A diarylprolinol in an asymmetric, catalytic, and direct crossed-aldol reaction of acetaldehyde

Article abstract of DOI:10.1002/anie.200704870

(Chemical Equation Presented) No over-reacting: A diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of acetaldehyde, affording β-hydroxy α-unsubstituted aldehydes in good yield with excellent enantio

Full text of DOI:10.1002/anie.200704870

Communications
DOI: 10.1002/anie.200704870
Organocatalysis
A Diarylprolinol in an Asymmetric, Catalytic, and Direct Crossed-
Aldol Reaction of Acetaldehyde**
Yujiro Hayashi,* Takahiko Itoh, Seiji Aratake, and Hayato Ishikawa
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday
The aldol reaction is recognized to be one of the most
important carbon–carbon bond-forming processes in organic
synthesis.[1] Acetaldehyde, the simplest aldehyde, generates
versatile b-hydroxy a-unsubstituted aldehydes when used as
the nucleophilic component in this reaction [Eq. (1)]. In spite
of its synthetic importance, we are not aware of any examples
of a successful direct, enantioselective aldol reaction of this
type except for the enzymatic reaction.[2] Indirect methods
reported include the chiral Lewis base mediated aldol
reaction of trimethyl siloxyethene, a synthetic equivalent of
acetaldehyde described by Denmark and Bui,[3] while Yama-
moto and Boxer have recently developed an acetaldehyde
super silyl enol ether that reacts in racemic fashion.[4]
problem. In fact, Barbas and co-workers reported that
5-hydroxy-2-hexenal, a trimerization product of acetalde-
hyde, was obtained in 12% yield with 84% ee when acetal-
dehyde was treated with proline.[8] In this communication we
disclose the first, direct, enantioselective crossed-aldol reac-
tion of acetaldehyde.
The aldol reaction of acetaldehyde with o-chlorobenzal-
dehyde was selected as a model (Table 1). As the aldol
product was unstable, it was reduced to the corresponding
diol, which was isolated. The efficacy of various catalysts was
Table 1: The effect of catalyst and solvent on the aldol reaction of
acetaldehyde and o-chlorobenzaldehyde[a]
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
proline[d]
DMF
DMF
DMF
DMF
DMF
neat[e]
H2O[f]
DMSO
THF
12
85
15
33
11
40
86
76
40
71
47
99
75
85
78
83
93
99
95
98
Even among organocatalyst-mediated[5] aldol reactions,
there is no successful reaction of acetaldehyde in spite of the
extensive research on this class of reactions in recent years.[6,7]
As the aldol product generated when acetaldehyde is
employed is unsubstituted at the a position, it is expected to
act both as a reactive electrophile [Eq. (2)] and nucleophile
[Eq. (3)]. Thus, the suppression of over-reactions is a difficult
1
2
3
4
1
1
1
1
1
CH3CN
[a] Unless otherwise indicated, reactions were performed employing
o-chlorobenzaldehyde (0.4 mmol), acetaldehyde (2.0 mmol), catalyst
(0.04 mmol), and solvent (0.4 mL) at 48C for 72 h. [b] Yield of isolated
product. [c] Optical purity was determined by HPLC analysis on a chiral
phase. [d] Proline (30 mol%) was employed; structures of other catalysts
shown in Figure 1. [e] Solvent was not employed. [f] Water (5 equiv) was
added.
examined first. Proline is known to be a suitable catalyst for
the crossed-aldol reactions of aldehyde/ketone[9] and alde-
hyde/aldehyde combinations.[10] When proline was employed
under several different conditions, hardly any crossed-aldol
product was obtained, and crotonaldehyde, generated by the
self-aldol reaction followed by dehydration, was formed
(entry 1, Table 1). While the diphenyl- and dixylylprolinols 3
and 4 (Figure 1) provided the aldol with good enantioselec-
tivity, the yields were low (entries 4 and 5, Table 1). In
contrast to these failures, when the trifluoromethyl-substi-
tuted diarylprolinol 1 was employed, the crossed-aldol
product was generated in good yield with nearly complete
enantiopurity (entry 2, Table 1). It should be noted that a
[*] Prof. Dr. Y. Hayashi, T. Itoh, S. Aratake, 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
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[**] This work was partially supported by the Toray Science Foundation
and by a Grant-in-Aid for Scientific Research from MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2082
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Angewandte
Chemie
Table 2: Catalytic asymmetric aldol reaction of acetaldehyde with various
aldehydes[a]
Entry
Aldehyde
R1 =H
T [8C] t [h] Yield [%][b] ee [%][c]
1[d]
2
23
120 53
99
96
99
97
98
R1 =NO2 23
24
72
96
96
85
74
77
71
Figure 1. Organocatalysts examined in this study.
3
R1 =CF3
R1 =Br
4
23
4[e]
5[e]
R1 =OTf 23
diarylprolinol silyl ether,[11–13] which has been developed
independently by our[11] and Jørgensenꢀs[12] groups, is not
effective (entry 3, Table 1). This is in marked contrast to the
Michael reactions of aldehydes with nitroalkenes,[11a] for
which the silyl ether is more reactive than the corresponding
alcohol (vide infra). Solvent screening using H2O, CH3CN,
THF, DMSO, and DMF showed that while water affords good
results,[14] the best combination of yield and enantioselectivity
is realized with DMF (entry 2, Table 1). A second aldol
reaction, in which the aldol product of acetaldehyde partic-
ipates as an acceptor, was not observed because of the facile
formation of the cyclic hemiacetal from the aldol product and
acetaldehyde.[10b]
As excellent results had been obtained for the model
system, the generality of the reaction was examined (Table 2).
The reaction proceeds efficiently with both electron-deficient
aromatic aldehydes and olefinic aldehydes, affording the
corresponding aldol products in good to excellent yield with
excellent enantioselectivity. The reaction also proceeds with
non-activated aldehydes, such as benzaldehyde and 2-naph-
thaldehyde, though this requires the addition of 5 equiv of
acetaldehyde every 24 h repeated three times to give the
nearly optically pure aldol products in moderate yield.
Heteroaromatic aldehydes such as 4-pyridinecarbaldehyde
can also be employed as the electrophilic component. In the
case of pentafluorobenzaldehyde, the reaction was performed
in the presence of water in order to suppress the dehydration
reaction. Dimethoxyacetaldehyde was also a useful electro-
philic aldehyde, and it could be used as its commercially
available aqueous solution to afford a highly functionalized
aldol. Excellent enantioselectivity was observed in most cases.
The results for the aliphatic aldehydes are not as good as
aromatic aldehydes.
6[d]
23
120 50
97
7
8
R2 =Cl
4
72
72
85
89
99
97
R2 =NO2 23
9
23
23
72
72
89
82
97
96
10
11
4
4
96
76
99
98
12[f]
24
43
91
83
13
23
4
99
98
80
14[g]
15[h]
120 53
72 92
4
[a] Unless otherwise indicated, the reaction was performed employing
electrophilic aldehyde (0.4 mmol), acetaldehyde (2.0 mmol),
1
(0.04 mmol) and DMF (400 mL) at the indicated temperature. [b] Yield
of isolated product. [c] Optical purity was determined by HPLC analysis
on a chiral stationary phase; see the Supporting Information for details.
[d] Acetaldehyde (5 equiv) was added at 24-h intervals three times; see
the Supporting Information. [e] 30% catalyst was employed. [f] Water
(5 equiv) was added. [g] Starting material was recovered in 45% yield.
[h] Commercially available aqueous solution (60 wt%) was employed.
The aldol product of benzaldehyde (Table 2, entry 1) was
reduced with NaBH4 to afford the corresponding diol, which
is a key intermediate in the synthesis of fluoxetine (Prozac),[15]
a widely used selective serotonin-reuptake inhibitor. The
absolute configuration of this aldol adduct was determined to
be R by comparison of its optical rotation with that in the
literature.[16]
Figure 2. Intermediate enamine 5 and the transition state. Ar=3,5-
bis(trifluoromethyl)phenyl.
The reaction is thought to proceed as follows: Diaryl-
prolinol catalyst 1 reacts with acetaldehyde to generate
enamine 5, which reacts with an electrophilic aldehyde as
shown in Figure 2. This model can explain the absolute
configuration of the aldol product. Barbas and co-workers
reported that prolinol is an effective organocatalyst in an
enantioselective fluoroaldol reaction, in which a similar
transition state was proposed.[17] Though the electrophile
attacks from the side opposite to the bulky diphenylmethyl
moiety in the reaction catalyzed by a diphenylprolinol silyl
ether,[11] the aldehyde reacts on the more hindered face of the
catalyst in the present case. This is because the aldehyde is
activated by coordination to the proton of the hydroxy group
through a hydrogen bond. This interaction would be stronger
in the case of the trifluoromethyl-substituted catalyst 1 than in
diphenylprolinol 3 owing to the higher acidity of its OH
group. The importance of this hydrogen bond is also evident
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Communications
Chem. Int. Ed. 2004, 43, 5138; c) Y. Hayashi, J. Syn. Org. Chem.
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from the lowreactivity of the corresponding silyl ether
catalyst 2.
Though diarylprolinol silyl ether is widely used as an
effective organocatalyst, the present reaction is a rare
example of its precursor, diarylprolinol, acting as an out-
standing catalyst,[18] and the first example of the use of
diarylprolinol in an enantioselective aldol reaction. The
b-hydroxy a-unsubstituted aldehydes generated are versatile
synthetic intermediates and are obtained with excellent
enantioselectivity. Thus, the present aldol reaction of acetal-
dehyde is a synthetically useful process.
[6] Reviews, see: a) “Amine-catalyzed Aldol Reactions”: B. List in
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Experimental Section
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Typical procedure (Table 2, entry 7): Acetaldehyde (112 mL,
2.0 mmol) was added to a mixture of (S)-2-{bis-[3,5-bis(trifluorome-
thyl)phenyl]hydroxymethyl}pyrrolidine (21 mg, 0.04 mmol) and 2-
chlorobenzaldehyde (45 mL, 0.40 mmol) in anhydrous DMF
(0.40 mL) in a sealed tube (ACE GLASS, product number 5027-05)
at 48C. After the reaction mixture had been stirred for 72 h, MeOH
(1 mL) and NaBH4 (74 mg, 2.0 mmol) were added. The resulting
reaction was stirred for an additional 1 h at 08C, before it was
quenched with pH 7.0 phosphate buffer solution. The organic
materials were extracted with ethyl acetate three times. The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo after filtration. Purification by preparative thin
layer chromatography (ethyl acetate/hexane 1:1) gave (1R)-1-(2-
chlorophenyl)propane-1,3-diol (63 mg, 0.34 mmol) in 85% yield.
Enantiometric excess was 99% ee.
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Received: October 20, 2007
Published online: February 8, 2008
Keywords: acetaldehyde · aldol reaction · asymmetric catalysis ·
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