The effectiveness of proteinogenic amino acids in the asymmetric aldol reaction in DMSO and aqueous DMSO

Article abstract of DOI:10.1055/s-2008-1077789

The effects of twenty proteinogenic amino acids have been investigated in the aldol reaction of aldehyde and ketone in DMSO and aqueous DMSO (in the presence of three equivalents of water). Not only proline but also other amino acids promote the al-dol re

Full text of DOI:10.1055/s-2008-1077789

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1565
The Effectiveness of Proteinogenic Amino Acids in the Asymmetric Aldol
Reaction in DMSO and Aqueous DMSO
P
roteinogenic Ami
u
no
A
cids in
j
A
sym
m
i
etric
A
r
ldol
R
ea
o
ctioninDMSO Hayashi,* Takahiko Itoh, Norio Nagae, Masahiro Ohkubo, Hayato Ishikawa
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
Fax +81(3)52614631; E-mail: hayashi@ci.kagu.tus.ac.jp
Received 2 February 2008
is employed.12 In these reactions, water plays an essential
role by increasing the diastereo- and enantioselectivities.
Abstract: The effects of twenty proteinogenic amino acids have
been investigated in the aldol reaction of aldehyde and ketone in
DMSO and aqueous DMSO (in the presence of three equivalents of
water). Not only proline but also other amino acids promote the al-
dol reaction enantioselectively. The effect of water varies with ami-
no acid, and water does not affect the enantioselectivity in most
cases, the exceptions being Pro, Ser and His. In the case of Pro,
large positive effects on diastereo- and enantioselectivities were ob-
served in the reaction of a-substituted methyl ketone, while no ef-
fect was observed in that of methyl ketone.
Except for MacMillan’s13 and Maruoka’s14 catalysts, most
of the organocatalysts developed for the asymmetric aldol
reactions have been based on the proline skeleton. Is pro-
line special? In the seminal paper of 20003 it was reported
that proline promotes the enantioselective aldol reaction
of acetone and p-nitrobenzaldehyde in DMSO, while His,
Val, Tyr and Phe do not. However, there are reports that
other amino acids can promote the aldol reaction, and in
some cases, excellent enantioselectivity has been
achieved. For instance, Cordova and co-workers exam-
ined the aldol reaction of p-nitrobenzaldehyde and cyclo-
hexanone using 13 of the 20 proteinogenic amino acids
and discovered that excellent enantioselectivity was ob-
tained when either Val or Ile was used as the catalyst un-
der aqueous conditions, with ten equivalents of water
employed in DMSO.7l Lu examined seven amino acids in
the same reaction in the presence of water without using
organic solvent and found that Trp afforded the aldol
product in 96% ee.8a He also reported that the aldol reac-
tion of cyclohexanone and benzaldehyde does not proceed
in the presence of water with any of five amino acids, Ser,
Thr, Val, Leu, and Ile, but that siloxythreonine is an effec-
tive catalyst.8e These reactions were performed in aqueous
DMSO or in the presence of water. Is the water essential?
Does water increase the diastereo- or enantioselectivity?
A thorough comparison of the reactions in organic solvent
and aqueous solvent in the presence of each amino acid is
necessary. As no systematic study has been made of all
the proteinogenic amino acids in the aldol reaction in or-
ganic solvent and aqueous solvent, we have investigated
the reaction in detail, with the results we describe in this
paper.
Key words: asymmetric synthesis, aldol reactions, organocatalyst,
amino acids, water
The aldol reaction is one of the most important carbon–
carbon bond-forming reactions in organic synthesis.1 In
1997, Shibasaki and co-workers reported the first highly
enantioselective, direct, catalytic aldol reaction based on
an organometallic catalyst.2 In 2000, List, Barbas and
Lerner discovered the proline-mediated direct, asymmet-
ric, catalytic intermolecular aldol reaction.3 Since this
seminal discovery, many kinds of organocatalysts have
been developed for the enantioselective aldol reaction.4,5
Reactions using water as a solvent have attracted a great
deal of attention because water possesses unique proper-
ties and is a safe medium, avoiding the problems of pollu-
tion inherent with organic solvents.6 Several aldol
reactions have been reported to proceed by the use of or-
ganocatalysis in aqueous conditions, and increases in dia-
stereo- and enantioselectivities have been reported.7,8 In
spite of the many endeavors to perform the aldol reaction
in the presence of water without organic solvent,9 there
had been no highly enantioselective examples until our10
and Barbas’11 groups developed such a reaction at the end
of 2005. We have reported that siloxyproline is an effec-
tive organocatalyst, which promotes the enantioselective
aldol reaction even in the presence of a large amount of
water. Recently we also found that the aldol reaction of
ketone and aldehyde proceeds catalyzed by proline under
wet conditions (in the presence of three equivalents of wa-
ter), and that the ‘wet’ conditions are essential, because
the enantioselectivity decreases without water, while the
yield decreases when a larger amount of water (18 equiv)
We chose p-nitrobenzaldehyde and cyclohexanone for our
model reaction. The reaction was performed at room tem-
perature in water-free DMSO,15 or in aqueous DMSO
containing three equivalents of water, with the results
summarized in Table 1. The reaction proceeded with all
the proteinogenic amino acids except Cys, and aldol prod-
ucts were obtained enantioselectively except with Gly.
The yield and diastereo- and enantioselectivity were de-
pendant on the amino acid. With the exceptions of Phe,
Lys, Arg, Asp, and Gln, in most cases the diastereoselec-
tivity increased when the reaction was performed in aque-
ous DMSO. A marked increase in the diastereoselectivity
was observed when Pro was employed: An excellent de
SYNLETT 2008, No. 10, pp 1565–1570
x
x
.x
x
.2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1077789; Art ID: Y00708ST
© Georg Thieme Verlag Stuttgart · New York

1566
Y. Hayashi et al.
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(anti:syn = 10.3:1) was obtained in aqueous DMSO in action (dehydration) occurred, giving the dehydrated a,b-
spite of the low de (1.5:1) in DMSO. For most of the ami- unsaturated ketone as a side product. Thus, we quenched
no acids the enantioselectivity was the same for the reac- the reaction within two hours and the yield was low in
tions in water-free and aqueous DMSO. Only when Pro, DMSO (entry 15), while a good yield of 79% was ob-
Ser and His were employed did water have a positive ef- tained in aqueous DMSO (entry 16, vide infra).
fect, increasing the enantioselectivity. For Pro the reaction
was faster compared with other amino acids, but over-re-
Table 1 The Effectiveness of Amino Acids for the Aldol Reaction in DMSO and in Aqueous DMSOa,16
OH
O
O
O
30 mol%
amino acid
+
syn isomer
H
+
DMSO
or DMSO–H2O
r.t.
O2N
O2N
Entry
1
Amino acid
Gly
Gly
Ala
Ala
Val
Val
Leu
Leu
Ile
Solvent
Time (h)
Yield (%)b
73
anti:sync
1.7:1
5.7:1
4.5:1
13.7:1
5.6:1
15.1:1
4.1:1
10.6:1
5.4:1
13.0:1
2.1:1
2.8:1
2.5:1
3.8:1
1.5:1
10.3:1
1.8:1
5.3:1
3.9:1
9.8:1
1.8:1
4.6:1
nde
ee (%)d
0
DMSO
30
30
12
12
6
2
aq DMSO
DMSO
75
0
3
74
90
90
93
96
94
95
96
97
70
69
79
81
84
96
75
91
92
96
85
82
nde
nde
84
84
59
4
aq DMSO
DMSO
72
5
79
6
aq DMSO
DMSO
6
65
7
16
16
24
24
11
11
7
73
8
aq DMSO
DMSO
83
9
84
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ile
aq DMSO
DMSO
84
Phe
Phe
Trp
Trp
Pro
57
aq DMSO
DMSO
70
78
aq DMSO
DMSO
7
81
2
41
Pro
aq DMSO
DMSO
2
79
Ser
48
48
12
12
24
24
48
48
9
79
Ser
aq DMSO
DMSO
84
Thr
Thr
Tyr
Tyr
Cys
Cys
Met
Met
His
78
aq DMSO
DMSO
80
76
aq DMSO
DMSO
84
<5
<5
70
aq DMSO
DMSO
nde
2.6:1
8.2:1
2.7:1
aq DMSO
DMSO
9
79
24
80
Synlett 2008, No. 10, 1565–1570 © Thieme Stuttgart · New York

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Proteinogenic Amino Acids in Asymmetric Aldol Reaction in DMSO
1567
Table 1 The Effectiveness of Amino Acids for the Aldol Reaction in DMSO and in Aqueous DMSOa,16 (continued)
OH
O
O
O
30 mol%
amino acid
+
syn isomer
H
+
DMSO
or DMSO–H2O
r.t.
O2N
O2N
Entry
28
29
30
31
32
33
34
35
36
37
38
39
40
Amino acid
His
Solvent
Time (h)
Yield (%)b
anti:sync
3.7:1
2.2:1
2.8:1
0.9:1
0.8:1
2.1:1
2.7:1
4.3:1
6.6:1
2.2:1
8.7:1
5.5:1
5.9:1
ee (%)d
67
aq DMSO
DMSO
24
30
30
18
18
44
44
3
82
75
76
29
47
77
77
65
47
73
89
77
78
Lys
75
Lys
aq DMSO
DMSO
79
Arg
–24
–18
77
Arg
aq DMSO
DMSO
Asp
Asp
Asn
Asn
Glu
aq DMSO
DMSO
69
89
aq DMSO
DMSO
3
91
12
12
48
48
88
Glu
aq DMSO
DMSO
71
Gln
88
Gln
aq DMSO
87
a Reaction conditions: p-nitrobenzaldehyde (0.4 mmol), cyclohexanone (2.0 mmol), amino acid (0.12 mmol), DMSO (400 mL), with or without
H2O (22 mL), r.t.
b Isolated yield.
c Determined by 1H NMR.
d Enantiomeric excess of the major anti isomer as determined by chiral phase HPLC analysis.
e Not Determined.
In the reaction using proline, a marked increase in enantio- fect the moderate enantioselectivity that was observed
selectivity was observed. Is this a general phenomenon (Table 2, entries 5–8). We further investigated the reac-
with proline? Excellent enantioselectivity was also ob- tion of other acyclic ketones such as methyl ethyl ke-
tained by the use of Val and Ile. Are Val and Ile also ef- tone,7k,m,8d for which interesting results were obtained
fective in other aldol reaction? We next examined the (Table 3, entries 1 and 2): Two regioisomers were formed
aldol reaction catalyzed by Pro, Val and Ile in detail using and the effect of water was different for each of these. Wa-
other combinations of ketone and aldehyde. The reaction ter had a positive effect on the reaction in which the ethyl
using proline was fast at room temperature, causing over- side of the ketone reacted, while no effect was observed
reaction (vide supra), and so testing was performed at with the other pathway, i.e. reaction on the methyl side.
lower temperature (4 °C), whereas the reaction was car- Thus, while adding water led to an increase in enantiose-
ried out at room temperature in the cases of valine and iso- lectivity for an a-substituted methyl ketone, no such effect
leucine. These results are summarized in Tables 2 and 3.17 was observed in the unsubstituted case (Figure 1).
First, proline was examined as a catalyst. As expected, a
O
O
clean reaction proceeded without the formation of dehy-
drated product. Even under these conditions, the enantio-
selectivity of the product obtained in DMSO was low,
while an excellent result was obtained in aqueous DMSO.
These results indicate that any kinetic resolution at the de-
hydration stage can be ruled out. In the case of both p-ni-
tro- and o-chlorobenzaldehyde, water exhibited a positive
effect on diastereo- and enantioselectivities. In contrast to
these positive effects, when acetone was employed as the
nucleophilic ketone, water either decreased or did not af-
R
H
R
H
O
Me
excellent ee
water is effective
moderate ee
water is not effective
Me
Figure 1 Difference in reactivity between methyl and ethyl substi-
tuents in the proline-mediated aldol reaction
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Y. Hayashi et al.
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Table 2 The Effect of Ketone in the Amino Acid Mediated Aldol Reaction in DMSO and Aqueous DMSOa,16
O
OH
O
30 mol%
O
amino acid
+ syn isomer
+
R2
R
R2
R
H
solvent, 48 h
R1
R1
Entry Product
Amino acid
Solvent
Temp. (°C)
Yield (%)b
anti:sync
ee (%)
OH
O
1
2
Pro
Pro
DMSO
aq DMSO
4
4
61
79
5.8:1
15.9:1
80d
93d
O2N
Cl
OH
O
3
4
Pro
Pro
DMSO
aq DMSO
4
4
65
76
6.4:1
>20:1
82d
98d
OH
O
5
6
Pro
Pro
DMSO
aq DMSO
4
4
63
72
75e
61e
O2N
7
8
9
Pro
Pro
Val
Ile
DMSO
4
4
23
23
75
82
26
34
68e
67e
40e
47e
Cl
OH
O
aq DMSO
aq DMSO
aq DMSO
10
a Unless otherwise noted, the reaction conditions were as follows: aldehyde (0.4 mmol), ketone (2.0 mmol), amino acid (0.12 mmol), DMSO
(400 mL), with or without H2O (22 mL), indicated temperature, 48 h.
b Isolated yield.
c Determined by 1H NMR.
d Enantiomeric excess of the major anti isomer as determined by chiral phase HPLC analysis.
e Enantiomeric excess determined by chiral phase HPLC analysis.
Next valine and isoleucine were employed in aqueous reaction of methyl ethyl ketone, anti:syn ratio was also
DMSO (Table 2, entries 9 and 10; Table 3, entries 3 and low. These results indicate that Val and Ile, which gave
4). Although the reaction was performed at room temper- excellent results in the aldol reaction of cyclohexanone,
ature, the reaction was slow, affording the aldol products are poor catalysts in the reaction of acyclic ketones in
in low yield. Both in the reaction of acetone and methyl terms of the reactivity, diastereoselectivity and also enan-
ethyl ketone, low enantioselectivity was observed. In the tioselectivity.
Table 3 The Effect of Pro, Val and Ile in the Aldol Reaction of 2-Butanonea
Cl
O
Cl
OH
O
Cl
OH
O
30 mol%
O
amino acid
+
+
+
syn isomer
H
Me
Me
solvent, r.t.
48 h
Me
Me
Me
2
1
1
2
Entry
Amino acid
Solvent
DMSO
Yield (%)b
ee (%)c
65
Yield (%)b
anti:synd
2.6:1
ee (%)e
89
1
2
3
4
Pro
Pro
Val
Ile
45
46
9
16
25
14
15
aq DMSO
69
>20:1
2.8:1
98
aq DMSO
aq DMSO
55
74
11
59
2.9:1
63
a Reaction conditions: aldehyde (0.4 mmol), ketone (2.0 mmol), amino acid (0.12 mmol), DMSO (400 mL), with or without H2O (22 mL), r.t.,
48 h.
b Isolated yield.
c Enantiomeric excess determined by chiral phase HPLC analysis.
d Determined by 1H NMR.
e Enantiomeric excess of the major anti isomer as determined by chiral phase HPLC analysis.
Synlett 2008, No. 10, 1565–1570 © Thieme Stuttgart · New York

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Proteinogenic Amino Acids in Asymmetric Aldol Reaction in DMSO
1569
solvent, see: Blackmond, D. G.; Armstrong, A.; Coombe,
V.; Wells, A. Angew. Chem. Int. Ed. 2007, 46, 3798.
(7) For organocatalysis-mediated asymmetric aldol reaction in
aqueous solvent, see: (a) Torii, H.; Nakadai, M.; Ishihara,
K.; Saito, S.; Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43,
1983. (b) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett
2004, 1891. (c) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.
G.; Mi, L.-Q.; Jiang, Y. Z. Org. Lett. 2004, 6, 2285.
(d) Casas, J.; Sunden, H.; Cordova, A. Tetrahedron Lett.
2004, 45, 6117. (e) Ward, D. E.; Jheengut, V. Tetrahedron
Lett. 2004, 45, 8347. (f) Ibrahem, I.; Cordova, A.
In summary, we have investigated use of all the proteino-
genic amino acids in the aldol reaction of aldehyde and
ketone in DMSO and aqueous DMSO, and found that
most of them promote the aldol reaction of cyclohexanone
enantioselectively. A positive water effect on diastereose-
lectivity has been observed with some of the amino acids,
while water afforded a positive effect on enantioselectivi-
ty only when Pro, Ser or His were employed. For the pro-
line-mediated aldol reaction, a large positive effect on
diastereo- and enantioselectivities was observed in the re-
action of a-substituted methyl ketone, while no effect was
observed in that of methyl ketone. Whereas valine and
isoleucine afforded excellent results in the aldol reaction
of cyclohexanone, they are not suitable catalysts in the re-
action of acyclic ketones.
Tetrahedron Lett. 2005, 46, 3363. (g) Amedjkouh, M.
Tetrahedron: Asymmetry 2005, 16, 1411. (h) Cordova, A.;
Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W.
Chem. Commun. 2005, 3586. (i) Wu, Y.-S.; Chen, Y.; Deng,
D.-S.; Cai, J. Synlett 2005, 1627. (j) Dziedzic, P.; Zou, W.;
Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38.
(k) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A.
I.; Kaavi, J. A. Tetrahedron 2006, 62, 317. (l) Cordova, A.;
Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.
Eur. J. 2006, 12, 5383. (m) Guillena, G.; Hita, M. C.;
Najera, C. Tetrahedron: Asymmetry 2006, 17, 729.
(n) Recently, Blackmond and co-workers reported the role of
water in aldol reaction. See: Zotova, N.; Franzke, A.;
Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007,
129, 15100.
Acknowledgment
This work was partially supported by the Toray Science Foundation
and a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
References and Notes
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reduced pressure after standing over CaH2 overnight:
Armarego, W. L. F.; Chai, C. L. L. Purification of
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(16) Typical Experimental Procedure (Table 1): To a DMSO
solution (0.40 mL) or aq DMSO solution (DMSO: 0.40 mL;
H2O: 22 mL) of amino acid (0.12 mmol) were added p-
nitrobenzaldehyde (60.5 mg, 0.4 mmol) and cyclohexanone
(207 mL, 2.0 mmol) under an argon atmosphere at r.t. When
the reaction was complete, it was quenched with pH 7.0
phosphate buffer solution. The organic materials were
extracted with EtOAc (3 ×) and the combined organic
extracts were dried over anhyd Na2SO4, and concentrated in
vacuo after filtration. The residue was purified by flash
chromatography to give an aldol product.
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Blackwell Publishing: Oxford, 2007. (f) For the criticism
toward the notion that water is an environmentally friendly
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Y. Hayashi et al.
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Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Diastereoselectivity was determined by 1H NMR (400
MHz). Enantiomeric excess was determined by HPLC
analysis with a Chiralpak AS-H column (hexane–2-pro-
panol = 10:1, l = 231 nm), 1.0 mL/min; major enantiomer
tR = 11.5 min, minor enantiomer tR = 18.7 min.
Chem. 2005, 3, 84. (b) 2-(2-Chlorophenylhydroxy-
methyl)cyclohexanone: Chen, J.; Lu, H.; Li, X.; Cheng, L.;
Wan, J.; Xiao, W. Org. Lett. 2003, 5, 4369. (c) 4-Hydroxy-
4-(4-nitrophenyl)-2-butanone: Rodriguez, B.; Bruckmann,
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Chlorophenyl)-4-hydroxy-2-butanone: Maya, V.; Raj, M.;
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phenyl)-1-hydroxy-3-pentanone and 4-(2-chlorophenyl)-4-
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(17) All compounds are known: (a) 2-(Hydroxy-4-nitrophenyl-
methyl)cyclohexanone: Cobb, A. J. A.; Shaw, D. M.;
Synlett 2008, No. 10, 1565–1570 © Thieme Stuttgart · New York

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