(S)-Histidine-based dipeptides as organic catalysts for direct asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2005.04.027

The structure/activity relationships for some (S)-histidine-based dipeptide catalysts in direct aldol reactions have been examined. The reactivities and stereoselectivities are shown to be dependent upon the intramolecular cooperation of side-chain functi

Full text of DOI:10.1016/j.tetasy.2005.04.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1947–1951
(
S)-Histidine-based dipeptides as organic catalysts for
direct asymmetric aldol reactions
*
Svetlana B. Tsogoeva and Shengwei Wei
Institut f u¨ r Organische und Biomolekulare Chemie der Georg-August-Universit a¨ t G o¨ ttingen, Tammannstrasse 2,
7077 G o¨ ttingen, Germany
3
Received 15 February 2005; accepted 27 April 2005
Abstract—The structure/activity relationships for some (S)-histidine-based dipeptide catalysts in direct aldol reactions have been
examined. The reactivities and stereoselectivities are shown to be dependent upon the intramolecular cooperation of side-chain func-
tional groups and the presence of a suitable combination and sequence of amino acids. Good yields (up to 96%) and enantioselec-
tivities (up to 76% ee) were obtained with electron-deficient aromatic aldehydes in the presence of H-Leu-His-OH. The influence of
different chiral and achiral co-catalysts on the reaction rates, yields and enantioselectivities has also been evaluated. Significant
increases in the acceleration of the reaction, most remarkable for achiral trans-2,5-dimethylpiperazine as co-catalyst and the
improved yields, were demonstrated.
Ó 2005 Elsevier Ltd. All rights reserved.
2
1
1
. Introduction
linear dipeptides H-His-Leu-OH and H-Leu-His-OH.
Herein, we report the catalysis of an asymmetric direct
2
2
The use of short peptides as asymmetric organic cata-
1
aldol reaction (initially reported by List et al. and
23
–3
4
lysts, pioneered by Inoue et al.
continues to receive growing interest for different impor-
and Lipton et al.,
Barbas et al. ), with some synthetic (S)-histidine-based
dipeptides.
5
–7
tant transformations
such as enantioselective conju-
11
asymmetric acylation reactions,
8
–10
gate additions,
1
2
enantioselective phosphorylation,
1
Strecker synthe-
Baylis–Hillman reactions and enantioselective
2. Results and discussion
3,14
15
sis,
direct aldol reactions.
1
6–20
Initially, we evaluated some dipeptides as catalysts for
the known model reaction of acetone with 4-nitrobenz-
aldehyde (Table 1). Reactions were run at room temper-
ature in DMSO under conditions employing 0.3 equiv of
dipeptide relative to substrate and were allowed to pro-
ceed until completion.
The linear and cyclic dipeptides containing (S)-histidine,
initially discovered by Inoue et al., have successfully
been used for the asymmetric synthesis of cyanohy-
1
–3
drins.
However, no further attempts to apply InoueÕs histidine-
based dipeptide catalysts to other C–C bond formation
reactions are known in the literature. This prompted our
present study.
Over the course of our studies, it was found that dipep-
tides with amino acids containing both one basic and
one neutral residue are generally better suited to pro-
duce good conversions when compared to dipeptides
of amino acids with other combinations of functional-
ities (Table 1, entries 1, 2, 4 and 6 vs entries 3 and 5).
We became interested in extending the application of
(
S)-histidine-based dipeptide catalysts to other carbon–
carbon bond forming reactions. We have recently
reported asymmetric Michael additions catalyzed by
The reactivities and stereoselectivities seem to be depen-
dent upon the intramolecular cooperation of side-chain
functional groups and the presence of a suitable combi-
nation and sequence of amino acids. Thus, H-His-
Leu-OH, which has the reversed sequence of amino acid
residues, is much less stereoselective (86%, 22% ee, entry
*
Corresponding author. Tel.: +49 (0)551 393285; fax: +49 (0)551
99660; e-mail: stsogoe@gwdg.de
3
0
957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.027

1948
S. B. Tsogoeva, S. Wei / Tetrahedron: Asymmetry 16 (2005) 1947–1951
Table 1. Dipeptides tested as catalysts for the asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde
Dipeptide
0.3 equiv)
OH O
O
(
O
H
+
DMSO, rt
(R)-1
O N
2
O N
2
a
b
a
c
Entry
Dipeptide
Reaction time (days)
Conv. (%)
Reduced rates (%/h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
H-Phe-His-OH
H-His-Phe–OH
H-Leu-Phe-OH
H-Leu-His-OH
H-Lys-His-OH
H-His-Leu-OH
cyclo-[(S)-Leu-(S)-His]
H-Leu-His-OMe
Z-Leu-His-OMe
1
8
3
92
87
17
96
13
94
31
92
45
0.48
1.21
0.09
0.40
0.05
1.31
0.13
0.38
0.19
79
77
11
87
11
86
24
81
31
27
40
67
71
26
22
3
8
10
10
3
10
10
10
60
20
a
b
c
Determined by H NMR of crude mixture after completion of the reaction.
Conv. (%)]/[reaction time (h)].
Enantioselectivities were determined by chiral HPLC analysis (Daicel Chiralpak AS) in comparison with authentic racemic material.
[
6
) than H-Leu-His-OH (87%, 71% ee, entry 4), but
The fact that suitable achiral or chiral additives and co-
catalysts can enhance the yield and in many cases also the
enantioselectivity as well, which has been discussed in the
shows a higher conversion rate (Table 1, reduced rates:
.31 with H-His-Leu-OH vs 0.40 with H-Leu-His-OH).
1
In the case of H-His-Phe-OH and H-Phe-His-OH, we
observed similar results in terms of reaction rates, but
reversed behaviour with respect to enantioselectivities
regarding the position of the basic residue: H-His-Phe-
OH catalyzes the reaction faster and gives better ees
Table 2. Aldol reactions of acetone with several aromatic aldehydes
catalyzed by H-Leu-His-OH
OH
O
O
H-Leu-His-OH
0.3 equiv)
(
Table 1, reduced rate 1.21; 77%, 40% ee, entry 2) than
O
(
H-Phe-His-OH (Table 1, reduced rate 0.48; 79%, 27%
ee, entry 1). We suppose that those shifts in selectivity
observed for catalysis by these peptides may have been
caused by a combination of steric and structural
influences.
H
+
DMSO, 10 d, rt
X
X
a
Conv. (%) Yield (%) ee (%)
a
b
Entry Product
OH
O
Interestingly, the cyclic dipeptide cyclo-[(S)-leucyl-(S)-
2
1
96
82
87
62
71
72
histidyl], which has been shown by Inoue et al. to
catalyze asymmetric Strecker synthesis, was not active
for the direct aldol reaction (Table 1, 24%, 3% ee, entry
1
O N
2
OH
O
7
). H-Leu-His-OMe and Z-Leu-His-OMe are less reac-
2
3
4
5
6
tive and stereoselective (entries 8 and 9 of Table 1) than
H-Leu-His-OH (entry 4), which confirms the impor-
tance of the N-terminal amino group and, possibly that
of the C-terminal carboxyl group (as hydrogen bond
donor) for the catalysis.
2
NO2
OH
O
100
89
96
65
67
53
76
68
60
50
3
Cl
Next, we performed the corresponding reaction with a
set of different aromatic aldehydes in the presence of
dipeptide H-Leu-His-OH, which appears to be the most
effective with respect to the reaction yield (87%) and
enantioselectivity (71% ee). We observed that H-Leu-
His-OH catalyzed the aldol reaction with varying yields
and enantioselectivities, depending on the nature of the
substrate used. The formation of different amounts of
aldol condensation product was observed as well (Table
OH
O
4
Br
Cl
OH
OH
O
94
5
2
).
O
65
Typically, good yields (up to 96%) and enantioselectivi-
ties (up to 76% ee) were obtained with electron-deficient
aldehydes such as 2- or 4-nitrobenzaldehyde, 2- or 4-
chlorobenzaldehyde and 4-bromobenzaldehyde (Table
6
a
1
Determined by H NMR of crude mixture after completion of the
reaction.
b
2, entries 1–5) with respect to less active naphthaldehyde
Table 2, entry 6).
Enantioselectivities were determined by chiral HPLC analysis (Daicel
Chiralpak AS) in comparison with authentic racemic material.
(

S. B. Tsogoeva, S. Wei / Tetrahedron: Asymmetry 16 (2005) 1947–1951
1949
Table 3. Co-catalysts tested for the asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde
OH
O
O
O
H-Leu-His-OH
Co-catalyst
H
+
(R)-1
DMSO, rt O N
O N
2
2
a
a
b
Entry
H-Leu-His-OH (equiv)
Co-catalyst (equiv)
Reaction time (h)
Conv. (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
0.3
0.3
0.3
0.3
0.3
0.3
0.3
—
—
—
—
—
—
—
1
(R)-2-Methylpiperazine (0.1)
(S)-2-Methylpiperazine (0.1)
L-Norephedrine (0.1)
25
72
80
90
96
84
97
91
97
56
58
72
53
86
100
28
80
90
86
78
87
90
53
42
42
43
44
40
55
1
72
72
(R)-Phenylethylamine (0.1)
L-Aspartic acid (0.1)
72
72
1,1,3,3-Tetramethylguanidine (0.1)
trans-2,5-Dimethylpiperazine (0.1)
(R)-2-Methylpiperazine (0.3)
(S)-2-Methylpiperazine (0.3)
L-Norephedrine (0.3)
c
22
97
168
168
240
240
120
4
56
48
54
28
65
95
26
5
10
11
12
13
14
2
(R)-Phenylethylamine (0.3)
L-Aspartic acid (0.3)
4
14
—
—
1,1,3,3-Tetramethylguanidine (0.3)
trans-2,5-Dimethylpiperazine (0.3)
168
a
b
c
Determined by H NMR of crude mixture after completion of the reaction.
Enantioselectivities were determined by chiral HPLC analysis (Daicel Chiralpak AS) in comparison with authentic racemic material.
Isolated yield after silica gel chromatography.
2
4
excellent review by Shibasaki et al., encouraged fur-
ther study. The aldol reaction of acetone with 4-nitro-
benzaldehyde was examined with H-Leu-His-OH in the
presence of different co-catalysts (Table 3).
are hard to make and it is also hard to explain why an
additive is beneficial. Indeed, surprisingly, the combina-
tion of dipeptide H-Leu-His-OH and 1,1,3,3-tetrameth-
ylguanidine gave product with 90% yield and 40% ee in
72 h (Table 3, entry 6), while the H-Leu-His-OH/trans-
It is interesting to note that the reaction rate was in-
creased to a different extent, depending on the nature
of co-catalyst used. The reaction time was shortened
from 10 days (87%, entry 4 of Table 1) to 25 h (80%,
entry 1 of Table 3) in the presence of (R)-2-methylpiper-
azine (0.1 equiv), while only to 72 h (90%, entry 2 of
Table 3) in the presence of its enantiomer, (S)-2-methyl-
piperazine (0.1 equiv). Similar results (rate enhancement
to 72 h) were observed with further chiral co-catalysts:
L-norephedrine, (R)-phenylethylamine and L-aspartic
acid (Table 3, entries 3–5).
2,5-dimethylpiperazine combination provided aldol with
97% yield and 55% ee in just 22 h (Table 3, entry 7). No
condensation product has been observed in both cases.
In general, much higher reaction rates in the presence
of both dipeptide and co-catalyst with respect to first
the dipeptide (Table 1, entry 4) or co-catalysts (Table
3, entries 8–14) indicate the possibility of synergistic ef-
fects. The significant increases in the acceleration of the
reaction, most remarkable for achiral trans-2,5-dimeth-
ylpiperazine and the improved yields (up to 97%), were
paid for by lower enantioselectivities (up to 55% ee,
Table 3, entries 1–7 vs 71% ee, Table 2, entry 1). The results
obtained however demonstrate that even with co-cata-
lysts, which give only 0–14% ees, when acting indepen-
dently (Table 3, entries 8–14), the dominating influence
on enantioselectivities comes from the dipeptide H-
Leu-His-OH.
Interestingly, no condensation product was observed
with (R)-2-methylpiperazine and (S)-2-methylpiperazine
(
Table 3, entries 1 and 2), while still significant amounts
were produced when L-norephedrine, (R)-phenylethyl-
amine and L-aspartic acid (Table 3, entries 3–5) were
used as co-catalysts.
These results demonstrate that the use of suitable co-
catalysts with matching chirality for this reaction might
result in higher yields and enantioselectivities and in
markedly accelerated reactions without side products.
Next we tested trans-2,5-dimethylpiperazine, which has
2
5
already been described by Hanessian and Pham as
an additive for L-proline catalyzed conjugate additions,
and 1,1,3,3-tetramethylguanidine as achiral co-catalysts.
Whereas the use of trans-2,5-dimethylpiperazine alone
provides the product in only 26% yield in 168 h (Table
3. Conclusion
3
, entry 14), the 1,1,3,3-tetramethylguanidine alone pro-
duces the aldol product with 95% yield in 4 h. Consider-
ing these results one might suggest that the application
of 1,1,3,3-tetramethylguanidine as co-catalyst could sig-
nificantly improve the reaction rate with respect to
trans-2,5-dimethylpiperazine. However, as it was
In summary, we have described here for the first time
structure/activity relationships for some linear (S)-histi-
dine-based dipeptide catalysts, testing them on known
model aldol reactions.
2
4
already noted by Shibasaki et al. a priori predictions
of which from a variety of additives may be beneficial
The reactivity and stereoselectivity seems to be depen-
dent upon the intramolecular cooperation of side-chain

1950
S. B. Tsogoeva, S. Wei / Tetrahedron: Asymmetry 16 (2005) 1947–1951
functional groups and the presence of a suitable combi-
nation and sequence of amino acids.
min, k = 254 nm: tR (major) = 15.01 min, tR (minor) =
11.61 min.
The synthetic scope of the selected dipeptide catalyst (H-
Leu-His-OH) has been demonstrated. Good yields (up
to 96%) and enantioselectivities (up to 76% ee) were ob-
tained with electron-deficient aromatic aldehydes.
4.5. (4R)-(2-Chlorophenyl)-4-hydroxy-2-butanone 3
1
H NMR (300 MHz, [D ]DMSO) d 7.60 (dd, 1H), 7.27–
6
7.42 (m, 3H), 5.53 (d, 1H), 5.38 (m, 1H), 3.33–3.35 (s,
1
H), 2.62–2.65 (m, 2H), 2.18 (s, 3H); HPLC: n-hexane/
2-propanol = 80:20, flow rate 1 ml/min, k = 210 nm: tR
Furthermore, the influence of different chiral and achiral
co-catalysts on the reaction rates, yields and enantiose-
lectivities have been examined. Significant increases in
reaction rates, most notable for achiral trans-2,5-
dimethylpiperazine (22 h of reaction time), and the im-
proved yields (up to 97%) with moderate enantioselec-
tivities (up to 55% ee) were found.
(major) = 9.38 min, t (minor) = 7.68 min.
R
4.6. (4R)-(4-Bromophenyl)-4-hydroxy-2-butanone 4
1
H NMR (300 MHz, CDCl ) d 7.42 (d, 2H), 7.20 (d,
3
2H), 5.08–5.12 (m, 1H), 2.80 (m, 2H), 2.19 (s, 3H);
HPLC: n-hexane/2-propanol = 75:25, flow rate 1 ml/
min, k = 210 nm: tR (major) = 9.43 min, tR (minor) =
11.67 min.
More effective stereochemical features may be observed
with other suitable co-catalysts and in different other
solvents. This may also be of considerable interest in
the study of various co-catalystÕs effects, as well as in
the detailed mechanistic understanding of the role of
co-catalysts and/or additives.
4.7. (4R)-(4-Chlorophenyl)-4-hydroxy-2-butanone 5
1
H NMR (300 MHz, [D ]DMSO) d 7.37 (s, 4H), 5.41 (d,
6
1
H), 5.0 (m, 1H), 2.68–2.72 (m, 2H), 2.11 (s, 3H);
HPLC: n-hexane/2-propanol = 75:25, flow rate 1 ml/
min, k = 210 nm: tR (major) = 8.82 min, tR (minor) =
10.86 min.
4. Experimental
4
.1. General
4.8. (4R)-4-(2-Naphthalenyl)-4-hydroxy-2-butanone 6
1
DMSO was distilled prior to use. Reagents obtained
from commercial sources were used without further
purification. TLC chromatography was performed on
precoated aluminium silica gel SIL G/UV254 plates
H NMR (300 MHz, CDCl ) d 7.80–7.83 (m, 4H), 7.43–
3
7.48 (m, 3H), 5.29–5.34 (m, 1H), 2.91–2.95 (m, 2H), 2.20
(s, 3H); HPLC: n-hexane/2-propanol = 90:10, flow
rate 1 ml/min, k = 210 nm: tR (major) = 21.84 min, tR
(minor) = 23.98 min.
(
Marcherey, Nagel Co.) or silica gel 60-F254 precoated
1
glass plates (Merck). H NMR spectra were recorded
with Varian Unity 300.
Acknowledgements
4
.2. General procedure for the aldol reactions
The authors gratefully acknowledge the BMBF and
Fonds der Chemischen Industrie for generous financial
support. The authors also thank Dr. Zoya Ardemasova
for providing most of the dipeptides as well as Dr.
Michael Mauksch for useful discussions.
Dipeptide (30 mol %) was added to a dry acetone–
DMSO (1:4) mixture and was stirred for 20 min. The
aromatic aldehyde (0.05 M) was added and the resulting
mixture stirred at room temperature under nitrogen.
After completion of the reaction, the mixture worked
up as described in the literature. All reaction products
had NMR spectra in accordance with the literature
data. Enantioselectivities of all products were deter-
mined by chiral HPLC analysis (Daicel Chiralpak AS).
2
3
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