Dipeptide-catalyzed direct asymmetric aldol reaction

Article abstract of DOI:10.1055/s-2004-831324

(L)-H-Pro-(L)-Phe-OH (4) were found to be efficient catalysts for direct asymmetric aldol reactions between acetone and various aldehydes. The reaction conditions use a DMSO-NMM-PEMG 5000 system at 0 °C in high yields (62-96%) and enantioselectivities (up to >99% ee).

Full text of DOI:10.1055/s-2004-831324

LETTER
2215
Dipeptide-Catalyzed Direct Asymmetric Aldol Reaction
D
L
ipeptide-Catal
a
yze
d
D
irec
n
t
A
symmetri
-
c
A
ldol
R
X
eaction iang Shi, Qi Sun, Ze-Mei Ge, Yong-Qiang Zhu, Tie-Ming Cheng, Run-Tao Li*
School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. China
Fax +86(10)62346154; E-mail: Lirt@mail.bjmu.edu.cn
Received 18 June 2004
O
HO
O
Abstract: (L)-H-Pro-(L)-Phe-OH (4) were found to be efficient cat-
O
alysts for direct asymmetric aldol reactions between acetone and
various aldehydes. The reaction conditions use a DMSO–NMM–
PEMG 5000 system at 0 °C in high yields (62–96%) and enantiose-
lectivities (up to >99% ee).
N
S
N
N
H
N
N
H
N
H
HO2C
HO2C
HO2C
1
2
3
Key words: aldol reaction, organocatalysis, enamine catalysis,
dipeptides
CH2Ph
HO
CH Ph
O
O
2
H
H
N
H
COOH
N
H
COOH
N
H
N
H
Since List and Barbas III and their co-workers demon-
strated that a simple organic molecule, proline, can act
like an enzyme in promoting reactions between acetone
4
5
1
Figure 1 The small organic molecules evaluated in this study
and various aldehydes, metal-free organocatalysts have
attracted much attention to organic chemists and are inten-
2
,3
sively studied. Several kinds of efficient organocata-
Table 1 Direct Aldol Reaction of 4-Nitrobenzaldehyde with
lysts have been found for the directed asymmetric aldol Acetone Catalyzed by Organic Molecules 1–5
reactions, such as L-proline and 5,5-dimethyl thiazolidin-
O
4
O
OH
O
ium-4-carboxylate (DMTC), L-proline amino alcohol
Cat (20 mol%)
r.t.
5
6
+
amides, and some peptides. However, the class of effi-
cient organic catalysts is still scarce, and only a few suc-
cessful examples catalyzed by peptides were investigated.
Therefore, it is necessary to explore more potential orga-
nocatalysts with high stereoselectivity and broad sub-
strates. We herein report our new results in this field.
H
NO2
NO2
Catalyst
Time (h)
192
Yield (%)a
ee (%)b
13
1
2
3
4
66
45
Based on the structure of proline and the mechanism of
204
16
7
proline-catalyzed asymmetric aldol reaction, we de-
216
<10
87
n.d.c
59
signed and synthesized five new dipeptide catalysts 1–5
(
Figure 1). In these catalysts, the L-proline or L-4-hydrox-
192
ylproline moieties at the N-terminus retain the character
of L-proline. Introduction of cyclic amino acid is expected
to increase the steric hindrance effect. L-Phenylalanine
portion was selected from the known effective peptide
5
192
80
46
a
Isolated yields after column chromatography.
The ee values were determined by chiral-phase HPLC analysis.
Not determined.
b
c
6
b
catalyst H-Pro-Glu-Leu-Phe-OH.
Initially, we selected the reaction of 4-nitrobenzaldehyde
with neat acetone as model to examine the efficiency of ent conditions. The results were showed in Table 2. It is
the catalysts 1–5. The results were summarized in interesting to note that the reaction rate was obviously in-
Table 1. It was found that catalysts 4 and 5 showed signif- creased by using N-methylmorpholine (NMM) as base to
icantly catalytic activity producing the aldol product in adjust the reaction system to pH = 8. For instance, in the
good yields (4, 87%; 5, 80%) and enantioselectivities (4, absence of NMM, the reaction required 192 hours (entry
5
9% ee; 5, 46% ee). The lower catalytic activity of cata- 1, 87%, 59% ee). On the contrary, the reaction time was
lysts 1–3 may be due to the absence of hydrogen in tert- shortened from 192 hours to 96 hours with unchanged
amide.
yield and enantioselectivity (entry 2, 87%, 59% ee). In the
presence of NMM, when DMSO was used as the solvent,
not only the reaction time was further shortened, but also
an excellent yield and good enantioselectivity were ob-
tained (entry 3, 18 h at 25 °C, 93% yield with 58% ee; en-
try 4, 30 h at 0 °C, 95% yield with 66% ee). Replacing
NMM with triethylamine under the same conditions, the
result is unsatisfied (entry 5, 95% yield with 51% ee).
Next, using 20 mol% of 4 as catalyst, we examined the re-
action of 4-nitrobenzaldehyde with acetone under differ-
SYNLETT 2004, No. 12, pp 2215–2217
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831324; Art ID: U17404ST
0
1
.1
0
.2
0
0
4
©
Georg Thieme Verlag Stuttgart · New York

2
216
L.-X. Shi et al.
LETTER
Table 2 (L)-H-Pro-(L)-Phe-OH-Catalyzed Aldol Reaction of Acetone with 4-Nitrobenzaldehyde under Different Conditions
Entry
Solvent
Acetone
Acetone
DMSO
DMSO
DMSO
NMP
Base
Surfactant
Time (h)
192
96
Temp (°C)
Yield (%)a
ee (%)b
59
1
2
3
4
5
6
7
8
9
25
25
25
0
87
87
93
95
95
77
80
96
96
95
95
94
79
NMM
NMM
NMM
59
18
58
30
66
Et N
24
0
51
3
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
30
25
0
71
NMP
35
63
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
PGME 5000
PGME 5000
PEG400
24
0
73
24
0
56c
65
1
1
1
1
0
1
2
3
24
0
SDS
24
0
69
TBAB
24
0
57
PGME 5000
30
0
69
a
b
c
Isolated yields after column chromatography.
The ee values were determined by chiral-phase HPLC analysis.
Proline as catalyst.
Similarly, using N-methyl-2-pyrrolidinone (NMP) as sol- hydes (entries 1–7) or aliphatic aldehydes (entries 8 and
vent provided the aldol product in 77% yield and 71% ee 9), took place smoothly and afford corresponding aldol
at 25 °C, and 80% yield and 63% ee at 0 °C, respectively adducts in moderate to high yields (62–96%) and good
(
entries 6 and 7). Adding the NMM, the catalyst 4 may be
formed the corresponding carboxylate. The formation of
carboxylate can increase the solubility; meanwhile, the
six-membered ring of NMM may be favorable to establish
stable transition states with substrates, which could en-
hanced enantioselectivity.
Table 3 Substrate Screen for Aldol Reaction between Acetone and
Aldehydes Catalyzed by (L)-H-Pro-(L)-Phe-OH 4
O
O
OH
Cat. 4 (20 mol%)
+
R
CHO
NMM / DMSO / PGME 5000
R
0
°C
Additionally, according to the reports8,9 that aldol reac-
tions could be accelerated by surfactant in a buffer solu-
tion or in aqueous micelles, we also tested the effect of the
different surfactants including polyethylene glycol
monomethyl ether 5000 (PGME 5000), polyethylene gly-
col 400 (PEG 400), sodium dodecyl sulfate (SDS), tet-
rabutylammonium bromide (TBAB) on the reaction in
DMSO–NMM systems at 0 °C. Among surfactants exam-
ined, PGME 5000 is the best one affording the desired al-
dol product in the highest yield of 96% with good
enantioselectivity of 73% ee (entry 8). This result is better
than those obtained with proline as catalyst (entry 9, 96%,
a
b
Entry Product
R
Time (h) Yield (%) ee (%)
1
2
3
4
6a
6b
6c
6d
4-Nitrophenyl
Phenyl
24
36
24
96
62
84
80
73
64
67
83
3-Nitrophenyl
2-Nitro-3,4-methyl- 28
enedioxyphenyl
5
6
7
8
9
6e
6f
2-Chlorophenyl
30
81
72
70
92
80
90
55
61
3,4-Dichlorophenyl 32
5
6% ee). We also added the PGME 5000 in the system of
6g
6h
6i
2-Methoxyphenyl
i-Propyl
36
48
48
24
53
NMP–NMM, providing 79% yield and 69% ee (entry 13).
Therefore, 20 mol% of catalyst 4 in the DMSO–NMM–
PGME 5000 system at 0 °C was verified to be the best
condition. The action of PGME may be to increase the
mutual solubility of substrates and catalyst.
77
Cyclohexanyl
2-Nitrophenyl
79
10
6jc
>99
a
The generality of catalyst 4 in catalyzing direct aldol reac-
tions with various aldehydes was examined under optimal
conditions. The results were displayed in Table 3. As it
can be seen, all the reactions, no matter the aromatic alde-
Yield of product isolated after silica gel chromatography.
The ee values were determined by chiral-phase HPLC analysis using
b
chiralpak AD-H columns (Daicel chemical industries).
c
Acetone was instead with cyclohexanone; nearly 100% anti confor-
mation was determined by NMR after column chromatography.
Synlett 2004, No. 12, 2215–2217 © Thieme Stuttgart · New York

LETTER
Dipeptide-Catalyzed Direct Asymmetric Aldol Reaction
2217
enantioselectivities (up to 83% ee). Three nitro-substitut- entries 8–12 in Table 2; entries 1–10 in Table 3 and entries 1–4 in
Table 4), or in 5 mL of acetone–NMP (1:4) with NMM as base and
ed aromatic aldehydes (entries 1, 3 and 4) provided higher
surfactant (5 mol%, entry 13 in Table 2), was stirred at the indicated
yields and enantioselectivities than the other substituted
temperature for the indicated time. The reaction mixture was added
aromatic aldehydes. Moreover, cyclohexanone was used
sat. aq NH Cl solution, filtered and washed with EtOAc to recover
the catalyst. The filtrate was extracted with EtOAc. The combined
4
to react with 2-nitrobenzaldehyde affording nearly 100%
anti conformation product 6j in 90% yield with >99% ee
organic layers were washed with aq sat. NaCl, dried over anhyd
Na SO . The solvent was removed under reduced pressure and the
(
entry 10).
Finally, we studied the recovery and reuse of the catalyst
. It was found that the recovery of the catalyst was very
2
4
residue was purified by flash column chromatography on a silica gel
eluent: petroleum–EtOAc = 3:1) to afford the corresponding aldol
(
4
adducts.
easy. After reaction, adding saturated aqueous ammonium
chloride solution into the reaction mixture, the catalyst
was precipitated, and then, filtrated and washed with ethyl
acetate to recover the catalyst in over 84%. The recovered
Acknowledgment
The authors are grateful to National Natural Science Foundation of
catalyst was reused for three times, and the yield and China for the financial support (NSFC 20172006).
enantioselectivity did not decrease (Table 4). These
results suggested that many rounds of catalyst use and
recovery could be possible.
References
(
(
1) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc.
Table 4 Recovery and Reuse of the Catalyst 4a
2000, 122, 2395.
2) For recent reviews, see: (a) Gröger, H.; Wilken, J. Angew.
Chem. Int. Ed. 2001, 40, 529. (b) Dalko, P. I.; Moisan, L.
Angew. Chem. Int. Ed. 2001, 40, 3726. (c) List, B. Synlett
25,b
Entry Reuse time [a]D
Recovery rate Yield
ee
(%)
(
%)
(%)
2
001, 1675. (d) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002,
1
2
3
0
1
2
3
–36.8°
–36.8°
–36.6°
–36.8°
96
73
72
73
73
58, 2481. (e) List, B. Tetrahedron 2002, 58, 5573.
(
f) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002,
85
84
87
95
1595. (g) Alcaide, B.; Almendros, P. Angew. Chem. Int. Ed.
2003, 42, 858.
96
(
3) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(b) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3,
4
96
5
73. (c) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
a
Reaction of 4-nitrobenzaldehyde and acetone catalyzed by 4 under
Soc. 2002, 124, 6798. (d) Hoang, L.; Bahmanyar, S.; Houk,
K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. (e) Pan, Q.
B.; Zou, B. L.; Wang, Y. J.; Ma, D. W. Org. Lett. 2004, 6,
optimal conditions.
b
Measured in aqueous solution of hydrochloride acid according to the
reference.10 {Lit. [a]D –37° (c 1.0, 1 N HCl)}.
25
1009.
(
(
4) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III. J. Am.
Chem. Soc. 2001, 123, 5260.
5) Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A.
Q.; Jiang, Y. Z.; Wu, Y. D. J. Am. Chem. Soc. 2003, 125,
In summary, we have found that dipeptide, (L)-H-Pro-(L)-
Phe-OH (4), could efficiently catalyze the direct asym-
meric aldol reactions between ketone and various alde-
hydes in DMSO–NMM–PGME 5000 system at 0 °C in
high yields (62–96%) and enantioselectivities (up to
5262.
(
6) (a) Martin, H. J.; List, B. Synlett 2003, 1901. (b) Kofoed, J.;
Nielsenb, J.; Reymonda, J. L. Bioorg. Med. Chem. Lett.
2003, 13, 2445. (c) Tang, Z.; Yang, Z. H.; Cun, L. F.; Gong,
L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett. 2004, 6, 2285.
7) (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475. (b) Córdova, A.; Notz, W.;
Barbas, C. F. III. J. Org. Chem. 2002, 67, 301.
>99% ee).
(
General Procedure for Aldol Reactions
A suspension of catalyst (20 mol%) and aldehyde (1 mmol) in 4 mL
of acetone (Table 1), or in 4 mL of acetone with NMM as base (en-
try 2 in Table 2), or in 5 mL of acetone–DMSO (1:4) with NMM as
base (entries 3 and 4 in Table 2), or in 5 mL of acetone–NMP (1:4)
with NMM as base (entries 6 and 7 in Table 2), or in 5 mL of
acetone–DMSO (1:4) with NMM as base and surfactant (5 mol%,
(
8) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002, 124,
3220.
(9) Peng, Y. Y.; Ding, Q. P.; Li, Z. C.; Wang, P. G.; Cheng, J. P.
Tetrahedron Lett. 2003, 44, 3871.
(
10) Mazur, R. H.; Schlatter, J. H. J. Org. Chem. 1963, 28, 1025.
Synlett 2004, No. 12, 2215–2217 © Thieme Stuttgart · New York