Chiral bisguanidine-catalyzed inverse-electron-demand hetero-diels-alder reaction of chalcones with azlactones

Article abstract of DOI:10.1021/ja1046928

A new type of C₂-symmetric chiral bisguanidine was designed as a highly efficient catalyst in the inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones for the first time. A wide variety of γ, I-unsaturated I-lactone derivatives with α-quaternary-ss- tertiary stereocenters were obtained in high yields (up to 88%) with excellent enantioselectivities (up to 99% ee). Hydrogen bonds were considered to be crucial for the activation and stereoinduction of the reaction. In all cases, the major was HDA adducts, which were obtained as a single diastereomer along with little amount of Michael addition products.

Full text of DOI:10.1021/ja1046928

Published on Web 07/21/2010
Chiral Bisguanidine-Catalyzed Inverse-Electron-Demand Hetero-Diels-Alder
Reaction of Chalcones with Azlactones
Shunxi Dong, Xiaohua Liu, Xiaohong Chen, Fang Mei, Yulong Zhang, Bo Gao, Lili Lin, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry,
Sichuan UniVersity, Chengdu 610064, P. R. China
Received April 25, 2010; E-mail: xmfeng@scu.edu.cn
Scheme 1. Two Possible Base-Catalyzed Reactions of Chalcones
with Azlactones
Abstract: A new type of C2-symmetric chiral bisguanidine was
designed as a highly efficient catalyst in the inverse-electron-demand
hetero-Diels-Alder reaction of chalcones with azlactones for the first
time. A wide variety of γ,δ-unsaturated δ-lactone derivatives with
R-quaternary-ꢀ-tertiary stereocenters were obtained in high yields
(up to 88%) with excellent enantioselectivities (up to 99% ee).
Hydrogen bonds were considered to be crucial for the activation and
stereoinduction of the reaction. In all cases, the major was HDA
adducts, which were obtained as a single diastereomer along with
little amount of Michael addition products.
Table 1. Optimization of the Reaction Conditionsa
The inverse-electron-demand hetero-Diels-Alder (IEDDA) reac-
tion1 has been demonstrated to be one of the most powerful strategies
for construction of six-membered oxygenated heterocycles.2 Cinna-
maldehyde and activated enones have been successfully identified for
IEDDA reactions with electron-rich olefins,3 while simple R,ꢀ-
unsaturated ketones, such as chalcones, have usually been used as
classical Michael acceptors rather than dienes.4 To date, few examples
of catalytic asymmetric IEDDA reactions of chalcones have been
reported.1c Azlactones, as versatile reactants,5a have been employed
as Michael donors in the synthesis of potentially bioactive R,R-
disubstituted R-amino acids.5b-d It was rationalized that Michael
addition involving chalcones and azlactones was prone to occur
(Scheme 1, route a). However, we found that an unexpected IEDDA
reaction of chalcones and azlactones6 occurred preferentially in the
presence of a new type of C2-symmetric chiral bisguanidine, affording
chiral γ,δ-unsaturated δ-lactones with a quaternary stereocenter
(Scheme 1, route b).
yield (%)
b
5ab c
6a and 6a′
ee of 5a (%)d
,
entry
cat.
T (°C)
1
2
3
1a
2a
2b
2c
2c
2c
0
0
0
45
30
65
61
78
73
5
20
18
13
6
-13
25
30
82
89
4
0
5e
-20
-20
6e f
,
8
96
Chiral guanidines,7 because of the characteristics of high pKa values
and hydrogen-bonding activation, have been shown to be efficient
catalysts for enantioselective reactions. Initially, the reaction of chalcone
3a and azlactone 4a was carried out with chiral guanidine7d catalyst
1a at 0 °C in THF. Unexpectedly, the major product was cyclic adduct
5a, which was obtained as a single diastereomer in 45% yield and
13% ee along with a 5% yield of the Michael addition products 6
(Table 1, entry 1). Encouraged by this interesting result, we synthesized
and evaluated a number of chiral guanidines. Enhanced enantioselec-
tivities were obtained using bisguanidines with achiral or chiral linkers
(Table 1, entries 2-4). Chiral guanidine 2c derived from (S,S)-1,2-
diphenylethylenediamine gave δ-lactone 5a in 61% yield with 82%
ee (Table 1, entry 4). Fortunately, 73% yield with 96% ee was obtained
when the reaction temperature was decreased to -20 °C and THF/
CHCl3 was used as solvent (Table 1, entries 5 and 6). To understand
the pathway for obtaining cyclic adduct 5a,8 Michael products 6a and
6a′ were isolated and resubjected to the reaction system; neither could
perform intramolecular nucleophilic addition to give 5a, which
suggested that the cyclic adduct 5a was obtained via the IEDDA
reaction of the chalcone at the C4 and C5 positions of the azlactone
(Scheme 1, route b).
a Unless otherwise noted, all of the reactions were carried out with
guanidine (10 mol %), 3a (0.2 mmol), and 4a (0.1 mmol) in THF (1.0 mL)
for 48 h. b Isolated yield. c Only a single diastereomer of 5a was obtained.
d Determined by chiral HPLC analysis. e For 72 h. f THF/CHCl3 [1/1 (v/v)]
was used as the solvent.
and electron-rich chalcones (Table 2, entries 1-15 and 17-23) as well
as heterocyclic examples (Table 2, entries 16, 24, and 25) underwent
the IEDDA reaction smoothly, giving the corresponding δ-lactones
in good yields (40-88%) with excellent enantioselectivities (89-99%
ee). Generally, chalcones with electron-withdrawing groups on the
aromatic substituents exhibited higher reactivity than those with
electron-donating groups. In all cases, only a single diastereomer of 5
was obtained.
The scope of the IEDDA reaction of chalcone 3a with various
azlactones was also surveyed. As shown in Table 3, regardless of the
electronic nature and steric hindrance of the R3 substituent on the
aromatic ring of 4, high yields and excellent enantioselectivities
(92-97% ee) were obtained (Table 3, entries 1-5). Furthermore,
azlactones derived from other amino acids were also tolerated (Table
3, entries 6 and 7). To further evaluate the synthetic potential of the
catalytic system, the reaction was conducted on a gram scale to afford
5a with similar results (1.511 g, 70% yield, 93% ee). In addition, chiral
Under the optimized conditions, a series of chalcone derivatives
were examined. As summarized in Table 2, both electron-deficient
9
10650 J. AM. CHEM. SOC. 2010, 132, 10650–10651
10.1021/ja1046928  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Asymmetric IEDDA Reaction of Chalconesa
Figure 1. Proposed transition state for the IEDDA reaction of chalcone 3a
with azlactone 4a.
the N-H moiety of the amide could act as a Brønsted acid to activate
the chalcone and lower its LUMO energy through a hydrogen bond.
Azlactone 4a could be enolized and recognized by the guanidine
moiety, associating with the N-H proton of the amide on the other
side via dual intermolecular hydrogen bonds. The enolized azlactone
could attach only from the Re face of the chalcone to form the major
(3S,4R) product, in accordance with the experimental results.
In conclusion, the first catalytic enantioselective IEDDA reaction
of chalcones with azlactones has been realized using a novel C2-
symmetric chiral bisguanidine as a catalyst. It performed well over a
wide range of substrates, affording chiral γ,δ-unsaturated δ-lactones
containing a quaternary stereocenter in high yields (up to 88%) with
excellent enantioselectivities (up to 99% ee). Hydrogen bonds were
considered to be crucial for the activation and stereoinduction of the
reaction. More endeavors to understand the mechanism of the reaction
are underway.
Acknowledgment. We thank the National Natural Science
Foundation of China (20732003 and 20872097), PCSIRT (IRT0846),
and the National Basic Research Program of China (973 Program,
2010CB833300) for financial support. We also thank Sichuan Uni-
versity Analytical & Testing Center for NMR analysis.
a All of the reactions were carried out with 10 mol % 2c, 3 (0.2 mmol),
and 4a (0.1 mmol) in 1.0 mL of THF/CHCl3 [1/1 (v/v)] at -20 °C for
72-96 h. b Isolated yield. c Only a single diastereomer was obtained.
d Determined by chiral HPLC analysis. e The absolute configuration was
(3S,4R), as determined by X-ray analysis.9
Supporting Information Available: Experimental procedures, spec-
tral and analytical data for catalysts and products, and crystallographic
data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
Table 3. Scope of the Asymmetric IEDDA Reaction of Azlactonesa
(1) For reviews of hetero-Diels-Alder reactions, see: (a) Jørgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 3558. (b) Jørgensen, K. A. Eur. J. Org. Chem.
2004, 2093. (c) Merino, P.; Marque´s-Lo´pez, E.; Tejero, T.; Herrera, R. P.
Synthesis 2010, 1.
(2) For reviews, see: (a) Larrosa, I.; Romea, P.; Urp´ı, F. Tetrahedron 2008, 64,
2683. (b) Nu´n˜ez, M. G.; Garc´ıa, P.; Moro, R. F.; D´ıez, D. Tetrahedron 2010,
66, 2089.
(3) For selected examples, see: (a) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc.
1998, 120, 4895. (b) Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37, 2404. (c) Gademann, K.; Chavez, D. E.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2002, 41, 3059. (d) Juhl, K.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 1498. (e) He, M.; Uc, G. J.; Bode, J. W.
J. Am. Chem. Soc. 2006, 128, 15088.
entry
R3
R4
t (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-MeC6H4
3-MeOC6H4
Ph
Bn
Bn
Bn
Bn
Bn
CH3
72
72
72
84
96
84
84
72
72
76 (5z)
95
92
95
97
93
92
90
93
93
78 (5aa)
80 (5ab)
71 (5ac)
68 (5ad)
76 (5ae)
78 (5af)
70 (5a)
(4) A domino Michael lactonization reaction of R,ꢀ-unsaturated ketones and ketene
silyl acetals has been reported. See: Tozawa, T.; Nagao, H.; Yamane, Y.;
Mukaiyama, T. Chem.sAsian J. 2007, 2, 123.
(5) (a) Hewlett, N. M.; Hupp, C. D.; Tepe, J. J. Synthesis 2009, 2825. (b) Cabrera,
S.; Reyes, E.; Alema´n, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A.
J. Am. Chem. Soc. 2008, 130, 12031. (c) Uraguchi, D.; Ueki, Y.; Ooi, T.
J. Am. Chem. Soc. 2008, 130, 14088. (d) Alba, A. N.; Companyo´, X.; Valero,
G.; Moyano, A.; Rios, R. Chem.sEur. J. 2010, 16, 5354.
(6) For their use in asymmetric cycloaddition reactions, see: Jiang, J.; Qing, J.; Gong,
L. Z. Chem.sEur. J. 2009, 15, 7031.
(7) For reviews of chiral guanidine catalysts, see: (a) Ishikawa, T.; Isobe, T.
Chem.sEur. J. 2002, 8, 552. (b) Leow, D.; Tan, C. H. Chem.sAsian J.
2009, 4, 488. For selected examples, see: (c) Ishikawa, T.; Araki, Y.; Kumamoto,
T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245. (d) Yu, Z. P.;
Liu, X. H.; Zhou, L.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2009,
48, 5195. (e) Fu, X.; Loh, W. T.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H. J.;
Wang, J. M.; Tan, C. H. Angew. Chem., Int. Ed. 2009, 48, 7387. (f) Ube,
H.; Shimada, N.; Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858. (g)
Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc. 2010, 132, 6286.
(8) For details, see the Supporting Information.
(9) CCDC 763202 (2c), CCDC 763200 (5d), and CCDC 778528 (6a) contain the
supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
7
Ph
Ph
Ph
MeS(CH2)2
8d
9e
Bn
Bn
70 (5a)
a Unless otherwise noted, all of the reactions were carried out with 10
mol % 2c, 3a (0.2 mmol), and 4 (0.1 mmol) in 1.0 mL of THF/CHCl3 [1/1
(v/v)] at -20 °C for 72-96 h. b Isolated yield. c Determined by chiral
HPLC analysis. d The reaction was carried out on a 5 mmol scale. e The
catalyst was recovered in 85% yield and reused on a 4.25 mmol scale of 4a.
catalyst 2c was recovered from the reaction mixture and reused without
any loss of catalytic activity or enantioselectivity (Table 3, entries 8
and 9).
On the basis of the X-ray structures9 of guanidine 2c and product
5d, a bifunctionally activated transition state for the IEDDA reaction
of chalcone 3a with azlactone 4a is proposed.8 As shown in Figure 1,
JA1046928
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10651