Diphenylprolinol silyl ether as a catalyst in an enantioselective, catalytic michael reaction for the formation of α,α-disubstituted α-amino acid derivatives

Full text of DOI:10.1002/asia.200800394

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DOI: 10.1002/asia.200800394
Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic
Michael Reaction for the Formation of a,a-Disubstituted a-Amino Acid
Derivatives
Yujiro Hayashi,*[a, b] Kazuki Obi,[a] Yusuke Ohta,[a] Daichi Okamura,[a] and
Hayato Ishikawa[a]
Enantiomerically pure a,a-disubstituted a-amino acids
are extremely important organic substances as they are
found in many biologically active compounds.[1] Much atten-
tion has been paid to enantiomerically pure non-natural a-
amino acids such as the a,a-disubstituted ones. A Michael
reaction of an a-substituted a-amino acid equivalent and an
electron-deficient alkene is one of the methods that can be
used for the preparation of such a,a-disubstituted a-amino
acids. Although there are several synthetic methods for the
formation of a-monosubstituted amino acids by the Michael
reaction of a-unsubstituted a-amino acid equivalents,[2]
there is no efficient method for the formation of chiral a,a-
disubstituted a-amino acid derivatives with high enantiose-
lectivity from an asymmetric Michael reaction.
However, rapid advances have been made with the reac-
tion using a small organic molecule as catalyst, a so-called
organocatalyst.[3] Our group[4] and Jørgensen and co-work-
ers[5] independently developed diarylprolinol silyl ether as
an effective organocatalyst that has subsequently been
widely used by many research groups.[6] Our group devel-
oped the ene reaction,[4b] the Diels–Alder reaction,[4c,g] the
Michael reaction of nitroalkane,[4e] and the formal aza-[3+3]
cycloaddition reaction.[4f] These reactions proceed via an
iminium ion intermediate, generated from an a,b-unsaturat-
ed aldehyde and diarylprolinol silyl ether. We thought that
4-substituted 2-aryl-2-oxazoline-5-one would act as a syn-
thetic equivalent of an a-substituted a-amino acid. Whereas
MacMillan and co-workers used a silyl enol ether of oxazoli-
none as a Michael donor in one of the examples of the cas-
cade reaction,[7] we thought that oxazolinone could be used
directly, without transformation to its silyl enol ether, to
afford the synthetically versatile chiral a,a-disubstituted a-
amino acid derivatives. Herein we report on the direct and
enantioselective Michael reaction of an a,b-unsaturated al-
dehyde and 4-substituetd-2-aryl-2-oxazoline-5-one using di-
phenylprolinol silyl ether as catalyst. In this reaction quater-
nary and tertiary chiral centers would be continuously gen-
erated, and the control of not only enantioselectivity but
also diastereoselectivity would be a key issue. During the in-
vestigation of this reaction, Jørgensen and co-workers re-
ported the same Michael reaction.[8] However, their best re-
action conditions and the catalyst used are slightly different
to ours.
The reaction of cinnamaldehyde and 4-methyl-2-phenyl-2-
oxazoline-5-one was selected as a model, and the Michael
reaction was examined using diphenylprolinol trimethylsilyl
ether 1 (Figure 1) as the catalyst. The product was treated
with a Wittig reagent, and the corresponding a,b-unsaturat-
ed ester was isolated and characterized (Table 1). The enan-
tiomeric excess was determined by chiral HPLC analysis of
the ester. First, the solvent was screened using 20 mol% of
the catalyst 1 at room temperature (Table 1). Polar solvents
[a] Prof. Dr. Y. Hayashi, K. Obi, Y. Ohta, D. Okamura, Dr. H. Ishikawa
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
[b] Prof. Dr. Y. Hayashi
Research Institute for Science and Technology
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200800394.
Figure 1. Organocatalysts examined in this study.
246
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Chem. Asian J. 2009, 4, 246 – 249

Table 1. The effect of solvent in the reaction of cinnamaldehyde and
ether was used as catalyst 1 (Table 2, entry 2). Similar find-
ings were observed when using the tert-butyldimethylsilyl
ether catalyst 2. Whereas 67% ee was observed in the reac-
tion of the phenyl-substituted substrate (Table 2, entry 3),
good enantioselectivity was realized when p-methoxyphenyl
oxazolinone was used (Table 2, entry 4). When the reaction
was conducted at 08C, the best enantioselectivity (97% ee)
was obtained, along with an increase in the diastereoselec-
tivity (Table 2, entry 5). However, under the same reaction
conditions the trifluoromethyl-substituted diarylprolinol silyl
ether 3 was not effective; it afforded the Michael adduct in
17% yield with recovery of the starting material (Table 2,
entry 6). When the reaction was performed at room temper-
ature using catalyst 3, the yield increased to 74% and good
enantioselectivity (89% ee) was obtained (Table 2, entry 7).
These results indicate that the diphenylprolinol tert-butyldi-
methylsilyl ether 2 is the best catalyst under the present re-
action conditions in terms of the enantioselectivity, diaste-
reoselectivity, and reactivity.
phenyl oxazolinone catalyzed by 1.[a]
Entry
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
toluene
CH2Cl2
AcOEt
hexane
Et2O
MeCN
DMF
benzene
xylene
68
79
69
59
60
66
44
52
50
51
1.2:1
1.1:1
1.2:1
1.2:1
1.5:1
1:1
1.1:1
1.5:1
1.2:1
1.4:1
79
56
58
71
65
22
40
68
63
72
9
10
mesitylene
[a] Unless otherwise shown, reactions were performed employing cinna-
maldehyde (0.15 mmol), oxazolinone (0.23 mmol), catalyst 1 (0.03 mmol),
and solvent (0.3 mL) at room temperature for 2 h. [b] Yield of isolated
product. [c] Diastereomeric ratio was determined by 1H NMR. [d] Opti-
cal purity of the major isomer, which was determined by chiral HPLC
analysis.
The scope of the reaction was investigated once the opti-
mal reaction conditions had been determined. First, the gen-
erality of the Michael acceptor was investigated using a 4-
methyloxazolinone derivative as a Michael donor (Table 3).
such as MeCN and DMF gave low enantioselectivity, where-
as good results were obtained using aromatic solvents. The
best enantioselectivity (79% ee) was obtained when toluene
was used.
Table 3. Catalytic asymmetric Michael reaction of 4-methyloxazolino-
ne.[a]
During these investigations, we found that the substituent
at the 2-position of oxazoline affected the enantioselectivity.
Thus the catalyst was examined using both phenyl- and p-
methoxyphenyl-substituted oxazolinone in toluene at 08C or
at room temperature (Table 2). While good enantioselectivi-
Entry
R1
R2
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph
An
An
An
An
An
Ph
An
Ph
Ph
18
18
16
17
6
73
73
83
76
74
72
63
66
77
70
74
2.2:1
2.0:1
2.2:1
97
93
92
73
97
97
98
99
99
99
92
2-naphthyl
p-ClC4H4
An
Me
Me
cyclohexyl
cyclohexyl
Et
iPr
iBu
Table 2. The effect of organocatalyst in the Michael reaction.[a]
1.7:1
>20:1
>20:1
9.2:1
7.6:1
>20:1
14:1
5
30
30
5
9
7
9
10
11
Entry
Cat.
R
T [8C]
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
Ph
Ph
>20:1
1
2
3
4
5
6
7
1
1
2
2
2
3
3
Ph
An
Ph
An
An
An
An
0
0
0
23
0
17
16
19
2
18
48
20
64
68
71
79
73
17
74
1.3:1
2.1:1
1.2:1
1.2:1
2.2:1
1:1
81
90
67
89
97
91
89
[a] Unless otherwise shown, reactions were performed employing alde-
hyde (0.24 mmol), oxazolinone (0.2 mmol), catalyst 2 (0.02 mmol), and
toluene (0.4 mL) at 08C for the indicated time; An=pMeOC6H4-.
[b] Yield of isolated aldehyde. [c] Diastereomeric ratio was determined
by 1H NMR. [d] Optical purity of the major isomer; see the Supporting
Information for the determination of the enantioselectivity.
0
23
1.3:1
[a] Unless otherwise shown, reactions were performed employing cinna-
maldehyde (0.24 mmol), oxazolinone (0.2 mmol), catalyst (0.02 mmol),
and toluene (0.4 mL) at 08C or 238C for the indicated time; An=p-
MeOC6H4-. [b] Yield of isolated aldehyde. [c] Diastereomeric ratio was
determined by 1H NMR. [d] Optical purity of the major isomer, which
was determined by chiral HPLC analysis of the a,b-unsaturated ester by
the reaction of aldehyde with Ph3P=CHCO2Et.
In terms of the substituents at the b-position of acrolein, not
only a phenyl and a naphthyl group (Table 3, entries 1, 2)
but also an aryl group possessing an electron-withdrawing
group (Table 3, entry 3) were successfully used to afford the
Michael product with excellent enantioselectivity. However,
the electron-rich aromatic group afforded the product in
good yield with moderate enantioselectivity (Table 3,
entry 4). In the reaction of alkyl substituents, the reaction
ty (81% ee) was obtained with the phenyl-substituted sub-
strate (Table 2, entry 1), the p-methoxyphenyl derivative
gave higher enantioselectivity (90% ee) when trimethylsilyl
Chem. Asian J. 2009, 4, 246 – 249
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www.chemasianj.org
247

Y. Hayashi et al.
COMMUNICATION
proceeded in
a
highly diastereo- and enantioselective
aldehydes with 4-substituted oxazolinone. The obtained Mi-
chael products, which are a,a-disubstituted, quaternary a-
amino acid derivatives possessing the g-formyl functional
group, are useful chiral synthetic intermediates, as has also
been shown by Jørgensen and co-workers.[8]
manner. When the b substituents of acrolein were methyl
and cyclohexyl, then good to excellent enantio- and diaste-
reoselectivities were obtained in the reactions of both 2-
phenyl- and 2-methoxyphenyl-substituted oxazolinone
(Table 3, entries 5–8). Thus, in the alkyl-substituted acrolein
derivatives the generality was examined using 2-phenyl oxa-
zolinone. Nearly perfect enantioselectivity and excellent dia-
stereoselectivity were realized in the reaction of b-alkyl-sub-
stituted acroleins (Table 3, entries 9–11).
Next, the Michael donor was investigated using crotonal-
dehyde as a Michael acceptor (Table 4). In terms of the sub-
stituent at the 4-position of oxazolinone, not only the
methyl group but also the isobutyl, benzyl, indolylmethyl,
and methylthioethyl groups were successfully used to afford
the Michael product in good yield and with excellent enan-
tioselectivity. The chiral a,a-disubstituted amino acids of
alanine, leucine, phenylalanine, tryptophan, and methionine
derivatives can be synthesized with excellent enantioselec-
tivities.
Experimental Section
Typical experimental procedure (Table 3, entry 1): To a mixture of oxazo-
linone (35 mg, 0.2 mmol), catalyst 2 (6.5 mg, 0.02 mmol), and toluene
(0.4 mL) was added cinnamaldehyde (30 mL, 0.24 mmol) successively at
08C. The reaction mixture was stirred for 18 h at that temperature. The
reaction mixture was directly purified by silica gel column chromatogra-
phy (ethylacetate/hexane=1:5 to 1:3) to afford (3S)-3-((S)-4,5-dihydro-4-
methyl-5-oxo-2-(4-methoxyphenyl)oxazoyl-4-yl)-3-phenylpropanal
(49.2 mg, 0.15 mmol) in 73% yield as a diastereomeric mixture (major
isomer/minorisomer=2.2:1). The diastereomeric ratio was determined
1
by H NMR spectrum.
The product was converted into the corresponding a,b-unsaturated ester
using ethyl(triphenylphosphoranylidene)acetate, and the enantioselectivi-
ty was determined by HPLC using a Chiralpak IC column (30:1 hexane/
2-propanol), 1.0 mLminÀ1, major isomer tR =23.3 min, minor enantiomer
tR =21.1 min. Enantiometric excess of the major isomer was 97% ee.
In conclusion, we have found that diphenylprolinol tert-
butyldimethylsilyl ether 2 is an effective organocatalyst for a
highly enantioselective Michael reaction of a,b-unsaturated
Acknowledgements
This work was partially supported by
Table 4. Catalytic asymmetric Michael reaction of 4-substituted oxazolinone with crotonaldehyde.[a]
the Toray Science Foundation and a
Grant-in-Aid for Scientific Research
from The Ministry of Education, Cul-
ture, Sports, Science, and Technology
(MEXT).
Entry
1
Oxazolinone
Product
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
Keywords: amino
asymmetric catalysis · Michael
reaction · organocatalysis
acids
·
5
72
>20:1
97
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2
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K. A. Jørgensen, Chem. Commun.
>20:1
[a] Unless otherwise shown, reactions were performed employing crotonaldehyde (0.24 mmol), oxazolinone
(0.2 mmol), catalyst 2 (0.02 mmol), and toluene (0.4 mL) at 08C for the indicated time. [b] Yield of isolated al-
dehyde. [c] Diastereomeric ratio was determined by 1H NMR. [d] Optical purity of the major isomer; see the
Supporting Information for the determination of the enantioselectivity.
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Received: October 13, 2008
Published online: December 8, 2008
Chem. Asian J. 2009, 4, 246 – 249
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
249