Highly enantio- and diastereoselective organocatalytic asymmetric domino Michael-Aldol reaction of β-ketoesters and α,β-unsaturated ketones

Article abstract of DOI:10.1002/anie.200353364

Three to four contiguous stereogenic centers are formed in the title reaction (see scheme). The optically active cyclohexanones are formed as single diastereomers with excellent enantioselectivities (up to 99% ee) and can be transformed into synthetically

Full text of DOI:10.1002/anie.200353364

Communications
Addition Reactions
Highly Enantio- and Diastereoselective
Organocatalytic Asymmetric Domino
Michael–Aldol Reaction of b-Ketoesters
and a,b-Unsaturated Ketones**
Nis Halland, Pompiliu S. Aburel, and
Karl Anker Jørgensen*
The catalytic asymmetric formation of chiral building blocks
represents an increasingly important field in organic chemis-
try owing to the usefulness of these products in further
synthetic transformations. The catalytic enantioselective for-
[*] Dr. N. Halland, Dr. P. S. Aburel, Prof. Dr. K. A. Jørgensen
The Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
Fax:(+45)8919-6199
E-mail: kaj@chem.au.dk
[**] We are grateful to Dr. R. G. Hazell for X-ray crystallographic analysis
of compounds 6a,c,e. This work was made possible by a grant from
The Danish National Research Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353364
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Chemie
À
Table 1: Optimization of the diastereo- and enantioselective domino Michael–aldol reaction catalyzed
by (S)-1.
mation of C C bonds is a widely developed
method for achieving this goal and
a
number of reactions and methodologies
have been developed.[1] Among the various
À
asymmetric C C bond-forming reactions,
the direct catalytic domino[2] and cycloaddi-
tion[3] reactions are of particular interest as
multiple stereogenic centers can be formed
in a single reaction.
Entry
R
3
1 [mol%]
Solvent
5
t [h]
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
a
a
a
a
b
b
b
b
b
b
b
b
b
20
10
10
10
10
10
10
10
10
10
10
10
10
neat
a
a
a
a
b
b
b
b
b
b
b
b
b
110
144
93
93
96
120
96
80
44
190
44
89
60
<5
57
20
60
10
42
89
80
52
70
30
>97:3
>97:3
–
70
88
–
Recently we reported the environmen-
CH2Cl2
H2O
tally
benign
imidazolidine-catalyzed
Michael reaction of malonates,[4] cyclic b-
ketoesters,[5] and nitroalkanes.[6] Herein we
present the first organocatalytic asymmetric
domino Michael–aldol reaction of acyclic b-
ketoesters and unsaturated ketones to
afford optically active cyclohexanones with
up to four stereogenic centers with excellent
enantio- and diastereoselectivity. The
domino Michael–aldol reaction reported
herein is related to the proline-catalyzed
Robinson annulation pioneered by Wie-
chert and co-workers and by Hajos and
Parrish 30 years ago,[7] but was originally
discovered by Fischer and Dieckmann
almost a century ago and more recently
EtOH/H2O[d]
neat
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
87
94
95
99
94
89
95[e]
90
90
91[e]
neat
THF
CH2Cl2
EtOH
EtOH
MeOH
CH3CN
CH3CN
9
10
11
12
13
68
42
Experimental conditions: b-Ketoester 3 (1.0 mmol, 2 equiv) and catalyst (S)-1 were added to a solution
of benzylideneacetone 2a (0.5 mmol) in solvent (1.0 mL), and the reaction mixture was stirred at
ambient temperature for the time indicated in the table. [a] Yields of isolated products. [b] Determined
by 1H NMR spectroscopic analysis. [c] Determined by CSP-HPLC. [d] Performed in EtOH/H2O 4:1.
[e] Reaction performed at 108C.
reinvestigated by Christoffers.[8] The potential of this novel
catalytic enantioselective domino Michael–aldol reaction is
demonstrated by the easy formation of optically active
cyclohexanone and cyclohexanediol, as well as g- and e-
lactone building blocks in high yields and enantioselectivities.
The phenylalanine-derived imidazolidine catalyst 1 has
proved to be a powerful catalyst for the catalytic asymmetric
Michael reaction of unsaturated ketones 2 with various
Michael donors. Herein we present its application to the
catalytic asymmetric domino Michael–aldol reaction with
acyclic b-ketoesters 3 (Scheme 1).
Table 1.[9] The results of the initial screening experiments
revealed that catalyst 1 is an excellent catalyst for the domino
Michael–aldol reaction and that higher enantioselectivities
were obtained when using benzyl benzoylacetate (3b) than
when using ethyl benzoylacetate (3a). Furthermore, it was
observed that the reaction proceeded readily in various
solvents, as well as under solvent-free conditions; excellent
enantioselectivities were obtained in all solvents, although
yields varied somewhat. Protic solvents such as MeOH and
EtOH gave the highest reaction rates and up to 80% yield
with 95% ee could be obtained (Table 1, entries 9–11) and
therefore EtOH was chosen for further reactions. We also
tested other chiral amines as catalysts: for example, l-proline
gave a fast reaction, but the product was formed as a
racemate. Notably, to obtain analytically pure domino
Michael–aldol adducts no chromatography was required as
the optically active cyclohexanones precipitated from the
reaction mixture and were recovered by simple filtration,
washing with Et2O (to remove unconverted starting materi-
als), and drying under vacuum. This very simple work-up
procedure suggests that a continuous recrystallization takes
place during the reaction, but reactions purified by flash
chromatography afforded domino Michael–aldol adducts
with the same optical purity as those recovered by filtration.
After optimization of the reaction conditions, various a,b-
unsaturated ketones were treated with benzyl benzoylacetate
(3b) to determine the scope of the reaction ([Eq. (2)],
Table 2). The various a,b-unsaturated ketones 2 carrying
aromatic and heteroaromatic b-substituents (Ar1) all reacted
well with b-ketoester 3b, affording cyclohexanones in mod-
erate to good yields and with excellent enantioselectivities
(Table 2, entries 1–10). Furthermore, several other aromatic
b-ketoesters 3c,d could be employed in the reaction and led
An initial screening of reaction conditions was carried out
to optimize the reaction of benzylideneacetone (2a) with
several b-ketoesters 3 [Eq. (1)] and some representative
results obtained during the screening are presented in
Scheme 1. Domino Michael–aldol reaction of acyclic b-ketoesters 2
with a,b-unsaturated ketones 3 catalyzed by (S)-1.
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Table 2: Domino Michael–aldol reaction of a,b-unsaturated ketones 2 with b-ketoesters 3 catalyzed by (S)-1.
Entry
1
2
a
Ar1
Ph
R2
H
3
b
Ar2
Ph
R
t [h]
Product
5
b
Yield [%][a]
80
d.r.[b]
ee [%][c]
Bn
192
>97:3
95[d]
2
3
b
2-Np
H
b
Ph
Bn
95
c
85
>97:3
91
c
c
4-Cl-Ph
4-Cl-Ph
H
H
b
b
Ph
Ph
Bn
Bn
95
240
d
d
60
80
>97:3
>97:3
97
93[c]
4
d
4-HO-Ph
H
b
Ph
Bn
95
e
20
>97:3
99
5
6
7
e
f
2-NO2-Ph
2-furyl
H
H
H
H
b
b
b
b
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
125
140
165
240
f
56
40
52
84
>97:3
>97:3
>97:3
>97:3
96
g
h
i
85
g
h
2-thienyl
2-pyrimidyl
83
8
9
89[d]
i
i
Ph
Ph
Me
Me
b
b
Ph
Ph
Bn
Bn
95
165
j
j
50
61
>97:3
>97:3
95
96
10
j
Ph
H
b
Ph
Bn
140
k
70
>97:3
86
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Table 2: (Continued)
Entry
2
Ar1
R2
H
3
c
Ar2
R
t [h]
Product
5
l
Yield [%][a]
d.r.[b]
ee [%][c]
11
a
Ph
4-F-Ph
Me
160
44
>97:3
92
12
a
Ph
H
d
4-MeO-Ph
Et
165
m
22
>97:3
90
Experimental conditions: b-Ketoester 3 (1.0 mmol, 2.0 equiv) and catalyst (S)-1 (10 mol%) were added to a,b-unsaturated ketone 2 (0.5 mmol) in
EtOH[14] (1.0 mL), and the reaction mixture was stirred for the time indicated in the table. [a] Yields of isolated products. [b] Determined by 1H NMR
spectroscopic analysis. [c] Determined by CSP-HPLC. [d] Reaction performed at 108C.
to the formation of cyclohexanones with excellent
enantioselectivities, although the yields were
moderate (Table 2, entries 11 and 12). The low
yield of 5e (Table 2, entry 4) is due to low
conversion because of the electron-donating sub-
stituent at the para position of Ar1 in 2d.
In all cases only a single diastereomer of the
domino Michael–aldol adduct was formed, some-
thing that is easily rationalized. The reaction
proceeds through initial formation of the Michael
adduct 4, which bears two stereogenic centers, but
only the Ar1-substituted stereogenic carbon
center is stable, whereas the stereogenic carbon
Scheme 2. Diastereoselectivity in the domino Michael–aldol reaction.
center with both the ketone and ester substituents
epimerizes in the reaction mixture as the proton is
highly acidic and therefore the Michael adduct 4 exists as a
mixture of syn and anti isomers (Scheme 2).
The assignment of the relative stereochemistry of the
cyclohexanones is based on X-ray crystallographic studies
(see Supporting Information) of cyclohexanol 6a formed by a
diastereoselective reduction of cyclohexanone 5n as outlined
below [Eq. (3)].[10]
As we were unable to obtain X-ray-quality crystals of the
domino Michael–aldol adduct 5j with four stereogenic
centers, we subjected 5j to Baeyer–Villiger oxidation fol-
lowed by a translactonization as outlined below [Eq. (4)].[11]
Fortunately, the intramolecular aldol reaction proceeds in
a highly diastereoselective fashion to form the six-membered
ring so that all large substituents are equatorial and thus are
controlled by the stable stereogenic center formed in the
initial Michael reaction. It should be noted that the high-
energy diastereomers cis-5 are not observed in the course of
the reaction. Furthermore, in contrast to the intermolecular
Michael reaction, which is catalyzed by the
chiral imidazolidine catalyst, the intramolecu-
lar aldol reaction is believed to be base-
catalyzed, as shown by Dieckmann and
Fischer and by Christoffers,[8] with the imida-
zolidine catalyst acting as the base. The
catalyst plays three roles in the reaction: a) it
activates the Michael acceptor by iminium-ion
formation, b) it generates the active Michael
donor by deprotonation of the b-ketoester,
and c) it acts as a base in the intramolecular
aldol reaction. However, it cannot be com-
pletely excluded that the intramolecular aldol
reaction is catalyzed by the imidazolidine
compound and proceeds through an enamine
mechanism.
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This afforded the g-lactone 6c, which readily afforded X-ray-
To demonstrate the potential of the domino Michael–
aldol reaction, several product modifications were performed
on the domino Michael–aldol adducts to determine the
versatility of the cyclohexanone derivatives 5 (Scheme 3).
Baeyer–Villiger oxidation of 5b proceeded smoothly, with
complete regioselectivity, in the presence of urea–hydrogen
peroxide (UHP) and trifluoroacetic anhydride (TFAA) as a
very convenient way of generating trifluoro peroxyacetic acid,
giving the optically active e-lactone 6 f in 96% yield.[13] The e-
lactone 6 f was easily translactonized to g-
quality crystals upon recrystallization from MeOH, and the
relative stereochemistry of 6c was determined by X-ray
crystallography, thus providing information on the relative
stereochemistry of the a-keto compound (see Supporting
Information).[12]
The absolute stereochemistry of the domino Michael–
aldol adducts was similarly determined from the g-lactone 6e
derived from domino Michael–aldol adduct 5d [Eq. (5)].
lactone 6g in good yield by brief exposure to
LiOH/MeOH, maintaining the high enan-
tiopurity. Furthermore, the cyclohexenone
6h could be formed by acid-catalyzed
dehydration of 5b, although some epimeri-
zation occurred at C4 under the reaction
conditions. However, diastereoselectivities
of up to 18:1 were obtained. Lastly, the
cyclohexanediols 6i,j were prepared in
The absolute stereochemistry of g-lactone 6e was deter-
mined to be R,R,R by X-ray crystallography, and the absolute
configuration of the domino Michael–aldol adduct 5d was
therefore determined to be 3R,4S,5R, as indicated in Equa-
tion (5).[12]
good yields as single diastereomers by reduction of the
corresponding cyclohexanones 5b,j with L-selectride.
These optically active building blocks with up to five
contiguous stereogenic centers are all formed in one or two
simple high-yielding transformations, without racemization,
from the domino Michael–aldol adducts.
In summary, we have developed the first highly enantio-
and diastereoselective organocatalytic domino Michael–
aldol reaction of acyclic b-ketoesters and a,b-unsaturated
ketones in the presence of an imidazolidine catalyst, which is
easily prepared from phenylalanine. The reaction proceeds
for a number aromatic and heteroaromatic b-ketoesters and
a,b-unsaturated ketones, forming adducts with 3–4 contig-
uous stereogenic centers. Furthermore, the synthetic scope of
the reaction was demonstrated by the easy formation of
various optically active building blocks.
Received: November 19, 2003 [Z53364]
Published Online: February 11, 2004
Keywords: aldol reaction · domino reaction · esters · ketones ·
.
Michael addition
[1] Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin, 1999.
[2] For recent examples of catalytic enantioselective domino
reactions in which multiple stereogenic centers are formed,
see: a) M. P. Sibi, J. Chen, J. Am. Chem. Soc. 2001, 123, 9472;
b) L. A. Arnold, R. Naasz, A. J. Minnaard, B. L. Feringa, J. Org.
Chem. 2002, 67, 7244; c) H. M. L. Davies, B. D. Doan, J. Org.
Chem. 1999, 64, 8501; d) D. F. Cauble, J. D. Gipson, M. J.
Krische, J. Am. Chem. Soc. 2003, 125, 1110; e) J. Tian, N.
Yamagiwa, S. Matsunaga, M. Shibasaki, Angew. Chem. 2002,
114, 3788; Angew. Chem. Int. Ed. 2002, 41, 3636; f) A. Alexakis,
S. March, J. Org. Chem. 2002, 67, 8753; g) O. Knopff, A.
Alexakis, Org. Lett. 2002, 4, 3835; h) S.-I. Watanabe, A.
Córdova, F. Tanaka, C. F. Barbas III, Org. Lett. 2000, 2, 4519;
i) A. Córdova, C. F. Barbas III, Tetrahedron Lett. 2003, 44, 1923;
j) N. Halland, T. Velgaard, K. A. Jørgensen, J. Org. Chem. 2003,
68, 5067.
Scheme 3. Transformations of cyclohexanones 5.
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[3] For some recent examples of direct catalytic asymmetric cyclo-
addition reactions, see: a) W. S. Jen, J. J. M. Wiener, D. W. C.
MacMillan, J. Am. Chem. Soc. 2000, 122, 9874; b) A. B.
Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
2458; c) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243; d) K. Juhl, K. A. Jørgensen, Angew.
Chem. 2003, 115, 1536; Angew. Chem. Int. Ed. 2003, 42, 1498;
e) A. S. Gothelf, K. V. Gothelf, R. G. Hazell, K. A. Jørgensen,
Angew. Chem. 2002, 114, 4410; Angew. Chem. Int. Ed. 2002, 41,
4236; f) K. A. Jørgensen, Angew. Chem. 2000, 112, 3702; Angew.
Chem. Int. Ed. 2000, 39, 3558, and references therein; g) J. S.
Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325, and
references therein; h) K. Gademann, D. E. Chavez, E. N.
Jacobsen, Angew. Chem. 2002, 114, 3185; Angew. Chem. Int.
Ed. 2002, 41, 3059; i) E. J. Corey, Angew. Chem. 2002, 114, 1724;
Angew. Chem. Int. Ed. 2002, 41, 1650;j) D. A. Evans, J. Wu, J.
Am. Chem. Soc. 2003, 125, 10162; k) D. B. Ramachary, N. S.
Chowdari, C. F. Barbas III, Angew. Chem. 2003, 115, 4365;
Angew. Chem. Int. Ed. 2003, 42, 42 33; l)Cycloaddition Reactions
in Organic Synthesis (Eds.: S. Kobayashi, K. A. Jørgensen),
Wiley-VCH, 2000.
[4] N. Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2003,
115, 685; Angew. Chem. Int. Ed. 2003, 42, 661.
[5] N. Halland, T. Hansen, K. A. Jørgensen, Angew. Chem. 2003,
115, 4955; Angew. Chem. Int. Ed. 2003, 42, 5105.
[6] N. Halland, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2002,
67, 8331.
[7] a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492;
Angew. Chem. Int. Ed. Engl. 1971, 10, 496; b) Z. G. Hajos, D. R.
Parrish, J. Org. Chem. 1974, 39, 1615; see also; c) T. Arai, H.
Sasai, K.-I. Aoe, K. Okamura, T. Date, M. Shibasaki, Angew.
Chem. 1996, 108, 103; Angew. Chem. Int. Ed. Engl. 1996, 35, 104;
d) T. Bui, C. F. Barbas III, Tetrahedron Lett. 2000, 41, 6951.
[8] a) W. Dieckmann, K. Fischer, Ber. Dtsch. Chem. Ges. 1911, 44,
966; b) J. Christoffers, J. Chem. Soc. Perkin Trans. 1, 1997, 3141,
see also: F. Tanaka, R. Thayumanavan, C. F. Barbas III, J. Am.
Chem. Soc. 2002, 124, 8523.
[9] The 4,5-diphenyl-imidazolidine-2-carboxylic acid catalyst
recently reported for the catalytic enantioselective formation
of warfarin,[5] also promoted the domino Michael–aldol reaction
in up to 90% ee in moderate yield.
[10] CCDC-224447 (6a), CCDC-224448 (6c), and CCDC-224449
(6e) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[11] Baeyer-Villiger oxidations generally occur with retention of
stereochemistry at the migrating center; see, for example:
Comprehensive Organic Synthesis (Ed.: B. M. Trost), Pergamon,
Berlin, 1991.
[12] Inversion of the a-carbonyl stereogenic center was observed
during the translactonization procedure.
[13] M. S. Cooper, H. Heaney, A. J. Newbold, W. R. Sanderson,
Synlett 1990, 533.
[14] The reaction rate is strongly concentration-dependent (see
Supporting Information).
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