 4.1:1
-3 100:0
53 59:1
3d quinine -
1:1.5
2
100:0
4d QD-3
5d Q-4
-
-
p-TSA
34 100:0
-3
-
1:2.5
-
6
7
8
9
Q-4
Q-4
Q-4
Q-4
1:2.9
CF3SO3H
1:4.2 -3 100:0
C6H5CO2H
N-Boc-Phenyl glycine-D rt, 24
N-Boc-Phenyl glycine-L
1:1.3 -21
14
40 1.6:1
1:2.3
2:1
10 Q-4
11 Q-4
12 Q-4
13 QD-4 TFA
14 Q-2 TFA
rt, 24
rt, 24
0, 96
0, 96
1:1.1
TFA
TFA
-89
6:1
-97 11:1
98 10:1
rt, 24 <5
-
-
-
a Unless noted, reactions were run with 0.15 mmol of 5a, 0.30 mmol of
6 in 75 µL of CH2Cl2; see Supporting Information for details. b Determined
by 1H NMR analysis. c Determined by HPLC analysis. d Reaction was run
with 10 mol % catalyst.
Figure 1. The structures of cinchona alkaloids.
In light of the poor efficiency afforded by various cinchona
alkaloids containing hydrogen bond donors and acceptors, we began
to search for an alternative strategy to achieve efficient asymmetric
catalysis for the D-A reaction of 5 and 6 (Figure 1). MacMillan
demonstrated that chiral secondary amines could serve as effective
catalysts to activate R,â-unsaturated ketones for asymmetric D-A
reactions through imminium catalysis.2a Recent studies by Ishihara6
established that chiral primary amines could activate R,â-unsaturated
aldehydes for highly enantioselective D-A reactions. Although only
electron-rich dienes were employed in these chiral primary and
secondary amine-catalyzed D-A reactions of R,â-unsaturated
ketones and aldehydes, we envisaged that the readily available
9-NH2 cinchona alkaloids 47,8 might be able to promote an efficient
asymmetric D-A reaction via its ability to simultaneously activate
5 and 6 with its primary amine and quinuclidine motifs, respectively.
Accordingly, we began an investigation of the D-A reaction of
5 and 6 at room temperature in dichloromethane with 5 mol % of
the 9-NH2 cinchona alkaloid Q-4. In the absence of any acid, the
reaction with Q-4 readily proceeded to near completion but provided
the Michael adduct 9 as the major product. The D-A adduct was
formed not only as a minor product but also in very poor
diastereoselectivity and enantioselectivity (entry 5, Table 1). The
D-A adduct/Michael adduct ratio could be improved significantly
when the 4-catalyzed reaction was performed in the presence of
certain acids. We were particularly pleased to find that, with 20
mol % of trifluoroacetic acid (TFA), the reaction with Q-4 afforded
the exo-D-A adduct 7A as the major product in good enantiomeric
excess (entry 11, Table 1). The exo-selectivity and the enantiose-
lectivity could be further enhanced by lowering the reaction
temperature to 0 °C, at which the D-A adduct/Michael adduct ratio
as well as the exo-selectivity reached a synthetically useful level,
while the exo-adduct 7A was produced in 97% ee (entry 12, Table
1). Under the optimized condition, QD-4 furnished comparable
diastereoselectivity and enantioselectivity (entry 13, Table 1).
Importantly, the primary amine functionality in catalyst 4 is critical
9
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J. AM. CHEM. SOC. 2008, 130, 2422-2423
10.1021/ja078251w CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. D-A Reaction with 2-Pyronesa
Scheme 1. Decarboxylation of 7A4c
2-pyrones. Notably, the diastereoselectivity and enantioselectivity
of the reaction did not fluctuate significantly when the aromatic
substituent was changed to an aliphatic substituent. The diastereo-
selectivity and enantioselectivity decreased with a 2-pyrone bearing
an electron-withdrawing group (5d), although the corresponding
exo-D-A adduct was still formed in 90% ee.
In summary, we have discovered a readily available cinchona
alkaloid-derived catalyst for asymmetric Diels-Alder reactions.
Notably, this catalyst proved to be highly effective for the
asymmetric D-A reaction of simple R,â-unsaturated ketones 6 with
2-pyrones 5, an unprecedented enantioselective D-A reaction
involving two readily available but challenging classes of D-A
reactants. This reaction should provide a useful asymmetric route
to a wide range of bicyclic chiral building blocks amenable for
further synthetic elaborations (Scheme 1).4c,9
entry
dienophile
temp (
°
C)
drc (7:8)
yield % 7
+
8/7d
eee (%)
0
0
0
0
0
0
0
80:20
(82:18)
81:19
79:21
(79:21)
81:19
(81:19)
84:16
80:20
84:16
80:20
80:20
84:16
75:25
94:6
87/69
98
(96)b
98
1
2
3
6A
6B
6C
(91)/(74)
92/74
89/69
(95)/(74)
96/76
(95)/(76)
99/81
81/63
68/57
85/67
71/56
92/77
95/70
99/93
92/70
83/63
99/96
90/82
98/91
98
(96)b
97f
(97)b
97
4g
6D
5
6
7
8
6E
6F
6G
6H
6I
-20
0
0
0
0
97
97
99
99
99
99
99
99
96
99
99
96
9
10
11
12
13b
14h
15g
16g
17g
6J
-30
-30
-20
-20
-20
-20
-20
-20
Acknowledgment. We are grateful for financial support from
NIH (GM-61591). We thank Bruce Foxman and Chen-Hsing (Josh)
Chen for X-ray crystallographic analysis and the NSF for the partial
support of this work through Grant CHE-0521047 for the purchase
of a new X-ray diffractometer.
6K
6L
6M
6N
6O
6P
6Q
76:24
76:24
97:3
92:8
93:7
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Unless noted, reactions were run with 0.25 mmol of 5a, 0.50 mmol of
6 in 125 µL of CH2Cl2. b The results in parentheses were obtained with
Q-4; see Supporting Information for details. c Determined by 1H NMR
analysis. d Isolated yields of pure exo-7. e Enantiomeric excess of 7 as
determined by HPLC analysis. f The absolute configuration was established
by X-ray crystallographic analysis (see Supporting Information). g Reaction
was run for 72 h. h Reaction was run for 120 h.
References
(1) For recent reviews of enantioselective Diels-Alder reactions, see: (a)
Maruoka, K. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; p 467. (b) Evans, D. A.; Johnson, J. S. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 3, p 1177. (c)
Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
Table 3. D-A Reaction with Substituted Pyronesa
(2) (a) For a discussion of challenging issues in the development of catalytic
asymmetric D-A reactions with simple R,â-unsaturated ketones, see:
Northrup, A. B.; MacMillian, D. W. C. J. Am. Chem. Soc. 2002, 124,
2458. For reviews of asymmetric imminium catalysis, see: (b) Lelais,
G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (c) Erkkila¨,
A.; Majamder, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416.
(3) For chiral Lewis acid catalyzed asymmetric D-A reactions with simple
R,â-unsaturated ketones, see: (a) Ryu, D. H.; Lee, T. L.; Corey, E. J. J.
Am. Chem. Soc. 2002, 124, 9992. (b) Ryu, D. H.; Corey, E. J. J. Am.
Chem. Soc. 2003, 125, 6388.
(4) For reviews of D-A reaction with 2-pyrones, see: (a) Afarinkia, K.;
Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111.
(b) Woodard, B. T.; Posner, G. H. AdV. Cycloaddit. 1999, 5, 47. For
synthetic applications of Diels-Alder reactions of 2-pyrones, see: (c)
Corey, E. J.; Kozikowski, A. P. Tetrahedron Lett. 1975, 2389. (d)
Nicolaou, K. C.; Liu, J. J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K. J.
Chem. Soc., Chem. Commun. 1992, 1118. (e) Nicolaou, K. C.; Yang, Z.;
Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.;
Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature
1994, 367, 630. (f) Okamura, H.; Shimizu, H.; Nakamura, Y.; Iwagawa,
T.; Nakatani, M. Tetrahedron Lett. 2000, 41, 4147. (g) Shimizu, H.;
Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron 2001, 57, 1903.
(h) Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.
(5) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am.
Chem. Soc. 2007, 129, 6364.
(6) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504. (b)
Sakakura, A.; Suzuki, K.; Nakano, K.; Ishihara, K. Org. Lett. 2006, 8,
2229. (c) Sakakura, A.; Suzuki, K.; Ishihara, K. AdV. Synth. Catal. 2006,
348, 2457.
(7) Cinchona alkaloid 4 was first reported by: Brunner, H.; Bu¨gler, J.; Nuber,
B. Tetrahedron: Asymmetry 1995, 6, 1699.
a Unless noted, reactions were run with 0.15 mmol of 5, 0.30 mmol of
6 in 75 µL of CH2Cl2 with 5 mol % of QD-4 and 20 mol % of TFA for 96
h. b Determined by 1H NMR analysis. c Isolated yields of pure exo-7.
d Enantiomeric excess of 7 as determined by HPLC analysis. e The absolute
configuration of the D-A adduct was established by X-ray crystallographic
analysis (see Supporting Information).
to its activity, as replacing the amine with a thiourea group abolishes
the catalytic activity (entry 14 vs 11, Table 1). Moreover, the
presence of TFA is essential to the selectivity of 4 (entry 11 vs 5,
Table 1), although TFA itself does not promote the D-A reaction.9
These results suggest that 4 activates 6A for the D-A reaction
through imminium catalysis. We also found that, in contrast to 5a,
electron-rich dienes bearing neither a hydrogen bond acceptor nor
donor such as cyclopentadiene and cyclohexadiene were inactive
for the D-A reaction with 6A in the presence of 4 and TFA.9 These
results indicate that the activation of 5a by catalyst 4 is also required
for the D-A reaction to occur.
(8) For 4-catalyzed asymmetric conjugate addition reactions, see: (a) Xie,
J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu,
Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389. (b) Xie,
J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org.
Lett. 2007, 9, 413. (c) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (d) McCooey, S. H.;
Connon, S. J. Org. Lett. 2007, 9, 599.
Significantly, the high enantioselectivity afforded by catalyst 4
could be readily extended to â-aryl (6A-I), â-alkyl (6J-N), and
â-unsubstituted (6O-Q) R,â-unsaturated ketones (Table 2). As
illustrated in Table 3, the catalyst also tolerates substituted
(9) See Supporting Information for details.
JA078251W
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