Enantioselective michael reaction of α-alkyl-β-keto esters and enones under multifunctional catalysis

Article abstract of DOI:10.1021/ol102256v

An efficient approach for the enantioselective Michael additions of β-alkyl-β-keto esters to β-substituted α,β-unsaturated ketones has been developed. The Michael products could be obtained in good to excellent yields (75-98%) with excellent diastereosele

Full text of DOI:10.1021/ol102256v

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5218-5221
Enantioselective Michael Reaction of
r-Alkyl-ꢀ-keto Esters and Enones under
Multifunctional Catalysis
Juanjuan Yang, Wenjun Li, Zhichao Jin, Xinmiao Liang, and Jinxing Ye*
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
Education, School of Pharmacy, East China UniVersity of Science and Technology,
130 Meilong Road, Shanghai 200237, China
yejx@ecust.edu.cn
Received September 20, 2010
ABSTRACT
An efficient approach for the enantioselective Michael additions of ꢀ-alkyl-ꢀ-keto esters to ꢀ-substituted r,ꢀ-unsaturated ketones has been
developed. The Michael products could be obtained in good to excellent yields (75-98%) with excellent diastereoselectivities (up to >99:1 dr)
and enantioselectivities (up to 96% ee) and could easily be transformed into a synthetically useful hexahydrophenanthrene structure under
mild conditions in good yield.
Of those common methods for construction of valuable
compounds in modern organic synthesis, the Michael addi-
tion has been the most fascinating and powerful one,1 whose
product might also be a key intermediate for further
transformations such as the Robinson annulation reaction
affording a variety of substituted cyclohexenones.2 Therefore,
the asymmetric version has been increasingly attractive to
most scientists either in natural product preparations or in
enantioselective organic synthetic methodologies.3 The past
few decades have witnessed a tremendous development of
various efficient methodologies for asymmetric synthesis
involving enzyme catalysis, organometallic catalysis, and
more recently, organic catalysis.4 Among those powerful
approaches for enantioselective catalysis, the asymmetric
organocatalytic synthesis has been one of the most outstand-
ing methods mainly due to its high efficiency, low toxicity,
and ready availability.5 Up until now, great efforts have been
made in this field, and remarkable progress has been achieved
in both aldehyde and ketone activations through certain
catalytic modes such as iminium, enamine, and SOMO
activation.6 Nevertheless, compared with the magnificent
achievements in asymmetric aldehyde activation,7 the or-
gano-catalytic Michael addition involving R,ꢀ-unsaturated
ketone, whose reactivity is generally weak, remains a
(1) For the very recent reviews of Michael addition, see: (a) Sato, K.;
Tarui, A.; Omote, M.; Ando, A.; Kumadaki, I. Synthesis 2010, 1865. (b)
Amslinger, S. Chem. Med. Chem. 2010, 5, 351. (c) Dalpozzo, R.; Bartoli,
G.; Sambri, L.; Melchiorre, P. Chem. ReV. 2010, 110, 3501.
(2) For limited reviews of Robinson annulation, see: (a) Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481. (b) Simon, C.; Constantieux, T.;
Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
10.1021/ol102256v  2010 American Chemical Society
Published on Web 10/18/2010

challenging task, and the control of stereoselectivity is
another formidable issue for this transformation. Moreover,
the formation of an all-carbon chiral center and a simulta-
neous construction of a vicinal chiral tertiary carbon center
with complete stereocontrol would certainly add to those
difficulties greatly.8 During the past couple of years, R-alkyl-
ꢀ-keto esters have been applied frequently in such transfor-
mations with a variety of conjugate electrophilic Michael
acceptors to conquer those difficulties involving both organic
and organometallic catalysts,9 and of course, a number of
investigations of the Michael addition of ꢀ-keto esters with
different vinyl ketones had also been implemented.
For example, Hermann and Wynberg reported a seminal
work on the enantioselective conjugate additions of ꢀ-keto
esters to methyl vinyl ketone using natural cinchona alkaloid
as catalyst,10 and the highly enantioselective conjugate
addition reaction of ꢀ-keto esters with methyl vinyl ketone
had been disclosed by Sasai and Shibasaki.11 Moreover, there
were also excellent reports employing chiral organometallic
catalysts such as scandium(III) catalysts,12 palladium cata-
lysts,13 and ruthenium catalysts,14 as well as the phase
transfer catalysis reported by Maruoka and co-workers.15
More recently, an efficient cinchona alkaloid catalyst which
has been developed by Deng and co-workers also represented
an outstanding work in this transformation.16
(3) For recent books, see: (a) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2004. (b) Dalko, P. I.
EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, Germany, 2007.
(c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asymmetric
Catalysis; Springer: Berlin, 1999. For recent reviews of asymmetric Michael
addition reactions, see: (d) Krause, N.; Hoffmann-Ro¨er, A. Synthesis 2001,
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to methyl vinyl ketone catalyzed by a variety of chiral Lewis
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Org. Lett., Vol. 12, No. 22, 2010
5219

of our best effort to overcome those barriers. Herein, we report
our new development of the enantioselective Michael addition
of R-alkyl-ꢀ-keto esters to ꢀ-substituted R,ꢀ-unsaturated ketones
under multifunctional catalysis with excellent diastereo- and
enantioselectivities, and the products could also be easily
transformed into synthetically useful chiral cyclohexenones
through the Robinson annulation.
The reaction of 8a and 9a was first investigated as the
model reaction, and optimizations of catalyst and solvent were
carried out, whose representative results were shown in Table
1. A variety of chiral primary amine catalysts were tested in
catalyst, but with very low enantioselectivity of 22% (Table 1,
entry 1). However, moderate enantioselectivity of 47% and
diastereoselectivity of 68/32 were obtained using (1R,2R)-
diphenylethylene-1,2-diamine 2 as catalyst (entry 2). Increas-
ingly, when 9-amino (9-deoxy) epiquinine 3 was used as
catalyst, 87/13 dr and 77% ee were achieved (entry 3). Acidic
additives, such as trifluoroacetic acid, decreased both diastereo-
and enantioselectivity (entry 4). To our great delight, when
multifunctional catalysts were used, both the diastereo- and
enantioselectivity improved (entries 5-8). After a series of
attempts, catalyst 4 was found to be the best one. Examination
of solvent effects found that toluene, ethyl acetate, acetonitrile,
and THF were all good solvents for this Michael reaction
(entries 9-18). Finally, the result proved best when using
catalyst 4 in toluene with a concentration of 1.0 M based on
8a at ambient temperature (entry 19).
Table 1. Primary Screening Resultsa
Under the optimized conditions, we next explored the
scope of the asymmetric Michael addition of R-alkyl-ꢀ-keto
esters to ꢀ-substituted R,ꢀ-unsaturated ketones. Experimental
data showed that the reaction proceeded very well with a
variety of alkyl vinyl ketones, and the substituents on the
R-alkyl-ꢀ-keto esters had little effect on the results. All these
Michael products were obtained in good to excellent yields
and high diastereoselectivities with excellent ee values (Table
Table 2. Expanding the Scope of the Asymmetric Michael
Additions of R-Alkyl-ꢀ-keto Esters to ꢀ-Substituted
R,ꢀ-Unsaturated Ketonesa
entry
cat.
solvent
conv %b
drc
ee %d
1
2
1
2
3
3
4
5
6
7
4
4
4
4
4
4
4
4
4
4
4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
EtOAc
CH3CN
DMF
DMSO
CHCl3
MTBE
THF
65
6
5
90:10
68:32
87:13
77:33
99:1
97:3
95:5
84:16
97:3
94:6
84:16
86:14
37:63
96:4
96:4
94:6
97:3
92:8
98:2
22
47
-77
51
90
92
86
90
91
91
90
86
75
85
86
94
85
51
93
3
yield %b drc ee %d e
,
entry
R1
R2
R3
R4
4e
5
15
88
76
41
38
93
97
90
60
52
92
96
85
97
73
95g
1
Me
Me
Me
Me
Me
Me
Me
Et
n-Bu
Me
Me
Me
Me
Me
Me
Me
Et
n-Pr
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
95, 10a 98:2 94
82, 10b 99:1 95
86, 10c 98:2 96
97, 10d 98:2 91
97, 10e 98:2 96
95, 10f 99:1 95
93, 10g 98:2 93
95, 10h 99:1 96
80, 10i 98:2 95
92, 10j 98:2 92
2
Me
6
7
8
9
3
n-Bu
n-Pen
n-Hex
Me
n-Hex
Me
Me
n-Pen
n-Bu
Me
n-Hex
n-Bu
n-Pr
n-Pen
Me
4
5
6
7
Et
10
11
12
13
14
15
16
17
18
19f
8
Me
Me
Me 7-OMe
Me 7-OMe 82, 10k 98:2 97
Me 6-OMe 92, 10l 97:3 93
Me 6-OMe 90, 10m 98:2 93
9
10
11
12
13
14
15
16
17
18
19
20
21
Me 6-Br
Me 6-Br
Me 6-Cl
Me 6-Cl
85, 10n 97:3 93
87, 10o 98:2 92
92, 10p 98:2 87
93, 10q >99:1 95
75, 10r >99:1 86
95, 10s >99:1 91
89, 10t >99:1 93
75, 10u >99:1 92
85, 10v 77:23 15 (82)
98, 10w 57:43 65 (82)
90, 10x 60:40 94 (92)
Et2O
MeOH
toluene
Me
Me
Et
i-Bu
(CH2)2Ph Me
Me
Me
Me
Me
H
H
a All reactions were carried out using 1.0 equiv of 8a (0.10 mmol, 0.5
M), 2.0 equiv of 9a, and 0.10 equiv of catalyst. b Conversion was determined
by GC. c Diastereoselectivity was determined by 1H NMR of the crude
reaction mixture. d Enantiomeric excess of the major diastereoisomer,
determined by chiral HPLC. e With 10 mol % of CF3CO2H as additive.
f The reaction was carried out using 1.0 M of 8a. g Isolated yield of the
final product.
Me 6-Br
Me 6-Cl
Me H
Me Me
Me Me
n-Bu
22f Ph
23
24
-(CH2)3-
-(CH2)4-
a All reactions were carried out using 1.0 equiv of 8 (0.50 mmol, 1.0 M),
2.0 equiv of 9, and 0.10 equiv of 4. b Isolated yield of both diastereoisomers.
c Diastereoselectivity was determined by 1H NMR of the crude reaction mixture.
d Enantiomeric excess of the major diastereoisomer, determined by chiral HPLC.
e The value in parentheses was enantiomeric excess of the minor diastereoi-
somer, determined by chiral HPLC. f 30 mol % of 4 was used.
this transformation, and a high diastereoselectivity of 90/10 was
obtained when (1R,2R)-diaminocyclohexane 1 was used as
5220
Org. Lett., Vol. 12, No. 22, 2010

2, entries 1-21). Notably, several cyclic vinyl ketones also
participate well in this reaction, and the products could be
gathered as a mixture of two diastereoisomers in excellent
yields with moderate to excellent enantiomeric excesses,
albeit with generally moderate diastereoselectivities (entries
23-24). However, only a moderate ee value could be
observed when benzylideneacetone was employed as the
electrophilic reagent, and the corresponding product was
collected as a mixture of two diastereoismers with a 77:23
ratio in 85% yield (entry 22). What’s more, no reactions
occurred when the more bulky Michael acceptors such as
chalcones were used as the electrophilic reactant.
The absolute configuration of the Michael product 10t was
determined by single-crystal X-ray analysis.17 This result
prompted us to assume a possible process for the asymmetric
Michael addition based on our previous works,18 as sum-
marized in Scheme 1.
to apply this approach in some useful synthetic transforma-
tions. As shown in Scheme 2, a Robinson annulation could
Scheme 2. Robinson Annulation of 10a
easily be promoted by use of sodium in methanol,19 and the
corresponding hexahydrophenanthrene derivative could be
obtained in 75% yield as a white solid.
In conclusion, we have developed an efficient approach
for the enantioselective Michael additions of R-alkyl-ꢀ-keto
esters to ꢀ-substituted R,ꢀ-unsaturated ketones with excellent
diastereo- and enantioselectivities, and the product could
easily be transformed into synthetically useful hexahydro-
phenanthrene structure under mild conditions in good yield.
Further applications of this methodology are currently well
under way and will be published soon.
Scheme 1
.
Assuming Process of the Asymmetric Michael
Addition
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20902018),
111 project (B07023), the Fundamental Research Funds for
the Central Universities, and Shanghai Pujiang Program
(08PJ1403300).
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC chro-
matograms of the products and cif file of enantiopure 10t.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Having successfully extended the scope of the Michael
addition with a wide range of substrates, we also were eager
(17) For more details, see Supporting Information.
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(b) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J.
Org. Lett. 2009, 11, 753. (c) Wen, S.; Li, P.; Wu, H.; Yu, F.; Liang, X.;
Ye, J. Chem. Commun. 2010, 46, 4806.
OL102256V
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