Proline-catalyzed asymmetric direct aldol reaction assisted by D-camphorsulfonic acid in aqueous media

Article abstract of DOI:10.1055/s-2005-869864

Asymmetric aldol reactions of aromatic aldehydes with various ketones catalyzed by L-proline with D-camphorsulfonic acid as co-catalyst have been developed in aqueous media. High reactivity and modest to excellent enantioselectivity has been achieved. Geo

Full text of DOI:10.1055/s-2005-869864

LETTER
1627
Proline-Catalyzed Asymmetric Direct Aldol Reaction Assisted by
D-Camphorsulfonic Acid in Aqueous Media
a
a
a
P
Y
roline-Catalyzed
i
A
sym
m
n
etric
D
irect
-
Aldol
R
S
a
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China
Chemistry college, Hebei Normal University, Shijiazhuang 050016, P. R. China
Fax +86(20)84112245; E-mail: puscjw@zsu.edu.cn
b
lent enantioselectivity can be achieved in aqueous media
by combining proline and CSA as co-organocatalysts. As
far as we are aware, there is no report on the additive ef-
fect of CSA on the catalytic efficiency of proline itself in
aqueous media.3
Abstract: Asymmetric aldol reactions of aromatic aldehydes with
various ketones catalyzed by L-proline with D-camphorsulfonic
acid as co-catalyst have been developed in aqueous media. High re-
activity and modest to excellent enantioselectivity has been
achieved.
a,5
Keywords: asymmetric direct aldol reaction, co-catalyst, proline,
camphorsulfonic acid, aqueous media
Table 1 Different Types of Co-Catalyst for L-Proline-Catalyzed
Asymmetric Aldol Reaction of Acetone with p-Nitrobenzaldehyde
OH
O
1
O
CHO
+
Since the pioneer work reported by List and Barbas that
Catalyst
H2O , r.t.
*
L-proline, a natural amino acid with stunning simplicity,
can catalyze intermolecular asymmetric direct aldol reac-
tion in DMSO or other aprotogenic solvents, extensive in-
vestigation has been conducted to increase the scope of
both the substrates and solvents, as well as to optimize the
O2N
O2N
1
2
3
Entry Catalysta
Time (h) Yield (%) ee (%)
2
catalytic efficiency and enantioselectivity of L-proline
3
–5
1
2
3
4
5
6
7
8
9
0
L-Pro
24
24
24
24
24
24
24
24
24
24
24
47
34
n.d.
61
47
43
38
58
50
n.d.
18
8
and its derivatives. However, it is noted that amino ac-
ids and amines are much more effective catalysts in non-
aqueous or aprotogenic solvents where the amine func-
tionality can be maintained in its reactive unprotonated
state. Synthetically useful aldol reactions in aqueous
media are rare and usually involve enzymes. Indeed,
even though it was reported that proline-catalyzed ketone-
aldehyde aldol reactions are accelerated by water, direct
aldol reaction carried out in aqueous media catalyzed by
native proline generally proceeded with low enantioselec-
D-CSA
n.d.
74
L-Pro/D-CSA
1
b
L-Pro/ L-Tyr-SO H
61
3
6
L-Pro/ L-Try-SO
L-Pro/1,5ndsb
H
58
3
7
52
L-Pro/CF
SO
H
29
3
3
2
a,6–9
tivity.
Proline-catalyzed aldol reactions in a phos-
L-Pro/Tartaric acid
L-Tyr/D-CSA
46
6
8
phate buffer and aqueous micelles showed that there was
no obvious enantioselectivity. While direct aldol reaction
catalyzed by a proline-containing chiral Lewis acid, Zn-
proline, in aqueous media was reported with moderate
n.d.c
38
1
L-Phe/D-CSA
enantioselectivity and very limited substrate scope.10 11
L-Try/D-CSA
33
Therefore, native proline-catalyzed, synthetically useful
asymmetric direct aldol reaction in aqueous media re-
a
Amino acid–acid, 2:1.
b
1
,5nds = 1,5-naphthalenedisulfonic acid.
mains a challenging subject, which deserves to be ex-
plored in order to develop an environmentally benign and
biomimetic aldol reaction. Aiming to explore the potential
application of simple and readily available chiral com-
pounds as organocatalysts for reactions carried out in
c
Not determined.
Table 2 Affect of the Ratio of L-Proline/D-CSA on the Asymmetric
Aldol Reaction of Acetone with p-Nitrobenzaldehyde
aqueous media, we have employed camphorsulfonic acid Entry Catalyst
CSA) as a catalyst in direct Mannich reactions in aqueous
Ratio
(mol)
Time
(h)
Yield
(%)
ee
(%)
(
1
1
media. Herein, we wish to report that, by using the acid-
1
2
3
4
5
L-Pro/D-CSA
L-Pro/D- CSA
L-Pro/D- CSA
L-Pro/D-CSA
L -Pro/D-CSA
1:0
4:1
3:1
2:1
1:1
24
24
24
24
24
47
70
70
74
44
34
57
34
61
59
3
b
base designing methodology to develop a multifunction-
al catalytic system, asymmetric aldol reactions with excel-
SYNLETT 2005, No. 10, pp 1627–1629
1
7
.0
6
.2
0
0
5
Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869864; Art ID: U05405ST
©
Georg Thieme Verlag Stuttgart · New York

1
628
Y.-S. Wu et al.
LETTER
When catalyzed by 20mol% L-proline alone in acetone– The ratio of proline and CSA on the catalytic efficiency
water (4:1), the reaction between acetone and p-nitrobenz- and selectivity was evaluated and the results are shown in
aldehyde proceeded in moderate yield 47% and enantio- Table 2. The best combination was as 2:1 mixture of pro-
meric excess 34%. CSA alone could not catalyze the line and CSA. The solvent composition has a significant
reaction under the same reaction conditions. However, impact on both the catalytic efficiency and selectivity and
when CSA was added as a co-catalyst to proline (1:2 the results are shown in Table 3; increasing the amount of
ratio), the yield and enantiomeric excess were increased water, resulted in a dramatic decrease in enantioselectivi-
1
2
significantly to 73% and 61%, respectively. In order to ty. The reaction still proceeded with moderate yield, but
identify the essential features of the co-catalyst leading to no selectivity, when the amount of water exceeded 30%
the improved activity and selectivity, achiral 1,5-naphtha- When the amount of water exceeded 50%, the reaction did
lenedisulfonic acid (1,5nds), CF SO H, chiral sulfonated not proceed.
3
3
amino acids, and tartaric acid were used instead of CSA.
Either the yield or the enantioselectivity, or both of them,
were increased, though to a lesser extent in comparison
with that of CSA. On the other hand, when other natural
amino acids, namely L-tyrosine, phenylalanine, and tryp- Entry Acetone–Water
tophan were used instead of proline, both yield and enan-
tiomeric excess diminished significantly. In the case of
tyrosine, the reaction did not proceed at all. These results,
shown in Table 1, indicate that proline is essential to
achieve moderate to good enantioselectivity, while CSA
carrying a sulfonic group adjacent to a chiral center is the
best auxiliary co-catalyst to enhance the catalytic activity
and enantioselectivity of proline.
Table 3 Influence of Water on the Asymmetric Aldol Reaction of
Acetone with p-Nitrobenzaldehyde Catalyzed by L-Proline/D-CSA
(
2:1)
Time (h)
Yield (%)
74
ee (%)
61
1
2
3
4
5
6
4:1
24
24
24
24
24
24
3:1
63
54
2:1
39
1
1:1
n.d.
n.d.
10
n.d.
n.d.
n.d.
1:2
No water
Table 4 L-Proline/D-CSA (2:1) Catalyzed Aldol Reactions for Cyclic Ketones
O
OH
*
O
OH
O
CHO
Catalyst
H2O, r.t.
*
+
+
*
*
(
)n
( )n
( )n
R
R
R
7
8
n = 1
n = 2
99–12 n = 1
13–16 n = 2
99–12 n = 1
13–16 n = 2
1, 4, 5, 6
Syn
Anti
Entry
R
n
Time (h)
Yield (%)
syn/anti
ee (%)
1H NMRa
HPLC
1
2
3
4
5
6
7
NO2
NO2
CN
1
2
1
2
1
2
1
2
12
48
12
48
12
48
12
48
83
72
76
68
51
57
61
56
77/23
49/51
70/30
47/53
55/45
42/58
53/47
35/65
75/25
46/54
80/20
42/58
54/46
42/58
53/47
34/66
syn: >99
anti: 88
syn: >99
anti: >99
syn: >99
anti: >99
CN
syn: >99
anti: >99
Br
syn: 88
anti: 76
Br
syn: 44
anti: 63
b
b-Na
b-Na
syn: 71
anti: >99
8
syn: 61
anti: 77
a
Procedure to determine the syn/anti ratio is described in ref. 12.
b-Naphthyl aldehyde.
b
Synlett 2005, No. 10, 1627–1629 © Thieme Stuttgart · New York

LETTER
Proline-Catalyzed Asymmetric Direct Aldol Reaction
1629
Remarkably, when cyclic ketones were employed as do-
nors, excellent enantioselectivity for both syn- and anti-
isomers was obtained with enantiomeric excess up to
7386. (c) List, B. Tetrahedron 2002, 58, 5573.
(
d) Chandrasekhar, S.; Narsihmulu, C.; Reddy, N. R.;
Sultana, S. S. Tetrahedron Lett. 2004, 45, 4581.
e) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N.
(
9
9%. The results are shown in Table 4. In the case of cy-
Tetrahedron Lett. 2004, 45, 4353. (f) Pan, Q. B.; Zou, B. L.;
Wang, Y. J.; Ma, D. W. Org. Lett. 2004, 6, 1009.
clopentanone, after a reaction time of 12 hours, moderate
to good yields were obtained with good to excellent enan-
tioselectivity for both diastereoisomers. The reaction rate
for cyclohexanone is slower in comparison to that of cy-
clopentanone, however, excellent enantioselectivity was
also obtained. It is noted that the enantioselectivity for
both syn- and anti-aldol adducts of p-nitrobenzaldehyde
with cyclohexanone (99% ee for both syn- and anti-iso-
mer) or cyclopentanone (99% and 88% ee for the syn- and
anti-isomer respectively) are much higher than that ob-
tained in DMSO catalyzed by native proline, where the
best reported enantiomeric excess was 63% or 89% for the
anti-aldol adduct of cyclohexanone and p-nitrobenzalde-
hyde; 53% or 69% for the anti-aldol adduct of cyclopen-
(
g) Szollosi, G.; London, G.; Balaspiri, L.; Somlai, C.;
Bartok, M. Chirality 2004, 15, 90. (h) Liu, H. W.; Peng, L.
Z.; Zhang, T.; Li, Y. L. New J. Chem. 2004, 27, 1159.
(
i) Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.;
Solcaniova, E. Chem. Commun. 2002, 2510.
(
3) (a) Notz, W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res.
2
2
004, 37, 580. (b) Saito, S.; Yamamoto, H. Acc. Chem. Res.
004, 37, 570. (c) Nakadai, M.; Satio, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8167. (d) 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, 5262. (e) Tang, Z.; Jiang, F.;
Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755. (f) Hayashi,
Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.;
Shoji, M.; Hashizume, D.; Koshino, H. Adv. Synth. Catal.
1
b,3a
tanone and p-nitrobenzaldehyde.
Interestingly, when
2004, 346, 1435. (g) Berkessel, A.; Koch, B.; Lex, J. Adv.
the reaction of p-nitrobenzaldehyde and cyclopentanone
was carried out without the addition of water, the reaction
proceeded sluggishly, with only a 15% yield after 24
hours; the diastereoselectivity is moderate (syn/anti
Synth. Catal. 2004, 346, 1141. (h) Tang, Z.; Yang, Z. H.;
Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett.
2004, 6, 2285.
(
4) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
7
5:25), but the enantioselectivity decreased significantly
(
b) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
with only a 30% ee for the syn-isomer and 70% ee for the
anti-isomer.
2004, 15, 1831.
(
(
5) Mase, N.; Tanaka, F.; Barbas, C. F. III. Angew. Chem. Int.
Ed. 2004, 43, 2420.
6) Córdova, A.; Notz, W.; Barbas, C. F. III. Chem. Commun.
In summary, we have developed an organo-cocatalyst
which shows high reactivity and excellent enantioselec-
tivity for a class of aldol reactions in aqueous media, es-
pecially with cyclic ketones as donors. Our results
demonstrate that the acid-base methodology for designing
an effective catalyst3b can be extended to develop chiral
acid-chiral base co-catalyst for asymmetric direct aldol re-
action. The chiral co-catalyst can fine-tune the activity
and enantioselectivity of the native proline, and make di-
rect asymmetric aldol reaction achievable in a more envi-
2002, 3024.
(
(
7) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891.
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(
(
2004, 45, 8949.
(
12) Typical Procedure (Table 1, entry 3): Anhyd acetone (2.0
1
3
ronmentally friendly manner.
mL, dried with K CO before use) was added to p-nitro-
2
3
benzaldehyde (75 mg, 0.5 mmol), followed by L-proline (20
mol%) and D-CSA (10 mol%) dissolved in water (0.5 mL).
The resulting mixture was stirred at r.t. for 12 h. After
Acknowledgment
treating the reaction mixture with saturated aq NaHCO (5
We thank the Science and Technology Programs of Guangdong
Province for financial support (Grant No. 2003C104030).
3
mL), the aqueous layer was separated, and extracted with
EtOAc three times. The combined organic extracts were
washed with brine (5 mL), dried over anhyd Mg SO , and
2
4
References
concentrated. The residue was purified by preparative thin
layer chromatography (Silica gel plates GF254, hexane–
EtOAc) to give the aldol product (76.3 mg). The anti/syn
(
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1
ratio is established by H NMR; d = 4.83 ppm (J = 9.0 Hz) –
CH of the anti-isomer; 5.42 ppm (J = 2.7 Hz) – CH of the
syn-isomer (Table 4, entry 1). The ee values were
determined by HPLC, Daicel chiralpak AS-RH.
13) Mestres, R. Green Chem. 2004, 6, 583.
(
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(
Synlett 2005, No. 10, 1627–1629 © Thieme Stuttgart · New York