Highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol062718a

The highly enantioselective Michael addition of 1,3-cyclic dicarbonyl compounds to α,β-unsaturated ketones was reported to be catalyzed by an organic primary amine derived from quinine. A chiral anticoagulant drug, (S)-warfarin, was directly prepared in 96% ee, and other related important adducts were also obtained in excellent enantioselectivity (89-99% ee).

Full text of DOI:10.1021/ol062718a

ORGANIC
LETTERS
2007
Vol. 9, No. 3
413-415
Highly Enantioselective Michael Addition
of Cyclic 1,3-Dicarbonyl Compounds to
r,â-Unsaturated Ketones
Jian-Wu Xie,†,‡ Lei Yue,§ Wei Chen,§ Wei Du,§ Jin Zhu,† Jin-Gen Deng,† and
|
Ying-Chun Chen*,§,
Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan ProVince and
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, China, Key Laboratory of Drug-Targeting of
Education Ministry and Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan UniVersity, Chengdu 610041, China, State Key Laboratory of
Biotherapy, West China Hospital, Sichuan UniVersity, Chengdu, China, and Graduated
School of Chinese Academy of Sciences, Beijing, China
ycchenhuaxi@yahoo.com.cn
Received November 7, 2006
ABSTRACT
The highly enantioselective Michael addition of 1,3-cyclic dicarbonyl compounds to
r,â-unsaturated ketones was reported to be catalyzed by
an organic primary amine derived from quinine. A chiral anticoagulant drug, (S)-warfarin, was directly prepared in 96% ee, and other related
important adducts were also obtained in excellent enantioselectivity (89−99% ee).
The Michael addition to R,â-unsaturated systems is an
important carbon-carbon bond-forming reaction in organic
synthesis, and the development of enantioselective catalytic
protocols for this reaction has been the subject of intensive
research.1 In addition to the great success catalyzed by metal
complexes, the environmentally benign organocatalyst-
mediated asymmetric Michael reaction has undergone rapid
progress for various useful donor-acceptor combinations in
recent years.2 Among them, MacMillan and other chemists
developed a versatile strategy for nonchelating R,â-unsatur-
ated aldehydes and ketones through LUMO-lowering activa-
tion catalyzed by chiral secondary amines.3 Nevertheless, low
catalytic efficacy was generally noted for R,â-unsaturated
ketones even at room temperature.4 In an inventive example,
Jørgensen et al. reported the enantioselective Michael addi-
tion of cyclic 1,3-dicarbonyl compounds to R,â-unsaturated
ketones catalyzed by an imidazolidine 1a (Figure 1) derived
from chiral 1,2-diphenylethylenediamine, and this process
was elegantly applied to make a chiral drug, warfarin, a
(2) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Seayad, J.; List B. Org. Biomol. Chem. 2005, 3,
719. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520. For selected examples, see: (d) Peelen, T. J.; Chi, Y.; Gellman, S.
H. J. Am. Chem. Soc. 2005, 127, 11598. (e) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem. Int. Ed. 2005, 44, 4212. (f) Hoashi, Y.; Okino,
T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44, 4032. (g) Li, H.; Song,
J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948. (h) Xue, D.;
Chen, Y. C.; Cun, L. F.; Wang, Q. W.; Zhu, J.; Deng, J. G. Org. Lett.
2005, 7, 5293. (i) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.;
Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028. (j) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 4966. (k) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.;
Raabe, G. Nature 2006, 441, 861. (l) Huang, H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2006, 128, 7170. (m) Palomo, C.; Vera, S.; Mielgo, A.; Gomez-
Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984.
† Chengdu Institute of Organic Chemistry.
‡ Graduated School of Chinese Academy of Sciences.
§ West China School of Pharmacy, Sichuan University.
| West China Hospital, Sichuan University.
(1) For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
10.1021/ol062718a CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/06/2007

acetone 3a in DCM at room temperature. (S)-Warfarin 4aa
was cleanly isolated in 90% yield with a promising 92% ee
after 12 h (Table 1, entry 1). 9-Amino-9-deoxyepicinchonine
Table 1. Screening Studies of Organocatalytic Michael
Addition of 4-Hydroxycoumarin 2a to Benzylideneacetone 3aa
Figure 1. Structure of amine catalysts.
widely prescribed anticoagulant.4e,5 Unfortunately, less than
90% ee was observed for a range of substrates, and in
general, over 6 days were required in order to achieve good
yields at ambient temperature. This encouraged us to explore
this important asymmetric Michael reaction with our newly
developed 9-amino-9-deoxyepicinchona alkaloids as the
iminium catalysts (Figure 1).6
We were pleased to find that 9-amino-9-deoxyepiquinine
1b (Figure 1, 20 mol %) in the combination with TFA (40
mol %) exhibited high catalytic activity for the asymmetric
Michael addition of 4-hydroxycoumarin 2a to benzylidene-
entry
solvent
additive
yieldb (%)
eec (%)
1
2d
3
4
5
6
7
8
9
DCM
DCM
THF
TFA
TFA
TFA
TFA
TFA
TFA
CF3SO3H
HCl
HClO4
TFA
90
92
88
86
51
42
15
80
75
88
83
51
92
-92
86
60
85
65
85
83
73
DMF
toluene
MeOH
DCM
DCM
DCM
DCM
DCM
DCM
10e
11d,e
12f
96
-92
97
(3) (a) For a review, see: List, B. Chem. Commun. 2006, 819. For
selected examples, see: (b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370. (c) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 1172. (d) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 7894. (e) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-
J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482. (f)
Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 9328. (g) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 6660. (h) Wang, W.; Li, H.; Wang, J. Org. Lett.
2005, 7, 1637. (i) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura,
R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437. (j) Yang, J.
W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127,
15036. (k) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051. (l) Marigo, M.; Schulte, T.; Franze´n,
J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (m) Brandau, S.;
Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2006, 45, 4305. (n) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen,
Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563. (o) Wang,
W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354.
(4) For asymmetric reactions of R,â-unsaturated ketones catalyzed by
secondary amines, see: (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2,
2975 and references therein. (b) Northrup, A. B.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 2458. (c) Halland, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2002, 67, 8331. (d) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661. (e) Halland, N.;
Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955. (f)
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004,
43, 1272. (g) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A.
AdV. Synth. Catal. 2004, 346, 1077. (h) Prieto, A.; Halland, N.; Jørgensen,
K. A. Org. Lett. 2005, 7, 3897. (i) Knudsen, K. R.; Mitchell, C. E. T.; Ley,
S. V. Chem. Commun. 2006, 66. (j) Li, D.-P.; Guo, Y.-C.; Ding, Y.; Xiao,
W.-J. Chem. Commun. 2006, 799. (k) Tuttle, J. B.; Ouellet, S. G.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662.
TFA
TFA
a Unless otherwise noted, the reaction was performed with 0.1 mmol of
2a, 0.15 mmol of 3a, and 20 mol % of catalyst 1b in 2 mL of solvent at
room temperature for 12 h. b Isolated yield. c Determined by chiral HPLC
analysis. The absolute configuration was determined to be (S) according to
the optical rotation. d Catalyzed by 1c. e At 0 °C for 96 h. f Using 10 mol
% of 1b in 1 mL of DCM.
1c gave the same enantioselectivity while the adduct with
opposite configuration was obtained (entry 2). Subsequently,
we investigated the effects of solvents and acidic additives
with 1b. Good yields were obtained in THF and DMF but
the ee was reduced (entries 3 and 4). Both reactivity and enan-
tioselectivity were decreased in toluene or methanol (entries
5 and 6). The enantioselectivity was decreased in the pres-
ence of other acidic additives (entries 7-9). In addition, the
coupling reaction could proceed smoothly at 0 °C, and an
excellent ee (96%) was obtained in 88% yield after 96 h
(entry 10). However, we found that no beneficial effect on
ee was observed at 0 °C catalyzed by TFA salt of 1c (entry
11). Moderate yield was attained catalyzed by 10 mol % of
1b after 96 h in a more concentrated solution (entry 12).
With the optimal reaction conditions in hand, we then
examined a variety of cyclic 1,3-dicarbonyl compounds
(Figure 2) and R,â-unsaturated ketones to established the
(5) During the preparation of this paper, a vicinal diamine-catalyzed
synthesis of (R)-warfarin (92% ee) was reported, see: (a) Kim, H.; Yen,
C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. For other reports on
stereoselective warfarin synthesis, see: (b) Demir, A. S.; Tanyeli, C.;
Gu¨lbeyaz, V.; Akgu¨n, H. Tur. J. Chem. 1996, 20, 139. (c) Robinson, A.;
Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321. (d) Cravotto, G.;
Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahedron: Asymmetry 2001,
12, 707. (e) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006,
8, 4851. Optical resolution, see: (f) West, B. D.; Preis, S.; Schroeder, C.
H.; Link, K. P. J. Am. Chem. Soc. 1961, 83, 2676.
(6) (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.
For other examples of primary amines as iminium catalysts, see the
following. For R,â-unsaturated aldehydes: (b) Ishihara, K.; Nakano, K. J.
Am. Chem. Soc. 2005, 127, 10504. (c) Sakakura, A.; Suzuki, K.; Nakano,
K.; Ishihara, K. Org. Lett. 2006, 8, 2229. For R,â-unsaturated ketones: (d)
Tsogoeva, S.; Jagtap, S. B. Synlett 2004, 2624. (e) Martin, N. J. A.; List,
B. J. Am. Chem. Soc. 2006, 128, 13368. (f) See ref 5a.
Figure 2. Structures of cyclic 1,3-dicarbonyl compounds.
414
Org. Lett., Vol. 9, No. 3, 2007

general utility of the catalytic transformation. The Michael
reaction was generally conducted with 20 mol % of 1b at
0 °C for 96 h. As illustrated in Table 2, for the reactions of
observed even at room-temperature due to the very low
solubility of 2f in DCM, gratifyingly, the Michael reaction
proceeded very well at 40 °C, and an excellent ee (99%)
was achieved in 71% yield after 24 h (entry 16).
As previously reported, the ketimine cation intermediate
from 1b-(TFA)2 salt and benzylideneacetone 3a in the
asymmetric Michael addition would adopt a trans conforma-
tion (Figure 3, a).6a,8 The desired (S)-product could be
obtained through the si-face attacking of the iminium ion.
Table 2. Asymmetric Michael Addition of 1,3-Dicarbonyl
Compounds 2 to R,â-Unsaturated Ketones 3a
entry
2
R1
R2 (3)
4
yieldb (%) eec (%)
1
2
3
4
2a Ph
2a p-Cl-Ph
2a p-MeO-Ph Me (3c)
2a 2-furanyl
2a 2-thienyl
2a Ph
2a Ph
2a n-Pr
2a i-Pr
Me (3a)
Me (3b)
4aa
4ab
4ac
4ad
4ae
4af
88
87
81
81
83
90
82
93
88
55 (95)
78
87
80
82
68
71
96
97
95
94
93
99
97
95
98
90
94
99
98
98
89
99
Me (3d)
Me (3e)
Et (3f)
5
6d
7d
8d
9d
n-Pr (3g) 4ag
Me (3h)
Me (3i)
Et (3j)
4ah
4ai
4aj
4ak
4ba
4ca
4da
4ea
4fa
10d,e 2a n-Pr
11d
12
13
14
15
16
2a
-C4H8- (3k)
Figure 3. Possible iminium intermediate in the Michael reaction.
2b Ph
2c Ph
2d Ph
2e Ph
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
In conclusion, we have successfully demonstrated that
9-amino-9-deoxyepiquinine is an excellent iminium orga-
nocatalyst for the enantioselective Michael addition reaction
of cyclic 1,3-dicarbonyl compounds and R,â-unsaturated
ketones under mild conditions. The reaction scopes were
quite broad, and excellent enantioselectivity (89-99% ee)
was achieved for a number of cyclic 1,3-dicarbonyl com-
pounds and substituted R,â-unsaturated ketones. Moreover,
a chiral drug, (S)-warfarin, was directly prepared in high ee
(96%) and yield. Current studies are actively and well
underway to expand the synthetic utility of this reaction, as
well as of this catalytic system in other asymmetric trans-
formations.
2f
Ph
a Unless otherwise noted, the reaction was performed with 0.1 mmol of
2, 0.15 mmol of 3, and 20 mol % of catalyst 1b in 2 mL of DCM at 0 °C
for 96 h. b Isolated yield. c Determined by chiral HPLC analysis. The
absolute configuration of 4aa was (S), and the other adducts were assigned
accordingly. d For 6 days. e Yield in parentheses is based on recovered 2a.
4-hydroxycoumarin 2a, excellent results were achieved with
R,â-unsaturated ketones 3b-e bearing various â-aryl or
heteroaryl substitutions (entries 2-5). Other bulkier alkyl
enones 3f and 3g were also well tolerated to give excellent
ee while longer time was required (entries 6 and 7). On the
other hand, the enantioselectivity was quite satisfying when
â-alkyl R,â-unsaturated ketones 3h-j were applied (entries
8-10), and a high yield was observed even for enone 3i
with a branched substitution after 6 days (entry 9). Neverthe-
less, the isolated yield was moderate for ethyl enone 3j (entry
10). A high ee was also received in the case of cyclic enone
3k (entry 11). Subsequently, a few 4-hydroxycoumarin
derivatives 2b-d with different substitutions were investi-
gated. The electronic effect was very marginal and remark-
able enantioselectivity was achieved (entries 12-14). 4-Hy-
droxythiocoumarin 2e exhibited slightly lower reactivity,
while a high ee (89%) was still obtained (entry 15). In
comparison, only moderate ee (75%) was received in the
same reaction of 2e catalyzed by 1a.4e In addition, we tested
the asymmetric Michael addition reaction of 1-methyl-4-
hydroxycarbostyril 2f.7 Although sluggish reaction was
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(20502018), Ministry of Education of China (NCET-05-
0781), Fok Ying Tung Education Foundation (101037), and
Sichuan University. We thank Dr. Rui Li for his help with
the computational calculation studies.
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC chro-
matograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062718A
(7) For the Michael reaction of 4-hydroxycarbostyrils and benzylidene-
acetone in a racemic form, see: Boetius, M.; Carstens, E.; Meyer, C.
4-Hydroxycarbostyril derivatives. Patent DD 13870, 1957.
(8) The computational studies were conducted with hyperchem 7.5
software, see ref. 6a, Supporting Information
Org. Lett., Vol. 9, No. 3, 2007
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